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volume, first page, author or article title). http://europepmc.org/abstract/med/ cb conservation biology, pages – volume , no. , december the tyranny of population growth daniel h. pletscher* and michael k. schwartz wildlife biology program, school of forestry, the university of montana, missoula, mt – , u.s.a. the proximate cause behind the decline of biodiversity is most often reduction or change of habitat and isola- tion of wildlife populations. in the western united states, as in much of the world, these problems can ultimately be attributed to increases in human population and per- capita consumption. this journal has published several articles concerning the burdens of human population growth (e.g., meffe ; gehrt ); indeed, we have not met many conservation biologists who are not firmly aboard the malthusian ship. we argue that population growth also burdens personal liberty by creating a need for greater regulation. parsons ( ) discussed the rela- tionship between population and liberty; we extend that argument to conservation. people unmoved on the pop- ulation issue with conservation arguments may be moved by our regulation argument. the problems faced by conservationists have changed. one hundred years ago, the predominant problem facing wildlife in north america was overexploitation. water- fowl, forest carnivores, and ungulates were exploited, largely for market, and were minimally regulated, to the point where most were near extinction. deer ( odocoileus virginianus ) populations were especially depleted and heading toward extirpation throughout the eastern united states. the american colonies began limiting hunting methods, seasons, and equipment in the mid- s to deal with overexploitation (trefethen ). passage of the lace act of , which made it a federal offense to trans- port illegally killed wildlife across state borders, further defined the public right to wildlife and helped curb over- exploitation. these regulations marked the beginning of the end of wildlife populations being considered unpro- tected public property. unregulated taking had exacted a lasting toll on some north american wildlife. for ex- ample, the passenger pigeon ( ectopistes migratorius ), which once flew in flocks of billions, was extinct by , largely because of unregulated taking of pigeons for mar- ket (blockstein & tordoff ). at about the same time, carnivores such as lynx ( lynx canadensis ) and moun- tain lions ( puma concolor ) were exploited to local ex- tinction in the northeastern united states (godin ). as the human population grew, wildlife conservation and management developed as an applied scientific disci- pline with a focus on reducing or controlling consump- tion by humans and increasing production of wildlife. specifically, the works of aldo leopold, particularly game management (leopold ) and “the upshot” (in a sand county almanac , leopold ), focused our attention on wildlife as a renewable but finite resource and halted our illusion of boundless wildlife populations. as conservationists we can be proud of our many suc- cesses. game species have rebounded, and predators— long maligned for their way of life—are making tremen- dous comebacks. mountain lions have returned to much of their former range in the western united states and are slowly returning in the east. the wolf ( canis lupus ) has gradually returned to the rocky mountains, and there is even an active campaign to reintroduce the grizzly bear ( ursus arctos horribilis ) to parts of its former range. the u.s. public has demonstrated through laws, regulation, and private actions that it values these species and their habitats, at least in certain places and times, more than competing human uses. our glaring failure, however, has been in treating the symptoms of wildlife conservation problems rather than their root causes. the world’s human population, currently approxi- mately billion, is growing ( births minus deaths) at a rate of people per second, or approximately , people each day (united nations ). natural resource managers must deal with this growth, and plant and ani- mal life must adapt or perish. what happens when we compromise in the conflict between wildlife habitat and the demands of more people? the trade-offs almost al- ways mean a net increase in the proportion of earth’s productivity allocated to human use and a net decrease in the proportion allocated to wild areas and wild life. the effect of humans on our environment is a func- tion of per capita consumption of resources times the number of people consuming those resources. in some cases we have done a fair job of convincing people to re- duce consumption and protect some habitat. if, how- ever, we reduce per capita consumption but the num- * email pletsch@forestry.umt.edu paper submitted january , ; revised manuscript accepted may , . conservation biology volume , no. , december pletscher & schwartz population growth ber of humans increases by similar or higher rates, what have we gained? in addition, if we protect some habitat but the human population increases by higher rates, what have we gained? we argue that we have lost: space per individual, wild species, and wild areas. in addition, by ignoring the population problem, we lose individual freedoms because of the need for increased regulation. for example, years ago, people in the western united states could harvest bison at any rate they wished. with an increased market and more harvesters, laws and regulations were enacted to stop overharvest (trefethen ). at the turn of the last century, people could dump their wastes into rivers with little noticeable effect. now, with an in- creased number of residents and more wastes per capita, laws and regulations are in place to maintain water quality. we examined the montana laws restricting fishing, hunting, and access to lands for these activities and found that in the general laws required only sections of code and pages of text (montana territorial legislature ; montana legislature ). today, montana has sections of code spanning pages of text (montana legislature ). population growth is not the only fac- tor causing increases in regulations, but we believe it to be the primary and most overlooked, factor. we continue to pass more laws and regulations to control both supply and demand in an over-taxed system; thus, our individual free- doms are inversely proportional to our population. one of our most basic freedoms is our reproductive freedom, but uncontrolled population growth leads to a reduction in all other freedoms, a tyranny of population growth. despite this tyranny, taking away reproductive freedom is not morally acceptable, socially feasible, or politically possible. what we can do, quite easily, is raise awareness that human population growth is the cause of most of our environmental ills and leads to increased regulation. few conservation issues are unaffected by human population pressures, and we must demonstrate these relationships. for instance, when talking about the effects of subdivided land on biodiversity, we can point out the root of the problem. when talking about problems of access on pri- vate lands or the institution of recreation fees, we can in- dicate why they are occurring. and when we discuss air- quality regulations that prevent open burning or require tougher industrial standards, we should discuss the ulti- mate root of the problem. the tradeoffs should be identi- fied explicitly. increased human population equals in- creased pressure for regulation. furthermore, we must not only preach to the converted. these messages should be delivered to groups outside the society for conserva- tion biology, especially to those people who traditionally are uninterested in the outdoors but who have an interest in seeing government reduced. in other words, if popula- tion growth is the primary culprit hindering the conserva- tion of biodiversity, we should not stop short of enlisting political groups who are interested for different reasons. let conservation make strange bedfellows. we must continue to encourage a reduction in con- sumption and work on increasing efficiency on those lands producing goods and services. we must also con- tinue to encourage shared uses of our wild lands and nat- ural resources. but if this is all we do, we will continue to tinker while our wildlife legacy is lost. we must point out to anyone who will listen—and to recognize ourselves— that human population growth is a grave threat to indi- vidual freedom and to all that we as conservationists hold dear. there are no easy answers, but education is a start. thomas jefferson, the third american president and framer of the u.s. constitution, argued that it is the re- sponsibility of the current generation to undertake ac- tions that will maintain the freedom of the next genera- tion. by ignoring the population issue, we not only lose our valuable wild areas and wild life, but we infringe on the freedoms of the next generation. the earth belongs to each of these generations during its course, fully and in its own right. the second generation receives it clear of the debts and encumbrances of the first, the third of the second, and so on. for if the first could charge it with a debt, then the earth would belong to the dead and not to the living generation. thomas jefferson ( ) ( foner : ) acknowledgments we thank j. w. thomas, g. schildwachter, j. belsky, j. burchfield, and two anonymous reviewers for comment- ing on an early draft of this essay. literature cited blockstein, d. e., and h. b. tordoff. . gone forever: a contempo- rary look at the extinction of the passenger pigeon. american birds : – . foner, p. s., editor. . letter from thomas jefferson to james madi- son. pages – in basic writings of thomas jefferson. willey book company, new york. gehrt, s. d. . the human population problem: educating and changing behavior. conservation biology : – . godin, a. j. . wild mammals of new england. johns hopkins uni- versity press, baltimore. leopold, a. . game management. scribner’s sons, new york. leopold, a. . a sand county almanac and sketches here and there. oxford university press, new york. meffe, g. k. . human population control: the missing awareness. conservation biology : – . montana legislature. . montana codes annotated. montana legis- lative services division, helena. montana legislature. . montana codes annotated. montana legis- lative services division, helena. montana territorial legislature. . revised statutes of montana. george e. boos, helena. parsons, j. . population versus liberty. pemberton books, london. trefethen, j. b. . an american crusade for wildlife: highlights in con- servation progress. the telegraph press, harrisburg, pennsylvania. united nations. . department of economic and social affairs, pop- ulation division. world population . publication st/esa/ser.a/ , no. e. . . . united nations, new york. sscience publisher: richard s. nicholson editor-in-chief: daniel e. koshland, jr. editor: ellis rubinstein managing editor: monica m. bradford deputy editors: philip h. abelson (engineering and ap- plied sciences); john i. brauman (physical sciences); tho- mas r. cech (biological sciences) editorial staff assistant managing editor: dawn bennett senior editors: eleanore butz, r. brooks hanson, barbara jasny, katrina l. kelner, david lindley, linda j. miller, phillip d. szuromi, david f. voss associate editors: gilbert j. chin, pamela j. hines, paula a. kiberstis, suki parks, l. bryan ray letters: christine gilbert, editor; steven s. lapham book reviews: katherine livingston, editor; annette theuring, assistant editor; susan randolph, editorial as- sistant contributing editor: lawrence i. grossman editing: lois schmitt, valerie jablow,senior copy editors; douglas b. casey, harry jach, erik g. morris, christine m. pearce copy desk: ellen e. murphy, supervisor; joi s. granger, beverly shields, 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l. good james d. watson harry b. gray richard n. zare editorial a scientific approach to governing science. dr. noitall, you are one of the great political scientists of all time, the man who engineered harry truman's comeback, the man who wrote winston churchill's speech- es, the man who got arthur elected king of the round table. noitall. a vast understatement of my true worth. science. have you come up with any new ideas on the political scene? noitall. of course. i have a brilliant new idea which avoids the vicious dictatorships of the right and the left and the impotence and gridlock of democracy and will solve the prob- lems of automation, diversity, and overpopulation. science. and what brilliant new device could possibly do that? noitall. it is called a "benevolent dictatorship." science. could anyone ever find a benevolent dictator one could trust? noitall. i have just spent the weekend at monticello going into the background and career of thomas jefferson, statesman, scientist, diplomat, inventor, activist, revolutionary, and member of the establishment. science. what was his attitude toward science? noitall. he was always a great supporter of science and considered that the three great- est men in the world at the time (whose pictures he hung on the walls of his house) were newton, locke, and bacon. he not only supported science funding but believed science was the mechanism for improving the standard of living, and he was himself an inventor and innovater. science. but could he perform the role of a dictator? noitall. not only was he able to push most of his proposals through an extremely balky and fractionated legislature, but he founded the university of virginia, designed its architec- ture, and then supervised its construction by observing it through a telescope from his planta- tion. he selected all the initial professors for the university. science. was jefferson environmentally sound? noitall. he voluntarily gave up growing tobacco a century ahead of the first surgeon general's report. science. isn't there one small problem, namely, that jefferson is dead? noitall. quite the contrary. today presidents are surrounded by image-makers, and the candidate's image turns out to be far more important than what he really does. if you are dead you can't make mistakes, and your image-makers can develop a consistent reputation with- out any new changes of mind that would be confusing to the voters and disastrous for legisla- tive success. most people believe that a secret machiavellian group is governing any presi- dent or prime minister anyway, and therefore it would not be surprising to them that the leader is actually dead instead of just sleeping. confirmation of their deepest conspiratorial suspicions should make them happy. the minor campaigning disadvantages are easily offset by the fact that there are already busts and statues of jefferson all over the country, and there is no problem of name recognition. science. what was his approach to social security and health care? noitall. jefferson was particularly solicitous of his slaves' welfare, educating them to help increase their skills and providing for security and the best health care that era could offer. science. slaves! how could you even suggest a man who kept slaves. noitall. jefferson called the whole system of slavery an "abomination" and worked to abolish it. this type of ambiguity is a political advantage because the public who sees a person on both sides of an issue always assumes the candidate's heart is on their side, but that his words to the opposition are campaign oratory. individuals of high principles who stick to one viewpoint rarely get elected. science. dr. noitall, are there any other political devices that you are inventing to strengthen modern leaders? noitall. i have been looking into (i) "ruling by decree" as an alternative to legislative gridlock, (ii) "divine right of kings" as an alternative to lengthy and costly campaigns, and (iii) "off with their heads" as a more effective way of dealing with the opposition than nega- tive campaigning. daniel e. koshland, jr. science * vol. * july o n a p ril , h ttp ://scie n ce .scie n ce m a g .o rg / d o w n lo a d e d fro m http://science.sciencemag.org/ a scientific approach to governing daniel e. koshland jr. doi: . /science. . . ( ), . science article tools http://science.sciencemag.org/content/ / / .citation permissions http://www.sciencemag.org/help/reprints-and-permissions terms of serviceuse of this article is subject to the is a registered trademark of aaas.sciencescience, new york avenue nw, washington, dc . the title (print issn - ; online issn - ) is published by the american association for the advancement ofscience by the american association for the advancement of science o n a p ril , h ttp ://scie n ce .scie n ce m a g .o rg / d o w n lo a d e d fro m http://science.sciencemag.org/content/ / / .citation http://www.sciencemag.org/help/reprints-and-permissions http://www.sciencemag.org/about/terms-service http://science.sciencemag.org/ hp impact of direct to consumer advertising—the consumer search for information abstracts medication (p = . ); more likely to become frustrated (p = . ) and annoyed (p < . ) with the patient for asking to try a medication; and less likely to provide samples (p = . ) or a prescription (p < . ) for a medication. conclusion: clinicians are amenable to patients asking for drug information and medications, but their level of receptiveness is associated with the source from which the patient’s questions originate. hp relationship of direct-to-consumer advertising spending and drug pricing for the top twenty drugs from to : an exploratory study parthan ag, anantharaman rt, shepherd md the university of texas at austin, austin, tx, usa there exists an ongoing debate regarding the effect of direct-to-consumer (dtc) advertising spending on drug prices. the two opposite views are: (a) increase in dtc advertising spending would be added to drug prices (b) dtc advertising would increase competition and thus reduce drug prices. objective: explore the relationship of dtc advertis- ing spending and drug pricing for the top twenty drugs from to . methods: top twenty drugs were selected on the basis of their dtc advertising spending (source: competitive media reporting, ny) for . for analysis, average wholesale price (awp) per unit was used from the blue book awp unit pricing. for each of the top twenty drugs, the following trend graphs were plotted for to : (a) the total dtc advertising spending and per unit price of the drug; (b) the percent changes in the dtc advertis- ing spending and drug price. the percent change in dtc advertising spending and drug price for a year was calculated as percent change from the previous year. results: only sildenafil (viagra) and sibutramine (meridia) showed an increase in the actual drug price with an increase in the dtc advertising spending. however, for these two drugs in year , the percent change in dtc advertising spending decreased and the percent change in drug price increased. no trend was evident from the graphs of the other eighteen drugs. on an average dtc advertising spending for most of the drugs decreased with time while drug prices continued to increase. conclusion: results indicate a very weak relation- ship between dtc advertising spending and drug prices. the increase in drug price in spite of the decrease in the dtc advertising spending contradicts both rationale i.e. dtc advertising spending reduces drug price through competition or increase in drug price is due to increase in dtc advertising spending. hp impact of direct to consumer advertising—the consumer search for information belazi dt , crawford a , pizzi l thomas jefferson university & abbott laboratories, philadelphia, pa, usa; thomas jefferson university, philadelphia, pa, usa objective: the purpose of this study is to identify factors associated with consumers’ seeking various infor- mation sources about medications sought in response to direct to consumer advertising. methods: in the spring and summer of , the fda, division of drug marketing, advertising, and commu- nication conducted a national telephone survey of adults regarding direct-to-consumer (dtc) promotion of prescription drugs and its effects on visits to the doctor. in addition to consumer attitudes, opinions and responses to direct to consumer advertising, the survey also elicited responses regarding consumer utilization of information sources such as reference books, -telelphone number, and health care providers. there were total respon- dents, of whom completed the required questions regarding information sources. chi square analysis was used to assess associations between consumer demographic information and the different types of informational resources that consumers used after exposure of direct to consumer advertising. results: the analysis showed significant associations (p £ . ) between gender, race, education, health status, self-perceived knowledge of health, prescription medication use, and internet use and many of the following information resources: reference books, asking friends/neighbors, -telephone number, primary doctor, pharmacist, specialist, and nurse. across all information sources, female gender, decreased health status, low education, and higher than average medica- tion use were the variables that had the strongest associ- ations. a model was developed depicting the associations between these findings. results pertaining to specific sources will be presented. conclusions: this study evaluated how different consumers seek information from different sources as a result of direct to consumer advertising. this study will assist those interested in identifying and further educat- ing consumers about their health and novel treatments or therapies. hp fda regulatory actions against misleading or unsubstantiated economic and quality-of-life claims: an analysis of warning letters and notices of violation stewart ka, neumann pj harvard school of public health, boston, ma, usa pmt : linguistic validation of the vascular quality of life questionnaire (vascuqol) in languages abstracts pmt linguistic validation of the vascular quality of life questionnaire (vascuqol) in languages conway k , uzun v , girod i , morgan m , koch p mapi research institute, lyon, france; mapi values, lyon, france; lewisham hospital, london, uk; boehringer ingelheim, ingelheim, germany introduction: measuring quality of life (qol) has become a vital part of assessing lower limb ischemia and peripheral vascular disease in international studies. the -item vascuqol was developed in uk english and investigates domains: symptoms, pain, activities, social life and emotional state. prior to use in an international trial the measure underwent linguistic validation in lan- guages. methods: a qol specialist coordinated the translation process in each target country using the fol- lowing methodology: ) two forward translations by pro- fessional, native speaking translators of the target lan- guage fluent in english; ) comparison and reconciliation of the translations by a qol specialist and translators; ) backward translation by a native english speaker; ) comparison of the source and backward versions; ) re- view of the translation by a clinician in each country; ) comprehension test in a sample target population; ) in- ternational harmonization. results: linguistic and conceptual issues emerged when translating idiomatic phrases and response scales. linguistic equivalents had to be found for expressions such as “being (or becoming) housebound” and “social activities”. the notions of “discomfort”/“distress” did not have direct equivalents in some languages where a single notion had to be used. in most languages the frequency scale expressed in amounts of time had to be simplified to establish equidis- tant responses. conclusions: a rigorous translation methodology was performed to ensure conceptual equiv- alence and acceptability of translations. international feedback obtained through the translation process re- vealed issues regarding the original instrument, indicating that future amendments to the original may be necessary. future psychometric testing will be conducted to ensure reliability and validity of each translation, appropriate- ness of the questionnaire in each country and compara- bility of data across countries. pmt assessing physician practice profitability using an activity based costing model stephens jm, bell cf, klingman d parexel international, outcomes research group, alexandria, va, usa physicians are increasingly challenged to maintain prac- tice profits in the face of tightening reimbursements from payers. while office visits generate a revenue stream for physicians, it is not clear whether frequent lower com- plexity visits (e.g., nurse visits to administer injections) are actually profitable for physician practices. objec- tive: to develop an adaptable model and methodology to evaluate profitability and financial incentives for vari- ous in-office services provided by physicians and their staff. methods: a literature and expert opinion based model was developed from the physician practice per- spective and was designed to be flexible for a variety of office-based services. the practice cost component of the model was developed using activity-based costing princi- ples and included direct (drug acquisition, supplies, clini- cal labor time, office visits) and indirect (malpractice in- surance, office rent) expenses. the practice revenue component of the model consisted of the reimbursement amount from payers, including: drug reimbursement; of- fice visits for physician evaluation, injections, end of treatment follow-up and adverse events; and laboratory tests. results: practice profitability is inversely pro- portional to the number of low complexity office visits per year. payer mix is also an important determinant of profitability for in-office services, with medicare reim- bursements generally resulting in a net loss for practices (� loss per office visit for the lowest complexity ser- vices) and typical managed care reimbursements provid- ing only small profits (approximately per low complex- ity visit). conclusions: frequent low-complexity office visits for administration of drug therapies do not appear profitable for physician practices under medicare reimbursement. alternative modes of drug delivery such as implantable drug delivery devices or patient self-ad- ministration may be more profitable for physician prac- tices by allowing substitution of more highly reimbursed office services. pmt valuing non-workplace productivity lost in migraineurs: human capital approach and replacement cost method kim ss, lofland jh office of health policy and clinical outcomes at thomas jefferson university hospital, philadelphia, pa, usa objective: to determine the non-workplace produc- tivity costs (nwpc) for migraineurs using the human capital approach (hca) and replacement cost method (rcm). method: this was a supplemental analysis to a prospective, observational migraine outcomes study conducted at a managed care organization. migraineurs self-reported their work status, occupational category, number of days missed from normal ‘activities’ outside of paid job(s) due to migraine symptoms, number of days performing normal ‘activities’ with migraine symptoms, and percent effectiveness while performing normal ‘activ- ities’ with migraine symptoms, at baseline, months, and months after the initiation of sumatriptan. daily occu- pational wages were obtained from the bureau of labor statistics. nwpc were calculated using the hca and plbi _ - .indd plos biology | www.plosbiology.org if you ask the average ten year old in america what a scientist looks like, they almost always describe an older man with crazy white hair and a lab coat. if you ask a group of adolescents how many have looked through a microscope, few raise their hands. if you discuss the implications of genetic research with a group of high school students, they’re likely to cut your next class. the reason why these students have such profound stereotypes of scientists and are less than enthusiastic about science’s impact on society is simple—the lack of exposure they receive during their pre-college education. according to a preliminary study conducted at leicester university in england, students are often repeatedly confronted with stereotypes of science and scientists via television, cartoon, and comic book characters as well as uninformed adults or peers (mcduffi e ). a university set in a major city has the resources to change the mindset of urban students and engage them in the exciting fi eld of science. at thomas jefferson university (tju), located in philadelphia, pennsylvania, a team of scientists and educators has developed a program that breaks down the stereotypes of the science fi eld and allows students to engage in real, live experiments at their own schools. why are such programs necessary? around the world, educators face diffi cult choices in focusing educational goals with limited resources. in the united states, the no child left behind act, which guides school funding policy, currently places an emphasis on literacy and math in schools, with the result that best programs and practices in education are increasingly directed toward these two areas. unfortunately, science education has become a lesser priority. teachers are not given adequate resources to allow students to “get their hands dirty” during science lessons. if we want a society that is interested and knowledgeable about the need for scientifi c research, the basic principles of the life sciences need to be integrated early in the pre- college curriculum (sylwester ). we developed the thomas jefferson university science outreach program (tjusop) to address this key issue and provide inquiry-based educational strategies through collaborative efforts between the university’s faculty and partnering school districts. how are we making a difference? using the tju facilities and laboratories, this innovative program integrates life science into the education of students between the ages of eight and eighteen from pennsylvania, new jersey, and delaware. the mission of the october | volume | issue | e | e open access, freely available online community page breaking down the stereotypes of science by recruiting young scientists jamie schaefer*, steven a. farber citation: schaefer j, farber sa ( ) breaking down the stereotypes of science by recruiting young scien- tists. plos biol ( ): e . copyright: © schaefer and farber. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduc- tion in any medium, provided the original work is properly cited. abbreviations: tju, thomas jefferson university; tju- sop, thomas jefferson university science outreach program jamie schaefer and steven farber are at the kimmel cancer center, thomas jefferson university, philadel- phia, pennsylvania, united states of america. *to whom correspondence should be addressed. e-mail: jamie.schaefer@mail.tju.edu doi: . /journal.pbio. plos biology | www.plosbiology.org october | volume | issue | e tjusop is to foster an enthusiasm for science education, promote interest in future participation in biology- related fi elds, and allow all students the opportunity to learn life science through a hands-on, student-centered approach to instruction. the program is a supplement to the established curriculum, developed to support the content knowledge that is taught at each grade level. teachers are invited to attend a professional development workshop held at the beginning of the school year where they receive training and resources for the units. then, tjusop educators assist the teachers and students in their own classroom in running a weeklong experiment. this allows a large amount of group work to be completed simultaneously, even when teachers are faced with time constraints and large class sizes. this program is at no cost to the districts participating and is funded through the jefferson medical college and the kimmel cancer center, as well as through the generosity of several local and national groups including glaxo smith kline, the christopher ludwick foundation, the joan and joseph fernandez family foundation, the brook j. lenfest foundation, the foerderer foundation, drinker biddle and reath, and the pennsylvania department of agriculture. since its inception in august of , this program has reached over , students and teachers through our one-week zebrafi sh classroom experiments, our hands- on zebrafi sh and drosophila facility tours in conjunction with dr. james jaynes (a drosophila scientist at the kimmel cancer center), and our high school mentorship program held each summer. one of the main goals of tjusop is to reach students from ethnic and economic groups that are underrepresented in the scientifi c community. we have successfully partnered with the school district of philadelphia, where . % of the students come from ethnic backgrounds other than northern european and % of the students are eligible for free or reduced-cost meals. this district, among many others, receives pre- and post-instruction for all teachers and students at no cost to the district, allowing it to improve the quality of its science education. although we target these school districts, it is important to note that the us is facing a problematic decrease in the number of americans, of any background, entering the science and engineering workforce. according to a national science foundation report, “if action is not taken now to change these trends, we could reach and fi nd that the ability of u.s. research and education institutions to regenerate has been damaged and that their preeminence has been lost to other areas of the world” (national science board committee ). in regard to this unsettling discovery, tjusop welcomes all districts to participate and hopes to secure funding to double the number of students reached per year. anyone can be a scientist our pedagogical approach to experiments allows students and teachers to become scientists, following the scientifi c process from beginning to end. our live, one- week classroom experiments for the fourth, seventh, and tenth grades use zebrafi sh, a popular model organism for genetic research. a curriculum sample is as follows: in the seventh-grade unit, the students mate albino (recessive trait) male and a wild-type (dominant trait) female zebrafi sh in order to observe what the offspring will look like. students form hypotheses, such as that the young offspring will look like the mother and the older offspring will be striped. throughout the week, students observe and record embryos developing a head, tail, and notochord and pigment development. by the end of the experiment, a live heartbeat can be seen as well as the individual blood cells fl owing throughout the larvae using a stereomicroscope tjusop provides (figure ). grade-specifi c scientifi c journals are given to the students. the journals contain an introduction to tjusop and the experiment, background information about zebrafi sh in research, scientifi c vocabulary words used throughout the unit, and a word search activity. students are given the title of “junior scientists” in grades and and “student scientists” in grade and are asked to record the research question, a hypothesis, daily observations, and the conclusion of the experiment (figure ). doi: . /journal.pbio. .g figure . a philadelphia student uses the zeiss stereomicroscope during the weeklong experiment doi: . /journal.pbio. .g figure . an example of a seventh-grade journal entry plos biology | www.plosbiology.org how to break the stereotypes of what science is tjusop allows student participants to use scientifi c tools, talk with real scientists, and gain scientifi c knowledge so they can become informed members of their communities. upon asking a fourth-grade student why she thought it was important to learn about science using zebrafi sh and the microscope, the student wrote, “i think it is important because we can fi nd facts about oursefs [sic].” this sounds like a good start. for more information about the program, or if you would like to get involved in the initiative, please contact jamie schaefer, at jamie. schaefer@mail.jci.tju.edu or visit http:⁄⁄www.kimmelcancercenter.org/ scienceoutreachprogram. � references mcduffi e te jr ( ) scientists—geeks and nerds? dispelling teachers’ stereotypes of scientists. sci children may: – . national science board committee ( ) an emerging and critical problem of the science and engineering labor force: a companion to science and engineering indicators (nsb - ). national science foundation. available: http:⁄⁄www.nsf.gov/sbe/srs/nsb /start.htm via the internet. accessed august . sylwester r ( ) genetics: the new staff development challenge. educ leadership : – . october | volume | issue | e | e open access, freely available online people in political science activities felipe aguero, department of politi- cal science, ohio state university, is a fellow at the north/south cen- ter, university of miami, during - . gregory caldeira, department of political science, was named a uni- versity distinguished scholar at ohio state university. harold d. clarke, regents profes- sor of political science, university of north texas, has been ap- pointed co-editor of electoral stud- ies with iain mclean, nuffield col- lege, oxford, and bo sarlvik, university of goteborg. milton c. cummings, jr., professor of political science, johns hopkins university, received an honorary doctor of letters degree from the state university of new york. the degree was conferred at the winter commencement at suny plattsburgh, where cummings has served as a visiting distinguished professor. parris n. glendening parris n. glendening, associate professor of political science, uni- versity of maryland, has been elected governor of the state of maryland; formerly county execu- tive of prince george's county, maryland. richard gunther, department of political science, ohio state uni- versity, is fellow at the juan march institute in madrid, spain, during - . jaroslaw piekalkiewicz, professor of political science and russian and east european studies program, university of kansas, was named the first university distinguished lecturer of western civilization. piekalkiewicz has recently pub- lished (with alfred wayne penn), a book, politics of ideocracy, state university of new york press, . garrett ward sheldon, professor and chair, department of political science, clinch valley college of the university of virginia will have his book, the political philosophy of thomas jefferson, become the first english language book on jef- ferson to be translated into russian and published in moscow. after its publication by republica press, sheldon will deliver a series of lec- tures on jeffersonian political the- ory at moscow university. steven a. shull, research professor of political science, university of new orleans, will edit a book se- ries "politics and policy in ameri- can institutions" for garland pub- lishing inc. kimberly m. zisk, department of political science, ohio state uni- versity, is in her second year of a two-year ssrc/macarthur foun- dation fellowship on peace and security in a changing world. zisk is spending the - year at the mershon center at ohio state uni- versity. garrett ward sheldon administrative appointments henry s. bienen, president, north- western university; formerly wood- row wilson school, princeton uni- versity. gayle binion, director, washington center for university of california, santa barbara. ann l. craig, provost, eleanor roosevelt college of the university of california, san diego; formerly director of undergraduate studies, department of political science, university of california, san diego. james w. hottois, president, lewis-clark state college; for- merly provost and dean of aca- demic affairs, eastern oregon state college. john r. johannes, vice president for academic affairs, villanova uni- versity, effective august , ; formerly professor of political sci- ence and dean, college of arts and sciences, marquette university. susan ann kay, chair, department of political science, miami (oh) university. ps: political science & politics activities and appointments ruth mandel ruth mandel, director, eagleton institute of politics, rutgers uni- versity. wally miles, chair, department of political science, san diego state university. anthony mughan, director, under- graduate international studies pro- gram, ohio state university. new appointments james adams, assistant professor, department of political science, university of california, santa bar- bara. ivelaw griffith, assistant professor, department of political science, florida international university; formerly john jay college. heidi h. hobbs, assistant profes- sor, department of political science, florida international university; formerly central illinois univer- sity. dean lacy, assistant professor, de- partment of political science, ohio state university; formerly duke university. paul lewis, assistant professor, de- partment of political science, flor- ida international university; for- merly princeton university. william reno, assistant professor, department of political science, florida international university; formerly hamilton college. randall schweller, assistant profes- sor, department of political science, ohio state university; formerly columbia university. helene silverberg, assistant profes- sor, department of political science, university of california, santa bar- bara. margaret jane wyszomirski, profes- sor of political science with tenure, and director, arts management program, weatherhead school of management, case western re- serve university; formerly director, graduate public policy program, georgetown university and direc- tor, policy planning, research and budget, national endowment for the arts. promotions ryan j. barilleaux, professor of political science, miami university. peter digeser, associate professor with tenure, department of political science, university of california, santa barbara. wolfgang drechsler, professor of public administration and political science, university of tartu, estonia. fernando lopez-alves, associate professor with tenure, department of political science, university of california, santa barbara. joel s. migdal, robert f. philip professor of international studies, henry m. jackson school of inter- national studies, university of washington. paul a. rahe, jay p. walker pro- fessor of american history, uni- versity of tulsa. harvey l. schantz, professor of political science, state university of new york, plattsburgh. shannon ishiyama smithey, assis- tant professor, department of politi- cal science, university of pittsburgh. john white, professor, department of political science, catholic uni- versity of america. retirements haruhiro fukui, department of po- litical science, university of cali- fornia, santa barbara. wolfram hanrieder, department of political science, university of cal- ifornia, santa barbara. john e. moore, department of po- litical science, university of cali- fornia, santa barbara. a.e. keir nash, department of po- litical science, university of cali- fornia, santa barbara. robert c. noel, department of po- litical science, university of cali- fornia, santa barbara. thomas schrock, department of political science, university of cal- ifornia, santa barbara. visiting and temporary positions paul r. abramson, professor of political science, michigan state university, was a lady davis vis- iting professor in the department of political science at the hebrew university of jerusalem from octo- ber through january . the appointment was supported by a grant from the lady davis fellow- ship trust, jerusalem. paul r. abramson june people in political science stanley renshon, professor of polit- ical science, the city university of new york, is on sabbatical for and has been appointed visit- ing scholar at the john f. kennedy school of government, harvard university. renshon will be work- ing with the school's leadership development project on curriculum to improve the quality of decision judgment for public policy develop- ers and decision makers. awards macarthur grants awarded the john d. and catherine t. macarthur foundation has awarded nineteen research and writing grants to twenty-three scholars and writers from the u.s. and around the world. the grants, totaling al- most $ , , are intended to sup- port these individual scholars studying issues of peace and inter- national cooperation. the research and writing grants, which are part of the foundation's program on peace and international cooperation, are designed to en- courage analysts to explore interna- tional issues and to seek out inno- vative approaches to new policy dilemmas emerging in the rapidly changing world arena. the grants are open to individuals of any na- tionality who have a proven ability to do creative work; recipients have included scholars, journalists, and practitioners, among others. the grants range up to $ , for individuals or $ , for a two-person team, and extend up to eighteen months in duration. recip- ients may carry out research at the institution or location of their choice. there are no age, academic affiliation, or geographic restric- tions on recipients. the purpose of the grants is to serve the following goals: • to broaden and strengthen the community of scholars and writ- ers engaged in policy-oriented work on international peace and security. • to encourage the reconceptual- ization of security issues in light of changing international events, and to encourage attention to new developments that have not been adequately understood as peace and security issues. • to foster integrated consideration of emerging relationships among economic, social, political, tech- nological, and environmental as- pects of global change. the twenty-three grant winners are: nancy barnes, maputo, mozam- bique anne f. bayefsky, university of ottawa ms. pascale m. combelles, blag- nac, france beth osborne daponte and timo- thy cote, university of pittsburgh and national institutes of health haleh esfandiari, potomac, maryland jonathan fox, massachusetts in- stitute of technology warren goldstein, amherst, massachusetts gennady gorelik, massachusetts institute of technology katrin jellema, grand haven, michigan michael t. klare, hampshire college nathalie lebon, university of florida thabane vincent maphai, uni- versity of western cape judith matloff, johannesburg, south africa r.t. naylor, mcgill university kevin j. o'brien and lianjiang li, ohio state university and nan- kai university yezid sayigh, oxford, uk beth stephens, center for consti- tutional rights, new york, new york susan willett and peter batchelor, kings college, london, uk snjezana krezo and dusko ilic, sibenik, croatia and tokyo, japan pi sigma alpha award stephen horn, united states representative from california's th district and a political scien- tist with over thirty-five years of experience as a participant in na- tional policy making and service as a scholar, teacher, and university administrator, has received the na- tional capital area political sci- ence association pi sigma alpha award. the award, recog- nizing the outstanding contributions of a political scientist to public ser- vice, was presented march , , at mount vernon college. prior to his election to congress in , representative horn served as trustee professor of po- litical science at california univer- sity, long beach, with a specialty in the legislative process. congress- man horn's career began as a polit- ical appointee in the eisenhower administration, where he was ad- ministrative assistant to secretary of labor james p. mitchell. he then served for five years as legis- lative assistant to senator thomas h. kuchel of california, who at the time was deputy republican leader (whip) of the u.s. senate. during that time, he worked on major legislation, including the civil rights act of , the voting rights act of , medicare, and water policy for the western states. congressman horn has also been a senior fellow at the brookings institution and dean of graduate studies and research at the amer- ican university. from - , he served as president of california state university, long beach. in addition, he served part-time for sixteen years as a founding member and past chair of the national in- stitute of corrections of the u.s. department of justice, and for thir- teen years as a member and vice chair of the u.s. commission on civil rights. carrie chapman catt prize for research cheryl logan sparks, university of north carolina at chapel hill was awarded the carrie chapman prize for research for "how grand- mother won the war: strategic and organizational lessons from the struggle for suffrage." lisa young, university of toronto and visiting fulbright scholar at american uni- versity received honorable mention for "the relationship between wo- men's movements and political ps: political science & politics mp p bax in neuroendocrine lung tumors. am j pathol ; : – . . umpiere sa, burke tw, tornos c, ordonez n, levenback c, morris m. immunohistochemical analysis of uterine papil- lary serous carcinomas for estrogen and progesterone recep- tors. int j gynecol pathol ; : – . . nanbu k, konishi j, komatsu t, mandai m, yamamoto s, kurada h, et al. expression of heat shock proteins hsp and hsp in endometrial carcinomas: correlation with clinicopathology, sex steroid receptor status and p protein expression. cancer ; : – . . bergeron g, ferenczy a, shyamala g. distribution of estro- gen receptors in various cell types of normal, hyperplastic, and neoplastic human endometrial tissues. lab invest ; : – . . zaino rj, sartwaswaroop pg, mortel r. the relationship of histologic parameters to progesterone receptor status in en- dometrial adenocarcinoma. gynecol oncol ; : – . . creasman wt. prognostic significance of hormone recep- tors in endometrial cancer. cancer ; (suppl): – . . rose pg. endometrial carcinoma. n engl j med ; : – . book review fenoglio-preiser cm, noffsinger ae, stemmer- mann gn, lantz pe, listrom mb, rilke fo: gastrointestinal pathology plus on cd- rom, philadelphia, lippincott williams & wilkins, ($ ). the second edition of gastrointestinal pathology is now available on cd-rom. the electronic ver- sion contains an expanded text and more illus- trations. it runs under windows or macintosh operating systems and requires at least mb of ram. i have run it on windows , , and nt. installation notes recommend setting virtual memory at mb or greater for optimal pictorial quality. a good rule of thumb is to set virtual memory at twice the amount of ram, but keep in mind that windows prefers to self-manage vir- tual memory for most applications. the produc- tion disk contains mb of data, with approx- imately % of the space devoted to pictures and diagrams. a combination of software products are bundled together to run this reference work. the vendors include folio corporation for text retrieval and iterated systems for image display. navigation around the disk is easy at the top level but awkward when paging through individ- ual chapters. there are shortcuts to individual topics via the go to option, but one needs to enter a numerical address. hyperlinks to pictures and illustrations allow you to overlay windows for side-by-side comparisons with the written text, and there is a clever pop-up option to view immediately any cited reference. an effective search engine that uses boolean logic is available for names or key words, and there are shortcuts to jump to your results. instructions on printing text items and exporting images are available in the read me files. overall, this disk contains sufficient tools to keep most users occupied for a long time. the text and illustrations have been revised for the second edition, and references are up- dated through (some through ). a se- lective review of dysplasia in ulcerative colitis shows it to be clear, concise, and complete. the recommendations for dysplasia-associated le- sions or masses are practical. the section on gastritis generally follows the sydney system with the usual caveats. however, i was disap- pointed not to find the article by dixon et al. concerning the updated principles and grad- ing data. a discussion of gastroesophageal reflux disease, -h acid testing, and short-segment barrett esophagus is lacking. gross photographs, radiographs, and diagrams are of excellent qual- ity. unfortunately, photomicrographs appear pixelated and rapidly degraded when zoomed. the combination of content, search capabil- ities, and the ability to print text and export images makes this cd a powerful reference work. the one disadvantage of this format is the quality of the photomicrographs. keeping in mind that the capacity of an ordinary -cent disk is mb and the availability of file compression tech- nology, one would think that medical publishers could produce higher quality microscopic im- ages. peter a. mccue thomas jefferson university philadelphia, pennsylvania modern pathology 	book review keloid pathogenesis: potential role of cellular fibronectin with the eda domain | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /jid. . corpus id: keloid pathogenesis: potential role of cellular fibronectin with the eda domain @article{andrews keloidpp, title={keloid pathogenesis: potential role of cellular fibronectin with the eda domain}, author={jonathan p. andrews and j. marttala and e. macarak and j. rosenbloom and j. uitto}, journal={the journal of investigative dermatology}, year={ }, volume={ }, pages={ - } } 	jonathan p. andrews, j. marttala, + authors j. uitto 	published 	biology, medicine 	the journal of investigative dermatology fibronectins (fns) are high molecular weight glycoproteins present in extracellular connective tissue matrices (ecm) and extracellular fluids, including blood plasma. the human fn gene consists of exons, and the primary mrna transcripts are alternatively spliced to form up to different mrna variants (white et al., ). the fns interact with other matrix proteins, such as collagens, glycosaminoglycans and fibrin, as well as cell surface receptors, including integrins α β , α β and αvβ … expand view on pubmed jidonline.org save to library create alert cite launch research feed share this paper citationsbackground citations view all figures and topics from this paper 	 figure 	keloid 	fibronectins 	specimen 	inorganic phosphate 	incubated 	norepinephrine 	buffers 	radioimmunoprecipitation assay 	edetic acid 	pulmonary fibrosis 	congenital abnormality 	staining method 	transcript 	betadine 	glycosaminoglycans 	fn-tgm complex 	exons 	status epilepticus 	fluorides 	reducing agents 	extraction 	null value 	connective tissue 	molecular weight 	nervous system disorder citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency integrin α β and tlr cooperate to induce fibrotic gene expression in response to fibronectin's eda domain. 	rhiannon kelsh-lasher, a. ambesi, c. bertram, p. mckeown-longo 	biology, medicine 	the journal of investigative dermatology 	 	 	pdf save alert research feed keloid disorder: fibroblast differentiation and gene expression profile in fibrotic skin diseases 	e. macarak, p. wermuth, j. rosenbloom, j. uitto 	medicine, biology 	experimental dermatology 	 	 	 save alert research feed fibronectin extra domain a (fn-eda) elevates intraocular pressure through toll-like receptor signaling 	a. l. roberts, t. mavlyutov, + authors c. mcdowell 	chemistry, medicine 	scientific reports 	 	 	pdf save alert research feed knockdown of fibronectin extra domain b suppresses tgf-β -mediated cell proliferation and collagen deposition in keloid fibroblasts via akt/erk signaling pathway. 	j. cui, zhouna li, c. jin, zhe-hu jin 	chemistry, medicine 	biochemical and biophysical research communications 	 	 save alert research feed eda fibronectin in keloids create a vicious cycle of fibrotic tumor formation. 	rhiannon m kelsh, p. mckeown-longo, r. clark 	chemistry, medicine 	the journal of investigative dermatology 	 	 	pdf 	view excerpts, cites background save alert research feed tlr ligands selectively synergize to induce expression of il- . 	lauren m valenty, christine m. longo, carol horzempa, a. ambesi, p. mckeown-longo 	biology, medicine 	advances in wound care 	 	 	pdf 	view excerpt, cites background save alert research feed sorafenib exerts an anti-keloid activity by antagonizing tgf-β/smad and mapk/erk signaling pathways 	w. wang, m. qu, + authors yue-lei chen 	medicine 	journal of molecular medicine 	 	 	pdf 	view excerpt, cites background save alert research feed keloids: the paradigm of skin fibrosis - pathomechanisms and treatment. 	jonathan p. andrews, j. marttala, e. macarak, j. rosenbloom, j. uitto 	medicine 	matrix biology : journal of the international society for matrix biology 	 	 	 save alert research feed long non-coding rna expression profiling in the lesional tissue and derived fibroblasts of keloid 	chunyu yuan, wen-bo bu, + authors h. gu 	medicine 	postepy dermatologii i alergologii 	 	 	pdf 	view excerpt, cites background save alert research feed integration of canonical and noncanonical pathways in tlr signaling: complex regulation of the wound repair program 	j. mckeown-longopaula, j. higginspaul 	biology 	 	 	 save alert research feed ... ... references showing - of references sort byrelevance most influenced papers recency new insights into form and function of fibronectin splice variants 	e. white, f. baralle, a. muro 	medicine 	the journal of pathology 	 	 	 	view excerpt, references background save alert research feed the extra domain a of fibronectin activates toll-like receptor * 	y. okamura, m. watari, + authors j. strauss 	biology, medicine 	the journal of biological chemistry 	 	 , 	pdf save alert research feed regulated splicing of the fibronectin eda exon is essential for proper skin wound healing and normal lifespan 	a. muro, a. chauhan, + authors f. baralle 	biology, medicine 	the journal of cell biology 	 	 	pdf 	view excerpt, references background save alert research feed fibronectineda promotes chronic cutaneous fibrosis through toll-like receptor signaling 	s. bhattacharyya, zenshiro tamaki, + authors j. varga 	biology, medicine 	science translational medicine 	 	 	 	view excerpt, references background save alert research feed transforming growth factor β regulates the levels of different fibronectin isoforms in normal human cultured fibroblasts 	e. balza, l. borsi, g. allemanni, l. zardi 	biology, medicine 	febs letters 	 	 	view excerpt, references background save alert research feed fibronectin (fn) in hypertrophic scars and keloids 	c. ward kischer, maryj.c. hendrix 	chemistry, medicine 	cell and tissue research 	 	 	highly influential 	view excerpts, references background save alert research feed fibronectin gene expression differs in normal and abnormal human wound healing 	jill c. sible, e. eriksson, steven p. smith, n. oliver 	chemistry, medicine 	wound repair and regeneration : official publication of the wound healing society [and] the european tissue repair society 	 	 	highly influential 	view excerpts, references background save alert research feed the vitronectin receptor alpha v beta binds fibronectin and acts in concert with alpha beta in promoting cellular attachment and spreading on fibronectin 	i. charo, l. nannizzi, j. smith, d. cheresh 	biology, medicine 	the journal of cell biology 	 	 	highly influential 	pdf 	view excerpts, references background save alert research feed regulation of fibronectin eda exon alternative splicing: possible role of rna secondary structure for enhancer display 	a. muro, m. caputi, r. pariyarath, f. pagani, e. buratti, f. baralle 	biology, medicine 	molecular and cellular biology 	 	 	pdf 	view excerpt, references background save alert research feed keloids: current concepts of pathogenesis (review). 	g. bran, u. goessler, k. hormann, f. riedel, h. sadick 	medicine 	international journal of molecular medicine 	 	 	 	view excerpt, references background save alert research feed ... ... related papers 	abstract 	figures and topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue prm cc.dvi journal of pediatric rehabilitation medicine: an interdisciplinary approach ( ) doi . /prm- ios press dr. michael alexander receives the first molnar, pediatric pm&r lifetime achievement award jprm is pleased to recognize dr. michael alexan- der as the inaugural winner of the gabriella molnar, md pediatric lifetime award from the foundation of pm&r. dr. michael alexander has dedicated his en- tire career to the pursuit improving this subspecialty of pediatric pm&r. dr. alexander served as the chief of rehabilitation medicine at the alfred i. dupont hospital for chil- dren in wilmington, de for over years and has two decades of experience as a professor at thomas jefferson medical college. he was selected as physi- cian of the year by the pennsylvania governor’s committee on employment of the handicapped in and received the american academy of physi- cal medicine and rehabilitation’s distinguished clinician award. he is a past president of the amer- ican academy of cerebral palsy and developmental medicine and the medical society of delaware. dr. alexander received his doctorate of medicine from the university of virginia school of medicine and completed a combined residency of pediatrics and physical medicine from ohio state university and children’s hospital in columbus, ohio. started his academic career at ohio state, then served at dt watson rehab hospital for children’s in pitts- burgh for eight years and then spent the following years at ai dupont. he has held board certifications in pediatrics, physical medicine and rehabilitation, electrodiagnostic–subspecialty board - pediatric re- habilitation medicine. during his career, dr. alexander has been responsi- ble for training over two dozen pediatric rehab physi- cians. he is also the co-editor of the pediatric rehabil- itation principles and practice textbook, now in prepa- ration for its fifth edition. dr. alexander feels the pediatric rehabilitation was the perfect field for him – “pediatric rehab medicine gave me the chance to work with children today, with my eye set on their future”. dr. alexander currently resides in hockessin, delaware. he has three children and two granddaugh- ters whom he now watches two days a week in his retirement. personally, his hobbies include choral singing for the past years as a tenor in the new ark chorale and counts one of his performance highlights as appearing at st. peters cathedral in rome. his group also performed the premiere of the requiem for / by wilson somers, nov. in wilmington, de. he also enjoys aquatic container gardening. academically, he continues to be involved at ai dupont and provides weekly resident lectures and maintains his academic appointment at thomas jeffer- son. dr. alexander is an emeritus medical staff mem- ber at ai dupont. dr. alexander will be providing the inaugural gabriella molnar lectureship at the aapm&r meeting in san diego, his working title is “societies’ treatment of the disabled and their families over the centuries”. - / /$ . c© – ios press and the authors. all rights reserved << /ascii encodepages false /allowtransparency false /autopositionepsfiles true /autorotatepages /none /binding /left /calgrayprofile (dot gain %) /calrgbprofile (srgb iec - . ) /calcmykprofile (u.s. web coated \ swop\ v ) /srgbprofile (srgb iec - . ) /cannotembedfontpolicy /error /compatibilitylevel . /compressobjects /tags /compresspages true /convertimagestoindexed true /passthroughjpegimages true /createjobticket false /defaultrenderingintent /default /detectblends true /detectcurves . 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c e f f d f b d e f d e f f b b b f b c e d f b d e e b e e e f c c f e c c e e> /pol <feff e f f a e f b d e f a a e a f e f b f f b a a b f b e f b d e d f c e f f d f f e e f a d e> /ptb <feff c a f e e f f d f d e f f d f e d d f c c e f f d e f f f d f f d f f f f e f f f e> /rum <feff c a e f d e f e c f e f d e c f f c f e f e c c f e> /rus <feff f e b c d d b d e a b f e d f e a c d e f c c a c b c d e f e e f b f b e a e a d d e e e f d e e b e e e d d b d e a c d b c e d e e a b c f e c e c e f f e e b f e d e> /sky <feff f e e f e e e e f b d e f f c b f e e a c f e b c e fa c d e f e e f b d e d f e e e f f f d f f f e e f ed e> /slv <feff e f a a e a f b d e f f c b f e a d e a a b b f f e f b e a f e b e a e f b d e a d f f d f a f e f e e e f a d e> /suo <feff b e e e e e b c b e c f c e e e e e e b e c d c f f e f f d f b d e a e c f d f b d e f e f c c a f e a c c a d d c c e> /sve <feff e e e e e e c c e e e f d c c b f d f b d e f d e c e d c f d b d f b c e b d f b d e b e f e f f f e f e e> /tur <feff fc b b b c c f e a d b e e c b f c c f c f d b e e c b c c e e e f c f c e c c f f e f e e b fc fc d c c e c c e> /ukr <feff a e e f c b f e d d f e a c d f c f a d a f e f c b f e a e f a d e e f a e e e a e e d e a c d c e d a f f e e f d e e> /enu (use these settings to create adobe pdf documents best suited for high-quality prepress printing. created pdf documents can be opened with acrobat and adobe reader . and later.) >> /namespace [ (adobe) (common) ( . ) ] /othernamespaces [ << /asreaderspreads false /cropimagestoframes true /errorcontrol /warnandcontinue /flattenerignorespreadoverrides false /includeguidesgrids false /includenonprinting false /includeslug false /namespace [ (adobe) (indesign) ( . ) ] /omitplacedbitmaps false /omitplacedeps false /omitplacedpdf false /simulateoverprint /legacy >> << /addbleedmarks false /addcolorbars false /addcropmarks false /addpageinfo false /addregmarks false /convertcolors /converttocmyk /destinationprofilename () /destinationprofileselector /documentcmyk /downsample bitimages true /flattenerpreset << /presetselector /mediumresolution >> /formelements false /generatestructure false /includebookmarks false /includehyperlinks false /includeinteractive false /includelayers false /includeprofiles false /multimediahandling /useobjectsettings /namespace [ (adobe) (creativesuite) ( . ) ] /pdfxoutputintentprofileselector /documentcmyk /preserveediting true /untaggedcmykhandling /leaveuntagged /untaggedrgbhandling /usedocumentprofile /usedocumentbleed false >> ] >> setdistillerparams << /hwresolution [ ] /pagesize [ . . ] >> setpagedevice preserving today's scientific record for tomorrow | the bmj skip to main content intended for healthcare professionals 	 subscribe 	 my account 	my email alerts 	 bma member login login 	 username * password * forgot your log in details? need to activate bma member log in log in via openathens log in via your institution edition: us 	uk 	south 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they could be sent (prferarably as a word or rtf and pdf files) or through e-mail as file attachment. all correspondence (requests for subscrip- tions, manuscripts, books for review-two copies, please exchange copies of journals, advertisements, etc.) to: the editor, jnanadeepa, jnana-deepa vidyapeeth, pune , india tel (office): + - - , (res): + - - e-mail: <journalpune@gmail.com> <kuru@jdv.edu.in> subscriptions could be sent from india either by money order or demand draft. from foreign countries internationnal money order or crossed cheque is pre- ferred. from commonwealth countries british postal order is preferred. all pay- ments (cheque, drafts, etc. are to be made in the name of jnana deepa vidyapeeth. typeset & print: jdv computer centre publisher: kuruvilla pandikattu for jnana deepa publications. issn: - jnanadeepa pune journal of religious studies chief editor kuruvilla pandikattu associate editor thomas kuriacose book review editor alphonse n. irudayadason advisory board henry d’almeida prasad lankapilli stephen jayard selva rathinam francis pudhicherry isaac parackal dinesh braganza konrad noranha mohan doss m. paul raj arjen tete stephen c. thadam thomas malipurathu thomas kattathara vadappuram m. jose vincent crasta george karuvelil joseph a. d’mello francis gonsalves biju joseph john karuvelil anil thomas naveen rebello jomin nirapel subscription rates country one year three years india ₹ ₹ saarc countries ₹ ₹ other countries (air mail) $ (€ ) $ (€ ) institutional rate $ (€ ) $ (€ ) j n a n a d e e p a / j a n - j u l y p u n e j o u r n a l o f r e l i g i o u s s t u d i e s c o n t e n t s editori al disse nt in democracy the demand of the day ............................... (un)democratising democracy victor ferrao .................................... paul’s radical dissent with the p ast life based on the law m.paul raj ........................................ democracy and vi gilantism stephen chundamthadam sj .......... ..... wi t h, against an d fo r t h e ot h e r nishant a. irudayadasan .................... resisting cultur al genocide arjen tete sj ..................................... fractured identit ies, invisible s el ves konrad noro nha sj ........................... dissent as a dem and for ascent s. stephen jayard ............................. homo faber: a p hilosophy of technology and ethical impl ications j. c. paul rohan. ............................ j n a n a d e e p a / j a n - j u n e fr. kurien kunnum puram: a man of vision and commitment thomas kari mundakkal sj ............ ... joy and happine ss of being a christian kuruvilla pa ndi kattu sj ................... a call to commitment gijo john msfs .............................. our contributors ................................................... dissent in democrac y: the demand of the day “the only thing worth globalising is dissent.” -arundhati roy “dissent is the highest form of patriotism” -attributed to thomas jefferson “we must not confuse dissent with disloyalty.” -edward r. murrow “what difference does it make to the dead, the orphans and the homeless, whether the mad destruction is wrought under the name of totalitarianism or in the holy name of liberty or democracy?” - mahatma gandhi kuru@jdv.edu.in typewritten text doi: . /zenodo. 	 . cover.pdf (p. ) 	jnanadeepa . jan dissent in democracy.pdf (p. - ) pnd determinants of emergency department utilization for migraine care a abstracts for to years in a us medicare health maintenance organi- zation. the study population was identified using icd- codes ( ; . ) for pd and a claim for at least one filled pd pre- scription identified using ndc codes. medication possession ratio (mpr) was estimated as proxy for adherence to pd med- ications, with a threshold of . indicating adherence. pd symptom progression was defined as increase in prescription strength, addition of another pd medication, an emergency room visit or hospitalization related to pd. demographic, clinical, and economic variables were extracted from the dataset. prevalence of non-adherence was calculated over all years and for each year of eligibility. logistic regression was used to assess relation between medication adherence and pd symptom progression. sensitivity analyses were conducted for mpr scores less than . , . , and . . results: the study population (n = patient- years) had mean mpr score of . (± . ). an average of % of study population was not adherent to their pd medications (mpr < . implies non-adherence). sensitivity analysis with mpr scores less than . , . , and . indicated an average of %, % and % were not adherent to their pd medications respectively. subjects adherent to their pd medications (mpr >= . ) had % less odds of experiencing pd symptom progres- sion (or = . ; ci: . – . ) compared to people not adher- ent to pd medications. all subjects with mpr < . experienced pd symptom progression. conclusion: high prevalence of non-adherence to pd medication and its association with pd symptom progression, irrespective of mpr threshold chosen, indicates it is a significant problem. there is a need for mecha- nisms to improve medication adherence in pd, namely improved patient understanding, simplified treatment regimens and improved tolerability profiles. pnd determinants of emergency department utilization for migraine care kwong wj university of georgia, athens, ga, usa objectives: over-utilization of emergency department (ed) services for non-urgent medical conditions has been noted as a problem for decades. headache is the sixth most common reason for ed visits. this study examined factors of ed use in a migraine population. methods: medical and rx claims of georgia medicaid beneficiaries who had at least one migraine medical claim (icd- of .xx) or one triptan/ergot claim between jan and dec , and were continuously eligi- ble from months before to months after first migraine claim were analyzed. subjects who had a narcotic claim and a medical claim for cancer (icd- – ), fractures ( – ), muscu- loskeletal and connective tissues disease ( – ), or sickle cell anemia ( . x) months before index date were excluded. likelihood of a migraine ed visit during the months after index date was estimated using logistic regression while con- trolling for age, gender, race, metropolitan status of county of residence, physician supply in county, butalbital and narcotic medication use months before index date. results: data from , subjects were analyzed. mean age was years (sd = ), % were male and % were caucasians. six percent of subjects had used butalbitals and % had used narcotics months before index date, and % subjects had at least one migraine ed visit months after index date. females, non-cau- casians, residents of metro counties or counties that had lower than average physician per , population ratio were more likely to have an ed visit (adjusted odds ratio, aor = . , . , . , and . respectively, p < . ). prior narcotic use signif- icantly increased the risk of ed visit (aor = . , p < . ). age and butalbital use had no effect on ed use. conclusion: local physician shortage and easy ed access encouraged ed use for non-urgent medical problems. improving access to primary care facilities is crucial for reducing non-urgent ed use. pnd developing a migraine quality of care measurement set leas b , gagne jj , goldfarb ni , rupnow mf , lofland jh , hopkins mm , nash d , silberstein sd thomas jefferson university, philadelphia, pa, usa, ortho-mcneil janssen scientific affairs, llc, titusville, nj, usa, thomas jefferson university hospital, philadelphia, pa, usa objectives: to develop a migraine quality of care measure- ment set at the health plan level, in order to begin measuring and improving migraine care processes and outcomes. methods: the measurement set was developed through: ) review of migraine care guidelines; ) literature review of quality mea- surement for migraine care; ) telephone interviews with thought leaders in migraine care and quality improvement; and ) assem- bly of a national advisory board consisting of prominent leaders within migraine care, quality measurement and managed care. the advisory board reviewed collected information from tasks – , discussed candidate measures, and established a consensus on target measures to be included in the set. results: the advi- sory board selected potential measures that could be imple- mented at the health plan level using administrative (claims) data. these measures capture information on: migraine diagno- sis and prevalence; use of preventive and therapeutic medica- tions; and, primary care, specialist, emergency, diagnostic radiologic, and inpatient service utilization. the measurement specifications have been developed to mirror technical specifica- tions for administrative measures in the health plan employer data and information set (hedis). conclusion: develop- ment of an evidence-based set of quality measures for migraine care is an important advance in seeking to measure and improve care for migraineurs. despite its prevalence, and impact on direct and indirect costs, migraine is not currently being addressed in the national quality measurement movement. the measurement set is now being pilot tested in health plans to assess feasibility of data collection, properties of the measures, and correlation among the measures. pnd understanding limitations of patient reported clinical outcomes in lupus wilke ct , jolly m , khandelwal s , rodby r , block ja , pickard as university of illinois at chicago, chicago, il, usa, rush university medical center, chicago, il, usa, rush medical university medical center, chicago, il, usa, college of pharmacy, university of illinois at chicago, chicago, il, usa objectives: patient knowledge is associated with their ability to manage their disease (self-efficacy). the objective of this study was to examine the extent to which patients with systemic lupus erythematosus (sle) reported specific organs/system involvement that was consistent with medical records. methods: in a cross- sectional study, patients with sle were asked to indicate whether the following organ systems were affected by their lupus: skin/hair/scalp, joints, kidneys, brain, heart/lungs, (abnormal) blood counts, blood clots (including stroke). a retrospective chart review was undertaken to examine organ involvement and tests as recorded by their physician. exact and kappa measures of agreement between physician and patient report were calculated for each organ system. results: the patient sample (n = ) pin the economic impact of methicillin resistance in staphylococcus aureus bacteremia in korea a abstracts parison purposes, the mortality rate of all inpatients with s. aureus infections was . %. patients with s. aureus csssis were older (mean age years vs. years for the comparison group) and were more likely to have congestive heart failure, diabetes with chronic complications and bacteremia/septicemia. relative to the comparison group, patients with s. aureus csssis had significantly (p < . ) longer mean length of stay ( . vs. . days) and higher average costs per stay ($ , vs. $ , ). after con- trolling for potentially confounding factors, the excess mean costs associated with s. aureus csssis were estimated to be $ , . conclusion: our findings suggest that the clinical and eco- nomic burden of complicated skin and skin structure infections (csssis) due to staphylococcus aureus among hospitalized patients is substantial. pin impact of s. aureus infections on expenditures and length-of-stay in u.s. hospitals noskin g , rubin r , schentag j , kluytmans j , hedblom e , jacobson c , smulders m , gemmen ek , bharmal m northwestern university feinberg school of medicine, chicago, il, usa, georgetown university, washington, dc, usa, university at buffalo school of pharmacy, buffalo, ny, usa, amphia hospital and vumc medical university, amsterdam, rk, the netherlands, m medical, st paul, mn, usa, quintiles, falls church, va, usa, quintiles strategic research & safety, falls church, va, usa objectives: evaluate the incremental impact of s. aureus infection stays on hospital charges and length-of-stay in u.s. hospitals in . methods: the nationwide inpatient sample data were analyzed. hospital discharges were classified as either a s. aureus–related infection stay or a non-s. aureus- related infection stay using a combination of several icd- codes. incremental effect of s. aureus infection on hospital charges and length-of-stay was estimated using multivariate regression models adjusting for hospital fixed effects and patient variables including age, gender, race, payer, diagnosis-related grouping and concomitant conditions including diabetes, dialy- sis and lung disease. results: s. aureus infection was reported as a discharge diagnosis for . % of all hospital inpatients, or , stays, in . s. aureus infection hospital stays were significantly more likely among male, older patients, stays that were paid by medicare, white or non-hispanics and hospital stays among individuals with diabetes, lung disease or dialysis. after adjusting for covariates, the mean incremental impact of s. aureus infection on hospital charges and length-of-stay was $ , ( % confidence interval (ci): $ , –$ , ) and . days ( % ci: . – . ) among all inpatient stays, $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among surgical stays, $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among invasive cardiovascular stays, $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among invasive orthopedic stays and $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among invasive neurosurgical stays. conclusion: s. aureus infections present a considerable economic burden to u.s hospitals. based on the prevalence of s. aureus infection and its incremental impact, the total economic impact of s. aureus among all hospital admissions was estimated at $ . billion in u.s. dollars. pin determinants of total hospital costs among inpatients with candidemia lee sp , bunz t , gagne jj , maio v , goldfarb ni , horn dl , swanson r thomas jefferson univeristy, philadelphia, pa, usa, thomas jefferson university, philadelphia, pa, usa, pfizer inc, new york, ny, usa objectives: to identify factors associated with total hospital costs among patients with candidemia in a large, urban, tertiary care, teaching hospital. methods: this retrospective cohort study examined hospitalizations during calendar years and at thomas jefferson university hospital in philadelphia, pa, using data from various hospital systems. candidemia cases were identified via the microbiological laboratory information system as those patients with at least one confirmed positive blood culture for any candida species at any point during the study period. demographic, economic, and clinical data, includ- ing length-of-stay (los), payer types, total costs, and diagnosis related group (drg) assignments were collected from the hos- pital cost accounting system. pharmacy data (i.e. medications administered and associated costs) were retrieved from the phar- macy electronic information system. a multivariate regression analysis, using the natural logarithm of total hospitalization costs as the dependent variable, was conducted. independent variables included demographic information, relative drg weights, and candida species. results: among , total hospitalizations during the study period, cases were con- firmed positive for candidemia. the mean age of cases was years, % were female, and % were caucasian. the mean los was . days and the average inpatient cost for candidemia cases was $ , (sd = $ , ; median, $ , ). the most common candida species was c. albicans (n = ; %). the most commonly used antifungal treatment was fluconazole (n = , %). age, and relative drg weights (p < . ) were significantly positively correlated with total hospital costs. older patients with higher relative drg weights were associated with the higher total costs. race, gender, and marital status were not associated with total costs. conclusion: relative drg weights, as well as age are associated with total hospital costs among patients with candidemia. candidemia is expensive to treat and results in lengthy hospital stay. early detection and treatment may significantly reduce resource use as well as improve outcomes. pin the economic impact of methicillin resistance in staphylococcus aureus bacteremia in korea park ej , lee ek , chae s korea institute for health and social afffairs, seoul, south korea, sookmyung women’s university, seoul, south korea, korea institute for health and social affairs, seoul, south korea objectives: the objective of this study is to examine the eco- nomic outcome of methicillin resistance in staphylococcus aureus bacteremia in korea, where mrsa is endemic in major- ity of hospitals. methods: we conducted retrospective case- control study of patients admitted to three university-based teaching hospitals in seoul, korea in . cases were defined as patients with methicillin-resistant s. aureus (mrsa) bac- teremia and controls were methicillin- susceptible s. aureus (mssa) bacteremia selected according to a priori matching cri- teria. cases and controls were identified. hospital charges were collected from hospitals’ billing system. results: the median hospital charge after the development of bacteremia was higher for cases with mrsa bacteremia ($ ) than for con- trols with mssa bacteremia ($ ). the median hospital a abstracts charge for pharmaceuticals of mrsa bacteremia patients was $ and that of mssa bacteremia patients was $ . the median length of hospitalization after the development of mrsa patients who survived was . days and that of mssa bac- teremia control patients who survived was days. conclu- sion: antibiotic resistance in staphylococcus aureus bacteremia increased direct medical cost by %. the results of this study indicate that the mrsa infection is associated with increased medical cost and prolonged hospital stay. pin direct costs of anemia among patients treated with zidovudine curkendall s , doan qv , everhard f , richardson j , emons mf cerner, vienna, va, usa, cerner, beverly hills, ca, usa, gilead sciences, foster city, ca, usa objectives: zidovudine (zdv) use has been shown to be associated with anemia. our objective was to assess the impact of anemia on medical resource use and cost in patients treated with a zdv-containing haart regimens. methods: case- control study using hiv insight, which contains medical chart data from us hiv care centers. zdv-naïve patients who began a zdv-containing haart regimen on any date from january to june were assessed for baseline anemia (hb < g/dl). those without anemia (n = ) were followed through june, or until they had anemia or changed to a non-zdv-containing regimen. those with anemia (n = ) were followed until anemia worsened (drop ≥ . g/dl). patients with an incident anemia event (initiating or worsening) with ≥ months of follow-up were selected as cases. controls were matched on baseline anemia, cd < , gender and time period. medical resource use was tabulated during the -year post anemia period. costs were estimated for health care encoun- ters using external data for prices expressed in $us. results: cases included patients with anemia ( initiat- ing, worsening.) cases had greater use of medical resources than controls: . vs . (p < . ) office visits per year, % vs % hospitalized (p < . ), % vs % treated with epo (p = . ) and % vs % (p = . ) with a transfusion. cases had higher average annual costs than controls; $ , vs $ , (p = . ). cost components included epo $ , vs $ (p = . ), antiretrovirals $ , vs $ , (p = . ), other drugs $ , vs $ , (p = . ) and hospital stays, $ , vs $ (p < . ). conclusion: patients treated with zdv who experienced anemia required significantly more medical care and reported higher medical cost than patients without anemia. pin impact of hiv and hcv co-infection on hospitalization and resource use among hemophilia enrollees in commercial health plans tencer t , friedman h , li-mcleod j , johnson ka university of southern california, los angeles, ca, usa, analytic solutions, llc, new york, ny, usa, baxter bioscience, westlake village, ca, usa objectives: determine the economic impact and resource uti- lization of adult hiv and hcv co-infected hemophilia patients in a managed care population in the united states. methods: retrospective claims database analysis from / to / . patients continuously enrolled for at least months and > years of age were included. hemophilia patients were identified using icd- cm, hcpcs, and ndc codes. four cohorts for analysis were established: hemophilia only hemophilia + hiv, hemophilia + hcv, hemophilia + hiv + hcv. the main out- comes of study were costs associated with all pharmacy and medical claims, inpatient hospitalizations (frequency and length of stay) and office visit distribution by physician specialty. results: annual cost of care was $ , for the hemophilia only cohort, $ , for the hiv cohort, $ , for the hcv cohort and $ , for hiv/hcv co-infected cohort in dollars. clotting factor accounted for approximately – % of total costs. the hemophilia only, hcv, hiv, hiv/hcv infected hemophilia cohorts had prescription drug costs of $ , , $ , , $ , and $ , , respectively. approximately % of hemophilia only, % of hcv, and % of the hiv/hcv cohorts were hospitalized during the study period (p = . ). hospitalizations that were hemophilia related accounted for % of total hospitalizations for the hemophilia only cohort and % for the hiv/hcv cohort (p = . ). no significant differ- ence in inpatient length of stay was found. there was a differ- ence in the mean number of office visits among the cohorts (p = . ) with the hiv/hcv cohort having more visits than the hemophilia only group, . vs. . , respectively (p = . ). conclusion: although we were not able to control for sever- ity, the presence of hiv and hcv co-infection in hemophiliacs is associated with an increase in annual costs by up to %. increased clotting factor use and prescription drug costs in the virally infected groups account for most of the increase in costs. pin using decision simulation model to evaluate the cost effectiveness of entecavir compared to adefovir therapy in lamivudine refractory chronic hepatitis b (chb) patients: analyses from a us payer perspective yuan y , iloeje u , parry d , hay jw , zammit d bristol myers squibb international corporation, plainsboro, nj, usa, bristol myers squibb company, wallingford, ct, usa, bristol myer squibb company, hounslow, middlesex, uk, university of southern california, los angeles, ca, usa, bristol-myers squibb, braine l’alleud, belgium objectives: to estimate the long-term health and economic impact of managing chb with entecavir instead of adefovir treatment in the us, based upon projected clinical benefits from hbv dna reduction observed in trials. methods: we took the perspective of a comprehensive payer responsible for all direct health care expenditures. a decision simulation model was developed to consider a hypothetical cohort of lamivudine refractory chb patients. multivariate-adjusted relative risks for five hbv dna categories were derived from the published r.e.v.e.a.l.-hbv study. these results were applied to the patients with simulation of their hbv dna data derived from summary statistics reported in separate entecavir and adefovir clinical trials. entecavir and adefovir daily costs were assumed $ . and $ . based on the wholesale acquisition prices. life expectancy estimates, direct medical cost of and utility scores for different phases of chb were estimated from pub- lished us specific data. viral resistance due to treatment was included. results: entecavir was superior to adefovir for the mean reduction in serum hbv dna by pcr assay (log copies/ml) adjusted for lamivudine effect, with reductions of . versus . , respectively. more patients reached unde- tectable viral load level with entecavir than adefovir treatment at week ( . % vs . %). in the reference case, for patients aged years, compared with adefovir, ten years of ente- cavir treatment avoided compensated cirrhosis, decompen- sated cirrhosis, and hcc, resulting in . quality-adjusted life year (qaly) gain at an incremental cost of $ per patient ( % discounted). the incremental cost of using entecavir was sites of slavery: citizenship and racial democracy in the post-civil rights imagination by salamishah tillet (review) sites of slavery: citizenship and racial democracy in the post-civil rights imagination by salamishah tillet (review) jesse a. goldberg callaloo, volume , number , winter , pp. - (review) published by johns hopkins university press doi: for additional information about this article [ access provided at apr : gmt from carnegie mellon university ] https://doi.org/ . /cal. . https://muse.jhu.edu/article/ https://doi.org/ . /cal. . https://muse.jhu.edu/article/ c a l l a l o o cal studies while moving beyond the limits of each. though the author avoids a heavy theoretical discussion of the subject, his approach invites the reader to consider what a productive relationship between literature and history might look like—an urgent ques- tion for the inevitably interdisciplinary field of caribbean studies. as a literary scholar, i admire and appreciate ocasio’s deft management of archival sources, though i am curious as to what he thinks about the relationship between the costumbrista articles he analyzes and the antislavery costumbrista fiction that scholars agree occupied a central place in the nineteenth-century cuban lettered sphere. for example, what light do little-known texts such as suárez y romero’s colección de artículos or villaverde’s costumbrista article shed on those authors’ canonical antislavery novels francisco ( ) and cecilia valdés ( )—both of which feature costumbrista types such as the black coachman and the tragic mulata that ocasio discusses in his book? this comment does not, however, detract from the value of ocasio’s multidisciplinary project, which elucidates a world in which reluctant creole and mixed-race writers struggle with both the shadow of their own prejudices and the iron fist of the colonial censor in order to set the bases of what would become cuba’s hybrid national culture. to his credit, ocasio refuses to judge the costumbristas, instead allowing their works to speak for them- selves. such a subtly nuanced study at times strains the reader’s ability to follow, but the book is well worth the effort. —thomas genova tillet, salamishah. sites of slavery: citizenship and racial democracy in the post-civil rights imagination. durham, nc: duke up, . in sites of slavery: citizenship and racial democracy in the post-civil rights imagination, salamishah tillet explores the way in which post-civil rights african americans return to “sites of slavery”—”the objects, texts, figures, places and narratives from the american past that provide tangible links between present-day americans and american chattel slavery”—in order to produce a “democratic aesthetic” which responds to the “civic es- trangement” of contemporary african american citizenship in the united states ( ). tillet defines “civic estrangement” as “the paradox post-civil rights african americans experience as simultaneous citizens and ‘non-citizens’” ( ). her notion of a “democratic aesthetic” both emerges and departs from michael bennett’s democratic discourses in drawing on the du boisian “twoness” of “the pessimism of civic estrangement and the privilege of american legal citizenship” ( ). ultimately, tillet’s argument is that “the recognition of slavery in the civic sphere [achieved by returning, as the figures in tillet’s book do, to sites of slavery,] will expand the parameters of african american citizenship” ( ). tillet weaves through a rich archive of cultural productions from literary fiction and legal cases to photography and film. as such, the book’s interdisciplinary approach draws on scholarship in literary and cultural studies, performance studies, history, and law, and will appeal to readers from a variety of disciplines. c a l l a l o o following a teachable introduction, chapter , “freedom in a bondsmaid’s arms,” combs the historical canon’s account of the sexual relationship between thomas jefferson and sally hemings. tillet begins with barbara chase-riboud’s novel sally hemings, which imagines a romantic relationship that “does not entertain the possibility that jefferson sexually exploited hemings” ( ). while it isn’t fully clear how the novel considers what saidiya hartman describes as slavery’s “condition of unredressed injury” ( )—despite tillet’s gloss of the “ambiguity” of the relationship—it is clear that it repositions black female subjectivity as central to american founding narratives. chapter then moves to historian and law professor annette gordon-reed’s books thomas jefferson and sally hemings: an american controversy ( ) and the hemingses of monticello: an american family ( ) as well as playwright robbie mccauley’s drama sally’s rape. tillet reads gordon-reed’s books both as illustrating african american civic estrangement’s roots in american slavery and as “democratizing the historical record” ( ). in contrast to chase-riboud and gordon-reed, who both imagine a romantic relationship between hemings and jefferson, mccauley’s play directly confronts the violence of interracial sexual relationships during slavery and posits them as “the historical foundation for racial inequalities, such as civic estrangement, in the present” ( ). also unlike the previous two authors, mccauley highlights a multiplicity of african american women’s voices as opposed to privileging one particular subject. such a multiplicity “reconstructs a lineage of critical patriotism that centers black women’s dissent” ( ). the author’s second chapter, “the milder and more amusing phases of slavery,” looks at how post-civil rights african american writers and artists return to uncle tom’s cabin not to reject its most problematic characters, uncle tom and topsy, but to reclaim them “as post-civil rights symbols of racial resistance or reconciliation” ( ). tillet pairs ishmael reed’s novel flight to canada ( ) and robert alexander’s play i ain’t your uncle: the new jack revisionist “uncle tom’s cabin” ( ) to examine the promise and limits of satire as they each displace harriet beecher stowe’s narrative authority and “recast tom as a figure who embodies the racial self-awareness and political pessimism of the post-civil rights era” ( ). her reading of flight to canada demonstrates the multi-directional reach of satire, as reed critiques not only stowe’s racism but also the black power movement, while her reading of i ain’t your uncle highlights the importance of returning to sites of slavery because this reveals an account that “originates modern-day police brutality in american racial slavery” ( ). the chapter then moves to the utopian vision of bill t. jones’s dance last supper at uncle tom’s cabin/the promised land ( ) before closing with an analysis of kara walker’s silhouette the end of uncle tom and the grand allegorical tableau of eva in heaven ( ). jones’s dance begins by satirizing stowe through gross exaggeration, but differs from reed and alexander in not satirizing tom. instead, he “stages a coup de theatre” in which the beating of tom is reversed ( ). jones’s dance, tillet argues, returns to a site of slavery to resurrect tom in order to reinstate the histories of dead enslaved african americans into national memory. this allows for the culmination of the play with scores of naked dancers performing a democratic aesthetic which “underscores the brutality of slavery while simultaneously positing democracy as beyond representation but nonetheless desir- able” ( ). the chapter closes by shifting focus from tom to topsy in walker’s silhouette, which opens up space for thinking about reparations in conjunction with revenge and c a l l a l o o re-foregrounds black female corporeality as central to african american counter-memory and critical patriotism. chapter , “a race of angels,” turns to african american “heritage tourism” to slave forts on the west coast of africa—most specifically the house of slaves at gorée island, senegal, and cape coast castle at cape coast, ghana. tillet pushes to consider the contra- dictions she sees in heritage tourism: the clash of desires of african americans to imagine a transnational diasporic identity and also to see these slave forts as sites of an american past which thus offer ways of entering into us national belonging. as a result, “heritage tourism to the slave forts often produces a visual rhetoric that results in a displacement of contemporary ghana and senegal” ( ). she reaches this conclusion through exam- ining the “visual rhetoric” of two photographers’ portrayals of the slave forts—chester higgins’s the door of no return in the house of the slaves ( ) and carrie mae weems’s elmina cape coast ile de goree ( )—and one filmmaker’s use of a slave fort as a narrative catalyst—haile gerima’s film sankofa ( ). the final chapter, “what have we done to weigh so little on their scale?” adds signifi- cantly to legal and historical scholarship of the “long history” of reparations in the united states by emphasizing “the pivotal role that aesthetics have always played within debates about reparations for slavery and racial equality” ( ). tillet offers generous readings of the lawsuits cato v. united states ( ) and re african-american slave descendants litigation ( ), randall robinson’s the debt: what america owes to blacks ( ), and mary frances berry’s my face is black is true ( ) in synthesizing her arguments that contemporary reparations movements are situated “within the broader post-civil rights movement to reclaim sites of slavery and reimagine democracy” and that “symbolic changes must be accompanied by a structural transformation of the american economy” ( , ). sites of slavery then brings the reader back to the connection between slavery and the presidency with an epilogue on the president’s house in philadelphia. while tillet’s book is already remarkably interdisciplinary, i was left wondering what might happen if the combination of history, literary studies, and performance theory had been pushed just a bit further. for example, in chapter she cites joseph roach’s concept of “surrogation,” but merely to describe the phenomena of present-day bodies standing in for past bodies. what might come from thinking not only about present bodies within sites of slavery, but also thinking about the sites themselves through the performance studies concepts of “ephemerality”—since in visiting a slave fort in one is not, in fact, visit- ing a “slave fort” as it was in the eighteenth century—and “remains”—since in visiting a slave fort in , one may indeed feel overwhelmed by the connection to a history one never personally lived? how might sites of slavery both accomplish and forestall the task of crossing temporal boundaries as the living speak with the dead? this is to take nothing away from the richness of tillet’s book. sites of slavery offers fresh vocabulary for thinking through the very old problem of african american civic estrangement, contributes to the growing bodies of scholarship resituating black women as central to long histories of art and activism, and adds aesthetic dimensions to arguments about what responsibilities remain in a modern economic world full of spaces still visibly haunted by the specters of the massive enslavement that made it possible. —jesse a. goldberg c a l l a l o o note . for example, see phelan on “ephemerality” and schneider on “remains.” works cited hartman, saidiya. scenes of subjection: terror, slavery, and self-making in nineteenth-century america. new york: oxford up, . phelan, peggy. unmarked: the politics of performance. new york: routledge, . schneider, rebecca. performing remains: art and war in times of theatrical reenactment. new york, ny: routledge, . johnson, sarah e. the fear of french negroes: transcolonial collaboration in the revolutionary americas. berkeley: u of california p, . the title of the book, the fear of french negroes, is an oft-mentioned expression in contem- porary accounts of the haitian revolution; the phrase draws attention both to the fears felt by blacks themselves and the implied anxiety of their oppressors (xx). with an emphasis of what the author has termed “transcolonial exchange,” the book uses various case studies to examine “the migration of people, ideas, and practices across colonial boundaries from s to the s” (xx). on one hand, sarah johnson stresses the importance of seeing the “french negroes” of revolutionary haiti “as subjects rather than objects and as the agents of radical change in hemispheric economic and social relations” (xxi). on the other hand, she argues that the transcolonial collaborations and relations between hemispheric blacks to contest the racialized violence endemic to european imperialism and creole-nation building projects were disparate and “not intrinsically emancipatory or progressive . . . their struggle to connect was where a hopeful politics existed, sometimes even thrived” ( ). the term “transcoloniality” (or “transcolonial”) denotes both “a set of strategic practices in the late eighteenth and early nineteenth centuries and a methodological approach in the present to reconstruct how people understood and experienced their worlds” ( ). chapter is an analysis of the proslavery dimensions of transcolonial encounters. it provides the context to understand the master/slave dividing binary, a vital phenomenon that explains conflicting inter-americanist visions. the author analyzes the colonial ex- perience between inter-island blacks by linking seminal events in colonial cuba, jamaica, and territorial florida with revolutionary events in saint-domingue. she observes that transcolonial and inter-american relations and alliances were used decisively for vicious and repressive objectives. the reader should remember that the slave system in the ameri- cas was a “veritable state of war,” as the author highlights, between opposing factions: masters, and men and women who were forced to work as slaves. it is from this perspec- tive that johnson demonstrates how colonial powers (uniting across frontiers)—french, british, spanish, and north-american slave-holding societies—collaborated and used warfare techniques such as canine torture (i.e. “bred dogs” trained by chasseurs) in the circum-caribbean to terrorize african slaves, feed upon black flesh, and subdue non-white researchers knock down gene to stop hiv in its tracks researchers knock down gene to stop hiv in its tracks last month, san francisco officials granted a city proclamation to gero hütter for his discovery that a bone marrow transplant could, it seems, cure a person of hiv. the german hematologist’s findings raised hopes for a new therapeutic treatment, but the shortage of tissue-matched donors has prompted some researchers to apply the lessons learned to new techniques. the hiv-resistant bone marrow donor in hütter’s study carried a rare mutation in the gene encoding c-c chemokine receptor type , or ccr , a surface protein essential for helping hiv attach and infect healthy cells (n. engl. j. med. , – , ). the absence of this molecular portal makes infection nearly impossible. however, individuals with the ccr mutation are rare, and their bone marrow is not always a good match for all recipients. to emulate the protection of this mutation, several research teams are devising ways to downregulate the expression of ccr so that hiv does not recognize and invade sensitive cells in susceptible individuals. one line of attack involves rna interference. last month, for example, irvin chen and his colleagues at the university of california–los angeles school of medicine reported that short hairpin rna could successfully knock down ccr expression in human induced pluripotent stem cells (hum. gene ther. doi: . /hum. . , ). chen, backed by a $ million grant from the california institute for regenerative medicine (cirm), has now partnered with the tuscon, arizona–based biotech startup calimmune to develop therapies based on the approach. another strategy takes advantage of a newly developed technology based on zinc finger nucleases. with this approach, pioneered by sangamo biosciences of richmond, california, engineered enzymes make precise cuts in the genome to disrupt gene function. in , carl june’s team at the university of pennsylvania in philadelphia used zinc finger nucleases to disrupt ccr expression in human t cells, which they injected into hiv-infected mice. the gene therapy lowered viral loads and increased t cell counts in the mice (nat. biotech. , – , ). sangamo, in collaboration with june, has since started extracting mature t cells from hiv-positive individuals, knocking down expression of the ccr gene with zinc fingers, and then re-infusing the cells back into the blood. preliminary results from their first patient indicate that the modified cells are tolerated and persist at stable levels. mighty marrow the t cell approach, however, offers only a treatment—not a cure. so other researchers are focusing instead on altering bone marrow stem cells to provide an everlasting resistance to hiv. last year, cirm funded a team led by john zaia at the city of hope in duarte, california, in collaboration with sangamo, to start pursuing preclinical research applying the same gene therapy tactic in bone marrow. jerome zack of the university of california- los angeles aids institute notes that bone marrow stem cell therapy has the advantage of potentially lasting a lifetime, unlike gene therapy aimed at t cells, which must be repeated over and over again after the mature immune cells die out. what’s more, says zack, who is not involved in these studies, bone marrow transplants should help achieve higher cell counts. “we do not lack ways to attack hiv,” says david strayer, a virologist at thomas jefferson university in philadelphia. “we lack ways to deliver genes adequately.” a potential obstacle to ccr -based gene therapy is that the protein is not the only receptor recognized by the virus—some viral strains bind the cxcr chemokine receptor instead. so june and his colleagues are also developing zinc finger nucleases that target cxcr . however, some scientists have increased concerns about this approach’s safety, because the receptor may have an important role in healthy cells to attract white blood cells to sites of inflammation or injury. “the problem is that [cxcr ] may be more important to the cell for its normal functions than ccr ,” says ramesh akkina, who studies hiv gene therapy at colorado state university in fort collins. what’s more, even strains that normally rely on ccr can evolve to use cxcr instead. instead of focusing solely on these receptors, zaia also recently completed a phase trial of an hiv gene therapy technique involving three genes—two that interfere with viral replication and one that blocks ccr . reporting last month, zaia’s team showed that patients with aids-related lymphoma expressed the modified genes in their blood and showed no signs of short-term toxicity (sci. trans. med. , ra ). gene therapy against hiv “is now within the realm of feasibility,” says zaia. “now we can design larger studies and figure out ways to improve it.” janelle weaver, san francisco n e w s nature medicine volume | number | july canadian beacon each year, around a million americans purchase cheap medicines from online canadian pharmacies to help make ends meet. according to the canadian international pharmacy association (cipa), which surveyed its member pharmacies for the best sellers to us consumers in , most people who turn to internet drugstores north of the border are buying everyday prescriptions to treat common chronic conditions, such as heart disease, diabetes and arthritis. “this is the mainstay of our business,” says tim smith, cipa’s general manager. “the bulk of our patients are people who are living on fixed income; they’re concerned about the high cost of drugs, and they have concerns about their ongoing medical conditions.” here, in no particular order, are the top selling drugs: plavix (anticoagulant) advair (treats asthma) flomax (muscle relaxant) asacol (anti-inflammatory, irritable bowel disease) nexium (antacid) synthroid (thyroid problems) celebrex (anti-inflammatory, arthritis) dilantin (anticonvulsant) zetia, lipitor, crestor (cholesterol lowering) premarin (female hormone replacement therapy) actos, januvia, prandin (control blood sugar) © n a tu re a m e ri c a , i n c . a ll r ig h ts r e s e rv e d . © macmillan magazines ltd high metabolic rates in running birds the ability to increase metabolic rate during locomotion has been important in the structural evolution and evolutionary suc- cess of both birds and mammals. greater endurance capabilities are conferred directly by greater maximal metabolic rates, which vary between species. these maximal rates are known for many mammals but have not been determined for birds. we have mea- sured oxygen consumption in a large flight- less bird, the rhea, rhea americana, while it was running on an inclined treadmill, and find an upper limit to aerobic metabolism that is times greater than the minimum resting rate, a factorial increase exceeding that reported for nearly all mammals. we trained two female rheas (average mass . kilograms) for two years to run on a treadmill while wearing clear plastic hoods. we then measured linear increases in rates of oxygen uptake while the birds ran up a ° incline. the maximum rate of oxygen uptake was . millilitres per kilo- gram of body mass per second, reached at a running speed of . metres per second. there were no further increases in oxygen uptake when running speeds were increased to . metres per second, and plasma lactate concentrations indicated an increasing reliance on anaerobic glycolysis to provide metabolic energy at these higher speeds. rates of lactate accumulation ( . to . mm min ) and peak concentrations ( . mm) matched values reported for mam- mals running at speeds above their aerobic maximum. remarkably, the aerobic scope (the maximum aerobic metabolic rate divided by the minimum resting rate ) of these relatively inactive birds is more than . times those of typical mammals , and equals those of some of the most capable mammalian endurance runners (fig. ). although the rheas’ factorial increase in anaerobic metabolism is . times greater than the highest previously reported avian values (fig. ), we believe that their aerobic scope is representative of birds in general. previous avian values do not provide evi- dence of being upper limits; they are proba- bly below species’ maxima, but to unknown extents. nonetheless, the minimum meta- bolic increase required for flight of times the resting value exceeds the aerobic power of a typical mammal by a factor of . , and most avian species can fly. even birds with more limited endurance, such as the pen- guin and domestic fowl, can increase their aerobic metabolism by as much as a typical mammal , . we suggest that, on average, the aerobic scope of birds exceeds those of mammals by a factor of two or more. the structural basis of the rheas’ aero- bic power indicates that respiratory structure–function relationships, previously undetermined for birds, are quantitatively similar to those of mammals throughout most of the respiratory system, and are consistent with the concept of reasonable animal design (table ). rheas, like aerobic mammals, achieve maximal high rates of oxygen uptake with existing cardiovascular and muscular structures, rather than by scientific correspondence nature | vol | january | www.nature.com humidity and climate variations related to the north atlantic oscillation , , showed that none of them, taken individually, is a good explanation for the observed positive trend in cirrus occurrence and its regional distribution. the trends in cirrus ‘amount when pre- sent’ over the previously defined regions of high fuel consumption are . % and . % for land and ocean, respectively (table ). the combination of a large posi- tive trend in cirrus occurrence associated with a negative trend in the cirrus amount when present is consistent with an increas- ing amount of condensation-trail cirrus covering a small portion of an otherwise clear sky at the cirrus cloud level. this results in a trend in cirrus coverage (cirrus occurrence cirrus amount when pre- sent) of . % averaged over land, rising to . % over the continental regions with most air traffic. over ocean, these values are . % and . %, respectively, because of the aforementioned contribution of the north pacific ocean to the global increase in cirrus occurrence. both radiative trans- fer calculations and earth radiation bud- get experiment measurements of the net change in radiation associated with high, thin clouds suggest a . w m cloud radiative forcing per % of condensation trail or high-level cloudiness. i therefore estimate that the trend in cirrus amount over the continental regions of high air traffic ( . %, as discussed above) would correspond locally to an additional cloud radiative forcing of about . w m between and . a larger forcing would be expected if calculated from the beginning of commercial jet traffic until the present time. however, we cannot rule out the possibility that the observed change in cirrus amount is not due solely to avia- tion, or that other climate processes have not masked an even larger aviation impact on cirrus cloudiness. for instance, a previ- ous analysis showed that other regions experienced large positive trends in cirrus amount between and . olivier boucher laboratoire d’optique atmosphérique, u.f.r. de physique, université de lille–i, villeneuve d’ascq cedex, france e-mail: boucher@loa.univ-lille .fr . seinfeld, j. h. nature , – ( ). . minnis, p. et al. geophys. res. lett. , – ( ). . schumann, u. meteorol. z. , – ( ). . jensen, e. j. & toon, o. b. geophys. res. lett. , – ( ). . hahn, c. j., warren, s. g. & london, j. edited synoptic cloud reports from ships and land stations over the globe, – , ndp b (carbon dioxide information analysis center, oak ridge national laboratory, tennessee, ). . baughcum, s. l., henderson, s. c., tritz, t. g. & pickett, d. c. scheduled civil aircraft emission inventories for : database development and analysis (nasa cr- , ). . mortlock, a. m. & van alstyne, r. military, charter, unreported domestic traffic and general aviation: , , , and emission scenarios (nasa cr- , ). . energy statistics and balances of non-oecd countries, – – (international energy agency, organization for economic cooperation and development, paris, ). ffiigguurree factorial increases in metabolic rates above resting minimum for rheas and athletic mammals at the aerobic maximum and for other avian species at the highest rates available. triangles, flying birds; squares, walking and running birds; circles, swim- ming birds; and diamonds, running mammals. . minnis, p., ayers, j. k. & weaver, s. p. surface-based observations of contrail occurrence frequency over the u. s., april –april (nasa reference publication , ). . jensen, e. j. & toon, o. b. geophys. res. lett. , – ( ). . hurrell, j. w. science , – ( ). . mächel, h., kapala, a. & flohn, h. int. j. climatol. , – ( ). . hartmann, d. l., ockert-bell, m. e. & michelsen, m. l. j. clim. , – ( ). . warren, s. g., hahn, c. j., london, j., chervin, r. m. & jenne, r. l. global distribution of total cloud cover and cloud type amounts over the ocean (ncar technical note tn- + str, boulder, colorado, ). . hahn, c. j., warren, s. g. & london, j. j. clim. , – ( ). supplementary information is available on nature’s world-wide web site (http://www.nature.com) or as paper copy from the london editorial office of nature. humming- bird budgerigar raven fox coyote rhea wolf pony ostrich emu turkeypigeonmost mammals penguin stork penguin . . . , body mass (kg) · e · e lo co / st d table mitochondrial volume densities and capillary densities of rhea muscles muscle bird a bird b vv (%) na (mm – ) vv (%) na (mm – ) iliotibialis lateral . . gastrocnemius . . pectoralis . . humerotriceps . . mean mitochondrial volume densities (vv) and capillary densities (na) for leg muscles (iliotibialis and gastrocnemius) were . % and mm– , respectively; values for wing muscles (pectoralis and humerotriceps) were . % and mm– , respectively, for the rheas. values for equivalent leg muscles of similarly sized mammals: for a -kg dog, vv . % and na mm – ; for a -kg goat, vv . % and na mm – . © macmillan magazines ltd the thomas jefferson paternity case the dna analysis of y-chromosome haplo- types used by foster et al. to evaluate thomas jefferson’s alleged paternity of eston hemings jefferson, the last child of his slave sally hemings, is impressive. how- ever, the authors did not consider all the data at hand in interpreting their results. no mention was made of thomas jeffer- son’s brother randolph ( – ), or of his five sons , . sons of sally hemings con- ceived by randolph (or by one of his sons) would produce a y-chromosome analysis identical to that described by foster et al. further collaborative data (for example, the whereabouts of any of those who might have been involved at conception) are needed to confirm that jefferson did indeed father his slave’s last child, as claimed in the title. we know thomas jefferson was there, but how about randolph jefferson and his sons? david m. abbey health science center, university of colorado, teakwood court, fort collins, colorado , usa e-mail: dabbey @aol.com if the data of foster et al. are accurate, then any male ancestor in thomas jefferson’s line, white or black, could have fathered eston hemings. plantations were inbred communities, and the mixing of racial types was probably common. as slave families were passed as property to the owner’s off- spring along with land and other property, it is possible that thomas jefferson’s father, grandfather or paternal uncles fathered a male slave whose line later impregnated another slave, in this case sally hemings. sally herself was a light mulatto, known even at that time to be thomas jefferson’s wife’s half sister , . gary davis evanston hospital, ridge avenue, evanston, illinois , usa foster et al. reply — it is true that men of randolph jefferson’s family could have fathered sally hemings’ later children. space constraints prevented us from expanding on alternative interpretations of our dna analysis, including the interesting one proposed by davis. the title assigned to our study was misleading in that it repre- sented only the simplest explanation of our molecular findings: namely, that thomas jefferson, rather than one of the carr broth- ers, was likely to have been the father of eston hemings jefferson. it had been suggested to us earlier (by herbert barger, who also helped to recruit the descendants of field jefferson who par- ticipated in our study) that isham jefferson, son of thomas jefferson’s brother ran- dolph, might have been the father of one or more of sally hemings’ children. barger’s proposal was based on a statement that isham was reared by thomas jefferson; he suggested that isham could have been at monticello or at snowden (snowden was across the james river from scottsville, which is about miles from monticello) when eston hemings was conceived. but it is not known for certain that isham was at monticello at that time, whereas it is docu- mented that thomas jefferson was. from the historical knowledge we have, we can- not conclude that isham, or any other member of the jefferson family, was as likely as thomas jefferson to have fathered eston hemings. we know from the historical and the dna data that thomas jefferson can neither be definitely excluded nor solely implicated in the paternity of illegitimate children with his slave sally hemings. when we embarked on this study, we knew that the results could not be conclusive, but we hoped to obtain some objective data that would tilt the weight of evidence in one direction or another. we think we have provided such data and that the modest, probabilistic interpretations we have made are tenable at present. e. a. foster*, m. a. jobling†, p. g. taylor†, p. donnelly‡, p. de knijff§, r. mieremet§, t. zerjal¶, c. tyler-smith¶ * gildersleeve wood, charlottesville, virginia , usa e-mail: eafoster@aol.com †department of genetics, university of leicester, adrian building, university road, leicester le rh, uk ‡department of statistics, university of oxford, south parks road, oxford ox tg, uk §mgc department of human genetics, leiden university, po box , ra leiden, the netherlands ¶department of biochemistry, university of oxford, south parks road, oxford ox qu, uk . foster, e. a. et al. nature , – ( ). . mayo, b. & bear, j. a. jr thomas jefferson and his unknown brother (univ. press of virginia, charlottesville, ). . brodie, f. m. thomas jefferson: an intimate history (norton, new york, ). . randall, w. s. thomas jefferson: a life (holt, new york, ). . history of todd county, kentucky ( ). scientific correspondence nature | vol | january | www.nature.com qualitative adjustment. rhea heart mass ( grams) conforms to that predicted for a mammal of the same body size and aero- bic power. volume densities of mitochon- dria in leg muscles are similar to those of mammals of the same size and aerobic capacity, whereas those in the relatively inactive flight muscles are only half as large and correspond to values reported for less aerobic mammals (table ). given that % of the rhea’s body mass consists of leg musculature, rates of oxygen uptake by mitochondria per millilitre dur- ing locomotion at the aerobic maximum appear to fall within the range reported for mammals. capillary densities in the rhea leg and flight muscles, like the mitochon- drial volume densities, also parallel values reported for the muscles of athletic and less mobile mammals. in contrast to the apparent conservation of structure–function relationships in most of the respiratory system, our results sug- gest that there are basic differences in the performance of the lungs of birds and mammals. we could not measure the lung volumes of the rheas directly, but in birds these are normally slightly more than half of those of mammals of the same mass , . the rheas therefore achieved maximum oxygen flux rates, equal to those of the most aerobic mammals of their size, using lungs that are probably only half as large. this supports the general belief that avian lungs provide relatively more function per unit volume than mammalian lungs , . although the aerobic limits of rheas and athletic mammals are similar, the metabolic power available in practice, and their func- tional needs, are not. unlike dogs, horses and other athletic mammals that sustain high metabolic rates for hours during pre- dation and migration, rheas do little or no sustained running and are poor at dissipat- ing metabolic heat loads . rheas have apparently not been under strong selective pressures like those that promoted the aero- bic power of extant running mammals. large flightless birds lead fairly inactive lives, and may have lost the ability to fly primarily because of a lack of predation. why rheas have an aerobic power that greatly exceeds their apparent functional needs remains a puzzle. matthew w. bundle*, hans hoppeler†, ruth vock†, june m. tester*, peter g. weyand* *museum of comparative zoology, harvard university, bedford, massachusetts , usa e-mail: pweyand@oeb.harvard.edu †department of anatomy, university of bern, buhlstrasse , ch bern , switzerland . seeherman, h. j., taylor, c. r., maloiy, g. m. o. & armstrong, r. b. respir. physiol. , – ( ). . lasiewski, r. c. & dawson, w. r. condor , – ( ). . ellington, c. p. j. exp. biol. , – ( ). . brackenbury, j. h. & el-sayed, m. s. j. exp. biol. , – ( ). . kooyman, g. l. & ponganis, p. j. j. exp. biol. , – ( ). . weibel, e. r., taylor, c. r. & hoppeler, h. proc. natl acad. sci. usa , – , ( ). . maina, j. n. & king, s. a. j. anat. , – ( ). . dubach, m. respir. physiol. , – ( ). . piiper, j. & scheid, p. in comparative physiology (eds bolis, l., schmidt-nielsen, k. & maddrell, s. h. p.) – (north- holland, ). . taylor, c. r., dmi’el, r., fedak, m. & schmidt-neilsen, k. am. j. physiol. , – ( ). corr insights®: tendon collagen crosslinking offers potential to improve suture pullout in rotator cuff repair: an ex vivo sheep study corr insights : tendon collagen crosslinking offers potential to improve suture pullout in rotator cuff repair: an ex vivo sheep study joseph a. abboud md where are we now? r otator cuff disease in patients older than years of age remains both common and therapeutically challenging. various forms of treatment, both nonoperative and operative, have been extensively explored. no single solution has emerged as dominant, and none is curative. in the hope of changing that, biologics in rotator cuff surgery have become something of a hot topic, as surgical success may be more depen- dent upon biologic healing than on the technical aspects of tendon fixation. the current authors set out to use an exogenous collagen crosslinking agent, genipin, to augment tendon repairs. the use of this agent to augment tendon healing has not been explored before. the study, conducted in a cadaveric (ex vivo) sheep model, allows us to make two conclusions pertaining to suture pullout strength: ( ) pullout strength is enhanced after tendon incu- bation in genipin for hours when utilizing the simple suture configuration repair technique, and ( ) incubation of the tendon in genipin for or hours did not make a difference in the pullout strength of tendons repaired using a modified mason-allen suture configuration. this suggests that the suture configuration may be the most important aspect of this repair model as opposed to the exposure to the exoge- nous crosslinking agent genipin. where do we need to go? what we really need to know is whether genipin has any real clinical utility. in other words, can we use genipin in humans with rotator cuff tears? does its mode of activation lend itself to uti- lization in vivo at the time of surgery? will its method of delivery allow for safe and effective clinical treatment in a timely fashion? will this provide any clinically enhanced levels of healing after surgical repair? while this study does not allow us to answer any of these questions, as a proof-of-concept effort, it paves the way for future studies that should be able to do so. how do we get there? future in-vivo rotator cuff animal studies in rats or sheep utilizing this this corr insights is a commentary on the article ‘‘tendon collagen crosslinking offers potential to improve suture pullout in rotator cuff repair: an ex vivo sheep study’’ by camenzind and colleagues available at: doi: . /s - - - the author certifies that he, or a member of his immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/ licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. all icmje conflict of interest forms for authors and clinical orthopaedics and related research editors and board members are on file with the publication and can be viewed on request. the opinions expressed are those of the writers, and do not reflect the opinion or policy of corr or the association of bone and joint surgeons . this corr insights comment refers to the article available at doi: . /s - - - j. a. abboud md (&) thomas jefferson university hospital, the rothman institute, chestnut st., th floor, philadelphia, pa , usa e-mail: abboudj@gmail.com corr insights published online: may � the association of bone and joint surgeons clin orthop relat res ( ) : – / doi . /s - - - clinical orthopaedics and related research® a publication of the association of bone and joint surgeons® http://dx.doi.org/ . /s - - - http://dx.doi.org/ . /s - - - http://dx.doi.org/ . /s - - - http://crossmark.crossref.org/dialog/?doi= . /s - - - &amp;domain=pdf http://crossmark.crossref.org/dialog/?doi= . /s - - - &amp;domain=pdf agent should look to quantify the level of improved crosslinking demonstrated at the collagen level. additionally, delivery vehicles such as liposomes or exosomes, which are anchor or suture based, may be designed to allow for local application in vivo of the genipin at the time of surgery. volume , number , august corr insights corr insights 	corr insightsreg: tendon collagen crosslinking offers potential to improve suture pullout in rotator cuff repair: an ex vivo sheep study 	where are we now? 	where do we need to go? 	how do we get there? pnd developing a migraine quality of care measurement set a abstracts for to years in a us medicare health maintenance organi- zation. the study population was identified using icd- codes ( ; . ) for pd and a claim for at least one filled pd pre- scription identified using ndc codes. medication possession ratio (mpr) was estimated as proxy for adherence to pd med- ications, with a threshold of . indicating adherence. pd symptom progression was defined as increase in prescription strength, addition of another pd medication, an emergency room visit or hospitalization related to pd. demographic, clinical, and economic variables were extracted from the dataset. prevalence of non-adherence was calculated over all years and for each year of eligibility. logistic regression was used to assess relation between medication adherence and pd symptom progression. sensitivity analyses were conducted for mpr scores less than . , . , and . . results: the study population (n = patient- years) had mean mpr score of . (± . ). an average of % of study population was not adherent to their pd medications (mpr < . implies non-adherence). sensitivity analysis with mpr scores less than . , . , and . indicated an average of %, % and % were not adherent to their pd medications respectively. subjects adherent to their pd medications (mpr >= . ) had % less odds of experiencing pd symptom progres- sion (or = . ; ci: . – . ) compared to people not adher- ent to pd medications. all subjects with mpr < . experienced pd symptom progression. conclusion: high prevalence of non-adherence to pd medication and its association with pd symptom progression, irrespective of mpr threshold chosen, indicates it is a significant problem. there is a need for mecha- nisms to improve medication adherence in pd, namely improved patient understanding, simplified treatment regimens and improved tolerability profiles. pnd determinants of emergency department utilization for migraine care kwong wj university of georgia, athens, ga, usa objectives: over-utilization of emergency department (ed) services for non-urgent medical conditions has been noted as a problem for decades. headache is the sixth most common reason for ed visits. this study examined factors of ed use in a migraine population. methods: medical and rx claims of georgia medicaid beneficiaries who had at least one migraine medical claim (icd- of .xx) or one triptan/ergot claim between jan and dec , and were continuously eligi- ble from months before to months after first migraine claim were analyzed. subjects who had a narcotic claim and a medical claim for cancer (icd- – ), fractures ( – ), muscu- loskeletal and connective tissues disease ( – ), or sickle cell anemia ( . x) months before index date were excluded. likelihood of a migraine ed visit during the months after index date was estimated using logistic regression while con- trolling for age, gender, race, metropolitan status of county of residence, physician supply in county, butalbital and narcotic medication use months before index date. results: data from , subjects were analyzed. mean age was years (sd = ), % were male and % were caucasians. six percent of subjects had used butalbitals and % had used narcotics months before index date, and % subjects had at least one migraine ed visit months after index date. females, non-cau- casians, residents of metro counties or counties that had lower than average physician per , population ratio were more likely to have an ed visit (adjusted odds ratio, aor = . , . , . , and . respectively, p < . ). prior narcotic use signif- icantly increased the risk of ed visit (aor = . , p < . ). age and butalbital use had no effect on ed use. conclusion: local physician shortage and easy ed access encouraged ed use for non-urgent medical problems. improving access to primary care facilities is crucial for reducing non-urgent ed use. pnd developing a migraine quality of care measurement set leas b , gagne jj , goldfarb ni , rupnow mf , lofland jh , hopkins mm , nash d , silberstein sd thomas jefferson university, philadelphia, pa, usa, ortho-mcneil janssen scientific affairs, llc, titusville, nj, usa, thomas jefferson university hospital, philadelphia, pa, usa objectives: to develop a migraine quality of care measure- ment set at the health plan level, in order to begin measuring and improving migraine care processes and outcomes. methods: the measurement set was developed through: ) review of migraine care guidelines; ) literature review of quality mea- surement for migraine care; ) telephone interviews with thought leaders in migraine care and quality improvement; and ) assem- bly of a national advisory board consisting of prominent leaders within migraine care, quality measurement and managed care. the advisory board reviewed collected information from tasks – , discussed candidate measures, and established a consensus on target measures to be included in the set. results: the advi- sory board selected potential measures that could be imple- mented at the health plan level using administrative (claims) data. these measures capture information on: migraine diagno- sis and prevalence; use of preventive and therapeutic medica- tions; and, primary care, specialist, emergency, diagnostic radiologic, and inpatient service utilization. the measurement specifications have been developed to mirror technical specifica- tions for administrative measures in the health plan employer data and information set (hedis). conclusion: develop- ment of an evidence-based set of quality measures for migraine care is an important advance in seeking to measure and improve care for migraineurs. despite its prevalence, and impact on direct and indirect costs, migraine is not currently being addressed in the national quality measurement movement. the measurement set is now being pilot tested in health plans to assess feasibility of data collection, properties of the measures, and correlation among the measures. pnd understanding limitations of patient reported clinical outcomes in lupus wilke ct , jolly m , khandelwal s , rodby r , block ja , pickard as university of illinois at chicago, chicago, il, usa, rush university medical center, chicago, il, usa, rush medical university medical center, chicago, il, usa, college of pharmacy, university of illinois at chicago, chicago, il, usa objectives: patient knowledge is associated with their ability to manage their disease (self-efficacy). the objective of this study was to examine the extent to which patients with systemic lupus erythematosus (sle) reported specific organs/system involvement that was consistent with medical records. methods: in a cross- sectional study, patients with sle were asked to indicate whether the following organ systems were affected by their lupus: skin/hair/scalp, joints, kidneys, brain, heart/lungs, (abnormal) blood counts, blood clots (including stroke). a retrospective chart review was undertaken to examine organ involvement and tests as recorded by their physician. exact and kappa measures of agreement between physician and patient report were calculated for each organ system. results: the patient sample (n = ) hp relationship of direct-to-consumer advertising spending and drug pricing for the top twenty drugs from to : an exploratory study abstracts medication (p = . ); more likely to become frustrated (p = . ) and annoyed (p < . ) with the patient for asking to try a medication; and less likely to provide samples (p = . ) or a prescription (p < . ) for a medication. conclusion: clinicians are amenable to patients asking for drug information and medications, but their level of receptiveness is associated with the source from which the patient’s questions originate. hp relationship of direct-to-consumer advertising spending and drug pricing for the top twenty drugs from to : an exploratory study parthan ag, anantharaman rt, shepherd md the university of texas at austin, austin, tx, usa there exists an ongoing debate regarding the effect of direct-to-consumer (dtc) advertising spending on drug prices. the two opposite views are: (a) increase in dtc advertising spending would be added to drug prices (b) dtc advertising would increase competition and thus reduce drug prices. objective: explore the relationship of dtc advertis- ing spending and drug pricing for the top twenty drugs from to . methods: top twenty drugs were selected on the basis of their dtc advertising spending (source: competitive media reporting, ny) for . for analysis, average wholesale price (awp) per unit was used from the blue book awp unit pricing. for each of the top twenty drugs, the following trend graphs were plotted for to : (a) the total dtc advertising spending and per unit price of the drug; (b) the percent changes in the dtc advertis- ing spending and drug price. the percent change in dtc advertising spending and drug price for a year was calculated as percent change from the previous year. results: only sildenafil (viagra) and sibutramine (meridia) showed an increase in the actual drug price with an increase in the dtc advertising spending. however, for these two drugs in year , the percent change in dtc advertising spending decreased and the percent change in drug price increased. no trend was evident from the graphs of the other eighteen drugs. on an average dtc advertising spending for most of the drugs decreased with time while drug prices continued to increase. conclusion: results indicate a very weak relation- ship between dtc advertising spending and drug prices. the increase in drug price in spite of the decrease in the dtc advertising spending contradicts both rationale i.e. dtc advertising spending reduces drug price through competition or increase in drug price is due to increase in dtc advertising spending. hp impact of direct to consumer advertising—the consumer search for information belazi dt , crawford a , pizzi l thomas jefferson university & abbott laboratories, philadelphia, pa, usa; thomas jefferson university, philadelphia, pa, usa objective: the purpose of this study is to identify factors associated with consumers’ seeking various infor- mation sources about medications sought in response to direct to consumer advertising. methods: in the spring and summer of , the fda, division of drug marketing, advertising, and commu- nication conducted a national telephone survey of adults regarding direct-to-consumer (dtc) promotion of prescription drugs and its effects on visits to the doctor. in addition to consumer attitudes, opinions and responses to direct to consumer advertising, the survey also elicited responses regarding consumer utilization of information sources such as reference books, -telelphone number, and health care providers. there were total respon- dents, of whom completed the required questions regarding information sources. chi square analysis was used to assess associations between consumer demographic information and the different types of informational resources that consumers used after exposure of direct to consumer advertising. results: the analysis showed significant associations (p £ . ) between gender, race, education, health status, self-perceived knowledge of health, prescription medication use, and internet use and many of the following information resources: reference books, asking friends/neighbors, -telephone number, primary doctor, pharmacist, specialist, and nurse. across all information sources, female gender, decreased health status, low education, and higher than average medica- tion use were the variables that had the strongest associ- ations. a model was developed depicting the associations between these findings. results pertaining to specific sources will be presented. conclusions: this study evaluated how different consumers seek information from different sources as a result of direct to consumer advertising. this study will assist those interested in identifying and further educat- ing consumers about their health and novel treatments or therapies. hp fda regulatory actions against misleading or unsubstantiated economic and quality-of-life claims: an analysis of warning letters and notices of violation stewart ka, neumann pj harvard school of public health, boston, ma, usa doi: . /j.bpj. . . monday, february , a the c terminus of milton is an important regulator of the mitochondria associated motors and is involved in conferring the calcium sensitivity from miro to the motors. milton - is sufficient for the mitochondrial binding, whereas the - amino acids are critical for the control of calcium sensitivity of mi- tochondrial motility. -pos biophysical properties of mitochondria undergoing fusion xingguo liu , orian shirihai , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, boston university, boston, ma, usa. emerging evidence shows the importance of genes controlling mitochondrial fusion in physiology and their deregulation in neurodegenerative and metabolic disorders. however, apart from djm, the biophysical properties of the fusion- competent mitochondria remain elusive. to evaluate the conditions of contact formation and fusion, we used organelle-targeted fluorescent proteins, includ- ing photoactivatable gfp, which allow tracking of individual mitochondria. in h c cells, almost every mitochondrion is aligned with microtubules that pro- vide the primary tracks for mitochondrial movement. our results show that ~ % of fusion events involve moving mitochondria. however, fusion occurs irrespective of mitochondrial speed. furthermore, ~ % of fusion events in- volve the tip portion of the mitochondrion, whereas only ~ % of these events involve organelle side. nocodazol, a microtubule disrupting agent that inhibits mitochondrial movements decreases the fusion frequency and changes mito- chondrial fusion sites. strikingly, - % of the physical contacts between ad- jacent mitochondria did not result in fusion events. to evaluate whether the fu- sion efficacy depends on the spacing between the outer and inner mitochondrial membranes we used drugs that alter the matrix volume. valinomycin, a k þ ion- ophore that induces matrix swelling evoked a decrease in mitochondrial motil- ity leading to fewer contacts among mitochondria but the number of fusion events was maintained, indicating an increase in fusion efficacy. this change occurred at a low valinomycin concentration ( . nm) that did not affect djm or opa cleavage. nigericin ( . mm), a k þ /h þ ionophore that induces shrinkage of the matrix elicited fusion inhibition and mitochondrial aggrega- tion. importantly, no motility inhibition or opa cleavage occurred at the same time and the djm was increased. these results suggest that mitochon- drial fusion is facilitated by mitochondrial motility, the key determinant of the inter-mitochondrial encounter numbers and preferentially involves the front-tip of the moving organelle. in addition, fusion efficacy depends on the mitochondrial matrix volume. -pos mitochondrial fusion dynamics in human skeletal muscle-derived cells veronica eisner, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. mitochondria have a fundamental role in both muscle physiology and pathol- ogy. mitochondrial fusion and fission are important for energy metabolism, calcium homeostasis and cell death. however, the mechanisms underlying mitochondrial dynamics are poorly understood, especially in physiological models such as skeletal muscle. here we evaluated mitochondrial fusion dy- namics in human skeletal muscle cells (husmc). skeletal muscle satellite cells were isolated from human muscle biopsies and were maintained and dif- ferentiated in cell culture. mitochondrial fusion events were evaluated by con- focal imaging of cells expressing mitochondria matrix targeted dsred and matrix targeted or outer mitochondrial membrane (omm) targeted photoacti- vatable-gfp. when we tagged the mitochondria in ~ % of total cellular area with photoactivated-gfp, we found those mitochondria undergoing matrix fusion with a frequency of . . events/min/cell (n= ). among the fusion events, % led to complete fusion and only % was followed by separation at the apparent fusion site within to seconds. both complete and transient fusion events resulted mostly from longitudinal mergers, involving end to end interaction or from mergers of adjacent mitochondria in side to side orien- tation. furthermore, we found that omm and matrix fusion are sequential and separable steps, displaying . seconds gap (n= ). finally, we evaluated the mitochondrial fusion dynamics in husmc derived from both normal and malignant hyperthermia susceptible individuals. at resting state, no significant differences were found in the number of events or in their characteristics. thus, mitochondrial fusion commonly occurs in husmc, and enables mixing of both soluble and integral membrane factors. this process would help to maintain the stability of mitochondrial metabolism. the relatively low frequency of the tran- sient fusion is probably due to the parallel organization of the cytoskeletal tracks for mitochondria and to the limited mitochondrial motility. -pos imaging interorganelle contacts and local calcium dynamics at the er-mitochondrial interface györgy csordás , péter várnai , tünde golenár , swati roy , george purkins , tamás balla , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary, national institutes of child health and human development, bethesda, md, usa. the local coupling between er and mitochondria is essential for proper cell function. a main role of the er-mitochondrial junctions is to provide a local calcium signaling domain that is important both for keeping energy production in line with demand and for the control of apoptotic mechanisms. so far it has not been possible to visualize the tiny er-mitochondrial contact points in living cells or to monitor the localized [ca þ] changes in the narrow space between er and mitochondria ([ca þ]er-mt). here, we exploited rapamycin-mediated heterodimerization of fkbp and frb domains of fluorescent protein constructs respectively targeted to the outer mitochondrial membrane and the er as drug-inducible inter-organelle linkers to identify er-mitochondrial contacts and to measure the [ca þ ]er-mt. high- resolution fluorescence imaging and d reconstruction revealed rapamycin-in- duced clustering of the er-targeted fluorescent linker-half to the contact areas with the mitochondria without major changes in the spatial arrangement of the er. essentially all mitochondria displayed contacts with the er in both rbl- h and h c cells. plasma membrane-mitochondrial contacts were less frequent with er stacks being inserted between the two organelles. single mitochondria display discrete patches of er contacts as well as continuous as- sociations. cytoplasmic and mitochondrial matrix [ca þ] showed robust er-mitochondrial ca þ transfer with considerable heterogeneity even among adjacent mitochondria. pericam-containing linkers revealed ip -induced [ca þ ]er-mt signals that were resistant to buffering bulk cytosolic [ca þ ]c in- creases and exceeded um. the largest [ca þ ]er-mt signals did not occur at the tightest associations, indicating space requirements for the ca þ transfer machinery and functional diversity among er-mitochondrial junctions. these studies provide direct evidence for the existence of high ca þ microdo- mains between the er and mitochondria in living cells, and open new possibil- ities to probe the functional importance of this specialized compartment. -pos dependence of er-mitochondria calcium transfer on different ip receptor isoforms tunde golenar , szava bansaghi , gyorgy csordas , david i. yule , suresh k. joseph , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, university of rochester medical center, rochester, ny, usa. ip receptors (ip rs) release ca þ from the er, which is locally relayed to the mitochondria to control several aspects of mitochondrial function. recent stud- ies have suggested that type ip rs (ip r ) are particularly important for me- diating the ca þ transfer at the er-mitochondrial interface. we set out to sys- tematically evaluate the respective role of each ip r isoform in chicken dt cell lines that express only one ip r isoform (double-knockout, dko , dko and dko ) or provide a null-background (triple-knockout, tko) for analysis of mammalian ip rs and their mutants. simultaneous imaging of cytoplasmic and mitochondrial matrix [ca þ] ([ca þ]c and [ca þ]m) was performed in either permeabilized cells chal- lenged with ip or in muscarinic receptor overexpressing intact cells stimulated with carbachol (cch), an ip -linked agonist. saturating ip evoked complete discharge of er calcium and resulted in comparable [ca þ]m increases in each dko. furthermore, the cch-induced [ca þ]c spike was closely followed by a [ca þ]m rise in each dko. when tko cells were rescued with rat ip r or ip r , the latter mediated a larger [ca þ]c transient but the [ca þ]m increases were very similar for both isoforms. the relationship between the [ca þ]c peak and the corresponding [ca þ]m response was also very similar for ip r and ip r . to assess the impact of the release kinetic through ip r in the mitochondrial ca þ transfer we used two point mutants of the ip r , which display either enhanced inhibition by ca þ (d n) or are relatively insensitive to ca þ inhibition (d n). d n showed dampened [ca þ]m signal and [ca þ]m vs. [ca þ]c relationship, whereas d n displayed a steeper [ca þ]m vs. [ca þ]c relationship than the wild type ip r . thus, each ip r isoform can support local er-mitochondrial ca þ transfer and their competence to activate mitochondrial ca þ uptake depends on their deactiva- tion kinetic. 	biophysical properties of mitochondria undergoing fusion 	mitochondrial fusion dynamics in human skeletal muscle-derived cells 	imaging interorganelle contacts and local calcium dynamics at the er-mitochondrial interface 	dependence of er-mitochondria calcium transfer on different ip receptor isoforms objective(s): diversity among health care providers is felt to be an important component in addressing health care disparities and may help improve patient communication. caucasian men have historically repre- sented vascular surgery (vs). we hypothesized that the -year integrated vs residency paradigm might foster increased diversity. table. applicants in vascular surgery training % independent ( � ) % integrated ( � ) year female cauc black asian nat am other no resp female cauc black asian nat am other no resp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . first year residents in integrated vascular residency first year fellows in vascular surgery # female # male % female in pgy year # female # male % female in first year fellowship % % % % % % % % % % methods: applicant sex and race status listed on the electronic resi- dent application system (eras) from to was evaluated on all applications to integrated ( -year) vs residencies and fellowships ( year). sex data were available for all of vs accredited council for graduate medical education (acgme) integrated residencies and fellowships. vs training programs were also reviewed to determine diversity of program directors and faculty. results: female applicants to vs integrated programs increased � - fold during the -year study period, from ( %) in to ( . %) in , compared with a . -fold increase in fellowship applicants. african american applicants to integrated programs during the study period ranged from % to . % and asian applicants from % to . % (table). there were no women ( %) in the integrated intern class and ( %) in the postgraduate year class, compared with ( %) and ( %), respec- tively, in the fellowships. of integrated vs programs in , three ( . %) program directors were women, one ( . %) was asian, and ( . %) were caucasian men. of the vs fellowship program directors, seven ( . %) were women, six ( . %) were asian, and ( . %) were caucasian men. one or more female vss were on staff at ( . %) of the vs divisions that had integrated training programs. conclusions: redesigning training in vs appears to appeal to women, with less effect on race. there remains room to increase diversity among trainees, program directors, and faculty in vs training programs. bravissimo: -month results from a large-scale prospective trial koen deloose, marc bosiers, joren callaert, koen keirse, jürgen verbist, patrick peeters . department of vascular surgery, a.z. sint- blasius, dendermonde, and department of cardiovascular and thoracic surgery, imelda hospital, bonheiden, belgium sponsored by rabih a. chaer, md objective(s): the belgian-italian trial investigating abbott vascular vascular iliac stents in the treatment of tasc a, b, c and d iliac lesions (bravissimo) study is a prospective, nonrandomized, multicenter trial, conducted at belgian hospitals and italian hospitals. the objective is to evaluate the long-term ( -month) outcome of the self-expanding nitinol absolute pro (abbott vascular) and the balloon-expandable omnilink elite (abbott vascular) stent in transatlantic intersociety concensus (tasc) a and b and tasc c and d iliac lesions. a separate analysis of both patient populations is performed. methods: primary study end point is primary patency at months, defined as a target lesion without a hemodynamically significant stenosis (� %, systolic velocity ratio � . ) on duplex ultrasound imaging and without target lesion revascularization (tlr) � months. the study included patients, of which presented with tasc a or b lesions and with tasc c or d lesions. analysis is performed comparing the results of the tasc a/b cohort with the results of the tasc c/d cohort. results: the study included patients with tasc a, with tasc b, with tasc c, and with tasc d aortoiliac lesions. demographic data were comparable for all tasc patient groups. of the tasc a patients, received omnilink elite stents, received absolute pro stents, and one received both stents. of the tasc b patients, received omnilink elite stents, received absolute pro stents, and mixed stent use was reported in two patients. in the tasc c group, patients were treated with onmilink elite, with absolute pro, and six with both stents. of the tasc d patients, received the omnilink elite, received the absolute pro, and received both. the -month primary patency rates were uniformly high, without statistically significant differences among tasc groups: a, %; b, %; c, %; and d, %. stratified by stent use, -month primary patency rates were % for self-expanding stents, % for balloon-expandable stents, and % for the patients treated with both types (p � . ). conclusion: primary endovascular treatment of symptomatic iliac artery occlusive disease produces -month patency � % irrespective of tasc classification. on the basis of these findings, endovascular therapy should be considered the treatment of choice for this condition; primary aortofemoral bypass is no longer indicated for isolated iliac artery occlusive disease. evolving treatment of popliteal artery aneurysm patrick a. stone, md, ali aburahma, md, priyanka jagannath, kim- ball knackstedt, do, stephanie thompson, phd, john campell, md, albeir mousa, md, james campbell, md . west virginia university and charleston area medical center, charleston, wva objective(s): during the past decade, the treatment of popliteal aneu- rysms has evolved at our institution from the sole operative intervention during the initial part of the study period, to combined surgical and endovascular treatment, and finally, to endovascular-centered management in more recent years. outcomes among treatment modalities for popliteal aneurysms were assessed. methods: this is a retrospective review of all patients with popliteal aneurysms treated at our institution from to . data collection included the indication for intervention, treatment details, interventional patency, limb salvage, perioperative outcome, and long-term survival. results: during this period, aneurysms were treated in patients. indications for intervention included ( %) with symptomatic presentations, and ( %) were asymptomatic. treatment included endovascular exclusion in , surgical repair in ( posterior approach and medial approach with bypass and exclusion), and primary amputation in one patient. nine aneurysms ( . %) received catheter-directed thrombolysis (fig). demographics were similar between the two treatment cohorts, except for age, with endovascular stenting patients significantly older ( . vs . years, p � . ). the mean length of stay was . vs . days (p � . ), favoring endovascular treatment. there were no perioperative ( -day) deaths in the endovascular group and one death in the surgical cohort. the mean patency follow-up was . vs . months. primary patency did not differ between endovascular and surgically treated patients at year ( . % vs . %, p � . ) and years ( . % vs . %, p � . ). no limbs were lost in the endovascular group during the follow-up period of . months. one late limb loss occurred in the surgical cohort (mean follow-up, . months). the long-term survival rate was % in the endovas- cular patients (mean follow up, . months) and . % in the surgical patients (mean follow up, . months, p � . ). conclusions: endovascular treatment of popliteal aneurysms provides similar short-term patency to that of the traditional gold standard approach fig. journal of vascular surgery september abstracts with surgical bypass, with shorter hospitalizations in symptomatic and asymptomatic patients. further long-term follow-up is required to compare these two treatment modalities for durability to determine the optimal popliteal aneurysm management. multifactorial disease severity score (dss) predicting the success of endovascular intervention of femoropopliteal peripheral arterial disease in-kyong kim, md, natalia egorova, phd, andrew j. meltzer, md, james f. mckinsey, md . columbia university, new york presbyterian hospital system, new york; mount sinai university, new york; and new york presbyterian hospital, new york, ny objective(s): the goal was to create a multifactorial disease severity score (dss) for characterization of femoropopliteal arterial lesions. by having a greater understanding of the effect of patient comorbidities and an in-depth method to characterize an arterial lesion, we may be able to better compare lesions in different studies and predict which therapy is most appropriate for each lesion undergoing an endovascular intervention (evi). methods: we evaluated lesion and patient characteristics in our prospectively maintained lower extremity arterial lesion database from to to create a gradated dss. results: we identified femoropopliteal lesions in patients. statistical analysis by multivariable cox proportional hazards model identi- fied variables that impact patency: seven lesion characteristics (table i) and nine patient characteristics or comorbidities (table ii). factors with the most impact were a chronic total occlusion (dss ), lesion length � mm (dss ), and no runoff vessels and stenosis of % to % (dss ). the following factors were considered baseline, or score of : stenosis � %, lesion length � mm, and three-vessel runoff. by adding these variable scores, a dss was created and used to predict patency of the evi. conclusions: the presence of a chronic total occlusion, lesion length � mm, poor runoff, and the presence of congestive heart failure have the most dramatic effect on patency after evi. a compre- hensive dss allows for the in-depth classification of lesion characteristics and factors that predict success of evi and can allow for comparison of distinct lesions. future comparisons of effectiveness of treatment modal- ities can be possible. table i. significant femoropopliteal lesion characteristics that negatively impact patency after endovascular intervention factor score hr ( % ci) chronic total occlusion . ( . - . ) stenosis %- % . ( . - . lesion length � mm . ( . - . ) vessel runoff . ( . - . ) . ( . - . ) . ( . - . ) lesion calcification . ( . - . ) ci, confidence interval; hr, hazard ratio. table ii. patient characteristics that impact patency after endovascular intervention factor (n � ) score cox coefficient hr ( % ci) chf . . ( . - . ) female sex . . ( . - . ) current smoker . . ( . - . ) former smoker . . ( . - . ) diabetes . . ( . - . ) cad . . ( . - . ) renal . . ( . - . ) age, years - . . ( . - . ) - � � . . ( . - . ) cad, coronary artery disease; chf, congestive heart failure; ci, confi- dence interval; hr, hazard ratio. defining the role of endovascular therapy in critical limb ischemia with tissue loss andrew j. meltzer, md, gisberto evangelisti, md, ashley graham, francesco aiello, md, peter h. connolly, md, harry l. bush, md, john k. karwowski, md, darren b. schneider, md. new york presbyterian hospital, new york, ny objective(s): we compare the utility of endovascular therapy (et) with bypass surgery for critical limb ischemia (cli) with tissue loss and identify risk factors for failure of et. table. hazard ratio (hr/ aor) % ci for hr/ aor p value overall survival dialysis dependence . . – . . angina . . – . . copd . . – . . amputation free survival rutherford . . – . . copd . . – . . limb salvage rutherford . . – �. wound healing at months diabetes . . – . current smoking . . – . patency loss . . – . methods: a retrospective review ( to ) of patients under- going et for tissue loss (rutherford class and ) provided data for multivariate models of overall survival, amputation-free survival (afs), limb salvage, and wound healing. comparisons were made with a bypass surgery cohort matched for tissue loss. results: ninety-four patients underwent et ( % transatlantic intersociety concensus [tasc] c/d; % tibial) for rutherford ( %) or rutherford ( %) cli with tissue loss of the heel ( %), forefoot ( %), toe(s) ( %), calf/ankle ( %), or multiple locations ( %). sustained limb salvage was % � %. overall survival was % � % and afs was % � % at years. predictors of failure by multivariate models are reported in the table. comparison between the rutherford wrsubgroup (n � ) and an rutherford bypass cohort (n � ), suggest equivalent limb salvage, with reduced afs (p � . ) and a trend toward reduced overall survival (p � . ). early would healing was higher after bypass: % vs % at months (p � . ) and % vs % at months (p � . ). conclusions: given the short life expectancy of patients with tissue loss, et permits sustained limb salvage in patients at high risk for bypass (particularly rutherford ). however, wound healing is slow compared with bypass and requires sustained patency. midterm results of limb salvage and stent patency with popliteal artery stenting across the knee joint aleksandra policha, md, neil moudgill, md, lily chang, bs, anu- meha whisenhunt, do, shawn pierce, crnp, luis eraso, md, paul dimuzio, md, atul rao, md, joshua eisenberg, md . department of general surgery and division of vascular and endovascular surgery, thomas jefferson university hospital, philadelphia, pa; thomas jefferson university college of medicine, philadelphia, pa; and division of vascular medicine, thomas jefferson university hospital, philadelphia, pa objective(s): this study evaluated the relationship of stent location on limb salvage and stent patency in patients undergoing popliteal artery stenting. methods: we performed a retrospective review of a prospectively collected database, identifying all patients undergoing popliteal artery stenting between september and february . patients were divided into two groups based on the position of the distal end of the stent in relation to the knee joint. the proximal popliteal stent group included patients receiving a stent ending above the patella (above the flexion point of the knee). the distal popliteal stent group included patients receiving a stent(s) ending below the patella (in the flexion zone). data collected included demographics, indication for surgery, journal of vascular surgery volume , number abstracts zurich open repository and archive university of zurich main library strickhofstrasse ch- zurich www.zora.uzh.ch year: editorial comment gonzález, r doi: https://doi.org/ . /j.juro. . . posted at the zurich open repository and archive, university of zurich zora url: https://doi.org/ . /uzh- journal article accepted version originally published at: gonzález, r ( ). editorial comment. the journal of urology, ( ): - . doi: https://doi.org/ . /j.juro. . . https://doi.org/ . /j.juro. . . https://doi.org/ . /uzh- https://doi.org/ . /j.juro. . . editorial comment ricardo gonzález kinderspital universität zürich, zurich, switzerland, kinderkrankenhaus auf der bult, hannover, germany; and thomas jefferson university, philadelphia, pennsylvania refers to yuval bar-yosef, miguel castellan, devandra joshi, andrew labbie, rafael gosalbez: total continence reconstruction using the artificial urinary sphincter and the malone antegrade continence enema. the journal of urology, volume , issue , april , pages - the authors reemphasize old concepts of ) the implantation of an artificial urinary sphincter with simultaneous intestinal surgery ( , ) and ) the importance of achieving urinary and fecal continence simultaneously ( ). the title should have included the term enterocystoplalsty since % of the patients needed it either to achieve continence or preserve the upper tracts. since the shortest followup is only months, i would anticipate that in the future more patients in this series will require augmentation and may become dependent on intermittent catheterization. finally, the conclusion that the results are durable needs to be taken with caution. with an average age at surgery of years, the real question is how these patients will fare at age and beyond. i perform reconstructive procedures for urinary and fecal incontinence in children but advise the parents that these solutions may be temporary. nevertheless, i believe that the achievement of a diaper-free status is important in childhood and adolescence. this article is worth reading to remind surgeons treating children with spina bifida of the importance of taking a holistic approach to the treatment of urinary and fecal incontinence. references . r. gonzález, d.h. nguyen, n. koleilat et al. compatibility of enterocystoplasty and the artificial urinary sphincter. j urol, ( ), p. . r. gonzález, b. ludwikowski, m. horst. determinants of success and failure of seromuscular colocystoplasty lined with urothelium. j urol, ( ), p. . r. gonzález, s. myers, j. franc-guimond et al. surgical treatment of neuropathic urinary incontinence in when, what, and how? j pediatr urol, ( ), p. 	editorial comment 	references wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ teaching video neuroimages: dancing epilepsy ritu bagla, md john s. khoury, md christopher skidmore, md a -year-old, right-handed man with refractory complex partial seizures after head trauma at age (figure ) was admitted for video-eeg monitoring. his girlfriend describes dancing movements with un- responsiveness lasting a few minutes (see video). the interictal eeg was suggestive of a left temporal focus (figure ); however, the ictal eeg was poorly local- ized and the overall localization was not determined. the dancing semiology is not typical of temporal lobe epilepsy, since automatisms involving proximal muscles and complex behaviors, such as bicycling, are suggestive of frontal lobe epilepsy. dancing is another behavioral manifestation of epilepsy that has not been previously reported. reference . kotagal p, arunkumar g, hammel j, mascha ed. com- plex partial seizures of frontal lobe onset: statistical analysis of ictal semiology. seizure ; : – . supplemental data at www.neurology.org figure interictal eeg interictal left anterior temporal sharp waves. sensitivity �v/mm. address correspondence and reprint requests to dr. john khoury, walnut st., suite , philadelphia, pa jskhoury@gmail.com from thomas jefferson university hospital (r.b., j.s.k., c.s.) and thomas jefferson medical college (c.s.), philadelphia, pa. disclosure: dr. skidmore has the following conflicts of interest to disclose for research support: ucb pharma, ortho mcneil, schwarz, medtronic, neuropace, ovation, marinus, nih. he is a consultant for the amarin corporation and a speaker for ucb pharma and ortho mcneil. figure fluid-attenuated inversion recovery coronal mri revealed encephalomalacia and gliosis in the left frontal and right anterior temporal regions resident & fellow section section editor mitchell s.v. elkind, md, ms e copyright © by aan enterprises, inc. doi . /wnl. b e a f ; ;e neurology ritu bagla, john s. khoury and christopher skidmore : dancing epilepsyimagesteaching video neuro this information is current as of june , services updated information & http://n.neurology.org/content/ / /e .full including high resolution figures, can be found at: supplementary material http://n.neurology.org/content/suppl/ / / / . .e .dc supplementary material can be found at: references http://n.neurology.org/content/ / /e .full#ref-list- this article cites articles, of which you can access for free at: subspecialty collections http://n.neurology.org/cgi/collection/video__eeg_use_in_epilepsy video/ eeg use in epilepsy http://n.neurology.org/cgi/collection/epilepsy_semiology epilepsy semiology 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http://n.neurology.org/cgi/collection/epilepsy_semiology http://n.neurology.org/cgi/collection/video__eeg_use_in_epilepsy http://www.neurology.org/about/about_the_journal#permissions http://n.neurology.org/subscribers/advertise binding of isoflurane to a bacterial voltage-gated sodium channel: structure and accessibility of distinct interaction sites a sunday, february , stabilized by surrounding hydrophobic residues. we propose that mutations of the asparagines affect activation-inactivation of the channels and drug action through destabilizing the open state. diversity of h-bonding partners explains different effects of mutations of individual asparagines on the channel activa- tion, inactivation, and drug sensitivity. supported by nserc grant to bsz, the ras program ‘‘molecular and cell biology’’ to dbt, and cihr award to ib. -pos board b binding of isoflurane to a bacterial voltage-gated sodium channel: structure and accessibility of distinct interaction sites srinivasa g. raju , vincenzo carnevale , david n. lebard , annika f. barber , michael l. klein . temple university, philadelphia, pa, usa, yeshiva university, new york, ny, usa, thomas jefferson university, philadelphia, pa, usa. the most likely targets for volatile anesthetics (va) are ion channels. the mechanism of volatile anesthetic action is not completely understood. identify- ing the molecular pathway for drug binding is crucial to understand the effect of va on voltage gated sodium channels. we use molecular dynamics simula- tions to identify the binding sites for a hydrophobic general anesthetic isoflur- ane, on voltage gated bacterial sodium channel nachbac. apart from the voltage sensing domain (s -s ), linker and the pore domain (s -s ), bacterial sodium channels also have fenestrations, which provide a hydrophobic tunnel through the lipid-embedded portion of the channel to the central cavity, where the known local anesthetic site is located. unbiased ‘‘flooding’’ simulations were performed on the activated open confirmation of nachbac. we per- formed a cluster analysis to identify all the possible binding sites of isoflurane. the three most important ones among them are: a region near the selectivity filter, called the extracellular site, a region near the s -s linker, called the linker site, and a region within the cavity, called the cavity site. the most important observation is that isoflurane enters the central cavity through the fenestrations. free energy perturbation method was employed to calculate the binding affinities of isoflurane for each of these sites. we also studied the interactions between isoflurane and the amino acids in these three binding sites. -pos board b a key gating charge interaction required for slow inactivation of the navab bacterial sodium channel tamer m. gamal el-din, todd scheuer, william a. catterall. university of washington, seattle, wa, usa. bacterial voltage-gated sodium (nav) channels are considered an ideal model for structure-function studies. the elucidation of the crystal structure of the bacterial channel navab (payandeh et al., nature , - , ) opened an avenue to understand electrical signaling in excitable cells at the structural level. navab expressed in hi insect cells as for structural studies has unusually negative voltage-dependent activation (va ~ mv). navab also has three phases of inactivation, a biphasic early inactivation process (t ~ ms, t ~ . s, at � mv) followed by an unusually strong and use-dependent slow-inactivation process. to search for the molecular basis for negative activation and slow inactivation of navab, we mutated the outer- most gating charge partner in the s segment, asn , to lys. this mutation shifted the activation curve ~ mv toward more positive potentials. surpris- ingly, it also completely abolished use-dependent slow inactivation. we showed previously that the equivalent residue in nachbac (asp ) interacts with the r gating charge in the s segment during activation using the disul- fide locking method (decaen et al, pnas ( ) - ). to test whether this interaction between r and n was critical for slow inactivation, we mutated navab r to cys. the resulting mutant navab_r c also had positively shifted channel activation (þ mv) and no use-dependent slow inactivation. the fact that these reciprocal mutations have the same functional effects suggests that interaction between r in the s segment and n in the s segment is an important link that stabilizes the activated state of the voltage sensor and triggers the slow inactivation process. -pos board b computational study of the prokaryotic sodium channel karen m. callahan, benoit roux. university of chicago, chicago, il, usa. ion-selective voltage-gated ion channels allow ions of a specific element or set of elements to pass, but exclude other ions. recently, the crystal structure of navab was published (payandeh et al ( ) nature , ), giving an un- ambiguous picture of the structure of the sodium channel selectivity filter (sf) of the prokaryote arcobacter butzleri. the filter is much wider than that of the narrow, carbonyl-lined potassium channels, allowing ions to penetrate with minimal dehydration, multiple pathways, and even to pass each other. previous computational studies have attempted to explain sodium selectivity, and claimed consensus (corry and thomas ( ) jacs , , furini and domene ( ) plos , e ). experimental ion selectivity determina- tion from pore-only constructs of a sodium channel with the same sf sequence shows stronger ion selectivity from reversal potential than from the ratio of the fluxes of sodium and potassium (shaya et al ( ) pnas , ), but selectivity, na þ/kþ, was still less than five. simulations based upon the closed-pore crystal structure could not determine selectivity directly from con- duction. to investigate this issue, we first calculated multi-ion potentials of mean force in the selectivity filter of pore-domain-only navab with an ex- tended equilibration period, and a replica-exchange molecular dynamics scheme, which allows for improved sampling. we then explored the non- equilibrium conduction of sodium and potassium in the presence of an applied electric field through a model navab pore truncated to mimic the conformation of the open pore. we also present multi-ion pmf calculations to illustrate similarities and differences between this model and the intact pore. when taken together, these two methods provide complementary views of ion selectivity and conduction based upon the conformation of the navab crystal structure of payandeh et al ( ). -pos board b volatile general anesthetic interactions with a bacterial sodium channel annika f. barber , srinivas g. raju , david lebard , vincenzo carnevale , michael l. klein , manuel covarrubias . thomas jefferson university, philadelphia, pa, usa, temple university, philadelphia, pa, usa. general anesthesia results from complex interactions involving ion channels in the brain. voltage-gated ion channels are modulated by halogenated inhaled general anesthetics, however the drug-channel interactions are generally believed to be non-specific making it difficult to investigate the molecular mechanisms of anesthetic action. we find, however, that the bacterial sodium channel nachbac exhibits differential regulation by different general anes- thetics, suggesting that there may be specific interactions. molecular dynamics (md) simulations have identified several possible binding sites for isoflurane in the nachbac channel structure. here, we have characterized the affinity, occu- pancy and hydrogen bonding for these sites and identified key interactions. in addition, experimental evidence suggests that both isoflurane and sevoflurane have dual actions on nachbac, possibly involving action at two different sites. consistent with pore block, sevoflurane accelerates the decay of the current ( % faster at . mm sevoflurane) but, at the same time, increases the peak current ( % increase with . mm sevoflurane), which argues against the blocking mechanism. we hypothesize that an additional mechanism involving a distinct site is necessary to explain the latter effect. we are currently employ- ing md simulation and structural modeling combined with mutagenesis and electrophysiology to test this two-site hypothesis and investigate the molecular mechanisms of these opposing effects. supported by ninds f ns (afb) and nigms p gm (mlk). -pos board b polymodal, high affinity actions of m-conotoxins on a bacterial voltage- gated sodium channel rocio k. finol-urdaneta , robert glavica , jeff r. mcarthur , robert j. french . university of calgary, calgary, ab, canada, rmit, melbourne, australia. m-conotoxins (mctxs) are potent blockers of eukaryotic sodium channels, and individual members of the mctx family are highly specific for particular nav isoforms. we have begun to explore mctx interactions with nachbac, a pro- karyotic nav channel closely related to navab, whose crystal structure was re- cently determined (payandeh et al, , nature : ). our data reveal actions on both ion conduction and gating, consistent with polymodal actions on the pore domain. under voltage clamp, whole-cell currents from nachbac expressed in tsa- cells were reduced, up to nearly complete block, by concentrations in the pm to mm range, for wildtype toxins and derivatives of mctx piiia and kiiia. for wildtype piiia, dose-response data ( . - , nm) yielded the following: ic = . nm; maximal fraction of current blocked = . ; hill coefficient = . . chen & chung ( , biophys. j. : ) predicted an ic of . nm for piiia when the navab channel is occupied by sodium ions. even at very low [piiia] ( pm), the unblocked currents showed increasing rates of inactivation as the peptides were washed in, suggesting a gating mod- ulation, that was not tightly associated with pore block. for mctx piiia ( . nm), or kiiia ( nm), inactivation accelerated by ~ -fold. substitution of key basic residues (piiia-r a and kiiia-k a) reduced blocking potency and decreased the speeding of inactivation to less than -fold. given the remarkably high selectivity and affinity that mctxs show for certain eukaryotic nav channels with highly asymmetric pores, it may seem surprising that they bind to symmetric bacterial nav channels with such high affinity. 	binding of isoflurane to a bacterial voltage-gated sodium channel: structure and accessibility of distinct interaction sites 	a key gating charge interaction required for slow inactivation of the navab bacterial sodium channel 	computational study of the prokaryotic sodium channel 	volatile general anesthetic interactions with a bacterial sodium channel 	polymodal, high affinity actions of μ-conotoxins on a bacterial voltage-gated sodium channel shuttling of membrane-bound cytochrome b between mitochondria and&nbsp;er sunday, february , a mitochondrial membranes which result in the dramatic increase of their perme- ability. this increase in permeability during necrosis is caused by the opening of a permeability transition pore - ptp in mitochondrial inner membrane. on the other hand apoptosis induces opening of a large non-selective channel (mito- chondrial apoptotic channel - mac) in the mitochondrial outer membrane. we used atomic force microscopy to study the structure and organization of native mitochondrial membranes isolated from necrotic and apoptotic cells. we com- plement our afm imaging with nanopatricle-based immnunoassays, where mi- tochondrial membranes are pretreated with nanoparticle-conjugated antibodies for recognition of specific proteins. we will present our data on morphological studies of these membranes and will discuss feasibility of this approach for visu- alization of mptp and mac channels in the native mitochondrial inner mem- branes (mim) and mitochondrial outer membranes (mom) using afm methods. -pos board b heterogeneity of cardiolipin regulation yi-fan lin, mei-jie jou. department of physiology and pharmacology, chang gung university, tao-yuan, taiwan. cardiolipin (cl), is a protective phospholipid located exclusively on the mito- chondrial inner membrane for stabilizing individual complex of mitochondrial respiratory chain for energy production, mitochondrial ca þ (mca þ) regula- tion and reactive oxygen spices formation. deficiency of cl has been associated with multiple mitochondrial dysfunctions upon pathological condition, diseases and aging. using fluorescence digital imaging microscopy this study investi- gated how cl is preciously regulated in rat brain astrocytes rba- . results demonstrate that at the resting stage, the distribution of cl is rather heteroge- neous within single cell. the perinulear mitochondria show lower cl than mi- tochondria from the peripheral area. heterogeneity of cl was observed even in single mitochondrion, which may affects mitochondrial fission and fusion mechanism. cl was found to be higher at the cross point area of mitochondrial network. thread-like mitochondria and granular-like mitochondria, however, contain similar level of cl. some of the thread-like mitochondria even contain lower cl than granular-like mitochondria. upon localized oxidative stress in- duced by nm laser irradiation, heterogeneous depletion of cl was observed among mitochondria populations within single cell. distribution of cl altered also mitochondrial dynamics that depletion of cl always occurred before fis- sion. intriguingly, although complete depletion of cl is irreversible upon high strength of laser irradiation, depleted cl recovered during lower strength of laser irradiation and occurred heterogeneously within mitochondria popula- tions. condensation of cl was observed upon various stresses including oxida- tive stress induced by nm laser irradiation, ionomycin-induced mca þ stress and arachidonic acid-induced lipid stress which crucially enhances pres- ervation of cl and its resistance to stress which may be of significance for mi- tochondrial protection and survival. unveiling pathophysiological regulation of cl thus may contribute significantly the prevention and treatment of cl asso- ciated pathological condition, diseases and aging. -pos board b mtdna t g mutation-induced mitochondrial complex v inhibition augments cardiolipin-dependent alterations of mitochondrial dynamics during oxidative, ca d and lipid insults in narp cybrids: a potential therapeutic target tsung-i peng , chia-wei hsiao , mei-jie jou . keelung chang gung memorial hospital, tao-yuan, taiwan, national tsing hua university, tao-yuan, taiwan, chang gung university, tao-yuan, taiwan. mitochondrial dynamics including morphological fission and mitochondrial movement are essential to normal mitochondrial and cellular physiology. this study investigated how mtdna t g (narp)-induced inhibition of mito- chondrial complex v altered mitochondrial dynamics in association with a pro- tective mitochondrial phospholipid, cardiolipin (cl), as a potential therapeutic target. narp cybrids harboring % of mtdna t g genes and its parental osteosarcoma b cells were studied for comparison, and protection provided by melatonin, a potent mitochondrial protector, was explored. we demonstrate for the first time that narp mutation significantly enhances apoptotic death as a result of three distinct lethal mitochondrial apoptotic insults including oxida- tive, ca þ and lipidstress. in addition, narpsignificantly augmented patholog- ical depletion of cl. narp-augmented depletion of cl results in enhanced retardation of mitochondrial movement and fission and later swelling of mito- chondria during all insults. these results suggest thatcl is a common and crucial pathological target formitochondrial apoptoticinsults. furthermore, cl possibly plays a central role in regulating mitochondrial dynamics that are associated with narp-augmented mitochondrial pathologies. intriguingly, melatonin, by differ- entially preserving cl during various stresses (oxidation > ca þ > lipid), res- cuesdifferentially cl-altered mitochondrial dynamics and cell death (oxidation > ca þ > lipid). thus, melatonin, in addition to being a mitochondrial antioxidant to antagonize mitochondrial oxidative stress, a mitochondrial permeability tran- sition modulator to antagonize mitochondrial ca þ stress, may stabilize directly cl to prevent its oxidization and/or depletion and, therefore, it exerts great po- tential in rescuing cl-dependent mitochondrial dynamics-associated mitochon- drial pathologies for treatment of narp-induced pathologies and diseases. -pos board b shuttling of membrane-bound cytochrome b between mitochondria and er david weaver , veronica eisner , peter varnai , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis medical university, budapest, hungary. cytochrome b type b has long been described as a tail-anchored protein of the outer mitochondrial membrane (cb -mito). using a fusion protein consisting of photoactivatable gfp fused to the c-terminus membrane-targeting segment of cb -mito, we have found that while this construct concentrates in the mitochon- drial membrane, it is continuously exchanged between the membranes of the mitochondrion and the endoplasmic reticulum. this effect does not depend on the presence of mitofusin or , as it occurs in mfn-null mefs as well as in wild type cells. interestingly, a point mutation in the hydrophobic, membrane-targeting sequence of cb -mito that was recently reported to prevent its association with autophagosome membranes, also eliminates its exchange with the er. while lipids and viral proteins have been shown to traffic from er to mitochondria, this is, to our knowledge, the first demonstration of such a back-and-forth shuttling, representing both a new aspect of the er- mitochondrial interface and an mfn-independent pathway for the exchange of an outer mitochondrial membrane protein. -pos board b dichotomy between mitochondrial ca d uptake and martix [ca d] in micu deficient cells tunde golenar , gyorgy csordas , fabiana perocchi , vamsi k. mootha , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. mitochondrial calcium uptake is central to cell physiology, but the underlying molecular mechanism remains elusive. recently, micu was identified as a mi- tochondrial protein required for ca þ uptake but dispensible for mitochondrial respiration or membrane potential generation. to study the specific role of micu in mitochondrial ca þ uptake, we used wild type hela cells (ctrl), micu knockdown by distinct shrnas (kd) and micu rescued cells (res- cue). first, we monitored the cytoplasmic and mitochondrial matrix [ca þ] ([ca þ]c and [ca þ]m, respectively) during store-operated ca þ entry. specif- ically, cells were preincubated in a ca þ-free buffer containing thapsigargin (tg), to deplete the er ca þ store, and then ca þ was added back and the en- suing [ca þ]c (fura ) and [ca þ]m (mitochondria-targeted pericams) changes were measured. in both ctrl and kd a [ca þ]c increase occurred that was asso- ciated with a [ca þ]m rise only in ctrl. the rescue behaved similarly to the ctrl. also, when ca þ was added to permeabilized cells, no [ca þ]m increase ap- peared in the kd. these results confirm that the shortage of micu causes sup- pression of the [ca þ]m signal. surprisingly, when the ca þ entry was followed byuncoupler additiontoreleasethemitochondrial ca þ content, ahuge[ca þ]c increase appeared in kd, however, when the uncoupler was added prior to ca þ entry, no [ca þ]c increase occurred. thus, mitochondria in the kd also accumu- lated ca þ during ca þ entry. mitochondrial ca þ uptake evoked by ca þ ad- dition was also documented in permeabilized kd by measurement of ruthenium red sensitive ca uptake and cytoplasmic ca þ clearance (fura ). thus, ca þ is accumulated by micu deficient mitochondria but it fails to result an increase in[ca þ]m.weare currentlyinvestigating, whether suppression ofthe [ca þ]m rise in the kd is due to enhanced matrix ca þ-buffering. -pos board b micu serves as a ca d-controlled gatekeeper for the mitochondrial ca d uniporter györgy csordás , tünde golenár , erin l. seifert , fabiana perocchi , vamsi k. mootha , györgy hajnózky . thomas jefferson university, philadelphia, pa, usa, department of systems biology, harvard medical school, boston, ma, usa. micu serves as a ca þ-controlled gatekeeper for the mitochondrial ca þ uniporter mitochondria are important targets and relay points of calcium signaling. ca þ is driven to the mitochondrial matrix via a low-affinity ca þ channel, the ca þ uniporter (mcu) that exhibits time-dependent 	heterogeneity of cardiolipin regulation 	mtdna t g mutation-induced mitochondrial complex v inhibition augments cardiolipin-dependent alterations of mitochondria ... 	shuttling of membrane-bound cytochrome b between mitochondria and er 	dichotomy between mitochondrial ca + uptake and martix [ca +] in micu deficient cells 	micu serves as a ca +-controlled gatekeeper for the mitochondrial ca + uniporter doi: . /epja/i - - - eur. phys. j. a , s , – ( ) epj a direct electronic only physics at the thomas jefferson national accelerator facility l.s. cardmana thomas jefferson national accelerator facility, jefferson avenue, newport news, va , usa and university of virginia, department of physics, mccormick rd., p.o. box , charlottesville, va - , usa / published online: may – c© società italiana di fisica / springer-verlag abstract. the continuous electron accelerator facility, cebaf, located at the thomas jefferson na- tional accelerator facility, is devoted to the investigation of the electromagnetic structure of mesons, nucleons, and nuclei using high energy, high duty-cycle electron and photon beams. selected experimental results of particular interest to the mami community are presented. pacs. . .+w electrostatic, collective, and linear accelerators – . .-x photonuclear reactions – . .bf elastic electron scattering – . .dh inelastic electron scattering to specific states personal comments it is an honor and a pleasure to be here to celebrate the achievements of mami and the distinguished careers of professors arenhövel, backe, drechsel, friedrich, kaiser, and walcher. we are all deeply aware of the extent to which the science we do builds on the achievements of those who have gone before us, and on the insights and hard work of our colleagues working in the field today. one of my very earliest memories as a scientist, dating from the days when i was a young graduate student, is that of attending “photonuclear physics boot camp” (otherwise known as the photonuclear gordon conference) and learning from (and with) many of those “retiring” today. thomas (walcher) was one of the very first scientists i ever knew beyond the boundaries of my own laboratory. he came to visit us (at yale), and i went and visited him and his colleagues at darmstadt. it has been a great plea- sure to follow his distinguished career in science, from low- q electron scattering to hadronic physics at cern and beyond, and finally to the leadership role he has played at mami for many years. hartmuth (arenhövel) has been the keeper of the flame of all knowledge about the deuteron, and a worthy succes- sor to gregory breit. you should know that i was a grad- uate student at yale, and it was one of professor breit’s missions in life to convince any and all who would listen that the deuteron was the essence of nuclear physics, and that until we understood the deuteron, we did not un- derstand anything. i think it is fair to call hartmuth the gregory breit of my generation; he has made so many contributions. a e-mail: cardman@jlab.org dieter (drechsel) has always been one of those peo- ple i have looked to as the source of the “big picture” in nuclear physics. he has provided us with deep insights, a sense of direction, and an understanding of what is really important. he has also been an inspiring example here at mainz of the tremendous benefits to everyone of having a close collaboration between theory and experiment. jörg (friedrich) has taught us all how to analyze and interpret electron scattering data with minimal prejudice (and, therefore, maximal honesty). it is a delight to see the same rigorous approach that was so successful in the study of nuclei and their excited states now being applied to nucleon structure. karl-heinz (kaiser) and his mentor, helmut herming- haus, taught the world how to build superb continuous- wave (cw) electron accelerators effectively and efficiently. karl-heinz, in particular, through the design and con- struction of the double-sided microtron, is leaving the in- stitute well positioned for another generation of superb experiments. in conclusion, on behalf of so many people i have worked with in nuclear physics, i want to thank each of you for your many contributions to our field, and to express the hope we all share that for each of you “retirement” is a formality, not a reality, and that you will continue to be active for years to come. research at jefferson laboratory the thomas jefferson national accelerator facility, also called jefferson lab (or jlab), operates the continu- ous electron beam accelerator facility (cebaf). ce- baf is a cw electron accelerator capable of delivering three electron beams for simultaneous experiments in the the european physical journal a three experimental areas. originally designed for gev, its present maximum energy is . gev. the cebaf user community consists of about physicists; more than half of them are actively involved in the experimental program. in addition to its main mis- sion, jlab contributes to the development and use of free electron lasers, to medical imaging, and to community outreach programs. the intellectual and technical foundations for the con- struction of cebaf were provided by the scientific suc- cesses of earlier electron accelerators (the generation that included saclay, mit-bates, nikhef, and, to some ex- tent, slac), and by the enhanced research opportunities provided by cw electron beams as demonstrated at fa- cilities such as mami. cebaf is a large, international laboratory with a broad research program; it has been in operation for some seven and a half year now. what are the goals of cebaf’s research program? ba- sically, we aim to understand strongly-interacting matter. how are the hadrons constructed from the quarks and glu- ons of qcd, and how does the nucleon-nucleon force arise from the strong interaction? we further aim to identify the limits of our understanding of nuclear structure by us- ing the high precision attainable with the electromagnetic probe and the possibiltiy of extending investigations to very small distance scales. a specific issue that motivated the construction of cebaf was our desire to gain insight into the question of where the description of nuclei based on nucleon and meson degrees-of-freedom fails and the un- derlying quark degrees-of-freedom must be taken into ac- count. one can ultimately characterize all of this as trying to understand qcd, not in the perturbative regime acces- sible at very high energies and very short distance scales, but in the strong interaction regime relevant to most of the visible matter in the universe. to make progress in these areas, there are other critical issues that must be addressed, such as the mechanism of confinement, the dy- namics of the quark interaction, and how chiral symmetry breaking occurs. to provides some shape and structure to the discussion of the experiments, the cebaf program can be organized into half a dozen broad thrusts. this presentation will concentrate on two of them: – how are the nucleons made from quarks and glue? – where are the limits of our understanding of nuclear structure how are the nucleons made from quarks and glue? among the most interesting puzzles in physics today are: why there is this effective degree-of-freedom in qcd, the nucleon; and how something as complicated as the resid- ual qcd interaction between quarks in nucleons can be characterized by a rather simple n-n potential? to pro- vide experimental insights that will help us solve the first of these puzzles, the jefferson lab research community has mounted an array of investigations in three broad areas: lung rock bartel arnold jourdan jourdan gao xu selected world data mit-bates: h(e → ,e’n → ) mainz a : h(e,e’n) nikhef: h(e,e’n) galster borkowski sill bosted walker andivahis . . . . . . . . . . . . . . . . g e n g m n µ n g d . . . . . . . . . µg e p g m p g m p µ p g d q (gev )q (gev ) q (gev ) q (gev ) fig. . nucleon form factor data available before the start of experiments using cebaf. top panels: electric form factors, bottom panels: magnetic form factors. left panels: proton form factors, right panels: neutron form factors (adapted from ref. [ ]). – what are the spatial distributions of the u, d, and s quarks in the hadrons? – what is the excited state spectrum of the hadrons, and what does it reveal about the underlying degrees- of-freedom? – what is the qcd basis for the spin structure of the hadrons? . what are the spatial distributions of the u, d, and s quarks in the hadrons? elastic electron scattering has provided most of our infor- mation on the spatial distributions of the quarks in the nucleons. the data on the four electromagnetic structure functions of the nucleon, ge and gm for both the proton and the neutron, available just prior to the start of exper- iments at cebaf is shown in fig. . the magnetic form factors of the proton and the neutron were known rea- sonably well, but the electric form factors were not. the electric form factor of the proton had not been determined accurately enough to distinguish between a wide range of theories based on rather different physics. first results on the electric form factor of the neutron were available from bates, mainz, and nikhef, but these data were limited to moderate momentum transfers and, therefore, not sen- sitive to the details of the distribution of charge inside the neutron. the measured form factor was consistent with the r.m.s. radius derived from neutron-electron scattering. the present status of the nucleon form factors is shown in fig. . the measurements of the polarization transfer from the incident electron to the elastically recoiling proton have shown that the electric and mag- netic form factors for the proton differ substantially. the systematic differences between the polarization transfer data and the rosenbluth results for ge/gm are likely l.s. cardman: physics at the thomas jefferson national accelerator facility . . . . . lung rock bartel arnold jourdan jourdan gao xu . . . . . . this measurement (with statistical errors) grey: estimated systematic error . . . . . . . . . borkowski sill bosted walker andivahis . . . . . mit-bates: h(e → ,e’n → ) jlab e - : h → (e → ,e’n) mainz a : h → e(e → ,e’n) mainz a : h(e → ,e’n → ) mainz a : h → e(e → ,e’n) nikhef: h → (e → ,e’n) schiavilla & sick: g q jlab e - : h(e → ,e’n → ) galster new fit µg e p g m p g e n g m p µ p g d g m n µ n g d q (gev ) q (gev )q (gev ) q (gev ) fig. . present status of the nucleon form factor data including the cebaf data (adapted from ref. [ ]). due to two-photon exchange effects modifying the results. theoretical estimates suggest that the modifications are much smaller for the polarization transfer data than for the rosenbluth data, so the former are likely to be more directly interpretable in terms of the nucleon form factors. the electric form factor of the neutron has now been measured up to a q of . (gev/c) using polarization transfer techniques, and the data taken with different methods agree quite well. the theoretical interpretation of the data is summa- rized in fig. . the theories that describe the data reason- ably well reveal two key aspects of nucleon structure: the importance of the pion cloud, and the importance of in- corporating the relativistic motion of the quarks into the theoretical description of the nucleon. when one looks at these form factors in a phenomeno- logical way with minimum prejudice [ ], what emerges is some of the clearest evidence we have for the nucleon’s pion cloud (see fig. ). similar results have been obtained using a different approach to model-independent analy- sis [ ] of nucleon form factors. we plan to extend the proton form factor data to ∼ (gev/c) , where we may see evidence for a diffraction minimum. the neutron form factor will also be extended to ∼ (gev/c) . further extensions of a factor of two are planned with the gev upgrade. such extensions have . . . µ p g e . . . . bijker (vmd) holzwarth (soliton) hammer (vmd + disp. rel.) miller (rel. qcm + “bag”) . . . . . . f /f ∝ ln (q /Λ )/q p g m p g e n g m p µ p g d g m n µ n g d q (gev ) q (gev ) q (gev ) q (gev ) fig. . theoretical descriptions of the nucleon form factor data [ ]. historically proven to be important, and we expect these data will provide further insight and sensitivity for com- pleting our understanding of how to construct nucleons from quarks and gluons. the european physical journal a - . - . . . . . . . . . . . . . r · ρ ( r; g e p p o l ) / f m - r / fm π+ -b p p b p n total - . - . . . . . . . . . . . . . . r · ρ ( r; g e n ) / fm - r / fm π− b n p ( - b n )n total fig. . neutron radial charge distribution (top) and the polar- ization term contribution to the proton radial charge distribu- tion (bottom) as inferred from an analysis using phenomeno- logical models [ ] of the world nucleon form factor data. the green solid lines show the pion cloud contribution. note that r ρ(r) is plotted, emphasizing the distribution at large radii. the strange quark form factors have become an in- teresting area of study that is both analogous and com- plementary to the classical electromagnetic form factors. by using the weak component of the electro-weak interac- tion we access the weak neutral current form factor, which can be interpreted very elegantly in terms of the strange quark distribution. because there are no valence strange quarks, this measurement provides a unique window on the sea quark distribution. the strange form factors can also be expected to provide us with interesting experi- mental insights into nucleon structure: by combining the electromagnetic and the weak neutral current form factors we should be able to separate the spatial distribution of the u, d, and s quarks. figure shows the world’s data on the strange proton form factor taken at forward angles as a function of q . one sees data from the a experiment at mainz [ , , ], from happex i and ii (jlab hall a) [ , , ], and from g (jlab hall c) [ ]. these difficult experiments would be impossible without highly polarized electron beams from magnificently stable accelerators. the fact that the data from different laboratories lie roughly on a smooth curve gives one confidence that the experimenters are do- ing it right. the first thing that strikes you about the data is that the form factor is rather small. this is to be expected, as all of the strange quarks emerge as quark-antiquark pairs popping in and out of the vacuum, and to get a finite form factor there must be some kind of a polarizing effect a g happex fig. . nucleon strange form factor data from parity-violating electron scattering at forward angles as a function of q . - - . . e s g m s g sample with calculationag he (' ) happex- a g (extrapolated)happex-h (' ) % c.l. q = . gev leinweber et al. ( ) + fig. . separated strange nucleon form factors at q = . (gev/c) [ ]. separating them spatially. even at the highest momentum transfers reached experimentally we are averaging over a distance scale that is roughly the size of the nucleon, so it is not too surprising that the result is small. there is an intriguing suggestion in the data for something that one would call vaguely pion-cloud like behavior, but it is fair to say that the statistical significance of this effect is not very high. the data taken at forward angles includes a mixture of electric and magnetic form factors. at q = . (gev/c) we have data at both forward and backward scattering angles, so we can separate these effects (see fig. ). the data favor a positive value of gsm , which is at variance with most of the theoretical models. experiments are in progress that will reduce the size of the error ellipse at this q value by a about a factor of , and additional experiments planned at both mami and jlab will permit separations at other q values. a broad, world-wide effort will provide the results we want. another interesting experiment is the measurement of the pion form factor. the pion is the simplest qcd bound system, the “positronium” of qcd. one expects that the pion form factor will provide us with evidence for the l.s. cardman: physics at the thomas jefferson national accelerator facility . . . q (gev/c) q f π bse+dse qcd sum rule cqm perturbative qcd amendolia π+e elastics previous p(e,e’π + )n jlab f π - results jlab f π - results pre limin ary fig. . pion form factor data [ ]. transition of the strong interaction from the perturbative (qed-like) to the strong (confinement) regime at the low- est possible momentum transfer. these data also constrain phenomenological models of the pion. measuring the pion form factor is not simple. at low q , one can scatter pions off atomic electrons, but a bowl- ing ball does not transfer energy to a ping-pong ball effi- ciently, and even with very high energy pions this exper- iment cannot reach high momentum transfers. to reach higher momentum transfer in the absence of a free pion target, one must scatter electrons off virtual pions inside a proton and extrapolate the data to the pion pole. the world’s data (see fig. ) is beginning to distinguish be- tween different theoretical approaches. with the gev upgrade, we expect to extend the data out to a momen- tum transfer of (gev/c) and to be able to infer the distance scale for the onset of perturbative behavior. . what is the excited state spectrum of the hadrons? if one looks at several decades worth of data on nucleon resonances and tries to use a simple quark model to clas- sify the states in terms of the excitation in units of h̄ω and the angular momentum of the three quarks, the states that have been identified so far fit nicely into this scheme, but there are many states that have been predicted but have not been found. it is an interesting fact that one can explain all of the states that have been seen so far by assuming that the nucleon and its excited states are a diquark-quark system. since most of the data have been obtained from pion-induced reactions, and many of the missing states are predicted not to couple to pions, it is also possible that the missing states may have been over- looked for experimental reasons. in atomic spectroscopy the line spacing is large com- pared to the line width, and measuring the complete spectrum is relatively straightforward. in nucleon spec- troscopy, the strong interaction causes the width to be comparable to the spacing. identifying weak states and fig. . w-dependence of the scattered electron rate for the p(e, e′)x reaction. clas data taken at gev primary beam energy. the energies of the known excited states are shown in black, while those of the states “missing” in the simple quark model description are shown in red. extracting the internal quark structure from the measured cross sections is a difficult task. the problem can be seen easily in fig. , which shows the inclusive electron scatter- ing cross spectrum from the proton for a gev electron beam. with a modern electron accelerator and a large ac- ceptance detector one can obtain data on the transition form factors over a large q -range [ → (gev/c) ] in a single shot. there is plenty of cross section in the region where the missing states (shown in red) have been pre- dicted, but extracting their individual strengths from the data is a real challenge. the combination of cw electron beams and modern, large solid angle detectors provides important advantages for addressing this problem experimentally. if one looks at the same data set of fig. but uses the information on the energy and momentum of the final state proton mea- sured in coincidence with the inelastically scattered elec- tron, it is straightforward to infer the missing mass asso- ciated with the decay of the excited state (see fig. ). one can see clearly from the raw missing mass spectrum that the “missing” states do not couple to pions, but rather to the η and ω. with the further information on the an- gular correlations of those decay particles relative to the momentum transfer axis one finally has the information necessary to decompose the spectrum of fig. , and learn just what is there. this effort naturally begins with the ∆( ), which decays predominantly into pion and nucleon. figure shows a comparison of separated structure functions from clas data for the p(e,e′p)πo reaction with theoretical fits and results from previous experiments. the ∆ → γ∗n-transition is characterized by three mul- tipoles: the electric quadrupole e, the magnetic dipole m, and the scalar multipole s. as we examine this transi- tion as a function of momentum transfer we expect that different aspects of the excitation will become apparent. at large distance scales (corresponding to low momentum transfers) we should see the effect of the pion cloud, while at large momentum transfer (corresponding to short dis- tances) we will eventually reach the limit given by pqcd the european physical journal a n( ) n( ) ∆( ) w (g e v ) π η ω m x (gev) π thresh. m is s in g s ta te s fig. . w vs. missing-mass mx for the same clas data shown in fig. [ ]. fig. . angular distributions of the separated structure func- tions for the p(e, e′p)πo reaction in the delta region [ ]. where rem = e/m → , and we further expect that the s/m ratio rsm will become constant. results from an early experiment at jlab and data from mami and bates, all in the low-q regime show the effect of the pion cloud clearly (see fig. ). as a function of q , rem remains small and negative at high q with a trend toward and a possible sign change. rsm continues to rise in magnitude with q . no trend is seen towards q - independence. we can only conclude that even at q of (gev/c) we are far from the pqcd regime. pion cloud models describe the data well (fitted to low and high-q points). unquenched lattice qcd gives the correct signs and approximate magnitudes. one of the most interesting examples of the impact of the pion cloud and of the value of measuring the tran- sition form factors for nucleon excitation is the roper fig. . ratios rem and rsm as a function of q for the ∆ → γ ∗n-transition [ ]. - - - a / ( - g e v - / ) p ( ) - - - s / ( - g e v - / ) p ( ) q (gev ) q (gev ) fig. . a (q ) and s (q ) multipoles for the p ( ) roper resonance [ ]. resonance. according to the constituent quark model the n∗( )p state is an n = radial excitation of the nu- cleon. however, the properties of this state such as its mass and photocouplings are not well described by this model. the new clas data (see fig. ) seem to explain this puzzle. at low momentum transfer, what one is measur- ing is dominated by the pion cloud. as you start squeezing down the distance scale, what emerges is the underlying quark structure of the roper, which is, in fact, roughly consistent with a radial excitation. investigation of nucleon excitation through the mea- surement of the transition form factors is now slowly mov- ing up in excitation energy. most of this analysis is at a preliminary stage, and what is really needed is a coher- ent study of many channels at many values of momentum transfer in a consistent (and comprehensive) analysis. it will be a long time before we have all the answers. as we search through this data, we are coming across intriguing evidence for states that have been “missing”. for example, there is evidence for a possible new n* state near mev visible in the Λ photo- and electro- production data. in the forward hemisphere, one sees a nice peak from a known n* state at . gev; in the l.s. cardman: physics at the thomas jefferson national accelerator facility w (gev) . . . . . b /s r µ . . . l σ l ∈ + t σ Λ = . (gev/c) ) < ., qkΘ- . < cos( known n* new n* ? fig. . w-dependence of the cross section for the p(e, e′k+)Λ reaction integrated over backward-going k+ [ ]. backward hemisphere (see fig. ), one sees an additional unexpected structure. a detailed analysis shows that the angular distribution can be fit nicely with the addition of a new p state at mev with a width Γ = mev to the known d ( ) and d ( ) states. intriguingly, a p state at mev is consistent with the symmetric quark model and su( ) × o( ) symmetry, but is incon- sistent with diquark-quark symmetry. i feel obliged to bring you up to date on the penta- quark (or lack thereof). there was a great deal of excite- ment for a while about what appeared to be evidence for a -quark state. there have three experiments at jlab pushing to substantially higher statistics, both in the γp and the γd channel, and for virtual photons as well. no evidence for a -quark state has been found in the first analyses of these new data. . what is the qcd basis for the spin structure of the hadrons? in addition to the investigation of the spatial distributions of charge and magnetization in the nucleon and its excited state spectrum, the third important experimental focus is the nucleon’s spin structure. the first thing to look at is the spin structure function of the valence quarks at high- x. the data for the proton was reasonable; the new clas data with somewhat tighter error bars are confirming the old results and improving the overall accuracy. there were no data of any statistical significance for the neutron above an x of . . the he experiment at jlab has provided three new data points (see fig. ). the new data, when folded into a global analysis of the parton distribution functions (pdf), show that the theoretical prejudices used in earlier analyses were wrong; in particular we now know that ∆d/d stays negative at high x. one can make predictions with a minimum of theoret- ical prejudice for the integrals of the spin structure func- tions at the two extremes of distance scales. in the limit of extremely small distances (i.e. for q → ∞), assuming only isospin symmetry and current algebra (or the opera- tor product expansion within qcd), bjorken showed that . . . . x . . . . . - . - . e ( he) jlab e - ( he) e ( he) hermes ( he)a n a p c q m ( is gu r) p q c d f it w ith h h c (l e a d e r e t a l.) statistical model (soffer et al.) pq c d fi t w /o h h c (l ea de r e t a l.) c h ira l s o lit o n ( w e ig e l e t a l.) b a g m o d e l (t h o m a s a t a l. ) x hf perturbed qm world data parm q = gev symmetric q wave function helicity / suppression spin / suppression su( ) pqcd . . . . . . . . . . clas-eb b q = . - . gev hermes smc slac - e slac - e fig. . (left) spin structure function of the neutron, an , derived from he data [ ]; and (right) spin structure function of the proton a p [ ]. fig. . gdh integral as a function of the upper limit νmax [ ]. the difference between the proton and the neutron inte- grals is related to the neutron β-decay coupling constant, with a small q dependent correction due to the running of the coupling constant. for very large distance scales (i.e. for q → ), there is a slightly less rigorous set of assumptions (lorentz in- variance, gauge invariance, unitarity, and the dispersion relation applied to the forward compton amplitude) that can be used to show that the difference between the helic- ity and total cross sections is related to the nucleon anomalous magnetic moment (this is the gdh sum rule). there has been a lovely set of data taken at elsa and mami that have determined the gdh integral as a function of the upper photon energy integration limit (see fig. ). the experiments were technically challeng- ing [ ], requiring the combination of polarized electrons, a polarized target, and large-acceptance detectors. theo- retical analysis and interpretation of these data show that the gdh sum rule is satisfied at the % level. the effort has also provided us with a better understanding of the physics of the reactions contributing to the integral. these data, and the precision with which they have defined the gdh integral at the photon point, provide the foundation for our studies of the q evolution of the moment of the nucleon’s spin structure functions. as one looks at the evolution of the moment of the proton spin structure function with q , one expects to see the european physical journal a q (gev ) Γ p ( n o e la st ic ) clas eg a slac e clas eg b hermes - . . . . . . . . . . . . fig. . integral of the spin structure function of the proton as a function of q [ ]. . . Γ p -n . . . . . . . q (gev/c) . fig. . bjorken integral (proton-neutron difference) as a function of q . the grey band shows the evolution of αeff(q ) predicted by pqcd [ ]. the anomalous magnetic moment of the proton in the long wavelength limit, whereas at infinite q the bjorken sum rule is valid. in the regime close to the long wavelength limit, chiral perturbation theory (χpt) allows us to make predictions. the transition between the two extremes is an important piece of information on how the nucleon is put together, and how nucleon structure emerges from the parton soup. we have data now, mainly from jlab, on the evolu- tion of the structure function’s integral for the proton (see fig. ) and the neutron approaching the gdh sum rule limit at q = , and approaching the bjorken limit at a surprisingly low momentum transfer of about (gev/c) . several experiments at jlab are investigating the region q (gev) α s( q )/ π α s,g / π world data α s,τ / π opal burkert-ioffe pqcd evol. eq. α s,g / π jlab α s,f / π gdh constraint . . . - fig. . effective strong-coupling constant as a function of q derived from the q -dependence of the bjorken integral [ ]. of very low momentum transfer with high precision to test the predictions of χpt. the first significant measurement of the q -depen- dence of the bjorken integral (see fig. ) was made for q = ( . − . ) (gev/c) . remarkably, pqcd-based q evolution matches the data down to a q of about . (gev/c) . deur et al. [ ] have made an interesting in- terpretation of the q -dependence of the bjorken integral in terms of an effective strong-coupling constant αef f (q ) (see fig. ). again, there is evidence for a transition oc- curring around q = (gev/c) . explore the limits of our understanding of nuclear structure as described above, experiments at jefferson lab are pro- viding essential new insights into nucleon structure. in a very similar way, the precision, spatial resolution, and in- terpretability of experiments performed using electromag- netic probes are being used to address long-standing issues in nuclear physics, including specifically nucleon-nucleon correlations and the identification of the limits of our un- derstanding of finite nuclei. . correlations in nuclei nucleon-nucleon correlations have been a subject of great interest since the beginnings of the field. in his fabled “bible” on nuclear physics, hans bethe estimated that these correlations should be of scale a third of what one observes in nuclear physics, and indeed they are. however, finding clear, interpretable evidence for these correlations has been a real challenge to experimentalists. the previous generation of (e,e′p) experiments car- ried out at saclay, nikhef, and mainz explored the spectral function strength for low-lying shells. only about / of the strength anticipated from a simple shell model was found. however, the interpretability of these measure- ments was limited by the uncertainties introduced by the l.s. cardman: physics at the thomas jefferson national accelerator facility a) b) x b c) . . r( f e / h e ) r( c / h e ) r( h e / h e ) fig. . ratio of inelastic scattering cross sections off nuclei relative to he as a function of bjorken-x [ ]. corrections necessary for the final-state interactions of the knocked-out protons. a new approach to nucleon-nucleon correlations avoids this problem by comparing the ratio of inelastic electron scattering off he, c, and fe to he in a kinematical regime where the scattering is basically from the quarks within the nucleons, and the scattering from the nucleons as coherent objects is highly suppressed. these data (see fig. ) tell us that at any given moment the number of cor- related nucleons in he, c, and fe is ∼ . , ∼ . , and ∼ . , respectively. so about % of the time a nucleon is involved in a nucleon-nucleon correlation. the measure- ments further show that three-nucleon correlations are clearly present (at x > ), and about an order of mag- nitude smaller than two-nucleon correlations. another approach [ ] to the study of correlations is to search explicitly for the strength that was identified as “missing” in the last generation of (e,e′p) experiments. we are using the (e,e′p) reaction at high momentum transfers and high missing energies, a region that was simply not accessible at the lower-energy, high duty-factor facilities previously available. the missing strength was, indeed, found (see fig. ), and agrees rougly with the predictions of correlated basis function theory (although the mo- mentum distribution is not described correctly in detail). in a third study correlated pairs have been measured directly in the he(e,e′pp)n reaction. in this experiment, the absorption of the virtual photon kicks out a proton, and the opening angle of the remaining pair shows a back- to-back peak. one can infer from the data the shape of the pair momentum distribution. similar, though somewhat less direct, information can be obtained from examining the he(e,e′p)x reaction at very high missing momentum. significant strength above what is predicted by pwia has been observed (see fig. ). the quantitative understanding of the results is work in progress. . . . e m (gev) e- e- e- e- e- e ( s m p , m v e m [ ) - r s - ] p m (g ev /c) . . . experiment correlated basis function theory fig. . spectral function for (e, e′p) at high momentum trans- fer and high missing energy [ ]. fig. . effective nucleon density for the he(e, e′p)x reaction as a function of missing momentum. bbu stands for two-body breakup [ ]. . the limits of our understanding of finite nuclei one of the key issues that motivated the construction of cebaf was our desire to gain insight into the ques- tion of where the description of nuclei based on nucleon and meson degrees of freedom fails and the underlying quark degrees-of-freedom must be taken into account. data on the elastic scattering from the deuteron and high- energy photodisintegration, together with accurate theo- retical calculations, are providing the answers. we begin with the elastic scattering form factors for the deuteron. the theory is in an advanced state: we use the best ab initio calculation of the structure of the deuteron with a potential vn n determined from a fit to n-n phase shifts, and then add exchange currents and rel- ativistic corrections. the data set for the deuteron elastic form factors demonstrate the technical accomplishments of modern accelerators and equipment: elastic e-d scat- tering has been measured down to cross sections charac- teristic of ν-scattering! the data for the electric and the magnetic form fac- tors, and for the tensor polarization (see fig. ) demon- strate that conventional nuclear theory works up to q of the european physical journal a q (gev ) - - - - - - - - - previous data hall a hall c mmd, s , d mmd, , d forest and schiavilla, ia forest and schiavilla, ia+pair a(q ) . . . . . . q (gev ) - - - - - - - - - b(q ) previous data mmd, s , d mmd, , d forest and schiavilla, ia hall a . . . . . q (gev ) - . - . - . . . . vepp bates vepp bates nikhef nikhef jlab/polder mmd, s , d mmd, , d forest and schiavilla, ia forest and schiavilla, t (q ) ia+pair fig. . electric and magnetic form factors of the deuteron (top panels) and the deuteron tensor polarization (lower left) together with the intrinsic shape of the deuteron inferred from these data (lower right) (adapted from [ ]). about (gev/c) , i.e. the nucleon-based picture is still valid at distance scales of about one half the size of a nu- cleon. why, we do not know; none of us expected it to work that well before the experiments were undertaken. the shape of the deuteron derived from the form fac- tor data is also shown in fig. ; one can see clearly that the nucleon spins are aligned “end-to-end” (resulting in a “dumbell”-shaped distribution) rather than anti-parallel (which would have yielded a “donut” shape). the photodisintegration of the deuteron was one of the first experiments done in nuclear physics (at ener- gies of only a few mev) and also one of the most re- cent ones (now at energies approaching gev). the reac- tion probes internal nucleon momenta well beyond those accessible in electron scattering because of the momen- tum mismatch between the photon and the nucleon. in a parton-based description of the reaction, one expects the cross section to scale like s− , where s is the cm energy squared. the data (see fig. ) demonstrate that s− scaling of the cross section is reached at photon en- ergies which change with the proton center-of-mass angle. the transition occurs consistently at a transverse momen- tum of about ( . − . ) gev/c, which shows that below ∼ . fm the nucleon-meson description of the deuteron is no longer valid, and a parton-based description is more appropriate. a more recent experiment [ ] using clas has extended these data to include angular distributions for a broad range of energies; the data is described by a quark-gluon string model. conventional nuclear theory fig. . cross sections for deuteron photodisintegration. the energies associated with a transverse momentum of . gev/c are indicated with a blue arrow in each panel [ ]. summary the cebaf accelerator at jlab is fulfilling its scientific mission to understand how hadrons are constructed from the quarks and gluons of qcd, to understand the qcd basis for the nucleon-nucleon force, and to explore the transition from the nucleon-meson to a qcd description. its success is based on the firm foundation of exper- imental and theoretical techniques developed world-wide over the past few decades, on complementary data pro- vided by essential lower-energy facilities, such as mami, and on the many insights provided by the scientists we are gathered here to honor. it is a pleasure to acknowledge the assistance of bernhard mecking in the development of this article, and thoughtful com- ments on the manuscript from volker burkert, kees de jager, john domingo, and rolf ent. this work has been supported through the southeastern universities research association, inc., which operates the thomas jefferson national accelera- tor facility under contract no. de-ac - with the u.s. department of energy. references . c. hyde-wright, c.w. de jager, annu. rev. nucl. part. sci. , ( ) and references therein. . j. friedrich, t. walcher, eur. phys. j. a , ( ). . j.j. kelly, aip conf. proc. , ( ). . t.m. ito et al., phys. rev. lett. , ( ). . d.t. spayde et al., phys. lett. b , ( ). . f.e. maas et al., phys. rev. lett. , ( ). . f.e. maas et al., phys. rev. lett. , ( ). . f. maas, these proceedings. l.s. cardman: physics at the thomas jefferson national accelerator facility . k.a. aniol et al., phys. rev. lett. , ( ). . k.a. aniol et al., phys. lett. b , ( ). . k.a. aniol et al., phys. lett. b , ( ). . k.a. aniol et al., phys. rev. c , ( ). . d.s. armstrong et al., phys. rev. lett. , ( ). . t. horn, private communication for the fπ collaboration. . v.d. burkert, eur. phys. j. a , ( ). . l.c. smith, invited talk, japan-us workshop on electro- magnetic meson production and chiral dynamics, osaka, japan (april ). . clas collaboration (v.d. burkert), int. j. mod. phys a , ( ). . i. aznauryan talk at n* , tallahasse, fl (october ), to be published. . x. zheng et al., phy. rev. lett. , ( ). . clas collaboration (k.v. dharmawardane et al.), sub- mitted to phys. rev. lett. ( ). . a. thomas, these proceedings. . a. deur, th int. workshop on deep inelastic scattering (dis ), aip conf. proc. , ( ). . a. deur, v. burkert, j.p. chen, w. korsch, arxiv:hep- ph/ . . k. egiyan et al., phys. rev. lett. , ( ). . d. rohe et al., phys. rev. lett. , ( ). . f. benmokhtar et al., phys. rev. lett. , ( ). . m. garçon, j.w. van orden, adv. nucl. phys. , ( ) and references therein. . m. mirazita et al., phys. rev. c , ( ). . e.l. schulte et al., phys. rev. lett. , ( ). 	personal comments 	research at jefferson laboratory 	how are the nucleons made from quarks and glue? 	what are the spatial distributions of the ensuremath {u}, ensuremath {d}, and ensuremath {s} quarks in the hadrons? 	what is the excited state spectrum of the hadrons? 	what is the qcd basis for the spin structure of the hadrons? 	explore the limits of our understanding of nuclear structure 	correlations in nuclei 	the limits of our understanding of finite nuclei 	summary proc. natl. acad. sci. usa vol. , pp. – , march medical sciences prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis d. craig hooper*, omar bagasra†, joseph c. marini*, anna zborek‡, s. tsuyoshi ohnishi§, rhonda kean*, jean m. champion*, ashit b. sarker†, lisa bobroski†, john l. farber¶, takaaki akaikei, hiroshi maedai, and hilary koprowski* *center for neurovirology, department of microbiology and immunology, dorrance h. hamilton laboratories, section of molecular virology, division of infectious diseases, and †departments of medicine and ¶pathology, thomas jefferson university, philadelphia, pa ; ‡instytut onkologii, zaklad biologii nowotworow, – gliwice, poland; §philadelphia biomedical research institute, king of prussia, pa ; and idepartment of microbiology, kumamoto university school of medicine, kumamoto , japan contributed by hilary koprowski, december , abstract in this study we provide further evidence associating activated cells of the monocyte lineage with the lesions of multiple sclerosis (ms). using a combination of immunohistochemistry and reverse transcriptase-dependent in situ polymerase chain reaction analysis, we have identified monocytes expressing inducible nitric oxide synthase (inos) tobeprevalent in theplaqueareasofpostmortembraintissue frompatientswithms.inaddition,wehaveobtainedevidence of the nitration of tyrosine residues in brain areas local to accumulations of inos-positive cells. in parallel studies we have assessed the effects of inhibitors of inos induction, as well as scavengers of nitric oxide and peroxynitrite in the experimental allergic encephalomyelitis model. significant therapeutic effects were seen with the inhibitor of inos induction, tricyclodecan- -xyl-xanthogenate, a nitric oxide scavenger, -phenyl- , , , -tetramethylimidazoline- -oxyl- - oxide, and a peroxynitrite scavenger, uric acid. in particular, treatment with high doses of uric acid virtually prevented clinical symptoms of the disease. together with our demon- stration of the presence of activated macrophages expressing high levelsof inosandevidenceofperoxynitrite formation in brain tissue from patients with ms, these findings are of importance in the development of approaches to treat this disease. evidence for the activation of the enzyme (inos) responsible for the production of the free radical nitric oxide (no) in an immuneresponseand the releaseofnoin thecentralnervous systems (cns) of animals with experimental allergic enceph- alomyelitis (eae) or viral encephalomyelitis ( – ) has led to further study of the role of no and its products in cns pathology. convincing evidence for the involvement of no overproduction in the pathogenesis of eae comes from studies that have correlated spinal cord and brain no levels with clinical symptoms in animals with eae ( , ). the relevance of these animal studies to multiple sclerosis (ms) is emphasized by the fact that high levels of mrna specific for inoscanbeobserved inbrain lesions frommspatients ( , ). in this case, therehasasyetbeennoconsensusas to thenature of the inos-positive cells with either cells of the monocyte lineage or astrocytes being implicated by different studies ( , ).todeterminemore specifically thenatureandoriginof the activated cells expressing inos in the ms brain we have expanded our analysis of ms brain tissue specimens using a refined combination of immunohistochemistry and reverse transcriptase in situ pcr (rt-is-pcr). several possibilities exist regarding the nature of no in- volvement in the pathogenesis of cns lesions. a variety of destructive effects have been postulated, both through direct interaction with cell surface and internal molecules ( ) and through chemical interactions with oxygen species, such as superoxide (o ), to form other potentially more toxic inter- mediates ( , ). one of these, peroxynitrite (onoo ), the reaction product of no and superoxide, is a potent oxidant ( ), which can be formed in an inflammatory response and cancauseavarietyof toxiceffects, including lipidperoxidation ( ) and tyrosine nitration ( ). it has therefore been sug- gested that peroxynitrite may be responsible for a significant proportion of the damage attributed to no. thus, peroxyni- trite may be an important factor in the generation of cns lesions. indeed, in a previous study we found evidence of tyrosine nitration in the brain tissue of ms patients ( ). to further clarify the direct or indirect role of no and peroxyni- trite in thepathogenesisofcns lesions,weanalyzed theeffect of substances thought to inhibit inos activation or to selec- tively scavengenoorperoxynitriteon thedevelopmentof the clinical symptoms of eae in an acute model. materials and methods brain tissue specimens. brain tissue was obtained post mortem from patients who had suffered with ms for at least years.brain tissuewasremovedwithin hrofdeathduring autopsy at thomas jefferson university and areas with and withoutplaqueswere immediately frozenondry iceandstored at c until use. the diagnoses of ms, based on clinical presentation, were confirmed by the post mortem histopatho- logical examination of brain tissues. all ms brains were found to contain pathognomonic ms plaques. in most cases autopsy sampleswereof frontal lobes,whichprovidedmixedwhiteand gray matter. immunohistochemistry and rt-is-pcr. to define cell types positive for inos mrna expression in frozen brain sections, immunohistochemistry was performed in conjunc- tionwithrt-is-pcrasdescribed( , ).stainingwascarried out with a variety of antibodies and lectins: (i) cells of the macrophageymicroglia cell lineage were identified with rho- damine-conjugatedricinus communisagglutinin (rca- ) lec- tin (sigma), which specifically binds these cells ( ); (ii) the publication costs of this article were defrayed in part by page charge payment. this article must therefore be hereby marked ‘‘advertisement’’ in accordance with u.s.c. § solely to indicate this fact. copyright q by the national academy of sciences of the usa - y y - $ . y pnas is available online at http:yywww.pnas.org. abbreviations: ms, multiple sclerosis; no, nitric oxide; eae, exper- imental allergic encephalomyelitis; rt-is-pcr, reverse transcriptase in situ pcr; inos, inducible nitric oxide synthase; cns, central nervous system; c-ptio, -phenyl- , , , -tetramethylimidazoline- - oxyl- -oxide; d , tricyclodecan- -xyl-xanthogenate; gfap, glial fibrillary acidic protein; vwf, von willebrand factor. d o w n lo a d e d a t c a rn e g ie m e llo n u n iv e rs ity o n a p ri l , microvascular endothelial cells were distinguished with poly- clonal antibodies specific for von willebrand factor (vwf; factor viii-related antigen), which is expressed in the cyto- plasm of human endothelial cells (sigma) ( ); (iii) astrocytes were identified using polyclonal antibodies against glial fibril- lary acidic protein (gfap) ( ); (iv) oligodendrocytes were stained with monoclonal antibodies to , -cyclic nucleotide- -phosphodiesterase (cnpase; sigma), which is specifically expressed in oligodendrocytes and schwann cells ( ); and (v) neurons were identified with a cocktail of three monoclonal antibodies (nf , nf , and nf ), which bind three different neurofilament epitopes ( ). antibodies to nitroty- rosine were purchased from upstate biotechnology (lake placid, ny). the gfap- and neurofilament-specific antibod- ies employed were kind gifts from john trojanowski (univer- sity of pennsylvania). all of the primary antibodies used in these studies were unconjugated and developed using appro- priate rhodamine-labeled secondary antibodies (sigma). the product of rt-is-pcr for inos mrna was identified by hybridization with a fluorescein isothiocyanate-conjugated oligonucleotide probe specific for the inos-amplified se- quence ( -mer oligonucleotide: -aacattgctgtgat- ccatagtftrc- ).using this approach,examinationwitha fluorescent microscope usually reveals cytoplasmic staining fig. . identification of cells expressing inos mrna in ms brain tissue. as described, sections from ms brain were concurrently stained with rt-is-pcr for inos mrna (green) and a panel of cell-specific reagents (redyorange). the sections were photographed through a fluorescent microscope at a magnification of using dual filters for orange and green fluorescence. (a) this section, from the region of a plaque, was stained for inos mrna (green) and rca- (orange). (b) a similar section was stained for inos mrna (green) and vwf (yellowyorange). (c) asimilar sectionwas stained for inosmrna(green)andneurofilamentantigensusingacocktailof threedistinctmonoclonalantibodies (orange). (d) this section, again from the vicinity of aplaque,was stained for inosmrna(green) andcnpase (orange). (e–h)different viewsof a single sectionstained for inosmrna(green), aswell asgfap(orange):e, thecenterof theplaque;f, theedgeof theplaque;g, mmfromtheplaque; h, mm from the plaque. medical sciences: hooper et al. proc. natl. acad. sci. usa ( ) d o w n lo a d e d a t c a rn e g ie m e llo n u n iv e rs ity o n a p ri l , for mrna versus nuclear staining for dna ( ). at least , cells per stain combination were examined for the immunohistochemistry and mrna signals. inductionofacuteeae.six- to -week-oldswxj- female mice were purchased from the jackson laboratory. for most experiments, – mice were included per treatment group or time point for analysis. eae was elicited by immunizing mice subcutaneously at two sites on days and with complete freund’s adjuvant and mg of the peptide plp – (plp; hslgkwlghpdkf) derived from the sequence of proteolipid protein, a major component of myelin. plp was synthesized by the peptide synthesis facility of the kimmel cancer center, thomas jefferson university. this immuniza- tionprotocol results inaprogressive,often fatal, formofacute eae in female swxj- mice ( , ). clinical symptoms in these mice manifest first as an ascending paralysis approxi- mately days after immunization, with rapid disease pro- gression until death at days – . the clinical signs of eae werescoredas: (i)piloerection, tailweakness; (ii) tailparalysis; (iii) tail paralysis plus hind limb weaknessyparalysis; (iv) tail, hind and fore limb paralysis; (v) moribund. no measurement. semiquantitative measurement of no levels in thebrain and spinal cordof control andexperimental animals was performed as described ( ). briefly, no was spin-trapped invivousingdiethyldithiocarbamate(detc)and iron administered subcutaneously at two separate sites. mice were euthanized min later, and spinal cord and brain tissue were snap-frozen for analysis by electron paramagnetic reso- nance(epr)spectroscopy.noconcentrationswereestimated from epr spectra using a calibration curve obtained as described ( ). treatment of acute eae. to test their action in the treat- ment of the development of acute eae, the compounds of interest were administered i.p. in pbs beginning on day or afterplpimmunization.administrationwascontinueddaily until at least days after all untreated plp-immunized mice became severely paralyzed. tricyclodecan- -yl-xanthogenate (d ) inhibits inos induction by blocking the activity of phosphatidylcholine-specificphospholipasec,akeyenzymein the signal transduction pathway leading to inos activation ( ). mice were given mg of d (biomol, plymouth meeting, pa), a dose which was selected as one-half the amount suspected to have toxicity based on in vitro experi- ments. a water soluble, carboxylated derivative of -phenyl- , , , -tetramethylimidazoline- -oxyl- -oxide (c-ptio) was used as a no scavenger in a dose range proven to be effective in the treatment of endotoxic shock in mice, apparently through the reductionofnolevels ( , ).c-ptio(dojindo chemical, bethesda) was administered at the doses indicated in the figure legends. uric acid ( , , -trihydroxypurine) was used to target peroxynitrite, based on evidence for its per- oxynitrite scavenging activity ( ) and its low level of toxicity as a natural product of purine metabolism in vivo. uric acid, which is poorly soluble in water, was administered as a suspension in anarbitrarily determineddose range as detailed in the figure legends. results identificationofcellsexpressing inosmrnainmsbrain tissue. in figs. and , cells in sections of brain tissue from ms patients have been double-labeled with rt-is-pcr for inos mrna (green fluorescein isothiocyanate probe) and antibodies specific for selective cell surface markers (orange stains). in fig. a, the cells staining positively for inos- specific mrna (green) are also stained with rca- (red), a lectin specific for cells of the monocyte lineage, the double stain appearing as patchy yellow. fig. b shows that cells stainedgreen for inos-specificmrnaareclearlydistinguish- able from those that stain with antibodies to vwf (yellowy orange) specific for endothelial cells. fig. c, reveals that neurons and neuronal processes, identified by staining with a cocktail of three monoclonal anti-neurofilament antibodies (nf) (orange), are negative for inos mrna (green), which is evident in other cells in the field. in fig. d, oligodendro- cytes stained with anti-cnpase antibody (orange) are distin- guished from cells identified as inos mrna-positive cells (green). expression of inos mrna in plaque versus nonplaque areas of ms brain. if local production of no is central to the pathogenesisofmsasappears tobethecase ineae( ), itmay beexpected thatareascontainingplaques inmsbrain sections should exhibit higher accumulations of inos mrna-positive cells thanareaswithoutpathology.asshowninfig. e–h, this appears to be the case. fig. e shows an ms plaque area with large numbers of cells resembling monocytes stained green after rt-is-pcr for inos. massive destruction of astrocytic processes (stained orange with antibodies for the astrocyte- specific marker gfap) is apparent. notably, none of the cells positive for inos mrna reacted with the gfap-specific reagent.fig. f is aphotographof the samems-positivebrain section taken at the edge of the ms plaque, showing partial tissue destruction. the astrocytic processes are positive for gfap (orange) and clearly distinct from the cells staining for inos-specific mrna (green). in fig. g, the same ms brain section is shown mmaway fromaplaque.onlya single inos mrna-positive cell (green) can be seen in this area, among a number of intact astrocytic processes stained with anti-gfap (orange). infig. h, a viewof the same section fromthe same ms brain, taken mm away from a plaque, is shown. at this fig. . identification of inos mrna-positive mononuclear cells in the lumen of a blood vessel in the vicinity of an ms plaque (a) and the association of inos mrna-positive cells with accumulations of nitrotyrosine in an ms plaque (b). (a) a brain section containing an ms plaque was stainedwith antibody to vwf(yellowyorange) andwithrt-is-pcrusinga fluorescein isothiocyanate-labeledprobe specific for inosmrna (green). (b) asectionof anmsplaquewas stained for inoswithrt-is-pcr(green)andantibodies tonitrotyrosine.the sectionswereprepared, stained, andvisualizedasdescribed inmaterials andmethodsand the legend tofig. .the image inawasphotographically enlargedapproximately . medical sciences: hooper et al. proc. natl. acad. sci. usa ( ) d o w n lo a d e d a t c a rn e g ie m e llo n u n iv e rs ity o n a p ri l , distance from the plaque, astrocytes stained with anti-gfap antibodies (orange) show no signs of damage and no inos mrna-positive cells are present. fig. a shows a blood vessel from a ms plaque containing inos mrna-positive mononuclear cells (green), evidently adherent to the luminal surface of the vessel (stained yellowy orange with antibody to vwf). careful microscopic examina- tion of the slide showed evidence of possible infiltration by diapedesis of the inos-positive cell through the vascular endotheliumintothebraintissue(arrows). infig. b, a section of an ms plaque area exhibiting monocytes positive for inos mrna (green) and accumulations of cell debris positive for nitrotyrosine residues (yellow) is shown. effect of an inhibitor of inos induction, d , on eae. clinical symptoms of eae in swxj- mice immunized with plp failed todevelop inparallelwithuntreated controlswhen themicewere treateddailywith mgofd beginning days after plp immunization and terminating on day after immunization (fig. ). twenty-four hours after concluding treatment, the first clinical signs of eae developed, progress- ing into significant disease over the next few days (fig. ). effect of the no scavenger ptio on eae. daily treatment witha singledoseof c-ptio( mgykg) fromdays – after plp immunization caused a delay in the onset and inhibited theprogressionof the clinical signs ofeae(fig. ).however, at this level of treatment, disease eventually developed (fig. a).administrationof thesameamountofc-ptiotwicedaily had a more profound therapeutic effect on the plp- immunizedmice, delaying theonsetof clinicaleaebyat least days (fig. b). when c-ptio treatment was terminated days after immunization the control mice were extensively paralyzed, whereas the treated animals exhibited only tail weakness and piloerection (fig. b). assessment of no levels in the brains and spinal cords of the mice day afterwards, revealed that spinal cord no was only marginally lower in c-ptio-treatedversusuntreatedmice (fig. ). incontrast, the level of no in brain tissue of c-ptio-treated mice was considerably lower than those of the untreated mice (fig. ). effect of the peroxynitrite scavenger uric acid on eae. analysis of swxj- mice treated with different doses of uric acid beginning days after plp immunization and continuing through day showed that as little as one dose of mg per day of uric acid can delay the onset of clinical signs of eae (fig. ). moreover, a daily dose of mg of uric acid completely protected the mice, whereas all the controls be- came severely paralyzed. as detailed in table , on the th dayafterplpimmunization,nolevels in thebrainsandspinal cords of mice treated with uric acid were significantly higher, like their untreated plp-immunized counterparts, than those of nonimmunized controls. nevertheless, three out of four of the uric acid-treated mice showed no signs of disease. fig. . effect of d on the development of eae in swxj- mice. swxj- mice were immunized with plp as described. mice were either left untreated (l) or treated with mg of d (m) daily from days through after immunization (arrow). severity scores were graded and are presented as a mean. fig. . effect of administration of c-ptio on eae in swxj- mice. four days after immunization with plp, swxj- mice were either left untreated (l) or treated (m) either once (a) or twice (b) daily with mg c-ptio. in both cases, treatment was continued until day after immunization (arrows). severity scores were graded and are expressed as a mean. fig. . effectofdailyadministrationofc-ptioonnolevels inbrain andspinalcordofswxj- miceimmunizedwithplp.nolevelsinbrain and spinal cords of the swxj- mice described in fig. a were semiquantitated using spin-trapping with detc and epr spectroscopy at day after immunization with plp and are presented as a mean. medical sciences: hooper et al. proc. natl. acad. sci. usa ( ) d o w n lo a d e d a t c a rn e g ie m e llo n u n iv e rs ity o n a p ri l , discussion our concurrent analysis of tissue sections from the brains of ms patients with rt-is-pcr for inos mrna and a battery of stains for subsets of cns resident or infiltrating cells demonstrated that cells expressing inos message also stained with rca- lectin, which selectively binds to cells of the monocyte lineage. stains for astrocytes, neurons, oligoden- drocytes, schwann cells, and endothelial cells were not found to react with the inos mrna-positive cells. cells positive for inos mrna were concentrated in regions immediately sur- rounding the ms plaque areas of extensive damage to white matter andadiminishing gradient of positives andevidenceof damage to astrocytes could be seen at increasing distances from the plaques. regions further removed ( mm) from plaques contained few if any inos mrna-positive cells and little evidence of the destruction of astrocytes. furthermore, nitration of tyrosine was evident in the vicinity of plaques implicating peroxynitrite in the pathogenesis of the lesions. while our reagents were unable to distinguish between monocyteymacrophages and glial cells, it is important to note that we observed cells positive for inos mrna either in the lumen of blood vessels or apparently adherent to the vascular endothelium in sections from ms brain. the apparent emer- gence of inos-positive cells from the blood vessel in the ms-plaque area indicates the likelihood that these are mono- cytes that have been activated in peripheral lymphoid tissues prior to infiltrating into the brain. in eae animal models, inhibition of the induction of inos hasbeen successfullyused for treatmentof clinical disease ( ). d indirectly suppresses severalbiologicalprocesses, includ- ing inos activation and tumor necrosis factor-a-induced apoptosis, by inhibiting the activation of phosphatidylcholine- specificphospholipasec,anenzyme involved in theregulation of the promoter nf-kb ( ). in our hands, plp-immunized swxj- did not develop eae while under treatment with mgofd (fig. ).clinical signsofeaeappeared hrafter discontinuing d . because the dosage of d was chosen more or less arbitrarily, it is possible that a higher dose or prolonged treatment may have a more lasting effect. alterna- tively, d -insensitive pathways leading to the formation of active inos may exist (e.g., ref. ). in the latter case, a scavenger of no, like c-ptio, would be expected to be more effective. indeed, c-ptio had significant effects on the development and severity of the clinical signs of eae in our experiments. the therapeutic action of c-ptio was improved by more frequent administration (fig. b) as expected based on the short biological half-life of c-ptio in the blood of experimen- tal animals. in fact, it has been reported that % of the c-ptio administered to mice is excreted within . hr ( ), raising the possibility that the therapeutic effects of c-ptio seen in this study might not entirely depend on its continued presence in vivo. the finding that no levels in the brains of plp-immunizedmice treatedwithc-ptioremainmuch lower than those in spinal cord evidently suggest that the clinical signsofeae, in thismodel,maybeassociatedwithhigh levels of no in brain rather than spinal cord (fig. ). even though c-ptiomayhaveaneffect on theotherbiological rolesofno in the nervous and circulatory systems ( , ), its strong therapeutic effect in eae was without notable side effects. we have found that treatment with uric acid, a known scavenger of peroxynitrite, can virtually block clinical disease in swxj- mice. the fact that mice remain healthy when treatedwithuricaciddespitehavingelevatednolevels intheir brains and spinal cords provides evidence for the assumption that no derivatives may be more toxic in eae than no itself. becauseuric acid is highly insoluble in aqueous solutions ( ), a significant proportion of the uric acid administered i.p. as a suspension in pbs accumulated in the peritoneum. it was therefore difficult for us to accurately determine the effective therapeutic dose. in the future, analysis of serum uric acid levels will be used to shed more light on this problem. since, in contrast to man, mice metabolize uric acid in an additional step to allantoin ( ), it is conceivable that this compound, although not known to be a free radical scavenger, may be the protective molecule rather than uric acid. however, based on its knownperoxynitrite binding activity,we speculate that uric acid is the active protective molecule in the mouse eae system. in this investigation we have shown that treatment with an inhibitor of inos activation and scavengers of no and per- fig. . effectof theadministrationof variousdosesofuric acidon the development of eae in swxj- mice. beginning on day after immunizationwithplp,swxj- micewereeither leftuntreated(l) or treated once daily with either mg (d), mg (å), mg (f), or mg(m)ofuricacidgiven i.p.treatmentwas terminatedonday after immunization. severity scores were graded and are expressed as a mean. table . effect of administration of uric acid on brain and spinal cord no levels in eae no. plp* uric acid treatment clinical severity no brain, mm no spinal cord, mm no none ; ; no none . . yes none . . yes none . . yes mgyday . . yes mgyday . . yes mgyday . . yes mgyday . . *swxj- mice, immunized with plp as detailed in materials and methods, were treated once daily with or mg of uric acid i.p. at day after immunization, clinical severity was scored and no levels in brain and spinal cord were assessed by epr as described. medical sciences: hooper et al. proc. natl. acad. sci. usa ( ) d o w n lo a d e d a t c a rn e g ie m e llo n u n iv e rs ity o n a p ri l , oxynitrite are effective inpreventing thedevelopmentofeae in an acute model. if these substances all function mechanis- tically as believed, they should also be effective in the treat- ment of chronic recurrent eae. we are now investigating the mode of action of d , c-ptio, and uric acid in mice with chronic recurrent eae. if treatment is successful under these circumstances,onemayconsider theuseof these substances in the therapy of chronic degenerative cns diseases of humans such as ms. thefactors involvedintheformationofplaques inthebrains ofmspatientshavebeenhithertounknown.ourdata strongly suggest that activated macrophages are causing these lesions through the production of no and, subsequently, peroxyni- trite. inhibitors of these substancesprovide a strong therapeu- tic effect in eae and, because the inhibitors act at the postinductioneffector stageof thedisease, shouldbeuseful in blocking the development of cns lesions in ms regardless of its etiology. the properties of c-ptio are not as well known as those of the natural compound uric acid, initially isolated in the late th century ( ). in the case of c-ptio, toxicity studies must beperformedbefore further experimentation,whichmay lead to applications in humans. in the case of uric acid, further studies are necessary to clarify our hypothesis that there is a negative association between uric acid on the one hand and peroxynitriteand itspathogenic role inmsontheother.these studies may include a determination of whether abnormalities in the metabolism of uric acid may have some effect on the incidence or course of ms. for instance, a statistical survey of patients with gout for incidence of ms may indicate that hyperuricemia may preclude the development of ms and provide a basis for the extension of our experimental studies to the treatment of ms with uric acid. we thank inglis house (philadelphia) for assisting in the procure- ment of tissue samples, dr. mark curtis (department of neurology, thomasjeffersonuniversity) forpreparationof tissuespecimens, and dr.robertkorngold (departmentofmicrobiology and immunology, thomas jefferson university) for valuable assistance in helping us establish the swxj- eae model. this work was supported by the biotechnology foundation at thomas jefferson university. . lin, r. f., lin, t.-s., tilton, r. g. & cross, a. h. 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( ) biochemistry (worth, new york), appendix a, p. . medical sciences: hooper et al. proc. natl. acad. sci. usa ( ) d o w n lo a d e d a t c a rn e g ie m e llo n u n iv e rs ity o n a p ri l , ppn : development of two instruments to capture ease-of-care outcomes in health-care providers who care for patients treated with pca delivery systems abstracts treatment among occupational injury cases. methods: an analysis of a state-based worker’s compensation claims data captured prescription reimbursement information of all injuries that occurred between january , and december , . payment information was followed over a -month period fol- lowing date of injury. a prescription sequence analysis was carried out to estimate treatment incidence rates of potential addiction due to narcotic analgesic use. results: of the , occupational injury cases, about % (n = ) received at least narcotic analgesic (therapeutic class h a). average length of therapy was days, with % of patients receiving nar- cotic analgesics for greater than days. the majority of nar- cotic prescriptions were for hydrocodone ( %). nine percent of patients received less than four different types of narcotic anal- gesics. from the prescription sequence analysis, we identified cases who received either methadone or clonidine, medications indicated for addiction treatment or detoxification. the inci- dence rate of receiving treatment for narcotic withdrawal or detoxification was per patients on narcotic analgesic therapy ( % ci: . , . ). among patients who received potential detoxification treatment, the median duration from ini- tiation of narcotic analgesic therapy to need for withdrawal or detoxification therapy was days. a cox proportional hazards model identified greater risk of suspected methadone use in oxycontin treated patients compared to other narcotic treated patients (p < . ). conclusions: to our knowledge, this is the first study that estimated the incidence rates of sus- pected addiction treatment due to narcotic analgesics used in the worker’s compensation population using sequential prescription analysis. the study has implications for developing strategies to manage narcotic analgesic prescribing practices and reduce the risk of addiction among injured workers who are narcotic anal- gesic users. pain pain—methods and concepts ppn development of an instrument to capture ease-of- care outcomes in patients treated with pca delivery systems harding g , vallow s , leidy nk , zhang m , olson w , hewitt d , viscusi e medtap international inc, bethesda, md, usa; janssen medical affairs, l.l.c, titusville, nj, afghanistan; ortho-mcneil pharmaceutical inc, raritan, nj, usa; ortho-mcneil pharmaceutical inc; thomas jefferson university department of anesthesiology patient controlled analgesia (pca) is a common method of post- surgical pain management. the extent to which this method is optimal in terms of overall convenience, ease of use, and effec- tiveness of managing pain from a patient’s perspective has not been determined. objectives: to develop a questionnaire to measure “ease-of-care” outcomes from the perspective of patients who use pca delivery systems for post-operative pain management. methods: we conducted qualitative interviews among a convenience sample of patients who had undergone hip or lower abdominal surgery and who received intravenous (iv) pca for their post-operative pain at thomas jefferson uni- versity medical center during june . a content analysis approach was used to identify domains of relevance and gener- ate an item pool. content validation of the draft “ease of care” questionnaire was performed by subjects who participated in the initial interviews. subjects were asked to rate the relevancy of each item on a scale of zero (not at all relevant) to four (highly relevant). each item was assessed for clarity and relevance, and revised as appropriate. cognitive debriefing interviews to evalu- ate patient experiences completing the instrument were conducted with a separate sample of patients from the same institution who completed the questionnaire approximately – hours post-surgery. results: the final patient ease-of-care ques- tionnaire consists of items and covers seven aspects associated with acute care pain management systems: control/self-efficacy, device function, mobility, quality of pain control, confidence, knowledge/understanding, and satisfaction. all items are scored on a -point likert scale. conclusion: we developed an instrument to capture “ease-of-care” outcomes among patients who use pca delivery systems for the management of their acute pain. the instrument is currently being used in clinical trials com- paring two pca delivery systems. psychometric properties of the instrument are currently being evaluated. ppn development of two instruments to capture ease-of-care outcomes in health-care providers who care for patients treated with pca delivery systems harding g , vallow s , leidy nk , zhang m , olson w , hewitt d , polomano r medtap international inc, bethesda, md, usa; janssen medical affairs, l.l.c; ortho-mcneil pharmaceutical, inc; pennsylvania state college of medicine objectives: to develop questionnaires to measure “ease-of- care” outcomes from the perspective of nurses and physical ther- apists who manage the care of patients treated for acute pain with pca delivery systems. methods: we conducted four focus group sessions of – participants to explore nurses’ and physical therapists’ experiences with patients using intravenous (iv) pca during july . a content analysis approach was used to identify general themes and specific issues and concerns associated with “ease of care” using the iv-pca. two item pools were generated for the development of two draft questionnaires, one from the perspective of nurses’ and the other from physical therapists, to address clinical and practical problems encoun- tered in routine care. items were selected based on relevance to the underlying concepts, clarity of item, and the overall flow and comprehensiveness of the instruments. subjects who participated in the focus group sessions also participated in a cognitive debriefing of the draft questionnaires. results: the final nurse and physical therapist ease-of-care questionnaires each consist of items that capture aspects of care delivery associated with acute care pain management systems. all items are scored on a -point likert scale. conclusion: we developed two instru- ments to capture “ease-of-care” outcomes among health-care providers to be used in upcoming studies of alternative pca delivery systems for the management of post-operative pain. the instruments are currently being used in clinical trials comparing two pca delivery systems. results will be used to examine the instruments’ psychometric properties. respiratory diseases/disorders respiratory diseases/disorders—clinical outcomes studies prs evaluation of monotherapy and combination antibiotic treatment regimens for pseudomonas aeruginosa pneumonia angalakuditi m, coley k, rea r university of pittsburgh, pittsburgh, pa, usa int. j. morphol., ( ): - , . a segmental hypoplastic anterior tibial artery coexisting with a hypertrophied perforating fibular artery a case report and clinical implications coexistencia de una arteria tibial anterior hipoplásica segmentaria con una arteria fibular perforante hipertrofiada. reporte de caso e implicancias clínicas olutayo ariyo* ariyo, o. a segmental hypoplastic anterior tibial artery coexisting with an hypertrophied perforating fibular artery a case report and clinical implications. int. j. morphol., ( ): - , . summary: vascular injuries of the lower limb, especially from penetrating gunshot wounds, and peripheral arterial diseases are on the increase and management of these and many other lower limb injuries involve increasing usage of vascular interventions like by-pass surgery, per-cutaneous transluminal angioplasty, arterial cannulation, arterial bypass graft or minimally invasive measures like percutaneous trans-arterial catheterization, among others. a thorough knowledge of infrapopliteal branching most especially their pathways and luminal diameters are important to surgeons in selecting appropriate surgical interventions or procedures. we report the case in which one of the terminal branches of the popliteal artery (ppa), the anterior tibial artery (ata) of good caliber size at origin became hypoplastic in the anterior leg region after giving off numerous muscular branches. continuing as an almost attenuated dorsalis pedis artery (adpa) in the dorsum of the foot, the latter was reinforced by an enlarged hypertrophied fibular artery. this case illustrates yet the importance of the fibular artery as the dominant of the infrapopliteal branching arteries, reinforcing or replacing the posterior tibial artery (pta) when it is weak or absent by a strong communicating branch or, reinforcing a weak ata and dorsalis pedis artery (dpa) by a strong perforating fibular artery as being reported. the pta however travelled a normal course yielding the medial and lateral plantar arteries posterior to the abductor hallucis muscle. this case demonstrates the importance of collateral communications and reinforcements from other infrapopliteal arteries, whenever one of its members or subsequent branches are absent or hypoplastic. a very sound knowledge of the various branching patterns of the ppa can be gained via pre-operatively vascular angiography, designed to guide the surgeon in the selection of appropriate surgical interventions, adding value to patients care in helping to reduce iatrogenic surgical vascular complications and reduction in total number of limb loss. key words: segmental hypoplastic anterior tibial artery; attenuated dorsalis pedis artery; hypertrophied fibular artery; infrapopliteal branching. introduction the popliteal artery is the continuation of the femoral artery beginning from the adductor hiatus. the artery des- cended laterally, crosses the popliteal fossa ending at the distal border of the popliteus where it divides to give the infrapopliteal terminal branches, the anterior tibial artery (ata), the posterior tibial/peroneal trunk (ptpt), the latter in turn gives rise to the peroneal artery about . cm distal to the ata. the latter runs in the fibrous canal between the tibialis posterior muscle and the flexor hallucis longus. embryologically, the sciatic artery is the embryonic vessels that supply the lower limbs. arising from the dorsal root of the umbilical artery, the sciatic runs through the thigh, knee and leg, lying between the tibia and popliteus. a perforating branch that communicates with the femoral artery arises from the distal border of popliteus. this branch called ramus communicans passes ventrally between fibular and the tibia to form the anterior tibial artery (ali & mohajir, ; brantley et al., ). persistent primitive arteria (ppa); segments, abnormal fusions, segmental hypoplasia or the absence of these arteries gave rise to anatomic variability. variations in the pattern of the ppa revolve around the “high division” of that trunk (keen, ) and the resulting differences in the arrangements of its terminal branches. the frequency of occurrence of “high division” of the popliteal artery are . % (poirier & charpy, ), about % (trotter, ), . % (adachi, ), while keen found times in * thomas jefferson medical college, thomas jefferson university, philadelphia, usa. limbs corresponding to %. trifurcation, is a popliteal arterial pattern where all the arteries may arise from the termination of the popliteal at exactly the same level or as long as the point of origin of the peroneal artery is mm or less from the main bifurcation (adachi). sometimes the ppa splits into trunks, an ata/peroneal (fibular) and posterior tibia trunk (ptt). infrapopliteal collaterals do exist between the branches of the major infrapopliteal arteries that do communicate to give vascular supply when one of these branches are weak or absent. such collaterals exist between the pa and the ata via the perforating fibular artery, between the peroneal and pta via a communicating branch. case report during routine academic anatomic dissection at thomas jefferson medical college of thomas jefferson university dissecting facilities, a very careful review of a pre-dissected lower limb by the undergraduate medical students, we observed that in the popliteal fossa, the infrapopliteal vessels were seen to be normal, yielding an initial trunks, a lateral one, which was the trunk to the ata, and a medial one, the posterior tibial and peroneal trunk (ptpt) which branched shortly to give the (pta) fig. . this image shows the anterior tibial artery travelling with the deep fibular nerve in the extensor compartment of the leg. the anterior tibial artery was of a good size proximally, but as it journeys inferiorly, it gives several muscular branches, becoming very hypoplastic. ata= anterior tibial artery, dfn= deep fibular nerve. hata= hypoplastic anterior tibial artery. fig. . this image shows the popliteal artery dividing to give it’s terminal branches, the anterior tibial, and common posterior tibial peroneal trunk which later divided to give fibular/peroneal artery and pos- terior tibia artery. at origin, all vessels including the anterior tibial artery tend to be of good caliber size. ppa= popliteal artery, ata= anterior tibial artery, ptpt= posterior tibial-peroneal trunk, fa/pa= fibular/ (peroneal) artery, pta= posterior tibial artery. and the pa (fig. ). both the pta and pa travelled normally in the posterior leg, the pta travelled with the tibial nerve and distally bifurcated posterior to abductor halluces giving the lateral and medial plantar arteries. the ata however gave several robust muscular branches, became hypoplastic and on the dorsum of the foot. an hypertrophied perforating fibular artery was observed going through the intermuscular membrane to reach the dorsum of the foot (fig. ). we observed the popliteal artery (ppa) ending normally at about the distal border of the popliteus muscle, where it divided to give the ata and a ptpt, and at . cm distal to the ata, this trunk bifurcated yielding an pa laterally and the pta medially. none of the immediate branches of the popliteal artery, ata, pta and pa at origin was hypoplastic (fig. ). the ata was of a good caliber size at origin (about . mm in diameter), passes through the oval aperture in the proximal part of the interosseous membrane to reach the extensor compartment where we observed the ata supplying very prominent muscular branches to muscles in the anterior leg compartment (fig. ). ariyo, o. a segmental hypoplastic anterior tibial artery coexisting with an hypertrophied perforating fibular artery a case report and clinical implications. int. j. morphol., ( ): - , . following the giving off of the muscular branches, the ata became progressively smaller becoming more and more hypoplastic (fig. ), and by the time it crossed the ankle joint, it has become very attenuated and continued as an almost aplastic dorsalis pedis artery (adpa) (fig. ). on the dorsum of the foot, we observed an hypertrophied perforating fibular artery (hpfa) traversing the interosseous membrane to enter the extensor compartment. the hpfa divided into medial and lateral branches (fig. ). the medial branch was the replacement vessel for the dpa while the lateral branch was joined by a small twig from the adpa both skirting regions normally supplied by the arcuate arteries and its branches (fig. ). in the extensor compartment of the leg, we did not observe any muscular abnormalities, and no evidence of wasting or hypertrophy of muscles located on the dorsum of the foot and no evidence of hypertrophy, the deep fibular nerve (dfn) maintained the same relationship with the ata, travelling together anterior to the interosseus membrane, the pta branching pattern was observed normal, bifurcating posterior to the abductor hallucis to give the medial and lateral plantar arteries. neither of the plantar arteries was abnormal in size as observed visually even though the lateral plantar was observed bigger and was the main participant of the deep plantar arch, receiving a communicating branch from the hpfa. the ppa and its infra popliteal branching patterns in the r lower limb were normal. discussion reported variants of the popliteal artery are many. the artery may divide into its terminal branches proximal to popliteus in which case the (ata) sometimes descend anterior to the muscle. the size of the peroneal artery is said to be usually inversely related to the size of the ante- rior and posterior tibial arteries, either of which function the pa may assume (standring, ). variations in the pattern of the ppa revolve around the high division of that trunk. this high division was described as “at a level above the middle of the posterior surface of the popliteus muscle” (adachi). another variant of the popliteal artery pattern is “trifurcation”. in the latter all the terminal branches arise together at the inferior border of the popliteus muscle. keen reported observing a trifurcation of the ppa in of dissected yielding an incidence rate of . %, . % (poirier & charpy), . % (trotter), . % (adachi). kropman et al. ( ) reported that the most frequent variations in branching of the popliteal artery are a high origin of the ata, the trifurcation of the ppa and a hypoplastic or aplastic pta. some reported important characteristics of the ata are as follows: (a-f) (a). the greatest diameter of the ata was characteristics of the trifurcation pattern (dobbs et al., ). b) of the of the three calf arteries, the ata was the predominant vessel in a trifurcation and in subtypes with anterior tibioperoneal trunk (lippert & pabst, ; kim et al., ). c). an association has been found between ata and bony malformations of the lower limbs (hootnick et al., ). hootnick et al., also concluded that in limbs that contain the remnant of a missing structure, that injury occurred after the mesenchyme was instructed to form that structure such abnormalities are termed “post-specification” defects, these being in contrast to those described as “pre-specification” malformations, of which a duplicated artery is an example of the latter, where the injury affected the signal before the instruction of the mesenchyme to develop into a specific structure was completed. (d). the luminal diameter of the ata is the most important determination of the patency fig. . this image shows the hypoplastic anterior tibial artery crossing the ankle joint, and becoming an attenuated dorsalis pedis artery in the foot. an enlarged/hypertrophied perforating fibular artery is observed emanating from the interosseus membrane and serves as the replaced dorsalis pedis artery in the dorsum of the foot. hata= hypoplastic anterior tibial artery, adpa= attenuated dorsalis pedis artery, hpfa= perforating fibular artery, rdpa= reinforcing dorsalis pedis artery, edb= extensor digitorum brevis. ariyo, o. a segmental hypoplastic anterior tibial artery coexisting with an hypertrophied perforating fibular artery a case report and clinical implications. int. j. morphol., ( ): - , . rate in anterior femorotibial graft (karmody et al., ; kremen et al., ). e). the luminal diameters of the ata closely correlated with the percentage of the three- year patency rate for bypass (karmody et al.; kremen et al.) and the cumulative limsalvage (karmody et al.). f) popliteal arterial variants and the normative data for ata are important in vascular surgery below the knee following an angiographic study of the ata in patients with aortoiliac occlusive disease (szpinda, ). it has been reported that on variant patterns of the foot, the most common variant was that in which supply to the distal pta arose from the peroneal artery. atanasova et al. ( ) also reported the case of an hypoplastic ata, ending above the ankle joint and was replaced distally by a large branch from the pta the latter crossing the lowest portion of interosseous membrane. in the case being reported, an attenuated dpa, a distal vessel from an hypoplastic ata was reinforced by an hypertrophied perforating fibular artery the fibular artery represents a significant contributory vessel to the foot. a segmental hypoplastic. ata is a very rare infrapopliteal variant, and its occurrence no doubt supports the hypothesis by lohan et al. ( ), that trifurcation vessel imaging should be a prerequisite to fibular free flap harvesting. variation in dpa. palpation of the dpa is essential, particularly in suspected cases of arterial disorders. the dpa is also subjected to variations. tuncel et al. ( ) reported the case of a bilateral anomalous origin for dorsalis pedis arteries originating from the fibular arteries because of the hypoplastic nature of both anterior tibial arteries. the artery is recognized to play an important role in the microvascular surgery of the foot during replantation, reconstructions and repair due to its unique anatomical position and bountiful supply to the foot (vijayalakshmi et al., ). a good knowledge of the infrapopliteal variants and their branching patterns are critical in assisting vascular, orthopedic and plastic surgeons in making well informed decisions before embarking on any surgical interventions in the lower limb. pre-operative mr angiographic study of infrapopliteal vessels and its branches will assist in revealing the presence of any existing malformations that may have important bearing on the choice of appropriate surgical procedures. acknowledgements the author would like to thank the giver of this body for her generosity, even after death continues to give contributions to human knowledge. thanks to the medical students who made an initial partial dissection on the cadaver, the friendly and scholarly environment provided by the various authorities of the department of pathology, anatomy and cell biology. the tireless efforts of david and karen of the medical media unit in taking the photographs are appreciated. ariyo, o. coexistencia de una arteria tibial anterior hipoplásica segmentaria con una arteria fibular perforante hipertrofiada. reporte de caso e implicacias clínicas. int. j. morphol., ( ): - , . resumen: las lesiones vasculares de los miembros inferiores, especialmente las heridas penetrantes por arma de fuego y enfermedades arteriales periféricas, están en aumento. su manejo, así como el de otras lesiones en los miembros inferiores, implican un mayor uso de intervenciones vasculares como la cirugía de by-pass, angioplastía transluminal percutánea, canulación arterial, injerto de derivación arterial o medidas mínimamente invasivas como el cateterismo transarterial percutáneo, entre otros. el conoci- miento profundo de las ramificaciones infrapoplíteas, muy especialmente sus vías y diámetros luminales son importantes para los cirujanos en la selección de las intervenciones o procedimientos quirúrgicos apropiados. presentamos un caso en el cual, una de las ramas terminales de la arteria poplítea (app), la arteria tibial anterior (ata), de buen calibre en su origen se hizo hipoplásica en la región anterior de la pierna después de un desprendimiento de numerosas ramas musculares. continuó como una arteria dorsal del pie (adp) casi atenuada en el dorso del pie; esta última se vio reforzada por una amplia arteria fibular hipertrofiada. este caso ilustra la importancia de la arteria fibular como dominante de las ramificaciones de las arterias infrapoplíteas, un refuerzo o sustitución de la arteria tibial posterior (atp) cuando es débil o está ausente, por una fuerte rama comunicante, o bien refuerzo de una débil ata y adp por una fuerte arteria fibular perforante como en el caso reportado. la atp sin embargo tenía un trayecto con un curso normal generando las arterias plantares medial y lateral, posterior al músculo abductor del hállux. este caso demuestra la importancia de las comunicaciones colaterales y refuerzos de otras arterias infrapoplíteas, cada vez que uno de sus componentes o ramas posteriores están ausentes o hipoplásicas. un conocimiento detallado de los diferentes patrones de ramificación de la app puede ser adquirido a través de una angiografía vascular previo a la cirugía, diseñada para guiar al cirujano en la selección de las intervenciones quirúr gicas adecuadas, agrega valor a la atención de los pacientes, ayuda a disminuir las complicaciones vasculares quirúrgicas iatrogénicas y reduce el número total de pérdidas de miembros inferiores. palabras clave: arteria tibial anterior hipoplásica segmentaria; arteria dorsal del pie atenuada; arteria fibular hipertrofiada; ramificación infrapoplítea. ariyo, o. a segmental hypoplastic anterior tibial artery coexisting with an hypertrophied perforating fibular artery a case report and clinical implications. int. j. morphol., ( ): - , . references adachi, b. das arteriensystem der japaner. vol. i. kyoto, verlag der kaiserlich-japanischen universitat, kenyusha press, . pp. , . ali, m. w. & mohajir, a. m. dorsalis pedis artery: variations and clinical significance. j. indian med. assoc., ( ): - , . atanasova, m.; georgiev, g. p. & jelev, l. intriguing variations of the tibial arteries and their clinical implications. int. j. anat. var., : - , . brantley, s. k.; rigdon, e. e. & raju, s. persistent sciatic artery: embryology, pathology, and treatment. j. vasc. surg., ( ): - , . dobbs, m. b.; gordon, j. e. & schoenecker, p. l. absent posterior tibial artery associated with idiopathic clubfoot. a report of two cases. j. bone joint surg. am., -a( ): - , . hootnick, d. r.; packard, d. s. jr.; levinsohn, e. m.; lebowitz, m. r. & lubicky, j. p. the anatomy of a congenitally short limb with clubfoot and ectrodactyly. teratology, ( ): - , . karmody, a. m.; leather, r. p.; shah, d. m.; corson, j. d. & naraynsingh, v. peroneal artery bypass: a reappraisal of its value in limb salvage. j. vasc surg., ( ): - , . keen, j. a. a study of the arterial variations in the limbs, with special reference to symmetry of vascular patterns. am. j. anat., : - , . kim, d.; orron, d. e. & skillman, j. j. surgical significance of popliteal arterial variants. a unified angiographic classification. ann. surg., ( ): - , . kremen, a. f.; mendez-fernandez, m. a.; geis, r. c. & henly, w. s. the dracon exs graft: patency in femoropopliteal and femorotibia surgery. j. cardiovasc. surg. (torino), ( ): - , . kropman, r. h.; kiela, g.; moll, f. l. & de vries, j. p. variations in anatomy of the popliteal artery and its side branches. vasc. endovascular surg., ( ): - , . lippert, h. & pabst, r. arterial variations in man: classification and frequency. munich, bergman verlag, . pp. - . lohan, d. g.; tomasian, a.; krishnam, m.; jonnala, p.; blackwell, k. e. & finn, j. p. mr angiography of lower extremities at t: presurgical planning of fibular free flap transfer for facial reconstruction. ajr am. j. roentgenol., ( ): - , . poirier, p. & charpy, a. traité d’anatomie humaine. l. paris, masson, . pp. , , , . standring, s. gray's anatomy: the anatomical basis of clinical practice. th ed. philadelphia, elsevier, . pp. , . szpinda, m. external diameters of the crural arteries in patients with chronic critical limb ischaemia. folia morphol. (warsz.), ( ): - , . trotter, m. the level of termination of the popliteal artery in the white and the negro. am. j. phys. anthropol., ( ): - , . tuncel, m.; mara, t.; celik, h. & tasçioglu, b. a case of bilateral anomalous origin for dorsalis pedis arteries (anomalous dorsalis pedis arteries). surg. radiol. anat., ( ): - , . vijayalakshmi, s.; gunapriya, r. & varsha, s. anatomical study of dorsalis pedis artery and its clinical correlations. j. clin. diagn. res., ( ): - , . correspondence to: olutayo ariyo, mbbs, mba thomas jefferson medical college thomas jefferson university rm f, jah, locust street philadelphia, pa usa email: olutayo.ariyo@jefferson.edu received: - - accepted: - - ariyo, o. a segmental hypoplastic anterior tibial artery coexisting with an hypertrophied perforating fibular artery a case report and clinical implications. int. j. morphol., ( ): - , . medical history, , : - . thomas jefferson's university of virginia and the paris hospitals on the eve of the french revolution by louis s. greenbaum * thomas jefferson's five years in paris as american ambassador ( - ) saw a period ofdynamic urban growth, public health reform' and massive building projects, both public and private in the french capital-churches, hospitals, monumental toll houses, schools, theatres, public squares, bridges, markets and h tels particuliers. jefferson acknowledged as much in a letter of august : i will observe to you that wonderful improvements are making here in various lines. in architecture the wall ofcircumvallation round paris and the palaces by which we are to be let in and out are nearly compleated [sic], hospitals are to be built instead ofthe old hotel-dieu, one of the old bridges has all it's [sic] houses demolished and a second nearly so, a new bridge is begun at the place louis xv. by his reference to the hotel-dieu, jefferson was alluding to a project which had won the widespread enthusiasm and financial support of parisians-the relocation of the ancient municipal hospital from its place in the shadow of notre dame cathedral, where it operated for years, and the construction of four new hospitals in less populous outlying sections of the city. * professor louis s. greenbaum, department of history, university of massachusetts at amherst, herter hall, amherst, ma , usa. variations of this paper were presented at the american society for eighteenth-century studies twentieth annual meeting (new orleans), march and the society for french historical studies thirty-seventh annual conference (vancouver) march . abbreviation: thepapers ofthomas jefferson, ed. j. p. boyd, vols, princeton university press, - , has been shortened throughout to papers tj. handily summarized by the surgeon and hospital-reformer, jacques tenon ( - ): "never under any reign, was there more effort to pierce new streets, to remove old houses from bridges, to build quays, to extend and multiply the number of public markets, to remove cemeteries, to transfer butcheries and slaughterhouses from the central city, in one word to get the air to circulate, to dry out the soil, to guarantee against dangerous effects of accumulated putrid materials. all these precautions more and more favour the health of the city, and they are so many debts we owe to the benevolence of louis xvi and to the zeal of his minister of the department of paris." memoires sur les h pitaux de paris, paris, , p. . h. rosenau, social purpose in architecture: paris and london compared, - , london, studio vista, , pp. - , - ; a. braham, the architecture of the french enlightenment, berkeley, university of california press, , pp. - ; h. c. rice, jr., thomas jefferson's paris, princeton university press, , pp. - . to david humphreys, papers tj, vol. , p. . available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core thomas jefferson's university of virginia and the paris hospitals public interest in hospitals had been sparked by the paris academy of sciences which, in december , had appointed an eminent committee under the chairmanship of the astronomer and future mayor of revolutionary paris, jean- sylvain bailly, to investigate the hotel-dieu. the committee worked for nearly three years under the sponsorship of louis-auguste le tonnelier, the baron de breteuil, powerful minister of the king's household and the department of paris, and published three reports given much publicity by the government, which thrust hospitals and health-care, as never before, into the limelight of public scrutiny. the academy gave scientific validation to long-standing prejudices against the hotel-dieu, popularly conceived as a death-trap because of its unhealthy location in the densely populated centre, and its crowded mass of , patients ( per cent of the cities and towns of france had fewer inhabitants) lying four to six in a bed, its mixing diseases in the same wards and even the same beds, its vitiated air, deficient water, disregard of safety, and the danger it posed as a fire-hazard, polluter of the water supply and source of contagion. the committee's point of departure was to disencumber the hospital from its traditional association as a refuge of christian charity, indigence and confinement. viewed rather as a "factory" or "healing machine" for patient-citizens, the hospital l. s. greenbaum, 'jean-sylvain bailly, the baron de breteuil and the "four new hospitals" of paris', clio medica, , : - and 'scientists and politicians: hospital reform in paris on the eve of the french revolution', the consortium on revolutionary europe, - , proceedings , gainesville, , pp. - . extrait des registres de l'academie royale des sciences du novembre . rapport des commissaires charges, par l'academie, de l'examen du projet d'un nouvel h tel-dieu, paris, , pp.; extrait des registres de l'academie royale des sciences du juin . rapport des commissaires charges, par l'academie, des projets relatifs ai l'etablissement des quatre h pitaux, paris, , pp.; extrait des registres de l'academie royal des sciences du mars . troisieme rapport des commissaires charges, par l'academie, des projets relatifs a l'etablissement des quatre hopitaux, paris, , pp. a. soboul, la france a la veille de la revolution. economie et societe, paris, societ& d'edition d'enseignement superieur, , p. . j. tenon, bibliotheque nationale (paris), manuscrits, nouvelles acquisitions frangaises , fol. . cf. l. s. greenbaum, "'measure of civilization": the hospital thought of jacques tenon on the eve of the french revolution', bull. hist. med., , : ; j.-b. leroy, 'precis d'un ouvrage sur les h pitaux, dans lequel on expose les principes resultant des observations de physique et de medecine qu'on doit avoir en vue dans la construction de ces edifices, avec un projet d'h pital dispose d'apres ces principes', memoires de l'academie royale des sciences, , paris, , pp. - . cf. l. s. greenbaum, 'tempest in the academy: jean-baptiste le roy, the paris academy of sciences and project of a new h tel-dieu,' arch. int. hist. sci., , : - . the pre-revolutionary french hospital has attracted a multitude of significant studies: m. foucault, the birth of the clinic: an archaeology ofmedical perception, transl. a. m. sheridan smith, new york, pantheon, ; m. foucault et al., les machines a gu&ir: aux origines de l'h pital moderne, paris, dossiers et documents d'architecture. institut de l'environnement, ; c. c. gillispie, science and polity in france at the end of the old regime, princeton university press, , esp. pp. - ; h. mitchell, 'politics in the service of knowledge: the debate over the administration of medicine and welfare in the late th century france,' soc. hist., , : pp. - ; j.-p. goubert, 'la medicalisation de la societe frangaise, - ', historical reflexions, (waterloo, canada) , vol. ; c. jones, charity and "bienfaisance": the treatment of the poor in the montpellier region, - , cambridge university press, , and his the charitable imperative. hospitals and nursing in ancien regime and revolutionary france, london and new york, routledge, ; t. m. adams, bureaucrats and beggars. french socialpolicy in the age of the enlightenment, oxford university press, , pp. - ; - . for the hospital within a wider context of institutional discipline and surveillance, cf. m. foucault, discipline and punish. the birth of the prison, transl. a. m. sheridan smith, new york, random house, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core louis s. greenbaum and its location, design, construction, organization and operation could no longer be left, as in the past, to accident, convention or expedience. with a death rate of per cent, purportedly the highest of any hospital in europe, the paris h tel-dieu not only deprived the state of thousands of productive citizens each year but retarded population growth and reduced the nation's workforce upon which depended its strength and wealth. the committee rejected traditional large block structures of the baroque like the hotel-dieu, bicetre and la salpetriere, which were either designed a century before by architects oblivious to health factors, or were structures converted from ecclesiastical or other usages and therefore unsuited to the care of the sick. in reaction, the scientists advocated a new kind of hospital design, a pavilion or isolated ward where patients would be separated by disease and housed in single beds. the new hospital was to be a place where innovations in physics, chemistry, pathological anatomy, surgery, medical technology, sanitation, architecture and hospital administration would be practised. the hospital commission applauded the pavilion concept in louis xiv's chateau of marly and found its ideal model in the british naval hospital at plymouth, built in and visited by two of its members in . the pavilion would become the regnant model for hospitals built all over europe and america during the course of the next century. on june , louis xvi ordered the building of four new hospitals of beds each, in symmetrical parallel pavilions along a main axis, six on either side of an open garden, with a central chapel building at its head and connected by covered walkways for convalescing patients." the new design promised superior ventilation, economy and efficiency, as well as cleanliness, privacy and safety while cutting down the risk of fire and contagion, and reducing noise. responding to the academy's public appeal for the best form of hospitals and health-delivery for the capital, one of thomas jefferson's closest french friends, the marquis de condorcet, permanent secretary of the academy of sciences, submitted a paper on hospital-planning to his academy colleagues. seeking to nationalize and laicize medical care, condorcet proposed a network of local, democratically organized health-centres, thereby transferring the main burden of medical care from , pp. - . and for a survey of medical personnel within the hospitals, cf. t. gelfand, professionalizing modern medicine: paris surgeons and medical science and institutions in the th century, westport, conn., and london, greenwood press, . tenon, op. cit., note i above, p. vii; greenbaum, op. cit., note above, p. . tenon and the physicist charles-augustin coulomb. in a letter to tenon, chairman bailly acknowledged that the plymouth hospital was the model hospital of all europe, more than amply justifying the committee's recommendations ". . most useful to find our great plan already executed ... an experiment already accomplished". b. n. manuscripts, nouvelles acquisitions frangaises, , fol. ; extrait des registres de l'academie royale des sciences du mars , see note above, p. ; tenon, op. cit., note above, pp. liii-liv; cf. l. s. greenbaum, "the commercial treaty of humanity": la tournee des h pitaux anglais par jacques tenon en ', rev. hist. sci., , : . ' j. d. thompson and g. goldin, the hospital: a social and architectural history, new haven and london, yale university press, , pp. - . troisieme rapport des commissaires, reproduced in rosenau, op. cit., note above, pp. - . extrait des registres de l'academie royale des sciences du novembre , see note above, pp. - ; tenon, op. cit., note above, pp. - . available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core thomas jefferson's university of virginia and the paris hospitals the hospital-long associated with indigence and christian charity.' another respondent to the academy was the physiocrat, physician and biographer of turgot, pierre-samuel du pont de nemours. du pont and jefferson became acquainted in and formed a friendship which lasted nearly thirty years. their ideas on agriculture, economics, and education reveal striking agreement.' so, too, their views on social welfare and the treatment of the sick poor. du pont's paper, ideas on the nature, form and extent ofassistance to give the sick poor in a large city, was written and published at the behest of the academy committee. in it the physiocrat urged that the ancient hotel-dieu be closed down, and that it be replaced by a more effective health programme for the city of paris not through hospitals but rather through a combination of home-care for families and those with a fixed abode, and a series of neighbourhood hospices and nursing homes for the homeless. du pont's paper must be located in the context of numerous french writers who were troubled by the ancient association of the hospital with indigence and confessional charity. while physiocrats like the elder mirabeau and quesnay and populationists like montyon argued persuasively for a numerous and healthy population in the interests of a rich and powerful state, philosophes like voltaire and diderot were forceful in their condemnation of the hospital as a retrograde institution, unknown to antiquity and an obstacle to the attainment of a rational, enlightened society. hospitals were alleged to foster laziness and vice, to afford an easy berth for loafers who, instead of cultivating the land, engendered misery and depopulation and robbed labour of honour and respectability. the hospital was blamed as a source of national impoverishment, since its many sturdy inmates who feigned illness escaped the obligation of gainful employment, threw their dependants into pauperism and diminished productivity, thereby adding to the burden of relief. to thoughtful critics like montesquieu and rousseau, the solution to poverty lay not l. s. greenbaum, 'condorcet's "memoire sur les h pitaux" ( ): an english translation and commentary', condorcet studies, eds l. c. rosenfield and r. h. popkin, vol , atlantic highlands, p. lang, , pp. - . both condorcet and du pont were prominent members of the americaniste circle of turgot who saw america rather than britain as the model of political reform in france. both were linked in friendship to franklin and jefferson. see j. appleby, 'america as a model of radical french reformers of ', william and mary quarterly, rd ser., , : p. . thomas jefferson and pierre-samuel du pont de nemours, - , ed. d. malone, boston and new york, houghton mifflin, ; the correspondence ofjefferson and du pont de nemours, ed. g. chinard, baltimore, chartres, . paris, moutard, , pp. principally through du pont's friend, lavoisier, cf. l. s. greenbaum, 'health-care and hospital-building in eighteenth-century france: reform proposals of du pont de nemours and condorcet', stud. voltaire th century, , : . du pont's paper was in jefferson's library, cf. e. m. sowerby, catalogue of the library of thomas jefferson, washington, , vol. , no. , p. . for the background of du pont's treatise in his economic thought cf. j. j. mclain, the economic writings of du pont de nemours, newark, university of delaware press, , pp. - . v. de riquetti, marquis de mirabeau, l'ami des hommes ou traite de lapopulation, avignon, - , vols. esp. part iv, pp. - ; f. quesnay, encyclopedie articles 'fermiers' ( ), 'grains' and 'hommes' ( ) in franrois quesnay et la physiocratie, paris, institut national d'etudes demographiques, , vol. , - ; moheau (pseud. for montyon), recherches et considerations sur la population de la france ( ), ed. r. gonnard, paris, geuthner, , pp. - . voltaire, dictionairephilosophique, article 'charite', oeuvres completes de voltaire, kehl edn., n.p., , vol. , - ; diderot, encyclopedie, article 'h pitar, vol. , paris, , pp. - . available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core louis s. greenbaum in more hospitals and charities, but rather in bridging the enormous gap between rich and poor and in instituting greater employment opportunity. du pont held that man through his own toil must be responsible for his needs in health as well as in sickness. when this was not possible he should then have recourse to family and neighbours to regain self-sufficiency. the dehospitalization of disease and poverty by medical assistance at home, du pont asserted, was more humane, healthier and cheaper than the hospital and promised greater therapeutic success free from cross-infection. it restored familial and social relationships in the natural domestic environment. domicilary care facilitated the patients' return to work, thereby discouraging beggary, and involved the local citizenry in the responsibility of aiding their neighbours as practised in england and holland. whereas the natural setting of the family, man and disease was the home, whose rehabilitative function would restore health and the resumption of familial and social obligations, the hospital was an artificial and unnatural assembly of diseases and death. while the home recreated human and material resources the hospital destroyed the healing function and life itself. treatment by family, the fundamental moral unit, whose care is a function of love and duty, is spontaneous and motivated by the desire to cure. removal to the hospital implied a double liability. on the one hand it deprived the sick of a better chance of recovery through the therapeutic ministrations of family and neighbours. on the other, the vastly greater mortality of the hotel-dieu threatened permanent loss of income and the viability of the family itself. on november , du pont sent jefferson a copy of his paper and wrote, "i congratulate myself for having affirmed several principles which i found in your notes on virginia".' in chapter xiv of the notes jefferson had described the provision of poor relief and health-care in virginia and expressed an aversion for hospitals which linked him closely to du pont and other liberal reformers of the french enlightenment. he described the parish relief system of his state as the most effective, inexpensive and compassionate scheme of self-help and home-care. parish assistance and household relief by friends and neighbours, jefferson asserted is without comparison better than in a general hospital, where the sick, the dying and the dead are crammed together, in the same rooms, and often in the same beds. the disadvantages, inseparable from general hospitals, are such as can never be counterpoised by all the regularities of medicine and regimen. nature and kind nursing save a much greater proportion in our plain way, at a smaller expense, and with less abuse. montesquieu, de l'esprit des lois, paris, edn. pleiade, , p. ; rosseau, encyclopedie article 'de l'economie politique', in the political writings of j.-j. rosseau, ed. c. e. vaughan, new york, wiley, , vol. , pp. - . for alternative public policies governing the poor-confinement, prison, hospital and family aid, cf. m. foucault, madness and civilization. a history of insanity in the age of reason, transl. r. howard, new york, random house, , pp. - . papers tj, vol. , p. . on the french background ofjefferson's notes on the state of virginia, cf. d. medlin, 'thomas jefferson, andre morellet and the french version of the notes on the state of virginia', william and mary quarterly, , : pp. - . thomas jefferson's 'notes on the state of virginia', ed. w. peden, chapel hill, university of north carolina press, , pp. - . in virginia material relief to needy sick in their homes or with neighbours pretty consistently followed similar practices in the other colonies. cf. a. deutsch, 'sick and poor colonial times', am. hist. rev., , : - ; d. j. rothman, the discovery of the asylum: social order and disorder in the new republic, boston, little brown & co., , pp. - . available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core thomas jefferson's university of virginia and the paris hospitals just as du pont believed that there would be no need for hospitals if there were no poor, so jefferson hoped that urban institutions like hospitals would not be needed in america, since the population they were meant to serve would not exist in a rural, agricultural and self-sufficient society. jefferson gave much thought as to how great disparities of wealth might be avoided in the new nation so that americans could be assured of prosperity, freedom, happiness, independence and moral virtue, so long as plentiful land, and with it the promise of a rising standard of living, would continue to be made available to citizens. two parallel lines of thinking, converging in the reformist climate of pre- revolutionary paris, afford an interesting illustration of the thesis that the enlightenment, while conceived in europe, was being realized in america. french reformers, constantly dogged by privilege, bureaucratic obstruction and institutional opposition, could note with satisfaction that their reformist ideas were being practised in the united states. confirming this, jefferson wrote to du pont on november that "... america furnished proof of the soundness of your theory". until the end of his life jefferson never changed his unfavourable attitude to hospitals, which he considered instruments of human degradation and indignity. it is certain that jefferson shared with parisians the excitement of plans to rebuild the hotel-dieu and to create new hospitals for the city of paris, one of the most popular events in the capital during his stay. at least five letters over a period of seven months mentioned the planned reform. not only was he aware of the pavilion system proposed by the academy commission, but he was friendly with two of its prominent members, the celebrated chemist lavoisier and the naturalist daubenton, close greenbaum, op. cit., note above, p. . papers tj, vol. , pp. - ; cf. j. appleby, 'what is still american in the political philosophy ofthomas jefferson', william and mary quarterly, , : - ; d. r. mccoy, the elusive republic: political economy in jeffersonian america, new york, norton, , pp. - . h. s. commager, the empire ofreason. how europe imagined and america realized the enlightenment, new york, doubleday, . for an older treatment, cf. d. echeverria, mirage in the west. a history of the french image of american society to , princeton university press, . papers tj, vol. , p. , cf. appleby, op. cit., note above, p. . durand echeverria noted that america was the "proving ground for [du pont's] beloved theories". in the s and s du pont had written that america furnished proof of the physiocratic doctrine that economic prosperity was the result of encouraging agricultural production, a numerous rural population, free trade and taxes derived from the land. op. cit., note above, pp. - , . papers tj, vol. , p. . as late as march du pont and jefferson were still discussing the merits of home-care. e. m. sowerby, op. cit., note above, vol. , p. note. as late as may jefferson described the hospital as "the last resource of poverty ... for it is poverty alone which peoples hospitals ... how many families ... would send their husbands, wives or children to a hospital, in sickness? to be attended by nurses hardened by habit against the feelings of pity, to lie in public rooms, harrassed by the cries and sufferings of disease under every form, alarmed by the groans of the dying, exposed as a corpse, to be lectured over by a clinical professor, to be crowded and handled by his students, to hear their case learnedly explained to them, its threatening symptoms developed, and its probable termination foreboded?" reprinted in r. j. honeywell, the educational work of thomas jefferson, cambridge, mass., harvard university press, , p. . papers tj, vol. , , p. . paul v. turner in his campus. an american planning tradition, cambridge, mass., mit press, , p. , wrote: "it is also likely that jefferson was interested in the architectural debates in paris over the plans for the new hospital of the h tel-dieu, which called for a 'pavilion' system of linked structures rather like his own later plan for the university." january- august ; papers tj, vol. , pp. - , , , - ; vol. , p. . available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core louis s. greenbaum associate of buffon. in addition he had contacts with the physicist, encyclope'diste, and lifelong friend of benjamin franklin, jean-baptiste le roy, a scientist actively engaged in projects of hospital design and ventilation, who claimed authorship of the academy's pavilion model. to the extent that jefferson's ideas furnished support to du pont's and condorcet's position, the american ambassador can be said to have taken part in the parisian hospital debate on the eve of the french revolution. much has been written about jefferson's geometric neo-classicism, the identification of his cubic architecture with the precise and simple forms of antiquity which symbolized reason and order, "proportional relationships to the sympathetic senses" which reinforced "one's intuitive affinity with the visible, physical world and abstractions from nature".. while jefferson's debts to french neo-classical and visionary architecture as well as the chateau of marly have been meticulously documented, he remembered the pavilion design of the paris hospitals when he came to sketch the buildings of the university of virginia years later-five symmetrical pavilions on either side of an open lawn, communicating by covered porches, with a dominating building at the central axis (see figures and ). pavilions numbers to and of the university of virginia appear strikingly similar to le roy's design for his hospital pavilions, in the form of a roman temple (seemingly derivative of the maison carree at nimes, but with a pedimented frontispiece of four columns instead of six). similarly jefferson's pantheon library, which was also used for "religious cf. jefferson's conferral of diplomas of membership in the american philosophical society, papers tj, vol. , pp. , , . papers tj, vol. , pp. - , - ; vol. , pp. , - , , , ; vol. , pp. , . cf. greenbaum, op. cit., note above, pp. - . summarized in b. pickens, 'mr. jefferson as a revolutionary architect', j. soc. arch. hist., , : . the eye of thomas jefferson, ed. w. h. adams, washington, national gallery of art, , pp. - ; f. d. nichols, 'jefferson: the making of an architect' in jefferson and the arts: an extended view, ed. w. h. adams, washington, national gallery of art, , pp. - ; and 'architecture' in thomas jefferson: a reference biography, ed. m. d. peterson, new york, scribners, , pp. - and thomas jefferson's architectural drawings, boston and charlottesville, the university press of virginia, , p. . h. c. rice, jr., op. cit., note above, p. , cites the work of the architectural historian fiske kimball, the first to suggest the marly connection. jefferson's first building at monticello, the south outchamber ( ), frequently called the "honeymoon cottage", to which he brought his bride in , was built in the form of a pavilion (pickens, op. cit., note above, p. ). in a stimulating essay, 'thomas jefferson et l'architecture metaphorique: "le village academique" a l'universite de virginie' (revue d'art canadienne. canadian art review, , : , pp. - ), gerard le coat theorizes a rich mix of influences in jefferson's academic architecture: utilitarian, didactic (socio-political, ethico-social), epistemological, philosophical, and especially masonic (". . . the comprehensive plan of the village was inspired by that of the lodge" [p. ]). following the example of the late eighteenth-century french architects jefferson is said to have incorporated the classical appeal to the senses: to move, to instruct and to induce admiration and from their "architecture of character and consciousness" to inform, instruct and convince" (pp. - ). dumas malone in the sage ofmonticello (vol. of jefferson and his time), boston, little, brown, , p. n., has shown that jefferson was also familiar with the plymouth hospital pavilions, the paradigm of the hospital committee (see note above). 'precis d'un ouvrage sur les h pitaux', pp. - and plates: elvation lat&ale sur la ligne a. b. tracee sur le plan general, et vue des bdtimens de service, des salles et de la coupe de l'eglise, bibliotheque nationale, paris, imprimes vp ; cf. greenbaum, op. cit., note above, pp. - ; p. a. bruce, history of the university of virginia, - , vol. , new york, macmillan, , p. ff.; w. b. o'neal, pictorial history of the university of virginia, charlottesville, university of virginia press, , pp. - . available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core thomas jefferson's university of virginia and the paris hospitals '~~~~~~~~~~~~~~~~~~~~~~~~ > ' _l-s. - % i l. l t_ r * .... /vv _'jbt l. *a, w,-a- iw- li_li at_ - i v a ....*... . . . v.. . .. . .. .... .d -d d i.. r ... -a e; ao .>-% . --, 'i x(z= c. available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core louis s. greenbaum ii~~~~~~~~~~~~~~~~~~~~~~~~~~~oi~~~~~~~~~~~~~~~~- - --- .... _:....,,-.- i~~~~~~~~~~~~~~~~~~~~~~~~~ sŵ lfa|'ffiĝ...............................................:::-at..*°t~hr........ hilt t. i t ,. , _- j : i = ~~~~j e~~~~~~~_ ....e .......................° q~~ ~x-dil sl t ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~b-ui j ]=. ,']s' ~ k~~~~~~~~~~~~~~ @! t- -~~~~~~ available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core thomas jefferson's university of virginia and the paris hospitals worship", looks a great deal like le roy's domed and columned central chapel flanked by twin rows of hospital pavilions (see figures and ). but why incorporate in the new university designs intended for a hospital? the answer lies in jefferson's preoccupation with health and medicine, concerns shared with the french scientists a generation earlier. the roman architecture of the university of virginia was not only aesthetically pleasing, functional and instructive, but it also comported best with health-promoting objectives. jefferson's appointment of a medical faculty at the university reflected not merely his lifelong interest in science and medicine but also his conviction that medical studies should be part of general education and that training physicians would enhance the health of citizens. jefferson believed that the task of maintaining health rested with each individual. to the author of the declaration of independence, good health was the indispensable prerequisite for the enjoyment of life, liberty and the pursuit of happiness. jefferson's own long life gave evidence of how the individual needs to pursue good health through regularity in diet, sleep, prudent hygiene and physical exercise. countless exhortations to family and friends underscored health as the fundamental natural right, "the first of all objects" central to the advancement of education ("a strong body makes the mind strong"), morality and human improvement. "you may promise yourself everything-but health, without which there is no happiness. an attention to health then should take place of every other object." in times of illness the sick person should seek recourse to enlightened medicine. jefferson was inoculated against smallpox in by the philadelphia physician william shippen. when he dislocated the wrist of his right hand in september , he was visited twenty times by one of the surgical luminaries of paris, antoine louis, permanent secretary of the royal academy of surgery. ' when his own daughters elevation gn&ale d'un projet d'h tel-dieu de m. le roy, de l'academie royale des sciences. imagine en . compose pour l'architecture et dessine en par ch. fr. viel architecte de ' h pital gcn&ale de paris; w. b. o'neal, jefferson's buildings at the university of virginia: the rotunda, charlottesville, university of virginia press, , p. . joseph-jacques ramee, five years before jefferson, had designed a campus formed around a rotunda with linked wings at union college in schenectady, new york. (r. g. kennedy, orders from france. the americans and the french in a revolutionary world, - , philadelphia, university of pennsylvania press, , pp. , ). one of jefferson's favourite maxims was "faber suae quisque fortunae." for the compatibility of his ideas and enlightenment notions regarding the preservation of health as "the first of all goods and the foundation of all other goods of this life" (descartes), cf. peter gay, the enlightenment: an interpretation, vol. , the science offreedom, new york, norton, , pp. - . see letter of march to dr vine utley in the writings ofthomas jefferson, ed. p. l. ford, vol. , new york, g. p. putnam's sons, , pp. - . cf. a. blinderman, 'thomas jefferson. administrator, practitioner and patient', n. y. state j. med., march , pp. - . the family letters of thomas jefferson, eds e. m. betts and j. a. bear, jr., columbia, university of missouri press, , pp. - ; papers tj, vol. , , p. ; vol. , pp. - ; vol. , p. ; vol. , pp. - ; family letters, p. ; ford, writings of tj, vol. , p. inter alia. papers tj, vol. , p. . d. malone, jefferson the virginian, boston, little, brown, , pp. - . massachusetts historical society (boston). ms account books, - . memorandum books or journal of expenditures. december . on louis, cf. p. huard, biographies medicales et scientifiques, paris, dacosta, , pp. - . available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core louis s. greenbaum were ill he nursed them. he had them inoculated along with his family, slaves, and neighbours at monticello. jefferson's efforts to improve conditions of american public health reach back as far as the revolutionary war when, as governor of virginia, he sought to heal suffering smallpox-infected soldiers. he voiced concern to improve sanitation, ventilation, water-supply and disease prevention in philadelphia, washington, and the louisiana territory. he was an active supporter of jenner's smallpox vaccine and collaborated in dr benjamin waterhouse's project of national vaccination. as early as january , jefferson had hit on an architectural model appropriate for his university. he ruled out a single large building (like the hotel-dieu or the college ofwilliam and mary) "always ugly, inconvenient, exposed to accident of fire, and bad cases of infection". five years later he termed his project design an "academical village" -referring to the healthiness and moral superiority of the countryside, free from disease and the vices of cities and built in a higher, more salubrious location than the old college at williamsburg located in the unhealthy lowlands. separate "lodges" would house classrooms and professors; "barracks" for students; and covered ways "to give dry communication between all schools". "an academic village instead of a large and common den of noise, filth and fetid air. it would afford the quiet retirement so friendly to study and lessen dangers of fire, infection and tumult." six years later, in april , he added, "this village form is preferable to a single great building for many reasons, particularly on account of fire, health, economy, peace and quiet." jefferson's plan compares strikingly with the pavilion hospitals of the paris academy in the s, not only by the same symmetrical placement of neo-classical buildings, but also because the french reformers had abandoned the huge hospital monolith for precisely the same motives enumerated by jefferson a generation later. the scientists had settled on pavilion architecture with its superior fenestration and h. bloch, 'thomas jefferson to . thoughts on medicine, child care and welfare', n. y. state j. med., (december , ), pp. - . for jefferson's activities as a vaccinator, cf. w. b. blanton, medicine in virginia in the eighteenth century, richmond, garrett & massie, , pp. - ; e. t. martin, thomas jefferson scientist, new york, h. schuman, , p. ; b. s. leavell, 'thomas jefferson and smallpox vaccination', trans. am. clin. and climatol. assoc., , : - . blanton, op. cit., note above, pp. ff.; h. gill, the apothecary in colonial virginia, williamsburg, colonial williamsburg foundation, , appendix i, 'revolutionary hospitals in williamsburg', pp. - . the portable thomas jefferson, ed. m. d. peterson, new york, viking, , pp. - ; jefferson to dr benjamin rush, ford, writings of tj, op. cit., note above, vol. , p. . r. a. halsey, how the president thomas jefferson and dr. benjamin waterhouse established vaccination as apublic health procedure, history of medicine series ... library of the new york academy of medicine, no. , new york, the author, . january , to littleton tazewell, quoted in d. guinness and j. t. sadler, mr. jefferson architect, new york, viking, , p. . ("in fact a university should not be a house but a village.") to the trustees for the lottery of east tennessee college may , in the complete jefferson, ed. s. k. padover, new york, duell, sloan & pearce, , pp. - . tj to joseph priestley, january , , ford, writings of tj, op. cit., note above, vol. , p. . on the connection between health and social environment, education and physical well-being, cf. g. rosen, 'political order and human health in jeffersonian thought', bull. hist. med., , : - . to governor nicholas of virginia, april , in honeywell, op. cit., note above, p. . available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core thomas jefferson's university of virginia and the paris hospitals ventilation against "mephytic exhalations" and "morbific miasms" and to isolate contagion and disease-the principal drawbacks of large structures which housed a numerous population. just as fire in a single building, either hospital or university, would mean the loss of the entire institution-and both the hotel-dieu and william and mary had sustained costly conflagrations-maladies and epidemics could spread more readily and rapidly in a single building. relatively small classroom pavilions would re-circulate air in a far more efficient manner and were easier to heat than one large building. erecting several dining hotels and student dormitories behind the faculty classroom pavilions multiplied the opportunity for isolating disease. likewise the university community would be protected from sickness-causing elements as they travelled from building to building under covered porches just as the scientists had advocated for improved convalescence and easy communication of all departments. what better health-inducing plan could jefferson propose for his university than that of a modern, carefully planned hospital? jefferson's university would not only attempt to safeguard the health of its students through salubrious site location and architectural design; medical instruction, deemed useful for the education of all students, would also advance public health. if the duty of the state was to protect and ensure the natural rights ofman, then the state also had an obligation to provide an educational institution which would further these rights by forming leaders to protect them. one such leader was the physician. while jefferson praised "surgery seated in the temple of the exact sciences . .. medicine [he believed] scarcely entered its threshold." the founder of the university of virginia was critical of the contemporary practice of medicine based on fanciful theories, presumption, inexperience and charlatanry. "it is in this part of medicine that i wish to see a reform, an abandonment of hypothesis for sober facts, the first degree of value set on clinical observation and the lowest of visionary theories," a medicine based on "observation and experiment". rigorously trained doctors would enhance the health of the citizenry and thereby increase the potential for the enjoyment of natural rights and the strength of the political system. one of the university's six professors would teach anatomy, surgery, history of the progress and theories of medicine, physiology, pathology, materia medica and pharmacy. the university of virginia provided the first full-time state-supported clinical faculty in a university medical school in the united states. the comprehensive medical and scientific curriculum planned by jefferson, the emphasis on preclinical training and clinical instruction under close supervision of the medical school faculty became the norm in on lavoisier's experiments on oxygen requirements in hospitals and other public buildings, cf. l. s. greenbaum, 'the humanitarianism of antoine laurent lavoisier', stud. voltaire th century, , : - , and the incorporation of this work into the recommendations of the paris hospital committee relating oxygen requirements into the design of hospital pavilions. cf. greenbaum, op. cit., note above, p. . quoted in s. a. bedini, thomas jefferson. statesman ofscience, new york, macmillan, , pp. - , - . on jefferson's views of physicians and contemporary medical practice, cf. s. x. radbill, 'thomas jefferson and the doctors', trans. stud. coll. physicians phila., ser., , : - ; c. r. hall, 'jefferson on the medical theory and practice of his day', bull. hist. med., , : - . bruce, op. cit., note above, vol. , p. ; j. s. spratt, 'thomas jefferson: the scholarly politician and his influence on medicine', southern med. j., , : . l. h. cohn, 'contributions of thomas jefferson to american medicine', am. j. surg., , : - . available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core louis s. greenbaum american medical schools. it was jefferson's good fortune to attract the gifted practitioner and scholar robley dunglison to assume the clinical chair, a man responsible for training numerous doctors in the young republic. a second faculty member, john patton emmett, professor of natural history, gave medical instruction in chemistry, botany and comparative anatomy. dr thomas johnston became the first demonstrator in anatomy and surgery. jefferson believed fervently in clinical and anatomical studies as the basis of medical education. no expense was spared in this area of university instruction. before march , jefferson had designed an "anatomical theatre" to perform dissections. construction was underway before his death a year later and completed in . a letter to dunglison of november included the draft of a prosposal for a university dispensary. approved by the board of visitors on april , only three months before jefferson's death, the clinic would provide vital learning experience to physicians in training, including surgery (which, jefferson had written earlier, was the only branch of the medical art lacking in virginia ) "for the purpose of dispensing medical advice, vaccination, and aid in surgical cases of ordinary occurrence to applicants needing them". those who could afford it would pay a fifty-cents fee; the indigent would receive services free. not only would medical science be served through the educational function of the dispensary, but the sick poor would receive life-promoting attention. no doubt in jefferson's mind the dispensary represented an efficient form of assistance, satisfying the moral responsibility of society to provide health services to those in need. clinical medicine was joined to compassionate care. the poor patient would be treated through the latest advancements of medical science and with humane consideration. reason and the moral sense came to form a sympathetic alliance, a merging of "head and heart" which perhaps best characterizes the 'jeffersonian position on health-care. viewed in this light, his university of virginia was not merely the emblem of freedom and progress through enlightenment but also an instrument for the improvement of the human condition through better health, and with it greater happiness, independence and material prosperity. jefferson esteemed the paris architecture he studied in the s as the standard by which to measure great buildings. he wrote that when the white house and capitol in washington were completed "the result will not be more beautiful than the a. de jarnette hart, jr., 'thomas jefferson's influence on the foundation of medical instruction at the university of virginia', ann. med. hist., , : . s. x. radbill, 'dr. robley dunglison and jefferson', trans. stud. coll. physicians of phila., ser., , : - ; the jefferson-dunglison letters, ed. j. m. dorsey, charlottesville, university of virginia press, . bruce, op. cit., note above, vol. , p. . w. b. bean, 'mr. jefferson's influence on american medical education', virginia med. monthly, , : ; b. s. leavell, 'jeffersonian ideals endowed the university of virginia', virginia med. monthly, , : - . o'neal, op. cit., note above, pp. - . op. cit., note above, pp. - . the hospital committee of the french academy of sciences had also proposed a series of "general dispensary" built in the parishes of paris to supplement the medical/surgical services of the four major hospitals. extrait des registres de l'academie royale des sciences du mars , op. cit., note above, p. . peden (ed.), op. cit., note above, p. . available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core thomas jefferson's university of virginia and the paris hospitals pavilions at the new gates of paris". when daniel webster visited the sage of monticello in december the whole conversation was french society, politics and literature as jefferson knew it in the s intermingled with the university of virginia. in passing judgment on jefferson's personality, henry adams concluded that "with all his extraordinary versatility of character and opinions, he seemed during his entire life to breathe with perfect satisfaction nowhere except in the liberal, literary and scientific air of paris in . , quoted in r. g. kennedy, op. cit., note above, p. . cf. a. vidler, claude-nicholas ledoux: architecture and social reform at the end of the ancien regime, cambridge, mass., mit press, , pp. - . rice, op. cit., note above, p. . ibid. available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core [pdf] adherence to positive airway pressure therapy in hospitalized patients with decompensated heart failure and sleep-disordered breathing. | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /jcsm. corpus id: adherence to positive airway pressure therapy in hospitalized patients with decompensated heart failure and sleep-disordered breathing. @article{sharma adherencetp, title={adherence to positive airway pressure therapy in hospitalized patients with decompensated heart failure and sleep-disordered breathing.}, author={s. sharma and a. chakraborty and a. chowdhury and umer mukhtar and l. willes and s. quan}, journal={journal of clinical sleep medicine : jcsm : official publication of the american academy of sleep medicine}, year={ }, volume={ }, pages={ - } } 	s. sharma, a. chakraborty, + authors s. quan 	published 	medicine 	journal of clinical sleep medicine : jcsm : official publication of the american academy of sleep medicine study objectives sleep-disordered breathing (sdb) has been implicated as a risk factor for the development of several adverse cardiovascular outcomes, but can be mitigated with positive airway pressure therapy (pap). the nonadherence of patients with sdb on pap in the outpatient setting ranges from % to %. however, adherence of pap in patients with congestive heart failure (chf) admitted for decompensated chf and in whom sdb has been diagnosed in the hospital setting is not known. we… expand view on pubmed jcsm.aasm.org save to library create alert cite launch research feed share this paper citationsbackground citations results citations view all figures, tables, and topics from this paper 	 figure 	 table 	 table 	 figure 	 table 	 table view all figures & tables 	congestive heart failure 	sleep apnea syndromes 	hospitalized patients 	compliance behavior 	polysomnography 	tertiary healthcare 	exclusion paper mentions interventional clinical trial motivational enhancement - acute decompensated heart failure and osa a feasibility randomized controlled trial will be conducted with a -month follow up to: examine the impact of early intensive telemedicine motivational enhancement (time) vs… expand 	conditions	acute decompensated heart failure, motivational enhancement, obstructive sleep apnea, (+ more) 	intervention	behavioral the cleveland clinic march - december citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency sleep-disordered breathing in hospitalized patients with congestive heart failure: a concise review and proposed algorithm 	a. gupta, s. quan, o. oldenburg, a. malhotra, s. sharma 	medicine 	heart failure reviews 	 	 	 save alert research feed opiate use and escalation of care in hospitalized adults with acute heart failure and sleep disordered breathing (opiateshf study). 	abesh niroula, veronica garvia, + authors s. sharma 	medicine 	annals of the american thoracic society 	 	 	pdf 	view excerpt save alert research feed recognition and treatment of sleep-disordered breathing in obese hospitalized patients may improve survival. the hosmed database. 	s. sharma, umer mukhtar, c. kelly, p. mather, s. quan 	medicine 	the american journal of medicine 	 	 	 save alert research feed racial disparities in positive airway pressure therapy adherence among veterans with obstructive sleep apnea. 	n. hsu, m. zeidler, a. ryden, c. fung 	medicine 	journal of clinical sleep medicine : jcsm : official publication of the american academy of sleep medicine 	 save alert research feed the clinical impact of systematic screening for obstructive sleep apnea in a type diabetes population—adherence to the screening-diagnostic process and the acceptance and adherence to the cpap therapy compared to regular sleep clinic patients 	k. westlake, v. dostálová, andrea plíhalová, m. pretl, j. polák 	medicine 	front. endocrinol. 	 	 	 	view excerpts, cites background and results save alert research feed hospital screening for obstructive sleep apnea in patients admitted to a rural, tertiary care academic hospital with heart failure 	r. stansbury, m. abdelfattah, j. chan, abhinav mittal, fahad al-qahtani, s. sharma 	medicine 	hospital practice 	 save alert research feed adherence to positive airway pressure treatment among minority populations in the us: a scoping review. 	d m wallace, n. williams, + authors w. wohlgemuth 	medicine 	sleep medicine reviews 	 	 	 save alert research feed references showing - of references sort byrelevance most influenced papers recency sleep disordered breathing and post-discharge mortality in patients with acute heart failure. 	r. khayat, d. jarjoura, + authors w. abraham 	medicine 	european heart journal 	 	 	pdf save alert research feed central sleep apnea is a predictor of cardiac readmission in hospitalized patients with systolic heart failure. 	r. khayat, w. abraham, + authors d. jarjoura 	medicine 	journal of cardiac failure 	 	 	 save alert research feed influence of obstructive sleep apnea on mortality in patients with heart failure. 	h. wang, j. parker, + authors t. bradley 	medicine 	journal of the american college of cardiology 	 	 	pdf save alert research feed obstructive sleep apnea in obese hospitalized patients: a single center experience. 	s. sharma, p. mather, + authors s. quan 	medicine 	journal of clinical sleep medicine : jcsm : official publication of the american academy of sleep medicine 	 	 	 save alert research feed determinants of continuous positive airway pressure compliance in a group of greek patients with obstructive sleep apnea. 	a. amfilochiou, v. tsara, + authors v. polychronopoulos 	medicine 	european journal of internal medicine 	 	 save alert research feed central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. 	s. javaheri, r. shukla, h. zeigler, l. wexler 	medicine 	journal of the american college of cardiology 	 	 	 save alert research feed photoplethysmographic signal to screen sleep-disordered breathing in hospitalized heart failure patients: feasibility of a prospective clinical pathway. 	s. sharma, p. mather, + authors d. whellan 	medicine 	jacc. heart failure 	 	 	pdf save alert research feed long-term therapy with continuous positive airway pressure in obstructive sleep apnea: adherence, side effects and predictors of withdrawal – a ‘real-life’ study 	w. galetke, l. puzzo, c. priegnitz, n. anduleit, w. randerath 	medicine 	respiration 	 	 	 save alert research feed sleep apnea in an urban public hospital: assessment of severity and treatment adherence. 	m. joo, j. herdegen 	medicine 	journal of clinical sleep medicine : jcsm : official publication of the american academy of sleep medicine 	 	 	pdf save alert research feed cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. 	y. kaneko, j. floras, + authors t. bradley 	medicine 	the new england journal of medicine 	 	 	pdf save alert research feed ... ... related papers 	abstract 	figures, tables, and topics 	paper mentions 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue mtdna t g mutation-induced mitochondrial complex v inhibition augments cardiolipin-dependent alterations of mitochondrial dynamics during oxidative, ca + and lipid insults in narp cybrids: a potential therapeutic target sunday, february , a mitochondrial membranes which result in the dramatic increase of their perme- ability. this increase in permeability during necrosis is caused by the opening of a permeability transition pore - ptp in mitochondrial inner membrane. on the other hand apoptosis induces opening of a large non-selective channel (mito- chondrial apoptotic channel - mac) in the mitochondrial outer membrane. we used atomic force microscopy to study the structure and organization of native mitochondrial membranes isolated from necrotic and apoptotic cells. we com- plement our afm imaging with nanopatricle-based immnunoassays, where mi- tochondrial membranes are pretreated with nanoparticle-conjugated antibodies for recognition of specific proteins. we will present our data on morphological studies of these membranes and will discuss feasibility of this approach for visu- alization of mptp and mac channels in the native mitochondrial inner mem- branes (mim) and mitochondrial outer membranes (mom) using afm methods. -pos board b heterogeneity of cardiolipin regulation yi-fan lin, mei-jie jou. department of physiology and pharmacology, chang gung university, tao-yuan, taiwan. cardiolipin (cl), is a protective phospholipid located exclusively on the mito- chondrial inner membrane for stabilizing individual complex of mitochondrial respiratory chain for energy production, mitochondrial ca þ (mca þ) regula- tion and reactive oxygen spices formation. deficiency of cl has been associated with multiple mitochondrial dysfunctions upon pathological condition, diseases and aging. using fluorescence digital imaging microscopy this study investi- gated how cl is preciously regulated in rat brain astrocytes rba- . results demonstrate that at the resting stage, the distribution of cl is rather heteroge- neous within single cell. the perinulear mitochondria show lower cl than mi- tochondria from the peripheral area. heterogeneity of cl was observed even in single mitochondrion, which may affects mitochondrial fission and fusion mechanism. cl was found to be higher at the cross point area of mitochondrial network. thread-like mitochondria and granular-like mitochondria, however, contain similar level of cl. some of the thread-like mitochondria even contain lower cl than granular-like mitochondria. upon localized oxidative stress in- duced by nm laser irradiation, heterogeneous depletion of cl was observed among mitochondria populations within single cell. distribution of cl altered also mitochondrial dynamics that depletion of cl always occurred before fis- sion. intriguingly, although complete depletion of cl is irreversible upon high strength of laser irradiation, depleted cl recovered during lower strength of laser irradiation and occurred heterogeneously within mitochondria popula- tions. condensation of cl was observed upon various stresses including oxida- tive stress induced by nm laser irradiation, ionomycin-induced mca þ stress and arachidonic acid-induced lipid stress which crucially enhances pres- ervation of cl and its resistance to stress which may be of significance for mi- tochondrial protection and survival. unveiling pathophysiological regulation of cl thus may contribute significantly the prevention and treatment of cl asso- ciated pathological condition, diseases and aging. -pos board b mtdna t g mutation-induced mitochondrial complex v inhibition augments cardiolipin-dependent alterations of mitochondrial dynamics during oxidative, ca d and lipid insults in narp cybrids: a potential therapeutic target tsung-i peng , chia-wei hsiao , mei-jie jou . keelung chang gung memorial hospital, tao-yuan, taiwan, national tsing hua university, tao-yuan, taiwan, chang gung university, tao-yuan, taiwan. mitochondrial dynamics including morphological fission and mitochondrial movement are essential to normal mitochondrial and cellular physiology. this study investigated how mtdna t g (narp)-induced inhibition of mito- chondrial complex v altered mitochondrial dynamics in association with a pro- tective mitochondrial phospholipid, cardiolipin (cl), as a potential therapeutic target. narp cybrids harboring % of mtdna t g genes and its parental osteosarcoma b cells were studied for comparison, and protection provided by melatonin, a potent mitochondrial protector, was explored. we demonstrate for the first time that narp mutation significantly enhances apoptotic death as a result of three distinct lethal mitochondrial apoptotic insults including oxida- tive, ca þ and lipidstress. in addition, narpsignificantly augmented patholog- ical depletion of cl. narp-augmented depletion of cl results in enhanced retardation of mitochondrial movement and fission and later swelling of mito- chondria during all insults. these results suggest thatcl is a common and crucial pathological target formitochondrial apoptoticinsults. furthermore, cl possibly plays a central role in regulating mitochondrial dynamics that are associated with narp-augmented mitochondrial pathologies. intriguingly, melatonin, by differ- entially preserving cl during various stresses (oxidation > ca þ > lipid), res- cuesdifferentially cl-altered mitochondrial dynamics and cell death (oxidation > ca þ > lipid). thus, melatonin, in addition to being a mitochondrial antioxidant to antagonize mitochondrial oxidative stress, a mitochondrial permeability tran- sition modulator to antagonize mitochondrial ca þ stress, may stabilize directly cl to prevent its oxidization and/or depletion and, therefore, it exerts great po- tential in rescuing cl-dependent mitochondrial dynamics-associated mitochon- drial pathologies for treatment of narp-induced pathologies and diseases. -pos board b shuttling of membrane-bound cytochrome b between mitochondria and er david weaver , veronica eisner , peter varnai , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis medical university, budapest, hungary. cytochrome b type b has long been described as a tail-anchored protein of the outer mitochondrial membrane (cb -mito). using a fusion protein consisting of photoactivatable gfp fused to the c-terminus membrane-targeting segment of cb -mito, we have found that while this construct concentrates in the mitochon- drial membrane, it is continuously exchanged between the membranes of the mitochondrion and the endoplasmic reticulum. this effect does not depend on the presence of mitofusin or , as it occurs in mfn-null mefs as well as in wild type cells. interestingly, a point mutation in the hydrophobic, membrane-targeting sequence of cb -mito that was recently reported to prevent its association with autophagosome membranes, also eliminates its exchange with the er. while lipids and viral proteins have been shown to traffic from er to mitochondria, this is, to our knowledge, the first demonstration of such a back-and-forth shuttling, representing both a new aspect of the er- mitochondrial interface and an mfn-independent pathway for the exchange of an outer mitochondrial membrane protein. -pos board b dichotomy between mitochondrial ca d uptake and martix [ca d] in micu deficient cells tunde golenar , gyorgy csordas , fabiana perocchi , vamsi k. mootha , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. mitochondrial calcium uptake is central to cell physiology, but the underlying molecular mechanism remains elusive. recently, micu was identified as a mi- tochondrial protein required for ca þ uptake but dispensible for mitochondrial respiration or membrane potential generation. to study the specific role of micu in mitochondrial ca þ uptake, we used wild type hela cells (ctrl), micu knockdown by distinct shrnas (kd) and micu rescued cells (res- cue). first, we monitored the cytoplasmic and mitochondrial matrix [ca þ] ([ca þ]c and [ca þ]m, respectively) during store-operated ca þ entry. specif- ically, cells were preincubated in a ca þ-free buffer containing thapsigargin (tg), to deplete the er ca þ store, and then ca þ was added back and the en- suing [ca þ]c (fura ) and [ca þ]m (mitochondria-targeted pericams) changes were measured. in both ctrl and kd a [ca þ]c increase occurred that was asso- ciated with a [ca þ]m rise only in ctrl. the rescue behaved similarly to the ctrl. also, when ca þ was added to permeabilized cells, no [ca þ]m increase ap- peared in the kd. these results confirm that the shortage of micu causes sup- pression of the [ca þ]m signal. surprisingly, when the ca þ entry was followed byuncoupler additiontoreleasethemitochondrial ca þ content, ahuge[ca þ]c increase appeared in kd, however, when the uncoupler was added prior to ca þ entry, no [ca þ]c increase occurred. thus, mitochondria in the kd also accumu- lated ca þ during ca þ entry. mitochondrial ca þ uptake evoked by ca þ ad- dition was also documented in permeabilized kd by measurement of ruthenium red sensitive ca uptake and cytoplasmic ca þ clearance (fura ). thus, ca þ is accumulated by micu deficient mitochondria but it fails to result an increase in[ca þ]m.weare currentlyinvestigating, whether suppression ofthe [ca þ]m rise in the kd is due to enhanced matrix ca þ-buffering. -pos board b micu serves as a ca d-controlled gatekeeper for the mitochondrial ca d uniporter györgy csordás , tünde golenár , erin l. seifert , fabiana perocchi , vamsi k. mootha , györgy hajnózky . thomas jefferson university, philadelphia, pa, usa, department of systems biology, harvard medical school, boston, ma, usa. micu serves as a ca þ-controlled gatekeeper for the mitochondrial ca þ uniporter mitochondria are important targets and relay points of calcium signaling. ca þ is driven to the mitochondrial matrix via a low-affinity ca þ channel, the ca þ uniporter (mcu) that exhibits time-dependent 	heterogeneity of cardiolipin regulation 	mtdna t g mutation-induced mitochondrial complex v inhibition augments cardiolipin-dependent alterations of mitochondria ... 	shuttling of membrane-bound cytochrome b between mitochondria and er 	dichotomy between mitochondrial ca + uptake and martix [ca +] in micu deficient cells 	micu serves as a ca +-controlled gatekeeper for the mitochondrial ca + uniporter patch-clamp analysis of mitochondrial ca + uniporter in different tissues tuesday, february , a agent colchicine that is known to increase free tubulin, mitochondrial potential, as measured by tetramethylrhodamine methyester (tmrm) uptake, decreased. inhibition of pka activity with h increased mitochondrial potential and, fur- thermore, reversed mitochondrial depolarization induced by colchicine. to fur- ther explore a role vdac-tubulin interaction in cell proliferation and survival, we studied the effect of erastin, the selective anti-tumour agent involved in the ras-raf-mek signalling pathway, on vdac blockage by tubulin. we found that erastin reverses tubulin blockage of vdac isolated from hepg cells, pro- moting the unblocked state of the channel. our findings suggest a novel func- tional link between serine/threonine kinase signalling pathways, mitochondrial respiration, and highly dynamic microtubule network which is characteristic of carcinogenesis and cell proliferation. -plat the isoform specific n terminus of vdac is dispensable for tbid induced cytochrome c release shamim naghdi , peter varnai , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, department of pathology anatomy and cell biology, philadelphia, pa, usa, semmelweis university, faculty of medicine, department of physiology, budapest, hungary. vdac proteins represent a main component of the outer mitochondrial mem- brane (omm). the vdac family is composed of isoforms with more than percent similarity. although their primary role was known to be in ion and me- tabolite transport between mitochnodria and cytosol, it has been discovered that vdacs are involved in apoptotic pathways. we have recently found that spe- cifically the vdac isoform is needed for tbid-induced cytochrome c release, due to its role in supporting bak insertion to the omm (roy et al. . embo rep. : - ). sequence analysis of the mammalian vdac isoforms shows a unique n terminal end in vdac , which is likely to be exposed to the cyto- plasm. to test the functional significance of this n terminus, the first amino acids were removed from vdac or were added to vdac . vdac -/- mef cells that are resistant to tbid, were rescued with these constructs and cyto- chrome c release was monitored in permeabilized cells by single cell imaging and immunoblotting. these studies revealed that cytochrome c release upon tbid application is effectively supported by both full length vdac and the vdac n-terminal deletion mutant. furthermore, vdac extended by the n terminus of vdac failed to restore cytochrome c release in vdac -/- mefs. thus the n terminus of vdac seems to be dispensible for tbid- induced omm permeabilization. currently, we are designing different muta- tions which target some addititional unique sequences in vdac to find the specific domain that is essential for tbid induced cytochrome c release. -plat patch-clamp analysis of mitochondrial ca d uniporter in different tissues francesca fieni, yuriy kirichok. ucsf, san francisco, ca, usa. the mitochondrial ca þ uptake has been recognized as a central player in cel- lular pathophysiology for decades. pathways of ca þ transport across the inner mitochondrial membrane (imm) were investigated indirectly with biochemical techniques and most recently by applying the patch clamp technique to mito- plasts isolated from mammalian systems. patch-clamp recording of the imm have proved to provide an unambiguous picture of mitochondrial ca þ uptake under strictly controlled conditions. in this study, we evaluated and compared the biophysical properties of mito- chondrial ca þ uptake in different mouse tissues. freshly isolated mitoplasts from mouse heart, skeletal muscle, liver, kidney, spleen and brown adipose tis- sue were patch clamped in the whole-mitoplast configuration. voltage step and ramp protocols covering the whole range of physiological potentials were ap- plied to elicit the inwardly rectifying ca þcurrent sensitive to rur known as mcu. the distribution of mcu current densities between tissues was as fol- lows: spleen > brown adipose tissue z skeletal muscle > kidney > liver >> heart. interestingly, mcu current density in heart was about times smaller than in skeletal muscle. our results support the view of a differential tissue activity of mcu, which can be explained by either a different distribution of mcu channel and/or by a different expression of its regulatory subunits confer- ing various modes of physiological regulation. further on, in order to investigate the putative direct contribution of uncou- pling protein isoform and (ucp / ) to the uniporter, we investigated mcu properties in wild type (wt) mouse tissues where these two proteins have been found to have a major role and compared its properties in the corre- spondent tissues of ucp and ucp ko mice. we found no significant differ- ences in calcium currents of any of the wt tissues studied compared to their ucp / ko counterparts. -plat sr-mitochondrial ultrastructure in the heart of normal and ethanol-fed rats gyorgy csordas , david mankus , tanvir shaikh , xing meng , jan hoek , carmen mannella , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, wadsworth center, albany, ny, usa. chronic alcoholism causes various forms of stress in the heart, and this is often accompanied by mitochondrial dysfunction. a putative source of mitochondrial dysfunction is sr-mitochondrial stress and the ensuing mitochondrial ca þ overload. to test this possibility, first we isolated mitochondria from chronic ethanol-fed ( months) and paired control rats, and documented ethanol- dependent sensitization to ca þ and ros-induced permeabilization. to evalu- ate the ultrastructural basis of the mitochondrial impairments, we performed transmission electron microscopy (tem) and electron tomography studies of left ventricular muscle. the overall ultrastructure of the myocytes became less organized in the ethanol-fed condition. also, a considerable fraction of the mitochondria lost the highly ordered structure of the cristae and showed an increase in the cross-sectional area. however, the size of the sr- mitochondrial associations and the gap-width at the interface was unchanged. evaluation of the sr-mitochondrial tethers by electron tomography indicates that they occur in clusters and display heterogeneity in length, as previously re- ported for er-mitochondrial tethers in normal rat liver (csordas et al, , j cell biol, : ). overall tether length distribution appears to be unaltered by alcohol ingestion. analyses of effects of alcohol ingestion on tether membrane-surface density and structural classes (linear, v, y and more com- plex shapes) is in progress, as is d analysis of ser and mitochondrial inner- and outer-membrane topologies. (supported by nih grant rc aa .) -plat bcl-xl increases bax mitochondrial localization and activation in non- apoptotic cells laurent m. dejean , thibaud t. renault , oscar teijido , gisele velours , yogesh tengarai ganesan , nadine camougrand , bruno antonsson , stephen manon . california state university of fresno, fresno, ca, usa, cnrs, institut de biochimie et de génétique cellulaires, bordeaux, france, nih, nichd, bethesda, md, usa, memorial sloan kettering cancer center, new york, ny, usa, merck serrono s.a., geneva research center, geneva, switzerland. we report that, in non-apoptotic pro-lymphocyte cells, bcl-xl induced an in- crease of the mitochondrial localization of bax up to the level found in apopto- tic cells. furthermore bcl-xl stimulated both the active conformation of bax and increased the total amount of bax inserted in the outer mitochondrial mem- brane. in order to further investigate the molecular mechanisms involved in this effect, different bax and bcl-xl mutants were co-expressed in yeast. we found that wild-type bcl-xl increased the mitochondrial localization of both wild- type bax and of an active mutant bax-s d, while mutant bcl-xl-g a did not have this effect. further, wild-type bcl-xl protected bax-s d against proteolytic degradation. finally, we found that a c-terminally truncated mutant of bcl-xl, that lost its capacity to inhibit bax-induced release of cyto- chrome c, still increased the mitochondrial localization of wild-type bax, thus promoting the release of cytochrome c. these data suggest that bcl-xl, by act- ing as a modulator of mitochondrial bax localization, may play an active role along the pathway leading to bax activation. -plat the physiological response of intact ex vivo mitochondria upon apopto- tic stress: insight into the regulation of apoptosis at a mitochondrial level martin n. lidman , marcus wallgren , olivier keech , yong-zhi guo , tor ny , gerhard gröbner . chemistry department, umeå university, umeå, sweden, umeå plant science center, umeå, sweden, medical chemistry and biophysics, umeå university, umeå, sweden. apoptosis - programmed cell death - is vital for multicellular organisms to dis- pose of redundant, damaged or infected cells. this mechanism becomes dys- functional in cancer where tumor cells survive drug-induced death signals. reversely, upregulated apoptosis can induce premature neuronal cell death in amyloidogenic diseases such as alzheimer’s disease (ad) or amyotrophic lateral sclerosis (als). mitochondrion, the power plant of the cell, contains an arsenal of proteins which regulate programmed cell death. there, the pro- and anti-apoptotic bcl- proteins meet at the mitochondrial membrane to decide the fate of a cell. how the molecular activities of the anti-apoptotic 	the isoform specific n terminus of vdac is dispensable for tbid induced cytochrome c release 	patch-clamp analysis of mitochondrial ca + uniporter in different tissues 	sr-mitochondrial ultrastructure in the heart of normal and ethanol-fed rats 	bcl-xl increases bax mitochondrial localization and activation in non-apoptotic cells 	the physiological response of intact ex vivo mitochondria upon apoptotic stress: insight into the regulation of apoptosis a ... with surgical bypass, with shorter hospitalizations in symptomatic and asymptomatic patients. further long-term follow-up is required to compare these two treatment modalities for durability to determine the optimal popliteal aneurysm management. multifactorial disease severity score (dss) predicting the success of endovascular intervention of femoropopliteal peripheral arterial disease in-kyong kim, md, natalia egorova, phd, andrew j. meltzer, md, james f. mckinsey, md . columbia university, new york presbyterian hospital system, new york; mount sinai university, new york; and new york presbyterian hospital, new york, ny objective(s): the goal was to create a multifactorial disease severity score (dss) for characterization of femoropopliteal arterial lesions. by having a greater understanding of the effect of patient comorbidities and an in-depth method to characterize an arterial lesion, we may be able to better compare lesions in different studies and predict which therapy is most appropriate for each lesion undergoing an endovascular intervention (evi). methods: we evaluated lesion and patient characteristics in our prospectively maintained lower extremity arterial lesion database from to to create a gradated dss. results: we identified femoropopliteal lesions in patients. statistical analysis by multivariable cox proportional hazards model identi- fied variables that impact patency: seven lesion characteristics (table i) and nine patient characteristics or comorbidities (table ii). factors with the most impact were a chronic total occlusion (dss ), lesion length � mm (dss ), and no runoff vessels and stenosis of % to % (dss ). the following factors were considered baseline, or score of : stenosis � %, lesion length � mm, and three-vessel runoff. by adding these variable scores, a dss was created and used to predict patency of the evi. conclusions: the presence of a chronic total occlusion, lesion length � mm, poor runoff, and the presence of congestive heart failure have the most dramatic effect on patency after evi. a compre- hensive dss allows for the in-depth classification of lesion characteristics and factors that predict success of evi and can allow for comparison of distinct lesions. future comparisons of effectiveness of treatment modal- ities can be possible. table i. significant femoropopliteal lesion characteristics that negatively impact patency after endovascular intervention factor score hr ( % ci) chronic total occlusion . ( . - . ) stenosis %- % . ( . - . lesion length � mm . ( . - . ) vessel runoff . ( . - . ) . ( . - . ) . ( . - . ) lesion calcification . ( . - . ) ci, confidence interval; hr, hazard ratio. table ii. patient characteristics that impact patency after endovascular intervention factor (n � ) score cox coefficient hr ( % ci) chf . . ( . - . ) female sex . . ( . - . ) current smoker . . ( . - . ) former smoker . . ( . - . ) diabetes . . ( . - . ) cad . . ( . - . ) renal . . ( . - . ) age, years - . . ( . - . ) - � � . . ( . - . ) cad, coronary artery disease; chf, congestive heart failure; ci, confi- dence interval; hr, hazard ratio. defining the role of endovascular therapy in critical limb ischemia with tissue loss andrew j. meltzer, md, gisberto evangelisti, md, ashley graham, francesco aiello, md, peter h. connolly, md, harry l. bush, md, john k. karwowski, md, darren b. schneider, md. new york presbyterian hospital, new york, ny objective(s): we compare the utility of endovascular therapy (et) with bypass surgery for critical limb ischemia (cli) with tissue loss and identify risk factors for failure of et. table. hazard ratio (hr/ aor) % ci for hr/ aor p value overall survival dialysis dependence . . – . . angina . . – . . copd . . – . . amputation free survival rutherford . . – . . copd . . – . . limb salvage rutherford . . – �. wound healing at months diabetes . . – . current smoking . . – . patency loss . . – . methods: a retrospective review ( to ) of patients under- going et for tissue loss (rutherford class and ) provided data for multivariate models of overall survival, amputation-free survival (afs), limb salvage, and wound healing. comparisons were made with a bypass surgery cohort matched for tissue loss. results: ninety-four patients underwent et ( % transatlantic intersociety concensus [tasc] c/d; % tibial) for rutherford ( %) or rutherford ( %) cli with tissue loss of the heel ( %), forefoot ( %), toe(s) ( %), calf/ankle ( %), or multiple locations ( %). sustained limb salvage was % � %. overall survival was % � % and afs was % � % at years. predictors of failure by multivariate models are reported in the table. comparison between the rutherford wrsubgroup (n � ) and an rutherford bypass cohort (n � ), suggest equivalent limb salvage, with reduced afs (p � . ) and a trend toward reduced overall survival (p � . ). early would healing was higher after bypass: % vs % at months (p � . ) and % vs % at months (p � . ). conclusions: given the short life expectancy of patients with tissue loss, et permits sustained limb salvage in patients at high risk for bypass (particularly rutherford ). however, wound healing is slow compared with bypass and requires sustained patency. midterm results of limb salvage and stent patency with popliteal artery stenting across the knee joint aleksandra policha, md, neil moudgill, md, lily chang, bs, anu- meha whisenhunt, do, shawn pierce, crnp, luis eraso, md, paul dimuzio, md, atul rao, md, joshua eisenberg, md . department of general surgery and division of vascular and endovascular surgery, thomas jefferson university hospital, philadelphia, pa; thomas jefferson university college of medicine, philadelphia, pa; and division of vascular medicine, thomas jefferson university hospital, philadelphia, pa objective(s): this study evaluated the relationship of stent location on limb salvage and stent patency in patients undergoing popliteal artery stenting. methods: we performed a retrospective review of a prospectively collected database, identifying all patients undergoing popliteal artery stenting between september and february . patients were divided into two groups based on the position of the distal end of the stent in relation to the knee joint. the proximal popliteal stent group included patients receiving a stent ending above the patella (above the flexion point of the knee). the distal popliteal stent group included patients receiving a stent(s) ending below the patella (in the flexion zone). data collected included demographics, indication for surgery, journal of vascular surgery volume , number abstracts slide . % . % . % . % received book (n = ) recommended book (n = ) n u m b e r o f p a rt ic ip a n ts book status vs. amount of book read read at least some of book did not read book prospective randomized control trial using best-selling smoking cessation book james foshee; anita oh, md; adam luginbuhl, md; joseph curry, md; william keane, md; david cognetti, md thomas jefferson university hospital, department of otolaryngology – head and neck surgery patients recruited between april and august • patients with long-term follow-up scheduled before sept. eligible for follow-up • patients voluntarily unenrolled • patients could not be reached for follow-up • patients had disconnected or non- working phone numbers • patient died during the course of the study • patients voluntarily unenrolled • patients could not be reached for follow-up • patients had disconnected or non-working phone numbers abstract: this study aimed to evaluate the efficacy of the educational, self-help book the easy way to stop smoking by allen carr in achieving smoking cessation in patients being screened or currently being treated for cancers of the head and neck. a prospective, randomized control trial was conducted involving patients being screened or undergoing treatment for head and neck cancer at the thomas jefferson university hospital department of otolaryngology. participants completed surveys assessing readiness to quit smoking, amount of tobacco usage, and amount of time actively smoking. the easy way to stop smoking was provided to half of the participants, while the other half received a recommendation to purchase the book. all patients received physician directed smoking cessation counseling. phone surveys were conducted at short and long-term follow-up intervals to determine if the patients had purchased and/or read the book and whether they were still smoking. of the patients recruited, were eligible for follow-up, and only completed the long-term follow-up survey. the remaining participants were lost to follow-up for various reasons. those who received the book for free were more likely to read at least some of the book, p = . , although reading the book did not appear to correlate with successful smoking cessation, p = . . only % of patients who received the book (n = ) quit, while % of patients (n = ) who were recommended the book quit smoking, although this difference was not significant, p = . . patients who indicated “readiness” or “actively trying” to quit (n = ) appeared more likely to be successful than those who would only “consider” quitting (n = ), but the differences were not significant, p = . . smoking cessation rates did not appear to be impacted by reading allen carr’s the easy way to stop smoking. cessation rates between groups who read and did not read the book were similar, and the small differences were not statistically significant. despite a majority of the cohort indicating at least a readiness to quit smoking, only a small portion of patients managed to achieve successful smoking cessation. this study seems to support the notion that there is no single method to promote cessation, and that patient motivation remains an important factor in achieving long-term smoking abstinence. introduction: smoking is the most common preventable risk factor in the development of head and neck cancers[ ]. patients who smoke can be up to times more likely to develop cancers of the head and neck than non-smokers[ ]. oral cancer patients who continue to smoke are also at increased risk for developing additional primary malignancies[ ]. smoking cessation can reduce the risk of oral cancer by % within the first five years. after ten years, the risk of developing oral cancer approaches the risk of non-smokers[ ]. as such, it is extremely important to promote smoking cessation counseling in all patients who smoke, particularly those who have already been diagnosed with a head and neck malignancy. even after diagnosis, successful smoking cessation can improve survival rates. there are a variety of programs and interventions aimed at smoking cessation, although maintaining smoking abstinence is always a challenge. printed education materials have been found to improve physician practices, but their efficacy is as of yet inconclusive for patient outcomes[ ]. in the thomas jefferson university hospital department of otolaryngology, we believe one method that may be effective in convincing patients to quit smoking is the best-selling self-help book the easy way to stop smoking, by allen carr. this book explores the reasons people smoke, aiming to change smoker’s feelings about their addictions and challenge misconceptions in order to promote cessation. this study aimed to evaluate the efficacy of the educational, self-help book the easy way to stop smoking by allen carr in achieving smoking cessation in patients being screened or currently being treated for cancers of the head and neck. additionally, this study aimed to determine if providing the book for free improved the likelihood patients would read the book over recommending the purchase of the book. methods: study participants over the age of were recruited during office visits to the thomas jefferson university hospital – department of otolaryngology. current smokers who either underwent screening or were actively being treated for cancers of the head and neck were eligible for recruitment in this study. consenting participants were randomized into two treatment groups: intervention group: received physician counseling on smoking cessation with a recommendation to purchase the book the easy way to stop smoking by allen carr. control group: received physician smoking cessation counseling in addition to a free copy of the book the easy way to stop smoking books were provided by research nurses to allow for adequate blinding of the study physicians. recruited patients completed an “intake questionnaire” to determine, among other things, amount of cigarettes smoked per day, obstacles to quitting, family support, and readiness to quit smoking (evaluated on the following likert scale): = “not planning to quit” = “would consider [quitting] if a reasonable solution was provided” = “ready to take action” = “actively trying to quit” after the initial intake survey, patients were followed-up via phone at short (two weeks to six months) and long term intervals (six months to one year). timing of follow-ups depended on ability to reach the patients via phone. discussion: the easy way to quit smoking does not appear to be an effective intervention to promote smoking cessation by itself. reading the book did not appear to be associated with an increased likelihood to quit smoking. interestingly, those patients who did not read the book at all had the highest percentage of smoking cessation ( . %), as well as the highest mean cigarette reduction ( . %), although neither of these values were statistically significant, p = . and p = . , respectively. additionally, those patients who read the entire book (compared to those who read some or none of the book) showed the lowest average cigarette reduction ( . %), p = . . a cancerous diagnosis correlated with a minor increase in the likelihood that patients would quit smoking, although it was not a significant difference, p = . . these findings are inconsistent with the literature, as cancer has been shown to be an effective motivator for smoking cessation[ , ]. anecdotally, several patients surveyed admitted their cancer diagnosis was the major reason for their smoking cessation, and not the easy way to stop smoking. providing the intervention (i.e. allen carr’s book) free-of-charge ensured patients were more likely to utilize the intervention. those who received the book free of charge from the tjuh department of otolaryngology were more likely to read the book ( . %) than those who were only recommended to purchase the book ( %), p = . . when suggesting other smoking cessation interventions, cost to the patient may be a factor affecting compliance. identifying patients who are ready or motivated to quit smoking may be useful in targeting smoking cessation interventions, as these patients may be more likely to successfully quit smoking. finding the motivation to quit seems to be a major obstacle in smoking cessation, and is supported in the literature[ ]; those who are motivated to quit smoking are more likely to be successful. many of the study participants enjoyed reading the book, although few managed to successfully quit smoking during the study. patients who initially reported readiness to quit or were actively trying to quit smoking were successful in higher percentages ( . % and . %, respectively) than those who would only consider quitting ( %), p = . . despite a lack of statistical significance, these trends are certainly interesting. a similar study illustrated that patients with low motivation or low readiness to quit were unlikely to benefit from self-help materials, such as a smoking cessation book[ ]. the small sample size and large participant attrition are limitations of this study. while some attrition was expected, we did not anticipate losing the number of patients we did ( %). conducting the follow-up surveys via phone also presented challenges, as many of the study participants were either undergoing or recovering from treatment for head and neck cancers. likely, the stress and hardships associated with a cancer diagnosis contributed to some of the participant loss. another limitation was the study’s reliance on self-reported data collected in surveys. patients have been known to underestimate their cigarette intake[ ], and it’s entirely possible some patients may have overestimated the amount of the book they read. conclusion: nearly every patient surveyed that read the book enjoyed the the easy way to stop smoking, finding it both helpful and informative, although only a small percentage of patients managed to translate the book’s message into practice and achieve smoking cessation. due to the small sample size, it is difficult to make any concrete conclusions about the efficacy of allen carr’s the easy way to stop smoking, although the small percentage of patients who did quit smoking suggests there is no single “magic-bullet” approach that can tackle the intense nature of nicotine addiction. identifying a patient’s motivation to quit may be a useful tool in tailoring future cessation strategies and treatment, but achieving long-term smoking cessation still remains a major challenge to both patients and otolaryngologists. any attempts at promoting smoking abstinence should likely involve a multi- faceted approach. f( , ) = . , p = . acknowledgements: tara difabio, amy wotlinksi, and kristin loeb for their help in recruiting study participants. elizabeth duddy for coordinating the study, as well as recruiting and following-up with study participants. results: # c ( , n = ) = . , p = . . % . % . % . % received book (n = ) recommended book (n = ) n u m b e r o f p a rt ic ip a n ts book status vs. smoking status quit smoking did not quit smoking % . % . % % % % % % % would consider quitting (n = ) ready to quit (n = ) actively trying to quit (n = ) p a rt ic ip a n ts w h o q u it s m o k in g ( % ) readiness to quit vs. smoking status . % . % . % . % . % . % . % . % . % . % read entire book (n = ) read some of book (n = ) did not read book (n = ) m e a n c ig a re tt e r e d u c ti o n ( % ) mean cigarette reduction vs. amount of book read c ( , n = ) = . , p = . % % % % % % % % self-reported obstacles to quitting anxiety or stress exposure to smokers at work/home craving for nicotine or habit of smoking fears of weight gain, depression, or boredom feels unable to quit or lacks willpower enjoy smoking or does not want to quit no obstacle reported multiple obstacles reported references: . marur, shanthi, and arlene a forastiere. “head and neck cancer: changing epidemiology, diagnosis, and treatment.” mayo clinic proceedings. mayo clinic , no. (april ): – . doi: . / . . . . day, terry a, angela chi, brad neville, and james r hebert. “prevention of head and neck cancer.” current oncology reports , no. (march ): – . . marron m., boffetta p., zhang z-f., et al. “cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk.” int j epidemiol , ( ): – . . giguère, anik, france légaré, jeremy grimshaw, stéphane turcotte, michelle fiander, agnes grudniewicz, sun makosso-kallyth, fredric m wolf, anna p farmer, and marie-pierre gagnon. “printed educational materials: effects on professional practice and healthcare outcomes.” the cochrane database of systematic reviews ( ). . pinto, bernardine m., elizabeth eakin, and nancy c. maruyama. “health behavior changes after a cancer diagnosis: what do we know and where do we go from here?” annals of behavioral medicine , no. (march , ): - . . blanchard, chris m., maxine m. denniston, frank baker, stuart r. ainsworth, kerry s. courneya, danette m. hann, dean h. gesme, douglas reding, thomas flynn, and john s. kennedy. “do adults change their lifestyle behaviors after a cancer diagnosis?” american journal of health behavior , no. (may , ): – . . hymowitz, n, k m cummings, a hyland, w r lynn, t f pechacek, and t d hartwell. “predictors of smoking cessation in a cohort of adult smokers followed for five years.” tobacco control suppl ( ): s – . . dijkstra, a, h de vries, and j roijackers. “targeting smokers with low readiness to change with tailored and nontailored self-help materials.” preventive medicine , no. (february ): – . . morales, nelson a, michelle a romano, k michael cummings, james r marshall, andrew j hyland, alan hutson, and graham w warren. “accuracy of self-reported tobacco use in newly diagnosed cancer patients.” cancer causes & control: ccc , no. (june ): – . % . % . % . % cancerous diagnosis (n = ) non-cancerous diagnosis (n = ) n u m b e r o f p a rt ic ip a n ts diagnosis vs. smoking status quit smoking did not quit smoking c ( , n = ) = . , p = . c ( , n = ) = . , p = . n = c ( , n = ) = . , p = . . % . % . % % % % % % read entire book (n = ) read some of book (n = ) did not read book (n = ) p a rt ic ip a n ts w h o q u it s m o k in g ( % ) amount of book read vs. smoking status s o u r c e : h t t p s : / / d o i . o r g / . / b o r i s . | d o w n l o a d e d : . . xvii-xviii. bulletin de la société d'études anglo-américaines des xviie et xviiie siècles william howard adams, the paris years of thomas jefferson michèle crogiez labarthe citer ce document / cite this document : crogiez labarthe michèle. william howard adams, the paris years of thomas jefferson. in: xvii-xviii. bulletin de la société d'études anglo-américaines des xviie et xviiie siècles. n° , . pp. - ; https://www.persee.fr/doc/xvii_ - _ _num_ _ _ fichier pdf généré le / / https://www.persee.fr https://www.persee.fr/collection/xvii https://www.persee.fr/collection/xvii https://www.persee.fr/collection/xvii https://www.persee.fr/doc/xvii_ - _ _num_ _ _ https://www.persee.fr/doc/xvii_ - _ _num_ _ _ https://www.persee.fr/authority/ https://www.persee.fr/doc/xvii_ - _ _num_ _ _ notes de lecture fets d'éclairage par le haut (zénithal ou latéral). on retrouve aussi le recours, dans la décoration des salles, à la couleur vive, aux surfaces vernies et aux miroirs. soane manifeste aussi sa virtuosité dans l'organisation du confort de l'habitat, avec la généralisation des parcours séparés pour les domestiques et pour les maîtres, l'aménagement de cabinets de toilette et même de bains souterrains. deane rappelle aussi l'intérêt architectural des bâtiments de service, plus modestes mais toujours élégants et parfois originaux, comme la laiterie "primitiviste" de betchworth (surrey), directement inspirée des théories de laugier sur l'origine de l'architecture. le plaisir du lecteur est en outre redoublé grâce à l'inclusion d'une admirable iconographie comprenant des photographies originales dues à martin charles et de très nombreux dessins aquarelles de l'auteur rendant bien la luminosité si particulière des intérieurs de soane. jacques carrÉ université de paris - sorbonne - paris iv adams, william howard. the paris years of thomas jefferson. new haven: yale up, . x + pp. £ . . la rencontre de jefferson avec paris est bien autre chose qu'un épisode biographique. pour un francophile convaincu, arrivant dans un pays et à une époque où l'expérience américaine rend imaginable un renouvellement, voire des innovations (qu'on n'appelle pas encore révolutionnaires), ces cinq années d'activité diplomatique importantes dans les relations franco-américaines ( ) rendent compte également d'une expérience individuelle fondamentale. car la francophilie, le goût de la culture classique et des beaux-arts, non pas seulement pour leur valeur élégante ou mondaine, mais pour leur signification politique, préexistaient chez lui à son séjour en europe. cette francophilie justifie la démarche du livre, essentiellement thématique et rétrospective: elle s'ouvre sur les derniers jours du séjour parisien, en septembre , et va présenter les relations (franklin, lavoisier, la fayette, le duc de la rochefoucauld, les cosway, hubert robert, david et ledoux), les sujets d'observations (notamment architecturales) et les thèmes de la pensée politique auxquels l'envoyé de la jeune république est confronté et qui rejoignent souvent des préoccupations anciennes évoquées en parallèle; les conséquences de ces découvertes parisiennes sur la suite de son action privée à monticello ou publique au gouver- notes de lecture nement sont également évoquées thème par thème. la construction de l'ouvrage rend la lecture très agréable; l'index détaillé des noms et surtout des notions facilitera la consultation érudite. après deux chapitres de biographie intellectuelle, la présentation détaillée du paris des années (ch. ) montre à quel point la modernisation de la ville était en cours. féru d'architecture et par ailleurs à la recherche de modèles pour le pays qu'il aurait à bâtir, jefferson se passionna naturellement pour le nouveau palais royal, les constructions de le- doux et les nouveaux hôtels (ch. ). l'auteur traite avec nuance du décalage entre ses goûts personnels raffinés, dont témoignent ses dessins et ses achats parisiens (conservés aujourd'hui encore à monticello pour certains), et sa vision de la vertu américaine qui ne peut se conserver qu'hors du luxe et des grandes villes (ch. ). les chapitres et , les plus denses, présentent le diplomate et l'époque troublée de sa mission. la question délicate de l'esclavagisme est traitée ici sans complaisance, qui montre jefferson coincé entre ses exigences morales et les nécessités économiques et politiques de la virginie. l'étude restitue l'exigence intellectuelle d'un homme qui a su affronter les conflits de son temps, une sorte néanmoins d " intégriste" de la liberté ( ) qui en viendra à regarder comme prix à payer pour elle les morts en martyrs de ses amis aristocrates: image concrète d'un jefferson dont l'historiographie n'a jamais pu réduire ni expliquer la double nature idéaliste et empirique. l'étude constate l'importance politique que jefferson a toujours accordée à l'éducation, celle aussi des relations personnelles, y compris dans les cercles féminins alors si importants (ch. ), aussi bien pour le mécénat artistique, pour l'évolution de la théorie politique (liens avec les journalistes, traducteurs, imprimeurs) que pour les choix politiques des années suivantes: tout cela trouve sa racine dans sa culture philosophique et architecturale classique, mais actualisée dans la france bouillonnante de l'ancien régime finissant, au contact des élites du temps et devant le spectacle des misères dont il rendait cet ordre ancien responsable. ce "jefferson à paris," qui fourmille de références précises pour pousser plus loin l'enquête, porte, en fait, sur "jefferson et paris" et montre que cette interaction fut constitutive de sa vie et de sa pensée. les nombreuses illustrations, judicieusement placées et légendées, sont bienvenues pour concrétiser l'exposé. michèle crogiez université de berne 	 	pagination 	 	 transatlantica, | transatlantica revue d’études américaines. american studies journal  | state of the union nicole fouché. benjamin franklin et thomas jefferson : aux sources de l’amitié franco-américaine - . paris : michel houdiard, . p. nathalie caron Édition électronique url : http://journals.openedition.org/transatlantica/ doi : . /transatlantica. issn : - Éditeur afea référence électronique nathalie caron, « nicole fouché. benjamin franklin et thomas jefferson : aux sources de l’amitié franco- américaine - . », transatlantica [en ligne], | , mis en ligne le avril , consulté le septembre . url : http://journals.openedition.org/transatlantica/ ; doi : https://doi.org/ . /transatlantica. ce document a été généré automatiquement le septembre . transatlantica – revue d'études américaines est mis à disposition selon les termes de la licence creative commons attribution - pas d'utilisation commerciale - pas de modification . international. http://journals.openedition.org http://journals.openedition.org http://journals.openedition.org/transatlantica/ http://creativecommons.org/licenses/by-nc-nd/ . / http://creativecommons.org/licenses/by-nc-nd/ . / http://creativecommons.org/licenses/by-nc-nd/ . / http://creativecommons.org/licenses/by-nc-nd/ . / nicole fouché. benjamin franklin et thomas jefferson : aux sources de l’amitié franco-américaine - . paris : michel houdiard, . p. nathalie caron spécialiste des relations franco-américaines, nicole fouché propose une comparaison presque terme à terme entre deux pères fondateurs de renom, benjamin franklin et thomas jefferson. ce choix, comme la brièveté de l’ouvrage, le nombre limité de notes, la présence d’une courte bibliographie et l’absence d’index, répond aux exigences de la collection « biographies américaines », dirigée par annick foucrier, dont l’objectif est de « présenter l’histoire des etats-unis à travers les vies de deux personnages emblématiques, montrés en miroir, dans la comparaison, la coopération ou l’affrontement ». ici, le moment de l’histoire américaine que ce choix éditorial permet d’appréhender est la naissance des relations franco-américaines, de — lorsque la déclaration d’indépendance des colonies américaines impose la nécessité de trouver une aide extérieure et donc de lancer une politique étrangère — à , date à laquelle se termine le deuxième mandat présidentiel de jefferson et se confirme la volonté américaine d’adopter une position de neutralité vis-à-vis de la france. si le choix s’est porté sur franklin et jefferson, c’est qu’ils furent les deux premiers ministres plénipotentiaires américains à la cour de versailles et sont, pour l’auteur qui ne cache pas son admiration pour tous deux, les « initiateurs de l’amitié, si riche d’avenir », entre la france et les États-unis. leurs séjours respectifs à paris — de à pour franklin, de à pour jefferson — recouvrent d’ailleurs la période de formation des États-unis, de la déclaration d’indépendance à l’élection du premier président, george washington. après une préface de claude folhen, l’étude s’ouvre par un chapitre intitulé « le cadre et les personnages », où est décrit, de façon très didactique, le contexte historique, depuis la guerre de sept ans, qui opposa la france et l’angleterre sur le sol américain entre et , jusqu’à la recherche d’une aide extérieure indispensable à la nicole fouché. benjamin franklin et thomas jefferson : aux sources de l’amiti... transatlantica, | poursuite de la rébellion américaine contre la couronne britannique, c’est-à-dire jusqu’à la tentative faite par les nouveaux États-unis d’obtenir un traité d’alliance avec la france, rivale de l’angleterre. sont ensuite présentés franklin et jefferson avant leur départ pour la france, leurs origines sociales et familiales, leur jeunesse et leur personnalité respectives. l’accent est mis sur les différences entre les deux personnages, sans que soit toujours évitée la schématisation. non seulement franklin est de dix-sept ans l’aîné de jefferson, mais il est également de naissance plus modeste ; l’un est né en amérique, l’autre en angleterre ; l’un est citadin, l’autre planteur ; l’un est joueur et extroverti, l’autre sérieux et introverti ; tous deux sont mariés, mais si l’épouse de franklin n’occupe pas une grande place dans sa vie, celle de jefferson, vouée à un destin tragique, fut passionnément aimée, etc. de façon plus pertinente au regard du propos général, l’ouvrage met finalement l’accent sur l’anglophilie de franklin, qui évolua de telle façon qu’il se rangea finalement, en , du côté des insurgés, à la francophilie de jefferson, qui, lorsqu’il fut président, le fit pencher en faveur d’une neutralité raisonnée. de même — aux deux chapitres suivants qui traitent tour à tour de franklin puis de jefferson — l’auteur remarque que les missions des deux ministres intervinrent dans des contextes bien différents, puisque franklin dut se rendre en france pour demander une aide militaire à la cour de versailles et négocier un traité d’amitié en temps de guerre, alors que jefferson eut à confirmer et développer l’alliance française en temps de paix. toutefois, franklin réussit dans sa mission d’une façon plus éclatante que jefferson, puisqu’il obtint, grâce à ses négociations mais aussi parce que la france voyait là un moyen de contrer sa rivale, la signature des deux traités franco-américains de février , à savoir d’une part le traité d’amitié et de commerce et, de l’autre, le traité d’alliance militaire qui en permit l’envoi de troupes françaises sur le territoire américain et assura ainsi la victoire aux colonies rebelles. jefferson, lui, dut œuvrer dans un contexte de crise financière, la france affrontant alors une angleterre en pleine croissance économique, et faire face à la mauvaise volonté des français qui en signèrent un traité commercial, dit traité d’eden, avec l’angleterre. si les succès diplomatiques de jefferson furent limités, ses efforts vinrent consolider les acquis de franklin, dans la mesure où ils favorisèrent les transferts culturels entre france et etats-unis. c’est ce qui ressort des trois chapitres suivants où sont décrits les réseaux de connaissances — officiels et privés — de franklin et de jefferson. n. fouché insiste sur la continuité entre les deux ministres sur le plan social et sur leur complémentarité, même si jefferson ne bénéficia pas du même accueil à la cour que son prédécesseur. jefferson, comme franklin, entretint des liens amicaux étroits avec les philosophes et plus généralement les membres de l’élite française, confirmant ainsi l’amitié franco-américaine amorcée d’une façon tout à fait remarquable par son prédécesseur. À l’initiative des deux hommes, de nombreux échanges culturels et intellectuels eurent lieu, qui permirent à la france et aux États-unis de mieux se connaître et comprendre. À l’instar de franklin, dont les expériences sur l’électricité lui valurent d’être félicité par louis xv et admis à l’académie des sciences de paris, jefferson s’intéressait à la science — il proposa lavoisier comme membre de l’american philosophical society de philadelphie. il se passionnait tout particulièrement pour l’horticulture, importa des plants américains et chercha à faire partager son goût pour le vin français. c’est par l’intermédiaire de franklin que le duc de la rochefoucauld d’enville traduisit en français les constitutions de colonies américaines. de son côté, jefferson fit paraître en france ses notes on the state of virginia et collabora à la nicole fouché. benjamin franklin et thomas jefferson : aux sources de l’amiti... transatlantica, | rédaction de la déclaration des droits de l’homme et du citoyen. curieux, alerte, plus jeune que franklin lors de son séjour en france, jefferson est défini par n. fouché comme un moderne, issu de l’encyclopédisme des lumières, qui non seulement transmit à ses compatriotes une certaine image de la france — à travers l’architecture par exemple qu’il chercha à reproduire en virginie — mais aussi proposa aux français une incarnation de la spécificité américaine. jefferson toutefois ne vit pas tout de la france ; et en particulier ne vit rien de la misère du peuple. il ne semble pas avoir été conscient des fractures de la société française qui furent à l’origine des événements de , date à laquelle il est rappelé aux États-unis. les relations franco-américaines furent ensuite ternies par la venue du ministre plénipotentiaire français, genêt, qui en déclencha une vague de francophobie chez les partisans de washington, par le traité de jay en , qui remit en cause les traités de , et surtout par l’affaire xyz et la quasi- guerre avec la france en . président à partir de , jefferson acheta la louisiane à bonaparte tout en adoptant une position de neutralité vis-à-vis de la france. en somme, voilà un petit livre clair, de lecture facile et agréable, plus descriptif qu’argumentatif, qui intéressera tous ceux qui souhaitent faire le point sur le rôle des deux ministres en france, ou qui cherchent à en savoir plus sur le contexte des lumières et sur la place de franklin et de jefferson dans les cercles français de sociabilité entre et . toutefois, outre la tendance à la schématisation notée plus haut, soulignons le flou de certains passages, qui contraste avec le parti pris pédagogique du chapitre d’introduction. ainsi un lecteur non averti regrettera probablement l’absence de détails sur le contenu du traité de paris de . de même, la présentation de la venue de genêt est incomplète puisque l’accent est mis sur la francophobie déclenchée par les actions du ministre, sans que soit souligné le fait que cette francophobie ne s’étendait pas aux membres des sociétés démocratiques- républicaines, qui continuèrent à soutenir genêt même après son renvoi. index thèmes : recensions auteur nathalie caron université paris — nanterre nicole fouché. benjamin franklin et thomas jefferson : aux sources de l’amiti... transatlantica, | 	nicole fouché. benjamin franklin et thomas jefferson : aux sources de l’amitié franco-américaine - . received / / review began / / review ended / / published / / © copyright zhang et al. this is an open access article distributed under the terms of the creative commons attribution license cc-by . ., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. finding the ‘qr’ to patient safety: applying gamification to incorporate patient safety priorities through a simulated ‘escape room’ experience xiao chi zhang , gretchen diemer , hyunjoo lee , rebecca jaffe , dimitrios papanagnou . emergency medicine, thomas jefferson university, philadelphia, usa . medicine, sidney kimmel medical college at thomas jefferson university, philadelphia, usa . department of emergency medicine, stony brook university hospital, stony brook, usa . hospital medicine, thomas jefferson university, philadelphia, usa  corresponding author: xiao chi zhang, xzhang @gmail.com disclosures can be found in additional information at the end of the article abstract medical errors are the eighth leading cause of mortality in the united states and contribute to over one million preventable injuries. in an effort to prevent medical errors, reporting systems serve as invaluable tools to detect patient safety events and quality problems longitudinally. historically, trainees (i.e., students and residents) rarely submit incident reports for encountered patient safety threats. the authors propose an immersive learning experience utilizing gamification theory and leveraging the increasingly popular ‘escape room’ to help resident trainees identify reportable patient safety priorities. all incoming intern physicians at the thomas jefferson university (jefferson) were enrolled in the patient safety escape room study as part of their residency orientation (june ). the residents were randomly divided into teams. each team was immersed in a simulated escape room, tasked with identifying a predetermined set of serious patient safety hazards, and successfully manually entering them into the jefferson event reporting system within the time allotted to successfully ‘win the game’ by ‘escaping the room’. quick response (qr) codes were planted throughout the activity to provide in-game instructions; clues to solve the puzzle; and key information about patient safety priorities at jefferson. all participants underwent a formal debriefing using the feedback capture grid method and completed a voluntary post-study survey, adapted from brookfield’s critical incident questionnaire (ciq). the study was irb exempt. thematic analysis of the post-activity ciq survey ( n = ) revealed that interns were engaged during the immersive learning experience (n = ) and were specifically engaged by having to independently identify patient safety threats (n = ). participants identified team role assignment (n = ) and effective communication (n = ) as the two most helpful actions needed to successfully complete the activity. participants were overall surprised by the success of the education innovation (n = ) and reported that it changed how they viewed patient safety threats. areas for improvement include clearer game instructions and using a more streamlined event reporting process. the escape room patient-safety activity allowed interns to actively engage in an innovative orientation activity that highlighted the importance of patient safety hazards, as well as providing them with the opportunity to document event reports in real-time. next steps will include longitudinally tracking the quantity of error reports entered by this cohort to determine open access technical report doi: . /cureus. how to cite this article zhang x, diemer g, lee h, et al. (february , ) finding the ‘qr’ to patient safety: applying gamification to incorporate patient safety priorities through a simulated ‘escape room’ experience. cureus ( ): e . doi . /cureus. https://www.cureus.com/users/ -xiao-chi-zhang https://www.cureus.com/users/ -gretchen-diemer https://www.cureus.com/users/ -hyunjoo-lee https://www.cureus.com/users/ -rebecca-jaffe https://www.cureus.com/users/ -dimitrios-papanagnou- the effectiveness of this educational intervention. categories: medical education, medical simulation keywords: medication error reporting, medical simulation, graduate medical education, gamification, escape room, advedrse event reporting, innovation introduction in the united states, medical errors are the eighth leading cause of mortality, with an estimated , to , unnecessary deaths occurring each year, and over one million preventable injuries [ ]. estimated medical errors have resulted in nearly $ billion of lost income secondary to disability and additional healthcare costs [ ]. specific medical error risk factors include inexperienced clinicians (i.e., postgraduate trainees), introduction to new procedures, prolonged hospital stays, complex patient care, and extremes in age [ ]. despite numerous national and institutional efforts to prevent medical errors, reporting errors through mandatory or voluntary means (i.e., patient safety event reporting systems) remain an invaluable tool in identifying and tracking patient safety events and threats to clinical quality. in the groundbreaking report released by the institute of medicine’s (iom) report, ‘to err is human: building a safer health system’, the authors found that more than % of errors were preventable, and the successful reporting of these errors could provide critical data that would inform future efforts to improve patient safety [ - ]. mandatory error reporting systems for serious patient injuries and/or death aim to ) ensure further investigation and follow-up; ) provide incentives to avoid potential penalties and public exposure; and ) ultimately improve patient safety [ ]. voluntary reporting systems, in contrast, are based on a passive form of surveillance, requiring personnel directly involved in a near-miss event to provide essential information and details [ ]. the latter system has the benefit of capturing true events or near misses that would assist in investigating and learning more about the circumstances surrounding the event [ ]. despite the confidentiality that comes with voluntary reporting, there are numerous limitations and barriers to effective, voluntary event reporting. common physician barriers for submitting incident reports include: ) lack of incident follow-up; ) long forms; ) perceived ‘trivial’ nature of the incident; ) lack of time; and ) unclear responsibility for making the report [ ]. furthermore, increased public pressure on preventable errors, coupled with the threat of legal action and additional psychological sequelae (i.e. guilt, anger, inadequacy, and depression) associated with these errors, can perpetuate a culture of blame and avoidance, and deter helpful voluntary incidental reporting [ - ]. while both reporting systems are integral for detection and improvement of existing infrastructure weaknesses, efforts are required to encourage the use of voluntary reporting system. clinician educators are tasked with teaching physicians-in-training medical and patient safety practices. teaching patient safety and error reporting to the graduate medical education (gme) audiences, however, is challenging. only a minority of event reports are contributed by resident physicians and fellows at thomas jefferson university (jefferson). in the setting of the aforementioned barriers to reporting, the authors also recognize that a new, unfamiliar system would potentially further deter new interns from reporting events. in effort to augment active learning and engagement with teaching voluntary event reporting, the authors developed an interactive, immersive learning experience incorporating gamification and leveraging the increasingly popular ‘escape room’ design to incoming jefferson intern and resident physicians to better identify potential patient safety priorities and zhang et al. cureus ( ): e . doi . /cureus. of practice logging these events into the jefferson event reporting system. ‘escape rooms’ have risen in popularity in creating a high-fidelity, foreign environment that rewards players for working together, solving clues, and completing successions of mind-bending tasks in order to ‘escape the room’ in a limited amount of time. notably, the immersive and adaptive nature of the escape room has enabled this team-building activity to be incorporated as an innovative educational tool for a multitude of medical specialties [ - ]. we propose that exposing incoming interns and residents to various team-based activities on critical patient safety priorities, as well as providing them with the opportunity for guided reflection during a facilitated debriefing, will allow them to ) identify local patient safety priorities; ) physically enter an event report using the jefferson event reporting system; and ) practice using teamwork skills to address patient safety threats. technical report study setting four standard simulation rooms at the rector clinical skills and simulation center at thomas jefferson university in philadelphia, pennsylvania (pa) were secured to create four separate escape rooms that were operated concurrently: two of these rooms simulated a hospital inpatient room, and the other two rooms simulated a patient room in the emergency department (ed). the activity took place in june , during new intern and resident orientation. study participant selection all participants were interns (i.e., post-graduate year one, pgy- , residents) beginning their training at thomas jefferson university hospitals. there were no exclusion criteria. all participants consented to participate in the activity. all incoming pgy- residents were asked to attend this activity as part of their orientation curriculum prior to starting their respective residency programs. materials required participants were not asked to bring any additional tools or materials to the escape room. specific equipment required for the escape rooms has been listed in table . zhang et al. cureus ( ): e . doi . /cureus. of patient safety escape room materials hospital bed mannequin computer (with internet connection to enter error report) ventilator sequential compression devices isolation cart with gowns opened lumbar puncture kit (with sharps removed for safety) identification bracelet falls risk bracelet allergy bands adult diaper yellow falls socks urinal restraints incentive spirometer quick response (qr) codes door sign paper chart clipboard with blank list for recording hazards and clues (appendix: hazard list) table : equipment and materials required for the patient safety escape room simulation cases personnel requirements in order to coordinate, facilitate, and set-up the rooms for each session, faculty members were recruited to supervise the events. there were four simulation facilitators, four simulation observers, two traffic controllers, and two debriefing facilitators. simulation facilitators were present in each of the rooms to provide any necessary hints, suggestions, or technical support to effectively guide the learners through the cases. observers were able to remotely view all of the student activity in a control room via video streaming through an encrypted, institution wireless network. traffic controllers helped organize and coordinate learners moving from room to room. the debriefing facilitators were tasked with debriefing teamwork skills used during the activity, as well as discussing patient safety hazards noted in the rooms. zhang et al. cureus ( ): e . doi . /cureus. of group structure all incoming interns were randomly divided into teams, each comprising seven to eight residents. teams were tasked to work together to identify a predetermined series of patient safety threats that were planted in each simulated escape room, and successfully enter these events into the jefferson event reporting system within the allotted time of minutes in order to successfully ‘escape the room’ and win the game. simulation sessions ran throughout the afternoon. groups were staggered, and interns were assigned a specific time to arrive at the simulation center. prior to arrival, they received a - minute didactic session on the jefferson event reporting system, which was led by the principal investigators (rj). participants received a brief primer on the concept of the escape room activity. they were then led to their respective escape rooms. the day was broken down into four -minute blocks (blocks - ) and took place from pm to pm (figure ). figure : participant flow for the escape room challenge etr: escape the room detailed activity description four simulation rooms were set up for the escape room activity, allowing four teams (up to players) to be assessed concurrently. half of the simulation rooms were designated as case (internal medicine case), and the other half were designated as case (emergency medicine case). cases and represented two distinct simulated clinical environments with a unique set of respective challenges and patient safety hazards (figures - ). each case was developed and revised by a multi-disciplinary team composed of senior faculty clinicians of different medical specialties in order to ) mitigate cognitive load; ) standardize chart content; and ) effectively link case content with the medical record, room setup, and patient safety hazards/learning goals. each case contained a ‘patient chart’ that included: ) an objective structured clinical encounter (osce) style ‘door note’ that consisted of a one-sentence introduction to frame the activity; ) a physician note; ) a nursing note; ) a procedure section; ) a clinical data section (i.e., imaging, laboratory results, electrocardiogram); and ) an orders section. all props were obtained through the simulation center. there were no sharps or dangerous objects used. figures and demonstrate different styles of illustrating the zhang et al. cureus ( ): e . doi . /cureus. of https://assets.cureus.com/uploads/figure/file/ /lightbox_e eeb fc e e bbf a f be -figure- _participant-flow.png overlay of the cases with pertinent relevant patient safety hazards and props. figure : schematic diagram of the potential clues and overlay of the simulation for case # case # represented a simulated inpatient hospital room with possible hazards and hidden quick response (qr) codes figure : schematic diagram of the potential clues and overlay of the simulation for case # zhang et al. cureus ( ): e . doi . /cureus. of https://assets.cureus.com/uploads/figure/file/ /lightbox_ed a fd e bfda f f ae df-figure- _case- -diagram.png https://assets.cureus.com/uploads/figure/file/ /lightbox_ bb c c c e c a d c f-case- .png case # represented a simulated emergency room with possible hazards and hidden qr codes qr: quick response each team was given minutes to escape the room, followed by a -minute team debriefing facilitated by the simulation observer. a larger -minute group debriefing with all of the participants during each block was also conducted after each group completed both cases. quick response (qr) codes were used to provide teams with instructions, clues, and prompts. qr codes can be accessed with or without paid ‘apps’ by aiming a smartphone camera directly onto the picture. each qr code linked to a web page on a secured network with the associated information on the safety hazard or clue to be solved (figure ). codes were associated with some, but not all, hazards (i.e., - hazards per room). each code contained key information about the patient safety priority, as well as the jefferson event reporting login, password, and/or patient identifier. there were over patient safety hazards shared between the two cases, such as lowered bedrails, elevated beds, wrong medication administration, missing patient-identifying wrist bands, ill-positioned breathing equipment, chart errors, soiled procedure stations, missing restraints, and ill-placed trash items. these safety hazards were selected based on a delphi model with special consideration with implementation feasibility for this simulated study. all elements were required to be documented in the final event report. in order to successfully ‘escape the room’, participants were encouraged to practice teamwork skills (e.g., situation monitoring, closed-loop communication, leadership, and shared mental models) to solve each unique challenge. figure : sample qr associated clue and information sample qr associated clue and information regarding hand hygiene as a safety hazard qr: quick response zhang et al. cureus ( ): e . doi . /cureus. of https://assets.cureus.com/uploads/figure/file/ /lightbox_ f c e e fedb da aec-qr-code.png debriefing after each team completed their respective escape rooms, two faculty co-facilitators debriefed participants using the feedback capture grid method (figure ). the feedback capture grid [ ] consisted of four quadrants, each with a guiding question, such as ‘what went well?’ or ‘what would have you done differently?’ to capture different perspectives. the unique features of the feedback capture grid allow both learners and facilitators to address the strengths and potential weaknesses of the teaching activity in an organized manner, as well as provide opportunities for facilitators to address important patient safety concerns or teamwork dynamics. figure : feedback capture grid for a large group debriefing feedback capture grid for large group debriefing. the 'plus' sign represents things that worked well. the 'triangle' shape represents what could have been done differently. the 'lightbulb' represents any new ideas. the 'question mark' represents any new questions that this activity may have raised. activity evaluation following the debriefing, participants were asked to complete a voluntary post-study survey, adapted from brookfield’s ciq [ ]. the five-item ciq asked participants to provide anonymous responses based on different aspects of the teaching session. this allowed investigators to model critical thinking and reflection; appreciate learning preferences; and identify potential ideas for improvement during future iterations of the activity. responses from the questionnaire were evaluated for thematic codes through open-axial qualitative data analysis (xcz, dp). results one-hundred thirty total interns participated in the activity. all teams were able to successfully escape the room within the -minute time limit. thematic analysis of the post- activity ciq survey (n = , with a . % survey response rate) revealed that the learners were highly engaged by the format of the learning experience (n = ) and the opportunity to identify safety threats (n = ). furthermore, participants found that role assignment (n = ) and zhang et al. cureus ( ): e . doi . /cureus. of https://assets.cureus.com/uploads/figure/file/ /lightbox_ f fe e a d d b -figure- _feedback-capture-grid.png communication (n = ) were the two most helpful actions needed to succeed in the activity. participants were surprised by the overall success of the educational innovation (n = ) and reported that it changed the way they perceived patient safety threats, especially identifying easily-missed errors and the large heterogeneity that exists with regards to safety threats (n = ). areas for improvement focused primarily on logistical details, where the learners identified the documentation process (n = ) and the task completion ( n = ) of the jefferson event reporting interface as the most cumbersome, distancing and confusing elements of the activity. table illustrates a detailed thematic analysis of the ciq questionnaire. ciq indices number of themes identified thematic codes generated (with frequencies, n) most engaged immersion in an active learning experience ( ); discovering safety threats ( ); debriefing ( ); task performance ( ); effective communication ( ); teaming/team building ( ); having a designated role ( ) most distanced error reporting documentation ( ); the escape room experience ( ); confusion on the instructions of the activity ( ); debriefing ( ); not having a clear role ( ); poor group communication ( ) action most helpful role assignment ( ); communication ( ); feedback/debriefing ( ); time-out ( ) action most confusing task completion ( ); role clarity ( ); difficulty in identifying patient safety threats ( ); challenges in communication ( ); event reporting ( ); team dynamics ( ) surprised you most success of the educational innovation ( ); paradigm shift in how patient safety threats are viewed ( ); value of teamwork ( ); error reporting ( ) table : thematic analysis of the ciq from the escape room event specific ciq questionnaires can be found in appendix a. ciq: critical incident questionnaire discussion the authors propose that escape rooms can be utilized to teach patient safety hazards and serve as an effective teambuilding activity. open-axial qualitative analysis of the participants ciq responses revealed that residents recognized the importance of identifying patient safety hazards and felt fully immersed in this innovative method for teaching patient safety and team-building. additional aspects of the program that residents appreciated included the importance of closed-loop communication, team-work building skills (i.e. taking notes, assigning a team leader), and formal debriefing. participants also identified areas of improvement that distanced themselves from completing the objectives, such as complex event reporting, confusing instructions (e.g. how to escape the room), and unclear role clarity among teams, which was limited to the team dynamic of the individual groups, rather than the overall zhang et al. cureus ( ): e . doi . /cureus. of escape room activity. participants, however, were appreciative that efforts were made to incorporate the institution’s official patient safety reporting system into the simulation experience, as it allowed them to feel more confident and comfortable with navigating the software for future use. in order to address these issues, future iteration includes increased instruction time during the -minute didactic session on the goals of the escape room activities, as well as providing the teams extra preparation time to discuss teamwork tactics or leadership selection before entering the rooms. there are several limitations worth noting. the simulations only included some of the common patient errors found in the inpatient and ed setting. the inclusion of these patient safety issues can unintentionally limit learners’ focus on these case-specific details. furthermore, while we encouraged event reporting through active practice within the simulations, additional studies will need to be performed on this cohort to see whether this intervention will lead to an increased number of reporting rates over time. conclusions the escape room patient-safety activity was well received by incoming resident physicians at the thomas jefferson university. the activity allowed learners to actively engage in a fun, non- threatening, low-stakes activity that illustrated the expansive world of patient safety hazards, as well as providing them with the opportunity to document event reports in real time. next steps will include tracking the quantity of error reports entered by this cohort longitudinally to determine the effectiveness of this educational intervention on behavioral change. appendices appendix a – critical incident questionnaire [ ]. . at what moment during the activity did you feel most engaged with what was happening? . at what moment during the activity did you feel most distanced from what was happening? . what action did anyone (i.e., faculty member or peer) take during the activity that you found most affirming and helpful? . what action did anyone (i.e., faculty or peer) take during the activity that you found most puzzling or confusing? . what about the activity this week surprised you the most? (this could be something about your own reactions to what went on, or something that someone did, or anything else that occurs to you.) additional information disclosures human subjects: consent was obtained by all participants in this study. thomas jefferson university issued approval n/a. this study was reviewed and exempted by the thomas jefferson university irb. animal subjects: all authors have confirmed that this study did not involve animal subjects or tissue. conf licts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in zhang et al. cureus ( ): e . doi . /cureus. of the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. references . clemmer tp, spuhler vj, oniki ta, horn sd: results of a collaborative quality improvement program on outcomes and costs in a tertiary critical care unit. crit care med. , : - . . baggs jg, ryan sa, phelps ce, richeson jf, johnson je: the association between interdisciplinary collaboration and patient outcomes in a medical intensive care unit. heart lung. , : - . . validating the trust in teams and trust in leaders scales . 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( ). accessed: november , : https://www.interaction-design.org/literature/article/test-your- prototypes-how-to-gather-feedback-and-maximise-learning. . brookfield s: becoming a critically reflective teacher . jossey bass, san francisco; . zhang et al. cureus ( ): e . doi . /cureus. of https://www.ncbi.nlm.nih.gov/pubmed/ https://www.ncbi.nlm.nih.gov/pubmed/ http://cradpdf.drdc-rddc.gc.ca/pdfs/unc /p _a b.pdf http://cradpdf.drdc-rddc.gc.ca/pdfs/unc /p _a b.pdf http://scottnicholson.com/pubs/erfacwhite.pdf http://scottnicholson.com/pubs/erfacwhite.pdf https://dx.doi.org/ . /inr. https://dx.doi.org/ . /inr. https://dx.doi.org/ . / - . https://dx.doi.org/ . / - . https://dx.doi.org/ . /cpr. . https://dx.doi.org/ . /cpr. . https://dx.doi.org/ . /j. - . . .x https://dx.doi.org/ . /j. - . . .x https://dx.doi.org/ . /aet . https://dx.doi.org/ . /aet . https://dx.doi.org/ . /cureus. https://dx.doi.org/ . /cureus. https://dx.doi.org/ . / . . https://dx.doi.org/ . / . . https://dx.doi.org/ . /j.jsurg. . . https://dx.doi.org/ . /j.jsurg. . . https://dx.doi.org/ . /nnd. https://dx.doi.org/ . /nnd. https://dx.doi.org/ . /ajpe https://dx.doi.org/ . /ajpe https://dx.doi.org/doi: . /ofid/ofy . https://dx.doi.org/doi: . /ofid/ofy . https://www.interaction-design.org/literature/article/test-your-prototypes-how-to-gather-feedback-and-maximise-learning https://www.interaction-design.org/literature/article/test-your-prototypes-how-to-gather-feedback-and-maximise-learning https://www.wiley.com/en-us/becoming+a+critically+reflective+teacher% c+ nd+edition-p- 	finding the ‘qr’ to patient safety: applying gamification to incorporate patient safety priorities through a simulated ‘escape room’ experience 	abstract 	introduction 	technical report 	study setting 	study participant selection 	materials required 	table : equipment and materials required for the patient safety escape room simulation cases 	personnel requirements 	group structure 	figure : participant flow for the escape room challenge 	detailed activity description 	figure : schematic diagram of the potential clues and overlay of the simulation for case # 	figure : schematic diagram of the potential clues and overlay of the simulation for case # 	figure : sample qr associated clue and information 	debriefing 	figure : feedback capture grid for a large group debriefing 	activity evaluation 	results 	table : thematic analysis of the ciq from the escape room event 	discussion 	conclusions 	appendices 	additional information 	disclosures 	references borderline ovarian tumors: diverse contemporary viewpoints on terminology and diagnostic criteria with illustrative images. | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /j.humpath. . . corpus id: borderline ovarian tumors: diverse contemporary viewpoints on terminology and diagnostic criteria with illustrative images. @article{seidman borderlineot, title={borderline ovarian tumors: diverse contemporary viewpoints on terminology and diagnostic criteria with illustrative images.}, author={j. seidman and r. soslow and r. vang and j. berman and m. stoler and m. sherman and e. oliva and a. kajdacsy-balla and d. berman and l. copeland}, journal={human pathology}, year={ }, volume={ }, pages={ - } } 	j. seidman, r. soslow, + authors l. copeland 	published 	medicine 	human pathology the national cancer institute sponsored a borderline ovarian tumor workshop held in august in bethesda, md. this report was developed from discussions at the workshop. the participants acknowledged several areas of disagreement on basic terminology issues and agreed that a glossary with example images would help clarify many commonly misunderstood issues. this report defines terminology used in the pathological description of borderline tumors and their variants, and illustrates examples… expand view on pubmed doi.org 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clinicopathologic analysis 	j. rutgers, r. scully 	medicine 	cancer 	 	 	 save alert research feed is micropapillary serous carcinoma for real? 	d. gershenson 	medicine 	cancer 	 	 save alert research feed serous tumors of the ovary (borderline tumors and carcinomas) with and without micropapillary features. 	j. prat 	medicine 	international journal of gynecological pathology : official journal of the international society of gynecological pathologists 	 	 save alert research feed treatment of micropapillary serous ovarian carcinoma (the aggressive variant of serous borderline tumors) 	j. seidman, r. kurman 	medicine 	cancer 	 	 save alert research feed ovarian mullerian mucinous papillary cystadenomas of borderline malignancy. a clinicopathologic analysis 	j. rutgers, r. scully 	medicine 	cancer 	 	 	 save alert research feed ovarian mucinous tumors of low malignant potential: a clinicopathologic study of tumors of intestinal and müllerian type. 	s. siriaunkgul, k. robbins, l. mcgowan, s. silverberg 	biology, medicine 	international journal of gynecological pathology : official journal of the international society of gynecological pathologists 	 	 save alert research feed ovarian serous borderline tumors with stromal microinvasion : a report of cases 	d. bell, r. scully 	medicine 	 	 save alert research feed serous borderline tumors of the ovary. 	prat 	medicine 	advances in clinical pathology : the official journal of adriatic society of pathology 	 	 save alert research feed ... ... related papers 	abstract 	topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue reactive oxygen species (ros) suppress mitochondrial motility a wednesday, february , co-expression and co-evolution with mcu. micu has been demonstrated to be a ca þ -sensing protein, which both sets a threshold for low ca þ concentration while it assures cooperative activation during high ca þ rises. mitochondrial ca þ uptake shows tissue specific differences and interestingly, mrna level for micus and mcus also displays tissue specificity. we set out to investigate if the stoichiometry between micu and mcu could account for the previously described differences between heart and liver in mitochondrial ca þ uptake. immunoblotting showed higher expression for all micu , micu and mcu in mouse liver versus heart mitochondria, and a . fold higher micu to mcu ratio in liver. in fluorometric measurements of mitochondrial ca þ uptake, heart mitochondria displayed a decreased threshold and lesser cooperativity compared to liver mitochondria. additionally, nad(p)h elevation was detect- able after exposure to moderate [ca þ ] elevations only in heart mitochondria. overexpression of micu in the heart using aav -micu tail-vein injection significantly increased the micu protein level without any changes of micu or mcu. this increased the micu to mcu ratio in the heart and led to increased thresholding and cooperativity, reproducing the liver-like mito- chondrialca þ uptakephenotype.viceversamicu downregulationintheliver has been shown to lower the threshold and cooperativity of mitochondrial ca þ uptake in hepatocytes. thus, heart and liver mitochondria show different levels of ca þ threshold and cooperative activation of ca þ uptake, which seem to result from differential quantitative relationship between micu and mcu. -pos board b er calcium release is tuned by mitochondrial redox nanodomains david m. booth , balázs enyedi , miklós geiszt , péter várnai , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, department of physiology, semmelweis university, budapest, hungary. spatially and temporally controlled increases of h o emerge as an intracellular signal. we hypothesized that ros and ca þ interact locally, in the restricted vol- ume of the er-mitochondrial interface. these physically tethered structures host enrichments of ion transport proteins such as the ip receptor, which support elevated nanodomains of ca þ during signalling events and are sensitive to h o . we used the genetically encoded h o sensor hyper incorporated into an inducible linker system to probe the redox environment at the er- mitochondrial interface in hepg cells. we found a moderately elevated h o nanodomain which developes into a h o transient following ip receptor- mediated er ca þ release and mitochondrial ca þ uptake. pharmacological in- hibition showed that the transient was dependent upon er ca þ, mitochondrial membrane potential and functional electron transport chain. hyper measure- ments of the mitochondrial intermembrane space revealed significantly elevated h o within this volume. using electron microscopy we found that hepg mito- chondria possess a cohort of dilated cristae, which disappeared following ip - linked ca þ release. paxilline that inhibits mitochondrial bkca channels blocked the cristae reshaping and also abolished the h o transient at the inter- face. furthermore, paxilline caused suppression of the ip -linked calcium signal, whereas interface targeted killer red, a photoactivated h o source, induced sensitization to the ip -linked agonist. we conclude that the intermembrane/ cristae volume of mitochondria represents an oxidized pool fed by the electron transport chain. ca þ -uptake stimulates expansion of the mitochondrial matrix via kþ and concomitant water uptake, squeezing the oxidized volume of the cristae to the interface. here, a transient h o nanodomain sensitizes ip recep- tors to further stimulation. we demonstrate a physiological setting where ca þ release may autoregulate using mitochondrial h o released from the cristae. -pos board b reactive oxygen species (ros) suppress mitochondrial motility valentina debattisti, masao saotome, sudipto das, gyorgy hajnoczky. mitocare center, thomas jefferson university, philadelphia, pa, usa. mitochondrial distribution and transport play pivotal roles for many cellular functions, including cell differentiation, cell division to ensure proper inheri- tance, apoptosis, atp supply at the local sites of demand, ca þ buffering for intracellular ca þ homeostasis. we previously showed that mitochondrial motility (mito-motility) is regulated by the cytosolic ca þ concentration ([ca þ]c), providing the basis for a homeostatic circuit in which the organelles decrease their movements along microtubules to locally buffer high [ca þ ]c and contribute to atp supply. mito- chondria are also a major site for production and scavenging of ros that serve as both a messenger and regulator of calcium signaling and are particularly rele- vant for the control of mitochondrial function. here we tested the hypothesis that ros target mito-motility to control mitochondrial function. h c myoblast cells were transfected with a mitochondrial matrix targeted yfp and then loaded with fura , to monitor the mito-motility simultaneously with [ca þ ]c. h o ( mm) caused a decrease in mito-motility ( %) and an elevation in [ca þ ]c (from to nm) at the same time. when the cells were incu- bated in a ca þ -free medium and were pretreated with thapsigargin to prevent ca þ entry and intracellular ca þ mobilization, respectively, h o continued to inhibit the mito-motility dose-dependently without any changes in [ca þ]c. these results indicate that h o can cause suppression of mito-motility through a ca þ independent mechanism we are currently analyzing. -pos board b miro is dispensable for calcium-mediated inhibition of mitochondrial movement david b. weaver , agnieszka lewandowska , tammy t. nguyen , valentina debattisti , janet m. shaw , gyorgy hajnoczky . mitocare center, dept of pathology, anatomy and cell biology, thomas jefferson university, philadelphia, pa, usa, biochemistry, university of utah school of medicine, salt lake city, ut, usa. miro and are (rhot and ) are two highly similar gtpases that are bound to the surface of mitochondria and possess ef-hand calcium binding motifs. several groups have reported that miro is involved in mitochondrial motility and inheritance, and particularly its calcium regulation, but the roles of the two isoforms have not been established. genetic deletion of miro in mouse is lethal at birth (nguyen et al., ) and fibroblasts (mefs) derived from miro ko em- bryos show abnormal mitochondrial distribution, but the calcium-dependent in- hibition of motility is unaffected and the respiratory and calcium buffering capacities are normal. neuron-specific knockout of miro leads to progressive deficits of upper motor neuron function, however mitochondria in processes of cortical neurons from miro ko and wild-type embryos showed comparable calcium-sensitive motility inhibition. while no significant increase in miro pro- tein was observed in miro ko mefs, these data raise two possibilities: miro and are interchangeable with regard to calcium regulation of mitochondrial motility or miro is the key player in this regard. to finally resolve this question, we are in the process of generating miro ko and miro / ko cell lines. -pos board b mitochondrial fusion dynamics in the heart veronica eisner , ryan cupo , erhe gao , györgy csordás , lan cheng , jessica ibetti , j. kurt chuprun , walter j. koch , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, center for translational medicine, temple university school of medicine, philadelphia, pa, usa, center for translational medicine, thomas jefferson university, philadelphia, pa, usa. heart physiology depends on oxidative metabolism that likely requires dy- namic and permanent reorganization of mitochondria by fusion and fission. to directly evaluate mitochondrial fusion dynamics in cardiomyocytes (cm), mitochondrial matrix-targeted photoactivatable gfp and dsred were intro- duced either in vitro or in vivo by adenovirus and were followed by confocal microscopy. four conditions were analyzed: to h cultured neonatal and in vitro transduced adult cm, and cm from in vivo infected rat hearts. in the latter case, cm were isolated - days after infection and were imaged promptly or - h post harvesting. neonatal cm mitochondria form a highly connected network, whereas both in vitro and in vivo transformed cultured cm displayed only some connectivity. impressively, in vivo transduced adult cm that were imaged promptly after harvesting, unveiled a significantly higher con- nectivity among mitochondria than the - h cultured adult cm. furthermore, fusion events (f.e./ square micrometers/min) were almost absent in cultured in vitro transduced cm, meanwhile in vivo transduced and cultured cm showed . . f.e./min, whereas isolated, freshly-imaged cm displayed . . f.e./min. imaging in perfused whole heart ex vivo, showed consider- able mitochondrial continuity and fusion activity in ventricular cm. to study more directly the role of cm’s contractile activity in mitochondrial fusion, cm were incubated with verapamil ( mm), that blocked spontaneous contrac- tion and partially suppressed the fusion activity of mitochondria. also, mito- chondrial fusion activity appeared to be higher after spontaneous contraction or short term field stimulation in isolated freshly-imaged cm. thus, mitochon- dria are dynamic in both neonatal and adult cm, but under culture conditions, adult cm lose mitochondrial fusion activity. this might be at least in part, because cardiomyocyte contractile activity is altered in culture and contractions likely provide some factors to support mitochondrial fusion activity. -pos board b mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide venkat r. pannala, ranjan k. dash. bioengineering and biotechnology, department of physiology, medical college of wisconsin, wauwatosa, wi, usa. the thioredoxin system plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (h o ). specifically, 	er calcium release is tuned by mitochondrial redox nanodomains 	reactive oxygen species (ros) suppress mitochondrial motility 	miro is dispensable for calcium-mediated inhibition of mitochondrial movement 	mitochondrial fusion dynamics in the heart 	mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide miro is dispensable for calcium-mediated inhibition of mitochondrial movement a wednesday, february , core metadata, citation and similar papers at core.ac.uk provided by elsevier - publisher connector co-expression and co-evolution with mcu. micu has been demonstrated to be a ca þ -sensing protein, which both sets a threshold for low ca þ concentration while it assures cooperative activation during high ca þ rises. mitochondrial ca þ uptake shows tissue specific differences and interestingly, mrna level for micus and mcus also displays tissue specificity. we set out to investigate if the stoichiometry between micu and mcu could account for the previously described differences between heart and liver in mitochondrial ca þ uptake. immunoblotting showed higher expression for all micu , micu and mcu in mouse liver versus heart mitochondria, and a . fold higher micu to mcu ratio in liver. in fluorometric measurements of mitochondrial ca þ uptake, heart mitochondria displayed a decreased threshold and lesser cooperativity compared to liver mitochondria. additionally, nad(p)h elevation was detect- able after exposure to moderate [ca þ ] elevations only in heart mitochondria. overexpression of micu in the heart using aav -micu tail-vein injection significantly increased the micu protein level without any changes of micu or mcu. this increased the micu to mcu ratio in the heart and led to increased thresholding and cooperativity, reproducing the liver-like mito- chondrialca þ uptakephenotype.viceversamicu downregulationintheliver has been shown to lower the threshold and cooperativity of mitochondrial ca þ uptake in hepatocytes. thus, heart and liver mitochondria show different levels of ca þ threshold and cooperative activation of ca þ uptake, which seem to result from differential quantitative relationship between micu and mcu. -pos board b er calcium release is tuned by mitochondrial redox nanodomains david m. booth , balázs enyedi , miklós geiszt , péter várnai , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, department of physiology, semmelweis university, budapest, hungary. spatially and temporally controlled increases of h o emerge as an intracellular signal. we hypothesized that ros and ca þ interact locally, in the restricted vol- ume of the er-mitochondrial interface. these physically tethered structures host enrichments of ion transport proteins such as the ip receptor, which support elevated nanodomains of ca þ during signalling events and are sensitive to h o . we used the genetically encoded h o sensor hyper incorporated into an inducible linker system to probe the redox environment at the er- mitochondrial interface in hepg cells. we found a moderately elevated h o nanodomain which developes into a h o transient following ip receptor- mediated er ca þ release and mitochondrial ca þ uptake. pharmacological in- hibition showed that the transient was dependent upon er ca þ, mitochondrial membrane potential and functional electron transport chain. hyper measure- ments of the mitochondrial intermembrane space revealed significantly elevated h o within this volume. using electron microscopy we found that hepg mito- chondria possess a cohort of dilated cristae, which disappeared following ip - linked ca þ release. paxilline that inhibits mitochondrial bkca channels blocked the cristae reshaping and also abolished the h o transient at the inter- face. furthermore, paxilline caused suppression of the ip -linked calcium signal, whereas interface targeted killer red, a photoactivated h o source, induced sensitization to the ip -linked agonist. we conclude that the intermembrane/ cristae volume of mitochondria represents an oxidized pool fed by the electron transport chain. ca þ -uptake stimulates expansion of the mitochondrial matrix via kþ and concomitant water uptake, squeezing the oxidized volume of the cristae to the interface. here, a transient h o nanodomain sensitizes ip recep- tors to further stimulation. we demonstrate a physiological setting where ca þ release may autoregulate using mitochondrial h o released from the cristae. -pos board b reactive oxygen species (ros) suppress mitochondrial motility valentina debattisti, masao saotome, sudipto das, gyorgy hajnoczky. mitocare center, thomas jefferson university, philadelphia, pa, usa. mitochondrial distribution and transport play pivotal roles for many cellular functions, including cell differentiation, cell division to ensure proper inheri- tance, apoptosis, atp supply at the local sites of demand, ca þ buffering for intracellular ca þ homeostasis. we previously showed that mitochondrial motility (mito-motility) is regulated by the cytosolic ca þ concentration ([ca þ]c), providing the basis for a homeostatic circuit in which the organelles decrease their movements along microtubules to locally buffer high [ca þ ]c and contribute to atp supply. mito- chondria are also a major site for production and scavenging of ros that serve as both a messenger and regulator of calcium signaling and are particularly rele- vant for the control of mitochondrial function. here we tested the hypothesis that ros target mito-motility to control mitochondrial function. h c myoblast cells were transfected with a mitochondrial matrix targeted yfp and then loaded with fura , to monitor the mito-motility simultaneously with [ca þ ]c. h o ( mm) caused a decrease in mito-motility ( %) and an elevation in [ca þ ]c (from to nm) at the same time. when the cells were incu- bated in a ca þ -free medium and were pretreated with thapsigargin to prevent ca þ entry and intracellular ca þ mobilization, respectively, h o continued to inhibit the mito-motility dose-dependently without any changes in [ca þ]c. these results indicate that h o can cause suppression of mito-motility through a ca þ independent mechanism we are currently analyzing. -pos board b miro is dispensable for calcium-mediated inhibition of mitochondrial movement david b. weaver , agnieszka lewandowska , tammy t. nguyen , valentina debattisti , janet m. shaw , gyorgy hajnoczky . mitocare center, dept of pathology, anatomy and cell biology, thomas jefferson university, philadelphia, pa, usa, biochemistry, university of utah school of medicine, salt lake city, ut, usa. miro and are (rhot and ) are two highly similar gtpases that are bound to the surface of mitochondria and possess ef-hand calcium binding motifs. several groups have reported that miro is involved in mitochondrial motility and inheritance, and particularly its calcium regulation, but the roles of the two isoforms have not been established. genetic deletion of miro in mouse is lethal at birth (nguyen et al., ) and fibroblasts (mefs) derived from miro ko em- bryos show abnormal mitochondrial distribution, but the calcium-dependent in- hibition of motility is unaffected and the respiratory and calcium buffering capacities are normal. neuron-specific knockout of miro leads to progressive deficits of upper motor neuron function, however mitochondria in processes of cortical neurons from miro ko and wild-type embryos showed comparable calcium-sensitive motility inhibition. while no significant increase in miro pro- tein was observed in miro ko mefs, these data raise two possibilities: miro and are interchangeable with regard to calcium regulation of mitochondrial motility or miro is the key player in this regard. to finally resolve this question, we are in the process of generating miro ko and miro / ko cell lines. -pos board b mitochondrial fusion dynamics in the heart veronica eisner , ryan cupo , erhe gao , györgy csordás , lan cheng , jessica ibetti , j. kurt chuprun , walter j. koch , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, center for translational medicine, temple university school of medicine, philadelphia, pa, usa, center for translational medicine, thomas jefferson university, philadelphia, pa, usa. heart physiology depends on oxidative metabolism that likely requires dy- namic and permanent reorganization of mitochondria by fusion and fission. to directly evaluate mitochondrial fusion dynamics in cardiomyocytes (cm), mitochondrial matrix-targeted photoactivatable gfp and dsred were intro- duced either in vitro or in vivo by adenovirus and were followed by confocal microscopy. four conditions were analyzed: to h cultured neonatal and in vitro transduced adult cm, and cm from in vivo infected rat hearts. in the latter case, cm were isolated - days after infection and were imaged promptly or - h post harvesting. neonatal cm mitochondria form a highly connected network, whereas both in vitro and in vivo transformed cultured cm displayed only some connectivity. impressively, in vivo transduced adult cm that were imaged promptly after harvesting, unveiled a significantly higher con- nectivity among mitochondria than the - h cultured adult cm. furthermore, fusion events (f.e./ square micrometers/min) were almost absent in cultured in vitro transduced cm, meanwhile in vivo transduced and cultured cm showed . . f.e./min, whereas isolated, freshly-imaged cm displayed . . f.e./min. imaging in perfused whole heart ex vivo, showed consider- able mitochondrial continuity and fusion activity in ventricular cm. to study more directly the role of cm’s contractile activity in mitochondrial fusion, cm were incubated with verapamil ( mm), that blocked spontaneous contrac- tion and partially suppressed the fusion activity of mitochondria. also, mito- chondrial fusion activity appeared to be higher after spontaneous contraction or short term field stimulation in isolated freshly-imaged cm. thus, mitochon- dria are dynamic in both neonatal and adult cm, but under culture conditions, adult cm lose mitochondrial fusion activity. this might be at least in part, because cardiomyocyte contractile activity is altered in culture and contractions likely provide some factors to support mitochondrial fusion activity. -pos board b mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide venkat r. pannala, ranjan k. dash. bioengineering and biotechnology, department of physiology, medical college of wisconsin, wauwatosa, wi, usa. the thioredoxin system plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (h o ). specifically, https://core.ac.uk/display/ ?utm_source=pdf&utm_medium=banner&utm_campaign=pdf-decoration-v 	er calcium release is tuned by mitochondrial redox nanodomains 	reactive oxygen species (ros) suppress mitochondrial motility 	miro is dispensable for calcium-mediated inhibition of mitochondrial movement 	mitochondrial fusion dynamics in the heart 	mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide hypothyroidism in pancreatic cancer: role of exogenous thyroid hormone in tumor invasion—preliminary observations research article hypothyroidism in pancreatic cancer: role of exogenous thyroid hormone in tumor invasion—preliminary observations konrad sarosiek, ankit v. gandhi, shivam saxena, christopher y. kang, galina i. chipitsyna, charles j. yeo, and hwyda a. arafat departments of surgery, jefferson pancreatic, biliary and related cancer center, thomas jefferson university, philadelphia, pa , usa department of biomedical sciences, university of new england, biddeford, me , usa correspondence should be addressed to galina i. chipitsyna; galina @gmail.com received october ; revised march ; accepted march academic editor: noriyuki koibuchi copyright © konrad sarosiek et al. this is an open access article distributed under the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. according to the epidemiological studies, about . % of american general elderly population has a pronounced hypothyroidism and relies on thyroid hormone supplements daily. the prevalence of hypothyroidism in our patients with pancreatic cancer was much higher, . %. a retrospective analysis was performed on patients who underwent pancreaticoduodenectomy (whipple procedure) or distal pancreatectomy and splenectomy (dps) at thomas jefferson university hospital, philadelphia, from to . the diagnosis of hypothyroidism was correlated with clinicopathologic parameters including tumor stage, grade, and survival. to further understand how thyroid hormone affects pancreatic cancer behavior, functional studies including wound-induced cell migration, proliferation, and invasion were performed on pancreatic cancer cell lines, miapaca- and aspc- . we found that hypothyroid patients taking exogenous thyroid hormone were more than three times likely to have perineural invasion, and about twice as likely to have higher t stage, nodal spread, and overall poorer prognostic stage (𝑃 < . ). pancreatic cancer cell line studies demonstrated that exogenous thyroid hormone treatment increased cell proliferation, migration, and invasion (𝑃 < . ). we conclude that exogenous thyroid hormone may contribute to the progression of pancreatic cancer. . introduction invasive pancreatic cancer is the fourth leading cause of can- cer death in the united states. most patients with pancreatic cancer have a dismal prognosis and a median survival rate of less than months [ , ]. at the time of diagnosis, the disease is often discovered to be in its late stages, as more than % of patients have tumors that have metastasized [ ]. currently, surgery remains one of the few options to decrease pancreatic cancer mortality. despite many advances in cancer biology over the past years, pancreatic cancer remains an elusive disease process that requires further studies to understand its molecular biology and investigate possible therapeutic targets. thyroid hormones (t and t ) are steroid hormones that regulate body growth, brain maturation, and metabolism. although the major product of the thyroid is t , most of it is converted to more biologically active t that binds to nuclear thyroid receptors and modulates the expression of proteins traditionally known to increase basal metabolic rate and enhance growth [ ]. disorders of the thyroid that result in either a deficiency or excess of thyroid hormones are extremely common and can have various effects on the human body. according to the nhanes national – survey, the prevalence of hypothyroidism in the general us population was . % [ ]. of note, the prevalence of thyroid disorders increases with age (up to . % for years and hindawi publishing corporation journal of yroid research volume , article id , pages http://dx.doi.org/ . / / http://dx.doi.org/ . / / journal of thyroid research older) and is consistent with females having higher rates of hypothyroidism than men [ – ]. due to the established effect of thyroid hormone on growth and development, many have hypothesized a con- nection between thyroid hormone and cancer. one of the first reports linking these two comes from a article that examines the relationship between supplemental thyroid hormone intake and breast cancer. in a study with , female patients, it was calculated that the rate of breast cancer in patients taking thyroid supplements for hypothyroidism was . % versus . % in a control group [ ]. since then, many studies have sparked a debate about a relationship between hypothyroidism and malignancy. a search of the literature reveals that hypothyroidism may be a risk factor for respiratory, colon, breast, and liver cancer [ – ]. cell line experiments in breast and prostate cancer corroborate these findings by demonstrating that treatment with t enhances cellular proliferation [ , ]. in this study, a retrospective analysis was performed on patients who underwent pancreaticoduodenectomy (whip- ple procedure) or distal pancreatectomy and splenectomy (dps) at thomas jefferson university hospital, philadel- phia, from to . the diagnosis of hypothyroidism was correlated with clinicopathologic parameters including tumor stage, grade, and survival. to further understand how thyroid hormone affects pancreatic cancer behavior, functional studies including wound-induced cell migration, proliferation, and invasion were performed on pancreatic cancer cell lines, miapaca- and aspc- . . materials and methods . . data collection. for this cross-sectional study, a database search was conducted for patients who underwent pancreati- coduodenectomy (whipple procedure) or distal pancreatec- tomy and splenectomy (dps) at thomas jefferson university hospital, philadelphia, pa, from to . the eligibility criteria consisted of patients with a diagnosis of invasive pancreatic cancer confirmed by biopsy. exclusion criteria consisted of patients with a history of noninvasive, benign pancreatic pathology or incomplete medical history. data collection included patient sex, age, body mass index (bmi), medical history, medications, surgical information, survival, tumor staging, and differentiation by hypothyroid status. the tnm staging system as outlined by the american joint committee on cancer (ajcc) was used to define pancreatic lesions. patients were defined to be hypothyroid if they had a positive medical hypothyroidism and were taking synthetic or desiccated thyroid hormone. the institutional review board of thomas jefferson university hospital, philadelphia, pa, approved this study. miapaca- (atcc crl- ) and aspc- (atcc crl- ) were purchased from atcc. mtt cell growth, migra- tion, and transwell invasion assays were performed as previ- ously described [ ]. . . statistical analyses. descriptive statistics were calculated on patient clinicopathological features. differences in gender, smoking status, venous-lymphatic invasion, perineural inva- sion, t stage, n stage, prognostic stage, and differentiation by hypothyroid status were determined by chi-square test. differences in age and bmi were determined by unpaired stu- dent’s 𝑡-test. survival analysis was performed using kaplan- meier curves and mantel-cox log rank test, where survival was defined as time between date of surgery and date of death or of last follow-up. all functional experiments were performed to times. functional studies were analyzed for statistical significance by student’s 𝑡-test analysis, or two- way anova. data are presented as mean ± sem. all tests of significance were two-sided with an alpha value of . . analyses were performed with the assistance of a computer program (prism . , graphpad software, inc., la jolla, ca). . results . . patient characteristics. an overview of the clinical patient data is summarized in table . of patients in the database, patients were found to be hypothyroid (of males, . % and, of females, . % were hypothyroid). as expected, the hypothyroid group had a significantly greater proportion of females than males (𝑃 < . ). the age of patients in the hypothyroid group ( . ) was similar to the age of patients in the euthyroid group ( . ). bmi was not significantly different in the hypothyroid group when compared to the euthyroid group ( . versus . , resp.). lastly, there was no significant difference in smoking status between two groups. . . pancreatic pathology. pancreatic tissue specimens strat- ified by pathology are shown in table . majority of the biopsies ( %) were invasive ductal adenocarcinoma. second most common pathology was invasive ipmn ( %), followed by endocrine, papillary, acinar cell, and mucinous cancers. . . clinicopathological parameters by hypothyroid status. as shown in table , there were no differences in survival (figure ), venous-lymphatic invasion, and differentiation between hypothyroid and euthyroid patients. compared to euthyroid patients, hypothyroid patients taking exogenous thyroid hormone were more than three times likely to have perineural invasion and about twice as likely to have a higher t stage, nodal spread, and overall poorer prognostic stage. . . t increases cell proliferation, migration, and invasion. to evaluate whether t was associated with cell viability, miapaca- cells were treated with t ( – nm) and quantified via the mtt assay (figure (a)). the addition of t significantly (𝑃 < . ) increased cell proliferation after and hours across all concentrations of t . additionally, miapaca- cells were treated with t to evaluate its role in cell migration (figure (b)). t significantly (𝑃 < . ) increased cell migration at - and -hour time points at and nm of t compared to the control. lastly, the role of exogenous thyroid hormone in invasion was evaluated via transwell infiltration assay. cells were treated with t ( – nm), and the extent of invasion was quantified via mtt assay (figure (c)). adding t significantly (𝑃 < . ) journal of thyroid research table : clinical characteristics of patients. hypothyroid euthyroid total (𝑛 = ) (𝑛 = ) (𝑛 = ) male,𝑛 (%) ( . ) ( . ) ( . ) female,𝑛 (%) ( . ) ( . ) ( . ) age, mean (sd) . ( . ) . ( . ) . ( . ) bmi, mean (sd) . ( . ) . ( . ) . ( . ) smoking status,𝑛 (%), yes ( . ) ( . ) ( . ) smoking status,𝑛 (%), no ( . ) ( . ) ( . ) table : pancreatic tissue specimens stratified by pathology. pancreatic malignancy 𝑛 (%) invasive ductal adenocarcinoma ( . ) invasive ipmn ( . ) endocrine ( . ) papillary ( . ) acinar cell ( . ) mucinous ( . ) all invasive pancreatic pathologies ( ) increased cell invasion. similar data (𝑃< . ) were obtained for aspc- cells (data not shown). . discussion the objective of this study was to evaluate the prevalence of hypothyroidism and thyroid hormone supplementation in patients with pancreatic cancer and to correlate hypothy- roidism diagnosis with various clinicopathologic parame- ters. furthermore, functional studies were performed on miapaca- and aspc- pancreatic cancer cell lines to study how exogenous thyroid hormone influences cell behavior. to our knowledge, this is the first study to suggest a higher prevalence of thyroid hormone supplementation in patients with pancreatic cancer and to demonstrate the proliferative effects of t in pancreatic cancer cell lines. the association between hypothyroidism and neoplasia remains controversial. despite conflicting reports in the literature, studies have shown that hypothyroidism may cor- relate with many cancers including respiratory, colon, breast, and liver cancer [ – ]. some studies even suggest that a diagnosis of hypothyroidism may result in poor response to therapy in patients with breast cancer [ ]. other studies argue that high levels of thyroid hormones induce cancer cell proliferation while low levels slow disease progress [ ]. a number of prospective case-control studies have indicated that subclinical hyperthyroidism increases risk of certain solid tumors and that spontaneous hypothyroidism may delay onset or reduce aggressiveness of cancers [ – ]. a controlled prospective trial of induced hypothyroidism beneficially affected the course of glioblastoma [ ]. in our study, the prevalence of patients with hypothy- roidism treated with medication was . % ( . % in males, . % in females). this percentage is much higher than the prevalence of overt hypothyroidism reported in the elderly months elapsed su rv iv al (% ) hypothyroid euthyroid figure : kaplan-meier curve comparing hypothyroid and euthy- roid patients. there was no difference in survival.𝑃= . . ( . %) and is consistent with females having higher rates of hypothyroidism than men [ – ]. metastasis is one of the most significant predictors of mortality in patients with pancreatic cancer. when com- paring hypothyroid and euthyroid patients with pancreatic cancer, hypothyroid patients on thyroid hormone supple- mentation were found to have significantly (𝑃< . ) higher rates of nodal spread and a t stage of t or higher, signifying that the tumor has already extended beyond the walls of the pancreas. it was not surprising that these patients were more likely to have a poorer prognostic stage (or . ). inter- estingly, patients on thyroid hormone supplementation also had significantly higher rates of perineural invasion (or . ). perineural invasion is a poorly understood process by which cancer cells metastasize to nerves and their surrounding neural sheaths [ ]. although metastatic spread via neural invasion is often overlooked, pdac has one of the highest rates of perineural invasion when compared to other malig- nancies, and it is a substantial cause of pain in pancreatic cancer patients [ ]. despite these poor prognostic factors, there was no significant difference in survival between patients taking thyroid hormone supplementation compared to patients who were not on medication. this might be due to the limitations of this study. one of the limitations was possible selection bias in the patient population. because surgery was reserved for patients with resectable disease only, our study might not accurately capture patients with advanced diseases. another limitation was little information available regarding the diagnosis of hypothyroidism. tsh measurement was not used to diagnose or quantify the degree of hypothyroidism. similarly, the date and duration of hypothyroidism and thyroid hormone implementation were not available at the time of the surgery. lastly, due to difficulties in patient follow-up after hospital discharge, the survival data were not the most current. however, because all patients with hypothyroidism were taking exogenous thyroid medication, one may hypothesize that exogenous thyroid hormone may be responsible for journal of thyroid research table : clinicopathologic parameters of hypothyroid and euthyroid patients with invasive pda. hypothyroid euthyroid or [ % ci] 𝑃value median survival (months) . . . venous-lymphatic invasion,𝑛 (%) . [ . – . ] . yes ( ) ( ) no ( ) ( ) perineural invasion,𝑛 (%) . [ . – . ] . ∗ yes ( ) ( ) no ( ) ( ) t stage,𝑛 (%) . [ . – . ] . ∗ low stage (t –t ) high stage (t -t ) nodal status,𝑛 (%) . [ . – . ] . ∗ n ( ) ( ) n ( ) ( ) prognostic stage,𝑛 (%) . [ . – . ] . ∗ low stage ( – a) ( ) ( ) high stage ( b- ) ( ) ( ) differentiation,𝑛 (%) . well ( ) ( ) moderate ( ) ( ) poor ( ) ( ) hypothyroid patients were found to have higher rates of perineural invasion, nodal spread, and advanced prognostic stage.∗𝑃< . . increasing growth and metabolism of pancreatic cancer cells, thus responsible for promoting tumor invasion and spread to nearby structures. functional assays that were performed demonstrated that treatment of miapaca- and aspc- cells with physiologic concentrations of thyroid hormone caused an increase in cell proliferation, migration, and invasion at h and h. these results are consistent with studies that demonstrate proliferative effect of t in breast cancer, prostate cancer, and hepatocellular carcinoma. it was also shown that t contributes to breast cancer cell prolifer- ation through estrogen response elements mediated gene expression, by promoting the effects of estrogens themselves [ ] or by upregulating tgf-𝛼 mrna expression [ ]. murine glioma cell lines and human prostatic carcinoma cells also revealed the increased proliferation in response to physiological concentrations of both t and t [ , , ]. t also promotes cell proliferation and invasion in human hepatoma cell lines in cooperation with tgf-𝛽 [ , ]. thyroid hormones enhance the development of gastric cancer in rats by stimulating the proliferation of gastric cancer cells [ , ]. additionally, thyroid hormones act as growth factors in both papillary and follicular human thyroid cancer cell lines [ ]. it was shown that both t and t caused proliferation of malignant glioma u- mg cells through pi -kinase, src kinase, and erk / signaling cascades [ ]. t and t promote both tumor cell division and angiogene- sis by activating mitogen-activated protein kinase (mapk) via binding to a hormone receptor on the 𝛼v𝛽 integrin, overexpressed on many human myelomas and other cancer cells [ , ]. other in vitro studies of thyroid hormones action in cancer cells implicated many molecular targets, including tgf-𝛽, hyperphosphorylation of rb, and map kinase pathways [ , , , , ]. thyroid hormones have also been shown to promote angiogenesis in cancer cells by upregulating hif- 𝛼 [ , ]. . conclusions this study demonstrates that there may be an association between thyroid hormone supplementation and pancreatic cancer invasion. although the use of exogenous thyroid hormone may not necessarily be involved in the initial insult responsible for tumorigenesis, it may contribute to the pro- gression of preexisting tumor. increased perineural invasion, higher t stage, nodal spread, and advanced prognostic stage in hypothyroid patients may be due to enhanced metabolism of malignant cells via thyroid hormone supplementation. the proliferative effects of t on miapaca- and aspc- cells support this hypothesis. we propose that spontaneous hypothyroidism might develop in cancer patients as a protection mechanism against tumor progress/spread, but thyroid hormone supplementa- tion might abolish this action. clinical studies have shown [ ] that interventional lowering of serum-free t may be associated with extended survival in patients with some terminal cancers, and compassionate medical induction of hypothyroxinemia could be considered for patients with advanced cancers to whom other avenues of treatment are closed [ ]. thus, accumulating clinical evidence may justify new, broadly based controlled studies in cancer patients to determine the possible contribution of thyroid hormone to tumor behavior. insights into molecular mechanism of this journal of thyroid research ∗ ∗ ∗ ∗ ∗ . . . . r el at iv e ce ll pr ol ife ra tio n h h h t concentration (nm) (a) time (hours) m ig ra tio n di st an ce ∗ ∗ nm nm nm (b) r el at iv e ce ll in va si on . . . . . ∗∗ t concentration (nm) (c) figure : effects of exogenous thyroid hormone treatment on pdac cells proliferation, migration, and invasion (𝑃< . ). (a) proliferation assay of miapaca- cells incubated with t . proliferation was increased at all concentrations after and hours. ∗𝑃< . . (b) migration assay of miapaca- cells incubated with t . cell migration was increased after and hours. ∗𝑃< . . (c) transwell infiltration assay of miapaca- cells incubated with t . cell invasion was increased by and nm t . ∗𝑃< . . process might uncover possible targets which would allow thyroid hormone supplementation without promoting cancer progression. competing interests all named authors have no financial interests in respect of this work and its publication or other interests that might be perceived to influence the results and/or discussion reported in this paper. acknowledgments authors acknowledge research support and funding they have received from the department of surgery, thomas jefferson university hospital, philadelphia, pa, and depart- ment of biomedical sciences, university of new england, biddeford, me, relevant to the work described. references [ ] a. f. hezel, a. c. kimmelman, b. z. stanger, n. bardeesy, and r. a. depinho, “genetics and biology of pancreatic ductal adenocarcinoma,” genes and development, vol. , no. , pp. – , . 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[ ] a. hercbergs, r. e. johnson, o. ashur-jabian et al., “medically induced euthyroid hypothyroxinemia may extend survival in compassionate need cancer patients: an observational study,” oncologist, vol. , no. , pp. – , . mitochondrial fusion dynamics in the heart a wednesday, february , co-expression and co-evolution with mcu. micu has been demonstrated to be a ca þ -sensing protein, which both sets a threshold for low ca þ concentration while it assures cooperative activation during high ca þ rises. mitochondrial ca þ uptake shows tissue specific differences and interestingly, mrna level for micus and mcus also displays tissue specificity. we set out to investigate if the stoichiometry between micu and mcu could account for the previously described differences between heart and liver in mitochondrial ca þ uptake. immunoblotting showed higher expression for all micu , micu and mcu in mouse liver versus heart mitochondria, and a . fold higher micu to mcu ratio in liver. in fluorometric measurements of mitochondrial ca þ uptake, heart mitochondria displayed a decreased threshold and lesser cooperativity compared to liver mitochondria. additionally, nad(p)h elevation was detect- able after exposure to moderate [ca þ ] elevations only in heart mitochondria. overexpression of micu in the heart using aav -micu tail-vein injection significantly increased the micu protein level without any changes of micu or mcu. this increased the micu to mcu ratio in the heart and led to increased thresholding and cooperativity, reproducing the liver-like mito- chondrialca þ uptakephenotype.viceversamicu downregulationintheliver has been shown to lower the threshold and cooperativity of mitochondrial ca þ uptake in hepatocytes. thus, heart and liver mitochondria show different levels of ca þ threshold and cooperative activation of ca þ uptake, which seem to result from differential quantitative relationship between micu and mcu. -pos board b er calcium release is tuned by mitochondrial redox nanodomains david m. booth , balázs enyedi , miklós geiszt , péter várnai , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, department of physiology, semmelweis university, budapest, hungary. spatially and temporally controlled increases of h o emerge as an intracellular signal. we hypothesized that ros and ca þ interact locally, in the restricted vol- ume of the er-mitochondrial interface. these physically tethered structures host enrichments of ion transport proteins such as the ip receptor, which support elevated nanodomains of ca þ during signalling events and are sensitive to h o . we used the genetically encoded h o sensor hyper incorporated into an inducible linker system to probe the redox environment at the er- mitochondrial interface in hepg cells. we found a moderately elevated h o nanodomain which developes into a h o transient following ip receptor- mediated er ca þ release and mitochondrial ca þ uptake. pharmacological in- hibition showed that the transient was dependent upon er ca þ, mitochondrial membrane potential and functional electron transport chain. hyper measure- ments of the mitochondrial intermembrane space revealed significantly elevated h o within this volume. using electron microscopy we found that hepg mito- chondria possess a cohort of dilated cristae, which disappeared following ip - linked ca þ release. paxilline that inhibits mitochondrial bkca channels blocked the cristae reshaping and also abolished the h o transient at the inter- face. furthermore, paxilline caused suppression of the ip -linked calcium signal, whereas interface targeted killer red, a photoactivated h o source, induced sensitization to the ip -linked agonist. we conclude that the intermembrane/ cristae volume of mitochondria represents an oxidized pool fed by the electron transport chain. ca þ -uptake stimulates expansion of the mitochondrial matrix via kþ and concomitant water uptake, squeezing the oxidized volume of the cristae to the interface. here, a transient h o nanodomain sensitizes ip recep- tors to further stimulation. we demonstrate a physiological setting where ca þ release may autoregulate using mitochondrial h o released from the cristae. -pos board b reactive oxygen species (ros) suppress mitochondrial motility valentina debattisti, masao saotome, sudipto das, gyorgy hajnoczky. mitocare center, thomas jefferson university, philadelphia, pa, usa. mitochondrial distribution and transport play pivotal roles for many cellular functions, including cell differentiation, cell division to ensure proper inheri- tance, apoptosis, atp supply at the local sites of demand, ca þ buffering for intracellular ca þ homeostasis. we previously showed that mitochondrial motility (mito-motility) is regulated by the cytosolic ca þ concentration ([ca þ]c), providing the basis for a homeostatic circuit in which the organelles decrease their movements along microtubules to locally buffer high [ca þ ]c and contribute to atp supply. mito- chondria are also a major site for production and scavenging of ros that serve as both a messenger and regulator of calcium signaling and are particularly rele- vant for the control of mitochondrial function. here we tested the hypothesis that ros target mito-motility to control mitochondrial function. h c myoblast cells were transfected with a mitochondrial matrix targeted yfp and then loaded with fura , to monitor the mito-motility simultaneously with [ca þ ]c. h o ( mm) caused a decrease in mito-motility ( %) and an elevation in [ca þ ]c (from to nm) at the same time. when the cells were incu- bated in a ca þ -free medium and were pretreated with thapsigargin to prevent ca þ entry and intracellular ca þ mobilization, respectively, h o continued to inhibit the mito-motility dose-dependently without any changes in [ca þ]c. these results indicate that h o can cause suppression of mito-motility through a ca þ independent mechanism we are currently analyzing. -pos board b miro is dispensable for calcium-mediated inhibition of mitochondrial movement david b. weaver , agnieszka lewandowska , tammy t. nguyen , valentina debattisti , janet m. shaw , gyorgy hajnoczky . mitocare center, dept of pathology, anatomy and cell biology, thomas jefferson university, philadelphia, pa, usa, biochemistry, university of utah school of medicine, salt lake city, ut, usa. miro and are (rhot and ) are two highly similar gtpases that are bound to the surface of mitochondria and possess ef-hand calcium binding motifs. several groups have reported that miro is involved in mitochondrial motility and inheritance, and particularly its calcium regulation, but the roles of the two isoforms have not been established. genetic deletion of miro in mouse is lethal at birth (nguyen et al., ) and fibroblasts (mefs) derived from miro ko em- bryos show abnormal mitochondrial distribution, but the calcium-dependent in- hibition of motility is unaffected and the respiratory and calcium buffering capacities are normal. neuron-specific knockout of miro leads to progressive deficits of upper motor neuron function, however mitochondria in processes of cortical neurons from miro ko and wild-type embryos showed comparable calcium-sensitive motility inhibition. while no significant increase in miro pro- tein was observed in miro ko mefs, these data raise two possibilities: miro and are interchangeable with regard to calcium regulation of mitochondrial motility or miro is the key player in this regard. to finally resolve this question, we are in the process of generating miro ko and miro / ko cell lines. -pos board b mitochondrial fusion dynamics in the heart veronica eisner , ryan cupo , erhe gao , györgy csordás , lan cheng , jessica ibetti , j. kurt chuprun , walter j. koch , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, center for translational medicine, temple university school of medicine, philadelphia, pa, usa, center for translational medicine, thomas jefferson university, philadelphia, pa, usa. heart physiology depends on oxidative metabolism that likely requires dy- namic and permanent reorganization of mitochondria by fusion and fission. to directly evaluate mitochondrial fusion dynamics in cardiomyocytes (cm), mitochondrial matrix-targeted photoactivatable gfp and dsred were intro- duced either in vitro or in vivo by adenovirus and were followed by confocal microscopy. four conditions were analyzed: to h cultured neonatal and in vitro transduced adult cm, and cm from in vivo infected rat hearts. in the latter case, cm were isolated - days after infection and were imaged promptly or - h post harvesting. neonatal cm mitochondria form a highly connected network, whereas both in vitro and in vivo transformed cultured cm displayed only some connectivity. impressively, in vivo transduced adult cm that were imaged promptly after harvesting, unveiled a significantly higher con- nectivity among mitochondria than the - h cultured adult cm. furthermore, fusion events (f.e./ square micrometers/min) were almost absent in cultured in vitro transduced cm, meanwhile in vivo transduced and cultured cm showed . . f.e./min, whereas isolated, freshly-imaged cm displayed . . f.e./min. imaging in perfused whole heart ex vivo, showed consider- able mitochondrial continuity and fusion activity in ventricular cm. to study more directly the role of cm’s contractile activity in mitochondrial fusion, cm were incubated with verapamil ( mm), that blocked spontaneous contrac- tion and partially suppressed the fusion activity of mitochondria. also, mito- chondrial fusion activity appeared to be higher after spontaneous contraction or short term field stimulation in isolated freshly-imaged cm. thus, mitochon- dria are dynamic in both neonatal and adult cm, but under culture conditions, adult cm lose mitochondrial fusion activity. this might be at least in part, because cardiomyocyte contractile activity is altered in culture and contractions likely provide some factors to support mitochondrial fusion activity. -pos board b mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide venkat r. pannala, ranjan k. dash. bioengineering and biotechnology, department of physiology, medical college of wisconsin, wauwatosa, wi, usa. the thioredoxin system plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (h o ). specifically, 	er calcium release is tuned by mitochondrial redox nanodomains 	reactive oxygen species (ros) suppress mitochondrial motility 	miro is dispensable for calcium-mediated inhibition of mitochondrial movement 	mitochondrial fusion dynamics in the heart 	mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - 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bullosa–associated squamous-cell carcinoma: an enigmatic entity with complex pathogenesis commentarysee related article on pg © the society for investigative dermatology www.jidonline.org recessive dystrophic epidermolysis bullosa–associated squamous-cell carcinoma: an enigmatic entity with complex pathogenesis ulrich rodeck and jouni uitto expression of either collagen vii or the noncollagenous (nc ) fragment derived from it has been suggested to be indispensable for the development of squamous- cell carcinomas (sccs) in patients affected by recessive dystrophic epidermoly- sis bullosa (rdeb). this view is challenged here by the observation that sccs do develop in rdeb patients lacking expression of collagen vii altogether. the aggres- sive behavior of rdeb-associated sccs remains unexplained. journal of investigative dermatology ( ) , – . doi: . /sj.jid. the term epidermolysis bullosa (eb) represents a heterogeneous group of mechanobullous disorders characterized by skin fragility and blister formation. in addition to the skin, a number of other specialized epithelia, including the oral mucous membranes as well as those of the respiratory, vesicourinary, and gas- trointestinal tract, can be affected (fine et al., ). in milder forms of eb, blis- ters may be confined to limited areas of the skin, primarily the hands and feet. in contrast, in the most severe forms of eb, minimal trauma can result in widespread blistering and cutaneous erosions that heal slowly, if at all. the clinical course of the recessive dystrophic form of eb (rdeb, the hallopeau–siemens type; omim# ) is unrelenting, and the affected patients develop severe mutilat- ing scarring and are at high risk of devel- oping squamous-cell carcinomas (sccs) of the skin. unlike sporadic sccs in the general population, the rdeb-associ- ated sccs readily metastasize and have emerged as a prevalent life-threatening complication in these patients (fine et al., ). the cutaneous fragility in rdeb is caused by mutations in the col a gene, which encodes type vii collagen, a structural component of anchoring fibrils at the cutaneous basement membrane zone (varki et al., ). wild-type colla- gen vii contributes to the structural integ- rity of the basement membrane zone by tethering the lamina densa of the dermo- epidermal basement membrane to the underlying papillary dermis (shimizu et al., ). a wide spectrum of col a mutations that affect either collagen vii protein production or fibrillar assem- bly have been linked to deb. in rdeb patients, premature stop codons are frequently observed, predicting expres- sion of truncated collagen vii, including the noncollagenous (nc ) domain, but lacking c-terminal sequences nec- essary for collagen vii assembly. the molecular genetic hallmark of the most severe rdeb is stop codon mutations in both alleles, spanning the entire length of the collagen vii polypeptide (varki et al., ). ortiz-urda and colleagues ( ) recently demonstrated that expression of the nc fragment was required for malignant transformation of a series of keratinocytes isolated from rdeb patients. in addition, they observed that expression of either full-length collagen vii or the nc fragment was necessary for tumorigenic conversion of normal keratinocytes from non-rdeb individu- als. pourreyron et al. ( , this issue) revisited the requirement of collagen vii expression for scc development in another series of scc cell lines isolated from rdeb patients. they demonstrate that of patients investigated devel- oped scc in the absence of collagen vii or nc expression and conclude that, in rdeb patients, expression of collagen vii fragments is not a necessary requirement for scc development. in support of this notion, we have identified in the debra molecular diagnostics laboratory muta- tion database seven rdeb patients who were compound heterozygotes with two col a stop codon mutations in trans upstream from the nc /c junc- tion (varki et al., ). these patients are predicted not to express nc , yet two of three, who were over years of age, have developed aggressive sccs (j. uitto, unpublished observations). can these seemingly contradictory results be reconciled? the answer may lie in the use of distinct experimental systems that were employed to assess malignant transformation. ortiz-urda et al. ( ) based their study on the use of an experimental model system to assess the tumorigenic potential of normal kera- tinocytes. to achieve tumorigenicity in immunodeficient mice, they retrovirally transduced normal keratinocytes with oncogenic ras (ha-ras-v ) and the nf-κb inhibitor iκbα. thus, expression of collagen vii appears to be an absolute requirement for tumor formation driven by ha-ras, leaving open the question of whether this observation can be general- ized to rdeb patients. pourreyron et al. ( ) resolve this question by demon- strating that expression of collagen vii or fragments thereof is not strictly required department of dermatology and cutaneous biology, jefferson medical college, and jefferson institute of molecular medicine, thomas jefferson university, philadelphia, pennsylvania, usa correspondence: dr ulrich rodeck, jefferson institute of molecular medicine, thomas jefferson university, s. th street, philadelphia, pennsylvania , usa. e-mail: ulrich.rodeck@mail.tju.edu | expression of collagen vii fragments is not a necessary requirement for scc development. http://www.jidonline.org http://www.nature.com/doifinder/ . /sj.jid. mailto:ulrich.rodeck@mail.tju.edu commentary journal of investigative dermatology ( ), volume for scc development in patients. clearly, their findings must be confirmed in a larger cohort of rdeb patients afflicted with sccs. however, their work high- lights the importance of molecular epi- demiology in patients to ascertain the relevancy of findings in experimental models of skin tumor development. of course, it is possible that the requirement of nc expression for scc development is restricted to a subset of rdeb patients in which ha-ras muta- tions occur. in sporadic sccs ras muta- tions are infrequent and typically occur late in tumor progression (campbell et al., ; clark et al., ). unfortunately, the activation state of ha- ras in rdeb-associated sccs is current- ly unknown. if a high frequency of ras mutations should be prevalent in rdeb- associated sccs, it would be of interest to determine whether the tumors formed in the absence of collagen vii expression exhibit deregulated signaling pathways normally dependent on the presence of either collagen vii or the nc domain (rodeck et al., ). regardless of the results of future efforts to resolve these issues, expression of the nc domain of collagen vii alone is not likely to pro- vide a reliable diagnostic tool to iden- tify patients at risk of scc development. instead, collagen vii joins a long list of extracellular matrix components that have been implicated in scc develop- ment at the microenvironment of the tumor–host interface, including collagen iv, collagen i, fibronectin, and laminin (formerly laminin ) (abelev and lazarevich, ; marinkovich, ). much like these, collagen vii may act as a “modifier” of the transformed state by enhancing the malignant potential of initiated keratinocytes. yet none of these extracellular matrix components is likely to be an absolute requirement for tumor progression. rdeb, more so than less aggressive forms of eb, is characterized by chronic wound healing and excessive scar for- mation that last decades before sccs are manifest. an interesting parallel to sccs arising in continuously remodeling scar tissue is marjolin’s ulcers—sccs that typically arise in burn scars many years after the initial scarring event (phillips et al., ). interestingly, these sccs are also very aggressive and invasive, much like rdeb-associated sccs. these paral- lels raise the question of whether, regard- less of collagen vii/nc expression sta- tus, chronic wound healing represents the driving force for the development of highly malignant sccs in both the gen- eral population and rdeb patients. conflict of interest the authors state no conflict of interest. references abelev gi lazarevich nl ( ) control of differentiation in progression of epithelial tumors. adv cancer res : – campbell c, quinn ag, rees jl ( ) codon harvey-ras mutations are rare events in non- melanoma human skin cancer. br j dermatol : – clark lj, edington k, swan ir, mclay ka, newlands wj, wills lc et al. ( ) the absence of harvey ras mutations during development and progression of squamous-cell carcinomas of the head and neck. br j cancer : – fine j-d, bauer ea, mcguire j, moshell a ( ) epidermolysis bullosa. johns hopkins university press, baltimore, md, – marinkovich mp ( ) tumour microenvironment: laminin in squamous-cell carcinoma. nat rev cancer : – ortiz-urda s, garcia j, green cl, chen l, lin q, veitch dp et al. ( ) type vii collagen is required for ras-driven human epidermal tumorigenesis. science : – phillips tj, salman sm, bhawan j, rogers gs ( ) burn scar carcinoma: diagnosis and management. dermatol surg : – pourreyron c, cox g, mao x, volz a, baksh n, wong t et al. ( ) patients with recessive dystrophic epidermolysis bullosa develop squamous-cell carcinoma regardless of type vii collagen expression. j invest dermatol : – rodeck u, fertala a, uitto j ( ) anchorless keratinocyte survival: an emerging pathogenic mechanism for squamous cell carcinomas in recessive dystrophic epidermolysis bullosa. exp dermatol : – shimizu h, ishiko a, masunaga t, kurihara y, sato m, bruckner-tuderman l et al. ( ) most anchoring fibrils in human skin originate and terminate in the lamina densa. lab invest : – varki r, sadowski s, uitto j, pfendner e ( ) epidermolysis bullosa. ii. type vii collagen mutations in phenotype–genotype correlations in the dystrophic subtypes. j med genet : – see related article on pg genital and nongenital nonmelanoma skin cancer: more epidemiological studies are needed andreas stang although black men in the united states have a lower mortality of nongenital nonmelanoma skin cancer (nmsc) than white men, they have a higher mortal- ity of genital nmsc than white men. mortality of nmsc has declined over time. ethnicity-specific incidence and survival analyses of nmsc can be used to deter- mine to what degree earlier detection and/or more efficient therapies have con- tributed to these observations. journal of investigative dermatology ( ) , – . doi: . /sj.jid. the burden of nonmelanoma skin cancer (nmsc) can be described by a variety of measures, including mortality. although death among people with nmsc is the exception rather than the rule, detailed analyses of routinely collected mortal- ity data provide important insights into the burden of disease. for example, although the age-standardized mortality rates of nmsc decreased in the territory clinical epidemiology unit, institute of medical epidemiology, biometry, and informatics, medical faculty, martin-luther-university of halle-wittenberg, halle, germany correspondence: dr andreas stang, clinical epidemiology unit, institute of medical epidemiology, biometry, and informatics, medical faculty, martin-luther-university of halle-wittenberg, magdeburger strasse , halle , germany. e-mail: andreas.stang@medizin.uni-halle.de a vascular cause of neck pain ce - medical illustration a vascular cause of neck pain brian reed curtis • evan fitchett received: october / accepted: december / published online: december � simi history and presentation a -year-old woman without any significant past medical history presented to her primary care physician with neck pain and tingling in her left arm. there was no history of trauma. on physical examination, she had left-sided neck pain. the upper extremity strength and reflexes were nor- mal, and the cranial nerves were intact. there were no visual field defects and no history of vision loss. the pupils were equal in size, and were reactive at the time of the visit with her physician. her pain was partially relieved with a short course of steroids, but she continued to have numb- ness and tingling in her left arm. one week prior to mri, she began to have headaches, and day prior to the mri, she noticed her pupils were uneven; her left pupil was smaller than the right. she also began to have visual scintillations. imaging a cervical spine mri shows no significant degenerative changes or disc herniations to explain the patient’s pain. however, there is an eccentric, crescent-shaped hyperin- tense signal encasing the anterior aspect of the left internal carotid artery on t - and t -weighted mri images, which is much more conspicuous on t imaging with fat sup- pression (fig. ). this finding is characteristic of a sub- intimal hematoma related to left internal carotid artery dissection. the proximal carotid arteries demonstrate a normal mri appearance for comparison (fig. ). clinical course the patient was brought to the hospital where she was evaluated by neurology and neurosurgery. she remained stable throughout treatment without signs of infarction or other complication from her internal carotid artery dis- section. although the spontaneity of our patient’s carotid dissection suggests a familial arterial disease, none has been confirmed. discussion there are many causes for neck pain, most of which are musculoskeletal in nature, including muscular or soft tissue etiologies, fractures, degenerative disc disease, and disc herniations. although relatively rare with an inci- dence of approximately in , , dissection of the carotid or vertebral arteries is an important cause of neck pain [ ]. craniocervical arterial dissection occurs more often in patients with familial arterial disease such as fibromuscular dysplasia. often, there is an inciting event, which can range from significant trauma to chiropractic maneuvers, or even minor events such as bending over. however, arterial dissection can rarely occur spontaneously. carotid artery dissection most often involves the extracranial internal carotid artery. it can present with a & brian reed curtis brian.curtis@jefferson.edu department of radiology, thomas jefferson university hospital, south th street, philadelphia, pa , usa sidney kimmel medical college, thomas jefferson university, philadelphia, usa intern emerg med ( ) : – doi . /s - - - http://crossmark.crossref.org/dialog/?doi= . /s - - - &amp;domain=pdf http://crossmark.crossref.org/dialog/?doi= . /s - - - &amp;domain=pdf partial horner’s syndrome with miosis and ptosis. miosis and oculosympathetic paresis are results of altered sym- pathetic pathways in the neck that normally contribute to pupil dilatation and partial elevation of the eyelid. in fact, one study reports that % of patients with internal carotid artery dissection presented with a painful horner syn- drome. furthermore, % have transient monocular vision abnormalities with scintillations, which our patient also eventually experienced, and this is attributed to choroidal hypoperfusion [ ]. these are important signs and symptoms to evaluate for while performing a history and physical examination on patients with neck pain. an mri is commonly ordered to evaluate neck pain, especially when there are neurologic symptoms, since its contrast resolution allows outstanding soft tissue charac- terization of disc herniations, nerve impingement and other common musculoskeletal disorders. clinicians may not suspect arterial dissection and dedicated vascular imaging may not be ordered; however, arterial dissection can be diagnosed on non-contrast cervical spine mri imaging fig. axial t -weighted (a), t -weighted (b) and t -weighted fat- suppressed (c) mr images at the level of the parotid glands (p) demonstrate left internal carotid artery dissection. a–c crescent- shaped bright signal caused by sub-intimal blood products (arrow- head) draped over the black left internal carotid artery flow void (short arrow). internal jugular vein flow void is noted (long arrow) just medial to the posterior belly of the digastric muscle (d). c darkening of fat (f), which makes the bright crescent-shaped left internal carotid artery sub-intimal hematoma (arrowhead) conspicu- ous. this is characteristic of arterial dissection. (sc—sternocleido- mastoid muscle) fig. axial t -weighted (a), t -weighted (b) and t -weighted fat- suppressed (c) mr images of the same patient in fig. at the level of the submandibular glands (sb) show normal flow voids in the more proximal carotid arteries. a–c normal black flow voids in the carotid arteries (short arrows) without surrounding crescent-shaped bright signal. the adjacent internal jugular vein flow voids (long arrows) are just medial to the sternocleidomastoid muscles (sc). note the darkening of fat (f) in c and the lack of bright signal surrounding the normal vasculature intern emerg med ( ) : – with diligent observation. therefore, it is important for all physicians interpreting imaging to specifically evaluate the neck vasculature. patent blood vessels with fast flowing blood create ‘‘flow voids’’ on mri that appear a black signal along the vessel course [ ]. this artifact is related to protons in the blood moving out of the region imaged in between the radiofrequency excitation pulse and the time that the excited protons relax, and release the radiofrequency that is measured to produce an image. this is a helpful artifact; if it is present, then the vessel can be considered patent, especially on t -weighted images. loss of a flow void can represent vascular occlusion or slow blood flow. our patient maintains a flow void in her left internal carotid artery indicating luminal patency, but there is an abnormal signal surrounding its anterior aspect on t - and t - weighted images. hyperintense signal on t -weighted images is caused by few materials found in the human body including blood products, fat, melanin, proteinaceous material, calcification and other mineralization. in vascular dissection, a tear in the tunica intima allows blood to dis- sect into the sub-intimal space and into the tunica media. extravascular blood products evolve from hemoglobin to methemoglobin, a change that is observed by signal intensity change on mri. subacute hemorrhage with methemoglobin appears bright on t images; this is seen around days after the formation of the initial hematoma, and remains up to months [ ]. the crescent-shaped t hyperintensity surrounding the anterior aspect of the left internal carotid artery is diagnostic of a sub-intimal hematoma related to a tear in the tunica intima that remains contained by the tunica adventitia. this finding is con- firmed and more conspicuous on t fat-saturated images, since the abundant normal t hyperintense fat is darkened and t hyperintense blood products remain bright. this can easily be overlooked on mri, especially without fat- suppressed t images (which are not typically included on routine cervical spine mri images), if the vessels are not diligently evaluated. compliance with ethical standards conflict of interest the authors declare that they have no conflict of interest. human and animal rights statement this article does not contain any studies with human participants or animals performed by any of the authors. informed consent for this type of study formal consent is waived. references . schievink wi, roiter v ( ) epidemiology of cervical artery dissection. front neurol neurosci : – . biousse v, touboul pj, d’anglejan-chatillon j, lévy c, schaison m, bousser mg ( ) ophthalmologic manifestations of internal carotid artery dissection. am j ophthalmol ( ): – . pandey s, hakky m, kwak e, jara h, geyer ca, erbay sh ( ) application of basic principles of physics to head and neck mr angiography: troubleshooting for artifacts. radiographics ( ):e –e . doi: . /rg. . kitanaka c, tanaka j, kuwahara m, teraoka a ( ) magnetic resonance imaging study of intracranial vertebrobasilar artery dissections. stroke ( ): – intern emerg med ( ) : – http://dx.doi.org/ . /rg. 	a vascular cause of neck pain 	history and presentation 	imaging 	clinical course 	discussion 	references . © hellenic society of gastroenterology www.annalsgastro.gr annals of gastroenterology ( ) , - o r i g i n a l a r t i c l e the impact of risk factors on gastroparesis at an urban medical center katherine duffeya*, michelle hannona*, joseph yoob, nicholas perkonsc, charles intenzod, stephanie moleskib, anthony j. dimarinob thomas jefferson university hospital; university of pennsylvania, philadelphia, usa abstract background gastroparesis is a complex and poorly understood disease. the literature is lacking with respect to the epidemiology of patient comorbidities and their effect on gastric emptying. we aimed to describe the most common comorbid conditions among patients with gastroparesis in an urban population and quantify the effect of these comorbidities on the severity of delayed gastric emptying (dge). methods we examined the medical records of all patients diagnosed with gastroparesis at a quaternary care center between and . the severity of dge was analyzed after patients were stratified for possible causative etiologies. likelihood ratio tests were used to assess the significance of demographic and scintigraphic variation in this population. results of the patients, . % were caucasian and . % were african american. among these patients, . % had evidence of medication-associated gastroparesis, . % had diabetes- associated gastroparesis, and . % had idiopathic disease. african american patients with gastroparesis were more likely to have diabetic gastroparesis than patients of other races (p= . ). there was a statistically significant relationship between the number of major risk factors and the severity of a patient’s dge (p= . ). conclusions among a diverse urban population, patients with dge often carry multiple comorbid conditions that serve as risk factors for the development of gastroparesis, including prescriptions for narcotic medications. greater numbers of these comorbid conditions are associated with more severe disease. demographics are significantly associated with the etiology and severity of gastroparesis; in particular, african american patients are more likely to have diabetic gastroparesis than patients of other races. keywords delayed gastric emptying, diabetes mellitus, narcotic medications ann gastroenterol ; ( ): - introduction gastroparesis is a syndrome of objective delayed gastric emptying (dge) in the setting of symptoms such as nausea, vomiting, early satiety, bloating, and upper abdominal pain, and in the absence of a mechanical obstruction [ , ]. the gold standard for diagnosis is gastric emptying scintigraphy (ges)  [ , ]. the epidemiology of gastroparesis in the community is not well described. two previous studies have described the epidemiology of the disease, but these were limited to relatively uniform suburban and rural locations [ , ]. while a multitude of etiologies of gastroparesis have been suggested, most studies group patients into categories: diabetic and idiopathic. diabetic gastroparesis has been extensively studied [ - ], but the most common form of gastroparesis is thought to be idiopathic, with a possible correlation to a prior viral infection [ , , ]. other cases of gastroparesis can be attributed to various medications, post- adepartment of medicine, division of internal medicine, thomas jefferson university hospital, philadelphia, pa (katherine duffey, michelle hannon); bdepartment of medicine, division of gastroenterology and hepatology, thomas jefferson university, philadelphia, pa (joseph yoo, stephanie moleski, anthony j. dimarino); cperelman school of medicine, university of pennsylvania, philadelphia, pa (nicholas perkons); ddepartment of radiology, division of nuclear medicine and molecular imaging, thomas jefferson university, philadelphia, pa (charles intenzo), usa *these authors contributed equally conflict of interest: none correspondence to: anthony j. dimarino, md, south th street, suite , philadelphia pa , usa, e-mail: anthony.dimarino@ jefferson.edu received august ; accepted january ; published online april doi: https://doi.org/ . /aog. . k. duffeya et al annals of gastroenterology surgical changes, neurologic diseases, autoimmune syndromes, and connective tissue disease [ - ]. the relationship between patient demographics, the objective severity of dge, and the specific etiology of the disease is not well understood. our goal was to describe the most common comorbidities among an urban patient population diagnosed with gastroparesis and to determine whether certain comorbidities correlate with disease severity. patients and methods this is a retrospective chart review including all patients who underwent ges at thomas jefferson university hospital in philadelphia, pa, between and . this study was evaluated and approved by the institutional review board at our institution (control # d. ). the electronic medical record was reviewed to collect information regarding patient demographics, medical history, medications prescribed at the time of diagnosis and ges data. data were collected and managed using redcap electronic data capture tools hosted at thomas jefferson university [ ]. patients were included in the study if their ges showed > % retention of gastric contents h following ingestion of a solid meal consisting of an egg and bread sandwich labeled with . mci of technetium m-sulfur colloid. this is the standard for diagnosing dge at our institution; it is based on industry standards for the philips medical systems’ jetstream software as well as institution-specific analyses. patients were excluded from the presented analyses if they had a mechanical gastric outlet obstruction precluding the diagnosis of gastroparesis. the presence of comorbid conditions serving as risk factors for the development of gastroparesis was evaluated for each patient in the study population. major risk factors were defined as comorbid conditions that have been well established in the literature to be strongly associated with gastroparesis. minor risk factors were defined as those postulated to be related to gastroparesis in in vivo studies or smaller case reports, but not consistently proven to be associated. patients were assigned to categories as outlined in fig. ; patients with one or more major risk factors were assigned to the appropriate mutually inclusive groups - , while patients with minor risk factors only or idiopathic disease were assigned to exclusive groups or . statistical analysis to analyze the significance of demographic and scintigraphic variation, likelihood ratio tests were performed on a linear model fit to predict the percentage of gastric contents retained at h, or a generalized linear model with a logit linking function to predict the presence of a particular etiologic category. p-values were calculated using chi-square test, which assessed the significance of individual variables within linear models when controlling for other potential sources of variation. all analyses were performed using r . . patients with gastroparesis ( ) major risk factor? minor risk factor? yes yes no no group : medication ( , . %) group : minor risk factor ( , . %) group : idiopathic ( , . %) group : diabetes ( , . %) group : other major risk factor ( , . %) narcotic prescription anticholinergic prescription type diabetes type diabetes post-surgical parkinson’s disease connective tissue disease other neurologic disease multiple sclerosis hypothyroidism autoimmune disease sarcoidosis tricyclic antidepressant calcium chennel blocker figure grouping of patients risk factors for gastroparesis annals of gastroenterology results there were patients who completed solid-phase ges at thomas jefferson university hospital during and . of these patients, had accelerated gastric emptying and had normal gastric emptying. ten patients were excluded because they had a physical gastric outlet obstruction, precluding a diagnosis of gastroparesis. in total, patients were included in the study. of these patients, . % were female; . % were caucasian and . % were african american; . % of patients had a diagnosis of diabetes mellitus; and . % of patients had an active prescription for narcotics or anticholinergic medications (table ). the mean body mass index (bmi) of patients included in the study was . kg/m . patients were grouped based on their comorbidities and risk factors for the purposes of our descriptive analysis. there were ( . %) patients who met the criteria for medication- associated gastroparesis; ( . %) had diabetic gastroparesis, ( . %) had gastroparesis associated with another major risk factor, ( . %) had minor risk factors but no major risk factors, and ( . %) were classified as true idiopathic gastroparesis. there was significant demographic variation among the etiologic categories. in a model comparing patients with and without diabetes- associated gastroparesis, patient race (p= . ), age (p= . ), sex (p= . ), and bmi (p< . ) were independent, statistically significant predictors of having diabetes-associated gastroparesis. while only . % of the study population was african american, . % of patients with diabetes-associated gastroparesis in this population were african american. men, patients with an elevated bmi, and patients diagnosed at an older age had a statistically significantly greater probability of having diabetes-associated gastroparesis than females, patients with a lower bmi, and younger patients (tables , ). in a model comparing patients with and without medication-associated gastroparesis, age (p= . ) and bmi (p= . ) were independent, statistically significant predictors of having medication-associated gastroparesis after controlling for patient sex and race. patients with a higher bmi or diagnosed at an older age had a higher likelihood of having medication-associated gastroparesis than patients with a lower bmi and those younger at diagnosis. among patients with idiopathic disease, there was also a statistically significant variation in age (p< . ) and bmi (p= . ) compared to patients in the study population without idiopathic disease after controlling for sex and race. patients with a lower bmi or those diagnosed at a younger age were more likely to have idiopathic disease than patients with a higher bmi or those older at diagnosis. two of the major risk factors significantly contributed to more severe delays in gastric emptying after controlling for race and sex: medications (p= . ) and diabetes (p= . ) (table ). in addition, after controlling for age, sex, bmi, and race, there was a statistically significant relationship between the number of major risk factors and the severity of a patient’s dge (p= . ) (table ). there was no statistically significant table overall patient characteristics category n (%) sex female ( . ) male ( . ) race caucasian ( . ) african american ( . ) other ( . ) major risk factors narcotic prescription ( . ) anticholinergic prescription ( . ) type diabetes mellitus ( . ) type diabetes mellitus ( . ) post-surgical ( . ) parkinson’s ( . ) connective tissue disease ( . ) minor risk factors hypothyroidism ( . ) multiple sclerosis ( . ) other neurologic disease ( . ) autoimmune disease ( . ) sarcoidosis ( . ) calcium channel blocker prescription ( . ) tricyclic antidepressant prescription ( . ) true idiopathic ( . ) relationship between the number of minor risk factors and the severity of dge (p= . ). discussion this study examined the most common comorbid conditions among an urban patient population diagnosed with gastroparesis. female patients represented . % of the study population, and . % of patients were from minority groups. the majority of patients carried at least one risk factor for gastroparesis, while % of patients had true idiopathic disease. a higher burden of major risk factors was significantly associated with a more severe delay in gastric emptying. to our knowledge, this is the first study to examine the comorbidities, or risk factors for dge among an urban population of gastroparesis patients, and the first to attempt to establish the impact of multiple comorbid conditions on the objective severity of dge. our patient demographics are similar to those in previous publications with regard to the average age of patients at the time of diagnosis and the k. duffeya et al annals of gastroenterology previous studies have attempted to correlate patient symptoms with the degree of dge, but few have examined the relationship between etiology of gastroparesis and the severity of dge [ - ]. we have shown that patients with diabetic or medication-associated gastroparesis and those with multiple major risk factors in combination had significantly more severe dge compared to those with idiopathic gastroparesis. a wide range of medications have been implicated in delaying gastric emptying. based on the available evidence, we considered narcotic analgesics and anticholinergic medications to be significantly related to dge [ - ]. in our study, % of patients had an active prescription for narcotics at the time of diagnosis – higher than the national opioid prescribing rate [ ]. calcium channel blockers and tricyclic antidepressants are thought to impact gastric motility, but data are lacking on a clear relationship with dge [ - ]. for this reason, we considered both of these medications to be minor risk factors for the disease. a majority of our patients had a prescription for at least one medication that has been implicated in delaying gastric emptying, a finding that has not previously been well described. according to the consensus recommendations for gastric emptying scintigraphy, most centers recommend that patients stop gastric motility-delaying agents - h prior to undergoing ges [ ]. perhaps it could be beneficial to perform ges while patients are still taking all medications; this would provide the most accurate representation of the patient’s dge as it occurs on a daily basis. table race and risk factors patient group total race (%) p-value* caucasian african american other overall . . . na medication-associated . . . ns diabetes mellitus . . . . other major risk factor . . . . minor risk factor only . . . ns true idiopathic . . . ns *p-values represent a controlled comparison between patients within a specific gastroparesis group and patients not in that group na, not applicable; ns, nonsignificant table demographics and risk factors patient group total average age (years) p-value average bmi p-value* overall . na . na medication-associated . . . . diabetes mellitus . . . < . other major risk factor . ns . ns minor risk factor only . ns . ns true idiopathic . < . . . *p-values represent a controlled comparison between patients within a specific gastroparesis group and patients not in that group na, not applicable; ns, nonsignificant; bmi, body mass index table risk factors and severity of delayed gastric emptying risk factors mean percent retained at h (%) medication-associated . (n= , sd= . ), p= . diabetes mellitus . (n= , sd= . ), p= . other major risk factor . (n= , sd= . ) minor risk factor only . (n= , sd= . ) true idiopathic . (n= , sd= ) overall . (n= , sd= . ) sd, standard deviation table number of risk factors and severity of delayed gastric emptying (p= . ) number of major risk factors mean percentage retained at h (%) . (n= , sd= . ) . (n= , sd= . ) . (n= , sd= . ) . (n= , sd= . ) (n= ) sd, standard deviation predominance of female patients [ , - ]. importantly, our study is among the first to include a significant representation of minority populations in its analysis. risk factors for gastroparesis annals of gastroenterology gastroparesis is a well-known complication of diabetes  [ , ]. in this study, african american patients were more likely to have diabetic-associated gastroparesis than gastroparesis patients of any other race. this supports the findings of prior studies with a smaller proportion of minority patients [ , ]. while rates of diabetes mellitus in the community are also greater among african americans ( . vs. . % for caucasians) [ ], our findings indicate a disproportionate impact on minority populations. medical conditions that have been clearly linked with gastroparesis include post-surgical nerve injury, parkinson’s disease, autoimmune diseases and connective tissue diseases, such as systemic sclerosis and sjögren’s syndrome [ , - , , - ]. interestingly, our population included a significant percentage of patients with hypothyroidism ( . %), significantly higher than the national prevalence of . % [ ]. while the hypothyroidism state is associated with delayed esophageal and gastric motility, we did not consider a diagnosis of hypothyroidism to be a major risk factor for gastroparesis, as evidence suggests that once patients are stabilized on appropriate medication, the impact on motility is typically resolved [ - ]. idiopathic gastroparesis is diagnosed when no other cause is identified, though it is often unclear in previous studies which potential causes were considered before patients were labeled with the diagnosis [ , , ]. as is standard in the literature  [ - ], we included patients with a post-viral syndrome as patients with idiopathic disease, assuming that they did not have a major risk factor. in our study, we relied on the available literature to describe exposures and comorbid conditions as risk factors for gastroparesis. our individual patient data were limited to the availability of details in the medical record. we were unable to gather information regarding indicators of the severity and control of patients’ underlying chronic diseases, or the doses of their prescribed medications, both of which can impact gastric emptying. in addition, the gold standard for evaluation of dge is -h nuclear emptying scintigraphy. however, at our institution patients classically undergo a -h scan unless there is doubt regarding the results. finally, it is difficult to determine which medications were held prior to scintigraphic testing and for how long. these patient instructions are physician- dependent and there is no clear documentation in our record system regarding the instructions provided to the patient or followed by the patient. in conclusion, the results of this retrospective study indicate that patients diagnosed with gastroparesis often have multiple comorbid conditions, and the number of risk factors that they carry significantly impacts the severity of their disease. if we continue to limit patients into broad categories of diabetic and idiopathic gastroparesis, we may be missing opportunities to better address the true underlying etiology of the disease and to treat patients optimally. in addition, we have demonstrated a racial disparity in the etiology of gastroparesis, with african american patients being more likely to have diabetic disease than patients of other races. further research should be done to better elucidate the impact of certain medications, comorbid conditions and socioeconomic status on gastric emptying. additionally, physicians should consider patients’ individual risk factors when ordering, protocoling, and interpreting ges studies in order to best evaluate the extent of the disease and to provide optimal medical management. summary box what is already known: •	 little	is	known	about	the	causes	of	gastroparesis	 beyond severe diabetes •	 many	 patients	 are	 characterized	 as	 having	 idiopathic gastroparesis what the new findings are: •	 a	large	proportion	of	gastroparesis	patients	receive	 narcotic prescriptions •	 african	 american	 patients	 seem	 to	 be	 at	 higher	 risk for diabetic gastroparesis than patients of other races •	 patients	 with	 more	 conditions	 known	 to	 be	 associated with gastroparesis had more severe objective delays in gastric emptying references . camilleri m, parkman hp, shafi ma, abell tl, gerson l; american college of gastroenterology. clinical guideline: management of gastroparesis. am j gastroenterol ; : - . . parkman hp, hasler wl, fisher rs; american gastroenterological association. american gastroenterological association technical review on the diagnosis and treatment of gastroparesis. gastroenterology ; : - . . abell tl, camilleri m, donohoe k, et al; american neurogastroenterology and motility society and the society of nuclear medicine. consensus recommendations for gastric 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energy of the dengue e protein in anionic membranes composed of popcþpopg is much greater than in membranes composed of popcþpope. -pos board b hiv fusion peptide perturbs membrane structure in a cholesterol dependent fashion alex liqi lai, jack h. freed. acert, cornell university, ithaca, ny, usa. the fusion between viral envelopes with host cell membranes is required for viral entry and infection, which is mediated by special glycoproteins anchored on the viral membrane. fusion peptide (fp) is the domain that initiates mem- brane fusion. however, the mechanism of membrane fusion is still unclear. we previously found that the influenza hemagglutinin fp increases the order of dmpc lipid bilayer. we hypothesize that inducing lipid ordering might be a critical step in fusion caused by a variety of fusion proteins. hiv gp fp plays a similar role as influenza ha fp. however, gp fp is polymorphic and changes from alpha helix to beta aggregation as cholesterol concentration in lipid increases. we used pc spin labels on the lipid head group and different positions on the acyl chain to detect the perturbation by gp fp to popc/ popg lipid bilayers with different cholesterol concentration ( % to %) by cw-esr. our data show that ) gp fp affects the lipid order in the same pat- tern as ha fp does, i.e., a cooperative effect vs. lipid/peptide ratio, thus sup- porting our hypothesis; ) gp fp induces membrane ordering in all tested lipid compositions, consistent with promoting membrane fusion in these com- positions; ) in the high cholesterol containing lipid bilayers, whereas gp fp is in the beta aggregation conformation, its effect on the lipid ordering reaches deeper into the bilayer, consistent with deeper membrane insertion for gp fp in this conformation. we are extending the esr studies to look for coexisting membrane microdomains induced by different conformations of fps and the fp partitioning between them and for precise separation of the effects of ordering and molecular motion. -pos board b cd binding induces an asymmetric transition of hiv- env from its native conformation into the prehairpin intermediate state mukta d. khasnis, konstantine halkidis, anshul bhardwaj, michael root. thomas jefferson university, philadelphia, pa, usa. hiv- membrane fusion is mediated by sequential binding of the viral homo- trimeric env (gp /gp ) to cellular cd and chemokine receptor (cxcr or ccr ). these binding events coordinate conformational transitions of the gp trimer from its native conformation into a prehairpin intermediate state (phi) and, subsequently, into its fusogenic trimer-of-hairpins structure (toh). in the phi, the gp trimer assumes an extended conformation that bridges the viral and cellular membranes, and exposes the n-hr and c-hr do- mains which are targeted by hiv- fusion inhibitors t and -helix, respec- tively. our previous work suggests that the phi-to-toh transition occurs in a concerted (symmetric) fashion. here, we investigate the transition from the native state to the phi using a functional complementation strategy that em- ployed heterotrimeric envs containing only one or two functional cd - and chemokine receptor-binding sites. additionally, by incorporating t - and -helix- resistance mutations into individual env protomers, we were able to interrogate exposure of discrete gp n-hr and c-hr domains. our data indicate that a single cd binding to an env trimer is sufficient to promote fusion. moreover, the first cd binding event appeared to expose only one of three possible binding sites for each fusion inhibitor, suggesting an asymmetric transition into the phi. this asymmetry was significantly more pronounced in the gp n-hr region compared to the gp c-hr region. these results can be used to explain the multiphasic titration of mutant env homotrimers that naturally form asymmetric n-hr domain structures. taken together, these data suggest that the native state-to-phi transition of env occurs in a multistep (asymmetric) fashion. -pos board b evolution of hiv- resistance to a cholesterol-linked d-peptide fusion inhibitor amanda e. siglin , nicholas francis , michael s. kay , micheal j. root . thomas jefferson university, philadelphia, pa, usa, university of utah, salt lake city, ut, usa. during hiv- entry, the n-hr and c-hr regions of the gp viral glycoprotein associate to form a trimer-of-hairpins critical for membrane fusion. the n-hr region contains a highly conserved hydrophobic pocket that is the target for a multivalent, d-peptide fusion inhibitor, pie -trimer. recently, a modified form of this inhibitor with a conjugated cholesterol (chol-pie -trimer) was shown to possess up to -fold increased potency, presumably due to mem- brane targeting. here, we determined the resistance profile of chol-pie - trimer starting from either inhibitor-naı̈ve or pie -trimer-resistant hiv- (nl - strain). viral propagation in increasing inhibitor concentrations pro- duced hiv- populations with - to -fold reduced sensitivity chol- pie -trimer. these viruses were also resistant to the parental, unconjugated inhibitor pie -trimer. using hiv- fusion inhibitors di-c and -helix, we were able to interrogate the effect of escape mutations on the exposure of the gp n-hr and c-hr regions, respectively. resistance to chol-pie - trimer resulted in a slight decrease in the temporal window of n-hr exposure, regardless of the starting viral population. exposure of the c-hr region was unchanged for resistant viruses generated from the inhibitor-naı̈ve viral pool. by contrast, the temporal window of c-hr exposure was significantly increased (> -fold) for resistant viruses that were generated from the pie -trimer-resistant viral pool. efforts to identify the mechanisms of chol- pie -trimer resistance and the decoupling of n-hr and c-hr exposure are underway. -pos board b fusogenic activity of the hiv- gp mper-tmd region: mechanism and targeting by immunogens and inhibitors jose l. nieva , beatriz apellaniz , carmen domene , nerea huarte , eneko largo . biophysics unit (csic-upv/ehu) and dept. of biochemistry, university of the basque country (upv/ehu), bilbao, spain, chemistry research laboratory, university of oxford, oxford, united kingdom. fusion of the viral envelope with the cell membrane marks the beginning of the hiv- replicative cycle. this event is targeted by inhibitors currently in clinical use and by preventive vaccines under development. antibodies e and e bind to the gp membrane proximal external region (mper)- transmembrane domain (tmd) junction and block fusion. these antibodies display the broadest viral neutralization known to date, which underscores the conservation and functionality of the mper-tmd region. in recent work, we have described that peptides representing this region have potent membrane-destabilizing effects. here, based on the outcome of vesicle assays, atomic force microscopy studies and molecular dynamics simulations, we propose a mechanism for the involvement of the mper-tmd region in hiv- fusion. in addition, we provide evidence that underpins the poten- tial use of its activity as a new target for inhibitor and immunogen development. -pos board b studies on the membrane-active behavior of outer membrane vesicles from a gram negative bacterium william bartos, rensa chen, donald y. kobayashi, paul r. meers. rutgers, the state university of new jersey, new brunswick, nj, usa. gram-negative bacteria are known to produce small ~ - nm vesicles by ‘‘blebbing’’ of their outer membranes. these outer membrane vesicles (omv) have been implicated in activities such as transmission of virulence fac- tors, horizontal gene transfer and development of biofilms. in this investigation, the interactions of omv from lysobacter enzymogenes (strain c ) with other membranes have been monitored using fluorescent assays for association and/or fusion. defined composition large unilamellar vesicles labeled with the fluorescence resonance energy transfer (fret) pair , -dipalmitoyl-sn- glycero- -phosphoethanolamine-n-( -nitro- - , -benzoxadiazol- -yl) (nbd- pe) and , -dipalmitoyl-sn-glycero- -phosphoethanolamine-n-(lissamine rho- damine b sulfonyl) (rh-pe) were incubated with isolated omv to observe the interaction via the fret ratio of donor/acceptor. omv substantially increased this ratio over the course of about an hour (t / ~ - min.) at �c, when added directly to vesicles comprising disordered or fluid lipids, such as -palmitoyl- -oleoyl-sn-glycero- -phospho-( ’-rac-glycerol) (popg), -pal- mitoyl- -oleoyl-sn-glycero- -phosphoethanolamine (pope) or -palmitoyl- - oleoyl-sn-glycero- -phosphocholine (popc). this apparent fusion was much more limited or absent with liquid ordered membranes of , -dipalmitoyl-sn- glycero- -phosphocholine/cholesterol (dppc/chol). in the case of popg/ pope / vesicles, apparent fusion was also confirmed by testing vesicles with exclusively inner monolayer fluorescent probes to diminish any fluores- cence changes from external interactions of outer monolayer fluorophores. when the omv were labeled with the fluorophore , -dioctadecyl- , , , - tetramethylindocarbocyanine, and incubated with a natural host, yeast cells (strain s ), association and/or fusion was observed by co-sedimentation of the omv label with yeast cells. these studies may help to elucidate the mech- anism of natural host-pathogen interactions and define the lipid specificity for 	hiv fusion peptide perturbs membrane structure in a cholesterol dependent fashion 	cd binding induces an asymmetric transition of hiv- env from its native conformation into the prehairpin intermediate state 	evolution of hiv- resistance to a cholesterol-linked d-peptide fusion inhibitor 	fusogenic activity of the hiv- gp mper-tmd region: mechanism and targeting by immunogens and inhibitors 	studies on the membrane-active behavior of outer membrane vesicles from a gram negative bacterium two types of novel allosteric modulators activate β -ar signaling, a g protein-coupled receptor involved in airway smooth muscle relaxation and asthma♦ papers of the week two types of novel allosteric modulators activate � -ar signaling, a g protein-coupled receptor involved in airway smooth muscle relaxation and asthma� � see referenced article, j. biol. chem. , , – development and characterization of pepducins as gs-biased allosteric agonists the � -adrenergic receptor (� ar) is a g protein-coupled receptor (gpcr) involved in hormonal signal transduc- tion and plays a role in many physio- logical processes including cardiac muscle contraction and airway smooth muscle relaxation. �-agonists, which stimulate the � ar, are commonly used as therapeutics in the treatment of asthma. however, desensitization of the receptor in response to �-ago- nists, which is largely mediated by gpcr kinases and �-arrestins, re- duces agonist efficacy. an agonist that can stimulate g protein signal- ing through the � ar while bypassing gpcr kinases and �-arrestins may be useful in the treatment of asthma. in this paper of the week, a team led by jeffrey benovic at thomas jefferson university screened lipidated pep- tides from the intracellular loops of the � ar, known as pepducins, and discovered two types of biased activa- tors of � ar signaling. one type was a receptor-dependent pepducin that stabilized a conformation of the � ar that was biased towards the gs het- erotrimeric g protein while a second group of pepducins directly activated gs. the investigators say that these molecules “provide a valuable tool for the continued study of � ar function and may prove useful as next-genera- tion asthma therapeutics.” doi . /jbc.p . gs-biased agonists do not promote � ar internalization or desensitization. this is an open access article under the cc by license. http://creativecommons.org/licenses/by/ . / 	papers of the week: two types of novel allosteric modulators activate β -ar signaling, a g protein-coupled receptor involved in airway smooth muscle relaxation and asthma crpc- - -ver -zheng_ p .. case report open access case report of recurrent metastatic pancreatic neuroendocrine tumor with gastric invasion: consequences of potential needle-tract seeding from fine-needle aspiration richard zheng, ,* sami tannouri, and harish lavu , abstract background: pancreatic neuroendocrine tumors (pnets) are relatively rare, and data guiding management of metastatic lesions are scarce. hepatic metastases are most common; here we describe a case of metastatic pnet implanted into the posterior gastric cardia. case presentation: this case study describes the progression of a -year-old man with a history of pancreatic neuroendocrine tumor (pnet) resected through distal pancreatectomy and splenectomy who developed recurrent disease in his stomach with extension into the left adrenal fossa months after initial resection. he subsequently underwent a total gastrectomy and left adrenalectomy with en bloc resection of this recurrence without compli- cation. final pathology revealed a morphologically similar pnet with positivity for cam . , chromogranin a, and synaptophysin. conclusion: the unusual location of his recurrence could suggest that his preoperative endoscopic ultrasound and fine-needle aspiration may have had a role in seeding the posterior gastric wall, highlighting the risk of per- forming this diagnostic procedure in the setting of suspected pancreatic malignancy. keywords: metastatic pancreatic neuroendocrine tumor; pnet introduction pancreatic neuroendocrine tumors (pnets) are fairly rare, accounting for less than – % of all pancreatic masses. although they tend to have a more favorable prognosis than pancreatic ductal adenocarcinoma, he- patic metastases are observed in more than % of pa- tients with pnets and are associated with a -year survival of only – % when untreated. data surround- ing treatment of other sites of metastatic spread are lim- ited. here, we report a case of metastatic pnet in the gastric cardia with extension into the left adrenal fossa, months after distal pancreatectomy and splenec- tomy. pre-operative endoscopic ultrasound (eus) and fine-needle aspiration (fna) may be implicated in the local implantation of this unusual lesion. case report a -year-old man initially presented with lightheaded- ness, palpitations, and tarry stools. he was found to be anemic with a hemoglobin of . g/dl. upper endoscopy revealed nonbleeding gastric varices. further workup through abdominal ct and mri demonstrated a large arterial-enhancing pancreatic mass, thought to be a pnet. no metastases were seen. the mass appeared to abut the splenic vein and portosplenic confluence with evidence of thrombus within the lumen of the portal department of surgery, thomas jefferson university hospital, philadelphia, pennsylvania. pancreas, biliary and related cancer center, thomas jefferson university, philadelphia, pennsylvania. *address correspondence to: richard zheng, md, department of surgery, thomas jefferson university hospital, s. th street, philadelphia, pa , e-mail: richard.zheng@jefferson.edu ª richard zheng et al. ; published by mary ann liebert, inc. this open access article is distributed under the terms of the creative commons license (http://creativecommons.org/licenses/by/ . ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. case reports in pancreatic cancer volume . , doi: . /crpc. . case reports in pancreatic cancer vein (fig. ). endoscopic ultrasound was performed with fna of the pancreatic mass. histopathological review of the fna sample revealed neoplastic cells, positive for anti-pan cytokeratin antibody, synapto- physin, and cd , suggesting pnet. an octreotide scan showed focally increased signal at the site of the pancreatic mass, without dissemination. the patient underwent resection of the tumor through distal pancreatectomy and splenectomy with en bloc por- tal vein resection and reconstruction as the tumor was di- rectly invading the splenic vein with thrombus extending into the portal vein. the patient tolerated this procedure well and his postoperative course was uncomplicated. pathology from this initial procedure revealed a grade ii pnet with / adjacent lymph nodes positive for metastatic carcinoma and negative margins with a ki- proliferative index of % (grade ii). seventeen months after resection, the patient began to have complaints of fatigue, exercise intolerance, and pal- pitation. he was again found to be anemic with a hemo- globin of . g/dl. before the aforementioned initial resection, serum pancreatic polypeptide and chromogra- nin a levels had been elevated to pg/ml and . ng/ ml, respectively; with the onset of these new symptoms, the pancreatic polypeptide level was found to be only pg/ml, but the chromogranin a level was elevated to ng/ml (fig. ). ca – levels remained normal throughout the patient’s full treatment course. diagnos- tic endoscopy to localize the source of bleeding revealed a cm malignant-appearing friable mass with central ulceration in the gastric cardia. ct scan findings con- firmed the presence of this gastric soft tissue mass and also revealed a posterior nodular extension toward the upper pole of the left kidney (fig. ). this lesion demon- strated uptake on octreotide scan, suggesting a pnet origin; a focus of uptake was also noted in the periportal region, suggesting the possibility of a metastatic lymph node. upon histopathological review of the material re- trieved at the endoscopy, the gastric lesion was identified to be morphologically similar to his previous pnet, with positivity for cam . , chromogranin a, and synaptophysin. after extensive discussion with the patient regarding his treatment options, he opted for reresection through an open total gastrectomy. after exploratory laparotomy and extensive lysis of adhesions, the tumor was noted to invade into the capsule of the left adrenal gland. both the stomach and the left adrenal gland were removed en bloc. no hepatic lesions were noted. alimentary tract recon- struction was performed through a roux-en-y esopha- gojejunostomy. the periportal region was skeletonized with removal of all nodal tissue. the patient’s postoperative course was uncomplicated. he was ultimately discharged to home on postoperative day on a low-volume clear liquid diet and total parenteral nutrition supplementation. surgical pathology revealed a pancreatic neuroendo- crine carcinoma in the gastric wall and adrenal gland with negative resection margins. the sampled peripor- tal lymph nodes were free of disease. the lesion was again confirmed to be morphologically similar to the patient’s previous pnet (fig. ). shortly thereafter, pancreatic polypeptide and chromogranin a normal- ized to pg/ml and ng/ml, respectively. fig. . hypervascular pancreatic body mass with intraluminal enhancement within portal vein consistent with tumor thrombus (arrow). fig. . cga and pp levels before, during, and after treatment course. cga, chromogranin a; pp, pancreatic polypeptide. zheng et al.; case reports in pancreatic cancer , . http://online.liebertpub.com/doi/ . /crpc. . discussion pnets are rare, and metastatic spread linked to fna is not well documented in the literature. surgical resec- tion remains the gold standard of treatment for func- tioning and nonfunctioning tumors. management of these metastases has not yet been standardized. surgi- cal management of hepatic metastases through partial hepatectomy has been shown to control symptoms of hormonal hypersecretion in patients with functional tumors and improve overall survival. hepatic-directed therapy such as transarterial chemoembolization has also been utilized for control of liver metastases. fig. . (a) initial abdominal ct scan demonstrating pancreatic body lesion (yellow circle). (b) abdominal ct scan year after distal pancreatectomy and splenectomy with gastric mass visible (yellow circle). (c) octreotide scan with enhancement of the posterior gastric wall (yellow circle). (d) sagittal cut of abdominal ct scan showing gastric mass extending posteriorly (yellow arrows) toward the left adrenal gland. (e) postoperative gastrographin swallow showing anatomical reconstruction through esophagojejunostomy. fig. . (a) original pancreatic mass with synaptophysin staining, · magnification. (b) original pancreatic mass with he staining, · magnification. (c) recurrent gastric mass with he staining, · magnification. he, hematoxylin and eosin. zheng et al.; case reports in pancreatic cancer , . http://online.liebertpub.com/doi/ . /crpc. . a case similar to ours was described in . in that re- port, a -year-old man was found to have a t n m moderate-to-well differentiated pancreatic adenocarci- noma sampled through eus/fna biopsy through the stomach wall. nine months after resection of the lesion, the patient was found to have a submucosal gastric re- currence upon follow-up endoscopy. this was man- aged through a subtotal gastrectomy, whereupon final pathology demonstrated a morphologically identical le- sion to his initial cancer. in comparison, our lesion had expanded aggressively into the retroperitoneum and appeared to involve the adrenal gland, so a total gas- trectomy and en bloc adrenalectomy were required for full resection. furthermore, as in the previously mentioned case report, fna played an important role in the preliminary diagnosis of pnet. given the atyp- ical foci of recurrence in the gastric cardia, this scenario brings to mind the rare phenomenon of needle-tract seeding that has been documented in sarcoma, prostate cancer, hepatocellular carcinoma, and other lesions. despite the theoretical fears of needle-tract seeding, however, data validating this phenomenon with regard to some forms of pancreatic cancer are generally limited to case reports. , furthermore, this is the first report of a pancreatic neuroendocrine neoplasm recurrence poten- tially from needle-tract seeding. a retrospective study of patients who underwent surgical resection of ma- lignant pancreatic neoplasms concluded that undergoing eus/fna of these lesions was not associated with a sta- tistically significant increase in the rate of either perito- neal or gastric metastases. similarly, use of eus/fna for diagnosis of pancreatic cancer was not associated with any difference in survival. multiple studies have also corroborated that the use of eus/fna for both pan- creatic cancer and intraductal papillary mucinous neo- plasm sampling was not associated with a statistically significant increase in peritoneal seeding when com- pared with patients who were not sampled. , alternative approaches for tissue sampling of pancreatic masses have not proven to be of benefit; one study demon- strated an increase in the rate of peritoneal carcinomato- sis in patients who had undergone a percutaneous fna when compared with those who had endoscopic tissue sampling. although large-scale data on pancreatic nee- dle biopsy seeding is yet unavailable, it is likely a rare occurrence as needle biopsy of pancreatic lesions is com- monplace and gastric metastases are seldom seen. in most cases, the benefits of direct tissue diagnosis out- weigh the theoretical risk of needle-tract seeding. however, no matter how remote the chance for seed- ing may be, it is up to clinicians to be selective in obtaining biopsies of lesions where a tissue diagnosis may change management and not subject a patient to undue risk. in this particular case, one could ques- tion the utility of two interventions before the initial operation—the distal pancreatectomy and splenecto- my: the fna done as part of the eus, and the octreo- scan. the patient had a classic appearance of a pnet on ct and mri, and he was symptomatic from anemia related to splenic vein occlusion. did the fna results alter management? did the octreoscan provide essen- tial information? in this era of cost consciousness in surgical care, we need to be asking these questions. author disclosure statement no competing financial interests exist. references . ikezawa k, uehara h, sakai a, et al. risk of peritoneal carcinomatosis by endoscopic ultrasound-guided fine needle aspiration for pancreatic can- cer. j gastroenterol. ; : – . . yoon wj, daglilar es, fernandez-del castillo c, et al. peritoneal seeding in intraductal papillary mucinous neoplasm of the pancreas patients who underwent endoscopic ultrasound-guided fine-needle aspiration: the pipe study. endoscopy. ; : – . . chong a, venugopal k, segarajasingam d, et al. tumor seeding after eus- guided fna of pancreatic tail neoplasia. gastrointest endosc. ; : – . . dickson pv, behrman sw. management of pancreatic neuroendocrine tumors. surg clin north am. ; : – . . volanis d, neal de, warren ay, et al. incidence of needle-tract seeding following prostate biopsy for suspected cancer: a review of the literature. bju int. ; : – . . tomonari a, katanuma a, matsumori t, et al. resected tumor seeding in stomach wall due to endoscopic ultrasonography-guided fine needle as- piration of pancreatic adenocarcinoma. world j gastroenterol. ; : – . . kudo t, kawakami h, kuwatani m, et al. influence of the safety and diagnostic accuracy of preoperative endoscopic ultrasound-guided fine-needle aspiration for resectable pancreatic cancer on clinical performance. world j gastroenterol. ; : – . . paquin sc, gariepy g, lepanto l, et al. a first report of tumor seeding because of eus-guided fna of a pancreatic adenocarcinoma. gastrointest endosc. ; : – . . ngamruengphong s, xu c, woodward ta, et al. risk of gastric or peritoneal recurrence, and long-term outcomes, following pancreatic cancer resec- tion with preoperative endosonographically guided fine needle aspiration. endoscopy. ; : – . cite this article as: zheng r, tannouri s, lavu h ( ) case report of recurrent metastatic pancreatic neuroendocrine tumor with gastric invasion: consequences of potential needle-tract seeding from fine- needle aspiration, case reports in pancreatic cancer : , – , doi: . /crpc. . . abbreviations used eus ¼ endoscopic ultrasound fna ¼ fine-needle aspiration pnets ¼ pancreatic neuroendocrine tumors zheng et al.; case reports in pancreatic cancer , . http://online.liebertpub.com/doi/ . /crpc. . founders online: early access: reflections on open access, crowd sourcing, and metadata standards research article how to cite: kurtz, william b. . “founders online: early access: reflections on open access, crowd sourcing, and metadata standards.” digital studies/le champ numérique, ( ):  , pp. – , doi: https://doi. org/ . /dscn. published: october peer review: this is a peer-reviewed article in digital studies/le champ numérique, a journal published by the open library of humanities. copyright: © the author(s). this is an open-access article distributed under the terms of the creative commons attribution . international license (cc-by . ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. see http://creativecommons.org/licenses/by/ . /. open access: digital studies/le champ numérique is a peer-reviewed open access journal. digital preservation: the open library of humanities and all its journals are digitally preserved in the clockss scholarly archive service. https://doi.org/ . /dscn. https://doi.org/ . /dscn. http://creativecommons.org/licenses/by/ . / kurtz, william b. . “founders online: early access: reflections on open access, crowd sourcing, and metadata standards.” digital studies/le champ numérique, ( ): , pp. – , doi: https://doi.org/ . /dscn. research article founders online: early access: reflections on open access, crowd sourcing, and metadata standards william b. kurtz university of virginia, us wkurtz@virginia.edu founders online, a digital initiative of the national historical publications and records commission (nhprc) of the u.s. national archives, launched in june . since its debut, the site has attracted over a million visitors interested in learning more about the creation of the united states of america in the words of six of its founding fathers. founders online contains , letters or other writings of these men and their contemporaries. widely used by academics and the general public, the site has demonstrated the value of digital humanities’ emphasis on free access. as a former assistant editor at documents compass, a program of the virginia foundation of the humanities, i served as a project manager on the early access portion of the project. we worked directly with the staffs of the currently active founding fathers documentary editing projects to make preliminary versions of unpublished documents available for early viewing on founders online. these early access documents will eventually be replaced by fully vetted and annotated versions to be completed later by the documentary editing projects. relying on a large staff of over thirty people, we transcribed or proofread over , early access documents from to . my early access experience demonstrated the need to give employees constant feedback, to reward them for good work, and to encourage specialization among project staff. my experience also reemphasized the need for unified metadata standards when aggregating different sets of data from multiple projects into a single digital platform. keywords: founders online; open access; transcription; metadata; crowd sourcing; digital history founders online, une initiative numérique de la national historical publications and records commission (nhprc) des archives nationales des États-unis, lancée en juin . depuis ses débuts, le site a attiré plus d’un million de visiteurs intéressés à en apprendre davantage au sujet de la création des États-unis d’amérique d’après six des pères fondateurs. https://doi.org/ . /dscn. mailto:wkurtz@virginia.edu kurtz: founders online founders online contient , lettres ou autres écrits de ces hommes et de leurs contemporains. largement utilisé par les universitaires et le public en général, le site a démontré la valeur de l’emphase des humanités numériques sur le libre accès. en tant qu’ancien rédacteur en chef adjoint à documents compass, un programme de la virginia foundation of the humanities, j’ai travaillé comme gestionnaire de projet pour la partie d’accès anticipé du projet. nous avons travaillé directement avec les membres du personnel des projets de montage documentaire de founding fathers actifs à l’heure actuelle, pour rendre disponibles en accès anticipé des versions préliminaires de documents non publiés sur founders online. ces documents en accès anticipé seront éventuellement remplacés par des versions entièrement approuvées et annotées qui seront complétées plus tard par les projets de montage documentaire. comptant sur un personnel nombreux de plus de trente personnes, nous avons transcrit ou relu plus de , documents d’accès anticipé entre et . mon expérience de l’accès anticipé a démontré le besoin de donner aux employés une rétroaction constante, de les récompenser pour leur bon travail, et d’encourager la spécialisation parmi le personnel du projet. mon expérience a de plus souligné davantage le besoin de normes de métadonnées communes en transposant différents ensembles de données de projets multiples en une plateforme numérique unique. mots-clés: founders online; libre accès; transcription; métadonnées; externalisation à grande échelle; histoire numérique founders online, a digital initiative of the national historical publications and records commission (nhprc) of the united states national archives, launched in june . designed and updated by david sewell and his staff at the university of virginia press, the site is an essential resource for scholars of early american history. since its debut, the site has attracted over a million visitors interested in learning more about the creation of the united states of america in the words of six of its “founding fathers”: george washington, john adams, thomas jefferson, james madison, benjamin franklin, and alexander hamilton. with over , letters or other writings of these men and their contemporaries who corresponded, lived, and worked with them, the site utilizes extensible markup language (xml) encoded documents hosted on a marklogic server to provide free, fast, and user- friendly access to the public. founders online has received praise from the larger scholarly community, including the society for history in the federal government, kurtz: founders online which awarded the site its prestigious thomas jefferson prize for its “outstanding contribution” to scholarship (ferriero b). this emphasis on reaching a much larger audience than documentary editors have traditionally served, the academic historian, should be considered a model for future digital editions regardless of their scale or subject. as stephen pinfield argued, “the major question associated with open access is no longer whether oa [open access] should be at the centre of the mainstream scholarly communication system, but how?” (pinfield ). as an assistant editor at documents compass, a program of the virginia foundation of the humanities that helps documentary editors publish their work digitally, i helped to manage the early access portion of the project from to . relying on a paid staff of over thirty people, most of whom had little experience in historical or digital work prior to joining our team, we transcribed or proofread over , early access documents. these temporary documents, meant to give the american public an early look at transcripts of historical documents not yet finished by the documentary editing projects, will eventually be replaced by permanent, professionally vetted and annotated versions. our project was led by documents compass director, susan h. perdue, with assistant editor laura k. baker and myself serving as project managers. the lessons i learned in managing our large staff and in working with a variety of editing projects with different editorial policies and methodological approaches suggest several best practices for other digital humanists considering crowd-sourcing projects utilizing volunteer labor or hoping to impose standardized metadata and workflow procedures when aggregating different projects under one digital roof. digital history meets documentary editing the appeal of publishing humanities work digitally cuts across disciplines and has increasingly become a priority for faculty hiring, cultural institutions hoping to celebrate and grant greater access to their holdings, and for scholars seeking to reach for more information on the technical infrastructure that hosts founders online, please see matt allen, “founder’s online: a lesson in performance” (allen ) and “founders online launches” (uva ). kurtz: founders online new audiences. in the field of history, the importance of writing and producing historical scholarship accessible beyond the walls of academia has become increasingly important even for those who do not consider themselves strictly public historians. in an era of decreasing faculty and research budgets for the humanities, proving that the study of history is valued by the american public is vital for history departments, universities, museums, and other historical entities that rely on public monies to cover their expenses. certainly projects such as the university of richmond’s atlas of the historical geography of the united states and american panorama have demonstrated that digital history can have a wide appeal beyond academia (stinson ). the value of publishing online is an important and ongoing debate within the historical subfield of documentary editing. founding-era documentary editing projects explore the lives of some of the most famous and important figures in united states history. the papers of thomas jefferson, begun in under the direction of renowned editor and historian julian p. boyd, is widely considered to be “the first modern historical documentary edition.” this project established standard guidelines and editorial practices that have strongly influenced other documentary editions (founders online a). by transcribing and annotating the complete works and correspondence of men such as jefferson, adams, and washington, these editorial projects are engaged in some of the most worthwhile publicly-funded historical work. a variety of private and government funders, most notably the nhprc and the national endowment for the humanities, have provided millions of dollars to make these projects possible and continue to be important funding sources today (founders online c). the tireless efforts of project editors and staff to provide accurate and scholarly editions of these men’s writing, however, are both time consuming and costly. in addition, the high cost of publishing their works in print ensures that only relatively few volumes are produced on a yearly basis. this means that the american public, which has demonstrated time and again its interest in the story of the creation of for a good discussion of the value of digital history, how it differs from traditional scholarship, and how it allows historians to reach wider audiences, see “a conversation with digital historians” (southern spaces ). kurtz: founders online its nation, has limited opportunities to benefit from this important work. while the most important editions did start to go online in the early st century, these projects, such as university of virginia press’s subscription-based service founding era collection, often existed behind a paywall that limited their use to universities able to pay for access (uvap founding era collection ). a digital edition success story: founders online founders online was a congressional initiative to fix this problem (senate hearing , – ). proposed in , funded in , and launched three years later in the summer of , founders online made freely available online some of the most important editions of the founding fathers. the site provides an intuitive search interface and the ability for anyone with an internet connection to access the letters and writings of george washington, john adams, thomas jefferson, james madison, alexander hamilton, and benjamin franklin. the site not only opened up these resources to universities who could not afford rotunda, but it also made access to the documents that explain the creation of the american republic easily available to k- educators and their students as well as the larger american public. the national archives underscored its goal of opening these documents to new audiences, particularly to educators, by having students participating in the national history day contest in washington, d.c., in attend the launch of the founders online website. these students demonstrated its use to an audience of editors, archivists, politicians, and journalists. since its launch, the site has attracted over one million visitors both inside and outside of the academic and scholarly history communities (national archives, , , and a). founders online’s simple site design, with a central search bar resembling google’s search engine page, is meant to make using the site and its historical documents as user friendly as possible. designed by the ivy group of charlottesville, virginia, the website was user tested on several occasions. in addition to ivy group’s user testing, students at bishop o’connell high school in arlington, virginia, also tested the site to assess its user friendliness for k- education. the site’s filters allow users to restrict searches by author, recipient, and date, and its recent addition of teaching resources highlighting important documents on specific subjects such kurtz: founders online as the louisiana purchase, native americans, and women, are all aimed at helping the non-specialist explore the site as easily as possible. this emphasis on the non- academic user sets founders online apart from other digital projects (ivy group ; national archives b; founders online b). founders online has proved useful to scholars and the general public in both expected and surprising ways. on accepting the thomas jefferson prize, archivist of the united states david ferriero lauded the many ways in which the site had been used since its launch. he noted that it was cited in articles in the prestigious historical journal, the american historical review, as well as a number of academic monographs such as joel kavorskey’s the true geography of our country: jefferson’s cartographic vision (uvap ). historian peter s. onuf’s popular massive open online course (mooc), “the age of jefferson,” made extensive use of documents on founders online as part of its required reading material (age of jefferson ). the archives’ own educational website, docsteach.org, links directly to founders online transcripts, and the national humanities center also helped to create lesson plans utilizing the site’s resources for k- teachers (docsteach ; ferriero a). users beyond historians have utilized letters on founders online in other exciting ways. anna berkes, a research librarian at monticello, has used the website to help expose fabricated quotations commonly attributed to thomas jefferson. the u.s. supreme court cited a document on founders online in its decision in the nlrb v. noel canning case. perhaps the most creative use of the site was by a composer and professor at the berklee college of music, gates thomas, who composed a cantata based on a letter by george washington. perhaps most gratifying has been the feedback from the many users of the site who have helped to identify a small number of errors, either in transcription or annotation, that have come to light and are easily fixed by uva press staff thanks to the site’s free and digital publication apparatus. founders online thus serves as a model for the digital history and humanities communities to reach larger audiences and shows the benefits of funding humanities research (walters ; supreme court ; with good reason ). https://www.docsteach.org kurtz: founders online early access: challenges in project management founders online’s emphasis on a user friendly experience is complimented by its creators’ decision to showcase early access documents that have not been fully vetted by professional editors. whereas most projects wait to publish letters only after they have been fully annotated, a decision was made early on that the american public should have access to over , documents that have yet to be completed by their relevant documentary editing project’s staff. thus the early access project was created to transcribe and proofread these documents, which will be temporary placeholders until professionally edited and annotated versions are completed. these early access letters provide insight into important parts of the founding fathers lives that the site’s users would have otherwise been without for many years. transcribing or proofreading these early access documents would not have been possible without the nhprc’s desire to give the american public access to as many documents as possible as quickly as possible (national archives ). in , documents compass received a contract from the u.s. national archives to complete a pilot project to show whether providing early access to unpublished letters was feasible. directors susan perdue and holly shulman, both veterans of the field of documentary editing and leaders in publishing digital editions, proved that the project was indeed possible, leading to a second contract awarded in . the early access project officially began on january and finished in december . the project employed a large staff of proofreaders, sometimes numbering over temporary or graduate student employees, working under the direction of myself and my colleague, laura baker. our proofreaders generally had degrees in the humanities and social sciences but were not experts in th century handwriting, history, politics, or culture. by the end of the project, however, they developed an ability to read even the most difficult penmanship and gained a much deeper understanding and appreciation for the founding fathers and their times. a number of them gained exceptional technical and editorials skills, which they used to help me reconcile data in our various databases, locate and digitize letters from kurtz: founders online microfilm, and conduct basic historical research to try to ensure our transcriptions’ accuracy. given that our staff was largely inexperienced in editing or historical work, we designed our processes to help ease employees through the various technical aspects of their work. for example, few of them had any experience with editing in xml. we realized that we needed a user-friendly xml software such as xmetal, a program whose interface closely resembles that of microsoft word. we found that the more popular and familiar program, oxygen, even in its out-of-the-box “author” view, was too technical and difficult for most of our staff. we also had to train our employees in the unique style guides employed by each project. we created instructions and processes that were simple and understandable in order to produce the best quality transcripts possible while adhering as closely as possible to project specific requirements. despite our limited time and ambitious goals, varying accessibility of manuscript sources necessary for transcription and proofreading, and the different requirements and methods of each project, we believe that by the end of our project our employees had improved their speed and accuracy considerably. our proofreaders benefited from regular in-person and online feedback about their work from our project managers, and, as they gained experience, they became more adept at deciphering late th and early th century handwriting. they mastered the basics of xml editing and utilized historical techniques such as using other letters to decipher difficult words or using online resources to look up basic information about people, historic places, and past events. ultimately, our staff produced here, i would like to recognize early access team members mark hawking, jeffrey diehm, dena radley, jeffrey zvengrowski, and james ambuske for their exceptional contributions to the project. several of our proofreaders were so moved by their experience that they took part in a special episode of with good reason, a public radio show featured locally on national public radio (npr), in order to tell the wider community of their newfound appreciation for early american history (with good reason ). for example, our first goal was to proofread and publish , letters from the papers of george washington and papers of james madison projects. both projects have unique style guides of differing complexity and specificity about how to handle superscripts, double punctuation, capitalization, etc. the need to train employees simultaneously in two different style guides greatly increased the difficulty of our work. kurtz: founders online preliminary transcripts that will be useful to founders online’s users as they wait for the documentary editing projects to complete their work. lessons from early access my experience in founders online: early access not only convinced me of the importance of taking into account a larger, non-academic audience in designing digital humanities projects, but i also believe it has provided several important lessons for digital humanists seeking to use crowd-sourcing, non-specialist volunteer labor as part of their workflow. it is unlikely that a similar project to early access with a large, paid staff will happen to be funded again anytime soon. still, despite its use of paid employees, my experience as an early access project manager speaks to the need for constant feedback to project participants and methods of quality control for crowd-sourced projects relying on voluntary and free labor. projects such as the library of virginia’s virginia memory do provide a method of limited peer review, but a more robust method of communication between the editorial staff and volunteers, in my experience, is necessary. it is not always helpful to create a one-size list of “do’s and don’ts” for participants, for different volunteers will need more instruction or correction on different points of transcription. we found that constant individual feedback in person, through email, or via our project management software called basecamp was the best way to ensure the best transcription and proofreading results possible. i also believe projects need a reward mechanism to acknowledge their best contributors to keep them engaged and motivated to continue working through to a project’s completion. transcribe bentham, a very successful crowd-sourced project based out of university college london, does a good job of explaining the benefits for participants and has a “hall of fame” where it lists the usernames of everyone who has participated in the project. however, the hall of fame does not distinguish the virginia memory project relies on transcribe, an omeka-based transcription plugin, to allow users to review transcriptions done by their peers. created in part by roy rosenzweig center for history and new media at george mason university and the university of iowa library, for more information on transcribe please see “about the project,” (diy history ). kurtz: founders online users by the number of images transcribed, or by the speed or accuracy of their work. needless to say when your labor force is working for free it is very important that top performers are encouraged and recognized for their exemplary contributions (see “about us” and “hall of fame,” transcribe bentham a and b). we achieved this in early access primarily by giving our employees raises, an option admittedly not applicable to crowd-sourced projects. however, we also found non-monetary ways to reward employees. for example, i rewarded my best employees by assigning them particularly interesting writers and batches of correspondence such as thomas jefferson’s letters with john and abigail adams. i also made a point of acknowledging our best employees’ contributions publicly through basecamp, or praising them during our training meetings. many similar opportunities for rewarding excellent work exist for crowd-sourced projects, whether that is using the principles of gamification as seen on popular language-learning programs like duolingo or the digital crowd sourcing project old weather in which the best users are rewarded for their good work with increasingly high nautical ranks for transcribing weather logs from old ship manifests. highlighting the names of individuals who made significant contributions to the project directly on its website in this way is very important. david rumsey’s listing of his top ten geo-coders on his maps collection site is a perfect example (rumsey ). finally, it is a very good idea to encourage specialization. particular writers’ handwriting or some data sets may be harder to transcribe or record than others. instead of letting anyone edit or transcribe a document as is done on some omeka- based sites, volunteer transcribers should have to demonstrate a proficiency in deciphering the difficult handwriting of such historical figures as abigail adams or james monroe before getting full access to these writers’ letters. not only does this ensure a higher quality of work in the finished product, but we also found that giving access to this important yet difficult subset of letter writers was a useful non-monetary reward that could be copied by others relying on non-expert, volunteer labor. founders online also demonstrates the difficulties inherent in bringing different projects together under one roof that follow different style guides, metadata conventions, and methodology. differences across projects are inevitable confusing kurtz: founders online to users not familiar with the methods of documentary editing. for example, instead of using a single standard convention to indicate that a word or phrase is difficult to read (e.g. surrounding the word with [brackets]), there were several different ways to represent this common editorial issue across different projects. for better or worse, founders online did not attempt to standardize these conventions. similarly, even though the same historical figures appear in different documentary editing projects, the projects have not agreed on a standardized way to spell their names. hence the marquis de lafayette’s long french name appears differently across projects, making a single search for his letters on founders online impossible. while adopting a standard methodology or style guide may prove impossible, the adoption of a names authority lists, perhaps by using the library of congress’s authority files and adding new names as necessary, would help users. another documents compass project titled people of the founding era, a collective biography of the th century u.s., has done considerable work to reconcile different naming conventions across projects, and thus might serve as another potential starting point for standardizing metadata across digital projects focused on early american history. conclusion founders online: early access was a complex, digital project with a large paid staff that was finished at the end of . early access’s successful completion provides a useful model for dealing with the technical issues of large-scale digital humanities work. it shows the need for rewarding hard-working, accurate volunteers while also imposing uniform standards across disparate sets of data. ultimately, founders online’s continued importance will be its emphasis on free access and user friendliness to professional historians as well as the general public. its emphasis on digital methods of access will prove useful to more traditional scholars studying larger topics of interest to the public, while its emphasis on being useful to the public and thinking about the non-scholarly world will help make digital history even more appealing to potential funders. such projects should be encouraged in the future, whether they are similar collections of freely available transcriptions related to a particular topic in american history such as the american civil war, the kurtz: founders online great depression, or the civil rights movement, or large collections of data or other records useful and accessible to researchers, educators, and the general public. competing interests wk was a paid project manager working on founders online: early access from to . references age of jefferson. . “syllabus”. accessed january . https://www.coursera.org/ learn/ageofjefferson#syllabus. allen, matt. . “founder’s online: a lesson in performance”. marklogic, accessed november . http://www.marklogic.com/blog/founders-online-lesson- performance/. diy history. . “about the project”. accessed november . https://diyhistory. lib.uiowa.edu/about. docsteach. . accessed january . https://www.docsteach.org/. ferriero, david. a. “what have you found in founders online?”. aotus blog, february . accessed november , . http://aotus.blogs.archives. gov/ / / /what-have-you-found-in-founders-online/. ferriero, david. b. “thomas jefferson prize for founders online”. aotus blog, april . accessed november , . http://aotus.blogs.archives. gov/ / / /thomas-jefferson-prize-for-founders-online/. founders online. a. “about the papers of thomas jefferson”. accessed november . http://founders.archives.gov/about/jefferson. founders online. b. “lesson plans using founders online”. accessed november . http://founders.archives.gov/content/lesson_plans. founders online. c. “major funders of the founding fathers projects”. accessed november . http://founders.archives.gov/content/funders. ivy group. . “usability testing for founders online”. october . accessed november , . http://ivygroup.com/news/usability-testing-for-founders-online/. national archives. . “national archives to put the founders online”. december . accessed november , . https://www.archives.gov/press/press- releases/ /nr - .html. https://www.coursera.org/learn/ageofjefferson#syllabus https://www.coursera.org/learn/ageofjefferson#syllabus http://www.marklogic.com/blog/founders-online-lesson-performance/ http://www.marklogic.com/blog/founders-online-lesson-performance/ https://diyhistory.lib.uiowa.edu/about https://diyhistory.lib.uiowa.edu/about https://www.docsteach.org/ http://aotus.blogs.archives.gov/ / / /what-have-you-found-in-founders-online/ http://aotus.blogs.archives.gov/ / / /what-have-you-found-in-founders-online/ http://aotus.blogs.archives.gov/ / / /thomas-jefferson-prize-for-founders-online/ http://aotus.blogs.archives.gov/ / / /thomas-jefferson-prize-for-founders-online/ http://founders.archives.gov/about/jefferson http://founders.archives.gov/content/lesson_plans http://founders.archives.gov/content/funders http://ivygroup.com/news/usability-testing-for-founders-online/ https://www.archives.gov/press/press-releases/ /nr - .html https://www.archives.gov/press/press-releases/ /nr - .html kurtz: founders online national archives. . “online access to the founding fathers papers”. accessed november , . https://www.archives.gov/press/press-releases/ / nr - .html. national archives. a. “national archives launches -founders online- website”. accessed november , . https://www.archives.gov/press/press- releases/ /nr - .html. national archives. b. “public release of founders online website”. accessed november , . https://www.archives.gov/press/press-releases/ / nr - .html. pinfield, stephen. . “making open access work: clustering analysis of academic discourse suggests oa is still grappling with controversy”. the impact blog, october . accessed november , . http://blogs.lse.ac.uk/ impactofsocialsciences/ / / /making-open-access-work-clustering- analysis-academic-discourse-controversy/. rumsey, david. . “david rumsey map collection”. accessed january . http:// www.davidrumsey.com/. southern spaces. . “a conversation with digital historians”. accessed november , . http://www.southernspaces.org/ /conversation-digital-historians. stinson, liz. . “american panorama is an interactive atlas for the st century”. wired.com. january . accessed november , . https://www.wired. com/ / /american-panorama-is-an-interactive-atlas-for-the- st-century/. the us supreme court. . “internet sources cited in opinions for the term: nlrb v. noel canning”. accessed november , . http://www.supremecourt. gov/opinions/cited_urls/ . transcribe bentham. a. “about us”. accessed november . http://blogs.ucl. ac.uk/transcribe-bentham/about/. transcribe bentham. b. “hall of fame”. accessed november . http://blogs. ucl.ac.uk/transcribe-bentham/hall-of-fame/. us congress. senate. committee on the judiciary. . the founding fathers’ papers: ensuring public access to our national treasures. cong., d sess. s. hrg. – . accessed on november , . http://www.gpo.gov/fdsys/ pkg/chrg- shrg /html/chrg- shrg .htm. https://www.archives.gov/press/press-releases/ /nr - .html https://www.archives.gov/press/press-releases/ /nr - .html https://www.archives.gov/press/press-releases/ /nr - .html https://www.archives.gov/press/press-releases/ /nr - .html https://www.archives.gov/press/press-releases/ /nr - .html https://www.archives.gov/press/press-releases/ /nr - .html http://blogs.lse.ac.uk/impactofsocialsciences/ / / /making-open-access-work-clustering-analysis-academic-discourse-controversy/ http://blogs.lse.ac.uk/impactofsocialsciences/ / / /making-open-access-work-clustering-analysis-academic-discourse-controversy/ http://blogs.lse.ac.uk/impactofsocialsciences/ / / /making-open-access-work-clustering-analysis-academic-discourse-controversy/ http://www.davidrumsey.com/ http://www.davidrumsey.com/ http://www.southernspaces.org/ /conversation-digital-historians https://www.wired.com https://www.wired.com/ / /american-panorama-is-an-interactive-atlas-for-the- st-century/ https://www.wired.com/ / /american-panorama-is-an-interactive-atlas-for-the- st-century/ http://www.supremecourt.gov/opinions/cited_urls/ http://www.supremecourt.gov/opinions/cited_urls/ http://blogs.ucl.ac.uk/transcribe-bentham/about/ http://blogs.ucl.ac.uk/transcribe-bentham/about/ http://blogs.ucl.ac.uk/transcribe-bentham/hall-of-fame/ http://blogs.ucl.ac.uk/transcribe-bentham/hall-of-fame/ http://www.gpo.gov/fdsys/pkg/chrg- shrg /html/chrg- shrg .htm http://www.gpo.gov/fdsys/pkg/chrg- shrg /html/chrg- shrg .htm kurtz: founders online uvap founding era collection. . accessed january . http://www.upress. virginia.edu/rotunda/collections/american-founding-era/. uvap (university of virginia press) blog. . “founders online launches”. june . accessed november , . http://www.upress.virginia.edu/ / / / founders-online-launches. walters, daniel. . “spotting a bogus thomas jefferson quote”. inlander, august . accessed november , . http://www.inlander.com/bloglander/ archives/ / / /spotting-a-bogus-thomas-jefferson-quote. with good reason. . “reading the founding fathers’ mail”. virginia foundation for the humanities, december . accessed november , . http://withgoodreasonradio.org/episode/reading-the-founding-fathers-mail/. how to cite this article: kurtz, william b. . “founders online: early access: reflections on open access, crowd sourcing, and metadata standards.” digital studies/le champ numérique, ( ): , pp. – , doi: https://doi.org/ . / dscn. submitted: october accepted: october published: october copyright: © the author(s). this is an open-access article distributed under the terms of the creative commons attribution . international license (cc-by . ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. see http://creativecommons.org/licenses/by/ . /. open access digital studies/le champ numérique is a peer-reviewed open access journal published by open library of humanities. http://www.upress.virginia.edu/rotunda/collections/american-founding-era/ http://www.upress.virginia.edu/rotunda/collections/american-founding-era/ http://www.upress.virginia.edu/ / / /founders-online-launches http://www.upress.virginia.edu/ / / /founders-online-launches http://www.inlander.com/bloglander/archives/ / / /spotting-a-bogus-thomas-jefferson-quote http://www.inlander.com/bloglander/archives/ / / /spotting-a-bogus-thomas-jefferson-quote http://withgoodreasonradio.org/episode/reading-the-founding-fathers-mail/ https://doi.org/ . /dscn. https://doi.org/ . /dscn. http://creativecommons.org/licenses/by/ . / 	digital history meets documentary editing 	a digital edition success story: founders online 	early access: challenges in project management 	lessons from early access 	conclusion 	competing interests 	references recasting the significant: the transcultural memory of alexander von humboldt’s visit to philadelphia and washington, d.c. humanities article recasting the significant: the transcultural memory of alexander von humboldt’s visit to philadelphia and washington, d.c. james f. howell department of german studies, university of arizona, n. oak shadows pl., tucson, az , usa; jfhowell@email.arizona.edu academic editor: bernd fischer received: may ; accepted: june ; published: july abstract: alexander von humboldt was internationally known as a world traveler, having collected data and analyzed samples from five of the world’s seven continents. he spoke several languages fluently, and split most of his adult life between the cosmopolitan centers of berlin and paris. the great deal of time humboldt spent in latin america, along with his staunch belief in human equality, led to his reverence in those countries. indeed, humboldt was a world citizen in the truest sense of the word. but what of the united states? what claim can this nation make to the heritage and legacy of the world-exploring baron? a brief stop in philadelphia and washington, d.c. at the end of humboldt’s expedition to the equatorial regions of the americas seems to suffice. this short stay, along with the humboldt-jefferson correspondence, constitutes the great american link in humboldt studies, a link whose nature and importance has, over the years, received an exaggerated amount of attention from authors writing for an american audience. the following analysis, using the tools of transcultural memory studies, investigates why this relatively insignificant event in a long and storied life assumes an inflated role in current accounts of the life and work of alexander von humboldt. keywords: alexander von humboldt; cultural memory; transcultural memory; thomas jefferson; founding fathers . humboldt’s arrival in the united states on may , alexander von humboldt arrived in philadelphia, marking the beginning of his one and only visit to the united states. between his arrival and departure on june th of the same year, humboldt traveled between philadelphia and washington, d.c., meeting with scientists and dignitaries at every stop. humboldt was the talk of the new republic, indeed the world, after the completion of his five-year scientific and ethnographic survey of south and central america. during his almost six weeks in the united states, humboldt’s inquisitive hosts received him warmly, and he returned the warmth, remarking that the time spent in washington and philadelphia was “the most delightful of [my] life” ([ ], p. ), and that he considered himself from then on to be “half an american” ([ ], p. ix). although humboldt did enjoy his stay in the united states and appreciated the connections he made there, he wrote very little about this pleasant and short detour in his long and storied travels. when later summarizing the final phase of his voyage, humboldt merely remarked that he sailed from havana to bordeaux “by the way of philadelphia” ([ ], p. ). this succinct characterization seems almost unthinkable when compared to recent textual depictions of humboldt published in the united states. with the notable exception of mary louise pratt’s volume imperial eyes: travel writing and transculturation, humboldt and his work have experienced an overwhelmingly positive reception in the united states over the past years. in addition to this general positivity, another hallmark of humanities , , ; doi: . /h www.mdpi.com/journal/humanities http://www.mdpi.com/journal/humanities http://www.mdpi.com http://www.mdpi.com/journal/humanities humanities , , of american humboldt literature is the aforementioned visit to philadelphia and washington, d.c. in the late spring of . recently, writers in the united states have interpreted this short stay not merely as a cornerstone of humboldt’s influence on american culture during the nineteenth century, but also as a defining moment in the prussian baron’s life and intellectual career. although humboldt’s visit and his connection to the founding fathers certainly did not damage his notoriety in the united states during the course of the nineteenth century, it is problematic to overemphasize the relevance of these encounters. indeed, the connections and correspondence humboldt initiated with numerous american scientists and artists in paris and berlin after were more important in terms of his impact on american science and exploration. contrary to the representations in many current accounts, the most probable source of the respect and popularity humboldt enjoyed in the united states came from the translation and publication of the first several volumes of his magnum opus, kosmos. this work was an international sensation, and within the united states its impact was felt and celebrated by the likes of ralph waldo emerson, walt whitman, henry david thoreau, and edgar allan poe. why, then, does this brief and marginally relevant chapter in a life otherwise overflowing with acquaintances and accolades take such a central role in america’s modern understanding and representation of alexander von humboldt? this investigation will demonstrate the ways in which humboldt and his visit to the united states are currently presented to american audiences, as well as analyze the transcultural and mnemonic processes involved in the reintroduction of alexander von humboldt to american cultural memory. . framing humboldt’s visit one need not look far to find the narrative centrality of humboldt’s visit in contemporary american texts. humboldt’s presence on the eastern seaboard and his subsequent relationship with the founding fathers represent the starting point, the turning point, or the conclusion of american accounts of his life and works. aaron sachs, the author of the humboldt current: nineteenth-century exploration and the roots of american environmentalism, begins his work with the following harrowing and adventurous account: “it would have been easier to sail straight back to europe. politics and weather both favored the conservative course: to make the detour from havana to philadelphia, his ship would be forced to brave a british naval blockade and risk a dangerous stretch of water at the beginning of hurricane season” ([ ], p. ). here, humboldt’s visit to the united states serves as the introduction to humboldt and his biography. only later does the reader learn in full detail from sachs about humboldt’s background and accomplishments. the explorer’s scientific influence and contributions to american environmentalism—sach’s central themes—initially assume a secondary role to the establishment of humboldt’s true credentials: his connection to the founders, and thereby to the founding, of the new republic. this association bestows a level of authenticity and indigeneity to the influence humboldt exercised on the imagination and training of early american explorers and scientists. humboldt impacted the american intellectual tradition not only through books and articles as a distant european scholar; rather by highlighting and prioritizing the dangerous passage from havana to philadelphia and the subsequent stay in the united states, humboldt’s story becomes, in part, an american story. laura dassow walls, author of passage to cosmos: alexander von humboldt and the shaping of america, employs humboldt’s visit to philadelphia and washington, d.c. as a turning point in the narrative of humboldt’s biography, as well as in her own investigation. although walls’ account of humboldt’s life does not begin with his time in philadelphia and washington, d.c., these events are afforded special attention and are represented in a way reminiscent of sach’s narrative. as seen in the following selection, walls frames humboldt’s decision to brave the bahama strait in familiarly courageous and daring terms: “beyond the ‘moral obligation’ he felt to see the world’s lone functioning republic, there was every reason to avoid the detour. humboldt was desperate to get himself, his friends, and his collections safely home to paris. [...] heading north risked losing everything they had with them to the british blockades of u.s. ports—assuming his ship was spared by the humanities , , of notorious atlantic storms” ([ ], p. ). this dramatic account of humboldt’s fateful decision to visit the united states initiates the second half of walls' analysis, in which she begins to shift her focus away from humboldt’s biography and onto his influence on nineteenth-century american literary culture. although humboldt’s fame in english-speaking north america would truly blossom with the first translations of kosmos in , walls, among others, claims that the seeds had already been planted in the late spring of . gerard helferich, in his work humboldt’s cosmos: alexander von humboldt and the latin american journey that changed the way we see the world, utilizes humboldt’s brief stopover in the united states to frame the remainder of the explorer’s biographical narrative after having completed his american travels. the twelfth and final chapter of helferich’s book bears the title of “washington, paris, and berlin” [ ]. this condensation of the final two-thirds of humboldt’s life is indeed noteworthy, as it seemingly gives his time spent in washington equal weight to his years spent living and working in paris ( – ) and in berlin ( – ). it should, of course, be noted that the biographical narrative crafted by helferich focuses on humboldt’s experiences in south and central america, and therefore leaves little space for details regarding his life prior to and following the years – . considering, however, the fact that the vast majority of humboldt’s scientific engagement and literary activity took place following his return to europe, helferich’s choice is truly remarkable. it suggests that visiting the united states and encountering thomas jefferson profoundly affected humboldt and his legacy in a way equal to the composition of kosmos, the russian expedition of , or participation in the nineteenth-century scientific discourses centered in paris. these accounts make it clear that visiting the united states was no mere fancy for humboldt on his return journey; indeed, american authors go to great lengths to suggest that some kind of imperative was at work, compelling humboldt to look upon this new republic with his own eyes, and meet the men and women who brought it about. perhaps the most interesting use of humboldt’s visit to frame a biographical narrative is employed by david mccullough in his essay on humboldt entitled “journey to the top of the world.” mccullough, like sachs, begins his account with humboldt’s arrival in the united states in may of ; unlike sachs, however, mccullough does not reveal humboldt’s identity until the reader has been introduced to a well-known cast of american characters. all the reader knows of the “aristocratic young german” on the first page is that he had “come to pay his respects to the president of the new republic, thomas jefferson, a fellow ‘friend of science,’ and to tell him something of his recent journeys through south and central america. for the next several weeks he did little else but talk, while jefferson, on their walks about the white house grounds; or james madison, the secretary of state; or the clever mrs. madison; or albert gallatin, the secretary of the treasury; or those who came to dine in with the president or to do business with him, listened in awe” ([ ], p. ). only after the reader is securely ensconced in the thoroughly american context does mccullough reveal on the second page that “the young man’s name was humboldt, alexander von humboldt—friedrich wilhelm karl heinrich alexander von humboldt—or baron von humboldt, as he was commonly addressed” ([ ], p. ). although not even lasting six weeks, humboldt’s presence in the newly established united states and his subsequent relationship with the founding fathers constitute an axis around which current american historical narratives revolve. . humboldt and the founding fathers recent american accounts associate humboldt’s imperative to visit the united states with his desire to meet and consult with one particular founding father. as joyce appleby succinctly puts it in her volume shores of knowledge: new world discoveries and the scientific imagination: “the purpose of this final leg of their voyage was to meet the president, thomas jefferson [...]” ([ ], p. ). sachs echoes appleby’s assertion in more detail: “if any particular person in the young republic could have quieted humboldt’s wanderlust for a more prolonged period, it would probably have been thomas jefferson himself. president not only of the nation, but also of its foremost philosophical society, jefferson seems to have been the real object of humboldt’s visit to the united states” ([ ], p. ). humanities , , of humboldt had introduced himself to jefferson in a letter, expressing his interest in discussing some of his paleontological finds from the andes with the president. he soon found in jefferson a gracious and intellectually equal host. as david mccullough states: “but there they were in washington for several days, two of the most remarkable men of their time, fellow spirits if ever there were, talking, talking endlessly, intensely, their conversation having quickly ranged far from fossil teeth” ([ ], p. ). the representation of jefferson in many of these texts appears as a personification of the new nation itself, an embodiment of its growth, curiosity, and potential. and in accordance, humboldt’s correspondence with jefferson has come to symbolize in many cases humboldt’s continued interest in and preoccupation with the united states. as helferich explains: “the two men would correspond for many years, and jefferson’s high regard for humboldt is obvious in his letters. [...] the friendship, rooted in their shared political philosophy and common love of science, would endure for more than twenty years, until jefferson’s death in ” ([ ], p. ). as will later be argued, however, this epistolary connection proves to be tenuous at best. jefferson is not the only founding father with ties to humboldt, a fact that is continually underlined in the american investigations of the last years. the best example of this connection between humboldt and the revolutionary generation is provided by walls in passage to cosmos. like mccullough and sachs, walls mentions in detail humboldt’s relationship with james and dolley madison. unlike her counterparts, though, walls goes on to discuss humboldt’s consultations with other, lesser-known founding fathers, such as dr. benjamin rush: “over several visits with the famous physician benjamin rush—the obstinate and passionate reformer who had ridden to the first continental convention with john adams and signed the declaration of independence next to benjamin franklin—humboldt shared his speculations over the moral influence of new world gold and silver” ([ ], p. ). a textual connection emerges among adams, franklin, and the signing of the declaration of independence through rush and his interactions with humboldt. walls again emphasizes this connection to franklin when she notes humboldt’s activities in philadelphia: “the members of the american philosophical society, the premier learned society of the united states (founded by benjamin franklin in ), adopted humboldt as one of their own, voting him to full membership at their next meeting. [...] it was probably in the fine new building of the library company of philadelphia (founded by franklin in ) that humboldt shouted for joy when he read the announcement that his irreplaceable manuscripts had arrived safely home” ([ ], p. ). here the reader is presented with humboldt’s connection to franklin expressed either in his membership in an organization, or in a joyous, yet merely probable, event. some of these connections are tenuous at best, but perhaps the most interesting is the way in which walls creates a textual connection between humboldt and george washington: “one day the party set off for mount vernon, where the visitors drank in the view while [charles wilson] peale mourned for the good old days when he sat and drank with george washington. peale introduced humboldt to billy lee, the last of washington’s slaves, who had been granted freedom and an annuity in his will” ([ ], pp. – ). in this passage, walls not only connects humboldt to the central figure among the founding fathers, she also connects him to the most problematic and divisive element of their legacy. the establishment of such a link to the founding fathers and the complexities of american slavery is remarkable, to be sure, as humboldt was a lifelong abolitionist and an ardent opponent of the slave trade in the americas. . the constitution of convention perhaps the most intriguing elevation of humboldt’s visit to the united states and his relationship with thomas jefferson comes in the form of two recent books written by european authors for american audiences. the first volume, humboldt and jefferson: a transatlantic friendship of the enlightenment by sandra rebok, a european scholar working out of the spanish national research council in madrid, appeared in , and fits neatly into the mold of american humboldt literature. in rebok’s account, the reader again finds humboldt’s imperative to visit the united states: “from cuba they initially intended to return to europe and thus conclude their expedition, but instead they took the spanish humanities , , of ship concepción to philadelphia and added five weeks in the united states to their journey. as we will see, this unplanned visit would assume a special importance in humboldt’s life” ([ ], p. ). the special importance alluded to by rebok takes the form of humboldt’s subsequent friendship and correspondence with jefferson. rebok identifies this relationship as being of extreme importance to both men, as well as being an exemplar of enlightened, transatlantic discourse in a cosmopolitan age. according to rebok, humboldt’s experience in the united states and his connection to its founders was indeed formative: “he had met the founding fathers and architects of the first independent nation on the american continent, and he had seen for himself the functioning of the first republican institutions in the new world. this was the realization of ideals he passionately embraced” ([ ], p. ). although rebok’s text is irreplaceable as perhaps the most detailed and thoroughly researched account of humboldt’s visit to philadelphia and washington, d.c., it contains information that undermines the supposedly strong epistolary connection between humboldt and jefferson celebrated in the title, as well as the overall importance of humboldt’s detour to the united states. rebok notes that humboldt was perhaps one of the most prolific letter writers of his day, penning an estimated fifty thousand letters in his lifetime. jefferson, although not nearly reaching humboldt’s total, still drafted some nineteen thousand letters. the number of extant letters written by the two men to one another, however, totals a mere fourteen: eight letters from humboldt to jefferson, and six letters from jefferson to humboldt ([ ], pp. , ). this sum certainly bespeaks neither a close and enduring friendship nor a passionate connection to an idealized state; rather it seems much more to be a sign of general good will and respectful interest on the part of both men. it is telling, for instance, that many of the succinct letters were written when the two correspondents sent, received, or requested each other’s publications as a gift. even a brief correspondence and the polite exchange of written materials can, to be sure, have a profound impact on a person’s life or an intellectual environment, but there simply is no evidence in the extant textual record to suggest that such was the case between humboldt and jefferson. in the end, rebok’s focus seems to be at times misplaced and her study, although thoroughly researched, faces many of the same interpretational issues experienced by her american counterparts. the second work on humboldt by a european author for an american audience is andrea wulf’s the invention of nature: alexander von humboldt’s new world, published in . in this—the most recent and best-selling work on humboldt to appear in the united states over the last several decades—all of the previously mentioned american humboldt conventions can be found. echoing the suspenseful depictions of the stormy passage from havana to philadelphia crafted by walls and sachs, wulf provides the following riveting account: it was as if the sea were about to swallow them. huge waves rolled on to the deck and down the stairway into the belly of the ship. humboldt’s forty trunks were in constant danger of flooding. they had sailed through a hurricane and for six long days the winds would not stop, pounding the vessel with such force that they could not sleep or even think. the cook lost his pots and pans when the water came gushing in, and was swimming rather than standing in his galley. no food could be cooked and sharks circled the boat. the captain’s cabin, at the ship’s stern, was flooded so high that they had to swim through it, and even the most seasoned sailors were tossed across the deck like ninepins. fearing for their lives, the sailors insisted on more brandy rations, intending, they said, to drown drunk. each wave that rolled towards them seemed like a huge rock face. humboldt thought that he had never been closer to death ([ ], p. ). and all of this so that humboldt could see with his own eyes the new country that supposedly embodied his most heartfelt political and philosophical beliefs, as well as “meet thomas jefferson, the third president of the united states. for five long years, humboldt had seen nature at its best—lush, magnificent and awe-inspiring—and now he wanted to see civilization in all its glory, a society built as a republic on the principles of liberty” ([ ], p. ). wulf also reminds the reader that it is not only jefferson with whom humboldt made a connection while in philadelphia and washington, d.c. madison and gallatin are also featured prominently in the narrative, along with other luminaries of humanities , , of the early republic. most notably, wulf employs a familiar literary tactic, which allows humboldt to forge associations with founding fathers in absentia. in a scene reminiscent of walls’ account, wulf describes how “humboldt travelled to mount vernon, george washington’s estate, some fifteen miles south of the capital. though washington had died four and a half years previously, mount vernon was now a popular tourist destination and humboldt wanted to see the home of the revolutionary hero” ([ ], p. ). another way in which wulf recapitulates american humboldt literary convention is in her representation of the jefferson-humboldt correspondence. in the twelfth chapter of the invention of nature, “revolutions and nature: simón bolívar and humboldt,” wulf presents the correspondence between humboldt and jefferson as a constant back and forth, in which the finer points of the latin american independence movements were discussed in detail. with no further point of reference provided by wulf, the humboldt-jefferson correspondence appears to be the primary source material for the political debates of the age. this implicit characterization is unfortunate, as the latin american struggles for independence were only explicitly thematized in four letters, and often in passing. in wulf’s narrative, however, this was a passionate and important exchange, in which “the former american president, thomas jefferson, bombarded humboldt with questions [...]” ([ ], p. ). in truth, a handful of questions spread out over a small number of short letters hardly constitutes a bombardment. as previously noted, the exchange of each other’s written works was the primary purpose of the humboldt-jefferson correspondence. here again, an otherwise thoroughly researched and responsibly constructed narrative of humboldt’s life and work overemphasizes a relatively minor event and the significance of a handful of encounters. . the transcultural synthesis of memory why is it then that so much recent scholarship and popular writing published in the united states inflates the significance of humboldt’s visit to philadelphia and washington, d.c.? although one might easily make charges of americentrism or intellectual imperialism, processes of cultural memory and cultural integration are actually at work. for example, sachs writes somewhat wistfully that: “it is tempting to wonder what humboldt might have contributed to american politics had he moved to washington and become an advisor to presidents instead of kings” ([ ], p. ). this statement does not advocate the explicit appropriation or annexation of humboldt into american culture; rather it expresses much more a desire to share in humboldt’s cultural and scientific legacy. instead of appropriation, the talk should be of incorporation. this process of incorporation can be at times a bit cumbersome and problematic, as evidenced by the exaggerated accounts in the selections above; but it is also the process by which a culture’s memory adapts and reconfigures itself, so as to include a new element. in the field of cultural memory studies, an element such as alexander von humboldt is best identified as a memory site. this terminology should not be understood as referring to a specific site of historical action; rather memory sites can take any number of forms, including, but not limited to, places, people, events, periods, and ideas. this distinction is essential, as cultural memory studies do not investigate actual past events per se; rather the investigation focuses on how actors in the present create representations and knowledge of the past and to what purpose. although cultural memory “operiert [...] in beiden richtungen: zurück und nach vorne,” and “rekonstruiert nicht nur die vergangenheit, es organisiert auch die erfahrung der gegenwart und zukunft” ([ ], p. ), this is a concept that functions exclusively in the present. in other words, the remembering individual, and thereby the culture to which it belongs, is always present and active, while the event being remembered “is of the past and thus absent” ([ ], p. ). in considering cultural memory as a process of the present, it is important to keep in mind the distinction between history and the past. history is the product of the collection and analysis of textual records of every kind, with the aim of reconstructing a realistic and accurate representation of things that have taken place. the past is also “eine kulturelle schöpfung” ([ ], p. ), but it is not the locus of thoughtful scholarly reflection as history is thought to be; rather the past serves as a necessary, humanities , , of cognitive point of reference and satisfies “das kollektive bedürfnis nach sinnstiftung” ([ ], p. ). the past, unlike the material collections and institutions of history, “ensteht überhaupt erst dadurch, daß man sich auf sie bezieht” ([ ], p. ). in other words, the past, along with the memory sites into which the past is divided, serves as a means of orientation that guides cultural actors in the present. if cultural memory is differentiated thus from history, the age of discovery or charlemagne are as much points of reference as the alamo or auschwitz; and they therefore constitute memory sites “nicht dank ihrer materiellen gegenständlichkeit, sondern wegen ihrer symbolischen funktion. es handelt sich um langlebige, generationen überdauernde kristallisationspunkte kollektiver erinnerung und identität, die in gesellschaftliche, kulturelle und politische Üblichkeiten eingebunden sind und die sich in dem maße verändern, in dem sich die weise ihrer wahrnehmung, aneignung, anwendung und Übertragung verändert” ([ ], p. ). and these sites, much like the cultural memory they constitute, are contextually specific. alexander von humboldt memory sites exist in numerous cultures, but each humboldt memory site interacts with each culture in a specific manner. the german humboldt, for instance differs from the venezuelan humboldt, and each fulfills a different role in the respective cultures. what then are the ways in which cultural memory functions? how is it that some things are remembered and celebrated while others are not? these questions get to the very heart of the representation and use of alexander von humboldt in recent american texts, as they highlight the role of forgetting in the processes of cultural memory. in addition to the aforementioned themes and conventions that pervade contemporary american humboldt literature, humboldt’s absence from twentieth and twenty-first-century american culture forms a cornerstone of almost every humboldt narrative published in the united states. as sachs notes following his depiction of humboldt’s rough passage from the caribbean to the delaware river: “as far as the twenty-first century memory of alexander von humboldt is concerned, he may as well have gone down with his ship: many people have never even heard of him” ([ ], p. ). helferich concurs with sachs, in that “[a]lthough many north americans have a vague sense of humboldt’s name [...] most would be hard pressed to give particulars” ([ ], p. xx). the name might seem familiar to many americans, considering the number of places and natural phenomena that have been named after humboldt; but even this, as appleby concludes, does not protect against cultural amnesia: “what astounds today is how little humboldt is remembered. [...] few great men have had their reputations fade so quickly, just leaving his name on a bay, peak, lake, current, sinkhole, penguin, lily, orchid, and oak whose namesake few remember” ([ ], p. ). this is truly astounding to mccullough, who reflects on the fact that humboldt’s “was a journey that would capture the imagination of the age, but that has been strangely forgotten in our own time. it is doubtful that one educated american in ten today could say who exactly humboldt was or what he did, not even, possibly, in humboldt, iowa, or humboldt, kansas” ([ ], p. ). some authors, such as walls, do not merely lament the level of american ignorance regarding humboldt. indeed, she sees it as a deficiency in america’s understanding of its own history that is in desperate need of correction: “that u.s. american literary and cultural studies have remained oblivious to alexander von humboldt is a scandal exactly equivalent to analyzing romanticism without goethe, naturalism without darwin, modernism in ignorance of einstein, or postmodernism without heisenberg” ([ ], p. x). american authors not only bemoan this absence, it serves as the stated raison d’etre for their work. the reintroduction of humboldt to american culture and the recovery of humboldt’s “environmental thinking” will allow for a host of progressive cultural advances, including “a global debate over capitalism and imperial power” ([ ], p. ). wulf alone slightly breaks with convention and reminds the american reader that not the entire world has forgotten humboldt in the same way: “though today almost forgotten outside of academia—at least in the english-speaking world—alexander von humboldt’s ideas still shape our thinking. and while his books collect dust in libraries, his name lingers everywhere” ([ ], p. ). fittingly enough, these images of dusty libraries and tomes of neglected toponyms allude to aleida assmann’s groundbreaking work on the role of forgetting in the processes of cultural humanities , , of memory. assmann has identified two types of memory that shape a culture’s understanding and representation of itself, and that are constantly engaged in dynamic interaction with one another. there is the active, or functional, memory of a culture, which is comprised of the memory sites being synthesized and utilized by a culture on a constant basis; and the stored, or saved memory of a culture. the functional memory of a culture can be thought of as a kind of canon that is continually invoked by cultural actors as a means of orientation and reference. no memory site in the functional memory of a culture may be assured of continued thematization, however, “[d]enn kanonisierung bedeutet obendrein auch die transhistorische selbstverpflichtung zu wiederholter lektüre und deutung. so bleiben die bestände des funktionsgedächtnisses trotz der bewegung beschleunigter innovation auf den lehrplänen der bildungsinstitutionen, auf den spielplänen der theater, in den sälen der museen, den aufführungen der konzerthallen und programmen der verlage. was einen platz im funktionsgedächtnis einer gesellschaft hat, hat anspruch auf immer neue aufführung, ausstellung, lektüre, deutung, auseinandersetzung” ([ ], p. ). in contrast, the archived memory extant within a culture should be understood much more as “a storehouse for cultural relicts,” in which memories “are not unmediated; they have only lost their immediate addressees; they are de-contextualized and disconnected from their former frames which had authorized them or determined their meaning” ([ ], p. ). the contents of a culture’s stored memory have not lost any of their productive power; rather their creative energy has gone from kinetic to potential. to be sure, there is a constant back and forth between a culture’s stored and functional memory; and this continual deactivation and reactivation “entsteht dadurch, dass die grenze zwischen funktions—und speichergedächtnis nicht hermetisch ist, sondern in beiden richtungen überschritten werden kann. aus dem vom willen und bewusstsein ausgeleuchteten ‘aktiven’ funktionsgedächtnis fallen beständig elemente ins archiv zurück, die an interesse verlieren; aus dem ‘passiven’ speichergedächtnis können neue entdeckungen ins funktionsgedächtnis heraufgeholt werden.” ([ ], p. ). the dynamic relationship between the two forms of cultural memory provides cultural actors with an almost unlimited set of memory sites with which to work. in turn, cultural actors select, activate, and modify these memory sites based on their current needs and aspirations. taking all of this into consideration, the textual representations of humboldt in the united states can be understood as an appeal to the reading public to reincorporate the humboldt memory site into the functional memory of american culture. time and again, these american and european authors decry humboldt’s absence as a loss, and advocate for him and his place in science to be venerated much as they were in the nineteenth century. this advocacy lays bare many of the ways in which cultural memory functions, and provides a fascinating look into the constitution of memory sites in a contemporary context. beyond even this utility, however, the humboldt memory site provides unprecedented insight into the potential of transcultural memory and transcultural influences on cultural memory. this investigation contends that the confluence of humboldt representation in the literary works of american and european authors indicates the initiation of a transcultural memory site. the depictions of humboldt in north america and europe, and more importantly, the cultural motivations and aspirations behind those depictions, have aligned to such an extent that a transcultural space has been created in which multiple cultures can communicate about pressing needs and concerns while drawing on common points of reference. rebok’s humboldt and jefferson and wulf’s the invention of nature demonstrate this transcultural coordination most clearly, as both exemplify the ease with which textual representations of humboldt, and the memory sites they constitute, flow back and forth from european and north american cultural discourses. most certainly, the litmus test of any element within cultural memory is its importance and relevance to the current conditions and needs of a given culture. fittingly, the majority of recent humboldt texts published in the united states and europe present humboldt either as a climate change activist avant-la-lettre, or an embodiment of enlightenment ideals and their potential. by connecting humboldt as securely as possible to the pantheon of the founding fathers and the olympus of the early republic, these contemporary authors elevate his relevance in a way that might affect the humanities , , of reaction of current audiences on both sides of the atlantic to the issues often associated with him, be it global warming or enlightened discourse. the texts investigated here demonstrate an effort, whether conscious or subconscious, coordinated or uncoordinated, toward reincorporating humboldt back into america’s active cultural memory. as andrea wulf states in the epilogue of the invention of nature, “now is the time for us and for the environmental movement to reclaim alexander von humboldt as our hero” ([ ], p. ). conflicts of interest: the author declares no conflict of interest. references . rebok, sandra. humboldt and jefferson: a transatlantic friendship of the enlightenment. charlottesville: university of virginia press, . . walls, laura dassow. the passage to cosmos: alexander von humboldt and the shaping of america. chicago: university of chicago press, . . sachs, aaron. the humboldt current: nineteenth-century exploration and the roots of american environmentalism. new york: penguin books, . . helferich, gerard. humboldt’s cosmos: alexander von humboldt and the latin american journey that changed the way we see the world. new york: gotham books, . . mccullough, david. “journey to the top of the world.” in brave companions: portraits in history. new york: simon and schuster, , pp. – . . appleby, joyce. shores of knowledge: new world discoveries and the scientific imagination. new york: w.w. norton & company, . . wulf, andrea. the invention of nature: alexander von humboldt’s new world. new york: alfred a. knopf, . . assmann, jan. das kulturelle gedächtnis: schrift, erinnerung und politische identität in frühen hochkulturen. münchen: c.h. beck, . . huyssen, andreas. present pasts: urban palimpsests and the politics of memory. stanford: stanford university press, . . françois, etienne, and hagen schulze. “einleitung.” in deutsche erinnerungsorte. edited by etienne françois and hagen schulze. münchen: verlag c.h. beck, , vol. , pp. – . . assmann, aleida. der lange schatten der vergangenheit: erinnerungskutlur und geschichtspolitik. münchen: c.h. beck, . . assmann, aleida. “canon and archive.” in a companion to cultural memory studies. edited by astrid erll and ansgar nünning. berlin: de gruyter, , pp. – . © by the author; licensee mdpi, basel, switzerland. this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc-by) license (http://creativecommons.org/licenses/by/ . /). http://creativecommons.org/ http://creativecommons.org/licenses/by/ . / 	humboldt’s arrival in the united states 	framing humboldt’s visit 	humboldt and the founding fathers 	the constitution of convention 	the transcultural synthesis of memory doi: . /j.bpj. . . tuesday, march , a -pos board b regulation of mitochondrial motility by milton-like proteins, oip and grif sudipto das, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. regulation of mitochondrial motility by milton-like proteins, oip and grif grif and oip are mammalian homologs of milton, a kinesin-binding protein that forms a complex with miro gtpase, an integral outer mitochon- drial membrane ef-hand protein. kinesin, milton and miro have been proposed to function together in the movement of mitochondria along the mi- crotubules. we report here the influence of overexpression of oip and grif on mitochondrial motility and its inhibition by agonist-induced cyto- plasmic [ca þ] ([ca þ]c) signals in h c cells. ha-tagged oip and grif were overexpressed at similar level and were localized to the mito- chondria as detected by immunocytochemistry. in oip and grif overex- pressing cells, elongated mitochondria with varied degree of aggregation were visualized both in live and in fixed, immunostained samples. mitochondrial motility at resting ca þ (< nm) was greatly enhanced by oip and to a lesser extent by grif ( . . and . motility units, respec- tively against a control value of . . motility units). furthermore, the ca þ-dependent inhibition of motility during stimulation by vasopressin ( nm) was suppressed by overexpressed oip ( . . %), whereas grif ( . . %) had no significant effect compared to control ( . . %). overexpression of oip or grif did not alter either basal [ca þ]c or agonist-induced [ca þ]c levels measured by fura . collectively, these data show that both oip and grif can modulate mitochondrial motility presumably, by promoting the association of mitochondria with the motor proteins. furthermore, oip seems to have greater efficacy in the control of mitochondrial movements. -pos board b mitochondrial localization and function relationship gyorgy csordas , sudipto das , peter varnai , tamas balla , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, school of medicine, budapest, hungary, nichd, nih, bethesda, md, usa. mitochondrial contribution to cell signaling and function relies on the associ- ation and local communication of mitochondria with the er and the plasma membrane (pm). we have recently shown that the local ca þ communication between er and mitochondria is supported by interorganellar tethers, and cre- ated synthetic linkers that connected the outer mitochondrial membrane (omm) to the er and sensitized mitochondria to er ca þ release. to study the kinetics and short-term effects of the linkage formation, we have now de- vised fluorescent protein pairs targeted to the omm and er or pm containing fkbp or frb domains. rapamycin causes heterodimerization of these pro- teins to form omm-er or omm-pm bridges. confocal imaging of the induc- ible fluorescent linker pairs revealed increased association of er or pm-patches with the mitochondria within minutes of rapamycin exposure. the linkage formation between the er and mitochondria was followed by a decrease in mi- tochondrial motility (> % in min) and by sensitization of mitochondria to ip receptor-mediated ca þ release. linkage formation between pm and mitochondria also suppressed mitochondrial motility. the initial kinetics and spatial distribution of linkage formation could be followed via recording fret between cfp-and yfp-containing linker partners. a longer version of the linker was found to show faster increase of the fret signal, supporting the idea that the rate of linkage formation positively correlates with the tight- ness of the er-mitochondrial contacts. currently, we are using the fret kinet- ics to visualize the areas of close er-mitochondrial interface and study its relevance in the ca þ signal propagation to the mitochondria. thus, inducible interorganellar linkers provide a tool to assess the distance between organelles in live cells, to establish rapid changes in the subcellular distribution and dynamics of the organelles and to evaluate the ensuing changes in organellar and cell function. -pos board b bak/bax-dependent apoptotic signaling in vdac -/- cells soumya sinha roy , william j. craigen , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, baylor college of medicine, houston, tx, usa. bid, a pro-apoptotic bcl- family protein, upon activation forms truncated bid (tbid) that binds to the outer mitochondrial membrane (omm) and engages bak/bax-dependent release of cytochrome c (cyto c) and other intermembrane space proteins from mitochondria to the cytosol to induce apoptosis. the volt- age-dependent anion channel (vdac) is the major permeability pathway for metabolites and ions in the omm but its role in the tbid-induced omm perme- abilization remains controversial. previously we reported that among the vdac isoform-specific knockout mouse embryonic fibroblasts (mefs), only vdac -/- mefs lack tbid induced complete cyto c release and loss of djm. here we show by single cell fluorescence imaging that permeabilized vdac -/- mefs expressing cyto c-gfp were resistant to tbid ( nm)-induced cyto c-gfp release. furthermore, by rescuing vdac -/- mefs with vdac the tbid-induced cyto c-gfp release was restored. in addition, tbid adenovirus infection caused less cell death in intact vdac -/- mefs than in wildtype (wt) mefs. it has been reported that vdac is required for proper targeting of bak in omm. indeed, bak did not appear in the membrane fraction of vdac -/- mefs. along this line we show that permeabilized bak -/- cells were more resistant to tbid induced cyto c release and loss of djm than wt and bax-/- mefs. strikingly, washout of the cytosol further desensitized the bak-/- mefs to tbid. unlike vdac -/- mefs, the bak-/- mefs constitutively overex- pressed bax that was primarily localized in the cytosol. however, recombinant bax ( nm) could induce cyto c release and depolarization in vdac -/- mefs and also supported the tbid-induced cyto c release. thus, in vdac -/- cells bak does not localize to the mitochondria and fails to interact with tbid and does not allow a compensatory increase in bax. the combination of these two mechanisms greatly attenuates tbid-induced omm permeabilization and apoptosis. -pos board b mitochondrial fusion-fission dynamics during hypoxia/reoxygenation xingguo liu, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. structural, biochemical, and functional abnormalities of mitochondria during hypoxia/reoxygenation (h/r) are widely believed to be important pathogenic factors that underlie cell injury. however, mitochondrial fusion-fission dynam- ics responses to h/r are unclear. we investigated the effect of h/r and chem- ical hypoxia evoked by kcn on cellular atp, djm, and on mitochondrial morphology and fusion. sixty min h caused cellular atp decrease to %. djm showed progressive decrease during h, gradually improved in the first minutes r and decreased again during longer r. mitochondrial fusion activity decreased to % during h and to % during r. in addition, anomalous fusion (autofusion and fusion at multiple sites among - mitochon- dria) produced donut-shaped mitochondria during r. cyclosporine a (csa), an inhibitor of the permeability transition pore (ptp) relieved the fusion inhibition ( %) and prevented donut formation during r. five mm and mm kcn could induce cellular atp decrease to % and %, and djm decrease to % and %, respectively. depolarized mitochondria were associated with donut-formation in mm kcn, and with massive swell- ing in mm kcn. fusion activity decreased to % in mm kcn and % in mm kcn, respectively. neither h nor kcn evoked cleavage of opa , the mitochondrial inner membrane fusion protein. thus, both physical and chem- ical h induced respiratory inhibition to gradually lower djm and cellular atp level, and caused fusion inhibition that was not dependent on opa cleav- age. this is sharp contrast of the uncoupler-induced fusion inhibition that has been attributed to the rapid djm dissipation-induced opa cleavage. a conse- quence of ptp opening, the matrix swelling seems to be a key to donut forma- tion since this could be evoked by both mastoparan, a potent ptp activator and by valinomycin, a potassium ionophore. -pos board b governing respiration: tubulin’s c-terminus interaction with vdac kely l. sheldon , dan l. sackett , claire monge , valdur saks , sergey m. bezrukov , tatiana k. rostovtseva . lpsb, nichd, the national institutes of health, bethesda, md, usa, limb, nichd, the national institutes of health, bethesda, md, usa, joseph fourier university, grenoble cedex , france. mitochondria have long been known to localize within and move along the tu- bulin-microtubule network. it was shown that tubulin binds to isolated mito- chondria with high-affinity and specifically associates with the mitochondrial voltage-dependent anion channel (vdac). we found that nanomolar concen- trations of dimeric tubulin vastly increase vdac sensitivity to voltage allow- ing for vdac blockage at low transmembrane potentials. tubulin interaction with vdac requires the presence of anionic c-terminal tails (ctt) on the in- tact protein. tubulin with proteolytically cleaved ctts does not block the channel. actin, also an acidic protein but lacking ctts, does not induce vdac blockage. two synthetic peptides with the sequences of mammalian a and b brain tubulin ctt do not induce detectable channel closure up to mi- cromolar concentrations. these results suggest a completely new role for 	regulation of mitochondrial motility by milton-like proteins, oip and grif 	mitochondrial localization and function relationship 	bak/bax-dependent apoptotic signaling in vdac -/- cells 	mitochondrial fusion-fission dynamics during hypoxia/reoxygenation 	governing respiration: tubulin’s c-terminus interaction with vdac wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top 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publishing subsidiary). this popular meeting, supported by ongoing industry strength, attracted a record attendance of about and a growing array of exhibiting companies that support led application mar- kets. attendees were offered a pleasing sce- nario of interesting papers on industry tech- nology, operating factors and market growth. the growth of high brightness light emit- ter applications categories and their relat- ed markets (hb leds and some lasers) continues to lead the semiconductor arena, with a product strength not seen for quite some time. specifically, only hb leds and non-telecom laser diodes have shown significant growth since .the past average annual growth rates (albeit from small initial values) for almost a decade have approached %, even allow- ing for minimal growth in , and annu- al growth rates of about % are still anticipated for at least the next five years. thus, this industry segment can only be described as very healthy. its market health includes not only the largest direct led application area of cell phone and other hand held lcd back lighting units, followed by the other large growth mar- ket segments, such as out door and indoor signs and auto lighting, but the smaller market segments such as architectural, marine and aviation lighting, road and rail signals and flash units for digital cameras. it has also contributed to record atten- dances at peripheral activities, such as last fall’s led conference and the recent strategies in light meeting. small led, spectacular growth a range of large area, high current and high power led chips are now available from several manufacturers, but the vast majority of the market units is comprised of the original small leds (the and mm packs and the surface mount units). however, according to robert steele, from strategies unlimited, the total value of this small device hb led market showed spectacular growth last year, reaching $ . bn, almost a % growth from . this degree of market growth is quite significant, because there was consider- able price erosion in , with increas- ing unit sales of nitride based devices (more than double those of ). this also accounted for more than % of the market value. the largest market segment in , as noted earlier, was that of back lighting for mobile appli- ances, which now provides about % of the hb led market on a value basis, increasing from % in . in back lighting growth was also supported by a significant increase in cell phones sold and by an increasing conversion to full colour displays. expanding capacity limited for the future, led back lighting is also being considered for the larger ( to inch) lcd displays. blue led key pads (and other colours) are also becoming a large unit market, but most of the hb leds used here are low specification diodes and tend not to be included in the market val- ues. in further support of the strength of this market, all the major players are expanding their capacity, with even more rapid expansion occurring in taiwan, korea and china, thus making non-japan asia the world’s volume supplier. yet the world market is still thought to be capa- city limited. for the future steele forecast growth in most market segments, includ- ing autos, for which the first forward white lighting application (running lights) was announced late in .the main exception to this scenario will be the back lighting market segment, because signifi- cant price competition is expected to erode value growth in the future.the net result of all this hb led growth will be an estimated sales value of almost $ bn in , with the big carrot of general illumi- nation to arrive in or later! how bright can this market get? dr alan mills reporting from san francisco. the thomas jefferson memorial, cloaked in a new light wardrobe from osram sylvania, cele- brating its th anniversary and working in partnership with the national park service and the national park foundation. http://www.sylvania.com/jefferson/ p .qxd / / : page http://www.sylvania.com/jefferson/ 	high bright markets for and beyond 	small led, spectacular growth 	expanding capacity limited outstanding reviewers of pharmaceutical research gratefully recognizes the outstanding service of the following reviewers, who provided comments and recommendations for at least four or more manuscripts during . rajesh agarwal, university of colorado denver yukio aso, national institute of health sciences youngro byun, seoul national university john f. carpenter, university of colorado denver jamshidkhan chamani, islamic azad university, mashhad branch anuj chauhan, university of florida guofeng cheng, chinese academy of agricultural sciences kun cheng, university of missouri–kansas city james t. dalton, gtx, inc. charles baldwin davis, glaxosmithkline michael danquah, university of tennessee health science center chandrasekar durairaj, allergan, inc. shelley durazo, university of colorado denver olga b. garbuzenko, rutgers university mike hageman, bristol-myers squibb andrea hawe, leiden university anthony j. hickey, university of north carolina at chapel hill guenther hochhaus, university of florida masakiyo hosokawa, chiba institute of science rong hu, china pharmaceutical university diksha kaushik, forest research institute tonglei li, university of kentucky raimar löbenberg, university of alberta enxian lu, novartis ram i. mahato, university of tennessee health science center bernd meibohm, university of tennessee health science center gauri misra, thomas jefferson university olga mykhaylyk, technical university munich sujit nair, amrita vishwa vidyapeetham university vitaly pozharov, institute of electrical & electronics engineers feng qian, bristol-myers squibb tong shen, eli lilly & co. yoshihisa shitara, chiba university jürgen siepmann, university of lille shivendra vikram singh, university of pittsburgh cancer institute ikumi tamai, kanazawa university tomohiro terada, kyoto university hospital ruchit trivedi, university of colorado denver iñaki f. trocóniz, university of navarra arun upadhyay, university of colorado denver guy van den mooter, university of leuven dong-an wang, nanyang technological university sarath yandrapu, university of colorado denver zhaoyang ye, east china university of science & technology siwang yu, rutgers university xuewu zhang , south china u niversity of technology pharm res ( ) : doi . /s - - - 	outstanding reviewers of bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action a wednesday, february , voltage-dependent anion channel isoform (vdac ). here, we show that hcc induced by carcinogenic compounds, aflatoxin or den is highly sensi- tized to tbid-induced omm permeabilization and cyto c release when com- pared to normal liver. expression levels of vdac and bak were also higher in hcc than in control liver. the role of the vdac -bak pathway in the differential tbid sensitivity was validated by overexpression of vdac in primary hepatocytes. in hcc cells, elevation of bak was also associated with an increased level of mcl- , an inhibitor of bak. furthermore, both constitutive and drug-induced genetic deletion of mcl- in mouse embryonic fibroblasts caused sensitization to tbid-induced omm permeabilization in the absence of a change in bcl-xl or bax . based on these results, we are evaluating the possibility of selective killing of hcc cells by the combination of a bak activator and an mcl- inhibitor. -pos board b which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c release? shamim naghdi , peter varnai , soumya sinha roy , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadlephia, pa, usa, semmelweis university, budapest, hungary. vdac proteins represent a main component of the outer mitochondrial membrane (omm). the vdac family is composed of isoforms with more than percent similarity. although their primary role was known to be in ion and metabolite transport between mitochondria and cytosol, it has been dis- covered that vdacs are also involved in apoptotic pathways. we have recently found that specifically the vdac isoform is needed for tbid-induced cyto- chrome c release, due to its role in supporting bak insertion to the omm (roy et al. . embo rep. : - ). to determine the domain(s) of vdac which supports bak insertion, vdac and vdac amino acid composition compared and the unique attributes of vdac sequencewereconsideredformutationalanalysis.totestfunctionalsig- nificance of the changes in vdac or vdac , vdac -/- mef cells that are resistant to tbid, were transfected with the mutants and insertion of bak to the omm and cytochrome c release were monitored in permeabilized cells by immunoblotting. previously, we showed that the vdac -specific n terminal tail and cysteins are dispensable for tbid-induced omm permeabilization. to approach the remaining differences four chimeras were prepared: vdac ( - )vdac ( - ), vdac ( - )vdac ( - )vdac ( - ), vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ). these studies revealed that tbid dependent omm permeabilization is only sup- ported by vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ), indicating that the first two third of vdac is required and sufficient for bak targeting to the omm and tbid induced cytochrome c release. -pos board b outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion david weaver , xingguo liu , veronica eisner , peter varnai , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary. cells and tissues deficient in mitochondrial fusion have been shown to have defects linked to the exchange of inner membrane (imm) and matrix compo- nents, particularly mitochondrial dna. outer membrane (omm) constituents originate in the cytoplasm, thus the role of intermitochondrial transfer of omm components by fusion remained unexplored. here we show that fibro- blasts lacking the gtpases responsible for omm fusion, mfn / , have a more heterogeneous distribution of omm proteins than wild-type cells, and in partic- ular that heterogeneity of pro-apoptotic bak leads to dysregulation of bid- dependent apoptotic signaling. homogeneous distribution of bak is partially rescued by introduction of mfn into mfn / -/- cells. furthermore, fusions be- tween mitochondria lacking and containing bak result in hybrids sensitive to bid. proteins with different modes of omm association display varying degrees of heterogeneity in mfn / /- cells and different kinetics of transfer during fusion in fusion-competent cells. efficient coupling of omm to imm fusion depends on the presence of both mfn isoforms and is antagonized by the mitochondrial fission protein, drp . thus, omm function depends on mitochondrial fusion and is a locus of dysfunction in conditions of fusion deficiency. -pos board b mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat veronica eisner , guy lenaers , gyorgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, inserm u- , institut des neurosciences de montpellier, montpellier, france. mitochondria are highly mobile and dynamic organelles in many cell types. however, in the muscle, mitochondria are crammed into the narrow space among the myofilaments. until now, it remained unclear if mitochondrial fusion occurs in and supports the contractile activity of skeletal muscle (sm). here we applied mitochondria matrix-targeted dsred and photoactiv- able gfp to study mitochondrial fusion in rat fdb sm fibers. in vivo electro- porated fibers were imaged by confocal microscopy. when we tagged the mitochondria in ~ % of cell area with twophoton photoactivation of gfp, rapid spreading of fluorescence showed subsets of interconnected mitochondria, mostly in longitudinal direction. matrix fusion occurred with a rate of . and . events/min in adult fibers and skeletal myotubes, respectively. expres- sion of autosomal dominant optical atrophy-causing mutants of the fusion protein opa or ethanol exposure caused suppression of fusion, which is fol- lowed by mitochondrial dysfunction and late onset myopathies. when chal- lenged by repetitive tetanic stimulation, ethanol exposed cells displayed intracellular ca þ dysregulation, appearing as a fatigue pattern. ethanol also induced a decrease in mfn protein levels, without significantly altering mfn , opa or deltapsi. depletion of mfn alone was sufficient to suppress mi- tochondrial fusion in fdb fibers. fusion inhibition was apparent before any cell dysfunction, suggesting that suppression of fusion is not secondary to other problems in the cells. to directly test the role of mfn in ca þ regulation, ryr -transfected control and mfn ko mefs were stimulated with caffeine. mfn ko cells showed oscillatory ca þ transients that decayed faster than that in the control. thus, fusion dynamically connects skeletal muscle mito- chondria and serves as a target mechanism of both mutations and environmen- tal cues to cause impaired excitation-contraction coupling. -pos board b bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action katarina stroffekova, lucia balogová, mária maslaňáková, lenka dzurová, pavol mi�skovský mi�skovský. safarik university, kosice, slovakia. apoptosis is a key process in the development and maintenance of tissue homeostasis. this process of controlled cell death is tightly regulated by a balance between cell survival and damage signals. we focused our attention towards the intrinsic mitochondrial apoptotic pathway, where bcl- family of proteins plays the major role. we were particularly interested in two pro- apoptotic players bak and bax. here we investigated their role in apoptosis triggered by photodynamic action. we show the localization of bax and bak in u- mg human glioma cells incubated with photosensitizer hypericin (hyp) before and after photodynamic action. apoptotic stimulus by hyp photodynamic action caused bax translocation into mitochondria. however our results suggest that under these condi- tions there are two populations of mito- chondria: one which contains bax and bak simultaneously, and is almost exclu- sively localized near the plasma mem- brane; the other which contains bax only and is distributed throughout the cell. the different protein content and spatial distri- bution of these two populations suggest that they can play different roles in re- sponse to apoptotic stimuli. -pos board b stimulation of bax mitochondrial localization by bcl-xl thibaud renault , oscar teijido , gisele velours , yogesh tengarai ganesan , florent missire , nadine camougrand , bruno antonsson , laurent dejean , stephen manon . ibgc-cnrs, bordeaux, france, nyu college of dentistry, new york, ny, usa, merck-serono sa, geneva research center, geneva, switzerland, california state university of fresno, fresno, ca, usa. cytochrome c release, the commitment step of apoptosis, is regulated at the mitochondria through protein-protein interactions between the bcl- family proteins. an imbalance of this interaction network due to the up-regulation of the proto-oncogenes bcl- and/or bcl-xl lead to a resistance to apoptosis and is associated with tumor formation. bcl-xl overexpression act at the level of the mitochondrial outer membrane (mom) by inhibiting bax-mediated apoptosis; more particularly mac formation and cytochrome c release. how- ever, the molecular mechanisms through which bcl-xl affect earlier steps of bax-mediated apoptosis are not fully understood. surprisingly, we found that mitochondrial bax redistribution and change of conformation were not inhibited but rather spontaneously increased in response of bcl-xl overexpres- sion. in order to further investigate the molecular mechanisms involved in this 	which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c re ... 	outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion 	mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat 	bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action 	stimulation of bax mitochondrial localization by bcl-xl s jra .. proportionate maiming: the origins of thomas jefferson’s provisions for facial disfigurement in bill * by emily cock            abstract. in , thomas jefferson proposed the use of nose-cutting to punish women convicted of specific offences, and the use of retaliation (lex talionis) for anyone who deliberately disfigured another person. these punishments were intended to replace the death penalty for these crimes, and as such formed part of jefferson’s attempt to rationalise the virginian law code in line with eight- eenth-century reform principles. jefferson drew on british laws from the anglo- saxon period to the coventry act for his bill, but his proposals contrast strikingly with british movements away from corporal marking as punishment used against their own citizens. this article examines the origins and fates of equivalent crimes and punishments in the law codes jefferson examined, and compares the legal and wider connotations of facial appearance and disfigurement that made these proposals coherent in virginia when they had long ceased elsewhere. tracing examples and discussion of these intersecting cases will greatly increase our understanding of jefferson’s proposals, and the relationships between facial dif- ference, stigma and disability in eighteenth-century america. crynodeb. ym , cynigiodd thomas jefferson y dylid cosbi menywod a oedd yn euog o droseddau penodol drwy dorri eu trwynau, a defnyddio dial (lex talionis) ar gyfer unrhyw un a anffurfiodd berson arall yn fwriadol. bwriad y cosbau hyn oedd disodli’r gosb eithaf ar gyfer y troseddau hyn, ac felly roeddent yn rhan o ymgais jefferson i resymoli cod cyfreithiol virginia yn unol ag egwyddorion diwygio’r ddeu- nawfed ganrif. cynlluniodd jefferson fesur ar sail cyfreithiau prydeinig o’r cyfnod eingl-sacsonaidd hyd at ddeddf coventry, ond roedd ei gynigion yn cyferbynnu’n drawiadol â symudiadau prydain oddi wrth gosbi ei dinasyddion yn gorfforol. mae’r erthygl hon yn edrych ar darddiad a thynged troseddau a chosbau cyfatebol *i would like to thank the audiences at diverse histories and the cardiff early modern history seminar, and the reviewers at the transactions, for their valuable feedback and sug- gestions on this article. i would also like to acknowledge a fellowship granted by the robert h. smith international centre for jefferson studies at monticello, and the warm support of their staff. transactions of the rhs  (), pp. – © royal historical society . this is an open access article, distributed under the terms of the creative commons attribution licence (http://creativecommons.org/licenses/by/./), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. doi:./s  cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the http://creativecommons.org/licenses/by/ . / https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core y cyfreithiau roedd jefferson yn eu harchwilio. mae’n cymharu’r arwyddocâd cyfreithiol ac ehangach o ymddangosiad y wyneb ac anffurfio’r wyneb, a olygodd bod y cynigion hyn yn rhesymegol yn virginia pan oeddent wedi dod i ben mewn mannau eraill ers amser maith. byddwn yn cynyddu’n dealltwriaeth o gyni- gion jefferson wrth olrhain enghreifftiau a thrafod yr achosion croestoriadol hyn, a’r berthynas rhwng anffurfio’r wyneb, stigma, ac anabledd yn america yn y ddeu- nawfed ganrif. i introduction announcing that thomas jefferson (–) proposed boring a hole in the noses of women convicted of certain moral offences, and introducing an eye-for-an-eye system of retaliation (lex talionis) for anyone who disfigured any other person, tends to provoke a strong reaction. even among those who see paradox in the author of the declaration of independence promot- ing equality of humanity while owning slaves, the punishments put forward by jefferson in his proposed overhaul of capital offences in virginian crim- inal law seem strange and anachronistic for a man thought preoccupied with eighteenth-century tastes for civility and legal reform. jefferson’s proposals were the result of impressive research on common and statutory laws, preserved in his ample manuscript annota- tions in modern and old english, latin and french. they never became law: thus, while frequently acknowledged as anomalous to jefferson’s broader humanitarian principles, they have received less attention from jefferson scholars. markus dirk dubber judged the bill a ‘remark- able failure’ in comparison to jefferson’s other reforms, symptomatic of the early republic’s widespread inability to grapple with the philosophy and extent of legitimate punishment, and the relationships between legal persons and authority. maurizio valsania has recently offered fascinat- ing close scrutiny of jefferson’s corporeality and attitudes towards others’ bodies, but omits discussion about these proposals for punitive mutila- tion. yet kathryn preyer argued that the bill, along with jefferson’s pro- posals for religious freedom, property reform and free education, formed ‘part of a single broad and energetic program of reform’, and further scholars have traced the revolutionary effects of many of his proposals. see e.g. merrill d. peterson, thomas jefferson and the new nation: a biography (new york, ); john d. bessler, cruel & unusual: the american death penalty and the founders’ eighth amendment (boston, ma, ), –. markus d. dubber, ‘“an extraordinarily beautiful document”: jefferson’s bill for proportioning crimes and punishments and the challenge of republican punishment’, in modern histories of crime and punishment, ed. markus d. dubber and lindsay farmer (stanford, ), n.p. (kindle edition). maurizio valsania, jefferson’s body: a corporeal biography (charlottesville, ). kathryn preyer, ‘two enlightened reformers of the criminal law: thomas jefferson in virginia and peter leopold, grand duke of tuscany’, in blackstone in america: selected        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core jefferson also included the provisions in notes on the state of virginia (), thus giving them a much wider, international circulation. to understand jefferson’s proposals it is necessary to examine the fate of equivalent crimes and punishments in the law codes he examined, especially britain’s, and to compare the legal and wider connotations of facial disfi- gurement that made these proposals coherent in virginia when they had long ceased elsewhere. prior to american independence, the common law of england was imported into the colonial courts, its decisions widely available in printed proceedings, and the privy council remained the highest appel- late court. jefferson’s ‘a bill for proportioning crimes and punishments in cases heretofore capital’ was bill  of the  bills prepared by himself, edmund pendleton and george wythe for the revision of virginia’s laws. the criminal laws were initially assigned to george mason, but jefferson soon took over after mason’s retirement. the committee submitted the bills to the legislature in . bill  restricted execution to first degree murder and treason (more narrowly defined), and predominantly prescribed hard labour in the public works, and transplantation for slaves. the lack of a prison in the commonwealth pre- cluded extensive incarceration. the two provisions that deal with facial disfigurement, as written in jefferson’s fair manuscript copy, are as follows: whosoever shall be guilty of rape, polygamy, or sodomy with man or woman shall be punished, if a man, by castration, if a woman, by cutting thro’ the cartilage of her nose a hole of one half inch diameter at the least. and whosoever on purpose and of malice forethought shall maim another, or shall disfigure him, by cutting out or disabling the tongue, slitting or cutting off a nose, lip or ear, branding, or otherwise, shall be maimed or disfigured in like sort: or if that cannot be for want of the same part, then as nearly as may be in some other part of at least equal value and estimation in the opinion of a jury, and moreover shall forfeit one half of his lands and goods to the sufferer. essays of kathryn preyer, ed. mary sarah bilder, maeva marcus and r. kent newmyer (cambridge and new york, ), –, at . further preyer, ‘crime, the criminal law and reform in post-revolutionary virginia’, law and history review,  (), –; holly brewer, ‘entailing aristocracy in colonial virginia: “ancient feudal restraints” and revolutionary reform’, the william and mary quarterly  (), –; matthew crow, thomas jefferson, legal history, and the art of recollection (cambridge, ). the original committee also included thomas lightfoot lee, but he died soon after: preyer, ‘crime’, .  ‘. a bill for proportioning crimes and punishments in cases heretofore capital,  june ’, founders online, national archives (usa), last modified  june , http:// founders.archives.gov/documents/jefferson/----- (original source: the papers of thomas jefferson, vol. , – june , ed. julian p. boyd (princeton, ), –); hereafter bill  online.    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the http://founders.archives.gov/documents/jefferson/ - - - - - http://founders.archives.gov/documents/jefferson/ - - - - - http://founders.archives.gov/documents/jefferson/ - - - - - https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core the collection was put to the assembly in the sessions of –, but only fifty-six bills were enacted into law. james madison suggested to jefferson (by then in paris) that desire to retain horse stealing as a capital offence had contributed significantly to the defeat of the entire bill. the offences subsequently remained capital. ii eighteenth-century law: death and violence the committee had agreed that the revisions to the criminal law should significantly reduce use of the death penalty, and jefferson desired them ‘strict and inflexible but proportioned to the crime’. he was influenced by writers like cesare beccaria, william eden, jean-jacques rousseau and montesquieu, who emphasised proportionality of punishment and restriction of the death penalty as guarantors of individual rights and a check on state abuse. the spectacle, ritual and vigour of corporal and capital punishments played a key role in performances of power by developing states in early modern europe, and would arguably con- tinue to do so in the fragile early republic. judicial wounds to the face allowed for the ongoing stigmatisation of the individual alongside perpet- ual testimony to the power of authority. the rise of a progressive penology from the late eighteenth century, emphasising reform rather than retribution, and especially the turn toward imprisonment, would significantly decrease or remove corporal and capital punishments from most european and american jurisdic- tions. scholars have highlighted a decreasing acceptance of violence in britain over the course of the eighteenth century, which accompanied the decline in public corporal punishments and eventually the death penalty. as randall mcgowen notes, scholarship on early modern punishments has nevertheless substantially complicated understanding of the move from bodily punishments to the mind (as michel foucault jefferson, autobiography, in the works of thomas jefferson, federal edition, ed. paul leicester ford ( vols., new york, ), ii, . james madison to jefferson,  february . all letters are taken from the national archives (usa), founders online, https://founders.archives.gov/. jefferson to pendleton,  august . frank mclynn, crime and punishment in eighteenth-century england,  (oxford, ), ; leon radzinowicz, a history of english criminal law and its administration from  ( vols., ), i, –. david garland, ‘modes of capital punishment: the death penalty in historical perspective’, in america’s death penalty: between past and present, ed. david garland, randall mcgowen and michael meranze (new york, ), –. peter king, ‘punishing assault: the transformation of attitudes in the english courts’, journal of interdisciplinary history,  (), –; robert shoemaker, ‘male honour and the decline of public violence in eighteenth-century london’, social history,  (), –.        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://founders.archives.gov/ https://founders.archives.gov/ https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core famously framed it), highlighting the role of shame, pain, sympathy and salvation within the symbolic universe in which these punishments oper- ated. medievalists have also highlighted the legitimation required for the infliction of disfiguring violence by rulers in that period. violence did not disappear from the british atlantic: one facet of the tense distinc- tion between not only britons and colonised peoples, but britons living in britain against those in the colonies, was acceptance of violence in per- ipheral zones, combined with emphasis on legal and customary niceties, which concealed contests of authority and justice. scholars of colonial- ism have complicated the modernising narrative of crime and punish- ment by highlighting ways in which penal practices followed different paths in colonies and regions within them, the fact that these subse- quently affected the metropoles, and that violence toward subjugated groups and individuals was integral to enlightenment philosophies. within a colony, infliction of ‘english’ punishments, even on settlers, was a means of reiterating authorities’ and the community’s adherence to ideals of civilisation. the american south remained rooted in codes of honour, including expectations of violence to defend it – whether eye-gouging, the duel or nose-pulling – and militarily active. randall mcgowen, ‘through the wrong end of the telescope: history, the death penalty and the american experience’, in america’s death penalty, ed. garland, mcgowen and meranze, –, at –; garland, ‘modes of capital punishment’, ; michel foucault, discipline and punish: the birth of the prison, , trans. alan sheridan (); robert shoemaker, ‘streets of shame? the crowd and public punishments in london, –’, in penal practice and culture, –, ed. simon devereuaux and paul griffiths (houndmills, ), –; pieter spierenberg, the spectacle of suffering: executions and the evolution of repression: from a preindustrial metropolis to the european experience (cambridge, ). patricia skinner, ‘visible prowess?: reading men’s head and face wounds in early medieval europe to  ce’, in wounds and wound repair in medieval culture, ed. larissa tracy and kelly devries (leiden, ), –. eliga h. gould, ‘zones of law, zones of violence: the legal geography of the british atlantic, circa ’, the william and mary quarterly,  (), –, at , ; and among the powers of the earth: the american revolution and the making of a new world empire (cambridge, ma, ), –. kerry ward, ‘defining and defiling the criminal body at the cape of good hope: punishing the crime of suicide under dutch east india company rule, circa – ’, in discipline and the other body: correction, corporeality, colonialism, ed. steven pierce and anupama rao (durham, nc, ), –, at ; lauren benton, law and colonial cultures: legal regimes in world history, – (cambridge, ). michael meranze, laboratories of virtue: punishment, revolution, and authority in philadelphia, – (chapel hill, ), . edward l. ayers, vengeance and justice: crime and punishment in the th-century american south (new york, ), ; kenneth s. greenberg, ‘the nose, the lie, and the duel in the antebellum south’, american historical review,  (), –; elliott j. gorn, ‘“gouge and bite, pull hair and scratch”: the social significance of fighting in the southern backcountry’, american historical review,  (), –.    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core studies of jefferson’s attitude toward physical punishments have focused on his reticence to use physical violence on his own slaves: he has been considered a ‘better’ sort of slave-owner in this respect, prefer- ring to sell off troublemakers. however, jefferson’s relation to violence has come under revision in light of insights into the manner in which vio- lence was entrenched and strategically manoeuvred in the period. there is also vital and growing scholarship on the disabling of enslaved commu- nities. as tristan stubbs notes, enlightenment patriarchs like jefferson in many cases displaced blame for violence onto figures such as overseers, while their own force was ‘subsumed into gentler rhetoric’. jefferson’s strategic use of supervision at monticello also introduced what scholars have recognised as principles of the panopticon to his plantation. jefferson argued that writers like beccaria ‘had satisfied the reasonable world of the unrighteousness and inefficacy of the punishment of crimes by death’. jefferson’s legal commonplace book demonstrates his exten- sive engagement with beccaria’s views. he stopped short of following beccaria’s call for abolition of the death penalty, nor does stuart banner find much evidence for disapproval of the punishment across colonial america. beccaria also objected to differentiation of punish- ments for repeat offenders, which was a major source of mutilation pun- ishments in the american context, including the benefit of clergy that jefferson removed. text added to the final bill suggests he was not alone in the opinion that ‘a hope of impunity’ encouraged offenders, and therefore the best thing for a strong law was the image of fair inflex- ibility. jefferson argued that restriction of the death penalty would be more humane, but also that ‘cruel and sanguinary laws’ accompanied by too much judicial discretion discouraged prosecutions, and induced joseph j. ellis, american sphinx: the character of thomas jefferson (new york, ), ; valsania, jefferson’s body, . e.g. dea h. boster, african american slavery and disability: bodies, property, and power in the antebellum south, – (). tristan stubbs, masters of violence: the plantation overseers of eighteenth-century virginia, south carolina, and georgia (columbia, ), . valsania, jefferson’s body, –; terrence w. epperson, ‘panoptic plantations: the garden sights of thomas jefferson and george mason’, in lines that divide: historical archaeologies of race, class, and gender, ed. james a. delle, stephen a. mrozowski and robert paynter (knoxville, ), –. jefferson, in works of thomas jefferson, ed. ford, i, . jefferson, jefferson’s legal commonplace book, ed. david thomas konig and michael p. zuckert (princeton, ), –. further preyer, ‘cesare beccaria and the founding fathers’, in blackstone in america, ed. bilder, marcus and kent, ch. . stuart banner, the death penalty: an american history (cambridge, ma, ), . cesare beccaria, on crimes and punishments, ed. richard bellamy, trans. richard davies (cambridge, ), ch. . the bill as presented to the assembly: works of thomas jefferson, ed. ford, ii, .        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core local judges to listen to evidence with ‘bias’, and ‘smother testimony’. the same publicness and deep ingratiation within local communities that made the application of the law, and especially shaming punish- ments such as the pillory, so effective, also threatened its impartial application. jefferson demonstrates a volte-face around the efficacy of shaming for criminal reform. even when sending a draft of bill  to wythe, he expressed concern that the punishments would ‘exhibit spectacles in exe- cution whose moral effect would be questionable’. nevertheless, the opening of the bill referred hopefully to the ‘reformed’ individuals serving as ‘living and long continued spectacles to deter others from com- mitting the like offences’. he also retained shaming punishments like the pillory, and ducking for pretensions to witchcraft. nevertheless, in his autobiography jefferson expressed dissatisfaction with the way humiliating public labour in pennsylvania ‘with shaved heads and mean clothing … produced in the criminals such a prostration of char- acter, such an abandonment of self-respect, as, instead of reforming, plunged them into the most desperate and hardened depravity of morals and character’. his inclination was thereafter toward imprison- ment, in which he coincided with the general shift across the country. iii jefferson’s sources jefferson covered bill  in neat annotations. the key legal authorities he cites are fleta, bracton and britton. ‘fleta’ (fl. –) is the name used for the author of a latin treatise on english law (fleta) that updated and reorganised henry of bratton’s (d. ) slightly earlier de legibus et consentudinibus angliae. the text only survives in one manu- script, but the later anglo-norman britton, based on fleta, enjoyed much greater circulation in the fourteenth century. fleta was then revita- lised as a legal authority in the early seventeenth century by sir edward coke. jefferson owned the first printed edition of fleta in latin (), a  edition of britton (also latin) and edmund wingate’s  english translation of bracton. he also draws on his copies of coke’s institutes bill  online. jefferson to whythe,  november . bill  online. see also jefferson to pendleton,  august . jefferson expands on public labour in bill . jefferson, in works of thomas jefferson, ed. ford, i, . adam jay hirsch, the rise of the penitentiary: prisons and punishment in early america (new haven, ); meranze, laboratories of virtue. david j. seipp, ‘fleta (fl. –)’, oxford dictionary of national biography, oxford university press, , www.oxforddnb.com/view/article/ (accessed  november ).    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the http://www.oxforddnb.com/view/article/ https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core of the laws of england (), the  translation of sir henry finch’s legal digest (law, or, a discourse thereof ) and sir william blackstone’s commentaries on the laws of england (–). coke and blackstone were the most widely read legal authorities in virginia, making them sensible sources to highlight, although jefferson always preferred what he considered coke’s whig mentality over blackstone’s toryism. jefferson framed his use of medieval law codes very carefully. he pro- fessed his role in the criminal law revisions as being ‘in general … to reduce the law to its antient saxon condition, stripping it of all the inno- vations & rigorisms of subsequent times, to make it what it should be’. the revision of the laws played an important part in the negotiation of independent american identity. europe and especially britain continued to be the benchmark against which american elites measured civility and rule of law, and this inferiority anxiety was a major driver of legal reforms. while all states addressed the status of laws inherited from england, some were content to distinguish american legal identity by retaining common law unless ‘repugnant’ to the constitution. one of the ways in which jefferson negotiated a break between ‘english’ and ‘american’ was to return to the world of the pre-norman-conquest anglo-saxon, positioning america as the inheritor of this tradition, and encouraging study of the laws, language and culture. he considered his own whig politics, grounded in the rights of parliament and the people, to be based ultimately in anglo-saxon codes, while the tory focus on hereditary rule and arbitrary authority found its roots in the norman influence. this positioning also accounts for notable omissions from virginian law. the most significant are the lawes divine, morall and martiall (dale’s laws), active in virginia from – but shaping virginia’s confirmed through thomas jefferson’s library catalogues: http://tjlibraries.monticello. org/search/search.html (accessed  september ). w. hamilton bryson, ‘legal education’, in virginia law books: essays and bibliographies, ed. w. hamilton bryson (philadelphia, ), –, at , ; dubber, ‘“an extraordinarily beautiful document”’. jefferson to skelton jones,  july . kariann akemi yokota, unbecoming british: how revolutionary america became a postcolonial nation,  (new york, ); ellen holmes pearson, ‘revising custom, embracing choice: early american legal scholars and the republicanization of the common law’, in empire and nation: the american revolution in the atlantic world, ed. eliga h. gould and peter onuf (baltimore, ), –. mary sarah bilder, the transatlantic constitution: colonial legal culture and the empire (cambridge, ma, ), . john d. niles, the idea of anglo-saxon england –: remembering, forgetting, deciphering and renewing the past (chichester, ), ; maría josé mora and maría josé gómez-calderón, ‘the study of old english in america (–): national uses of the saxon past’, journal of english and germanic philology,  (), –.        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the http://tjlibraries.monticello.org/search/search.html http://tjlibraries.monticello.org/search/search.html http://tjlibraries.monticello.org/search/search.html https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core authoritarian legal style through the seventeenth century. the lawes followed contemporary models from the star chamber in prescribing ear-cutting for accessories to the destruction of livestock (article ), or perpetrators of a range of food adulterations and thefts (article ), among other mutilations (there were no provisions for boring the nose). they had been published in london to reassure english investors that virginia was being run strictly and efficiently, and in close alignment with english law, thus representing a deviation from jefferson’s desired anglo-saxon models. iv the face in virginia jefferson’s provisions to both prevent and enforce forms of disfigurement attest to the importance of appearance. there has been increasing atten- tion paid to jefferson’s own face and body – health, decorum, dress and the construction of what biographers following merrill d. peterson have assessed as his ‘impenetrable’ image. the circulation of political por- traiture, including jefferson’s, was a valuable tool for the embodiment of ‘abstract ideals of civic virtue’ in post-revolutionary america. at the same time, portraits were afflicted with the classic conundrum of bal- ancing esteemed qualities of beauty and dignity, including influence from physiognomy, with the need to present a recognisable likeness. there was significant interest in appearance and identity among highly mobile populations disturbed by war, with frequent emigration to and between colonies, including receipt of banished legal, religious, political or criminal dissidents, where traditional markers like dress and speech did not necessarily correlate with social rank, national iden- tity or free status. visiting america in , alexis de tocqueville meranze, laboratories of virtue, .  for the colony in virginea britannia. lawes divine, morall and martiall, &c. (london: walter burre, ), sigs. cv, dv–dr; david thomas konig, ‘“dale’s laws” and the non- common law origins of criminal justice in virginia’, american journal of legal history,  (), –, at . david h. flaherty (introduction and ed.), for the colony in virginea britannia, lawes divine, morall and martiall, etc. compiled by william strachey (charlottesville, ), xx. peterson, thomas jefferson, viii, cited in peter s. onuf, the mind of thomas jefferson (charlottesville, ), ; valsania, jefferson’s body; david waldstreicher, ‘why thomas jefferson and african americans wore their politics on their sleeves: dress and mobilization between american revolutions’, in beyond the founders: new approaches to the political history of the early american republic, ed. jeffrey l. pasley, andrew w. robertson and david waldstreicher (chapel hill, ), –; g. s. wilson, jefferson on display: attire, etiquette, and the art of presentation (charlottesville, ). christopher j. lukasik, discerning characters: the culture of appearance in early america (philadelphia, ), . e.g. gwenda morgan and peter rushton, banishment in the early atlantic world: convicts, rebels and slaves (); lukasik, discerning characters, ch.  and passim.    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core commented on the ease with which offenders could move from state to state, avoiding recognition for their crimes in new communities. identity papers, passes for servants and slaves, hygiene practices, racial science, tattoos and other features were harnessed for the sake of con- structing, defining and reading difference between bodies. from the selective outward identification of specific deviant groups and indivi- duals, the development of the passport from the late eighteenth century marked a new interest in a system of identification and surveil- lance applicable to all citizens. the physiognomical theories of johann casper lavater contributed to scrutiny of character in the face, and jefferson was himself intrigued by racialised differences (and hierarchies) between bodies, including facial distinctions. v bill : reducing capital offences this was the context in which jefferson presented bill . the initial committee plan of january  did not include specific punishments for disfiguring or maiming, and only stipulated castration for rape, sodomy and bestiality. on  november  jefferson sent the bill to wythe, asking him to ‘scrupulously … examine and correct it’, including his notes on the law’s sources. in this letter he suggests that he has ‘strictly observed the scale of punishments settled by the committee, without being entirely satisfied with it’: the lex talionis, altho’ a restitution of the common law, to the simplicity of which we have generally found it so advantageous to return will be revolting to the humanised feel- ings of modern times. an eye for an eye, and a hand for a hand will exhibit spectacles in execution whose moral effect would be questionable; and even the membrum pro membro of bracton or the punishment of the offending member, altho’ long authorised by our law, for the same offence in a slave, has you know been not long since repealed in conformity with public sentiment. this needs reconsideration. simon a. cole, suspect identities: a history of fingerprinting and criminal identification (cambridge, ma, ), . kathleen m. brown, foul bodies: cleanliness in early america (new haven, ); nathan perl-rosenthal, citizen sailors: becoming american in the age of revolution (cambridge, ma, ); craig robertson, the passport in america: the history of a document (oxford, ). jane caplan and john torpey, ‘introduction’, in documenting individual identity: the development of state practices in the modern world, ed. jane caplan and john torpey (princeton, ), –, at . lukasik, discerning characters, ; charles a. miller, jefferson and nature: an interpretation (baltimore, ), ch. ; jay fliegelman, declaring independence: jefferson, natural language & the culture of performance (stanford, ), –.  ‘i. plan agreed upon by the committee of revisors at fredericksburg, [ january ]’, founders online, national archives, last modified  june , http://founders. archives.gov/documents/jefferson/---- (original source: the papers of thomas jefferson, vol. , ed. boyd, –). jefferson to wythe,  november .        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the http://founders.archives.gov/documents/jefferson/ - - - - http://founders.archives.gov/documents/jefferson/ - - - - http://founders.archives.gov/documents/jefferson/ - - - - https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core jefferson expressed similar sentiments in his later autobiography, profes- sing ‘how … [the lex talionis] came to obtain our approbation i do not remember.’ it is also absent from the only surviving record of the com- mittee’s meeting – mason’s notes – suggesting that its inclusion was actu- ally all jefferson. examining jefferson’s research through his notes, and the legal attitudes toward disfigurement in relevant jurisdictions can help to shed light on this decision. bestiality jefferson reasoned that bestiality was not ‘injurious to society in any great degree’ and was therefore outside the rights of criminal law. he also remarked that it ‘will ever be properly and severely punished by universal derision’, thus revealing his reliance on community shaming efforts. there were very infrequent cases in the commonwealth, which scholars have interpreted as reluctance among communities to prosecute the action as capital, rather than an accurate indication of the number of occurrences. while we await a full analysis of jefferson and animal rights, his quasi-vegetar- ianism and idealism in regard to agriculture and the civilising potential of animal husbandry (especially for native americans) are well-estab- lished parts of his character. suicide probably influenced by beccaria, jefferson quietly rescinded the forfeit- ure of property by anyone who committed suicide, considering it not only a useless deterrent to one really ‘so weary of his existence here’ but one that in practice had only led to fictitious judgements of insanity in order to preserve the inheritance of bereaved families. terri l. snyder highlights jefferson’s accordance with wider secularisation in the understanding of suicide, and that local authorities and juries had been reluctant to take action against suicides when it meant forgoing jefferson, in works of thomas jefferson, ed. ford, i, . dubber, ‘“an extraordinarily beautiful document”’. bill  online. john m. murrin, ‘“things fearful to name”’: bestiality in colonial america’, pennsylvania history: a journal of mid-atlantic studies,  (), –, at ; colleen glenney boggs, animalia americana: animal representations and biopolitical subjectivity (new york, ), –. valsania, jefferson’s body, ; virginia dejohn anderson, creatures of empire: how domestic animals transformed early america (oxford, ), ; m. l. wilson, ‘thomas jefferson – farmer’, proceedings of the american philosophical society,  (), –. jefferson, in works of thomas jefferson, ed. ford, ii, , including beccaria.    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core the deceased’s property to the crown and forcing local authorities to support their family. polygamy jefferson added polygamy himself, acknowledging that according to blackstone it had only been a capital offence in england since , where instead the law was satisfied with its ‘nullity’. polygamy was omitted from the final bill: it therefore remained capital in virginia until , when it was replaced with up to ten years’ incarceration, representing what john witte judges the ‘typical’ easing of its punish- ment across the country. jefferson might have been influenced as much by pennsylvania’s non-capital punishment as by general liberalism, but his ultimate reluctance to remove the crime speaks to the seriousness with which he judged the offence. rape jefferson had admitted to madison in december  that, in contrast to the success of his religious freedom bill, his lex talionis measures failed to find much approval in europe. utilising ‘retaliation’ for rape was judged ‘indecent and unjustifiable’. he appears to be speaking only of male cas- tration since he goes on to express concern that women will use a false rape charge as an ‘instrument of vengeance against an inconstant lover’. the virginian legislature had severely restricted punitive castra- tion, and in the nineteenth century it was limited to enslaved men con- victed of raping a white woman; other jurisdictions like new jersey and pennsylvania extended this punishment to native american and white men, respectively, even if there is no evidence for the latter that the sentence was ever carried out. sodomy virginia, leading the five southern colonies, had adopted the tudor definition and capital punishment for sodomy without enacting its own terri l. snyder, ‘what historians talk about when they talk about suicide: the view from early modern british north america’, history compass,  (), –, at , . bill  online; william blackstone, commentaries on the laws of england ( vols., oxford, –), iv, . john witte, the western case of monogamy over polygamy (new york, ), . jefferson to madison,  december . diane miller sommerville, rape and race in the nineteenth-century south (chapel hill, ), –.        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core statutes on the matter. subsequent english cases had established high levels of proof of penetration, the irrelevance of consent, etc., and it remained a rare prosecution; john m. murrin cites only one confirmed sodomy trial in colonial virginia. it seems unlikely that women would actually be considered legally capable of sodomy in prac- tice (or similarly, rape), but jefferson does include this possibility both through the specific punishment, and through including a supporting gloss from finch that sodomy denoted ‘carnal copulation against nature, to wit, of man or woman in the same sex’. vi disfigurement as a crime my search of the limited evidence we have for court decisions in virginia has failed to unearth any cases offering significant revision of, or prosecu- tion under, laws against inflicting disfiguring injuries. prior to the revolution, english statutory and common law was therefore the most relevant corpus available. the first reference for any lawyer of the period was of course blackstone’s commentaries. blackstone discusses common law mayhem’s stress on utility, specifically for battle: thus, ‘cutting off [a man’s] ear, or nose, or the like, are not held to be mayhems at common law; because they do not weaken but only disfigure him’. nevertheless, ‘striking out his eye or foretooth’ was classic- ally mayhem, showing the aesthetic component that carried into the common law. in his notes, jefferson quotes further from britton and fleta on the definition of mayhem as injury affecting capacity for battle. meanwhile, early modern statutes offered limited protection from crimes against the person not resulting in death. maliciously louis crompton, ‘homosexuals and the death penalty in colonial america’, journal of homosexuality,  (), –, at . jefferson cites  henry . c. . murrin, ‘“things fearful to name”’, . finch in jefferson, bill  online; henry finch, law, or, a discourse thereof (london, ), . jefferson, reports of cases determined in the general court of virginia. from , to ; and from , to  (charlottesville, ); virginia colonial decisions: the reports by sir john randolph and by edward barradall of decisions of the general court of virginia, –, ed. r. t. barton (boston, ma, ); william w. hening and william munford, reports of cases argued and determined in the supreme court of appeals of virginia ( vols., philadelphia, –); bushrod washington, reports of cases argued and determined in the court of appeals of virginia ( vols., richmond, –). blackstone, commentaries, iv, –; patricia skinner, living with disfigurement in early medieval europe (new york, ), . edmund wingate (ed.), britton, the second edition (london: john moore, ), sigs. fv–gv; ‘fleta’ and john selden, fleta seu commentarius juris anglicani sic nuncupatus (london: william lee and daniel pakeman, ), sigs. iv–ir. william holdsworth, a history of english law, th edn ( vols., ), vi, .    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core cutting out the tongue or eyes was felony under  hen. . c. . this was followed by  hen.  c. , which targeted malicious cutting of the ears, with a necessary exemption for ears cut ‘by authority of law’. the most important statutory intervention occurred in , and became known as the coventry act. this formed the basis of all subse- quent colonial disfigurement statutes, including jefferson’s revision. the act rendered it an unclergyable felony to on purpose and of malice forethought and by lyeing in waite … unlawfully cutt out, or disable the tongue, putt one out an eye, slitt the nose, cutt off a nose or lipp, or cutt off, or disable any limbe or member of any subjectt of his majestie with intention in soe doeing to maime or disfigure in any the manners before mentioned such his majestyes subject [or to be one of] their councellours ayders and abetters (knowing of and privy to the offence as aforesaid)[.] sir john coventry had provoked james scott, st duke of monmouth, by remarking on charles ii’s fondness for actresses in a parliamentary debate. subsequently, over twenty-five of the duke’s men lay in wait and cut coventry’s nose almost clean from his face. injuries to the nose carried specific symbolic weight, but debates show that parliament’s swift statutory response was as driven by the fact it was an attack on a sitting member as by horror at discovering the wound’s legal weakness. the lords were the most adamant that intention must be explicitly required for felony without benefit of clergy, and that a provision for lying in wait should prevent any ‘genuine’ fights that happened to result in otherwise actionable injuries from coming under the statute. these requisites would significantly restrict the act’s application. where they were not met, the defendant was liable for only a fine and imprisonment. the limitations of the act prompted further legislation to protect officials:  anne c.  made it an unclergy- able felony to attempt to kill, or strike, assault or wound a privy counsel- lor in the execution of his office. like coventry, this act was a direct response to a contemporary event, after the marquis de guiscard sir john gonson, sir john gonson’s three charges to several grand juries, nd edn (), . joseph chitty, a practical treatise on the criminal law, th edn ( vols., springfield, ), iii, ; frank aydelotte, elizabethan rogues and vagabonds,  (abingdon, ), .  ‘charles ii,  & : an act to p[re]vent malitious maiming and wounding’, in statutes of the realm: volume , –, ed. john raithby (s.l. ), –. british history online, www.british-history.ac.uk/statutes-realm/vol/pp- (accessed  september ).  ‘debates in : january (st–th)’, in grey’s debates of the house of commons: volume , ed. anchitell grey (), –. british history online, www.british-history.ac.uk/greys- debates/vol/pp- (accessed  september ).  ‘house of lords journal volume :  january ’, in journal of the house of lords: volume , – (–), –. british history online, www.british-history.ac.uk/ lords-jrnl/vol/pp- (accessed  september ).        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the http://www.british-history.ac.uk/statutes-realm/vol /pp - http://www.british-history.ac.uk/greys-debates/vol /pp - http://www.british-history.ac.uk/greys-debates/vol /pp - http://www.british-history.ac.uk/lords-jrnl/vol /pp - http://www.british-history.ac.uk/lords-jrnl/vol /pp - https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core stabbed the chancellor of the exchequer, robert harley, in the chest with a penknife in march . the virginia general assembly issued an act closely following coventry in . it allowed benefit of clergy, but did not require ‘malice’ or ‘lying in wait’. another  act focused on ‘gouging, pluck- ing or putting out an eye, biting, kicking, or stamping upon’ an individ- ual, which if ‘wilful or malicious’ should be met with a suit for damages, and the offender whipped if he failed to pay. a suit could also be brought by a third party if the victim failed to act, with damages split between the prosecutor and churchwardens for the support of parish poor. the privy council overruled the law for applying a criminal penalty to a civil suit. elliot j. gorn noted that the shift of emphasis in this statute reflected concern about the rough fighting popular in the virginia back- country, where eye-gouging was a winning blow, but without acknow- ledging the extent to which statutes enacted in different colonies merely built upon the coventry act. in the absence of virginian cases, english trials against the coventry act can shed significant light on the reception of disfigurement in the period, and legal attitudes to its restitution. in general, the reticence which met application of the act and its capital punishment are com- mensurate with jefferson’s rescinding of the death penalty. they also illu- minate the vagaries of the act’s application that led to dissatisfaction in the legal profession. jefferson had informed pendleton in his plans for the bill of his desire to ‘let the judge be a mere machine’. coventry act cases had seen them anything but. few cases were easily resolved. the very first was a notable exception, in which siblings william, robert and mary dine were indicted for attacking jane king in . it was a sensational trial, widely reported, and they were executed. but most prosecutions, even if successful, pro- duced worrying questions of law. in the case cited by blackstone, and widely elsewhere, a lawyer, arundel coke (aka cooke), was found guilty of slitting the nose of his brother-in-law edward crispe, with the assistance of john woodburne, in suffolk, . the trial became infamous for coke’s attempted defence that he had intended to murder crispe, and therefore did not meet the statute’s criteria, and the lord blackstone, commentaries, i, . william waller hening, the statutes at large; being a collection of all the laws of virginia, from the first session of the legislature, in the year  ( vols., philadelphia, –), vi, .  ibid., viii, –. preyer, ‘crime’, . gorn, ‘“gouge and bite”’, . jefferson to pendleton,  august . blackstone, commentaries, iv, ; the tryal and condemnation of arundel coke alias cooke esq; and of john woodburne labourer, for felony, in slitting the nose of edward crispe gent. ().    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core chief justice sir peter king’s rather convoluted ruling on the nature of intent in felony cases to ensure that they did not escape on such a defence. southwell jp ralph heathcote attacked the ruling in a legal treatise that jefferson owned, stating ‘that no true man of the profession was ever heard to speak with temper upon the case’. believing that they did indeed intend to kill rather than disfigure crispe, heathcote argued that the act was wrongfully construed, ‘and the same constructive violence, in the interpretation of laws, might often hang an honest man as well as a knave’. a related standard in english and therefore prior virginian law made it murder to accidentally kill someone in commission of an unlawful act, regardless of intention; jefferson’s bill explicitly rescinded this equivalence, formalising the need to prove intention for either manslaughter or murder. in another widely cited case, william lee was indicted under the act in  for cutting his sleeping wife agnis’s neck with a razor. here, the prosecution failed because he did not disfigure her face. the act was invoked in the high-profile case of william, earl of devonshire, striking colonel culpeper in the palace of whitehall in , though with quick resolution that the lack of premeditation and significant injury precluded it. the  trial of barny carrol and william king included an exchange with the attending surgeon about whether cranley thomas kirby’s nose was ‘slit’ (as per the act), or ‘divided’, ‘incised’, ‘cut’, ‘wounded’, etc, which was a recurring course of defence (e.g by coke/ cooke). they were found guilty, as was thomas hand for wounding joseph holloway in the arm with a pistol in . in contrast, samuel dale failed to have thomas brooks’s assault on him upgraded to a felony after he lost the sight in his eye, because unable to prove that brooks had lain in wait with intent. the actions required to satisfy ‘lying in wait’ in britain were substan- tially expanded by a ruling from justice sir james eyre in the trial of thomas mills in april , which held it sufficient ‘for a man who has a purpose in his mind to do such kind of mischief, and deliberately watches an opportunity to do it’. it would have little effect, however, as the  revision of the legislation removed the requirement entirely: ralph heathcote, the irenarch: or, justice of the peace’s manual, , rd edn (), –. his remarks on the case were reprinted in sylva; or, the wood (), which jefferson owned. trial of william lee, old bailey proceedings: accounts of criminal trials (hereafter obp),  july , ll ref: t-. t. b. howell, a complete collection of state trials ( vols., ), xi, –. trial of barny carrol and william king, obp,  july , ll ref: t-; trial of thomas hand, obp,  december , ll ref: t-. trial of thomas brooks, obp,  december , ll ref: t-. in thomas leach, cases in crown law, determined by the twelve judges, rd edn ( vols., ), i, –.        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core it remained an unclergyable felony in lord ellenborough’s act ( geo. iii, c.  []), before being subsumed by the offences against the person act (), which remains in force. commentators reasoned that by expanding the parameters to ‘grievous bodily harm’, the statute had more flexibility to incorporate wounds falling short of mayhem, and in places of the body generally covered and thus not ‘disfiguring’. while revisions of coventry throughout america are beyond the scope of this article, two examples show the diversity of responses. north carolina still divided the offences according to the principles in the henrician vs coventry statutes, and included disfiguring punishment. their  revision stipulated that anyone who would ‘of malice afore- thought, unlawfully cut out or disable the tongue, or put out an eye of any person with intent to murder, maim or disfigure’, and their accom- plices, will be pilloried, including loss of both ears, and whipped (first offence), then executed for a second offence. for other actions against the nose, lip, ear or ‘any limb or member’, performed ‘on purpose’ and ‘with intent to murder, or to maim or disfigure’ (thus a more cap- acious act than that requiring malice and lying in wait), the punishment was only six months’ imprisonment and a fine. new jersey, in contrast, combined the different actions in  into an offence punishable by fine and/or up to seven years’ imprisonment with hard labour. all jurisdic- tions took the offence seriously, and many removed or nuanced the cri- teria for malice and/or lying in wait. the early virginian revisions had already omitted the waiting requirement, shifting the onus onto the action and its intention. jefferson noted the lack of restriction to ‘wilful and malicious’ actions in the older laws, citing further research in finch, bracton, blackstone and others. in the final text sent to the assembly, the bill omitted the requirement for ‘malice forethought’, thus further removing the subjective assessment of the accused’s mental state from the role of the judiciary and bringing it closer in jefferson’s view to the older laws. when a revised felony act was passed on  december , it did not include a requirement to ‘lie in wait’, but stipulated that the eligible disfi- gurements must be inflicted deliberately. it did not preclude benefit of clergy, as the legislature did in the same period for offences like ‘buggery, with man or beast’, horse stealing and rape. it was not phil handler, ‘the law of felonious assault in england, –’, journal of legal history,  (), –.  the acts of the general assembly of the state of north carolina (newbern, ), ch. viii. william paterson, laws of the state of new jersey (new brunswick, ), . bill  online. jefferson, in works of thomas jefferson, ed. ford, ii, . samuel shepherd, the statutes at large of virginia, [–] … being a continuation of hening ( vols., richmond, ), i, –, .    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core until  that the commonwealth abolished benefit of clergy and restricted the death penalty to first-degree murder, facilitated in part by the construction of a new jail (opening in ). inefficiencies in prosecution may have encouraged the reduction of capital offences. some corporal punishments remained: misbehaviour within the jail could prompt extendable solitary confinement on bread and water and/or ‘moderate’ whipping/s. the  provision for disfigurement offered two forms for the offence: in the first, it reintroduced the requirement for ‘lying in wait’ alongside acting ‘on purpose and of malice aforethought’; on the other hand, it removed these requirements for any who ‘shall voluntarily, mali- ciously and of purpose, pull or put out an eye while fighting or otherwise’, giving theoretically greater protection against the local eye-gouging brawls, rather than the traditionally symbolic nose. if guilty, the offender and his or her ‘aiders, abettors and counsellors’ would be jailed for two to ten years, and fined up to $,, ‘three fourths whereof shall be for the use of the party grieved’. such compensation rules also removed any need for a separate civil suit by the victim. this act was revised again in . in addition to returning hanging to high treason, it was the first to explicitly exclude slaves as defendants from its provisions. a notable case of  held that it could neverthe- less protect slaves themselves from malicious disfiguring violence. the revision again rescinded the ‘lying in wait’ requirement, and created a new two-part offence wherein the key difference was the weapon used: biting, or stabbing or shooting. in each case, the penalty remained the same as in the  act. the case of john somerville, charged with maiming john g. jackson in  (he was ultimately found guilty of mis- demeanour assault), still retains reference to ‘lying in wait’, suggesting it remained an informally aggravating factor even outside of the active statute. nevertheless, henry st george tucker focused on mayhem as permanent injury that ‘disabled’ the individual from fighting, and  ibid., ii, , . preyer, ‘crime’, . shepherd, statutes at large, ii, .  ibid., . preyer, ‘crime’, . shepherd, statutes at large, ii, –. commonwealth v dolly chapple. the defence argued that as a slave could not own property s/he could not receive the stipulated damages. the prosecution successfully coun- tered that such logic would exclude femes covert from protection, which would be ‘monstrous’: william brockenbrough and hugh holmes, a collection of cases decided by the general court of virginia [–] (philadelphia, ), –. shepherd, statutes at large, ii, . commonwealth v john somerville, in brockenbrough and holmes, collection of cases, –.        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core the capacity for the court to increase damages if it thought the jury had been too lenient. while obviously a reduction from the death penalty, jefferson’s sug- gestion that an assailant should be disfigured ‘in like manner’ was extra- ordinary. in the bill he cites fleta, britton (which prescribed loss of the equivalent member for men, but loss of the offending hand for women) and the law of king alfred (ll. Ælfr. . ), rather than bracton on membrum pro membro as he referenced in his letter to wythe. he omits blackstone, who considered the action arcane and inadequate; however, he may have been influenced by blackstone’s opinion that one of its drawbacks was inability of repetition, in providing for retaliation against a part judged equivalent. there are precedents for this equivalency in english law. among the provisions for aggravated cases of affray, for example, anyone convicted for striking another with a weapon (or drawing with intent to do so) in a church or churchyard would be excommunicated, and ‘have one of his ears cut off; or, having no ears, be branded with the letter f in his cheek’. it seems unusual for jefferson to leave such an open field for the judging of this equivalency, given his professed intention to remove wiggle room in courts, but this too carries antecedents in the medieval wergeld that awarded damages for injury based on intricate valuations of body parts. vii disfigurement as a punishment the use of disfiguring punishments was by no means unknown in either europe or america, even if jefferson was a lone voice for the lex talionis. branding the hand for benefit of clergy remained a key form of both judi- cial discretion and physical marking employed by british and american courts, and arthur scott demonstrated its frequent use in pre-revolution- ary virginia. acts like coventry had to specifically preclude benefit of clergy for felonies. until  women could not claim benefit of clergy, and thereafter only for petty thefts; in , clergy was extended to them as freely as men. many individuals transported to virginia henry st george tucker, commentaries on the laws of virginia,  ( vols., winchester, va, ), ii, –. valerie allen, ‘when compensation costs an arm and a leg’, in capital and corporal punishment in anglo-saxon england, ed. jay paul gates and nicole marafioti (woodbridge, ), –; william e. miller, an eye for an eye (new york, ). blackstone, commentaries, iv, .  ibid., . arthur scott, criminal law in colonial virginia (chicago, ), –; jeffrey k. sawyer, ‘“benefit of clergy” in maryland and virginia’, american journal of legal history,  (), –. j. m. beattie, policing and punishment in london –: urban crime and the limits of terror (oxford, ), .    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core would have carried such marks, such as sarah plint, indicted for theft on  january  and transported for seven years after previously being branded for marrying five husbands. branding offenders also served as an ongoing shaming punishment. to do so in the face, or inflict other permanent injury on the only part of the body almost universally uncovered, was acknowledged as a weighted action. while other facial branding had been used in britain in the seventeenth century, clergy branding ‘in the most visible part of the cheek nearest the nose’ only appeared from  to , before it returned to the thumb until abolition in . the introduction formed part of a general harshening of property laws in the s, but local authorities were hesitant. in repealing the sentence, parliament noted that rather than acting as a deterrent or corrective, ‘such offenders, being rendered thereby unfit to be entrusted in any honest and lawful way, become the more desperate’, and in the minds of rehabilitative penal refor- mers like william eden the use of stigmatising marks impeded reintegration of a reformed individual into society. later american critics of judicial mutilations similarly emphasised that such practices were antithetical to civil societies, and that they fixed the individual as a permanent member of a criminal class unable to start afresh in another colony. branding on the cheek for offences like counterfeiting coins did, however, remain on the books. other facial marks were also inflicted: in london, , japhet crook, alias sir peter stranger, had his ears cut, and nostrils slit by the public hangman under an elizabethan forgery statue. facial marking would continue to be used in british colonies against subordinated bodies: from the branding and judicial disfiguring of enslaved individuals in the west indies, to the use of forehead tattoos known as godna detailing criminal status in indian penal law. yet, even if corporal punishments such as floggings remained in use in trial of sarah plint, obp,  january . ll ref: t-.  ‘william iii, : an act for the better apprehending prosecuting and punishing of felons that commit burglary housebreaking or robbery in shops ware-houses coach- houses or stables or that steal horses. [chapter xii. rot. parl.  gul. iii. . n. .]’, in statutes of the realm: volume , –, ed. john raithby (s.l., ), –. british history online, www.british-history.ac.uk/statutes-realm/vol/pp- (accessed  september ). beattie, crime and the courts in england – (oxford, ), ; beattie, policing, –.   anne c.  in william eden, principles of penal law, nd edn (), . ayers, vengeance and justice, . blackstone, commentaries, iv, . in his notes on the crime for bill , jefferson instead cites Æthelstan’s and cnut’s sentence of loss of hand, and common law provisions for it as a capital offence. elsa goveia, the west indian slave laws of the eighteenth century (barbados, ); clare anderson, legible bodies: race, criminality and colonialism in south asia (oxford, ).        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the http://www.british-history.ac.uk/statutes-realm/vol /pp - https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core britain and its colonial regions, forms of legitimate violence designed to ensure lasting stigmatisation were employed by the independent american authorities against their own citizens much later. jefferson observed that some of bill ’s punishments had precedent in the treatment of slaves. from testimonies, runaway advertisements and other sources, we see slaves marked in a wide variety of ways. ear-crop- ping is a recurring one, as is the branding of the master’s initials or the letter ‘r’ for ‘runaway’ on the face and/or body. a virginia law of  stipulated that a slave convicted of hog-stealing once would be whipped, and twice would have both ears torn at the pillory. the sen- tence was extended to any free person in . the threat was also thought a good equivalent to swearing on the bible in capital trials of slaves: ‘negros, mulattos, or indians, not being christians’ required to testify were to be informed that if they gave false evidence they would lose both ears at the pillory and be whipped. formal and informal disfigurements are found throughout british and american slaveholding regions, and were emphasised by anti-slavery writers keen to reveal how ‘american taskmasters … notch the ears of men and women, cut pleasant posies in the shrinking flesh, learn to write with pens of red-hot iron on the human face.’ lewis clark, an escaped slave from kentucky testifying to abolitionists in , also highlighted that disfigurement outside statute was hardly unexpected: ‘the law [of kentucky] don’t allow ’em to brand a slave, or cut off his ear; but if they happen to switch it off with a cow hide, nobody says anything about it.’ early laws based on english vagrancy punishments had marked runaway servants: in  a second- offender’s cheek was branded with ‘r’, before this moved to the shoulder in , and the hair close-cropped for all offenders. but restrictions on flogging as an increasingly racialised punishment in british colonies, see, e.g., amanda nettelbeck, ‘flogging as judicial violence: the colonial rationale of corporal punishment’, in violence, colonialism and empire in the modern world, ed. phillip dwyer and amanda nettelbeck (cham, ), –; david killingray, ‘the “rod of empire”: the debate over corporal punishment in the british african colonial forces, –’, journal of african history,  (), –. john hope franklin and loren schweininger, runaway slaves: rebels on the plantation (new york, ), –; gwenda morgan and peter rushton, ‘visible bodies: power, subordination and identity in the eighteenth-century atlantic world’, journal of social history,  (), –, at –; philip j. schwarz, twice condemned: slaves and the criminal laws of virginia, – (union, nj, ), . hening, statutes at large, iii, .  ibid., vi, .  ibid., iv, –. charles dickens, american notes for general circulation (new york, ), , .  national anti-slavery standard, – october ; john w. blassingame (ed.), slave testimony: two centuries of letters, speeches, interviews, and autobiographies (baton rouge, ), . hening, statutes at large, i, –, , –.    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core grew, while runaway slaves continued to be branded or dismembered (such as losing toes). into the nineteenth century, slaves faced capital charges for disfiguring white people in cases where white perpetrators would face only fines, pillory or imprisonment. as kirsten fisher notes, the continuation of such practices in the face of increased restraint against white bodies was one way in which racial difference was ingrained. but despite a significant imbalance in the acceptance, range and fre- quency of such punishments, corporal punishment including disfigure- ment was also used on free individuals well into the nineteenth century. alongside execution, which might be followed by dissection or hanging in chains, public whipping and other forms of judicial muti- lation ensured that the body was deeply integrated into ‘a public economy of punishment’. ear-cropping is the most frequent disfigure- ment meted out as a punishment in colonial america, including virginia, and carried british precedents. in , the ship captain robert cornish (alias williams) was executed in virginia for forcibly sodomising one of the ship’s boys, william couse. a number of men linked to the case criticised the execution (on unknown grounds), two of whom were punished by the loss of an ear and either one year of indentured servitude or whipping. north carolina included ear-cropping among its penal- ties for perjury: those guilty were fined, ineligible to give further testi- mony in any court, and pilloried for an hour before their ears were cut off and nailed to the pillory until sunset. new england was the most enthusiastic in its use of branding and other marks, but even pennsylvania – which virginia would shortly look to after the success of its new penitentiary – only removed remaining branding, ear crop- ping, etc., in . the army employed branding well into the nine- teenth century after it had left other (white) judicial punishments, see, for example, the case of abram in alabama , who successfully appealed a capital conviction for biting off a section of an overseer’s ear because () part of the ear was not mayhem, and () his life was in danger: in lawrence friedman, crime and punishment in american history (new york, ),  and n. the same offence by others – in language closely modelled on coventry – would be fined and pilloried: john g. aikin, a digest of the laws of the state of alabama, nd edn (tuscaloosa, ), . kirsten fischer, suspect relations: sex, race and resistance in colonial north carolina (ithaca, ), ; anthony s. parent, jr, foul means: the formation of a slave society in virginia, –  (chapel hill, ), , –. meranze, laboratories of virtue, . blackstone, commentaries, iv,  ( eliz. c. : ears nailed to the pillory for perjury),  (. eliz. c. : ears cut and nostrils slit for specific forgery offences). murrin, ‘“things fearful to name”’, ; crompton, ‘homosexuals’.  the acts of the general assembly of the state of north carolina (newbern, ), ch. vi.  the statute at large of pennsylvania, commonwealth of pennsylvania legislative reference bureau, www.palrb.us/default.php, xii.; lawrence henry gipson, ‘criminal codes of pennsylvania’, journal of criminal law and criminology,  (), –.        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the http://www.palrb.us/default.php https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core especially for desertion. william chester minor, a yale-trained surgeon in the union army, wrote a traumatised account of being tasked with branding an irish deserter in . marking the bodies of criminals was one way in which criminal identity could, in theory, be fixed, but this was never certain: cases of innocent disfigurement resembling the legal practices were recorded in kentucky courts, so that the individual could be defended against misreadings. in a rare gap, jefferson offers no citations for cutting women’s noses. his letter to pendleton shows an early intention to use castration to punish ‘rape, buggery, &c.’ but makes no mention of nose-cutting, or the use of retaliation for disfigurement. there is a long global tradition of inflicting nasal wounds upon sexual transgressors, with cases stretching from antiquity to the present, across egypt, europe and the middle east, through southeast asia and the pacific islands. punitive rhinotomy was practised by the blackfeet in the late nineteenth century, although it is not known how widely or for how long this might have existed in america. it was the status of injuries to the nose as inhonesta vulnera – dishonouring wounds – that was in part responsible for the emphatic punishment prescribed by coventry and related legislation. while male and female noses were protected by his disfigurement law, the dis- tinction between castration and nose-boring for the other offences shows his gendering of official judicial actions against this part of the body. as with the hebraic ‘eye for eye’, there was biblical precedent for rhi- notomy as a punishment for female sexual transgression (ezekiel :). slitting the nose of adulterous or otherwise sexually transgressive women was a widely known threat in early modern britain. while king edgar had used nose-cutting for some thefts, it was cnut (r. –) and archbishop wulfstan of york (fl. –) who introduced nasal mutila- tion – along with loss of the ears – for women convicted of adultery. jefferson does not refer to cnut here, but does elsewhere. his omission robert fantina, desertion and the american soldier, – (new york, ), ; simon winchester, the surgeon of crowthorne: a tale of murder, madness, and the oxford english dictionary,  (), –. ayers, vengeance and justice, . jefferson to pendleton,  august . jürgen wasim frembgen, ‘honour, shame, and bodily mutilation. cutting off the nose among tribal societies in pakistan’, journal of the royal asiatic society of great britain & ireland,  (), –; patricia skinner, ‘the gendered nose and its lack: “medieval” nose-cutting and its modern manifestations’, journal of women’s history,  (), –, and skinner, living with disfigurement, esp. ch. . adolf hungry-wolf, the blackfoot papers, vol. : pikunni biographies (skookumchuck, ), –. emily cock, rhinoplasty and the nose in early modern british medicine and culture (manchester university press, forthcoming ). ii cnut ; skinner, ‘gendered nose’, .    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core of cnut .–, which carried over edgar’s law of talion, is also strange. in the report of the revisors, the term was altered from ‘cutting’ to ‘boring’. this may have been intended to suggest restraint, but it also more closely echoes established laws in neighbouring jurisdictions, especially boring the tongue in new england. a final clue appears in jefferson’s legal commonplace book. here, he closely paraphrases a comment from henry home, lord kames’s history of the criminal law that according to diodorus siculus, in ancient egypt, ‘he who committed a rape was castrated. a woman committing adultery, lost her nose, that she might not again allure men to wantonness.’ kames holds this an example of egypt’s ‘perfection’ of the criminal law, since ‘revenge is thereby kept within the strictest bounds, and confined to its proper objects’. diodorus may have overstated the neat equivalency in this case, since adultery was more commonly met with death, but castration and rhinotomy were certainly used elsewhere. while a different crime, the note shows the alignment of rhinotomy with female sexual transgres- sion, their ‘allure’ to men, and the equivalency with male castration, which evidently had some appeal to jefferson. viii conclusion in notes on the state of virginia, jefferson presented his revised criminal code in an elegant table, arranged according to punishment: life, limb, and labour. the provisions under question are set out as follows: ii. crimes whose punishment goes to limb. . rape, ) dismemberment. . sodomy, . maiming, g retaliation, and the forfeiture of half the landsand goods to the sufferer. . disfiguring jefferson, legal commonplace book, ; henry home, lord kames, historical law- tracts, nd edn (edinburgh, ), . kames, historical law-tracts, . c. j. eyre, ‘crime and adultery in ancient egypt’, journal of egyptian archaeology,  (), –, at –. jefferson, in works of thomas jefferson, ed. ford, iv, .        cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core there is an element of obfuscation in placing castration behind the broader category of ‘dismemberment’. moreover, these laws had not passed when jefferson published the book. the summary echoes jefferson’s two ostentatiously careful manuscripts of bill , the notes arranged in columns to mirror legal heroes like coke. these carefully elu- cidatetheprecedents upon which jefferson wasrelying toput forward acode he desired to be marked by ‘accuracy, brevity and simplicity’. where dumas malone had seen the extensive notes as evidence of jefferson’s inter- est in the topic, julian boyd saw the annotations as jefferson’s ‘pedantic ostentation’, and dubber an excuse to ‘practice his penmanship’. considering the annotations and research alongside the problematic history of the coventry act in practice, however, illuminates why the keen lawyer struggled to find an adequate means of revising the provi- sions against disfigurement – one that even he grew to dislike. when beccaria’s appeal against capital punishment gained traction among reformers, those still in favour of the punishment were compelled to defend it with unprecedented vigour: vic gatrell notes that ‘elaborate pleading’ was newly necessary, ‘because older certainties had become uneasy’. jefferson’s exhausting annotations of the corporal punish- ments hint at similar strain to justify punishments that might seem ‘revolting’. virginia’s simplifying of the coventry act’s requirements of intention and circumstance, for all they fluctuated in different revisions, represented attempts to combat the real problems that the act had faced in practice in britain, and criticisms of its application. replacing the death penalty for this and the other offences with proportional punish- ments was supposed to increase efficacy, justice and rationality in post- revolutionary virginian law. i am inclined to agree with peterson that jefferson was in a sense ‘trapped by a misplaced desire for simplicity’, in striving for a code so straightforward, proportional and logical that mercy could never be at ‘the eccentric impulses of whimsical capricious designing men’. neither an out-of-the blue aberration, nor an over- looked hangover from earlier law, jefferson’s lex talionis approach to facial disfigurement as both a crime and a punishment drew on prece- dents from medieval england and closer to home, and reflected the anxious balance of punishment of body and mind at work in eight- eenth-century legal reforms. julian boyd, lyman h. butterfield and mina r. bryan (eds.), the papers of thomas jefferson (princeton, ), ii, ; dumas malone, jefferson and his time: jefferson the virginian (boston, ma, ), –. jefferson to wythe,  november . malone, jefferson and his time, ; boyd, butterfield and bryan (eds.), papers of thomas jefferson, ii, ; dubber, ‘“an extraordinarily beautiful document”’. vic gatrell, the hanging tree: execution and the english people – (oxford, ), . peterson, thomas jefferson, –; jefferson to pendleton,  august .    ’   cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core 	proportionate maiming: the origins of thomas jefferson's provisions for facial disfigurement in bill * 	introduction 	eighteenth-century law: death and violence 	jefferson's sources 	the face in virginia 	bill : reducing capital offences 	bestiality 	suicide 	polygamy 	rape 	sodomy 	disfigurement as a crime 	disfigurement as a punishment 	conclusion s y m p o s i u m : c o m p l i c a t i o n s o f s p i n e s u r g e r y complications of spine surgery editorial comment kristen e. radcliff md, alexander vaccaro md, phd published online: february � the association of bone and joint surgeons spine surgery, like other methods of invasive intervention, has specific common, and not so common, complications that may occur in the normal course of treatment. any physician so treating a problem must be cognizant of the anticipated course subsequent to his or her management to understand when recovery fails to proceed normally. such an acute awareness of treatment adverse events or com- plications will allow institution of appropriate remedial measures necessary for the best patient care and ultimately outcomes. as surgeons, we believe it is important to acknowledge and study our failures. this symposium reports original research on the potential complications of spine surgery to inform the orthopaedic and neurosurgical communities about possible best practices. the articles in this symposium encompass the spectrum of complications from diagnosis to surgical technique to postoperative healing. complication rate and common complications are explored in basic science and clinical research settings. we believe study of complications is essential to improving the ultimate outcome of spine care. we hope readers enjoy this symposium. fig. dr. radcliff is shown. fig. dr. vaccaro is shown. all icmje conflict of interest forms for authors and clinical orthopaedics and related research editors and board members are on file with the publication and can be viewed on request. k. e. radcliff, a. vaccaro rothman institute, thomas jefferson university, chestnut street, philadelphia, pa , usa k. e. radcliff (&) english creek avenue, egg harbor township, nj , usa e-mail: radcliffk@gmail.com clin orthop relat res ( ) : doi . /s - - -z clinical orthopaedics and related research® a publication of the association of bone and joint surgeons® 	complications of spine surgery: editorial comment wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ calcium-induced ros generation during ischemia triggers mptp-dependent cell death during reperfusion a monday, february , activates a novel, calcium-independent, pkca-dependent signaling pathway, which results in mitochondrial depolarization. as a result, mitochondrial dys- function is likely to be a key contributor to the pathophysiology of gas embo- lism injury. further, this connection between the endothelial surface layer and endothelial mitochondria may also play an important role in vascular homeo- stasis and disease. -plat calcium-induced ros generation during ischemia triggers mptp- dependent cell death during reperfusion lea k. seidlmayer, vanessa v. juettner, lothar a. blatter, elena n. dedkova. rush university medical center, chicago, il, usa. impairment of mitochondrial function is a central event of ischemia- reperfusion (i/r) injury leading to tissue damage and cell death. we studied the relationship between mitochondrial ca þ overload, reactive oxygen species (ros) generation, opening of the mitochondrial permeability transition pore (mptp) and cell death in rabbit ventricular myocytes exposed to simulated i/r. changes in mitochondrial ca þ ([ca þ]m) were measured with x-rhod- , ros generation with mito-sox red, mptp opening as mitochondrial calcein red release, and cell death as lactate dehydrogenase release. i/r was induced by exposing cells to glucose-free tyrode solution containing mm -deoxyglu- cose and mm nacn, ph . , followed by superfusion with standard tyrode solution. no cell death was observed after min of ischemia despite a signif- icant increase in [ca þ]m, ros and mptp opening, however cell death in- creased significantly after min of reperfusion. the ca þ uniporter blocker ru partially prevented [ca þ ]m increase and completely abolished ros generation and cell death when applied during i/r, however application of ru only during reperfusion did not protect from cell death. scavenging ros with superoxide dismutase mimetic mntbap or antioxidant trolox pre- vented reperfusion-induced cell death. blocking mptp during ischemia by cyclosporine a or depletion of mitochondrial inorganic polyphosphate did not provide protection against cell death during reperfusion, but instead led to increased mitochondrial ros accumulation. however, inhibiting mptp opening during reperfusion with cyclosporine a attenuated cell death. we con- clude that mptp-dependent cell death during reperfusion is mediated by ca þ- dependent ros generation during ischemia. moreover, our data suggest that mptp opening during ischemia could serve as ros escape pathway from mitochondria and thereby attenuate mitochondrial ros accumulation and ros-mediated cell damage during subsequent reperfusion. -plat dynamic measurement of ca d -induced changes in organelle-specific redox microdomains david m. booth , balázs enyedi , miklós geiszt , péter várnai , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary. multiple interactions between ca þ -signalling and reactive oxygen species (ros) production are thought to exist and be of both physiological and patho- physiological relevance. however, until recently, the study of ros in the con- text of ca þ-signalling has been hampered by ros probes limited in both specificity and targeting. to measure ros in discrete subcellular domains, we compared the genetically-encoded ratiometric h o sensor hyper with the redox de-sensitized derivative sypher to control for non-specific changes. these probes, targeted to the er lumen, er membrane (cytosolic face), cyto- sol, mitochondrial matrix and outer membrane (omm) and the ip -receptor, are positioned to assess redox changes at a local level. in resting conditions, the er lumen showed > -fold increased hyper ratio compared to the outside of the er membrane, bulk cytosol and mitochondrial matrix and omm. in the er lumen, ip -linked ca þ -mobilization induced a prounounced, downward shift in hyper ratio, whereas little or no change was detected in other compart- ments. in permeabilized cells, mitochondrial ca þ-overload was accompanied by substantial increase in h o detected in the matrix and at the omm. these data demonstrate that redox environments within individual cellular compart- ments constitute a complex and dynamic interrelationship with the concentra- tion of free ca þ . the er lumen is highly oxidized and exhibits profound decreases in h o concommitant with ca þ -release. interestingly, these changes are not transmitted to the outer leaflet of the er membrane or to other compartments. mitochondria resist redox changes under moderate stimulation, however, during mitochondrial ca þ-overload and collapsed membrane poten- tial, strong h o generation is detectible in the matrix and at the mitochondrial surface. the ros generated and detected at locations immediately apposed to ca þ -transport proteins, such as the ip -receptor, may modify their function at a local level and contribute to the feed-forward cycle of ca þ -dysregulation and subsequent cell death. -plat er-mitochondrial ultrastructure in the liver of normal and ethnaol-fed rats gyorgy csordas , david mankus , antony anil noronha , jan hoek , carmen mannella , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, wadsworth center, albany, ny, usa. chronic alcohol consumption causes severe pathology in liver, associated with altered metabolism and reduced atp production. liver mitochondria isolated from alcohol-fed animals show decreased capacity for electron transport and atp synthesis, impaired calcium handling, and increased ros. in parallel, the endoplasmic reticulum (er) also shows increased ros and a stress re- sponse. the close correlation between defects in mitochondria and er is matched by recent evidence of the functional integration of cellular responses (including calcium signaling) involving these organelles. to evaluate the ultra- structural basis of alcohol-induced changes, we performed transmission elec- tron microscopy and electron tomography studies of rat liver. hepatocytes showed a large number of mostly round mitochondrial cross sections, which oc- cupied ~ % of the cytoplasmic area. the cell cytoplasm in chronic ethanol- fed ( months) condition exhibited reduced particle density, indicative of cell swelling, and contained large lipid vesicles. the mitochondria were generally intact but showed narrower intermembrane spacings within cristae and at the organelle periphery, consistent with low-scale matrix swelling. in both control and ethanol-fed conditions, mitochondria were typically surrounded by exten- sive er, with cisternae sometimes sandwiched between neighboring mitochon- dria. in one case, er was prominent at a site of mitochondrial fusion/fission. as previously reported, regions of close er-mitochondrial association ( - nm) contained numerous ‘‘tethers’’ between outer mitochondrial membranes (omm) and adjacent er. while individual tethers were discernible, dense granular material (including ribosomes) within omm-er interfaces interfered with accurate quantitation of tethers. however, membrane spacings could be readily measured. it was found that the mitochondrial surface in close associ- ation with er was significantly reduced in the chronic ethanol-fed condition as compared to control ( . % vs. %). this might be expected to cause reduced calcium signaling between er and mitochondria in liver after chronic alcohol ingestion. -plat mitochondrial nm -h /ndpk-d is multifunctional: intermembrane cardiolipin transfer linked to apoptosis uwe schlattner , malgorzata tokarska-schlattner , sacnicte ramirez , yulia y. tyurina , andrew a. amoscato , zhentai huang , jianfei jiang , mathieu boissan , raquel f. epand , dariush mohammadsanyi , judith klein-seetharaman , richard m. epand , marie-lise lacombe , valerian e. kagan . joseph fourier university and inserm, grenoble, france, university of pittsburgh, pittsburgh, pa, usa, inserm, umpc université paris and hôpital tenon, paris, france, mcmaster university, hamilton, on, canada, inserm and umpc université paris , paris, france. nm -h /ndpk-d forms symmetrical homohexameric complexes in the mitochondrial intermembrane space. the well established function of the en- zyme is phosphotransfer activity as a nucleoside diphosphate kinase (ndpk), using mitochondrial atp to regenerate nucleoside triphosphates. nm -h is further known to strongly bind in vitro to anionic phospholipids, mainly cardi- olipin, and in vivo to inner mitochondrial membranes. we show here that such protein/lipid complexes inhibit ndpk activity but are necessary for nm -h to function in selective intermembrane lipid transfer. nm -h -deficient hela cells expressing either wild-type nm -h or a membrane-binding deficient mutant were analyzed by membrane fractionation and lc-esi-ms. data revealed that wild-type nm -h increased cardiolipin content in the outer mitochondrial membrane as compared to mutant enzyme. this correlated with higher susceptibility of wild-type enzyme expressing cells to rotenone-induced apoptosis as seen by increased annexin v binding, elevated caspase / activity and stimulated release of cytochrome c into the cytosol. molecular modeling of nm -h binding with cardiolipin reveals potential intermembrane transfer mechanisms. we propose that nm -h acts as a lipid-dependent mitochondrial switch with dual function, allowing either for phosphotransfer or for cardiolipin transfer, with a role in apoptotic signaling. 	calcium-induced ros generation during ischemia triggers mptp-dependent cell death during reperfusion 	dynamic measurement of ca +-induced changes in organelle-specific redox microdomains 	er-mitochondrial ultrastructure in the liver of normal and ethnaol-fed rats 	mitochondrial nm -h /ndpk-d is multifunctional: intermembrane cardiolipin transfer linked to apoptosis thorax ; : - intralobar pulmonary sequestration in conjunction with bronchial isomerism krishna k mohan, neil kramer, mitchell l margolis, robert m steiner, herbert e cohn from the division ofpulmonary diseases and departments ofmedicine, radiology, and thoracic surgery, thomas jefferson university hospital, philadelphia, pennsylvania pulmonary sequestration is an uncommon congenital anomaly characterised by a mass of non-functional, dysplastic lung parenchyma that docs not communicate with the normal tracheobronchial tree. such an anomaly commonly receives its blood supply from the systemic circulation. the sequestered pulmonary segment is considered to be intralobar if it is enclosed within the common pleura enveloping the normal lung and extralobar if it has its own separate pleural investment. intralobar pulmonary sequestration is only rarely associated with other congenital anomalies, whereas a large proportion ofcases of extralobar sequestration are associated with diaphragmatic hernias and other congenital anomalies. ' this case report describes a patient with an intralobar sequestration on the right side who also had a left-sided bronchial anatomy on the right (bronchial isomerism). to our knowledge this association has not been previously reported. case report a -year-old white woman who worked as an insurance executive was admitted to thomas jefferson university hospital because of recurring haemoptysis. blood-streaked sputum had been noticed by the patient over several years. there were no other symptoms referable to the respiratory system or cardiovascular system. she did not smoke cigarettes. physical examination showed nothing abnormal. the initial chest radiograph showed a well-demarcated, round soft-tissue density in the region of the medial basal segment of the right lower lobe, and the pulmonary vessels to the right lower lobe appeared abnormal. flexible fibreoptic bronchoscopy showed no bleeding sites or endobronchial lesions up to the fourth-generation bronchi. the bronchial anatomy on the right side, however, was a mirror image of that on the left. a relatively long right main-stem bronchus led to upper-lobe and lower-lobe bronchi; the upper-lobe bronchus led to a middle-lobe and a true upper-lobe bronchus. each of the lobar bronchi had two segmental divisions-an isomerism of the left-sided anatomy with upper-lobe and lingular counterparts. inspection of the right lower lobe showed hypoplasia of the lobar bronchus with regional inflammation. one apical and two of the four basal segmental bronchi could be identified, address for reprint requests: dr kk mohan, division of pulmonary disease, thomas jefferson university hospital, philadelphia, pa , usa. but these appeared to be rotated and displaced. selective bronchography on the right side confirmed left-sided pulmonary isomerism (fig la and lb). an abdominal aortogram showed that an aberrant artery arising from the abdominal aorta, cephalad to the coeliac axis, supplied the sequestered lung mass. the aberrant artery had a large aneurysmal dilatation in its course (fig ). the venous return from the sequestered lung segment was through a cluster of veins into the hepatic vein via a defect in the diaphragm. a clinical diagnosis of pulmonary sequestration with pulmonary bronchial isomerism was made. exploratory thoracotomy showed a bilobed right lung, the upper lobe providing a lingula counterpart. an intralobar sequestra- tion was located in the medial portion of the right lower lobe with its aberrant systemic arterial supply arising from below the diaphragm. the sequestrated lung segment was removed with its aneurysmal feeding vessel. the patient tolerated the procedure well and made a satisfactory recovery. discussion intralobar pulmonary sequestrations constitute - - % of all congenital pulmonary malformations. in a review of cases of intralobar pulmonary sequestration savic et al noted a concomitant congenital anomaly in only - % of the cases. in no case was bronchial isomerism identified, nor do other reports of pulmonary sequestration" mention coexisting bronchial isomerism. four types of bronchial isomerism have been described. so far none of these has been reported to be associated with pulmonary sequestration. type i, which predominates in males, consists of bilateral trilobed lungs and is associated with asplenia, malrotation of the gut, and congenital cardiovascular anomalies that include transposition of the great vessels, atrial septal defects, ventricular septal defects, and right-sided aortic arches. type ii bronchial isomerism consists of anisosplenia associated with the other features of type i isomerism. type iii combines bilateral bilobed lungs with polysplenia, gut malrotation, and congenital heart disease, and appears to have no sex predilection. type iv bronchial isomerism syndrome occurs most often in females and includes bilobed lobes with gut malrotation, anisosplenia, and a double outlet from the right ventricle. our patient decinedi to thave\ a liver or spleen scan but the aortographic study did show a normal splenic artery and left gastric arteries arising from the coeliac axis. bronchial isomerism almost never causes symptoms. o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://th o ra x.b m j.co m / t h o ra x: first p u b lish e d a s . /th x. . . o n ja n u a ry . d o w n lo a d e d fro m http://thorax.bmj.com/ mohan, kramer, margolis, steiner, cohn fig right selective bronchogram in (a) the anteroposterior and (b) the oblique projections shows a bilobar bronchial anatomy (left-sided isomerism). fig selective arteriogram illustrating the aberrant artery supplying the sequestered segment. the saccular aneurysm is seen in the mid-portion ofthe aberrant artery. o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://th o ra x.b m j.co m / t h o ra x: first p u b lish e d a s . /th x. . . o n ja n u a ry . d o w n lo a d e d fro m http://thorax.bmj.com/ intralobar pulmonary sequestration in conjunction with bronchial isomerism pulmonary sequestrations, on the other hand, when symptomatic, may lead to haemoptysis or recurrent infections in the sequestered lung segment. in either case early resection of the sequestration is the preferred treatment. the developmental origins of these uncommon congenital anomalies are of interest to embryologists, bronchoscopists, and surgeons. intralobar pulmonary sequestrations develop from accessory lung buds, which are enveloped by the normal lung and pleura during their caudal migration. on the other hand, bronchial isomerism as a phenomenon is more difficult to explain-presumably the bronchial pouch, budding off the laryngotracheal cleft before the th week of intrauterine life, fails to subdivide normally. clinicians must be aware of the multiple associated congenital anomalies of the lung, gut, abdominal viscera, heart, and blood vessels so that they can diagnose and treat any associated illnesses. references savic b, birtel fj, tholen w, funke hd, knoche r. lung sequestrations: report of seven cases and review of published cases. thorax ; : - . weekly clinicopathological exercises. pulmonary sequestration. n engl j med ; : - . o'mara cx, baker rr, jeyasinham k. pulmonary sequestration. surg gyn obst ; : - . landing bh. congenital malformations and genetic disorders of the respiratory tract (state of the art). am rev respirdis ; : - . szekely e, farkas e. pediatric bronchology. university park press, . fraser rg, pare ja. diagnosis of diseases of the chest. vol . philadelphia: wb saunders, : - . landing bh, lawrence tyk, rayne vc jun, wells tr. bronchial anatomy in syndromes with abnormal visceral situs, abnormal spleen and congenital heart disease. am j cardiol ; : - . gerle rd, jaretzki a, ashley ca, berne sa. congenital bronchopulmonary foregut malformation: pulmonary sequestration communicating with the gastrointestinal tract. n engl j med ; : - . tonkin ild, allen rg, riggs w, satterwhite c. double aortic arch associated with pulmonary sequestration. cardiovasc intervent radiol ; : - . o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://th o ra x.b m j.co m / t h o ra x: first p u b lish e d a s . /th x. . . o n ja n u a ry . d o w n lo a d e d fro m http://thorax.bmj.com/ guest editors oncogene ( ) , – . doi: . /sj.onc. dr nancy raab-traub received her bachelor of science from the university of michigan in in zoology and her phd in virology from the university of chicago in , where she began her studies on the epstein–barr virus (ebv), an important human tumor virus. ebv causes lymphoma development in immunocompromised individuals and is also linked to several major human cancers including nasopharyngeal carcinoma and hodg- kin’s lymphoma. several of the cancers linked to ebv occur with endemic patterns of incidence, suggesting that environmental or genetic factors also contribute to the development of these tumors. her earlier work analysed variation in the viral genome in tumors from various regions and also characterized ebv expression in the various malignan- cies associated with ebv. these studies contributed to the identification of the viral proteins that have potent effects on cell growth and regulation. she has shown that the viral protein lmp activates nfkb in epithelial and lymphoid cells, and in epithelial cells specifically activates expression of the epidermal growth factor. recent studies of the viral protein lmp have shown that it activates the akt kinase and wnt signaling. she is presently developing model systems to identify synergy between the effects of expression of viral proteins in specific cell types and cellular genetic changes. she is an editor of journal of virology and cancer research and serves on the editorial boards of virology, molecular carcinogenesis, virus genes, and molecular medicine. dr kamel khalili received his phd in microbiology from the university of pennsylvania. in that setting he was able to decipher the molecular pathway that leads to the inhibition of host gene expression upon infection of cells with adenovirus. following a postdoctoral fellow- ship at the wistar institute in philadelphia, he was the recipient of a prestigious fogarty international scholar- ship at the national cancer institute of the national institutes of health in bethesda, maryland. he spent years studying the molecular virology of polyoma- viruses, including sv and jcv in the laboratory molecular virology under the direction of the late dr george khoury. results from his studies on sv led to the identification of a novel viral-encoded protein termed selp, which is encoded by the early genome during the late phase of the lytic cycle. in , dr khalili joined the faculty as an assistant professor in the department of biochemistry and molecular biology and the jefferson institute of molecular medicine at thomas jefferson university. in , he established the molecular neurovirology section of the jefferson institute of molecular medicine. his research focused on the molecular pathogenesis of viral-induced neurological disorders, including progres- sive multifocal leukoencephalopathy induced upon reactivation of jcv in immunocompromised indivi- duals, regulation of hiv- in brain cells, and molecular pathogenesis of hiv- in the cns. dr nancy raab-traub dr kamel khalili oncogene ( ) , – & nature publishing group all rights reserved - / $ . www.nature.com/onc in , he established the center for neurovirology and cancer biology at temple university. this program is a synergistic effort between basic science and clinical departments. the goal of the center is to develop a dynamic multidisciplinary interdepartmental research and training program for devising novel therapeutic strategies for targeting a wide range of neurological disorders and training of scientists. he has assembled a group of highly qualified and motivated scientists, who have developed research programs in the areas of neurovirology, cancer biology and intervention, neuroaids, gene therapy, molecular therapeutics, and drug discovery and proteomics to achieve our objective. he has authored or coauthored more than papers, which have appeared in highly regarded, peer-reviewed journals. in , dr khalili established the journal of neuro virology and since that time he has served as editor-in-chief of this internationally distributed journal. dr khalili serves on the editorial boards of several journals, including cancer research and cancer biology and therapy. dr khalili’s major contributions have been in the field of molecular neurovirology as it relates to the regulation of human neurotropic viruses (jcv, hiv), gene expres- sion, and replication in the cns cells. the identification and cloning of genes of tissue-specific transcription factors in the cns, interaction of viral proteins with host regulatory protein, and the role of immunomodu- lators in the pathogenesis of diseases are examples of his contributions. oncogene guest editors 	guest editors cardioprotective roles of neuronal ca + sensor- during stress wednesday, february , a like ursodeoxycholic acid (udca) and tauroursodeoxycholic acid (tudca), are cytoprotective and inhibit cell death. the mechanisms associated with these distinct effects are not entirely clear. however, the effect of hydrophilic bile acids seems to be related with the blockage of a series of processes that converge on mitochondrial damage. bax is a pro-apoptotic protein that belongs to the superfamily of the bcl- proteins and is involved in mitochondrial pore formation. submicellar concentrations of cytoprotective bile acids have been shown to modulate bax concentration in mitochondria, suggesting that these molecules may interact directly with the protein. in this study, our objective was to evaluate the affinity of bile acids to recombinant bax protein, making use of fluorescence spectroscopy (fret and fluorescence anisotropy), as well as fluorescence correlation spectroscopy (fcs). our results show that the cytoprotective bile acids udca and tudca associate with recombinant bax protein with high affinity, while the cytotoxic bile acid dca only seems to be able to adsorb to the protein with much lower affinity. notably, the bind- ing site for udca seems to be located in a hydrophobic pocket of the protein. this interaction could be responsible for the disruption of bax translocation to the mitochondrial outer membrane in the presence of udca and/or tudca. supported from fct/portugal (projects ptdc/qui-biq/ / and reci/ctm-pol/ / ). t.s. and f.f. acknowledges fct grants sfrh/bd/ / and sfrh/ bpd/ / -pos board b mac inhibitors neutralize the pro-apoptotic effects of tbid pablo m. peixoto , oscar h. teijido , laurent m. dejean , evgeny pavlov , bruno antonsson , kathleen w. kinnally . natural sciences, baruch college - cuny, new york, ny, usa, national institute of child health and human development, baltimore, md, usa, chemistry, california state university of fresno, fresno, ca, usa, new york university college of dentistry, new york, ny, usa, merck serono, geneva research center, geneva, switzerland. since our initial characterization of the imacs, different di-bromocarbazole derivatives with anti-apoptotic function have been developed and tested in several mouse models of brain injury and neurodegeneration [ - ]. owing to the increased therapeutic potential of anti-apoptotic di-bromocarbazole de- rivatives, we sought to expand our knowledge of the mechanism of action of these small molecule inhibitors. we investigated the kinetics of mac inhibi- tion in mitochondria from wild type, bak, and bax knockout cell lines using patch clamp electrophysiology, fluorescence microscopy, elisa, and quantita- tive western blot analyses. our results show that imacs work through at least two mechanisms: ) by blocking relocation of the cytoplasmic bax protein to mitochondria and ) by disassembling bax oligomers in the outer membrane. a comparison of the inhibitory effects over channel conductance and cyto- chrome c release suggests that the imacs interacted with both bax and bak with similar kinetics. interestingly, wild type mitochondria were more suscep- tible to inhibition than the bak or bax knockouts. a quantitative western blot analysis showed that wild type mitochondria had lower steady state levels of bak, which suggests an uneven stoichiometry of the mac components. -pos board b tyrosine phosphorylation of mitochondrial ca d uniporter regulates mitochondrial ca d uptake jin o-uchi, stephen hurst, jyotsna mishra, xiaole xu, bong sook jhun, shey-shing sheu. depariment of medicine, center for translational medicine, jefferson medical college, thomas jefferson university, philadelphia, pa, usa. mitochondrial ca þ has a critical role for balancing cell survival and death. ca þ influx into mitochondrial matrix is mediated primarily by the mitochondrial cal- cium uniporter (mcu). however, the signaling pathways that regulate mcu channel functions via post-translational modifications of mcu are completely unknown. here we show that adrenergic signaling induces mcu tyrosine phos- phorylation and accelerates mitochondrial ca þ uptake in cardiac cells. adren- ergic signaling induces activation of proline-rich tyrosine kinase (pyk ) and translocation into the mitochondrial matrix; enhancing the interaction between pyk and mcu, which subsequently accelerates mitochondrial ca þ uptake via pyk -dependent mcu tyrosine phosphorylation. mcu contains tyrosine res- idues ( in the n-terminus, in the pore-forming region, in transmembrane do- mains and in the c-terminus), which are conserved across all eukaryotic species. among them, only of these tyrosine residues (y at n-terminus, y , and y at c-terminus in mouse mcu) remained as potential phosphor- ylation candidate sites for protein tyrosine kinases using phosphorylation predic- tion programs. we mutated these tyrosine residues to phenylalanine and generated non-phosphorylation mimetic mcu mutants (mcu-yfs). we confirmed that only two tyrosine sites were phosphorylated in response to adren- ergic stimulation in situ using cell lines stably expressing mcu-yfs. in addi- tion, overexpression of these mcu-yfs failed to increase mitochondrial ca þ uptake in response to cytosolic ca þ elevation by thapsigargin, whereas wild- type mcu transfection dramatically accelerates mitochondrial ca þ uptake compared to non-transfected cells. in summary, mcu contains pyk -specific phosphorylation site(s) and pyk -dependent tyrosine phosphorylation of mcu can modulate its channel functions and regulate mitochondrial ca þ uptake. -pos board b cardioprotective roles of neuronal ca d sensor- during stress tomoe y. nakamura-nishitani , shu nakao , shigeo wakabayashi . molecular physiology, natl.cer.cardiovasc.ctr., suita, japan, cardiac physiology, natl.cer.cardiovasc.ctrwakabayshi, suita, japan. dysregulation of ca þ homeostasis in cardiomyocytes often results in heart fail- ure. identifying molecular targets that regulate cardiomyocyte survival is of ther- apeutic importance. neuronal ca þ -sensor- (ncs- ) is an ef-hand ca þ - binding protein, which is important for excitable cell functions. we previously found that ncs- -deficient (ncs �/�) mice had excess neonatal mortality (circ. res. ).the aim ofthe present study isto examinewhether ncs- plays beneficial roles in cardiac survival during stress and the possible mechanisms un- derlying these effects. neonatal mouse ventricular myocytes orwhole hearts from wild-type (wt) and ncs �/� mice were subjected to stressors, and the resistance to stress was evaluated. ncs �/� mouse hearts were more susceptible to stress induced by oxidative impairment and ischemia-reperfusion injury. stress- inducedactivationofphosphatidylinositol -kinase (pi k)/akt signaling, a major survival pathway, was substantially reduced in the ncs �/�group, and overex- pressionofncs- ortheconstitutiveactive formofakt increased the survivalrate of ncs �/� myocytes. cellular atp levels, as well as mitochondrial respiration rates (both basal and maximal o consumption) were significantly depressed in ncs �/� myocytes; especially with oxidative stress. furthermore, intracellular ca þ handling was more easily dysregulated in stressed ncs �/� myocytes than wt myocytes. since ncs- levels were increased by stress, the data suggest that ncs- is a survival-promoting factor, which is upregulated by stress stimuli. interestingly, however,supra-physiological ncs- expression was toxic to cells. taken together, our data suggest that moderate ncs- expression during stress promotes cardiomyocyte survival by maintaining proper ca þ handling, which is required for activation of akt survival pathways and mitochondrial function. -pos board b initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart development gisela beutner, george a. porter, jr. pediatrics, university of rochester medical center, rochester, ny, usa. mitochondria in early embryonic hearts are not thought to produce atp, yet they do produce reactive oxygen species (ros) that regulate myocyte differen- tiation. to assess changes in atp and ros generation in the developing heart, we measured mitochondrial oxygen consumption, the activity of the complexes (cx) and of the electron transport chain (etc), etc supercomplex assem- bly, and ros in embryonic mouse hearts. at embryonic day (e) . , mitochon- drial etc activity and oxidative phosphorylation (oxphos) are not coupled, even though the etc complexes are present. we show that cx- is able to accept electrons from the krebs cycle, but enzyme assays that specifically mea- sure electron flow to ubiquinone or cx- show no activity at this early embry- onic stage. at e . , mitochondria appear functionally more mature; etc activity and oxphos are coupled and respond to etc inhibitors. in addition, the assembly of highly efficient respiratory supercomplexes containing cx � , � , and � , ubiquinone, and cytochrome c begins at e . , the exact time when cx- becomes functional activated. at e . , etc activity and oxphos of embryonic heart mitochondria are indistinguishable from adult mitochon- dria. in contrast, generation of reactive oxygen species (ros), as measured with amplex red, is high at e . and drops significantly by e . , coinciding with activation of the etc. in summary, our data suggest that between e . and e . dramatic changes occur in the mitochondria of the embryonic heart, which result in a decrease of ros generation and an increase in oxphos due to the activation of cx- and the formation of supercomplexes. -pos board b the stoichiometry between micu and mcu determines the different mitochondrial ca d uptake phenotypes in heart and liver melanie paillard, györgy csordás, tünde golenár, cynthia moffat, erin seifert, györgy hajnóczky. mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa. mitochondrial ca þ uptake is central to oxidative metabolism and cell death signaling. the first clues to its molecular mechanism have emerged from the recent identification of the mitochondrial ca þ uniporter’s pore forming protein (mcu) as well as its regulators. among the regulators, micu shows striking 	mac inhibitors neutralize the pro-apoptotic effects of tbid 	tyrosine phosphorylation of mitochondrial ca + uniporter regulates mitochondrial ca + uptake 	cardioprotective roles of neuronal ca + sensor- during stress 	initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart de ... 	the stoichiometry between micu and mcu determines the different mitochondrial ca + uptake phenotypes in heart and liver doi: . /j.bpj. . . a monday, february , mechanisms through which upregulation of bcl affects earlier steps of bax- mediated apoptosis are not fully understood. we found that bax insertion into the mom was the earliest apoptotic step inhibited by bcl overexpression. paradoxically, we also found that bax translocation to the mitochondria was not inhibited but rather spontaneously increased in this same genetic context. this increase in mitochondrial associated bax required a physical interaction be- tween bax and bcl . we therefore propose that, at least when upregulated, bcl behaves as a ‘decoy receptor’ which sequestrates bax at the mitochondria but inhibits its insertion into the mom, committing the cell to survive. supported by nyu research challenge funds to ld. -pos compartmentalization of bcl family proteins mediated by organelle lipid membranes rebecca j. boohaker, ge zhang, adina loosley, kathleen nemec, annette r. khaled. university of central florida, orlando, fl, usa. cancer is defined by a pronounced inhibition of cell death. the bcl family of proteins tightly regulates the delicate balance between life and death. one method of regulation is the compartmentalization of antagonistic members. for example, bax, a pro-apoptotic member of this family, acts as the penulti- mate factor in the apoptotic cascade by releasing apoptogenic factors such as cytochrome c from the mitochondrial lumen. the normally cytosolic protein translocates from one internal compartment to another through an elusive mechanism. individual organelles are defined not only by function (mediated by specific membrane bound proteins), but by the unique composition of their phospholipid membranes. in this work, we have evaluated the contribution of organelle lipids to the localization of of bcl proteins. -pos in search of the structure of mac in the mitochondrial outer membrane pablo m. peixoto , christian renken , shefali haldar , carmen mannella , kathleen w. kinnally . new york university college of dentistry, new york, ny, usa, wadsworth center, albany, ny, usa, academy of the holy names, albany, ny, usa. several groups have tried to determine the structure of the channel (mac) formed in mitochondrial outer membranes (om) of apoptotic cells or in syn- thetic membranes by bax and related proteins/peptides, using electron micros- copy (em), atomic force microscopy and x-ray diffraction. here, pore-like structures ~ - nm were handpicked from transmission em images of ura- nyl-acetate-stained oms isolated from control and apoptotic (il -deprived) fl . cells. these ‘‘candidate pores’’ were aligned by correlation procedures, and class averages defined by principal component and k-means analyses. main differences in the class averages were ( ) the presence of one or more dark (stain-filled) pores, and ( ) the nature of white (stain excluding) features around the pores. a class average consisting of a single -nm pore with pro- nounced white rim was rotationally averaged and used as a reference for cross-correlation searches of om images from control and apoptotic cells. searches using this -nm ‘‘donut’’ motif and the same motif doubled in size ( -nm ‘‘donut’’) yielded thousands of ‘‘hits’’ in both control and apoptotic membranes, which were subsequently aligned and classified as before. the pre- dominant stain-filled structures found with both motifs were not circular but elongated (up to ~ x nm), extending away from stain-excluding crescent- shaped features. the radial anisotropy ruled out reference bias and was in- consistent with pores formed by rings of evenly spaced protein subunits. we hypothesize that the different classes of structures detected represent stages in formation of mac as an increasingly large membrane bilayer defect (or ‘‘cleft’’) induced by successive aggregation or clustering of bax/bak molecules. a progressive assembly mechanism for mac has been recently suggested by real-time monitoring of mac conductances in isolated mitochondria by patch clamping (martinez-caballero et al. j biol chem : - ). supported by nih grant gm . -pos effects of mac formation on mitochondrial morphology pablo m. peixoto, shin-young ryu, robert range, kathleen w. kinnally. new york university college of dentistry, new york, ny, usa. accumulating literature associate mitochondrial dynamics with apoptosis, since regulation of either process has reciprocal effects. these processes seem to converge in formation of the mitochondrial apoptosis induced channel, mac, which releases cytochrome c and triggers the degradation phase of apo- ptosis. while bax and bak, core components of mac, were shown to interact with fusion and fission proteins, some studies also suggest proteins from the in- termembrane space could leak to the cytosol and further promote mitochondrial fission during apoptosis. the temporal relationship between apoptosis induc- tion, mac formation and mitochondrial fragmentation was investigated by time lapse microscopy. mac function was induced through staurosporine treat- ment and microinjection of tbid or cytochrome c. mac formation and mito- chondrial dynamics under these conditions were monitored in hela cells (clone ) that stably express low levels of gfp-bax and were transiently transfected with a pdsred- plasmid. gfp-bax relocation to mitochondria only during apoptosis signals mac formation, while pdsred- expression shows mito- chondrial structure as red fluorescence. treatment with staurosporine and microinjection with tbid or cytochrome c induced relocation of bax and col- lapse of the mitochondrial network. the temporal relationship between these two events was further analyzed. interestingly, pretreatment with imac , a spe- cific mac blocker, protected against cell death and prevented mitochondrial fragmentation after tbid injection. our results suggest a link exists between mac formation and collapse of the mitochondrial network during apoptosis. supported by nih grant gm . -pos mechanism of the mitochondrial cytochrome c release wave in bid-induced apoptosis soumya sinha roy, cecilia garcia-perez, erika davies, xuena lin, györgy hajnóczky. thomas jefferson university, philadelphia, pa, usa. bid, a bh -only bcl family protein, plays a central role in apoptosis. bid is cleaved by caspase- and other enzymes forming tbid that induce mitochon- drial outer membrane (omm) permeabilization and cytochrome c (cyto-c) re- lease. however a mystery remains how bid synchronizes the function of a large number of discrete organelles, particularly in mitochondria-rich liver or muscle cells. here we showed that tbid ( . - nm) elicited progressive omm perme- abilization and complete cyto-c release with a dose-dependent lag time and rate in h c cell populations. once started, the omm permeabilization was not pre- vented by tbid washout. in contrast, the dose-response for digitonin-induced omm permeabilization displayed quantal behavior. in single cell imaging studies, permeabilized h c and primary human cardiac cells transfected with cyto-c-gfp showed complete tbid-induced cyto-c-gfp release closely followed by mitochondrial depolarization. the cyto-c-gfp release started at discrete sites and propagated through the mitochondria with a constant velocity and a relatively stable kinetic of release in each organelle. similar tbid-induced cyto-c-gfp release wave was documented in intact h c cells transfected with tbid. the waves were not dependent on ca þ , caspase activation or permeabil- ity transition pore opening. however, treatment with mntmpyp, a ros scav- enger or overexpression of mitochondrial superoxide dismutase suppressed the coordinated cyto-c release and also inhibited tbid-induced cell death. on the other hand, both superoxide and hydrogen peroxide sensitized mitochondria to the tbid-induced permeabilization. thus, tbid engages a ros-dependent inter-mitochondrial signaling mechanism for spatial amplification of the apoptotic signal by mitochondrial waves. -pos role of milton domains in the calcium-dependent regulation of mito- chondrial motility sudipto das, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. the mammalian grif and oip , and the drosophila milton are kinesin- binding proteins that form a complex with the miro gtpase, an outer mitochon- drial membrane ef-hand protein, to support the movement of mitochondria along the microtubules. our study demonstrates that in h c cells overexpress- ing oip or grif , the basal motility of mitochondria is increased, whereas the sensitivity to calcium-induced movement inhibition is decreased. to dissect the interaction between milton, kinesin and miro, three different milton constructs were tested: milton ( - ), the soluble domain of milton; milton ( - ), lacking the kinesin heavy chain binding site and milton ( - ) that lacks additional ~ amino acid presumably containing part of the miro binding site. immunohistochemistry revealed that the overexpressed milton ( - ) was cytoplasmic, whereas the other two milton constructs showed mitochondrial localization. the basal mitochondrial motility was in- creased by milton ( - ) but was not altered by milton ( - ) or mil- ton ( - ). a plot of mitochondrial motility against slowly rising cytoplasmic [ca þ] induced by thapsigargin ( mm), shows that overexpression of milton ( - ) significantly reduced the calcium sensitivity of mitochondrial motil- ity reminiscent of oip and grif . by contrast, milton ( - ) or milton ( - ) did not have any effect. the thapsigargin-induced cytoplasmic calcium signal was not affected by any of the milton constructs. these data indicate that 	compartmentalization of bcl family proteins mediated by organelle lipid membranes 	in search of the structure of mac in the mitochondrial outer membrane 	effects of mac formation on mitochondrial morphology 	mechanism of the mitochondrial cytochrome c release wave in bid-induced apoptosis 	role of milton domains in the calcium-dependent regulation of mitochondrial motility biography—elisabeth i. heath, md facp # springer science+business media new york elisabeth i. heath, md facp dr. elisabeth heath is an active scientific member of the karmanos cancer institute (kci) in detroit, mi, usa. as professor of oncology and medicine, her research focus is conducting clinical and translational research trials in genito- urinary malignancies. dr. heath is the director of prostate cancer research and leads the prostate cancer research team (pcrt) at kci. she has been successful in focusing the pcrt to conduct innovative, translational research in prostate cancer as well as fostering team science. dr. heath also con- tinues to bring critical attention in the area of health disparity, particularly with regard to the poor accrual of minority patients to prostate cancer clinical trials. as the principal investigator of the department of defense grant supporting karmanos cancer institute/wayne state university involvement in the nationally and internationally recognized prostate clinical trials cancer consortium, dr. heath has been successful in increasing mi- nority accrual to prostate cancer clinical trials. she earned her medical degree from thomas jefferson university in philadelphia, pa, usa, completed her inter- nal medicine residency at georgetown university hospital, washington, dc, usa, and completed her medical oncol- ogy fellowship at johns hopkins school of medicine, baltimore, md, usa. dr. heath has also served on the scientific program committee of the developmental therapeutics-molecular therapeutics committee of the american society of clinical oncology (asco) and has served as program faculty for several annual genitourinary asco as well as the annual asco meetings. she also serves on the editorial board of the journal of clinical oncology. dr. heath currently serves as the president-elect for the kci medical executive committee, serves on the kci salary committee, is a member of the executive committee of the faculty senate at wayne state university school of medicine, and serves on the board of directors of the michigan cancer consortium. she has been the recipient of the national cancer institute clinical investigator team leadership award in . dr. heath has also been awarded the wayne state university school of medicine college teaching award in and as well as holds the top doc designation in hour magazine in , , , and . dr. heath serves as the faculty advisor for the gold humanism honor society and has been the recipient of the leonard tow humanism in medicine award. she is the recip- ient of the wayne state university school of medicine physician’s golden heart award in . dr. heath is a dedicated clinician, researcher, and teacher at wayne state university school of medicine. cancer metastasis rev ( ) : doi . /s - - - 	biography—elisabeth i. heath, md facp springer a++ viewer publisherinfo publishername : biomed central publisherlocation : london publisherimprintname : biomed central bag- can predict survival from breast cancer articleinfo articleid : articledoi : . /gb-spotlight- - articlecitationid : spotlight- - articlesequencenumber : articlecategory : research news articlefirstpage : articlelastpage : articlehistory : registrationdate : – – onlinedate : – – articlecopyright : biomed central ltd articlegrants : articlecontext : tudor toma email: ttoma@mail.dntis.ro measuring tumour levels of the protein bag- can predict which women with localised breast cancer are at greatest risk of metastases, according to a paper in the february journal of clinical oncology. bruce turner, from thomas jefferson universityin philadelphia, and colleagues studied women with early stage breast cancer. they analysed paraffin blocks of excised tumors and found that cytosolic immunostaining for bag- - a protein that inhibits apoptosis - was greater in of invasive breast cancers. interestingly, % of women who had tumours that contained high levels of bag- had a longer survival time and were still alive years after diagnosis, compared with % of women whose tumours contained low levels of the protein. no other biomarkers tested reached statistical significance for predicting survival (j clin oncol , : - ). patients with tumours containing low levels of bag- may benefit from more aggressive cancer treatments early in the course of the disease. references . turner bc, krajewski s, krajewska m, et al:bag- : a novel biomarker predicting long-term survival in early-stage breast cancer. j clin oncol , : - ., [http://www.jco.org/cgi/content/ abstract/ / / ] . thomas jefferson university, [http://www.tju.edu/] this pdf file was created after publication. http://www.jco.org/cgi/content/abstract/ / / http://www.jco.org/cgi/content/abstract/ / / http://www.tju.edu/ 	bag- can predict survival from breast cancer 	references wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( 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(typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ untitled  | cancer discovery�august www.aacrjournals.org news in brief precision medicine path for prostate cancer a mainstay of metastatic prostate cancer treatment is the suppression of hormones that fuel tumor cells. how- ever, almost all men with advanced prostate cancer develop resistance to these androgen-depleting therapies. recently, researchers showed that nearly % of patients with metastatic castration-resistant prostate cancer (mcrpc) have a genetic alteration that could be targeted by other clini- cal treatments. the fi ndings suggest individualized approaches for these patients (cell ; : – ). “this will have a major impact on how we move forward in [treating] this disease,” says johann de bono, md, a principal investigator in the study and head of the division of clinical stud- ies at the institute of cancer research in london, uk. “ninety-nine percent of our trials involve no patient prese- lection. with this information, we can now subdivide these patients, as we’ve done with breast and lung cancers.” in this fi rst multicenter, inter- national clinical trial, researchers conducted whole-exome and transcrip- tome sequencing of bone or soft-tissue biopsy samples from patients living with mcrpc. results showed that . % of the patients who had a genetic alteration had androgen recep- tor mutations, a fi nding in line with current understanding of the disease. more compelling, researchers found that of the nearly % of patients with genetic alterations, % had anoma- lies (other than androgen receptor mutations) that could be targeted by investigational or fda-approved drugs currently used for other cancers. among these alterations, almost % occurred in dna repair pathways. for instance, some tumors had brca or brca mutations, which, in ovarian and breast cancers, have shown sensi- tivity to parp inhibitors, drugs that interfere with dna repair and prevent tumor cells from dividing. in addition, researchers mapped more than a half dozen previously unknown genetic changes, such as mutations in the wnt signaling pathway, which leads to regulation of cell development and migration, and a pik cb mutation with cancer-activating effects similar to pik ca. they also found that % of patients with mcrpc had germline mutations. “this is a very important study on a number of fronts,” says karen knudsen, phd, director of the sidney kimmel cancer center at thomas jefferson university in philadelphia, pa, who was not involved in the study. “it’s the fi rst large study looking at the incurable stage of the disease, where the unmet clinical need is. the large cohort gives us confi dence and a much clearer picture of the drivers of disease, and they’ve uncovered new potential drivers that are targetable.” when the study is completed, research- ers will have mapped and sequenced the tumors of patients with mcrpc. amassing such data, says de bono, will lead to more targeted—and more afford- able—sequencing. “it will be critical to follow up with clinical trials that correlate clinical outcomes with molecular alterations,” says arul m. chinnaiyan, md, phd, a senior author on the study and direc- tor of the michigan center for trans- lational pathology at the university of michigan in ann arbor. “the longer- term goal is to have this information ahead of time and be able to direct patients in a more precise way to the best therapy.” ■ cellular backpackers deliver lymphoma drugs researchers have developed a new technique that enlists t cells to ferry chemotherapy drugs into tumors and that improves the effi ciency of drug delivery. cancer cells can elude chemo- therapy by hiding out in lymph nodes and other protected locations. even if a small amount of drug makes it to these refuges, it may not permeate the tissue to reach the tumor cells inside. researchers have tried to overcome these problems by having nanoparti- cles transport chemotherapy drugs, but not all tumors have the leaky blood vessels that enable the particles to leave the bloodstream and disperse into the tumor. people karen e. knudsen, phd, has been named director of the sidney kimmel cancer center at thomas jefferson university in philadelphia, pa, as well as chair of its department of cancer biology. she has been serving in these roles on an interim basis since january. an expert in the molecular basis of hormone-dependent prostate cancer, knudsen aims to prevent and treat the disease. her studies that identify tumor suppressor and hormone-receptor alter- ations have uncovered new targets for treating advanced disease and have led to innovative, biomarker-driven clinical trials. in addition, she is editor-in-chief of molecular cancer research. rolf apweiler, phd, and ewan birney, phd, have been appointed joint directors of the european molecular biology laboratory— european bioinfor- matics institute (embl-ebi), effective july . the european hub for big data in biol- ogy, embl-ebi is based on the wellcome trust genome campus in hinxton, uk. as part of embl, the institute collects, annotates, archives, and shares data from publicly funded life-science experiments with the global scientific community. apweiler and birney will continue to lead their respec- tive research groups. apweiler is involved in many internal col- laborations and initiatives, including the human proteome organization proteomics standards initiative. he has served on the editorial and advisory boards of several journals, and he has published more than papers and book chapters. birney played a vital role in annotating the genome sequences of the human, mouse, and other organisms. he led the analysis group for the encode project. his inter- ests include functional genomics and statisti- cal methods to analyze genomic information. e m b l -e b i e m b l -e b i rolf apweiler, phd ewan birney, phd on april , . © american association for cancer research. cancerdiscovery.aacrjournals.org downloaded from http://cancerdiscovery.aacrjournals.org/ ; : . cancer discovery people updated version 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submissions: t h e history of education society prize the history of education society awards a prize of $ biennially to the author of an article judged to be the most distinguished scholarly essay in educational history—broadly denned to cover a wide range of educational and cultural institutions inside and outside the united states (this includes work on schools and universities, teachers, students, and families)—published in any journal over the previous two-year period. the deadline for submissions is may , . submissions should be emailed (in microsoft word) to anelson@education. wisc.edu. manuscripts should adhere to the chicago manual of style, should be double-spaced in -point times new roman font, and should not ex­ ceed pages in length, including notes. the author's name should appear only on the cover page. for other instructions, see the history of education quarterly author guidelines. committee members: adam nelson (chair, university of wisconsin- madison), hilary moss (amherst college), and michelle purdy (michigan state university). direct any questions to: adam nelson, professor educational policty studies and history university of wisconsin-madison anelson@education.wisc.edu h ttp s://d o i.o rg / . /s d o w n lo ad ed fro m h ttp s://w w w .cam b rid g e.o rg /co re . c arn eg ie m ello n u n iversity , o n a p r at : : , su b ject to th e c am b rid g e c o re term s o f u se, availab le at h ttp s://w w w .cam b rid g e.o rg /co re/term s . http://wisc.edu mailto:anelson@education.wisc.edu https://doi.org/ . /s https://www.cambridge.org/core https://www.cambridge.org/core/terms claude a. eggertsen dissertation prize history of education society t h e history of education society is accepting submissions for the claude a. eggertsen prize for the dissertation judged to be most out­ standing in the field of history of education. t h i s includes work on schooling and educational institutions more broadly, and the disserta­ tion may have a 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'f;lrbara j. shirclifje h ttp s://d o i.o rg / . /s d o w n lo ad ed fro m h ttp s://w w w .cam b rid g e.o rg /co re . c arn eg ie m ello n u n iversity , o n a p r at : : , su b ject to th e c am b rid g e c o re term s o f u se, availab le at h ttp s://w w w .cam b rid g e.o rg /co re/term s . https://doi.org/ . /s https://www.cambridge.org/core https://www.cambridge.org/core/terms 	book review pini cost-utility of chronic hepatitis “câ€? treatment with thymosin alpha i in mexico abstracts from eight managed care organizations. index claims were out- patient or emergency department visits in – by indi- viduals aged – with a primary diagnosis of pneumonia, antibiotic prescription within three-days, chest x-ray on index date, continuous enrollment for -months prior, -days after index visit. exclusion criteria: antibiotic prescription, pneumo- nia diagnosis, or hospitalization in prior -days; initial therapy with multiple antibiotics; in prior -months residence in a long-term care facility or diagnosis of lung cancer, secondary malignancy, hiv/aids, cystic fibrosis, immunodeficiency. we considered the following comorbid illnesses: chronic liver, renal or lung disease; cerebrovascular disease; cardiac disease; diabetes mellitus; malignancy. follow-up claims were considered cap-related if the primary diagnosis, using the clinical classifications software, was pneumonia; septicemia; pleurisy, pneumothorax or pulmonary collapse; respiratory failure, insuf- ficiency or arrest; other lower respiratory infection. results: in total, cases met criteria; . % had no comorbidities, . % had one comorbidity, and . % had two or more comor- bidities. mean total charges were $ . : . % inpatient, . % outpatient, . % outpatient testing and diagnostics, . % antibiotic prescriptions, . % emergency department, . % presenting to the emergency department had initial mean charges of $ . compared with mean initial charges for out- patients of $ . . in total, . % utilized follow-up services with . % requiring hospitalization. mean total charges for those eventually hospitalized were $ , . compared with $ . for the . % of patients who failed initial treatment but were not hospitalized, and $ . for the . % of patients requiring no additional antibiotics. number of comorbidities was strongly associated (p < . ) with charges: $ . for those without comorbidities vs. $ . for those with multi- ple comorbidities. conclusion: cost of outpatient cap for non-elderly adults is large even for those without comorbid illness. pin impact of complicated skin and soft tissue infections on inpatient costs for an academic medical center patel n , goldfarb n , hartmann cw , maio v , horn dl , pizzi l jefferson medical college, philadelphia, pa, usa; thomas jefferson university, philadelphia, pa, usa objectives: to determine the additional costs and lengths of stay (los) attributable to complicated skin and soft tissue infec- tions (cssi) for patients admitted to thomas jefferson university hospital, an urban academic tertiary care hospital. methods: all patients admitted between january , and december , were identified using the hospital billing system. patients with a potential cssi were identified using the specific icd- diagnosis codes. costs of care and lengths of stay, based on the hospital’s true cost accounting system, were compared by diagnosis related group (drg) between the cssi population and the non-cssi population. results: of the , patient discharges in , , ( . %) included one of the cssi diag- nosis codes; these encompassed drgs. the mean cost for cssi cases was $ , higher than for non-cssi cases, and mean los was ten days higher for cssi cases. for surgical and medical drgs, mean cost of cssi added $ , onto the cost for cases in surgical drgs compared to an average increase of $ , added to cost of medical drgs. differences in costs and los were observed in analyses by major disease categories (mdcs) and individual drgs as well. for mdcs, myeloproliferative dis- orders, multiple trauma, and diseases of the nervous system, costs were $ , , $ , , and $ , , higher for the cssi cases, respectively. this difference was also reflected in additional days of stay of , , and days, respectively. for patients with cssi, the three specific drgs responsible for the maximum total health care dollars expended were bone marrow trans- plants, rehabilitation, and small and large bowel procedures. conclusions: cssis significantly increase hospital resource consumption and costs. the difference in costs is especially pro- nounced for patients undergoing surgical procedures. results suggest that measures taken to avoid or more effectively treat cssis could yield significant savings to hospitals. pin cost-utility of chronic hepatitis “c” treatment with thymosin alpha in mexico nevárez-sida a, garcía-contreras f, constantino-casas p, castro-rios a, mould j, garduño-espinosa j mexican institute of social security, mexico city, mexico objective: to estimate cost-utility of the following alterna- tives in the treatment of chronic hepatitis c (chc) in the mexican institute of social security (imss): peginterferon, peginterferon plus ribavirin, peginterferon plus ribavirin plus thymosin alpha- and finally, not using any drug. methods: in mexico, more that one million persons are infected with chc virus and % of them develop chronic infection that might lead to hepatic cirrhosis and other complications that affect quality of life and costs of health care institutions. cost-utility analysis was carried out using institutional perspective and time horizon of years, discount rate of % for both, costs and effective- ness. the base case was a -year-old man with chc without hepatic cirrhosis or cancer and cost and effectiveness data were taken from literature, a mexican expert panel and an on-going clinical trial, not yet reported. effectiveness data are reported in qalys and costs in usd. a decision tree using a bayesian approach and a markov model were developed. sensitivity analysis was univariate, bivariate, threshold and probabilistic. acceptability curves and health net benefits were estimated. results: triple therapy (peginterferon plus ribavirin plus thy- mosin alpha- ) was dominant over the rest of alternatives costing $ per qaly, while peginterferon plus ribavirin $ per qaly and peginterferon only $ per qaly. not using any drug was the most costly alternative with $ per qaly. sen- sitivity analysis confirmed the strength of the base study. triple therapy was not dominated in any comparative case. con- clusions: triple therapy had the best cost-utility ratio and not using any drug was the opposite, most expensive and with less utility than all the compared alternatives. although triple therapy is initially very expensive, it provides the highest gains in the long run, both in the improvement of quality of life and in saving costs. pin a comparison of methods to assess quality of life in economic analyses of hepatitis c treatments yeh ws, skrepnek gh, armstrong ep, malone dc university of arizona college of pharmacy, tucson, az, usa objectives: this study investigated the effect of using differ- ent utilities for a cost-utility analysis comparing peginterferon alpha- b plus ribavirin, interferon alpha- b plus ribavirin, and no treatment for chronic hepatitis c from a u.s. payer’s per- spective. methods: a markov model was developed to sim- ulate the lifetime disease progression of hepatitis c virus (hcv) for a -year-old male. the analysis was conducted by stratify- ing hcv genotypes. health-state utilities were obtained from previously published literature. standard gamble patient-elicited utilities were used as the base case. five other expert-estimated <b e c f b ebbbe c b b fac d bfacb b f b c c a f c f c edc fd e > 한국인의 행복감 결정요인* ) 신승배(shin, seungbae) 서강대학교 철학연구소 연구교수 sbsin @hanmail.net 국문요약 이 연구는 한국종합사회조사(kgss) 년 자료를 이용하여, easterlin과 sawangfa( ) 가 연구한 행복감과 삶의 영역별 만족도에 영향을 미치는 요인을 근거로 한국인의 행복감 에 영향을 미치는 결정요인을 검증하고자 하였다. 분석결과 한국인의 행복감은 행복을 둘러 싼 삶의 각 영역(일, 가정생활, 가계경제)에 대한 인식에 의해 더 잘 설명되며, 행복감에 인과적 영향을 미치는 요인은 모형마다 차이가 있지만 공통적으로 주관적 계층의식이 유의 미한 영향을 미치는 것으로 나타났으며, 영역별 만족도 가운데 가정생활만족도가 특히 더 많은 영향을 미치는 것으로 나타났다. 이것은 개인이 한국사회에서 어느 정도의 위치에 있 는가 하는 심리적 요인이 행복에 중요한 인과적 영향을 미치고 있으며, 우리가 살면서 행복 감을 느끼게 되는 가장 중요한 요인은 바로 가정의 행복이라는 것임을 의미한다. 핵심용어: 한국종합사회조사, 행복감, 영역별 만족도, 일, 가정생활, 가계경제 * 이 논문은 년 정부(교육부)의 재원으로 한국연구재단의 지원을 받아 수행된 연구임(nrf- s a b ). 본 논문의 초고는 년 월 일 서강대 철학연구소에서 열린 국내공동학술대회에서 발표되었다. 세심한 논평과 유익 한 제언을 해주신 심사위원 세 분께 감사드린다. 사 회 과 학 연 구 사회과학연구 ; ( ) journal of social science vol. , no. , ; - http://dx.doi.org/ . /khjss. . . . ㆍ사회과학연구 제 권 제 호 Ⅰ. 서론 최근 우리사회에서 행복에 대한 관심이 그 어느 때 보다 높아지고 있다. 행복은 모든 인간이 추구하고 있는 궁극적인 목표이다. 미국의 독립선언문을 기초했던 토머스 제퍼슨(thomas jefferson) 은 ‘생명, 자유, 행복추구권’을 남에게 양도할 수 없는 배타적 권리로 새겨 넣었다. 우리의 헌법 제 조에도 “모든 국민은 인간으로서의 존엄과 가치를 가지며, 행복을 추구할 권리를 가진다”라 고 천명하고, 자유권, 평등권과 더불어 행복추구권을 국민의 가장 중요한 기본권의 하나로 명시 하고 있다. 행복추구권에서 전제되는 행복은 객관화되기 어렵고 단지 추구만 할 수 있는 권리로 이해한다면, 행복을 실현하기 위해 노력해도 결코 가질 수 없는 것이 행복일 수도 있다. 고대부 터 현대에 이르기까지 ‘행복’은 많은 학자의 끊임없는 관심의 대상이 되어왔지만, 행복이 무엇인 지에 대한 개념적 정의부터 어떤 상태를 행복한 것으로 볼 것인지, 어떤 방법으로 그것을 객관 화할 수 있는지에 대해서는 여전히 많은 논란의 여지가 남아있다. 최근 유엔이 발표한 ‘ 세계행복보고서’에 따르면 전 세계 개 국가를 상대로 국민의 행복도를 조사한 결과, 한국은 점 만점에 총 . 점으로 위를 기록해 그런대로 괜찮은 성 적을 거둔 것으로 보인다. 이 조사는 gdp, 기대수명, 갤럽이 실시한 사회보장에 대한 인식과 선 택의 자유, 부패 등에 대한 세계여론조사 자료 등을 토대로 국가별 행복지수를 산출한 것이다. 행복을 측정하는 초기의 지표들은 모두 객관적으로 나타날 수 있는 경제적인 것이었다. 특히 사 회발전을 측정하는 중요한 지표로 활용된 gdp는 국민의 물질적 수준을 보여준다는 점에서 한 국가의 행복수준을 나타내는 객관적 지표로 지금까지 활용되고 있다. 하지만 최근 경제성장 위 주의 정책에 대한 회의적인 시각이 대두되면서 기존의 대표적 경제지표인 gdp가 국민의 행복 도를 적절하게 반 하지 못한다는 비판적 목소리도 설득력을 얻고 있다. easterlin( ; )은 후진국과 선진국, 사회주의와 자본주의 등 개 나라의 행복감을 측정 했다. 그 결과 경제 발전 단계와 사회체제와는 상관없이 소득이 높은 사람들이 높은 행복감을 나타냈지만, 일정 시점이 지나면 소득 수준이 더 높아져도 행복감은 더 이상 증가하지 않는다는 것을 발견해 경제규모나 소득수준이 반드시 국민 행복감과 일치하지 않는다는 ‘이스털린 역설 (easterlin paradox)’을 주장하고 gdp 한계를 지적한 바 있다. stiglitz 외( ) 역시 gdp와 같은 경제적 수치보다 삶의 질과 지속가능성에 대한 평가를 강조하고 gdp지표의 대안이 될 만한 적 절한 웰빙 지표를 개발해서 삶의 질을 실질적으로 개선할 것을 주장하고 있다(우성대, ). 차 용진( )은 이러한 gdp에 대한 비판에 대해 국내총생산이 한 국가의 경제력은 측정할 수 있 지만 국민의 행복감이나 사회발전 수준 등 보다 근본적인 부분에 대해서는 제대로 파악할 수 rachel fletcher division st. great barrington, ma usa rfletch@bcn.net keywords: thomas jefferson, descriptive geometry, geometric construction, octagon, root-two geometer’s angle thomas jefferson’s poplar forest abstract. a unique geometric construction known to thomas jefferson reveals a rich interplay of root-two geometric elements when applied to jefferson’s octagonal plan of poplar forest, his eighteenth-century villa retreat. thomas jefferson and classicism in colonial america, when buildings were typically “designed” by craftsmen and tradesmen, rather than architects, thomas jefferson was largely responsible for introducing the classical aesthetic to architecture. his designs reflect the neo-classical movement that emerged as humanism in renaissance europe, then flourished in the enlightenment from the s to the end of the eighteenth century. jefferson scholar fiske kimball considers that “directly or indirectly american classicism traces its ancestry to jefferson, who may truly be called the father of our national architecture” [kimball , ]. an “amateur” architect with no formal training, jefferson first became aware of classical architecture through books, then later gained first-hand experiences of ancient roman and eighteenth-century french buildings while serving as american minister to paris ( - ). he studied the written treatises of marcus pollio vitruvius, leon battista alberti, inigo jones, sebastiano serlio and others who relied on classical rules of architecture and mathematical techniques for achieving proportion [o’neal , ]. on architectural matters, jefferson is reported to have said that andrea palladio “was the bible,” even though he knew his buildings only through books. jefferson practiced the roman classical architecture of palladio and late eighteenth century france, and borrowed extensively from classical sources. he based the rotunda of the university of virginia in charlottesville on measured drawings of the pantheon published in giacomo leoni’s the architecture of a. palladio. models for the virginia state capitol in richmond, which he designed with the assistance of french architect and antiquarian charles-louis clerisseau, included the temple of balbec, the erechtheum in athens, and the ancient roman temple maison carrée at nîmes in france. this was the first government building designed for a modern republic, the first american work in the classical revival style, and the first modern public building in the world to adapt the classical temple form for its exterior [nichols , - ; kimball , ]. geometric proportion that jefferson followed classical rules for applying simple proportions involving whole numbers to the orders and other components of building design is well documented. but he also was familiar with techniques for achieving harmony through incommensurable ratios associated with elementary geometric figures. his designs often feature fundamental geometric shapes and volumes. the university rotunda, whose dome he describes as a “sphere within a cylinder,” presents an array of circles, squares and triangles. for the virginia capitol, he selected as sources “the most perfect examples of cubic architecture, as the pantheon of rome is of the spherical… .” the plans for his monticello residence present regular octagons, semi-octagons and elongated octagons. nexus network journal ( ) – nexus network journal – vol. , no. , doi . /s - - - ; published online june © kim williams books, turin rachel fletcher – thomas jefferson’s poplar forest there is some evidence that jefferson applied incommensurable proportions through geometric techniques. for the washington capitol he specified that neighboring properties “be sold out in breadths of fifty feet; their depths to extend to the diagonal of the square.” in other words, the lots conform to the incommensurable ratio : (“opinion on capitol,” november [ford - , vi: ]). his plan for the university rotunda expresses root-two, root-three, and perhaps even golden mean symmetries [fletcher ]. fig. . thomas jefferson, poplar forest, first floor plan. image (ca. ), inked, shaded and tinted by john neilson (atrributed). scale: about = . on heavy paper, not watermarked, with co-coordinate lines drawn by hand, x . . (n- , k-pl. ). courtesy of the jefferson papers of the university of virginia, special collections, university of virginia library, charlottesville, virginia poplar forest a clear example of incommensurable proportion is jefferson’s octagonal villa retreat at poplar forest, located on the eastern slope of the blue ridge mountains in bedford county, virginia, ninety miles southwest of monticello, his principle residence. building construction began in , while jefferson resided as president in washington, supervising the project remotely through written instructions, working drawings and sketches. the villa was made habitable by the time of his retirement in , but would nexus network journal – vol. , no. , require another sixteen years to complete [mcdonald , - ]. jefferson first proposed the octagonal house for his pantops farm, north of monticello, as a future residence for his grandson francis eppes. but instead he realized the plan at poplar forest, one of his working plantations where eppes eventually settled. poplar forest is of brick construction and octagonal in plan, containing a central square space, flanked on three sides by elongated octagonal rooms. on the fourth side, a short entry hall divides a pair of smaller rooms. the central dining room is skylit and measures x x , a perfect cube. on the east and west, alcove beds divide the two main bedrooms into sections [chambers , - ]. during construction, jefferson added pedimented porticoes on low arcades attached on the northern and southern facades, and stairwells east and west. fig. , attributed to jefferson’s workman john neilson, shows the first floor plan complete with additions to the original design. following a fire in , the interior was rebuilt leaving only the walls, chimneys and columns original. since , under the leadership of director of architectural restoration travis mcdonald, poplar forest has been the subject of extensive research and restoration. the goal is to enable the public to experience jefferson’s retreat according to our best understanding of his original design. jefferson’s regard for octagonal plans by robert morris, inigo jones, palladio and others has been reviewed extensively. c. allan brown observes octagonal symmetry in the landscape design at poplar forest. and in the building plan, e. kurt albaugh cites the “two-fifths” rule of proportion that closely approximates the octagon’s inherent root-two ratio [albaugh , - ; brown , - ; chambers , ; lancaster , - ]. in fact, a specific technique for constructing the octagon, drawn more than once by jefferson, offers compelling evidence of a consistent geometric approach to poplar forest’s design. fig. . jefferson’s sketches of octagons. a, left) dividing two sides of a square in root-two ratios; b, right) two completed octagons and the algebraic proof. images: objects; assorted sketches and calculations, page, undated, mhi . original manuscript from the coolidge collection of thomas jefferson manuscripts. massachusetts historical society [jefferson : mhi ] rachel fletcher – thomas jefferson’s poplar forest a page of jefferson’s notes and scribbles, possibly executed during a visit to poplar forest, includes a technique for drawing three sides of a regular octagon together with two sides of a larger octagon. both are accomplished by dividing two sides of a square, or the sides of a o right triangle, in root-two ratio (fig. a). a drawing of two completed octagons (fig. b) and an algebraic proof accompany the construction. how to draw three sides of an octagon on a given base draw a horizontal line ab. place the compass point at a. draw a semi-circle of radius ab that intersects the extension of line ba at point d. from point a, draw a line perpendicular to line bd that intersects the semi-circle at point c (fig. ). ab c d fig. connect points b, c and d. from point c, draw a circle of radius cb that intersects point d and the extension of line ca at point e (fig. ). ab d c e fig. connect points b, e and d. the result is two sides of a regular octagon inscribed within the circle of radius cb. complete the octagon (fig. ). nexus network journal – vol. , no. , ab d c e fig. from point e, draw a circle of radius eb that intersects line bc at point f and line cd at point g. connects points b, f, g and d. the result is three sides of a regular octagon inscribed within the circle of radius eb. complete the octagon. if radius cb of the large circle is , side be of its inscribed octagon equals ( - ) ( . …). radius eb of the small circle therefore equals ( - ) and side bf of its inscribed octagon equals ( - ) ( . …) (fig. ). ab d c e f g fig. rachel fletcher – thomas jefferson’s poplar forest we see from fig. a that jefferson knew how to proceed further with this geometric construction. from point f, draw an arc of radius fc that intersects and is tangent to line ba at point h. connect points f and h. extend line fh until it intersects line be at point i alternatively from point f, draw an arc of radius fg to point i. connect points g, f and i. the result is two sides of a square. complete the square (fig. ). ab d c e f g h i fig. root-two symmetry in fig. , the construction is scaled to jefferson’s plan for poplar forest. the small circle of radius eb circumscribes the octagonal footprint. each side of its inscribed octagon, such as bf, locates an exterior wall. center point c of the large circle locates the midpoint of the portico front. repeat the semi-circle of radius ce at each quadrant, as shown. the semi-circles intersect at points j, k, l and m. complete the regular octagon. the octagon divides into a center square, four root-two rectangles and four o right triangles. the square locates the center room of the poplar forest plan (fig. ). nexus network journal – vol. , no. , fig. . thomas jefferson. poplar forest, first floor plan, with geometric overlay by the author rachel fletcher – thomas jefferson’s poplar forest fig. . thomas jefferson. poplar forest, first floor plan, with geometric overlay by the author nexus network journal – vol. , no. , to construct the elongated octagonal rooms at each quadrant: divide each o right triangle in half, into smaller o right triangles. join a small o right triangle to each end of a root-two rectangle. the result is an elongated hexagon (fig. , right). locate the two sides of each small o right triangle. connect their midpoints, as shown (fig. , upper left). join the new shape to each end of a root-two rectangle. the result is an elongated octagon that locates the room at each quadrant. chimneys occupy the remaining spaces (fig. , left). fig. . thomas jefferson. poplar forest, first floor plan, with geometric overlay by the author connect points j, k, l and m. the result is a square that encloses the northern and southern porticoes. inscribe a circle within the square. inscribe a regular octagon within the circle. two edges of the octagon locate the stairwells east and west (fig. ). rachel fletcher – thomas jefferson’s poplar forest fig. . thomas jefferson. poplar forest, first floor plan, with geometric overlay by the author jefferson was proficient in a variety of mathematical disciplines that included arithmetic, algebra, geometry, trigonometry and newtonian calculus, as well as mechanical and natural applications such as navigation, surveying, astronomy and geography. geometry, which he explored in both planar and spherical configurations, held special interest. but rather than study mathematics for its own sake, jefferson endeavored to apply his knowledge in tangible ways, as at poplar forest, where a simple geometric construction yields a rich, harmonic composition. notes . colonel isaac a. coles to general john cocke, february [adams , ]. jefferson toured the agriculture of southern france and northern italy in , intending to visit palladio’s hometown of vicenza at a later date [nichols , , ]. . jefferson, “an account of the capitol in virginia,” no date, miscellaneous papers [lipscomb and bergh - , xvii: ]. . see [kimball ]. joseph lasala has analyzed the pavilions of jefferson’s university of virginia according to the palladian system of dividing a module, based on the lower diameter of a column, into minutes and seconds. from this are derived an order’s six major components: the base, shaft and capital of the column; and the architrave, frieze and cornice of the nexus network journal – vol. , no. , entablature. the order, once determined, fixes the size and distribution of other building components [lasala ]. . jefferson to william short, november [jefferson ]. . jefferson, “an account of the capitol in virginia,” no date, miscellaneous papers [lipscomb and bergh - , xvii: ]. . jefferson to john wayles eppes, june [jefferson ]. compare jefferson’s plan for the house at pantops, before , and the first floor plan of poplar forest drawn by john neilson [chambers , - , kimball , - , figs. , ]. . jefferson proposed the additions in a letter to bricklayer hugh chisolm following a visit to poplar forest in . jefferson to hugh chisolm, september , massachusetts historical society [chambers , - , kimball , - ]. . although presently attributed to neilson, kimball in credited the drawing to jefferson’s granddaughter cornelia j. randolph [kimball , ]. . see [chambers , ] on connecting the notes to a trip to poplar forest in . the construction appears elsewhere in jefferson’s notebooks during various phases of building and remodeling at monticello. one example is a theorem for drawing “three sides of an octagon” on a given base, dated (?), apparently in preparation for octagonal projections in the plan. see [jefferson : n ; k ]. a similar construction, dated - (?), accompanies studies for monticello’s remodeling. see [jefferson : n ; k ]. . jefferson’s preliminary sketches for pantops/poplar forest, before , produce octagonal rooms in this fashion. see [jefferson : n ; k ]. references adams, william howard, ed. . the eye of jefferson. washington: national gallery of art. albaugh, e. kurt. . thomas jefferson’s poplar forest: symmetry and proportionality in a palladian summer house. fine homebuilding (october/november ): - . brown, c. allan. . thomas jefferson’s poplar forest: the mathematics of an ideal villa. journal of garden history (april/june ): - . chambers, s. allen. . poplar forest and thomas jefferson. forest, va: the corporation for jefferson’s poplar forest. fletcher, rachel. . an american vision of harmony: geometric proportions in thomas jefferson’s rotunda at the university of virginia. nexus network journal , (autumn ): - . ford, paul leicester, ed. - . the works of thomas jefferson in twelve volumes. federal edition. new york: g. p. putnam’s sons. jefferson, thomas. . thomas jefferson papers: an electronic archive. boston: massachusetts historical society. http://www.thomasjeffersonpapers.org/ ———. . items from special collections at the university of virginia library. electronic text center. charlottesville: university of virginia library. http://etext.lib.virginia.edu/speccol.html kimball, fiske. . thomas jefferson: architect ( ). rpt. boston and new york: da capo press. lancaster, clay. . jefferson’s architectural indebtedness to robert morris. journal of the society of architectural historians , (march ): - . lasala, joseph michael. . comparative analysis: thomas jefferson’s rotunda and the pantheon in rome. virginia studio record , (fall ): - . ———. . thomas jefferson’s designs for the university of virginia. master thesis, university of virginia. lipscomb, andrew a. and albert ellery bergh, eds. - . the writings of thomas jefferson. washington, d. c.: the thomas jefferson memorial association. (electronic version: h-bar enterprises, .) mcdonald, travis. c., jr. . constructing optimism: thomas jefferson’s poplar forest. pp. - in people, power, places (perspectives in vernacular architecture ), sally mcmurry and annmarie adams, eds. knoxville: university of tennessee press. rachel fletcher – thomas jefferson’s poplar forest nichols, frederick doveton. . thomas jefferson’s architectural drawings. boston: massachusetts historical society, and charlottesville: thomas jefferson memorial foundation and the university press of virginia. ———. . jefferson: the making of an architect. pp. - in jefferson and the arts: an extended view, william howard adams, ed. washington d.c.: national gallery of art. o’neal, william bainter, ed. . jefferson’s fine arts library: his selections for the university of virginia together with his own architectural books. charlottesville: the university press of virginia. aabout the geometer rachel fletcher is a geometer and teacher of geometry and proportion to design practitioners. with degrees from hofstra university, suny albany and humboldt state university, she was the creator/curator of the museum exhibits “infinite measure,” “design by nature” and “harmony by design: the golden mean” and author of the exhibit catalogs. she is an adjunct professor at the new york school of interior design. she is founding director of the housatonic river walk in great barrington, massachusetts, co-director of the upper housatonic valley african american heritage trail, and a director of friends of the w. e. b. du bois boyhood homesite. she has been a contributing editor to the nexus network journal since . 	thomas jefferson's poplar forest 	abstract 	thomas jefferson and classicism 	geometric proportion 	poplar forest 	how to draw three sides of an octagon on a given base 	root-two symmetry 	notes 	references << /ascii encodepages false /allowtransparency false /autopositionepsfiles true /autorotatepages /none /binding /left 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/untaggedrgbhandling /usedocumentprofile /usedocumentbleed false >> ] >> setdistillerparams << /hwresolution [ ] /pagesize [ . . ] >> setpagedevice from individualized treatment of sickle cell pain to precision medicine: a -year journey articles © the authors | journal compilation © j clin med res and elmer press inc™ | www.jocmr.org this is an open-access article distributed under the terms of the creative commons attribution-noncommercial . international license, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited review j clin med res. ; ( ): - resselmer from individualized treatment of sickle cell pain to precision medicine: a -year journey samir k. ballas abstract in the s, sickle cell pain was treated with trial and error approach by increasing or decreasing the dose of an opioid or switching from one analgesic to another. this approach was controversial with criti- cism and doubt about its usefulness. since then, advances in deter- mining the structure of opioid receptors and the role of the cyp enzymes in metabolizing opioids revealed that these anatomic and metabolic findings are not the same in all persons, thus explaining the variability in response to opioids among patients. thus, the “trial and error approach” has a scientific basis after all. keywords: sickle cell disease; pain; individualized treatment; per- sonalized medicine; precision medicine introduction an infliction in the life expectancy figure of patients with sick- le cell disease (scd) occurred around the middle of the s (fig. ). this minimal increase in life expectancy coincided with my appointment at thomas jefferson university as the associate director of the newly created adult sickle cell center. the number of adults at that time was small and the transition from pediatrics to adult programs was at the age of years. the trickle of patients increased gradually and we were faced with adolescent and young adult african american patients who were in a state of confusion. stripped from the protective sphere of the pediatric world and the empathy of their pediatric hematologists and the pediatric ancillary staff, they were in a state of fear, anxiety, depression and, worst of all, severe pain. the world of adults was abject, withdrawn, busy, and status oriented. the fact that most patients were barely educated, many without a high school degree, unemployed, mediocre health coverage, and dysfunctional family structure conferred a logarithmic dimension to the problem. their main hope was to have pain relief. the steady stream of admissions of patients with acute painful vaso-occlusive crises (vocs) to the emergency depart- ment (ed) and hospital were not welcome by most providers, hospital administration, the house and nursing staffs. there was subtle resentment of the patients that sometimes extended to the hematologists who showed compassion to the patients. soon labels such as drug addicts, drug-seeking behavior, and hospital hopping and frequent flyer emerged. listening to and believing the patients and keeping de- tailed records of ed and hospital admissions and the analge- sics prescribed, revealed that most patients genuinely do not respond to a certain analgesic or a certain dose. increasing the doses of an analgesic or switching to another drug solved the problem in most patients. soon it became obvious that man- agement of sickle cell pain should be individualized. accordingly and with the approval of the institutional re- view board (irb), i issued an identification wallet-sized, plas- ticized card that was carried by patients and presented to the provider treating their voc in the ed, hospital or any other medical facility. information printed on both sides of the card included: ) demographic data and a recent photograph; ) he- matological data including reticulocyte count; ) medical data including the type of scd, its complications and co-morbid- ities if present; ) all medications being taken by the patient and the recommended treatment of vocs including the name, dose, and the route of administration of the analgesics in ques- tion; and ) my name and contact information for answering questions if needed. it was not expensive to issue these cards. a polaroid camera available at that time and a laminator were the only equipments needed to issue these cards. information on the card was revised and updated annually. details of this endeavor were published in [ ]. with the advent of com- puterization later on, information on the card was computer- ized and a printed copy was given to the patient. reactions to the implementation of this card were mixed. patients and their families loved it. the patients were very compliant in carrying it as faithfully as they carry their medical cards. some providers liked it very much because it facilitated having a concise history about the patients. others denounced it as a gimmick that would allow patients to abuse the system. pharmacology of opioids while this controversy was brewing, interesting developments manuscript accepted for publication march , cardeza foundation for hematologic research, department of medicine, jefferson medical college, thomas jefferson university, philadelphia, pa , usa. email: samir.ballas@jefferson.edu doi: http://dx.doi.org/ . /jocmr w articles © the authors | journal compilation © j clin med res and elmer press inc™ | www.jocmr.org management evolution of sickle cell pain j clin med res. ; ( ): - in basic science were in progress to understand the pharmaco- dynamics and pharmacokinetics of opioids. foremost among these was the mechanism of action of opioids in relieving pain. in the s, it was hypothesized that opioids have receptors to bind to and activate in order to relieve pain [ ] by blocking or minimizing the transmission of painful stimuli and raising the pain threshold. it did not take long after that to identify opioids as ligands that bind to stereospecific and saturable re- ceptors in the central nervous system and other tissues [ , ]. these receptors are transmembranous g proteins with opioids as ligands [ ]. in addition, recent elegant studies [ - ] have revealed a helical structure of the opioid receptors, which forms pockets in which the corresponding opioid (ligand) fits snugly (fig. a, b). receptors mediate two major functions, chemical recog- nition and physiologic action. recognition is highly specific, such that only l-isomers of certain opioids exert analgesic activity [ ]. the binding affinity varies considerably among opioids [ ]. fentanyl, for example, has higher binding affinity than morphine [ ]. the binding affinities of opioids appear to correlate with their analgesic potencies [ ]. physiologically, by binding to receptors, opioids initiate a series of biochemi- cal events including activation of g proteins, inhibition of adenylate cyclase, and extrusion of potassium ions, resulting in hyperpolarization of cell membranes [ - ]; this delays or prevents transmission of painful stimuli. thus, the riddle why some patients respond to one opioid but not another had a pathophysiologic explanation [ ]. parallel to the progress in the pharmacodynamics of opi- oids mentioned above, a concomitant advance in the phar- macokinetics of opioids was bubbling to the surface. the metabolism of opioids includes two major phases [ , ]. figure . helical structure of opioid receptors. (a) morphine-like molecule (yellow) in the deep pocket (blue) of the μ-opioid recep- tor. (b) μ-opioid receptors from an intimate pair when crystallized with a ligand (yellow) such as morphine. knowing how an opioid molecule (yellow) sticks in the pocket of its receptor (blue) could help scientists design better analgesics that are more effective and less addictive. credit: kobilka lab, nature. ; : - . used with permission. figure . life expectancy of patients with sickle cell disease from through . the arrow indicates the infliction point where life expectancy of patients with sickle cell disease began to increase. adapted from national heart, lung, and blood in- stitute. sickle cell research for treatment and cure (nih publication no. - ). bethesda, md: us department of health and human services. articles © the authors | journal compilation © j clin med res and elmer press inc™ | www.jocmr.org ballas j clin med res. ; ( ): - phase i involves the cyp enzymes and phase ii metabolism conjugates the drug to hydrophilic substances, such as glucu- ronic acid, sulfate, glycine, or glutathione. glucuronidation is the most important phase ii reaction. it is catalyzed by the enzyme uridine diphosphate glucuronyltransferase (ugt). morphine, hydromorphone and oxymorphone are metabo- lized by glucuronidation, whereas the majority of the other opioids are metabolized by the cytochrome p isoenzyme system. the net effect of an opioid depends on the availability of enzyme(s) to convert it into metabolites that could be active or inactive. briefly, the cyp d genotypes are categorized into phenotypes based on the activity of the variant enzymes. ultrarapid metabolizers (ums) have greater than normal activ- ity due to duplication or triplication, of active alleles [ - ], extensive metabolizers (ems) have normal enzyme activity, intermediate metabolizers (ims) have decreased enzyme activ- ity, and poor metabolizers (pms) have absent or little enzyme activity. thus, fentanyl, for example, is normally metabolized into inactive metabolites. patients who are ums of fentanyl would rapidly convert it into inactive metabolites with mini- mal or absent analgesic effect requiring increasing the dose of fentanyl. on the other hand, patients who are pms of fentanyl would experience prompt relief with relatively small doses of fentanyl but higher doses could be toxic due to the accu- mulation of unmetabolized fentanyl [ ]. phase i metabolism of opioids involves primarily the cyp a and cyp d en- zymes. the cyp a enzyme metabolizes more than % of all drugs; consequently, opioids metabolized by this enzyme have a high risk of drug-drug interactions [ ]. conclusion together, current data on the pharmacodynamics and phar- macokinetics of opioids show great variability of genotypes among patients and extreme variability in individual responses to opioids. determining the pharmacogenetics profile of each patient facilitates the choice of drugs that would be efficacious for that patient and avoid those drugs associated with harmful drug-drug interaction. this approach in diagnostics and thera- peutics ushers in the dawn of a new field for the management of individual patients based on their unique pharmacogenet- ics, phenotypic and biomarker characteristics. this future ap- proach is referred to as personalized medicine or, more recent- ly, precision medicine [ ]. it has already been implemented for certain cancer patients receiving chemotherapy. we hope that this methodology would be approved and sponsored by the insurance companies for patients with scd. in the mean- time, listening, believing and respecting the patient with sickle cell pain should be maintained for now as the approach to in- dividualized therapy. acknowledgement supported in part by the adult sickle cell program of the com- monwealth of pennsylvania for the philadelphia region. conflict of interest the author declares no competing financial interests. references . ballas sk. treatment of pain in adults with sickle cell disease. am j hematol. ; 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survey brandon rottinghaus, university of houston justin s. vaughn, boise state university abstract  debates about presidential greatness have been with us for decades, facilitated in part by numerous systematic surveys of scholars with expertise in american history and politics. nevertheless, the voice of political scientists in this debate has been relatively muted when compared particularly with the role that historians have had in making these determinations. this article introduces and assesses results of a recent effort to capture the attitudes of political science presidency experts about presidential greatness. by surveying the membership of the apsa presidents and executive politics section, we could identify and then compare specifically the attitudes of political scientists against the growing body of ratings and rankings of a phenomenon with long-standing interest and importance. the debate about who our greatest presidents have been is an age-old parlor game that has been played since americans elected a president not named washington. over time, as the number of presi-dents eligible for entry into the greatness debate grew, various sub-debates also became possible. not only could disputants present arguments in favor of or against one pres- ident or another as the greatest in all history, they also could squabble about which was the greatest commander-in-chief; which had the highest integrity and greatest moral courage; and, of course, which most exhibited a serious lack of greatness. related to these new arguments, the very definition of presiden- tial greatness has been contestable and contested as american history—and american political values— evolves. the subject of presidential greatness, particularly from a modern political science perspective, is the focus of this article. the contested concept of presidential greatness and the various scholarly efforts to capture and analyze the phenomenon are discussed briefly. we then introduce results of a new study of presidential greatness based on a large sample of political scientists who are engaged in the ongoing study of the american presidency. results of this study underscore some of the findings we have come to expect based on decades of analysis primarily from historians. the study also yielded intriguing results poten- tially related to the distinct disciplinary perspectives of political scientists about the presidency that separates them from scholars in other fields. what is presidential greatness? arguably, there are as many—if not significantly more—perspectives on what it means to be a great president as there have been pres- idents. indeed, a cnn story that attempted to ultimately understand the concept instead further indicated the variety of opinions, even as it queried well-known historians with largely similar methodological approaches to the study of the office and the individuals who have held it (cnn ). for example, richard reeves stated, “presidential greatness is determined by being in the white house at the right time—or the wrong time. the presidency is a reactive job and we judge the presidents by their handling of one or two big crises, usually unforeseen.” similarly, joseph ellis noted that the nation’s three greatest presidents— george washington, abraham lincoln, and franklin roosevelt— came to office in times of great crisis. h. w. brands, however, took a broader approach than reeves and ellis’s focus on crisis man- agement, arguing that “great presidents are those who change the course of american history.” he pointed out andrew jackson’s brandon rottinghaus is a professor of political science at the university of houston. he can be reached at bjrottinghaus@uh.edu. justin s. vaughn is an associate professor of political science and co-director of the center for idaho history and politics at boise state university. he can be reached at justinvaughn@boisestate.edu. mailto:bjrottinghaus@uh.edu mailto:justinvaughn@boisestate.edu ps • july ......................................................................................................................................................................................................................................................................................................................... involvement of ordinary people in the political process, abraham lincoln’s reversal of secession and slave emancipation, franklin roosevelt’s founding of the welfare state and defeat of fascism, and ronald reagan’s dismantling of much of the regulatory state he confronted on election to the position in . joan hoff took a different approach to determining what the greatest presidents had in common, observing that nearly all of them regularly at the top of scholarly surveys led the nation in time of war (except thomas jefferson and theodore roosevelt); however, she notes that merely conducting a war alone is not sufficient. aida donald invoked various other criteria, ranging from accomplishments to sound decision making to personal character. that leading figures from the same discipline at the same moment in time could take such distinct approaches to presi- dential greatness reinforces the notion that whereas presidential greatness is frequently discussed, it has not been defined entirely. therefore, the fact that psychologists take an equally distinctive perspective should not be a surprise. in a paper presented to the american psychological association, rubenzer, faschingbauer, and ones ( ) focused on what the greatest presidents had in common. rather than identifying factors such as the presence of crisis or successful management of major wars, they focused on the presidents’ cognitive processes and behavioral attributes. they concluded that factors such as presidents being achievement- oriented and inclined to assert their interests are determinative. dean simonton, a psychologist who pioneered much of his dis- cipline’s presidency-focused research, instead identified factors more likely to resonate with political scientists: number of years in office, number of years as a wartime commander-in-chief, an administration scandal, an assassination, and entering office with a reputation as a war hero (simonton ). other recent political science research has shown that economic performance (curry and morris ), policy productivity (rottinghaus and vaughn ), and public demand for progressive leadership (nichols ) also explain assessments of presidential greatness, whereas the one commonly believed explanation—prior experience— does not (balz ). conversely, karl rove, who was george w. bush’s strategist and adviser, sounded more like a psychologist than a political operative when he opined on the subject during a speech at the university of utah. according to rove, presidential greatness is a function of a few essential factors: clarity of vision, clar- ity of direction, the presence of a crisis, emotional intelligence (a phrase that he acknowledged was borrowed from the work of fred greenstein), a respect for public opinion, the presence of a strong team of advisors, and a “readiness to act and a com- fort in deciding” (rove ). although many of these factors may sound as if they are from a george w. bush stump speech— one he would have participated in authoring—rove did a mas- terful job of linking explanations ranging from individual char- acteristics to institutional con- text (see also kenney and rice ) in a rather broadminded and transdisciplinary approach to the concept of presidential greatness. studying presidential greatness virtually all of the previously mentioned social science research designed to explain presidential greatness used the growing body of surveys conducted among both experts and the mass public. famed historian arthur m. schlesinger other recent political science research has shown that economic performance (curry and morris ), policy productivity (rottinghaus and vaughn ), and public demand for progressive leadership (nichols ) also explain assessments of presidential greatness, whereas the one commonly believed explanation—prior experience—does not (balz ). f i g u r e presidential greatness survey rank and knowledge   ps • july ......................................................................................................................................................................................................................................................................................................................... t h e p r o f e s s i o n : p r e s i d e n t i a l g r e a t n e s s a n d p o l i t i c a l s c i e n c e pioneered the practice of surveying intellectual elites about their attitudes toward our greatest presidential leadership. n , life magazine published the results of his study of historians, which asked them to assign each president to one of five categories: great, near great, average, below average, and failure. abraham lincoln was the unanimous victor and, indeed, the only president to receive a “great” vote from every respondent (bose , ). fourteen years late, schlesinger conducted another survey, this time featuring historians, which was published in the new york times magazine. the results across these two studies were largely consistent, with the majority of presidential rank- ings remaining within a couple places of their counterparts. however, noteworthy exceptions included james monroe (- ranks, from to ), andrew johnson (- , from to ), chester arthur (- , from to ), and calvin coolidge (- , from to ). a few decades later, the new york times magazine recruited arthur m. schlesinger jr. to conduct another expert poll in . he also published an extended report in political science quarterly (schlesinger ). his method slightly departed from his father’s, however, because he decreased the number of respondents to and expanded the pool to include politicians governor mario cuomo and us senator paul simon. this makes a comparison imperfect but it provides insight into shifting perspectives on presidential greatness and how impressions of presidents have changed. the results of schlesinger jr.’s survey were consistent with the two conducted by his father; however, they provided evidence that several presidents experienced significant changes in reputation in the half-century since the first schlesinger poll was released. for example, presidents whose rankings dropped by more than five places between the surveys included john tyler (from to ), james buchanan (from to ), andrew johnson (from to ), ulysses s. grant (from to ), rutherford hayes (from to ), chester arthur (from to ), william howard taft (from to ), warren harding (from to ), and herbert hoover (from to ). dwight eisenhower’s rank increased, however, from in —when he had been out of office for less than two years—to in . by , the presidential rankings “cottage industry” had expanded to well beyond only the schlesinger family. between schlesinger sr.’s second study and schlesinger jr.’s first, there were several similar efforts, including a chicago tribune poll in and three polls produced by the siena research institute (sri) at siena college in , , and . since then, sri has conducted similar polls in and . in the years since the last schlesinger poll, there also have been two wall street journal-sponsored studies ( and ), two c-span studies ( and ), and various one-time studies conducted by news- week ( ), history news network ( ), the times of london ( ), and the united states presidency centre ( ) in london. some of these studies used more unorthodox methods or focused only on a segment of presidents, but all attempted to use the experts’ wisdom to put presidents in order of greatness. the net result has been not only a wide range of presidential- greatness surveys but also a change in the conversation about presidential leadership itself. indeed, mercieca and vaughn ( , ) suggested that the rising preponderance of these polls over time has affected the way that experts and ordinary citizens view presidential greatness as well as our greatest presidents (i.e., great presidents are heroes, not necessarily competent administrators). even with these decades of influential studies, however, assessments skew to the historical. to balance the exist- ing body of greatness studies, we developed and implemented a survey designed to capture politi- cal scientists’ attitudes toward our greatest presidents. presidential greatness, according to political scientists to develop the survey, we invited the entire membership of the apsa presidents and executive politics (pep) section (n = ) to participate in a qualtrics-based survey in early june . the survey was closed and data were collected on november , . during the survey time frame, we received complete responses, achieving a . % response rate. the resulting respondent pool varies meaningfully across several important indicators. for exam- ple, concerning ideology, . % of respondents identified as liberal, . % as somewhat liberal, . % as moderate, % as somewhat conservative, and . % as con- servative. similarly, . % con- sidered themselves a member of the democratic party, compared f i g u r e presidential skill ratings ps • july ......................................................................................................................................................................................................................................................................................................................... with . % for the republican party and . % for independents. of the respondents, % were affiliated with public institutions compared to % with private institutions; . % were affiliated with research institutions compared to % from teaching insti- tutions; and . % were affiliated with institutions that combined research and teaching emphases. the majority of respondents were full-time faculty members, with % of the pool consisting of full professors, . % associate professors, and . % assistant pro- fessors; . % were emeritus faculty; . % were adjunct or instruc- tional faculty; and . % were graduate students. respondents’ pedigrees included . % who received their highest degree from an ivy league institution compared to . % from a state flagship institution, . % from an elite private institution, and . % from a non-flagship public institution. finally, . % of respondents were male and . % were female. in addition to these demographic details, respondents were queried about their knowledge of and opinions about american presidents in various ways. they were asked on a scale of to how much information they knew about each president ( = nothing; = a lot). the resulting scores were averaged; over- all, respondents indicated the greatest familiarity with barack obama, george w. bush, and bill clinton, followed by ronald reagan, abraham lincoln, lyndon johnson, and richard nixon. they were least familiar with millard fillmore, franklin pierce, benjamin harrison, zachary taylor, and chester arthur. in general, the earlier a president had served, the less information political scientists knew about him. notable exceptions included popular and historically consequential presidents. each respondent also was given the opportunity to rate indi- vidual presidents on a -to- scale concerning their overall greatness. importantly, the survey did not stipulate a particular definition of greatness other than a brief indication that = failure, = average, and = great. the resulting scores were averaged across all respondents. abraham lincoln had the highest overall greatness ranking, followed by george washington and franklin delano roosevelt. the next tier of greatness included presidents theodore roosevelt, thomas jefferson, harry truman, and dwight eisenhower. the least great president was james buchanan, fol- lowed by warren harding, andrew johnson, franklin pierce, and william henry harrison. of the modern presidents, bill clinton earned the highest overall greatness rating and george w. bush earned the lowest. between these two were ronald reagan (no. with . %), lyndon baines johnson (no. with . %), john f. kennedy (no. with . %), george h. w. bush (no. with . %), barack obama (no. with . %), gerald ford (no. with . %), jimmy carter (no. with . %), and richard nixon (no. with . %). figure provides additional information about overall greatness ratings and rankings for each president, including both the rank in the pep membership study and an average rank across the six other major scholarly survey stud- ies conducted between and the pep study. this range of years was included because it balances several studies to aver- age across with a consistent grouping of presidents in each survey. all presidents through george w. bush were rated in each study, and barack obama is rated in one study. the six studies include the wall street journal’s and studies; siena college’s and studies; c-span’s study; and the united states presidency centre study, which surveyed united kingdom–based experts in american political history. by calculating the average rank of each president across the past six scholarly surveys, we could compare the political sci- ence perspective, as captured in the pep study, with an aggregated representation of largely (although not exclusively) historian-based studies. for most presidents, the pep ranking is consistent with the previous average ranking. indeed, for of the individual presidents (i.e., grover cleveland is counted only once), the pep ranking was within three slots (plus or minus) of the previous average ranking; for presidents, it was within . slots (plus or minus). the pres- idents for which there was a pep ranking of a three or more slots difference (plus or minus), however, yielded some interesting observations. bill clinton is easily the main outlier, with the pep study ranking him . slots higher than f i g u r e who should be the next president on mount rushmore? of the modern presidents, bill clinton earned the highest overall greatness rating and george w. bush earned the lowest. between these two were ronald reagan (no. with . %), lyndon baines johnson (no. with . %), john f. kennedy (no. with . %), george h. w. bush (no. with . %), barack obama (no. with . %), gerald ford (no. with . %), jimmy carter (no. with . %), and richard nixon (no. with . %).   ps • july ......................................................................................................................................................................................................................................................................................................................... t h e p r o f e s s i o n : p r e s i d e n t i a l g r e a t n e s s a n d p o l i t i c a l s c i e n c e his previous average. his predecessor, george h. w. bush (+ ), was the only other president in this group to rank higher in the pep study than the previous average ranking. every other noteworthy disjuncture represents an instance in which f i g u r e “best” and “worst” president total votes f i g u r e most “underrated” and “overrated” president the pep study ranked pres- idents several points lower than their previous average ranking, including james polk (- . ), herbert hoover (- . ), richard nixon (- . ), george w. bush (- . ), grover cleveland (- . ), william mckinley (- . ), james monroe (- . ), chester arthur (- . ), and warren harding (- . ). moreover, of these nine presi- dents, only richard nixon and george w. bush can be considered modern presidents, and both were among the most controversial and derided of all presidents in american history. the remaining presidents who compared nega- tively are premodern presidents, with more than half from the nineteenth century. from these observations, we tentatively con- cluded that political science experts on the american presidency— focused as they largely are on the modern presidency—were more likely to penalize premodern pres- idents for their lack of centrality to the contemporary institution in the form of lower greatness rat- ings. conversely, four of the most recent eight presidents have the biggest discrepancies between the pep study and their previ- ous average, suggesting their his- torical reputations are still in flux. this is underscored by the fact that two of the four presidents (i.e., bill clinton and george w. bush) were still in office when one or more of the studies included in the comparison average were conducted. because most political science research regarding presidential politics focuses on the modern era, several questions were asked to gauge respondents’ opinions about specific dimensions of presidential leadership concerning presidents only from theodore roosevelt to barack obama. scholars debate the onset of the modern presi- dency, but roosevelt’s expansion of the influence and power of the office and roots of institutionaliza- tion of the office took place during his presidency. this allowed us to narrow the scope to shorten the survey. these questions focused on the following dimensions: the president’s legislative skill, diplomatic skill, military skill, and integrity and whether he was a champion ps • july ......................................................................................................................................................................................................................................................................................................................... of the people. higher scores mean that the presidents rank higher ( better) on these dimensions. figure displays these character- istics by president. lyndon johnson ( ) and franklin roosevelt ( ) score the highest on legislative skill, befitting their significant legislative accomplishments while in office. presidents eisenhower and theodore roosevelt scored highest on military skill, and both roosevelts, eisenhower, and nixon ranked in the top four for dip- lomatic skill. for integrity, eisenhower, truman, and carter topped the list, whereas nixon ( ) and harding ( ) were at the bottom. clinton, impeached by congress but not removed, scored . cousins franklin and theodore roosevelt were at the top of those presidents deemed “champions of the people”—fdr received the highest score of any president ( ) on any dimension. truman was third ( ) and immediately below him was lyndon johnson ( ). in addition to being asked about their knowledge and assessment of the overall greatness of each president, respondents replied to several other questions designed to approach the idea of presiden- tial greatness from multiple perspectives. for example, one ques- tion asked which president they would add to mount rushmore. as depicted in figure , the overwhelming choice was franklin delano roosevelt, who was selected by . % of respondents when asked which president (hypothetically) should be placed next on the monument. the next highest choices were ronald reagan and dwight eisenhower ( . % each), followed by andrew jackson and lyndon johnson ( % each), john f. kennedy ( . %), and barack obama and james madison ( % each). other presidents receiving votes included john adams, james k. polk, woodrow wilson, bill clinton, ulysses s. grant, william mckinley, calvin coolidge, harry truman, richard nixon, and george w. bush. respondents also were asked to identify which presidents were the best/worst, most over/underrated, and most/least polarizing. for each question, they were asked to drag and then rank multiple presidents into a box to identify their corresponding assessments. the results of how frequently each president was specified as “best” or “worst” for each question are reported in figure . we then exam- ined the “top ” for both the best and worst presidents. regarding which presidents were the best and which were the worst, abraham lincoln was included in a respondent’s top list times, fol- lowed by franklin delano roosevelt ( ), george washington ( ), theodore roosevelt ( ), and thomas jefferson ( ). con- versely, james buchanan made the worst list times, followed by warren harding ( ), andrew johnson ( ), richard nixon ( ), and george w. bush ( ). it is interesting that the aggregate results of the respondents’ attitudes toward a few presidents indi- cated a degree of ambivalence; for example, scholars included ronald reagan in their top , whereas others included him in their worst . similar patterns emerged for andrew jackson ( best, worst), woodrow wilson ( best, worst), lyndon johnson ( best, worst), and barack obama ( best, worst). respondents also were asked to identify the five most “over- rated” and five most “under- rated” presidents (figure ). john f. kennedy was included on the most overrated list ( ), followed by ronald reagan ( ), andrew jackson ( ), woodrow wilson ( ), and thomas jefferson ( ). conversely, the most underrated president was dwight eisenhower ( ), followed by george h. w. bush ( ), harry truman ( ), james polk ( ), and john adams and gerald ford (tied at ). although they tied with votes for most underrated, the respond- ents demonstrated significantly f i g u r e most and least polarizing presidents we then asked respondents to identify the five most and least polarizing presidents. as shown in figure , george w. bush was included in the list of most polarizing presidents times, followed by barack obama ( ), andrew jackson ( ), abraham lincoln ( ), and richard nixon ( ).   ps • july ......................................................................................................................................................................................................................................................................................................................... t h e p r o f e s s i o n : p r e s i d e n t i a l g r e a t n e s s a n d p o l i t i c a l s c i e n c e more ambivalence about john adams, who also received votes for most overrated, whereas gerald ford did not make any most overrated list. other presidents exhibiting similar patterns included barack obama ( most overrated, most underrated), james madison ( most overrated, most underrated), bill clinton ( most overrated, most underrated), ulysses s. grant ( most overrated, most underrated), and george w. bush ( most overrated, most underrated). we then asked respondents to identify the five most and least polarizing presidents. as shown in figure , george w. bush was included in the list of most polarizing presidents times, followed by barack obama ( ), andrew jackson ( ), abraham lincoln ( ), and richard nixon ( ). by far, george washington was the least polarizing president, making that list times, followed by dwight eisenhower ( ), james monroe ( ), john f. kennedy ( ), and abraham lincoln ( ). lincoln made the top list for both most and least polarizing presidents, but he was not the only president in which the aggregate results indicated scholarly uncertainty: franklin roosevelt was viewed as one of the five most polarizing presidents by respondents and also as one of the five least polarizing presidents by different respondents. similar patterns emerged for ronald reagan ( most polarizing, least polarizing), thomas jefferson ( most polarizing, least polarizing), john adams ( most polarizing, least polarizing), and harry truman ( most polarizing, least polarizing). conclusion our survey of political scientists regarding presidential greatness puts them back into the discussion about presidential greatness. in the judgment of our respondents, the destiny of some presi- dents has been altered as compared to similar previous surveys: presidents clinton and eisenhower rose to the top whereas president andrew johnson sank to the bottom. a new, expanded mount rushmore would have a slightly more republican flavor: most scholars would include presidents reagan and eisenhower but only after adding franklin roosevelt’s famous jutting chin. president kennedy was judged to be the most overrated whereas presidents eisenhower and george h. w. bush were the most underrated. for the two most recent presidents (i.e., bush and obama), neither fared well in general but partisanship emerged because liberals were more likely to rank obama higher and con- servatives were more likely to rank bush higher. reflecting on the benefaction of presidents past, these results reminded us that history is always shaping and reshaping the leg- acy of former presidents. as new problems and policies emerge, we are obliged to reassess presidential greatness in the context of those who are currently making history. rising historical great- ness in the opinion of our political science respondents appears to be a compounding of time and longevity in office, combined with economic prosperity and effectively handling an international conflict. presidential greatness in more recent surveys appears to be as much about successful management of complex national problems as the promotion of big ideas (although these may be related). this combination just might result in a president’s face being etched for eternity in a future stone monument. acknowledgments the authors thank steven schier for his support in conducting this survey during his term as president of the apsa presidents and executive politics section; david lewis and jennifer mercieca for their feedback on a beta version of the survey discussed in this arti- cle; and the many members of the apsa section for contributing their time and knowledge to this study. n r e f e r e n c e s balz, john. . “ready to lead on day one: predicting presidential greatness from political experience.” ps: political science & politics ( ): – . bose, meena. . “presidential ratings: lessons and liabilities.” in the uses and abuses of presidential ratings, eds. meena bose and mark landis, – . hauppauge, ny: nova science. cnn. . “what is ‘presidential greatness’?” october . available at www.cnn. com/ / / /opinion/opinion-presidential-greatness. curry, jill l. and irwin l. morris. . “explaining presidential greatness: the roles of peace and prosperity?” presidential studies quarterly (september): – . kenney, patrick j. and tom w. rice. . “the contextual determinants of presidential greatness.” presidential studies quarterly (winter): – . mercieca, jennifer r. and justin s. vaughn. . “barack obama and the rhetoric of heroic expectations.” in the rhetoric of heroic expectations: establishing the obama presidency, eds. justin s. vaughn and jennifer r. mercieca, – . college station: texas a&m university press. nichols, curt. . “the presidential ranking game: critical review and some new discoveries.” presidential studies quarterly ( june): – . rottinghaus, brandon j. and justin s. vaughn. . “presidential greatness explained: the role of economic growth and policy productivity.” working paper. rove, karl. . “what makes a great president.” speech delivered on november at the university of utah. available at http://historynewsnetwork.org/ article/ . rubenzer, steven j., thomas faschingbauer, and deniz s. ones. . “personality traits of u.s. presidents.” paper presented at the annual conference of the american psychological association in washington, dc. schlesinger, arthur m., jr. . “rating the presidents: washington to clinton.” political science quarterly (summer): – . simonton, dean keith. . “presidential greatness: the historical consensus and its psychological significance.” political psychology : – . http://www.cnn.com/ / / /opinion/opinion-presidential-greatness http://www.cnn.com/ / / /opinion/opinion-presidential-greatness http://historynewsnetwork.org/article/ http://historynewsnetwork.org/article/ wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is 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people in political science activities louis fisher, congressional research service, was elected a fellow of the national academy of public admin- istration in . he is a senior specialist in separation of powers at crs and testifies frequently before congressional committees. during he testified on the balanced budget amendment and on proposals to expand presidential impoundment powers. louis fisher stuart s. nagel has been elected to the american association for the advancement of science. rein taagepera, professor of social and political science, university of california-irvine, is founding dean of school of social sciences, tartu university, estonia, sharing his time between the two institutions. he ended third in estonian presidential elections (september ), six per- centage points behind the second- round winner. administrative appointments charles e. ellison, head and director of graduate studies, school of plan- ning, university of cincinnati. osbin l. ervin, director, institute of local government, department of political science, southern illinois university at carbondale. mark p. gibney, associate professor of political science at purdue univer- sity, has been appointed director of purdue's programs for study abroad within the office of the dean of international programs. mark p . gibney eric b. herzik, chair, political sci- ence department, university of nevada. philip norton, professor of govern- ment, university of hull, founder director of the centre for legislative studies, university of hull. stanley a. renshon, executive officer (chair), m.a./ph.d. program in political science, the city university of new york graduate school and university center. jerel rosati, director of graduate studies in international studies, department of government and inter- national studies, university of south carolina. saundra schneider, director of the master of public administration pro- gram, department of government and international studies, university of south carolina. mitchell a. seligson, university of pittsburgh, has been appointed as a research professor of the university center for international studies. ian shapiro, director, yale univer- sity's program on ethics, politics, and economics, effective july , . richard l. siegel, professor of polit- ical science, to acting director of the center for justice studies, university of nevada, reno. laura woliver, director of graduate studies in political science, depart- ment of government and interna- tional studies, university of south carolina. new appointments g. matthew bonham, chair of inter- national relations and professor of political science, the maxwell school, syracuse university; formerly of the american university. richard davis, associate professor of political science, brigham young university. michael g. hansen, head of the management programs department, mitre corporation of mclean, virginia, and bedford, massachu- setts. gary l. mcdowell, director, insti- tute of united states studies, univer- sity of london. malik mufti, assistant professor, june people in political science g. matthew bonham michael g. hansen tufts university; formerly harvard university. reginald s. sheehan, assistant pro- fessor of political science, michigan state university; formerly university of north texas. shannon k. smithey, instructor, department of political science, uni- versity of pittsburgh. william h. stewart, chair, political science department at the university of alabama, tuscaloosa, alabama. promotions robert c. angel, associate professor with tenure, department of govern- ment and international studies, uni- versity of south carolina. ann o'm. bowman, professor, department of government and inter- national studies, university of south carolina. frances hagopian, associate pro- fessor of political science, tufts university. ido oren, assistant professor, depart- ment of political science, university of minnesota. jennifer ring, associate professor with tenure, department of govern- ment and international studies, uni- versity of south carolina. peter w. schramm, professor of political science, ashland university. leah j. wilds, associate professor with tenure, university of nevada, reno. laura woliver, associate professor with tenure, department of govern- ment and international studies, uni- versity of south carolina. dvora yanow, associate professor, department of public administration, california state university, hayward. retirements don w. wilson, head of the national archives. visiting and temporary appointments john gray of jesus college, oxford, has been appointed olmsted visiting professor in yale's ethics, politics, and economics program for spring of . randall kindley, assistant professor, department of political science, uni- versity of minnesota, - . ursula munch, assistant professor from university of munich, will be visiting the department of political science, university of minnesota, for spring quarter, . su shaozhi, visiting hill professor, will be visiting the department of political science, university of min- nesota, - . albert somit, former president and distinguished service professor emer- itus, southern illinois university at carbondale, lady davis visiting professor of social science, hebrew university, fall . award recipients newly appointed political scientists madeleine albright, united nations ambassador walter brodnax, deputy secre- tary for the department of health and human services- nominee joan spero, undersecretary for economic and agricultural affairs, department of state-nominee robert conquest named jefferson lecturer for robert conquest, historian of the soviet era, will deliver the jef- ferson lecture in the humanities, the highest honor bestowed by the u.s. government for distinguished intellec- tual achievement in the humanities. conquest, a senior research fellow at stanford university's hoover institution, was chosen for the honor by the national council on the humanities, the presidentially appointed advisory board of the national endowment for the humanities (neh). since , american scholars and writers have delivered the annual jefferson lecture in the humanities, an address on a humanities topic of broad public concern. the award, which carries a stipend of $ , , honors intellectual and civic accom- plishments as txemplified by thomas jefferson. this year marks the th anniversary of jefferson's birth. ps: political science & politics cnr_content c ur re nt n eu ro va sc ul ar r es ea rc h ���+��:=����+
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��� send orders for reprints to reprints@benthamscience.ae current neurovascular research, , , - research article temporal expression of mutant tdp- correlates with early amyotro- phic lateral sclerosis phenotype and motor weakness � qihua chen , jinxia zhou , cao huang , bo huang , fangfang bi , hongxia zhou ,* and bo xiao ,* department of neurology, xiangya hospital of central south university, changsha , p.r. china; department of neurology, thomas jefferson university, philadelphia, pa , usa � a r t i c l e h i s t o r y� received: october , revised: december , accepted: december , doi: . / � abstract: background: mutant transactive response dna-binding protein (tdp- ) is closely correlated to the inherited form of amyotrophic lateral sclerosis (als). tdp- transgenic rats can reproduce the core phenotype of als and constitutive expression of tdp- caused postnatal death. objective: the study aimed to understand whether neurologic deficiency caused by mutant tdp- is dependent on its temporal expression. method: transgenic rats were established that express mutant human tdp- (m v substitu- tion) in neurons, then a tet-off system was used to regulate its expression. results: tdp- mutant transgenic rats developed significant weakness after the transgene was activated. rats with expression of mutant tdp- at days showed a more aggressive pheno- type. more severe pathological changes in neurogenic atrophy were observed in these rats. conclusion: temporal expression of mutant tdp- in neurons promoted serious phenotype in rats. the dysfunction of tdp- had a profound impact on the development of motor neurons and skeletal muscles. keywords: amyotrophic lateral sclerosis (als), tar dna-binding protein , motor neurons, transgenic rats, cag, tet- responsive transactivator. . introduction amyotrophic lateral sclerosis (als) is the most fre- quent form of adult-onset motor neuron disease, in which loss of motor neurons leads to weakness and denervation atrophy of voluntary muscles. the disease often develops around middle life and inexorably progresses to paralysis [ , ]. although most als cases are sporadic, familiar als (fals) accounts for to % of cases with an autosomal dominant pattern of inheritance. transactive response dna-binding protein (tdp- ) is a heterogeneous nuclear rna binding protein encoded by tdp- gene. tdp- plays important roles in multipro- tein/rna complex and regulating gene expression [ ]. tdp- has been shown to promote neurodegeneration by impair- ing chromatin remodeling, accelerate age-dependent degen *address correspondence to these authors at the thomas jefferson univer- sity, jah, locust avenue, philadelphia, pa , usa; xiangya hospital of central south university, xiangya road, changsha, , p.r. china; tel: - ; fax: - - ; e-mail: @qq.com; xiaobo_xy@ .com eration of interneurons, and cause defects in dendritic growth [ - ]. accumulating evidence have implicated that the pathogenic mutation of tdp- causes an inherited form of als [ ]. mutation of tdp- gene has been identified re- sponsible for some familiar als. including m v muta- tion, no less than pathogenic tdp- mutants have been reported so far [ ]. using a tet-off system, inducible expression of human tdp- with a pathogenic mutation (m v substitution) successfully induced progressive paralysis in transgenic rats [ ]. the removal of mutant tdp- partly restored motor function in als rats expressing the causative gene in neu- rons and muscles, indicating that the motor neuron degenera- tion is partially reversible [ ]. however, it is unclear whether neurologic deficiency caused by mutant tdp- is correlated with the time of its expression. to address this question, we used tet-off system to produce inducible gene expression in transgenic rats, and the consequence events including the onset age and severity of illness were assessed in transgenic models. our findings support the hypothesis that earlier expression of mutant tdp- can cause a more aggressive phenotype of als in transgenic rats. - / $ . +. © bentham science publishers current neurovascular research, , vol. , no. chen et al. . materials and methods . . generation of transgenic rats the animal use protocol was approved by the ethical re- view board from thomas jefferson university, pa, usa. transgenic rats were established and maintained in a spra- gue dawley background. the tdp- gene was isolated from bac clone (rp - b ), and an m v substitu- tion was integrated into tdp gene by homologous recombi- nation in escherichia coli [ ]. tetracycline (tet)-inducible transgenic rats carried a mutant human tdp- (tdp- m v) transgene at the control of a tet-responsive element (tre) [ ]. selected cytomegalovirus enhancer fused to chicken beta actin promoter (cag) was used to drive tet- responsive transactivator (tta) gene. tre-tdp- m v transgenic rats were crossed with cag-tta positive rats. to selectively induce human tdp- gene expressed in rats, breeding rats and transgenic offspring were drunk with dox ( ug/ml) to inhibit transgene expression during embryonic and postnatal phase. then cag-tta/tre-tdp- m v double transgenic rats were deprived of dox to activate mu- tant tdp gene. the time of withdrawal of dox (dox-) was selected as -day-old and -day-old, to mimic the juvenile stage and adulthood of rats. . . behavioral tests and disease stages the onset and progression of the als phenotypes in transgenic rats were detected by mobility and grip strength. mobility was surveyed by open field test (med associates), which measured the total distance a rat travelled within min [ ]. grip strength was measured with a grip-strength meter (columbus instruments). we defined the disease onset as an irreversible reduction in travelled distance. paralysis was defined as dragging of legs or an inability to retract in- dividual legs. disease end stage was defined as the inability to retract two or more legs, or inability to right itself when the rat was placed on its side, or as a severe weight loss. re- lated data were compared using unpaired t-tests. p-value < . was regarded as statistically significant. . . immunofluorescence, immunohistochemistry and cresyl violet staining coronal forebrain sections and cross-sections of spine were used for immunohistochemistry and cresyl violet stain- ing. the colocalization of human tdp- with neun was detected by double-labelling immunofluorescence. primary antibodies used for immunofluorescence were; anti-human tdp- (abnova, clone e -d ), polyclonal antibody against neun from rabbits immunized with a peptide (maqpyppaqyppc) and affinity purified. immunostained tissues were visualized using a nikon microscope, and im- ages were acquired using a nikon digital camera as previ- ously reported [ ]. motor neurons in the spinal cord were observed by cresyl violet staining and quantified as previ- ously reported [ ]. the motor neurons in a long segment of lumbar cord (l -l ) were assessed to increase the accuracy of cell counting. the central segment of lumbar cord was cut into -um thick sections using a freezing microtome, and motor neurons were counted in every th section on both sides using a fractionator-based stereology software (stere- ologer). numbers of neurons were compared using unpaired t-tests. p-value < . was regarded as statistically signifi- cant. . . histology and histochemistry in skeletal muscles fresh gastrocnemius muscles were quick-frozen in isopentane/liquid nitrogen, then cut into cross sections ( �m) on a cryostat microtome. the structures of muscle were assessed by h&e staining, histochemistry for nonspecific esterase and atpase. nonspecific esterase activity was de- tected using a-napthyl acetate protocol. myosin atpase staining (ph . ) was used to discriminate three types of skeletal muscle fibers. . results . . tdp- transgenic rats had worse phenotype to examine whether mutant tdp- expressed in neu- rons could induce als-like phenotypes, we chose the regu- latory promoter of cag gene to control the activation of transgene and established cag-tta/tre-tdp- m v dou- ble transgenic rats, with their mutant human tdp- gene under the control of a tetracycline (tet)-responsive element (tre). then, we used the tet-off system to regulate the ex- pression of mutant tdp- in neurons. dox was used to in- hibit transgene expression during embryonic and postnatal phase. to mimic mutant tdp- expression in juvenile stage or adulthood, transgenic rats were deprived dox (dox-) at the age of days or days, respectively. both the groups of cag-tta/tre-tdp- m v double transgenic rats suf- fered from progressive weakness after dox (fig. a, b). in the group of dox- at the age of days (dox- days), transgenic rats began losing grip strength and mobility as early as days after dox- ( . ± . days after dox-), while the counterpart rats with dox- at the age of days (dox- days) developed early signs of paralysis (disease onset) not until days after dox- ( . ± . days after dox-) (fig. c-f). there were significant differences in the time of onset between the two groups (fig. a, b). . . severe loss of neurons in transgenic rats in the cortex and dentate gyrus, double-label fluores- cence staining demonstrated that mutant human tdp- was colocalized with the neurons (fig. a, b). cag-tta/tre- tdp- m v double transgenic rats showed apparent expres- sion of tdp- at the disease end stage, while tdp- was not detected in normal rats with matched age (fig. c). to accurately estimate motor neuron death in rats, we used un- biased stereological cell counting to count the number of motor neurons in a long segment of spinal cord (l -l ). compared with normal rats, stereological cell counting iden- tified more loss of neurons in transgenic rats with dox- at the age of days than in rats with dox- at the age of days (fig. ). . . neurogenic damages in transgenic rats as an outcome of motor neuron degeneration, we exam- ined skeletal muscle atrophy by h&e staining (fig. a , b ), and performed immunohistochemistry for nonspecific esterase (fig. a , b ) and atpase (fig. c , c ) in mut- ant tdp- transgenic rats at end stage. in addition, cag- tdp- worsen als-like phenotype current neurovascular research, , vol. , no. fig. ( ). mutant human tdp- expressed on days causes shorter onset and induces more severe paralysis in transgenic rats. double transgenic rats developed paralysis (a): dox- at the age of days, (b): dox- at the age of days). compared to control group, open-field assay (c) and the measured grip strength of paws (e) indicated an irreversible reduction of mobility in two groups of double-transgenic rats (*p< . ). compared with the rats deprived of dox at the age of days, the rats deprived of dox at the age of days developed more seri- ous paralysis (d and f). data are means ± sd (n= ). *p< . . stage : the time of dox-; stage : onset time; stage : middle stage; stage : end stage. (for interpretation of the references to color in this figure legend, the reader is referred to the web version of this paper). fig. ( ). the survival of transgenic rats. (a). the disease onset in two groups of rats deprived of dox at the age of and days, respec- tively. (b). the survival in two groups of rats deprived of dox at the age of and days, respectively. data are means ± sd (n= ). tta/tre-tdp- m v double transgenic rats with dox- at the age of days revealed a worse pathologic change than the rats of dox- days. in contrast, rats in control group with matched age had no sign of amyotrophy (fig. c). we also counted the cross areas of myofibers in all groups of rats on cross sections of gastrocnemius stained by atpase . , and found that the size of fibers was remarkably reduced in tdp- rats (fig. d). . discussion as a highly conserved ribonucleoprotein, tdp- plays an important role in gene expression. the level of tdp- is remarkably elevated in the brain and spine of patients in late stage als [ - ]. moreover, overexpression of either wild- type or mutant tdp- could cause cell death, suggesting the gain-of-function of tdp- in disease progress [ , ]. the previous study confirmed that mutant tdp- gene ex- current neurovascular research, , vol. , no. chen et al. fig. ( ). overexpression of mutant human tdp- (htdp- ) in neurons of transgenic rats. immunofluorescence showed that mutant tdp- was expressed in the cortex (a) and dentate gyrus (b) of cag-tta/tre-tdp m v double-transgenic rats after dox was deprived (dox-) at the age of days and days, respectively (green, a , b , a , b ), but was not detected in the normal group (c , c ). neuronal marker neun was stained in the cortex and dentate gyrus in transgenic groups and control group (red, a , b , c , a , b , c ). double-label fluorescence staining demonstrated that mutant human tdp- was colocalized with neun in the cortex and dentate gyrus in transgenic rats (a , b , a , b ), but not in control group (c , c ). scale bar: �m. (c). immunohistochemistry showed overexpression of tdp- in the cortex (a , b , c ) and dentate gyrus (a , b , c ). scale bar: �m. (for interpretation of the references to color in this figure legend, the reader is referred to the web version of this paper). fig. ( ). expression of mutant tdp- causes motor neuron death. (a-c) representative images of the lumbar cord of transgenic rats at end stage (a): dox- at the age of days, (b): dox- at the age of days) and normal control subjects at matched ages (c). scale bar: �m (a , b , c ) and �m (a , b , c ). (d) stereological cell counting demonstrated a significant loss of motor neurons (> �m in diameter) in the l -l cords of cag-tta/tre-tdp m v double-transgenic rats compared with normal rats. data are means ± sd (n= ). *p< . . tdp- worsen als-like phenotype current neurovascular research, , vol. , no. fig. ( ). overexpression of mutant human tdp- in early stage results in more severe muscular atrophy. (a-c) h & e staining (a , b ), immunohistochemistry for nonspecific esterase (a , b ) and atpase . (a , b ) indicated substantial atrophy of skeletal muscle in two group of double transgenic rats at the end stage, while the normal rats with matched ages showed no sign of amyotrophy (c , c , c ). scale bar: �m. (d) the cross areas of myofibers in all groups of rats were measured on cross sections of gastrocnemius stained by atpase . . data are means ± sd (n= ). pressed in motor neurons is sufficient to induce als-like symptoms [ ]. in this study, we used cag-tta/tre-tdp- m v double transgenic rats that express mutant human tdp- in neurons. dependent on tet-responsive element, we regulated the expression of mutant tdp- by admini- stration or withdrawal of dox. we validated that cag- tta/tre-tdp- m v double transgenic rats developed progressive severe weakness, atrophy and weight loss. in the end stage, transgenic rat models with dox- showed signifi- cantly reduced motor neurons in spinal cord and apparent neurogenic atrophy, consistent with the pathologic changes in als. notably, transgenic rats that expressed mutant human tdp- at days exhibited more devastating clinical phe- notypes as (a) the interval between dox- and disease onset was shorter, (b) there was an expedited proceeding to termi- nal stage, (c) their limb asthenia and muscle degeneration were more remarkable. it is unquestionable that the progres- sive loss of motor neurons plays a critical role in als, and significant decreases in motor neurons in spinal cord are observed in als transgenic rats. however, there was no significant difference between double transgenic rats. small sample size may explain the results because there were less motor units in transgenic rats with dox- days. it has been well established that the pathogenic mutation and elevated expression of tdp- are neurotoxic to motor neurons. although the detailed mechanisms of mutant tdp- induced motor neuron death are unclear, ubiquitin aggre- gation, gliosis and cytoplasmic accumulation of tdp- are all correlated to motor neuron degeneration [ ]. however, whether the adverse effect of mutant tdp- varied at dif- ferent periods in developmental process of motor system remains a conundrum. since the copies of mutant tdp- transgene are equal in both groups of transgenic rats, we speculate that normal function of tdp- is more crucial to the early development of motor neurons and skeletal mus- cles. increasing evidences suggested that the loss of tdp- function is involved in neurodegeneration and als symp- current neurovascular research, , vol. , no. chen et al. toms [ , ]. a motor neuron-specific tdp- knockout mice model demonstrated age-dependent motor impairment and morphological abnormalities in the motor neuron sys- tem, and the loss of tdp- function led to the pathogenesis of als [ ]. in addition, tdp- gene deletion resulted in early embryonic lethality in mammals [ , ]. embryonic tdp- expression was colocalized with the neuroepithe- lium that contains neural progenitors [ ]. given that in- terneuron subtypes and motor neurons were derived of neu- ral progenitors, it can be speculated that mutations in tdp- regulation may affect the development central nervous system, including the growth of motor neurons. since the early development of motor neurons is crucial to motor func- tion, it is possible that earlier disturbance to tdp- expres- sion gives rise to developmental anomalies of motor systems and causes more severe als-like pathological changes. therefore, our findings suggest that it is very important to perform early intervention to prevent or delay the progres- sion of tdp- induced als pathological changes, provid- ing new strategy for als treatment. conclusion in summary, our study suggests that mutant tdp- ex- pressed at juvenile stage of the rats can cause a more aggres- sive phenotype than mutant tdp- expressed at an adult stage of the rats. the normal function of tdp- is impor- tant to promote the development of motor neurons and skele- tal muscles. ethics approval and consent to partici- pate the animal use protocol was approved by the ethical re- view board from thomas jefferson university, pa, usa. human and animal rights no humans were used for studies that are base of this re- search. all the animals used were in accordance with the standards set forth in the th edition of guide for the care and use of laboratory animals (http:// grants.nih.gov/ grants/olaw/guide-for-thecare-and-use-of-laboratory-ani- mals.pdf) published by the national academy of sciences, the national academies press, washington dc, united states of america. consent for publication not applicable. conflict of interest the authors declare no conflict of interest, financial or otherwise. acknowledgements we would like to thank all participants in this study and dr. xugang xia from the thomas jefferson university for laboratory assistance. this work was supported by natural science foundation of china (no. , , ) and science fund for young scientists from xian- gya hospital of china (no. q ). references [ ] boillee s, yamanaka k, lobsiger cs, et al. onset and progression in inherited als determined by motor neurons and microglia. sci- ence ; ( ): - . 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[ ] arai t, hasegawa m, akiyama h, et al. tdp- is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. biochem biophys res commun ; ( ): - . [ ] neumann m, sampathu dm, kwong lk, et al. ubiquitinated tdp- in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. science ; ( ): - . [ ] neumann m, kwong lk, lee eb, et al. phosphorylation of s / of tdp- is a consistent feature in all sporadic and fa- milial forms of tdp- proteinopathies. acta neuropathol ; ( ): - . [ ] bilican b, serio a, barmada sj, et al. mutant induced pluripotent stem cell lines recapitulate aspects of tdp- proteinopathies and reveal cell-specific vulnerability. proc natl acad sci usa ; ( ): - . tdp- worsen als-like phenotype current neurovascular research, , vol. , no. [ ] sephton cf, good sk, atkin s, et al. tdp- is a developmentally regulated protein essential for early embryonic development. j biol chem ; ( ): - . [ ] lee eb, lee vm, trojanowski jq. gains or losses: molecular mechanisms of tdp -mediated neurodegeneration. nat rev neu- rosci ; ( ): - . [ ] halliday g, bigio eh, cairns nj, neumann m, mackenzie ir, mann dm. mechanisms of disease in frontotemporal lobar degen- eration: gain of function versus loss of function effects. acta neu- ropathol ; ( ): - . [ ] iguchi y, katsuno m, niwa j, et al. loss of tdp- causes age- dependent progressive motor neuron degeneration. brain ; (pt ): - . [ ] kraemer bc, schuck t, wheeler jm, et al. loss of murine tdp- disrupts motor function and plays an essential role in embryogene- sis. acta neuropathol ; ( ): - . [ ] wu ls, cheng wc, hou sc, yan yt, jiang st, shen ck. tdp- : a neuro-pathosignature factor, is essential for early mouse em- bryogenesis. genesis ; ( ): - . [ ] rowitch dh. glial specification in the vertebrate neural tube. nat rev neurosci ; ( ): - . � � 	temporal expression of mutant tdp- correlates with early amyotrophiclateral sclerosis phenotype and motor weakness 	abstract: background: 	objective: 	method: 	results: 	conclusion: 	keywords: 	introduction 	materials and methods 	results 	fig. ( ). 	fig. ( ). 	discussion 	fig. ( ). 	fig. ( ). 	fig. ( ). 	conclusion 	ethics approval and consent to participate 	human and animal rights 	consent for publication 	conflict of interest 	acknowledgements 	references rop volume issue cover and back matter straussian thought liberalism ancient and modern by leo strauss. with a new foreword by allan bloom."[this book] takes its place beside [the author's] what is political philosophy? as the most appropriate introduction to [his] thought."—national review. an agora paperback. $ . paper history and modernity in the thought of thomas hobbes by robert p. kraynak. "this is the first study of hobbes to bring out the view of history that underlies and inspires his political and scientific abstractions. despite hobbes's apparent neglect of all previous philosophy, he was preoccupied with its bad political consequences and determined to find a cure for them. kraynak shows the argument behind the arguments in a book that is fresh, original, vigorous, and direct."— harvey c. mansfield, jr., harvard university. $ . the political philosophy of montaigne by david lewis schaefer. arguing that montaigne was a far more systematic and radical figure than other scholars have recognized, schaefer demonstrates that montaigne offers important lessons about the theoretical foundations of modern politics and morality. $ . cloth, $ . paper calvin and the foundations of modern politics by ralph c. hancock. hancock argues that calvin should be consid- ered a founder of modern civilization along with such "secular" thinkers as machiavelli, hobbes, and descartes. $ . questions concerning the law of nature by john locke. edited and translated by robert horwitz, jenny strauss clay, and diskin clay. containing a substantial apparatus criticus, this new edition of locke's manuscript is faithful to locke's original intentions and to the format he chose for his discourse on the law of nature—a late-scholastic quaestio disputata. $ . rousseau's exemplary life the confessions as political philosophy by christopher kelly. in this stimulating reading of rousseau' s confessions, kelly breaks down the artificial distinction traditionally made between this autobiographical work and rousseau's overtly philosophical works. $ . the thinking revolutionary principle and practice in the new republic by ralph lerner. focusing on the efforts of prominent founders such as thomas jefferson, and john adams, lerner documents how their thought helped to shape public discourse, perceptions, and institutions in the new republic. $ . cornell university press roberts place ithaca, ny h tt p s: // d o i.o rg / . /s d o w n lo ad ed f ro m h tt p s: // w w w .c am b ri d g e. o rg /c o re . c ar n eg ie m el lo n u n iv er si ty , o n a p r a t : : , s u b je ct t o t h e c am b ri d g e c o re t er m s o f u se , a va ila b le a t h tt p s: // w w w .c am b ri d g e. o rg /c o re /t er m s. https://doi.org/ . /s https://www.cambridge.org/core https://www.cambridge.org/core/terms "a well-aimed broadside... ...a scholarly, methodical and exhaustive interpretation of strauss's teachings. many of drury's conclusions are most unconventional, indeed, not a little unnerving." — political studies strauss / ppjisbn - - - $ . cl. isbn - - - $ . pb. the only book length study on strauss available! "[drury] presents a comprehensive view of strauss's philosophy from a caustically anti-straussian perspective...a spritely written and abundantly documented book." — the review of politics shadia b. drury is professor of political science at the university of calgary in canada. st. martin's press fifth avenue • new york, n.y. to order, call - - - (in ny, - - ) h tt p s: // d o i.o rg / . /s d o w n lo ad ed f ro m h tt p s: // w w w .c am b ri d g e. o rg /c o re . c ar n eg ie m el lo n u n iv er si ty , o n a p r a t : : , s u b je ct t o t h e c am b ri d g e c o re t er m s o f u se , a va ila b le a t h tt p s: // w w w .c am b ri d g e. o rg /c o re /t er m s. https://doi.org/ . /s https://www.cambridge.org/core https://www.cambridge.org/core/terms thematic issue on the thought of leo strauss guest editors: kenneth l. deutsch walter nicgorski nathan tarcov stewart umphrey hillel fradkin john gunnell steven b. smith thomas l. pangle james v. schall, s.j. dante germino contributors thomas west christopher brnell david schaefer david lawrence levine susan shell david r. lachterman h tt p s: // d o i.o rg / . /s d o w n lo ad ed f ro m h tt p s: // w w w .c am b ri d g e. o rg /c o re . c ar n eg ie m el lo n u n iv er si ty , o n a p r a t : : , s u b je ct t o t h e c am b ri d g e c o re t er m s o f u se , a va ila b le a t h tt p s: // w w w .c am b ri d g e. o rg /c o re /t er m s. https://doi.org/ . /s https://www.cambridge.org/core https://www.cambridge.org/core/terms pmh : the impact of depression on health-related quality of life (hrql) abstracts the perceived health status of individuals with severe psychiatric illness, such as schizophrenia, is an important element of disease burden and quality of life. the effect of antipsychotic therapies on psychiatric symptoms is well-understood. however, more information about the effects of antipsychotics on health status is needed. ob- jective: to examine changes in health-related quality of life (hrql) from inpatient admission to follow-up of adult and geriatric patients with schizophrenia treated with conventional or atypical antipsychotic agents. methods: data were obtained from the cqi�sm out- comes measurement system, an oryx (jcaho) ac- cepted performance improvement system, which tracks patients admitted to adult or geropsychiatric inpatient programs in over general hospitals across states. health status was measured by the sf- at time of ad- mission and at three (geriatric) or six months (adult) post-discharge. patients with a primary discharge diagno- sis of schizophrenia (icd- -cm codes . – . ) who completed the sf- and were treated with antipsy- chotic agents were included. one sample t-tests were used to test the null hypothesis that the mean change is equal to zero. results: mean scores were higher (i.e., healthier) at follow-up, as compared to admission, on all eight domains of the sf- for the adult schizophrenic group (n � ) and seven of eight domains for the geriat- ric schizophrenic group (n � ). statistically significant improvements were noted on five of the eight scales. largest improvements were found on role physical (p � . ), role emotional (p � . ), and social func- tioning (p � . ). conclusions: marked improve- ment in diverse aspects of hrql among schizophrenic patients treated with conventional or atypical antipsy- chotic agents supports the humanistic value of antipsy- chotic medications beyond simple symptom ameliora- tion. pmh the impact of depression on health- related quality of life (hrql) mody sh , edell ws , durkin mb , adams be , repp ea janssen pharmaceutica, titusville, nj, usa; mental health outcomes, lewisville, tx, usa objective: to describe the effect of depression on health-related quality of life (hrql) utilizing the sf- health status survey. the scores of patients with depres- sion were compared to age and gender matched us popu- lation norms and contrasted to results of similar research on patients with other psychiatric disorders. methods: sf- scores were collected from patients admitted to adult (n � ) or geriatric (n � ) psychiatric pro- grams within acute care hospitals who had an icd- -cm discharge diagnosis of depressive disorder. adult and ge- riatric us population norms were simulated using data from the medical outcomes study manual and interpre- tation guide to match the age and gender distributions of the adult and geriatric depression groups. admission sf- scores for the adult and geriatric depression groups were compared to these age and gender matched us popula- tion norms using independent sample t-tests. the find- ings were then placed in context of sf- scores for other psychiatric conditions including schizophrenia, bipolar disorder, and cognitive disorder. results: hrql for both the adult and geriatric groups of depressed patients was significantly lower than the simulated us population norms for all eight domains of the sf- , for physical health as well as mental health (p � . ). the greatest differences were observed in the role physical, social functioning, and role emotional domains. adult inpa- tients with depression had similar scores on all domains to adult patients with the other psychiatric diagnoses studied. however, geriatric patients with depression had lower scores on hrql across all domains versus geriat- ric patients with other psychiatric illnesses. conclu- sions: depression has a strong negative association with both adult and geriatric patients’ perceived hrql. depressed patients not only had the expected decreases on mental health domains, but also scored significantly lower on physical health domains. finally, depression in geriatric patients is associated with greater decrements in hrql than other psychiatric illnesses examined. pmh quality of life differences between patients with episodic and transformed migraine meletiche dm , lofland jh , young wb , hopkins mm office of health policy and clinical outcomes, thomas jefferson university, philadelphia, pa, usa; jefferson headache clinic, thomas jefferson university hospital, philadelphia, pa, usa currently there are no published studies comparing the health-related quality of life (hrqol) of transformed and episodic migraneurs. objectives: the study objec- tive was to detect differences in hrqol between patients with transformed migraine (tm) and episodic migraine (em). methods: this retrospective study examined the hrqol of transformed and episodic migraneurs of the jefferson headache center during their first visit to the center. data collected included the short form (sf- ) and the migraine disability assessment (midas) questionnaires as well as demographic information. a t-test with bonferroni correction was used to test for sig- nificant differences in the sf- domains between the groups. results: to date, data has been collected on patients, from each group. there were no signifi- cant differences with respect to gender, race, age or the number of comorbid conditions between groups. over the last days prior to their first visit, patients with tm reported having a headache on an average of days compared to em patients who averaged days with headache (p � . ). compared to em patients, patients with tm had statistically and clinically significant (� point difference) lower mean scores on the mental com- wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ shieldsquare captcha we apologize for the inconvenience... ...but your activity and behavior on this site made us think that you are a bot. note: a number of things could be going on here. 	if you are attempting to access this site using an anonymous private/proxy network, please disable that and try accessing site again. 	due to previously detected malicious behavior which originated from the network you're using, please request unblock to site. please solve this captcha to request unblock to the website 	 		you reached this page when trying to access 		https://iopscience.iop.org/article/ . / /pdf from 		 . . . on 		april , : : utc 	 british medical journal volume june of the alimentary tract was intermittent or more localised than we explored, similar to the localised tender segments in the oesophagus described by edwards. alternatively, pain may arise in other areas such as the pancreas or biliary tract or in some cases from a non-alimentary source. referral of pain to extra-abdominal sites has now been shown from the small as well as the large bowel. a wider appreciation of the protean presentation of functional abdominal pain and the existence of potential tender areas throughout the whole gut should expedite the recognition of non-organic abdominal pain and prevent unnecessary investigations and even explora- tory laparotomy. kjm is in receipt of a medical research council training fellowship. references isselbacher kj. indigestion. in: isselbacher kj, adams rd, braunwald eb, petersdorf rg, wilson jd, eds. harrison's principles of internal medicine. th ed. maidenhead: mcgraw-hill, : . hawkins cf. the alimentary system. in: mann wn, ed. conybeare's textbook of medicine. th ed. edinburgh: churchill livingstone, : . way lw. abdominal pain and the acute abdomen. in: sleisenger mh, fordtran js, eds. gastrointestinal disease. nd ed. eastbourne: w b saunders, : - . rains ajh, ritchie hd, eds. the intestines. in: bailey and love's short practice of surgery. th ed. london: lewis, : . schwartz si, shires gt, spencer fc, storer eh, eds. manifestations of gastrointestinal disease. in: principles of surgery. rd ed. maidenhead: mcgraw-hill, : . jones cm. digestive tract pain. new york: macmillan, : . bentley fh, smithwick rh. visceral pain produced by balloon distension of the jejunum. lancet ;ii : . ray bs, neil cl. abdominal visceral sensation in man. ann surg ; : - . chapman wp, jones cn. variations in cutaneous and visceral pain sensitivity in normal subjects. j clin invest ; : - . wailer sl, misiewicz jj. prognosis in the irritable-bowel syndrome. lancet ;ii : - . manning ap, thompson wg, heaton kw, morris af. towards positive diagnosis of the irritable bowel. br medj' ;ii: - . swarbrick et, hegarty je, bat l, williams cb, dawson am. site of pain from the irritable bowel. lancet ;ii: - . connell am, hilton c, irvine g, lennard-jones je, misiewicz jj. variation of bowel habit in two population samples. br med j ; ii: - . hurst af. on the sensibility of the alimentary canal in health and disease. lancet ;i: , , . lennander kg. uber die sensibilitat der bauchhohle und uber lokale und allgemeine anasthesie bei bruchund bauchoperationen. zentralbl chir ; : . ryle ja. visceral pain and referred pain. lancet ;i: . payne ww, poulton ep. visceral pain in the upper alimentary tract. q j med ; : . payne ww, poulton ep. experiments on visceral sensation. j physiol ; : . morley j. visceral pain. br med] ;ii: . alvarez wc. abdominal pain: the sensitive regions of the abdomen and ways in which they may be stimulated to produce pain. jama ; : . dworken hj, biel fj, machella te. supradiaphragmatic reference of pain from the colon. gastroenterology ; : - . thompson wg, heaton kw. functional bowel disorders in apparently healthy people. gastroenterology ; : - . holdstock dj, misiewicz jj, waller sl. observations on the mechanism of abdominal pain. gut ; : - . connell am, jones fa, rowlands en. motility of the pelvic colon. iv. abdominal pain associated with colonic hypermotility after meals. gut ; : - . horowitz l, farrar jt. intraluminal small intestinal pressures in normal patients and in patients with functional gastrointestinal disorders. gastroenterology ; : - . kalser mh, zion de, bockus hl. functional diarrhoea: an analysis of the clinical and roentgen manifestations. gastroenterology ; : - . thompson dg, laidlow jm, wingate dl. abnormal small-bowel motility demonstrated by radiotelemetry in a patient with irritable colon. lancet ;ii: - . sekar asc, thompson wg, turner lj, barr r. duodeno-gastric reflux and gastritis in non-ulcer dyspepsia. clinical research ; : a. edwards daw. history and symptoms of oesophageal disease. diseases of the oesophagus. in: vantrappen g, hellemans j, eds. handbuch der inneren medizin. berlin, heidelberg, new york: springer-verlag, : . (accepted april ) short reports "scalded mouth" caused by angiotensin-converting-enzyme inhibitors captopril, an angiotensin-converting-enzyme inhibitor, is used to treat resistant hypertension.' side effects include rash, proteinuria, leukopenia, ageusia, angio-oedema, and aphthous and tongue ulcers; its sulphydryl moiety may be an aetiological factor.' enalapril, a new converting-enzyme inhibitor, does not contain a sulphydryl group. we describe three patients who reported a scalded sensation of the oral mucosa during treatment with captopril or enalapril. case reports case -a -year-old hypertensive woman receiving hydrochloro- thiazide mg daily was prescribed captopril - mg thrice daily in addition; she took no other medication. after two weeks the dosage of captopril was increased to mg thrice daily. six days later she complained of a burning sensation on the upper surface of her tongue, comparable to having been "scalded by a hot liquid," though she had no recollection of such an occur- rence. examination of her tongue and mouth was unremarkable. she re- ported no alteration in taste. with her consent the regimen was continued, the symptom persisted for five days and then dissipated despite two additional weeks of captopril treatment, without subsequent recurrence. case -during a research study a -year-old man with essential hyper- tension received enalapril mg twice daily. seven days later he said that his tongue and mouth felt as though they had been "scalded by coffee or pizza," though he could not recall such an occurrence. examination of the mouth showed only periodontal disease and questionable hyperaemia; neurological evaluation including taste perception was normal. he took no other medications. he continued treatment with enalapril for four additional days without resolution. the symptom abated, however, when enalapril was stopped, and he was treated with hydrochlorothiazide mg/day. two weeks later enalapril was restarted in a dose of mg daily, the diuretic being con- tinued. on the twelfth day of treatment he again complained of the "scalded- mouth" sensation, which was similar to but milder than the first episode. this continued for the next two days but abated when enalapril was stopped at the end of the trial. similar symptomatology did not recur. case -a -year-old hypertensive woman taking propranolol mg and hydrochlorothiazide mg daily was prescribed captopril mg thrice daily in addition. other medications included nitroglycerine and isosorbide dinitrate. after two weeks the captopril dosage was increased to mg thrice daily. nine weeks later she complained of a burning sensation in her throat, palate, and tongue. examination of the mouth was unremarkable. after two additional weeks of treatment with captopril the symptoms persisted and mild injection at the margins of the soft palate was noted; there was no alteration in taste. because of continued discomfort captopril was stopped with a distinct improvement during the next week; slight discomfort, however, localised to the tip of her tongue, persisted. comment although disorders of taste as well as aphthous and tongue ulcers have been reported during captopril treatment, the symptom de- scribed by our patients has not, to our knowledge, been previously associated with use of either captopril or enalapril. the mechanism of this side effect is unclear. neither fever nor eosinophilia accompanied the patients' complaints. no concomitant laboratory abnormalities were noted, and all the patients had normal renal function. since the side effect was noted with both captopril and enalapril the aetiology of this scalded-mouth reaction appears to be independent of the sulphydryl moiety of captopril. the hyperaesthesia of the oral mucosa abated during continued treatment with captopril in case , recurred o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .b m j.co m / b r m e d j (c lin r e s e d ): first p u b lish e d a s . /b m j. . . o n ju n e . d o w n lo a d e d fro m http://www.bmj.com/ british medical journal volume june on rechallenge with enalapril in case , and was troublesome enough to require captopril treatment to be stopped in case . doctors treating patients with converting-enzyme inhibitors should be aware of the potential occurrence of this side effect. requests for reprints should be addressed to: dr peter h vlasses, clinical pharmacology (m- ), thomas jefferson university hospital, th and walnut streets, philadelphia, pa , usa. 'ferguson rk, vlasses ph. clinical pharmacology and therapeutic applica- tions of the new oral angiotensin converting enzyme inhibitor, captopril. am heartcj ; : - . gavras h, biollaz j, waeber b, brunner hr, gavras i, davies ro. anti- hypertensive effect of the new oral angiotensin converting enzyme inhibitor "mk- ". lancet ;ii: - . s vlasses ph, ferguson rk. temporary ageusia related to captopril. lancet ;ii : . seedat yk. aphthous ulcers of mouth from captopril. lancet ;ii: - . nicholls mg, maslowski ah, ikram h, espiner ea. ulceration of the tongue: a complication of captopril therapy. ann intern med ; : . (accepted february ) division of clinical pharmacology, jefferson medical college, thomas jefferson university, philadelphia, pennsylvania, usa peter h vlasses, pharm d, associate director and clinical associate professor of medicine heschi h rotmensch, md, assistant director and clinical assistant professor of medicine roger k ferguson, md, director and professor of medicine and pharmacology department of pharmacy, thomas jefferson university hospital, philadelphia steven l sheaffer, pharm d, assistant director prenatal serological diagnosis of intrauterine cytomegalovirus infection cytomegalovirus commonly causes intrauterine infection. finding a primary or reactivated cytomegalovirus infection in the mother by isolating the virus from the throat, urine, cervix, or blood, or by maternal serology, does not necessarily indicate that the fetus will be infected. fetal infection appears to occur in no more than - % of even primary maternal infections. the presence of intrauterine infection has been established by culture of cytomegalovirus from amniotic fluid,' but such isolation may be time consuming. we report a case that shows that the availability of a sensitive radioimmunoassay for the detection of cytomegalovirus-specific jgm and the ability to obtain fetal cord serum mean that intrauterine serological diagnosis is possible. case report a -year-old rhesus-positive woman without atypical antibodies was referred at weeks' gestation after ultrasonography showed a hydropic fetus. she had felt well throughout the pregnancy, denied taking any medication, and reported no relevant personal or family history. at weeks' gestation an ultrasound scan had confirmed her dates and shown no major structural abnormalities. examination was unremarkable, with fundal height being consistent with dates. a further ultrasound scan confirmed a single fetus with gross ascites, but no other abnormalities were observed. fetoscopy was carried out and ml pure fetal blood and ml ascitic fluid collected. fetal serum showed appreciable hypoalbuminaemia of g/l (normal ± sd g/l (unpublished)). a fetal blood film showed severe erythroblastosis. a follow-up ultrasound scan showed re-collection of the ascites. intra- vascular fetal albumin infusion was planned but precluded by spontaneous premature rupture of the membranes at weeks' gestation. a conservative policy was adopted but labour ensued and a g severely depressed male infant delivered. resuscitative attempts were stopped after minutes. initial serology for cytomegalovirus on maternal sera showed an antibody titre of when a complement fixation test was performed on sera collected at weeks' and weeks' gestation. no cytomegalovirus-specific igm was detected in the fetal serum using indirect immunofluorescence (electro- nucleonics laboratories inc, maryland, usa). necropsy showed non-icteric hydrops fetalis (figure). macroscopically the only abnormal findings were a large liver with a finely nodular and mottled surface and massive ascites causing gross elevation of the diaphragm with consequent pulmonary hypoplasia. microscopy showed cytomegaly and intranuclear "owl's eye" inclusions in many organs, particularly the kidney (figure). the appearance was typical of cytomegalic inclusion disease. the liver showed extreme active erythropoiesis. cytomegalovirus was isolated from urine obtained at necropsy. ,,~~~~ .: ....i > .._ : i i! t . cm male fetus of g showing gross hydrops fetalis. inset: kidney showing cytomegalic cells with inclusion bodies. haematoxylin and eosin. x (original magnification). these findingsprompted a re-examination of stored maternal andfetal cord sera. the total igm content of the fetal serum was g/l. this is within the normal range for a fetus of this gestation as stated by alford et al. radio- immunoassay for cytomegalovirus igm showed that the fetal serum had a titre of . this is within the range seen in neonatal or cord serum from confirmed cases of symptomatic congenital cytomegalovirus. examination of the maternal serum for cytomegalovirus-specific igm by radioimmunoassay showed a titre of in the serum taken at weeks' gestation, but such igm was absent at weeks. these results were compatible with a primary infection occurring early in the pregnancy. comment cytomegalovirus is a recognised cause of hydrops fetalis, and intra- uterine cytomegalovirus infection was confirmed in this case by his- tology and isolation of the virus. initial serology for cytomegalovirus specific igm on fetal cord serum obtained at weeks' gestation was negative using an indirect fluorescence assay. when a sensitive radio- immunoassay was used, cytomegalovirus-specific igm was detected with ease, showing the increased sensitivity of this procedure for diagnosing congenital cytomegalovirus. we believe this to be the first case in which virus-specific igm has been shown in fetal serum ob- tained in utero. this work was supported by the national fund for research into crippling diseases. requests for reprints should be addressed to chr. davis le, tweek gv, stewart ja, et al. cytomegalovirus mononucleosis in a first trimester pregnant female with transmission to the fetus. pediatrics ; : - . o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .b m j.co m / b r m e d j (c lin r e s e d ): first p u b lish e d a s . /b m j. . . o n ju n e . d o w n lo a d e d fro m http://www.bmj.com/ history of education quarterly s p r i n g v o l u m e ix, number h ttp s://w w w .cam b rid g e.o rg /co re/term s . h ttp s://d o i.o rg / . /s d o w n lo ad ed fro m h ttp s://w w w .cam b rid g e.o rg /co re . c arn eg ie m ello n u n iversity , o n a p r at : : , su b ject to th e c am b rid g e c o re term s o f u se, availab le at https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core history of education quarterly e d i t o r i a l b o a r d a . c . f . beales, university of london edward k r u g , university of wisconsin paul nash, boston university wilson smith, university of california, davis o f f i c e r s o f t h e s o c i e t y ( - ) president d a v i d t y a c k , university of illinois vice president henry j . perkinson, new york university secretary-treasurer e z r i atzmon, new york university directors paul nash, boston university, past president merle borrowman, university of wisconsin david madsen, university of washington charles strickland, emory university editor henry j . perkinson, new york university associate editor paul mattingly, new york university contributing editor franklin parker, university of oklahoma corresponding secretary marianne komodore, new york university the h i s t o r y of e d u c a t i o n q u a r t e r l y is the official organ of the history of education society, published in cooperation with the school of education, new york university. membership dues for the society, which include sub­ scription to the q u a r t e r l y , are $ . annually. subscription to the q u a r ­ t e r l y is at the annual rate of $ . ; single copies, $ . . the q u a r t e r l y is indexed in the education index. library of congress catalog number - . contributions should be addressed to: editor, h i s t o r y o f e d u c a t i o n q u a r t e r l y , school of education, new york university, new york, n . y . . manuscripts should be submitted for consideration in two or more copies. i n matters of style, the manual of style, published by the university of chicago press, is considered definitive. h i s t o r y of e d u c a t i o n q u a r t e r l y , vol. i x , no. , spring . published spring, summer, fall and winter by new york university, washington square east, new york, n . y . . second-class postage paid at new york, n . y . copyright by new york university. h ttp s://w w w .cam b rid g e.o rg /co re/term s . h ttp s://d o i.o rg / . /s d o w n lo ad ed fro m h ttp s://w w w .cam b rid g e.o rg /co re . c arn eg ie m ello n u n iversity , o n a p r at : : , su b ject to th e c am b rid g e c o re term s o f u se, availab le at https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core history of education quarterly c o n t e n t s w i l l i a m chandler bagley's changing v i e w s on the relationship between psychology and education erwin v. johanningmeier cultural crisis i n orthodox r u s ' i n the sixteenth and seven­ teenth centuries as a problem i n education and social change' william k . medlin notes and documents i . michael john demiashkevich and the essentialist committee for the advancement of american education gurney chambers i i . john orville t a y l o r : a forgotten educator paul d. trovers i i i . a note on the educational w o r k of thomas jefferson roy j. honeywell h ttp s://w w w .cam b rid g e.o rg /co re/term s . h ttp s://d o i.o rg / . /s d o w n lo ad ed fro m h ttp s://w w w .cam b rid g e.o rg /co re . c arn eg ie m ello n u n iversity , o n a p r at 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clear. however, the effect of hydrophilic bile acids seems to be related with the blockage of a series of processes that converge on mitochondrial damage. bax is a pro-apoptotic protein that belongs to the superfamily of the bcl- proteins and is involved in mitochondrial pore formation. submicellar concentrations of cytoprotective bile acids have been shown to modulate bax concentration in mitochondria, suggesting that these molecules may interact directly with the protein. in this study, our objective was to evaluate the affinity of bile acids to recombinant bax protein, making use of fluorescence spectroscopy (fret and fluorescence anisotropy), as well as fluorescence correlation spectroscopy (fcs). our results show that the cytoprotective bile acids udca and tudca associate with recombinant bax protein with high affinity, while the cytotoxic bile acid dca only seems to be able to adsorb to the protein with much lower affinity. notably, the bind- ing site for udca seems to be located in a hydrophobic pocket of the protein. this interaction could be responsible for the disruption of bax translocation to the mitochondrial outer membrane in the presence of udca and/or tudca. supported from fct/portugal (projects ptdc/qui-biq/ / and reci/ctm-pol/ / ). t.s. and f.f. acknowledges fct grants sfrh/bd/ / and sfrh/ bpd/ / -pos board b mac inhibitors neutralize the pro-apoptotic effects of tbid pablo m. peixoto , oscar h. teijido , laurent m. dejean , evgeny pavlov , bruno antonsson , kathleen w. kinnally . natural sciences, baruch college - cuny, new york, ny, usa, national institute of child health and human development, baltimore, md, usa, chemistry, california state university of fresno, fresno, ca, usa, new york university college of dentistry, new york, ny, usa, merck serono, geneva research center, geneva, switzerland. since our initial characterization of the imacs, different di-bromocarbazole derivatives with anti-apoptotic function have been developed and tested in several mouse models of brain injury and neurodegeneration [ - ]. owing to the increased therapeutic potential of anti-apoptotic di-bromocarbazole de- rivatives, we sought to expand our knowledge of the mechanism of action of these small molecule inhibitors. we investigated the kinetics of mac inhibi- tion in mitochondria from wild type, bak, and bax knockout cell lines using patch clamp electrophysiology, fluorescence microscopy, elisa, and quantita- tive western blot analyses. our results show that imacs work through at least two mechanisms: ) by blocking relocation of the cytoplasmic bax protein to mitochondria and ) by disassembling bax oligomers in the outer membrane. a comparison of the inhibitory effects over channel conductance and cyto- chrome c release suggests that the imacs interacted with both bax and bak with similar kinetics. interestingly, wild type mitochondria were more suscep- tible to inhibition than the bak or bax knockouts. a quantitative western blot analysis showed that wild type mitochondria had lower steady state levels of bak, which suggests an uneven stoichiometry of the mac components. -pos board b tyrosine phosphorylation of mitochondrial ca d uniporter regulates mitochondrial ca d uptake jin o-uchi, stephen hurst, jyotsna mishra, xiaole xu, bong sook jhun, shey-shing sheu. depariment of medicine, center for translational medicine, jefferson medical college, thomas jefferson university, philadelphia, pa, usa. mitochondrial ca þ has a critical role for balancing cell survival and death. ca þ influx into mitochondrial matrix is mediated primarily by the mitochondrial cal- cium uniporter (mcu). however, the signaling pathways that regulate mcu channel functions via post-translational modifications of mcu are completely unknown. here we show that adrenergic signaling induces mcu tyrosine phos- phorylation and accelerates mitochondrial ca þ uptake in cardiac cells. adren- ergic signaling induces activation of proline-rich tyrosine kinase (pyk ) and translocation into the mitochondrial matrix; enhancing the interaction between pyk and mcu, which subsequently accelerates mitochondrial ca þ uptake via pyk -dependent mcu tyrosine phosphorylation. mcu contains tyrosine res- idues ( in the n-terminus, in the pore-forming region, in transmembrane do- mains and in the c-terminus), which are conserved across all eukaryotic species. among them, only of these tyrosine residues (y at n-terminus, y , and y at c-terminus in mouse mcu) remained as potential phosphor- ylation candidate sites for protein tyrosine kinases using phosphorylation predic- tion programs. we mutated these tyrosine residues to phenylalanine and generated non-phosphorylation mimetic mcu mutants (mcu-yfs). we confirmed that only two tyrosine sites were phosphorylated in response to adren- ergic stimulation in situ using cell lines stably expressing mcu-yfs. in addi- tion, overexpression of these mcu-yfs failed to increase mitochondrial ca þ uptake in response to cytosolic ca þ elevation by thapsigargin, whereas wild- type mcu transfection dramatically accelerates mitochondrial ca þ uptake compared to non-transfected cells. in summary, mcu contains pyk -specific phosphorylation site(s) and pyk -dependent tyrosine phosphorylation of mcu can modulate its channel functions and regulate mitochondrial ca þ uptake. -pos board b cardioprotective roles of neuronal ca d sensor- during stress tomoe y. nakamura-nishitani , shu nakao , shigeo wakabayashi . molecular physiology, natl.cer.cardiovasc.ctr., suita, japan, cardiac physiology, natl.cer.cardiovasc.ctrwakabayshi, suita, japan. dysregulation of ca þ homeostasis in cardiomyocytes often results in heart fail- ure. identifying molecular targets that regulate cardiomyocyte survival is of ther- apeutic importance. neuronal ca þ -sensor- (ncs- ) is an ef-hand ca þ - binding protein, which is important for excitable cell functions. we previously found that ncs- -deficient (ncs �/�) mice had excess neonatal mortality (circ. res. ).the aim ofthe present study isto examinewhether ncs- plays beneficial roles in cardiac survival during stress and the possible mechanisms un- derlying these effects. neonatal mouse ventricular myocytes orwhole hearts from wild-type (wt) and ncs �/� mice were subjected to stressors, and the resistance to stress was evaluated. ncs �/� mouse hearts were more susceptible to stress induced by oxidative impairment and ischemia-reperfusion injury. stress- inducedactivationofphosphatidylinositol -kinase (pi k)/akt signaling, a major survival pathway, was substantially reduced in the ncs �/�group, and overex- pressionofncs- ortheconstitutiveactive formofakt increased the survivalrate of ncs �/� myocytes. cellular atp levels, as well as mitochondrial respiration rates (both basal and maximal o consumption) were significantly depressed in ncs �/� myocytes; especially with oxidative stress. furthermore, intracellular ca þ handling was more easily dysregulated in stressed ncs �/� myocytes than wt myocytes. since ncs- levels were increased by stress, the data suggest that ncs- is a survival-promoting factor, which is upregulated by stress stimuli. interestingly, however,supra-physiological ncs- expression was toxic to cells. taken together, our data suggest that moderate ncs- expression during stress promotes cardiomyocyte survival by maintaining proper ca þ handling, which is required for activation of akt survival pathways and mitochondrial function. -pos board b initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart development gisela beutner, george a. porter, jr. pediatrics, university of rochester medical center, rochester, ny, usa. mitochondria in early embryonic hearts are not thought to produce atp, yet they do produce reactive oxygen species (ros) that regulate myocyte differen- tiation. to assess changes in atp and ros generation in the developing heart, we measured mitochondrial oxygen consumption, the activity of the complexes (cx) and of the electron transport chain (etc), etc supercomplex assem- bly, and ros in embryonic mouse hearts. at embryonic day (e) . , mitochon- drial etc activity and oxidative phosphorylation (oxphos) are not coupled, even though the etc complexes are present. we show that cx- is able to accept electrons from the krebs cycle, but enzyme assays that specifically mea- sure electron flow to ubiquinone or cx- show no activity at this early embry- onic stage. at e . , mitochondria appear functionally more mature; etc activity and oxphos are coupled and respond to etc inhibitors. in addition, the assembly of highly efficient respiratory supercomplexes containing cx � , � , and � , ubiquinone, and cytochrome c begins at e . , the exact time when cx- becomes functional activated. at e . , etc activity and oxphos of embryonic heart mitochondria are indistinguishable from adult mitochon- dria. in contrast, generation of reactive oxygen species (ros), as measured with amplex red, is high at e . and drops significantly by e . , coinciding with activation of the etc. in summary, our data suggest that between e . and e . dramatic changes occur in the mitochondria of the embryonic heart, which result in a decrease of ros generation and an increase in oxphos due to the activation of cx- and the formation of supercomplexes. -pos board b the stoichiometry between micu and mcu determines the different mitochondrial ca d uptake phenotypes in heart and liver melanie paillard, györgy csordás, tünde golenár, cynthia moffat, erin seifert, györgy hajnóczky. mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa. mitochondrial ca þ uptake is central to oxidative metabolism and cell death signaling. the first clues to its molecular mechanism have emerged from the recent identification of the mitochondrial ca þ uniporter’s pore forming protein (mcu) as well as its regulators. among the regulators, micu shows striking 	mac inhibitors neutralize the pro-apoptotic effects of tbid 	tyrosine phosphorylation of mitochondrial ca + uniporter regulates mitochondrial ca + uptake 	cardioprotective roles of neuronal ca + sensor- during stress 	initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart de ... 	the stoichiometry between micu and mcu determines the different mitochondrial ca + uptake phenotypes in heart and liver editor’s letter | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . / corpus id: editor’s letter @article{boissy editorsl, title={editor’s letter}, author={adrienne r. boissy}, journal={journal of patient experience}, year={ }, volume={ }, pages={ - } } 	adrienne r. boissy 	published 	medicine 	journal of patient experience view on sage journals.sagepub.com save to library create alert cite launch research feed share this paper related papers 	abstract 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding wednesday, february , a mitochondria in cell life and death -pos board b a step forwardin understanding the mechanismof vdac voltage-gating oscar teijido hermida , shay rappaport , rachna ujwal , jeff abramson , vicente m. aguilella , sergey m. bezrukov , tatiana k. rostovtseva . nichd, national institutes of health (nih), bethesda, md, usa, david geffen school of medicine, ucla, los angeles, ca, usa, universitat jaume i, castello de la plana, spain. the voltage-dependent anion channel (vdac) governs the exchange of ions and metabolites between the mitochondria and the rest of the cell. in its open state vdac exhibits high conductance and selectivity for anions that facilitates the passage of adp, atp, and other metabolites. at increased voltages (> mv) vdac switches to lower conducting states, termed as ‘‘closed’’ states. closed states are cation-selective and impermeable for atp. the voltage-induced transition from the open to closed states is referred to as voltage-gating. although it is well established that vdac voltage-gating in- volves large structural rearrangements, the precise molecular mechanism of this process is still under debate. we investigated vdac voltage-gating by sys- tematically titrating vdac charge residues and by using thermodynamic and kinetic approaches to study opening and closing of the channel. all the models proposed so far agree that n-terminal region plays a key role in vdac voltage- gating. according to the original idea, the n-terminal region is a part of a mo- bile voltage sensor domain, which slides in and out of the channel lumen in re- sponse to the applied voltage. the alternative models consider independent movement of the n-terminal region upon gating. in order to test the role of vdac n-terminal region in voltage-gating, we engineered a double cys mu- tant of murine vdac that cross-links the a-helix to the b-strand of the pore wall. the cross-linked vdac reconstituted into planar lipid membranes exhibited typical voltage gating, which suggests that the n-terminal a-helix is located inside the pore of vdac in the open state and remains associated with the pore wall during voltage gating. our findings support a model where b-bar- rel is not rigid but undergoes a conformational change that leads to a partial constriction upon transition to the closed states. -pos board b novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding kely l. sheldon , coert j. zuurbier , sergey m. bezrukov , tatiana k. rostovtseva . the natl. institutes of health, bethesda, md, usa, university of amsterdam, amsterdam, netherlands. the voltage dependent anion channel (vdac) is involved in regulation of me- tabolite flux across the mitochondrial outer membrane (mom). hexokinse ii (hk ) is known to bind the mom where it phosphorylates glucose into glucose- -phosphate (g p). high expression of hxk is a common phenotype of many cancers, where its concentration can be times of that in noncan- cerous cells, and is implicated in the warburg effect. it is believed that vdac serves as a hxk binding site in the mom. the amino acid n-ter- minal sequence of hxk is responsible for mitochondrial binding and, when conjugated to tat (tat-hk ), binds to mitochondria with higher affinity than native hxk , causing hxk detachment. we have previously found that dimeric tubulin reversibly binds and partially blocks vdac inhibiting me- tabolite flux across the mom. now we show that this binding can be attenuated by tat-hxk peptide as well as by full length hxk . we have found that tat-hxk and recombinant full length hxk inhibit tubulin blockage of vdac reconstituted into planar lipid bilayers without altering characteristic channel properties such as single channel conductance and selectivity. binding of hxk to vdac is verified by the generation of high-frequency excess cur- rent noise without channel closure. hxk bound to vdac prevents subse- quent tubulin binding, but only when added before tubulin, and inhibits tubulin-induced vdac blockage in a dose dependent manner. moreover, g p, which is known to cause hxk detachment from the mom, fully re- verses the inhibition of tubulin-vdac binding. this suggests that hxk de- tachment from vdac (and hence the mom) is caused by a hxk conformational change upon g p binding. thus we propose a novel mecha- nism of mitochondrial respiration control in cancer cells through the competi- tion between hxk and tubulin for vdac binding. -pos board b reprogramming of mitochondrial ca d handling in micu -deficient hela cells tünde golenár , györgy csordás , erin l. seifert , cynthia moffat , fabiana perocchi , yasemin sancak , david weaver , vamsi k. mootha , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. recent studies have revealed mcu as the pore forming domain and micu as a critical ca þ-sensitive regulator of the mitochondrial ca þ uniporter. how- ever, the exact role of micu in ca þ transport remains to be addressed. our previous studies showed that prolonged down-regulation of micu in hela cells (shmicu ) promotes mitochondrial ca þ uptake at low [ca þ ], which unexpectedly, fails to effectively increase matrix [ca þ ]. to determine the source of discrepancy between the mitochondrial ca þ uptake and the ma- trix [ca þ] phenotypes, first we simultaneously monitored ruthenium red- sensitive clearance of added ca þ from the cytoplasm and the corresponding matrix [ca þ] response in permeabilized shmicu cells. under conditions of similar cytoplasmic ca þ clearance, shmicu cells showed a smaller matrix [ca þ ] increase than the control, indicating enhanced buffering of ca þ in the matrix. enhanced ca þ binding in the matrix likely reflects alkalinization and enhanced phosphate transport. to test if upregulation of ca þ buffering is di- rectly linked to micu depletion, we also assessed mitochondrial ca þ han- dling after hr silencing of micu (simicu ). in simicu cells both mitochondrial ca þ uptake and the matrix [ca þ ] rise were effectively stimu- lated at low ca þ levels. thus, upregulation of matrix ca þ buffering seems to be a component of an adaptive response to sensitization of mitochondrial ca þ uptake in shmicu . the adaptive response is likely to be important to attenuate some micu -depletion induced cellular impairments that we found to manifest as attenuated mitochondrial atp production and cell proliferation. -pos board b micu -dependent threshold and cooperativity of mitochondrial ca d uptake in the liver györgy csordás , erin l. seifert , tünde golenár , cynthia moffat , sergio de la fuente perez , david weaver , roman bogorad , victor koteliansky , vamsi k. mootha , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, koch institute for integrative cancer research, mit, cambridge, ma, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. recent studies have revealed mcu as the pore forming domain and micu as a critical ca þ-sensitive regulator of the mitochondrial ca þ uniporter. how- ever, the mechanism of the complex ca þ dependence of the uniporter activity remains elusive. our previous studies showed that prolonged down-regulation of micu in hela cells causes lower threshold and decreased cooperativity of mitochondrial ca þ uptake. to study the functional significance of the effects of micu we used hepatocytes harvested from the liver of mice exposed to in vivo silencing ( weeks). silencing of micu or mcu resulted in > % decrease in their respective mrna levels. silencing of micu caused a left- ward-shifted dose response and decreased cooperativity of mitochondrial ca þ uptake in both permeabilized and intact hepatocytes. by contrast, silenc- ing of mcu resulted in slower ca þ uptake in the entire range of ca þ concen- trations without change in threshold. mitochondrial respiration and cellular atp content were unaffected in media containing both glycolytic and mito- chondrial fuels in either micu or mcu-deficient hepatocytes. however, si- lencing of micu caused an augmented loss of atp when the cells were confined to oxidative metabolism and an enhanced sensitivity to mitochondrial ca þ overload and permeabilization. during stimulation with vasopressin, a ca þ mobilizing hormone, both micu and mcu-deficient cells displayed an attenuated mitochondrial matrix [ca þ ] increase and stimulation of respira- tion. collectively, these results show that keeping the gate of mcu closed by micu at low [ca þ] is required to maintain healthy mitochondria, and micu -mediated control of mcu (cooperativity?) is required to support the propagation of short-lasting calcium spikes and oscillations to the mitochondria and the ensuing physiological stimulation of oxidative metabolism. -pos board b targeting mcl- and bak as a therapeutic tool to selectively induce apoptosis in hepaptocellualr carcinoma nima niknejad, soumya sinha roy, eric knudsen, györgy hajnóczky. thomas jefferson university, philadelphia, pa, usa. in this study we seek to identify novel drug targets to induce apoptosis in he- patocellular carcinoma (hcc) cells thus providing opportunities to develop novel treatments to improve the prognosis of liver cancer patients. several ap- optotic pathways are mediated through cleavage of bid (a bh domain-only, pro-apoptotic protein) to produce truncated bid (tbid). tbid induces apoptosis through induction of outer mitochondrial membrane (omm) permeabilization by activation of pro-apoptotic bak that resides in the omm or cytoplasmic bax. due to its localization, bak can mediate the early phase of the response to tbid. we have recently demonstrated that omm targeting of bak and the sensitivity to tbid-induced omm permeabilization is dependent on the expression of 	a step forward in understanding the mechanism of vdac voltage-gating 	novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding 	reprogramming of mitochondrial ca + handling in micu -deficient hela cells 	micu -dependent threshold and cooperativity of mitochondrial ca + uptake in the liver 	targeting mcl- and bak as a therapeutic tool to selectively induce apoptosis in hepaptocellualr carcinoma fatal massive hemoptysis in a patient on low-dose oral prednisone: chronic necrotizing pulmonary aspergillosis case reports fatal massive hemoptysis in a patient on low-dose oral prednisone: chronic necrotizing pulmonary aspergillosis bobbak vahid md and paul e marik md we report a case of chronic necrotizing aspergillosis in a -year-old man with chronic lung disease, who was on low-dose oral prednisone. the patient was treated with various antibiotics but had no improvement. samples obtained via bronchoscopy grew aspergillus, and the patient was started on lipid formulation amphotericin b. three days after admission the patient developed fatal massive hemoptysis, presumably secondary to acquired systemic-to-pulmonary vascular communication. this is an unusual presentation of a rare manifestation of pulmonary aspergillosis. a high index of suspicion is needed to diagnose this condition in susceptible patients. key words: chronic necrotizing aspergillosis, hemoptysis, pulmonary mycosis. [respir care ; ( ): – . © daedalus en- terprises] introduction chronic necrotizing pulmonary aspergillosis was first described in by gefter et al, who described pa- tients with locally invasive pulmonary aspergillosis. gefter et al used the term “semi-invasive pulmonary aspergillo- sis” to differentiate this clinical entity from colonization of the respiratory tract and frank pulmonary invasive aspergil- losis. in , binder et al cited cases in the literature that were consistent with the diagnosis of chronic necro- tizing pulmonary aspergillosis, and coined the term “chronic necrotizing aspergillosis.” terms that were used to de- scribe cases of chronic necrotizing pulmonary aspergillo- sis before were “primary pulmonary aspergillosis,” “pulmonary aspergillosis with cavitation,” and “symptom- atic pulmonary aspergilloma.” massive hemoptysis is a rare and potentially fatal com- plication of chronic necrotizing pulmonary aspergillosis. we describe a case of chronic necrotizing pulmonary as- pergillosis that was misdiagnosed as bacterial pneumonia for several months and led to massive hemoptysis, with a fatal consequence. case summary a -year-old african american man was admitted to the hospital for dyspnea, weight loss, and chronic cough. a chest radiograph and chest computed tomogram (fig. ) showed bilateral pulmonary consolidations. review of a chest radiograph from months before this presentation revealed progression of infiltrates in the left upper and left lower lobes. no cavitary lesions were seen. the patient had been treated with several courses of various antibiotics (azithromycin, levafloxicin, and doxycycline) during the several months before this presentation, but his fever, cough, and dyspnea progressed. his medical history was notable for chronic obstructive pulmonary disease (copd), hypertension, diabetes mellitus, and gastroesophageal re- flux disease. the copd was diagnosed years before this presentation. the patient reported frequent hospital admis- sions for copd exacerbations. his last spirometry showed severe airway obstruction (forced expiratory volume in the first second . l). the patient was a smoker for years. he also reported a tuberculosis exposure in the past, but his recent skin tuberculin test was nonreactive. he also had a substantial asbestos exposure when he worked at a navy shipyard. his medications on presentation to us in- cluded metformin, lisinopril, aspirin, oral prednisone ( mg/d for about years, for copd), and an as-needed bronchodilator. bobbak vahid md and paul e marik md are affiliated with the depart- ment of pulmonary and critical care medicine, thomas jefferson uni- versity, philadelphia, pennsylvania. the authors report no conflicts of interest related to the content of this paper. correspondence: bobbak vahid md, department of pulmonary and crit- ical care medicine, thomas jefferson university, walnut street, suite , philadelphia pa . e-mail: bobbak.vahid@mail.tju.edu. respiratory care • january vol no physical examination on admission showed a tempera- ture of . °c, blood pressure of / mm hg, heart rate of beats/min, respiratory rate of breaths/min, and oxygen saturation of % on room air. he was in mild respiratory distress. chest examination revealed bilateral crackles. the heart and abdominal examination was unre- markable. there was no peripheral edema or clubbing. laboratory findings were: white-blood-cell count . � /�l, hemoglobin . g/l, and creatinine of . mg/dl. bronchoalveolar lavage fluid collected during bron- choscopy grew aspergillus fumigatus. the bronchoalveo- lar lavage fluid bacterial, viral, and mycobacterial cultures were negative. chronic necrotizing pulmonary aspergillo- sis was suspected, and the patient was started on lipid formulation amphotericin b. three days after presentation, the patient developed massive hemoptysis and died sec- ondary to respiratory failure. the lungs at autopsy showed patchy pulmonary parenchymal invasion of fungal ele- ments, with involvement of the bronchial wall, consistent with chronic necrotizing pulmonary aspergillosis (fig. ). there was no vascular invasion. although there was pleu- ral thickening and chronic inflammation, we found no as- pergillus invasion of the pleura, nor disseminated aspergil- losis in other organs. the massive hemoptysis was thought to be secondary to acquired systemic-to-pulmonary vas- cular communications seen in chronic inflammatory and infectious diseases of the lung. discussion chronic necrotizing pulmonary aspergillosis is defined as an indolent but destructive inflammatory lung infection by invasive aspergillus species (usually a. fumigatus), and is characterized by local invasion of lung tissue by fungal elements, but absence of vascular invasion. although chronic necrotizing aspergillosis is progressive over sev- eral months, there is no dissemination to other organs. , chronic necrotizing pulmonary aspergillosis is usually seen in middle-age and elderly patients. symptoms are nonspecific and include fever, cough, hemoptysis, and weight loss of – months duration. most patients with chronic necrotizing pulmonary aspergillosis have either underlying chronic lung diseases or systemic diseases that predispose them to the disease. in one study, % of pa- tients had no reported risk factors and % of patients had multiple risk factors. the pulmonary risk factors include copd, interstitial lung disease, previous mycobacterial infections, asthma, cystic fibrosis, previous lung resection, sarcoidosis, and pneumoconiosis. – the systemic risk factors are diabetes mellitus, low-dose corticosteroids, rheu- matoid arthritis, ankylosing spondylitis, and malnutri- tion. , , other rare clinical manifestations are pneumotho- rax, immune reconstitution syndrome in patients infected with human immunodeficiency virus who are on antiret- roviral therapy, pulmonary infiltrates following crypto- coccal infection, and pancoast syndrome. radiographic findings include an infiltrative process in the upper lobes or superior segment of the lower lobes, and cavitary le- sions, with adjacent pleural thickening. a mycetoma (fun- gus ball) can be seen in about % of patients with cav- itary lesions. histologic examination of the lung parenchyma shows necrotizing granulomas, invasion and destruction of lung tissue by mycetoma, or primary bron- chiolar infection. , fig. . chest computed tomogram showing bilateral infiltrates. fig. . fungal elements, showing the ° branching that is con- sistent with aspergillus species (� silver stain). chronic necrotizing pulmonary aspergillosis respiratory care • january vol no diagnosing chronic necrotizing pulmonary aspergillosis can be challenging. diagnosis may be helped by histologic evidence of tissue invasion by fungus, clinical and radio- graphic features consistent with the diagnosis, and isola- tion of aspergillus from sputum or bronchoscopic samples after exclusion of other conditions. delayed diagnosis is common and can contribute to morbidity and mortality. in one study, the average delay in diagnosis ranged from months to months. treatment options include antifun- gal therapy with amphotericin b, itraconazole, or voricon- azole. although voriconazole is equal or superior to am- photericin b for invasive aspergillosis, there are few data on chronic necrotizing aspergillosis. surgical resection is limited to a small subset of patients with local infection, adequate pulmonary reserve, and acceptable surgical risk. , chronic necrotizing pulmonary aspergillosis should be included in the differential diagnosis of pulmonary infil- trates in a patient with pulmonary or systemic risk factors and fever, cough, dyspnea, and weight loss. massive he- moptysis is a potentially fatal complication of chronic ne- crotizing pulmonary aspergillosis. references . gefter wb, weingrad tr, epstein dm, ochs rh, miller wt. “semi- invasive” pulmonary aspergillosis: a new look at the spectrum of aspergillus infections of the lung. radiology ; ( ): – . . binder re, faling lj, pugatch rd, mahasaen c, snider gl. chronic necrotizing pulmonary aspergillosis: a discrete clinical entity. med- icine (baltimore) ; ( ): – . . saraceno jl, phelps dt, ferro tj, futerfas r, schwartz db. chronic necrotizing pulmonary aspergillosis: approach to management. chest ; ( ): – . . soubani ao, chandrasekar ph. the clinical spectrum of pulmonary aspergillosis. chest ; ( ): – . . kato t, usami i, morita h, goto m, hosoda m, nakamura a, shima s. chronic necrotizing pulmonary aspergillosis in pneumoconiosis: clinical and radiographic findings in patients. chest ; ( ): – . . hasse b, strebel b, thurnheer r, uhlmann f, krause m. chronic necrotizing pulmonary aspergillosis after tuberculosis in an hiv- positive woman: an unusual immune reconstitution phenomenon? aids ; ( ): – . . kobashi y, yoshida k, miyashita n, niki y, matsushima t. chronic necrotizing pulmonary aspergillosis complicated by a cavitary lesion caused by pulmonary mycobacterium-avium complex disease. in- tern med ; ( ): – . . hafeez i, muers mf, murphy sa, evans eg, barton rc, mcwhin- ney p. non-tuberculous mycobacterial lung infection complicated by chronic necrotising pulmonary aspergillosis. thorax ; ( ): – . . thurnheer r, moll c, rothlin m, krause m. chronic necrotizing aspergillosis complicated by pneumonthorax. infection ; ( ): – . . kitazaki t, osumi m, miyazaki y, kihara c, kinoshita a, tsuji h, et al. chronic necrotizing pulmonary aspergillosis following crypto- coccal infection of the lung. scand j infect dis ; ( ): – . . simpson fg, morgan m, cooke nj. pancoast’s syndrome associated with invasive aspergillosis. thorax ; ( ): – . chronic necrotizing pulmonary aspergillosis respiratory care • january vol no ep- : the identification of putative biomarkers of radioresistance in rectal cancer tissue using antibody microarray s rd estro forum ep- the identification of putative biomarkers of radioresistance in rectal cancer tissue using antibody microarray b. onal , l. bowden , s. seedat , s. maher , i.a. hunter , l. cawkwell university of hull, cancer biology proteomics group, hull, united kingdom university of hull, school of biological biomedical and environmental sciences, hull, united kingdom castle hill hospital, academic surgical unit, hull, united kingdom purpose/objective: despite significant research input aiming to improve therapy regimens, rectal cancer remains as one of the cancers with significant morbidity rates. radiotherapy has been shown to lower -year local recurrence by approximately %. a substantial number of rectal tumours fail to respond to radiotherapy which not only presents a barrier for effective cancer treatment bu also means that those patients with therapy resistant tumours endure the harmful side effects of radiotherapy for no therapeutic gain. therefore, it is important to identify biomarkers capable of predicting a tumour's response to radiotherapy prior to treatment which can improve therapy outcomes. the aim of this study is to identify putative protein biomarkers of radiotherapy resistance using rectal cancer tissue biopsy samples by employing comparative proteomic tools. ultimate aim is to translate these biomarkers into an assay panel for routine cancer screening aiding the personalisation of cancer treatment. materials and methods: following ethical approval (sheffield rec ref /h / ), two pairs of pre-treatment rectal cancer biopsy samples (radioresistant versus radiosensitive) were investigated using antibody microarray to identify differentially expressed proteins (deps) involved in mediating radiotherapy resistance. data obtained from the experiments were subjected to data mining using ingenuity pathway analysis (ipa) which mapped these deps onto their most relevant canonical signalling pathways. results: the antibody microarray analysis of the clinical samples revealed deps and deps from the first and the second experiment, respectively. the ipa analysis of these combined generated canonical pathways. amongst these, the most interesting pathways included p signalling ( deps mapped), death receptor signalling ( deps mapped), apoptosis signalling ( deps mapped) and egf signalling ( deps mapped). radiotherapy is known to initiate cellular apoptosis via the intrinsic (mitochondrial) apoptotic pathway. however, the identification of some regulatory proteins involved in the extrinsic pathway (death receptor) apoptotic pathway (figure ) has revealed a potential link between radiotherapy and this pathway. figure : death receptor signalling a total of deps were mapped onto the death receptor signalling pathway, namely cradd, tnfrsf , mapk , tnfsf , nfkb , tnfrsf a and tnf. conclusions: antibody microarray analysis of rectal cancer biopsy samples has enabled the identification of a number of deps which may be involved in mediating response to radiotherapy. however, further confirmation with western blotting and validation with immunohistochemistry are required before such biomarkers can be introduced into routine clinical management of cancer patients. ep- validation of a rectal cancer outcome prediction model in routine chinese patients l. shen , j. van soest , j. wang , j. yu , w. hu , y.u.t. gong , v. valentini , y. xiao , a. dekker , z. zhang shanghai medical college fudan university, radiation oncology department, shanghai, china grow school for oncology and developmental biology maastricht university medical centre, radiation oncology department, maastricht, the netherlands jefferson medical college of thomas jefferson university, radiation oncology department, philadelphia, usa università cattolica del sacro cuore, radiation oncology department, rome, italy purpose/objective: the risk of local recurrence, metastases and overall survival of locally advanced rectal cancer after preoperative chemoradiation and curative surgery can be estimated by prediction models and visualized using nomograms, which have been trained and validated in european clinical trial populations. this study aims to validate these prediction models in a routine clinical chinese cohort. materials and methods: from to , clinical data of consecutive locally advanced rectal adenocarcinoma patients treated with preoperative chemoradiation and curative surgery from a single chinese cancer center, were retrospectively collected and used for external validation. concordance index (c-index) and calibration curves were used to assess the performance of the previously developed drug duo disappoints in colorectal cancer news in brief september  cancer discovery |  drug duo disappoints in colorectal cancer the combination of genentech’s atezolizumab (tecentriq) and cobi- metinib (cotellic) is no more effective than standard of care for patients with previously treated metastatic colorectal cancer, according to results presented recently at the european society for medical oncology world congress on gastrointestinal can- cer in barcelona, spain (ann oncol ; [suppl_ ; abstr lba- ]). pd-l inhibitors such as atezoli- zumab have worked poorly as a monot herapy in patients with micro- satellite-stable colorectal cancer, which accounts for % of cases. however, a study of mice with colorectal tumors found that adding a mek inhibitor, such as cobimetinib, spurs t cells to enter the tumors and boosts the effectiveness of anti–pd-l immu- notherapy (immunity ; : – ). those results led to a phase ib trial of atezolizumab plus cobimetinib in patients with metastatic colorectal cancer. building on that study, the phase iii imblaze trial assessed the drugs in patients with inoperable, locally advanced or metastatic colorectal can- cer, . % of whom had cancers that were microsatellite-stable or showed a low degree of instability. patients received atezolizumab alone, atezoli- zumab with cobimetinib, or the multi- kinase inhibitor regorafenib (stivarga; bayer), the standard of care. at the congress, researchers pre- sented data for patients, and the results revealed no statistically signifi- cant difference in effectiveness between the combination and regorafenib. the median overall survival was . months for patients treated with the two drugs, . months for those who received regorafenib, and . months for those who received atezolizumab. the overall response rates were . % in the combi- nation therapy group and . % in the atezolizumab and regorafenib mono- therapy groups. progression-free survival was also similar across the three groups. the atezolizumab/cobimetinib combination was also comparable to regorafenib in severity and frequency of side effects. the rate of grade or higher adverse effects in patients who received the two drugs was %, versus % for the regorafenib group. among the patients who received the drug duo, % developed diarrhea, % developed a rash, and % suffered nausea. in the regorafenib group, the most common side effect was hand–foot syndrome, a condition that affected % of the patients. forty-three percent of the patients in this group reported fatigue, and % suffered diarrhea. “these results are very discourag- ing,” says patrick boland, md, of roswell park comprehensive cancer center in buffalo, ny, who wasn’t con- nected to the study. given that “there is virtually no response here,” he says, “it seems doubtful that we will identify a group of patients that’s going to benefit from this combination.” however, the two drugs may still prove useful, says adam snook, phd, of thomas jefferson university in phila- delphia, pa, who also wasn’t connected to the study. the work “seems to sug- gest that pd- /pd-l signaling is not the primary cause of immune suppres- sion in colorectal cancer,” snook says. therefore, treatments that target other checkpoint proteins, such as ox , might stimulate tumors to activate pd- /pd-l signaling and become vulnerable to atezolizumab/cobimetinib therapy. “i’m excited to see what these other checkpoint pathways are going to do,” he says. –mitch leslie n cdk changes telling in prostate cancer patients with prostate cancer and specific genetic alterations may be more likely to respond to immunotherapy: in a recent study, researchers determined that men with metastatic castration- resistant prostate cancer (mcrpc) who had mutations that inactivated both cdk alleles also exhibited other genetic changes that might make them more responsive to a pd- inhibitor (cell ; : – ). “checkpoint immunotherapy in general has not done well in patients with prostate cancer” compared with melanoma and lung cancer, possibly because prostate cancer has a compar- atively low tumor mutational burden, says arul chinnaiyan, md, phd, direc- tor of the michigan center for trans- lational pathology at the university of michigan in ann arbor, and one of the study’s senior authors. in a study, chinnaiyan and others established a landscape of molecular alterations in prostate cancer by sequencing tumor biopsies from men with mcrpc (cell ; : – ). in the process, they discovered a small percentage of patients with mutations that inacti- vated both cdk alleles. to further investigate, chinnaiyan and his team performed a comprehensive genomic analysis of tumor samples from men with mcrpc. they found that % of these men had mutations that inactivated both cdk alleles, and this inactivation was associated with genomic instability, tandem duplications throughout the genome, gene fusions, and higher levels of neoantigens. the researchers also found increased t-cell infiltration in the tumors.   a related retrospective study exam- ined four patients with mcrpc who harbored cdk mutations and who did not respond to conventional treat- ments. when treated with the pd- inhibitor pembrolizumab (keytruda; merck), two experienced a decrease in psa, one of whom also demonstrated a radiographic response.    the findings suggest that such patients might benefit from pd- inhibitors, which are already approved for melanoma, lung cancer, and other malignancies, chinnaiyan says. “i think it’s building upon the idea of identify- ing various subclasses of metastatic prostate cancer that would preferen- tially respond to specific treatments—so moving towards precision medicine.” researchers will soon launch a clini- cal trial to investigate how well patients with cdk mutations respond to checkpoint inhibitors. adam dicker, md, phd, of the sid- ney kimmel medical college & cancer center at thomas jefferson univer- sity in philadelphia, pa, who was not involved in the study, considers it a “major contribution” that provides new genomic insight into prostate cancer, and could help researchers determine who may benefit from immunotherapy and why. “i think there’s a lot more we need to figure out in the realm of prostate can- cer, “dicker says,” but it’s the beginning of a road map for precision oncology, research. on april , . © american association for cancercancerdiscovery.aacrjournals.org downloaded from published onlinefirst july , ; doi: . / - .cd-nb - https://doi.org/ . /annonc/mdy . https://doi.org/ . /annonc/mdy . https://doi.org/ . /j.immuni. . . https://doi.org/ . /j.immuni. . . http://dx.doi.org/ . /j.cell. . . http://dx.doi.org/ . /j.cell. . . http://dx.doi.org/ . /j.cell. . . http://cancerdiscovery.aacrjournals.org/ ; : . published onlinefirst july , .cancer discov drug duo disappoints in colorectal cancer updated version . / - .cd-nb - doi: access the most recent version of this article at: e-mail alerts related to this article or journal.sign up to receive free email-alerts subscriptions reprints and .pubs@aacr.orgdepartment at to order reprints of this article or to subscribe to the journal, contact the aacr publications permissions rightslink site. click on "request permissions" which will take you to the copyright clearance center's (ccc) .http://cancerdiscovery.aacrjournals.org/content/ / / . to request permission to re-use all or part of this article, use this link research. on april , . © american association for cancercancerdiscovery.aacrjournals.org downloaded from published onlinefirst july , ; doi: . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/lookup/doi/ . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/cgi/alerts mailto:pubs@aacr.org http://cancerdiscovery.aacrjournals.org/content/ / / . http://cancerdiscovery.aacrjournals.org/ adequate and predictable stem cell (sc) collection and&nbsp;low incidence of neutropenic fever (nf) with&nbsp;cyclophosphamide (c) and g-csf mobilization in&nbsp;multiple myeloma (mm) : a single center analysis figure . figure . abstracts / biol blood marrow transplant ( ) s es s asct disease status and details about post asct mainte- nance therapy. there were no statistically significant differ- ences between the groups in disease status or change in disease status at day post asct. although more patients in the c group received maintenance therapy post asct, this difference was not statistically significant. figures and show the relapse free survival (rfs)and overall survival (os) of both groups. the median rfs for c and o groups were . and . months (p ¼ . , log rank), respectively. the median os of the c and o groups were . and . month (p¼ . , log rank), respectively. our limited experience suggests that there was no effect of race in the post asct outcomes for mm pts with rd. asct was safe with acceptable transplant related mortality table c dose (mg/m ) < mg/m median age in years (range) . ( - ) number of patients median c dose in mg/m (range) ( - ) median total cd /kg in e (range) . ( . - . ) days to sc collection (range) ( - ) median days of documented neutropenia (range) ( - ) number of patients hospitalized for nf and good long-term outcomes for mm pts with renal dys- function. adequate and predictable stem cell (sc) collection and low incidence of neutropenic fever (nf) with cyclophosphamide (c) and g-csf mobilization in multiple myeloma (mm) : a single center analysis bhavisha patel , zheng zhou , juliet appiah , glen raffel , zankar desai , jayde bednarik , tzafra tessier , jenna l’heureux , jan cerny , muthalagu ramanathan , rajneesh nath . internal medicine, umass memorial medical center, worcester, ma; hematology/oncology, university of massachusetts, worcester, ma; hematology/ oncology, umass memorial medical center, worcester, ma; hematology/oncology section bmt, umass medical center, worcester, ma; stem cell laboratory, university of massachusetts medical center, worcester, ma; pharmacy, umass memorial health care, worcester, ma; umass memorial medical center, worcester, ma; department of medicine; division of hematology/oncology, university of massachusetts, worcester, ma background: g-csf alone or c with g-csf are most commonly used for sc mobilization in mm. the use of c can improve the efficacy of mobilization but is associated with increased neutropenia. it remains largely unclear how dose levels of c in mobilization quantitatively influence the cd yield and time to collection; as well as how these outcomes were influenced by patient’s age. we evaluated the efficacy and neutropenia secondary to c with g-csf in mm patients undergoing sc transplantation. subgroup analysis was done comparing patients greater than years and younger. methods: we retrospectively reviewed charts of all pa- tients with mm who mobilized using c with g-csf at umass memorial medical center from january to june . results: fifty-six patients were identified from the stem cell transplant database. there were males ( %) and fe- males ( %). median age was years (range - ). the median c dose received was mg/m (range - mg/m ). the median total cd collection was . x e /kg (range . - ). median time from c infusion to sc collection was days (range - ). number of days required for collection was (n¼ ), (n¼ ) and (n¼ ). three patients received plerixafor prior to day collection. median days of documented neutropenia was (range - ). only ( . %) patients were hospitalized for nf requiring intravenous antibiotics. optimal collection for two trans- plants (> x e cd /kg) was achieved in ( %) patients. patients ( %) were over age years. in comparison with the younger patient, they were noted to receive lower median dose of c ( mg/m vs. mg/m , p value - mg/m > mg/m p-value . ( - ) . ( - ) . - ( - ) ( - ) . . ( . - . ) . ( . e ) . ( - ) ( - ) . ( - ) ( - ) . . abstracts / biol blood marrow transplant ( ) s es s . ). they were also noted to collect slightly lower cd ( . e /kg vs. . e /kg, p value . ). there was no significant difference in days to sc collection or number of days of neutropenia. conclusion: our retrospective analysis showed that duration of neutropenia does increase significantly with increase in c dose, yet with an overall low nf hospitali- zation rate. higher c dose usage led to longer time to collection. there was no significant difference in cd yield, neu- tropenia, or nf hospitalization in patients > years. c+ g-csf is an effective method of mobilization as proven by optimal collection mantle cell lymphoma: outcomes after hematopoietic stem cell transplantation priyanka pathak, s vikas kumar, onder alpdogan, matthew carabasi, neal flomenberg, dolores grosso, ubaldo martinez-outschoorn, john wagner, mark weiss, barbara pro, joanne filicko-o’hara. medical oncology, thomas jefferson university, philadelphia, pa background: mantle cell lymphoma (mcl) is a b-cell non- hodgkin’s lymphoma (nhl) comprising % of adult nhl in the us with an incidence of - cases per million persons per year. initial therapy of mcl includes a regimen with r- chop or hyper-cvad. the best data for long term survival includes cytarabine based therapy followed by autologous hematopoietic stem cell transplantation (hsct). in the re- fractory/relapsed setting, allogeneic hsct has been used successfully. barriers to allogeneic hsct include lack of donors and potential toxicities. haploidentical donors broaden the donor pool. to our knowledge, there is no published data on outcomes with haploidentical hsct in mcl. methods: a retrospective chart review examining out- comes in patients with mcl who underwent either autol- ogous or allogeneic peripheral blood hsct at thomas jefferson university hospital from january to january . results: a total of patients with mcl underwent hsct between to . nine of patients were males. median age at transplant was years (range - ). me- dian time from diagnosis to hsct was . months. five of patients ( haploidentical & matched unrelated donor) underwent allogeneic hsct and of patients underwent autologous hsct. in the allogeneic hsct group, median number of prior therapies was . one of patients had re- sidual disease prior to hsct. two of patients had a mye- loablative regimen; had reduced intensity regimen. there were no relapses or deaths in the allogeneic hsct group. median progression free survival (pfs) as well as median overall survival (os) in this group was months. major complications in allogeneic hsct were acute skin gvhd ( / ), cmv reactivation( / ), hhv viremia( / ), and acute renal failure ( / ) requiring short term dialysis. in the autologous hsct group, the median number of prior thera- pies was . two of patients had refractory disease prior to autologous hsct. post autologous hsct / patients relapsed and / died. major complications in this group were dvt ( / ), enterocolitis ( / ), and chf ( / ). median pfs and os were and months respectively. our patients who un- derwent autologous hsct were transplanted earlier ( / - / ) than our patients who underwent allogeneic hsct ( / - / ), leading to the difference in sur- vival times. conclusions: haploidentical hsct offers a promising cura- tive treatment for patients with mcl with expected and manageable toxicities. although a small number of patients, this review of our data provides the background for further study of the use of haploidentical hsct in this group of patients. autologous hsct for patients with mcl can also provide long term disease survival. further follow up of both groups will provide better data regarding long term (> year) outcomes. therapy for mcl in the future is likely to include newer agents (e.g. ibrutinib) in the front line, but hsct will remain a viable option. outcome of patients with multiple myeloma with t( ; ) after autologous hematopoietic stem cell transplantation koji sasaki , rima saliba , gary lu , nina shah , qaiser bashir , krina patel , fabian bock , simrit parmar , chitra hosing , uday r. popat , ruby delgado , gabriela rondon , richard e. champlin , muzaffar h. qazilbash . leukemia, the university of texas md anderson cancer center, houston, tx; stem cell transplantation and cellular therapy, the university of texas md anderson cancer center, houston, tx; hematopathology, the university of texas md anderson cancer center, houston, tx background: the cytogenetic abnormality t( ; )(p ;q ) results in the fusion of immunoglobulin heavy chain (igh) gene on chromosome q with the fibroblast growth factor (fgfr ) gene on chromosome p in patients with multiple myeloma (mm), and is associated with shorter progression-free survival (pfs) and overall survival (os). recent studies indicate that treatment with proteasome inhibitors (pi) may overcome the adverse prognostic features. the aim of this study is to assess the outcome of patients with t( ; ) after high-dose chemo- therapy and autologous hematopoietic stem cell transplant (auto-hct). methods: we identified patients with mm who had t( ; ) on conventional cytogenetic or fluorescent in situ hybridization (fish) studies prior to auto-hct at our insti- tution between and . we compared their out- comes to a matched control group (n¼ ) without t( ; ) prior to hct who were treated during the same time period. matching was based on age and response to the last therapy prior to hct. results: patient characteristics are summarized in table . median follow-up intervals were months and months in the t( ; ) and control groups, respectively. pfs at years was % ( % confidence interval [ci], - ) in the t( ; ) and % ( % ci, - ) in the control group (fig. ), (p<. ; hazard ratio [hr], . ; % ci, . - . ). os at years was % ( % ci, - ) in the t( ; ) and % ( % ci, - ) in the control group (fig. ), (p<. ; hr, . ; % ci, . - . ). on multivariate analysis for pfs, t( ; ) (p <. ; hr, . ; % ci, . - . ) emerged as the only significant adverse prognostic factor. relapsed disease at auto-hct was associated with a trend for lower pfs (p¼ . ; hr, . ; % ci, . ). on multivariate analysis for os, t( ; ) (p <. ; hr, . ; % ci, . - . ) and relapsed 	adequate and predictable stem cell (sc) collection and low incidence of neutropenic fever (nf) with cyclophosphamide (c) an ... 	background 	methods 	results 	conclusion microsoft word - pps bf further section psychother. psychosom. ; : - varia competition the dr. heinz karger memorial foundation invites the submission of original research papers to compete for the and award, on the following subjects. : methods for the early diagnosis of genetic disorders : molecular biology of metabolic diseases submission date: manuscripts marked ‘competition’ must reach the publishers s. karger ag, arnold-böcklin-strasse , ch- basel (switzerland) not later than february of either year. the manuscripts must not exceed typewritten pages, including illustrations, tables and bibliography. they must be typewritten on one side only, double-spaced, and are to be submitted in quadruplicate, and in accordance with the instructions contained in ‘rules for the preparation of manuscripts’. this leaflet can be obtained free of charge from the publishers if the request is marked ‘competition’. language: english, german or french. publication: the winning papers will be published in english in one of the karger journals. the award for the prize will be sfr. , .-. the council of the foundation will judge the papers and confer the prize. objectif de la société internationale de psychomorphie favoriser, par des publications et des contacts personnels, un échange international d’informations entre praticiens dont Γactivité se rapporte à la personnalite tant psychique que morphologique. la psychomorphie est une activite pluridisciplinaire intéressant notamment psycholo-gues et medecins dont la specialisation ou le mode habituel d’activité revet un caractere “psychosomatique”. publication trimestrielle: revue psychomorphie. tous renseignements: dr robert maurin, société internationale de psychomorphie, , rue gounod, f- paris (france); telephone wag ( h- h). prix maurice-bouvet le prix maurice-bouvet de psychanalyse a été exceptionnellement attribué en à deux auteurs: jean-luc donnet, pour ses articles: l’antinomie de la resistance – revue: l’lncons-cient, no (oct.-déc. ); le divan bien tempéré – nouvelle revue de psychanalyse, no (automne ). sami-ali, pour son livre: l’espace imaginaire – coll.: connaissance de ∏nconscient (gallimard, ). varia xe congrès international de psychothérapie le congrès se tiendra à paris du au juillet sous Γégide de la federation internationale de psychothérapie medicale dont le president est le prof. p.b. schneider de lausanne, le prof. sivadon étant le president du congrès. le theme du congrès a trait au processus psychothérapique. des travaux collectifs sont prévus dont les sujets inscrits actuellement portent sur: relation transférentielle et théorie de la communication – valeurs humaines et reduction du symptome – enfant et adolescent face au milieu – developpement historique des psychotherapies. des groupes restreints, des tables rondes et des films sont également envisages. les langues officielles du congrès sont le français, Γanglais, Γallemand et Γespagnol. renseignementsscientifiques: oia.mathé, , avenue mozart, f- paris (france). e congrès international de psychosomatique ii sera organise par la société française de médecine psychosomatique et se tiendra à paris du au septembre . les themes principaux du congrès seront les suivants: (a) la place du corps dans la relation psychothérapique et medicale: le corps en milieu hospitaller – le medecin et la sexualité de son malade – corps malade et corps invalide – le corps dans Γespace théra-peutique – le corps et son statut socioculturel; (b) avenir et frontières de la fonction medicale: l’ideologie medicale en question – ce que le malade attend du medecin ou de la médecine – l’hôpital, pourquoi? – médecine et politique de la santé – la médecine et la demande non thérapeutique. les langues officielles du congrès seront le français et Γanglais. renseignements scientifiques: dr leon chertok, , rue legendre, f- paris (france). symposium über natur, funktionen und methoden der erforschung des unbewussten sowjetische wissenschaft wendet sich dem studium des unbewussten zu. die akademie der wissenschaften der georgischen sowjetrepublik, in zusammenarbeit mit der akademie der medizinischen wissenschaften der udssr in moskau, hat fúhrende westliche psychoanalytische wissenschaftler zu einem symposium über natur, funktionen und methoden der erforschung des unbewussten eingeladen. der kongress findet ende in tiflis/georgien statt. vorgesehen ist unter anderem eine diskussion über die derzeit führenden schulen der psychoanalyse, die die freudsche theorie des unbewussten weiterentwickelt haben: c.g. jung, a. adler, die amerikanischen neo-freudianer {erich fromm, karen homey u.a.), alexander mitscherlich, günter ammon, jaques lacan, melanie klein, marie langer usw. der weit über die grenzen der brd bekannte psychoanalytiker günter ammon wurde zu dieser tagung eingeladen, ein hauptreferat zum thema „psychodynamik des unbewussten bei psychosomatischen erkrankungen” zu halten. international conference on the interface between psychoanalysis and family therapy october – , , hilton hotel, civic center boulevard at th street, philadelphia, pa. varia this meeting is being sponsored by the eastern pennsylvania psychiatric institute (philadelphia, pa.). the american academy of psychoanalysis, the division of psychotherapy of the american psychological association, and thomas jefferson university (philadelphia) are co- sponsors. the conference chairman is claus b. bahnson, phd, of eastern pennsylvania psychiatric institute and jefferson medical college. f. for information contact ms. jane parsons conference coordinator department of behavioral sciences eastern pennsylvania psychiatric institute henry avenue philadelphia pa (usa). telephone: – or . masiello, francine r. ( ). senses of democracy. perception, politics and culture in latin america. austin: university of texas press. pages with a focus in latin american cultural production over the last two centuries, francine masiello has composed an extraordinary book that tells the history of what she describes as “sense work”. conceiving the evolution of the sensorium as part of political transformations and, funda- mentally, as a way of perceiving and being part of political and social changes, the author explores senses (feeling, looking, smelling, hearing) how they have changed and how they have been affected by technological transforma- tions. the combined impact of these dimensions provides a unique understanding of the region’s collective political body and its hidden mechanisms. masiello’s goals are ambitious. she puts latin american cultural production in a larger global context in which melville and paul klee might be brought into the con- versation in order to stress how specifically regional processes connected latin america with the world. the author assumes at least three simultaneous tasks in order to understand the place of the sensorium in the history of collective action: its centrality in the creation of the polity, its ambivalent relation with technological trans- formations, and the cultural production reflecting (and producing) the changes in those two realms. the intro- duction and five chapters are a journey through the inner workings of modernization. the introduction presents the book’s broad goal of analyzing the contentious and vital place of the body in politics, from the support of the mission of nations of training citizens to perceive with a shared and uniform ear and mind to the perception of violent abjection exerted against the body and to the ways in which the sensorium puts spectral presences into an intelligible perspective. though masiello’s reflection is about latin america, the focus of her exploration is mostly argentine political and intellectual life. chapter i analyzes the cen- trality of the senses in defining virtues and vices of public life and power in latin american early republican period. the works of the argentine writer esteban echeverría, his obsessive overlapping of the slaughterhouse with the political body, express how elites in the region incorpo- rated the ideas of the french ideologues, different from the rather cold approach to them by thomas jefferson in the united states. chapter ii, probably the most fas- cinating one, explores the way in which the irruption of technology challenges the sense work, but focused mostly in the way women are represented under these changes and in the way female writers revealed this conundrum. people are slaves of their eyes and ears, yet women (above all juana manuela gorriti) point out how as people develop a relation with technological advances as their new master, under which they also miss the more immedi- ate opportunity of the now. chapter iii explores the force- ful engagement with technology in the early twentieth century. horacio quiroga’s vision of “bodies of abnormal speed”, masiello sees not only the perplexity and fascina- tion with accelerated technological changes but also the reserved attitude towards an embodied knowledge that is muddling a desired form of communal life. in chapter iv, “a politics of perception”, the author dissects the penetrat- ing and prescient ideas of león rozitchner about politics, violence and the individual. as technology perfects forms of power and state oppression in the second half of the twentieth century, it also leaves exposed the bare latin american truth of the body as the locus of a prolific rela- tion between politics and violence. the last chapter and conclusion start by reflecting on the work of brazilian artist nuno ramos and his search for a sound (or lack of it) that expresses not only the deprivations of life in the sertāo, but also how technology transports those social relations over time so to become the now and here. it ends with a brief study of chilean writer diamela eltit and with how her work during the last years offers us the landscape semán, e. . masiello, francine r. ( ). senses of democracy. perception, politics and culture in latin america. austin: university of texas press. pages. iberoamericana – nordic journal of latin american and caribbean studies, ( ), pp.  – . doi: https://doi.org/ . /iberoamericana. university of bergen, no ernesto.seman@uib.no book review masiello, francine r. ( ). senses of democracy. perception, politics and culture in latin america. austin: university of texas press. pages ernesto semán review of francine r. masiello, senses of democracy. perception, politics and culture in latin america. austin: university of texas press, . keywords: latin american culture; democracy; history of senses; literature; modernity in latin america https://doi.org/ . /iberoamericana. mailto:ernesto.seman@uib.no semán: masiello, francine r. ( ). senses of democracy. perception, politics and culture in latin america an electronic environment that is increasingly self-sus- taining, and where that same alienation might be the source for new creativity. according to the book’s topic, and the sophisticated exploration of the place of senses in history, the book includes magnificent and excellently reproduced plates and illustrations covering hundred years of cultural production. as technology boosts state power over social life, the body produces forms of resistance. we can read the book as an attempt to reconstruct, through the senses, the history of the masses in latin america, a study about how their irruption and the bodies, environments and preferences that make up their own sense work have been describe, dissected and also violently repressed. in the analysis of historical politics from a literary perspective, senses of democracy moves one step further from masiello’s previ- ous work about the latin american polity. and as such, it is also a valuable addition from literary studies to the vibrantly growing field of the history of the senses. for example, in history books like adamovsky and buch’s la marchita, el escudo y el bombo. una historia cultural de los emblemas del peronismo, processes that have been widely analyzed in the past reemerge under a new and vivid light as authors see how political players felt (smelled, heard and saw) masses in different and opposite perspectives. fundamental for masiello’s ideas is to locate cultural production in latin america in connection with debates and taking place elsewhere: echeverría meeting antoine destutt de tracy, xul solar departing from paul klee in the connections between nature and geometry prompted by his spiritualist calling, or rozitchner’s elaboration on fear as a human engine emerging from his work with maurice merleau-ponty. they all describe an intellectual journey that has little to do with an absorbing of european ideas and more with mapping out a dynamic intellectual field. throughout the book, the author pays attention to oscar masotta and his work on perceptions and the senses as a field of critical studies. along with rozitchner and david viñas, masotta explored the perceptual space as part of the grupo contorno and then as part of the avant- garde of the instituto di tella. a psychoanalyst himself, he wore a hearing device that he would famously switch on and off whenever he deemed necessary or convenient, both publicly and private. technology and agency allowed him to disconnect himself from hearing without losing the capacity of being able to hear. regardless of his per- sonal reasons for this, few people could have understood more clearly than him the mighty power of managing one’s own senses, whether to enhance them or to cancel them. masiello’s book is a beautiful exploration of the long history of that power in latin america. competing interests the author has no competing interests to declare. how to cite this article: semán, e. . masiello, francine r. ( ). senses of democracy. perception, politics and culture in latin america. austin: university of texas press. pages. iberoamericana – nordic journal of latin american and caribbean studies, ( ), pp.  – . doi: https://doi.org/ . /iberoamericana. sumbitted: october accepted: october published: december copyright: © the author(s). this is an open-access article distributed under the terms of the creative commons attribution . international license (cc-by . ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. see http://creativecommons.org/licenses/by/ . /. open access iberoamericana – nordic journal of latin american and caribbean studies is a peer-reviewed open access journal published by stockholm university press. https://doi.org/ . /iberoamericana. http://creativecommons.org/licenses/by/ . / 	competing interests untitled  | cancer discovery�january www.aacrjournals.org news in brief cdk inhibitor triples pfs in breast cancer women with estrogen receptor (er)– positive breast cancer who took an investigational drug targeting cyclin- dependent kinases and (cdk / ) in combination with the aromatase inhibitor letrozole experienced a “dra- matic and clinically meaningful effect,” researchers reported on december at the cancer therapy and research center (ctrc) and american associa- tion for cancer research (aacr) san antonio breast cancer symposium in texas. based on the positive results, these researchers expect to launch a phase iii trial of the agent in . in the current phase ii study, patients who took pfi zer’s cdk / inhibitor pd- with letrozole (femara; novartis) achieved a progression-free survival (pfs) period of . months compared with . months for patients who were treated with letrozole alone. “this was a welcome result,” commented norman sharpless, md, deputy director of the lineberger comprehensive cancer center at the university of north caro- lina (unc) at chapel hill, who was not associated with the study. “a tripling of pfs in this disease is a great fi nding.” cdks, which participate in cell prolif- eration, tend to be overactive in cancer. richard finn, md, associate professor of medicine at the jonsson comprehensive cancer center at the university of california, los angeles, and the study’s principal investigator, explained that the primary function of cdk / is to phosphorylate the retinoblastoma (rb) protein, which ordinarily blocks early events in the cell cycle. phosphorylation inactivates rb so that cells can continue to divide. in some cancers, however, cdk / hypherphosphorylates rb, which can lead to uncontrolled cell growth. by inhibiting cdk / , pfi zer’s experi- mental drug prevents rb hyperphos- phorylation. moreover, finn added, it has minimal side effects. according to finn, preclinical stud- ies indicate that only er-positive breast cancer cells had robust responses to pd- . “er positivity appears to be a marker for an intact rb pathway,” he said. that’s noteworthy, unc’s sharp- less added, given that rb loss occurs in roughly % of all cancers. “the drug won’t work in patients who lack the rb pathway,” he noted, “so that gives us a good negative biomarker for who won’t respond to treatment. what we need now is a better posi- tive biomarker to identify those who might respond best in breast cancer and other cancer types.” ■ surveillance network aids prostate research up to % of men diagnosed with prostate cancer have a form of the disease that grows so slowly that it’s unlikely to ever threaten their health if left untreated. unfortunately, physicians currently have no precise way to determine which patients can forego treatment. “we need to fi nd out whether a tumor is a wolf in sheep’s clothing or if it’s really a sheep,” says stuart holden, md, director of cedars-sinai’s louis warschaw prostate cancer center in los angeles, ca, and medical director for the prostate cancer foundation, a philanthropic organization that funds research on the disease. thanks to a $ -million grant from the foundation, researchers from johns hopkins medicine in baltimore, md, and colleagues at cedars-sinai have launched the national proactive surveil- lance network (npsn), a repository of patient information that will advance understanding of who needs treatment. patients at the institutions who are diagnosed with early-stage, low-volume prostate cancer will be invited to join the program; other institutions will be added to the network in mid- to late . patients pursuing proactive surveil- lance defer treatments such as surgery and radiation therapy. instead, they are closely monitored with physical exams and medical tests every months and a prostate biopsy every year. if cancer progresses, they may opt for treat- ment. this strategy is also called active surveillance, expectant management, or watchful waiting. participants regularly complete detailed lifestyle and nutrition ques- tionnaires, and their blood and urine samples and biopsy tissue are banked people glenn dranoff, md, a professor of medicine at dana- farber cancer institute and harvard medical school in boston, ma, has been named the founding editor-in-chief of cancer immunology research. published by the american association for cancer research, the journal will launch online at the organiza- tion’s annual meeting in april, followed by monthly print issues beginning in june. the leader of the dana-farber/ harvard cancer center program in cancer immunology, dranoff has devoted his research efforts to under- standing tumor immunity and to the development of cancer vaccines. karen e. knudsen, phd, began a -year term as editor-in-chief of molecular cancer research this month. she succeeds michael b. kastan, md, phd, executive director of the duke cancer institute in durham, nc. knudsen is a professor in the depart- ments of cancer biology, urology, and radiation oncology at philadelphia’s thomas jefferson university and deputy director for basic science at the affili- ated kimmel cancer center. in addition to authoring book chapters and dozens of peer-reviewed articles, she has held several leadership roles on scientific publications, including cancer research. richard nakamura, phd, has been chosen as the new director of the nih’s center for scientific review (csr). he will lead scientists and administrative staff, overseeing their efforts to manage , nih grant applications a year, the majority of which are reviewed by csr peer review groups. the csr holds , review meetings a year. prior to joining the csr in , nakamura spent years at the national institute of mental health, serving as both its scientific and deputy director. c e n te r fo r s c ie n ti fi c r e v ie w on april , . © american association for cancer research. cancerdiscovery.aacrjournals.org downloaded from published onlinefirst december , ; doi: . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/ ; : . published onlinefirst december , .cancer discovery people updated version . / - .cd-nb - doi: access the most recent version of this article at: e-mail alerts related to this article or journal.sign up to receive free email-alerts subscriptions reprints and .pubs@aacr.org to order reprints of this article or to subscribe to the journal, contact the aacr publications department at permissions rightslink site. click on "request permissions" which will take you to the copyright clearance center's (ccc) .http://cancerdiscovery.aacrjournals.org/content/ / / . to request permission to re-use all or part of this article, use this link on april , . © american association for cancer research. cancerdiscovery.aacrjournals.org downloaded from published onlinefirst december , ; doi: . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/lookup/doi/ . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/cgi/alerts mailto:pubs@aacr.org http://cancerdiscovery.aacrjournals.org/content/ / / . http://cancerdiscovery.aacrjournals.org/ mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat a wednesday, february , voltage-dependent anion channel isoform (vdac ). here, we show that hcc induced by carcinogenic compounds, aflatoxin or den is highly sensi- tized to tbid-induced omm permeabilization and cyto c release when com- pared to normal liver. expression levels of vdac and bak were also higher in hcc than in control liver. the role of the vdac -bak pathway in the differential tbid sensitivity was validated by overexpression of vdac in primary hepatocytes. in hcc cells, elevation of bak was also associated with an increased level of mcl- , an inhibitor of bak. furthermore, both constitutive and drug-induced genetic deletion of mcl- in mouse embryonic fibroblasts caused sensitization to tbid-induced omm permeabilization in the absence of a change in bcl-xl or bax . based on these results, we are evaluating the possibility of selective killing of hcc cells by the combination of a bak activator and an mcl- inhibitor. -pos board b which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c release? shamim naghdi , peter varnai , soumya sinha roy , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadlephia, pa, usa, semmelweis university, budapest, hungary. vdac proteins represent a main component of the outer mitochondrial membrane (omm). the vdac family is composed of isoforms with more than percent similarity. although their primary role was known to be in ion and metabolite transport between mitochondria and cytosol, it has been dis- covered that vdacs are also involved in apoptotic pathways. we have recently found that specifically the vdac isoform is needed for tbid-induced cyto- chrome c release, due to its role in supporting bak insertion to the omm (roy et al. . embo rep. : - ). to determine the domain(s) of vdac which supports bak insertion, vdac and vdac amino acid composition compared and the unique attributes of vdac sequencewereconsideredformutationalanalysis.totestfunctionalsig- nificance of the changes in vdac or vdac , vdac -/- mef cells that are resistant to tbid, were transfected with the mutants and insertion of bak to the omm and cytochrome c release were monitored in permeabilized cells by immunoblotting. previously, we showed that the vdac -specific n terminal tail and cysteins are dispensable for tbid-induced omm permeabilization. to approach the remaining differences four chimeras were prepared: vdac ( - )vdac ( - ), vdac ( - )vdac ( - )vdac ( - ), vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ). these studies revealed that tbid dependent omm permeabilization is only sup- ported by vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ), indicating that the first two third of vdac is required and sufficient for bak targeting to the omm and tbid induced cytochrome c release. -pos board b outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion david weaver , xingguo liu , veronica eisner , peter varnai , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary. cells and tissues deficient in mitochondrial fusion have been shown to have defects linked to the exchange of inner membrane (imm) and matrix compo- nents, particularly mitochondrial dna. outer membrane (omm) constituents originate in the cytoplasm, thus the role of intermitochondrial transfer of omm components by fusion remained unexplored. here we show that fibro- blasts lacking the gtpases responsible for omm fusion, mfn / , have a more heterogeneous distribution of omm proteins than wild-type cells, and in partic- ular that heterogeneity of pro-apoptotic bak leads to dysregulation of bid- dependent apoptotic signaling. homogeneous distribution of bak is partially rescued by introduction of mfn into mfn / -/- cells. furthermore, fusions be- tween mitochondria lacking and containing bak result in hybrids sensitive to bid. proteins with different modes of omm association display varying degrees of heterogeneity in mfn / /- cells and different kinetics of transfer during fusion in fusion-competent cells. efficient coupling of omm to imm fusion depends on the presence of both mfn isoforms and is antagonized by the mitochondrial fission protein, drp . thus, omm function depends on mitochondrial fusion and is a locus of dysfunction in conditions of fusion deficiency. -pos board b mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat veronica eisner , guy lenaers , gyorgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, inserm u- , institut des neurosciences de montpellier, montpellier, france. mitochondria are highly mobile and dynamic organelles in many cell types. however, in the muscle, mitochondria are crammed into the narrow space among the myofilaments. until now, it remained unclear if mitochondrial fusion occurs in and supports the contractile activity of skeletal muscle (sm). here we applied mitochondria matrix-targeted dsred and photoactiv- able gfp to study mitochondrial fusion in rat fdb sm fibers. in vivo electro- porated fibers were imaged by confocal microscopy. when we tagged the mitochondria in ~ % of cell area with twophoton photoactivation of gfp, rapid spreading of fluorescence showed subsets of interconnected mitochondria, mostly in longitudinal direction. matrix fusion occurred with a rate of . and . events/min in adult fibers and skeletal myotubes, respectively. expres- sion of autosomal dominant optical atrophy-causing mutants of the fusion protein opa or ethanol exposure caused suppression of fusion, which is fol- lowed by mitochondrial dysfunction and late onset myopathies. when chal- lenged by repetitive tetanic stimulation, ethanol exposed cells displayed intracellular ca þ dysregulation, appearing as a fatigue pattern. ethanol also induced a decrease in mfn protein levels, without significantly altering mfn , opa or deltapsi. depletion of mfn alone was sufficient to suppress mi- tochondrial fusion in fdb fibers. fusion inhibition was apparent before any cell dysfunction, suggesting that suppression of fusion is not secondary to other problems in the cells. to directly test the role of mfn in ca þ regulation, ryr -transfected control and mfn ko mefs were stimulated with caffeine. mfn ko cells showed oscillatory ca þ transients that decayed faster than that in the control. thus, fusion dynamically connects skeletal muscle mito- chondria and serves as a target mechanism of both mutations and environmen- tal cues to cause impaired excitation-contraction coupling. -pos board b bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action katarina stroffekova, lucia balogová, mária maslaňáková, lenka dzurová, pavol mi�skovský mi�skovský. safarik university, kosice, slovakia. apoptosis is a key process in the development and maintenance of tissue homeostasis. this process of controlled cell death is tightly regulated by a balance between cell survival and damage signals. we focused our attention towards the intrinsic mitochondrial apoptotic pathway, where bcl- family of proteins plays the major role. we were particularly interested in two pro- apoptotic players bak and bax. here we investigated their role in apoptosis triggered by photodynamic action. we show the localization of bax and bak in u- mg human glioma cells incubated with photosensitizer hypericin (hyp) before and after photodynamic action. apoptotic stimulus by hyp photodynamic action caused bax translocation into mitochondria. however our results suggest that under these condi- tions there are two populations of mito- chondria: one which contains bax and bak simultaneously, and is almost exclu- sively localized near the plasma mem- brane; the other which contains bax only and is distributed throughout the cell. the different protein content and spatial distri- bution of these two populations suggest that they can play different roles in re- sponse to apoptotic stimuli. -pos board b stimulation of bax mitochondrial localization by bcl-xl thibaud renault , oscar teijido , gisele velours , yogesh tengarai ganesan , florent missire , nadine camougrand , bruno antonsson , laurent dejean , stephen manon . ibgc-cnrs, bordeaux, france, nyu college of dentistry, new york, ny, usa, merck-serono sa, geneva research center, geneva, switzerland, california state university of fresno, fresno, ca, usa. cytochrome c release, the commitment step of apoptosis, is regulated at the mitochondria through protein-protein interactions between the bcl- family proteins. an imbalance of this interaction network due to the up-regulation of the proto-oncogenes bcl- and/or bcl-xl lead to a resistance to apoptosis and is associated with tumor formation. bcl-xl overexpression act at the level of the mitochondrial outer membrane (mom) by inhibiting bax-mediated apoptosis; more particularly mac formation and cytochrome c release. how- ever, the molecular mechanisms through which bcl-xl affect earlier steps of bax-mediated apoptosis are not fully understood. surprisingly, we found that mitochondrial bax redistribution and change of conformation were not inhibited but rather spontaneously increased in response of bcl-xl overexpres- sion. in order to further investigate the molecular mechanisms involved in this 	which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c re ... 	outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion 	mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat 	bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action 	stimulation of bax mitochondrial localization by bcl-xl heterogeneity of cardiolipin regulation sunday, february , a mitochondrial membranes which result in the dramatic increase of their perme- ability. this increase in permeability during necrosis is caused by the opening of a permeability transition pore - ptp in mitochondrial inner membrane. on the other hand apoptosis induces opening of a large non-selective channel (mito- chondrial apoptotic channel - mac) in the mitochondrial outer membrane. we used atomic force microscopy to study the structure and organization of native mitochondrial membranes isolated from necrotic and apoptotic cells. we com- plement our afm imaging with nanopatricle-based immnunoassays, where mi- tochondrial membranes are pretreated with nanoparticle-conjugated antibodies for recognition of specific proteins. we will present our data on morphological studies of these membranes and will discuss feasibility of this approach for visu- alization of mptp and mac channels in the native mitochondrial inner mem- branes (mim) and mitochondrial outer membranes (mom) using afm methods. -pos board b heterogeneity of cardiolipin regulation yi-fan lin, mei-jie jou. department of physiology and pharmacology, chang gung university, tao-yuan, taiwan. cardiolipin (cl), is a protective phospholipid located exclusively on the mito- chondrial inner membrane for stabilizing individual complex of mitochondrial respiratory chain for energy production, mitochondrial ca þ (mca þ) regula- tion and reactive oxygen spices formation. deficiency of cl has been associated with multiple mitochondrial dysfunctions upon pathological condition, diseases and aging. using fluorescence digital imaging microscopy this study investi- gated how cl is preciously regulated in rat brain astrocytes rba- . results demonstrate that at the resting stage, the distribution of cl is rather heteroge- neous within single cell. the perinulear mitochondria show lower cl than mi- tochondria from the peripheral area. heterogeneity of cl was observed even in single mitochondrion, which may affects mitochondrial fission and fusion mechanism. cl was found to be higher at the cross point area of mitochondrial network. thread-like mitochondria and granular-like mitochondria, however, contain similar level of cl. some of the thread-like mitochondria even contain lower cl than granular-like mitochondria. upon localized oxidative stress in- duced by nm laser irradiation, heterogeneous depletion of cl was observed among mitochondria populations within single cell. distribution of cl altered also mitochondrial dynamics that depletion of cl always occurred before fis- sion. intriguingly, although complete depletion of cl is irreversible upon high strength of laser irradiation, depleted cl recovered during lower strength of laser irradiation and occurred heterogeneously within mitochondria popula- tions. condensation of cl was observed upon various stresses including oxida- tive stress induced by nm laser irradiation, ionomycin-induced mca þ stress and arachidonic acid-induced lipid stress which crucially enhances pres- ervation of cl and its resistance to stress which may be of significance for mi- tochondrial protection and survival. unveiling pathophysiological regulation of cl thus may contribute significantly the prevention and treatment of cl asso- ciated pathological condition, diseases and aging. -pos board b mtdna t g mutation-induced mitochondrial complex v inhibition augments cardiolipin-dependent alterations of mitochondrial dynamics during oxidative, ca d and lipid insults in narp cybrids: a potential therapeutic target tsung-i peng , chia-wei hsiao , mei-jie jou . keelung chang gung memorial hospital, tao-yuan, taiwan, national tsing hua university, tao-yuan, taiwan, chang gung university, tao-yuan, taiwan. mitochondrial dynamics including morphological fission and mitochondrial movement are essential to normal mitochondrial and cellular physiology. this study investigated how mtdna t g (narp)-induced inhibition of mito- chondrial complex v altered mitochondrial dynamics in association with a pro- tective mitochondrial phospholipid, cardiolipin (cl), as a potential therapeutic target. narp cybrids harboring % of mtdna t g genes and its parental osteosarcoma b cells were studied for comparison, and protection provided by melatonin, a potent mitochondrial protector, was explored. we demonstrate for the first time that narp mutation significantly enhances apoptotic death as a result of three distinct lethal mitochondrial apoptotic insults including oxida- tive, ca þ and lipidstress. in addition, narpsignificantly augmented patholog- ical depletion of cl. narp-augmented depletion of cl results in enhanced retardation of mitochondrial movement and fission and later swelling of mito- chondria during all insults. these results suggest thatcl is a common and crucial pathological target formitochondrial apoptoticinsults. furthermore, cl possibly plays a central role in regulating mitochondrial dynamics that are associated with narp-augmented mitochondrial pathologies. intriguingly, melatonin, by differ- entially preserving cl during various stresses (oxidation > ca þ > lipid), res- cuesdifferentially cl-altered mitochondrial dynamics and cell death (oxidation > ca þ > lipid). thus, melatonin, in addition to being a mitochondrial antioxidant to antagonize mitochondrial oxidative stress, a mitochondrial permeability tran- sition modulator to antagonize mitochondrial ca þ stress, may stabilize directly cl to prevent its oxidization and/or depletion and, therefore, it exerts great po- tential in rescuing cl-dependent mitochondrial dynamics-associated mitochon- drial pathologies for treatment of narp-induced pathologies and diseases. -pos board b shuttling of membrane-bound cytochrome b between mitochondria and er david weaver , veronica eisner , peter varnai , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis medical university, budapest, hungary. cytochrome b type b has long been described as a tail-anchored protein of the outer mitochondrial membrane (cb -mito). using a fusion protein consisting of photoactivatable gfp fused to the c-terminus membrane-targeting segment of cb -mito, we have found that while this construct concentrates in the mitochon- drial membrane, it is continuously exchanged between the membranes of the mitochondrion and the endoplasmic reticulum. this effect does not depend on the presence of mitofusin or , as it occurs in mfn-null mefs as well as in wild type cells. interestingly, a point mutation in the hydrophobic, membrane-targeting sequence of cb -mito that was recently reported to prevent its association with autophagosome membranes, also eliminates its exchange with the er. while lipids and viral proteins have been shown to traffic from er to mitochondria, this is, to our knowledge, the first demonstration of such a back-and-forth shuttling, representing both a new aspect of the er- mitochondrial interface and an mfn-independent pathway for the exchange of an outer mitochondrial membrane protein. -pos board b dichotomy between mitochondrial ca d uptake and martix [ca d] in micu deficient cells tunde golenar , gyorgy csordas , fabiana perocchi , vamsi k. mootha , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. mitochondrial calcium uptake is central to cell physiology, but the underlying molecular mechanism remains elusive. recently, micu was identified as a mi- tochondrial protein required for ca þ uptake but dispensible for mitochondrial respiration or membrane potential generation. to study the specific role of micu in mitochondrial ca þ uptake, we used wild type hela cells (ctrl), micu knockdown by distinct shrnas (kd) and micu rescued cells (res- cue). first, we monitored the cytoplasmic and mitochondrial matrix [ca þ] ([ca þ]c and [ca þ]m, respectively) during store-operated ca þ entry. specif- ically, cells were preincubated in a ca þ-free buffer containing thapsigargin (tg), to deplete the er ca þ store, and then ca þ was added back and the en- suing [ca þ]c (fura ) and [ca þ]m (mitochondria-targeted pericams) changes were measured. in both ctrl and kd a [ca þ]c increase occurred that was asso- ciated with a [ca þ]m rise only in ctrl. the rescue behaved similarly to the ctrl. also, when ca þ was added to permeabilized cells, no [ca þ]m increase ap- peared in the kd. these results confirm that the shortage of micu causes sup- pression of the [ca þ]m signal. surprisingly, when the ca þ entry was followed byuncoupler additiontoreleasethemitochondrial ca þ content, ahuge[ca þ]c increase appeared in kd, however, when the uncoupler was added prior to ca þ entry, no [ca þ]c increase occurred. thus, mitochondria in the kd also accumu- lated ca þ during ca þ entry. mitochondrial ca þ uptake evoked by ca þ ad- dition was also documented in permeabilized kd by measurement of ruthenium red sensitive ca uptake and cytoplasmic ca þ clearance (fura ). thus, ca þ is accumulated by micu deficient mitochondria but it fails to result an increase in[ca þ]m.weare currentlyinvestigating, whether suppression ofthe [ca þ]m rise in the kd is due to enhanced matrix ca þ-buffering. -pos board b micu serves as a ca d-controlled gatekeeper for the mitochondrial ca d uniporter györgy csordás , tünde golenár , erin l. seifert , fabiana perocchi , vamsi k. mootha , györgy hajnózky . thomas jefferson university, philadelphia, pa, usa, department of systems biology, harvard medical school, boston, ma, usa. micu serves as a ca þ-controlled gatekeeper for the mitochondrial ca þ uniporter mitochondria are important targets and relay points of calcium signaling. ca þ is driven to the mitochondrial matrix via a low-affinity ca þ channel, the ca þ uniporter (mcu) that exhibits time-dependent 	heterogeneity of cardiolipin regulation 	mtdna t g mutation-induced mitochondrial complex v inhibition augments cardiolipin-dependent alterations of mitochondria ... 	shuttling of membrane-bound cytochrome b between mitochondria and er 	dichotomy between mitochondrial ca + uptake and martix [ca +] in micu deficient cells 	micu serves as a ca +-controlled gatekeeper for the mitochondrial ca + uniporter doi: . /j.bpj. . . a monday, february , mechanisms through which upregulation of bcl affects earlier steps of bax- mediated apoptosis are not fully understood. we found that bax insertion into the mom was the earliest apoptotic step inhibited by bcl overexpression. paradoxically, we also found that bax translocation to the mitochondria was not inhibited but rather spontaneously increased in this same genetic context. this increase in mitochondrial associated bax required a physical interaction be- tween bax and bcl . we therefore propose that, at least when upregulated, bcl behaves as a ‘decoy receptor’ which sequestrates bax at the mitochondria but inhibits its insertion into the mom, committing the cell to survive. supported by nyu research challenge funds to ld. -pos compartmentalization of bcl family proteins mediated by organelle lipid membranes rebecca j. boohaker, ge zhang, adina loosley, kathleen nemec, annette r. khaled. university of central florida, orlando, fl, usa. cancer is defined by a pronounced inhibition of cell death. the bcl family of proteins tightly regulates the delicate balance between life and death. one method of regulation is the compartmentalization of antagonistic members. for example, bax, a pro-apoptotic member of this family, acts as the penulti- mate factor in the apoptotic cascade by releasing apoptogenic factors such as cytochrome c from the mitochondrial lumen. the normally cytosolic protein translocates from one internal compartment to another through an elusive mechanism. individual organelles are defined not only by function (mediated by specific membrane bound proteins), but by the unique composition of their phospholipid membranes. in this work, we have evaluated the contribution of organelle lipids to the localization of of bcl proteins. -pos in search of the structure of mac in the mitochondrial outer membrane pablo m. peixoto , christian renken , shefali haldar , carmen mannella , kathleen w. kinnally . new york university college of dentistry, new york, ny, usa, wadsworth center, albany, ny, usa, academy of the holy names, albany, ny, usa. several groups have tried to determine the structure of the channel (mac) formed in mitochondrial outer membranes (om) of apoptotic cells or in syn- thetic membranes by bax and related proteins/peptides, using electron micros- copy (em), atomic force microscopy and x-ray diffraction. here, pore-like structures ~ - nm were handpicked from transmission em images of ura- nyl-acetate-stained oms isolated from control and apoptotic (il -deprived) fl . cells. these ‘‘candidate pores’’ were aligned by correlation procedures, and class averages defined by principal component and k-means analyses. main differences in the class averages were ( ) the presence of one or more dark (stain-filled) pores, and ( ) the nature of white (stain excluding) features around the pores. a class average consisting of a single -nm pore with pro- nounced white rim was rotationally averaged and used as a reference for cross-correlation searches of om images from control and apoptotic cells. searches using this -nm ‘‘donut’’ motif and the same motif doubled in size ( -nm ‘‘donut’’) yielded thousands of ‘‘hits’’ in both control and apoptotic membranes, which were subsequently aligned and classified as before. the pre- dominant stain-filled structures found with both motifs were not circular but elongated (up to ~ x nm), extending away from stain-excluding crescent- shaped features. the radial anisotropy ruled out reference bias and was in- consistent with pores formed by rings of evenly spaced protein subunits. we hypothesize that the different classes of structures detected represent stages in formation of mac as an increasingly large membrane bilayer defect (or ‘‘cleft’’) induced by successive aggregation or clustering of bax/bak molecules. a progressive assembly mechanism for mac has been recently suggested by real-time monitoring of mac conductances in isolated mitochondria by patch clamping (martinez-caballero et al. j biol chem : - ). supported by nih grant gm . -pos effects of mac formation on mitochondrial morphology pablo m. peixoto, shin-young ryu, robert range, kathleen w. kinnally. new york university college of dentistry, new york, ny, usa. accumulating literature associate mitochondrial dynamics with apoptosis, since regulation of either process has reciprocal effects. these processes seem to converge in formation of the mitochondrial apoptosis induced channel, mac, which releases cytochrome c and triggers the degradation phase of apo- ptosis. while bax and bak, core components of mac, were shown to interact with fusion and fission proteins, some studies also suggest proteins from the in- termembrane space could leak to the cytosol and further promote mitochondrial fission during apoptosis. the temporal relationship between apoptosis induc- tion, mac formation and mitochondrial fragmentation was investigated by time lapse microscopy. mac function was induced through staurosporine treat- ment and microinjection of tbid or cytochrome c. mac formation and mito- chondrial dynamics under these conditions were monitored in hela cells (clone ) that stably express low levels of gfp-bax and were transiently transfected with a pdsred- plasmid. gfp-bax relocation to mitochondria only during apoptosis signals mac formation, while pdsred- expression shows mito- chondrial structure as red fluorescence. treatment with staurosporine and microinjection with tbid or cytochrome c induced relocation of bax and col- lapse of the mitochondrial network. the temporal relationship between these two events was further analyzed. interestingly, pretreatment with imac , a spe- cific mac blocker, protected against cell death and prevented mitochondrial fragmentation after tbid injection. our results suggest a link exists between mac formation and collapse of the mitochondrial network during apoptosis. supported by nih grant gm . -pos mechanism of the mitochondrial cytochrome c release wave in bid-induced apoptosis soumya sinha roy, cecilia garcia-perez, erika davies, xuena lin, györgy hajnóczky. thomas jefferson university, philadelphia, pa, usa. bid, a bh -only bcl family protein, plays a central role in apoptosis. bid is cleaved by caspase- and other enzymes forming tbid that induce mitochon- drial outer membrane (omm) permeabilization and cytochrome c (cyto-c) re- lease. however a mystery remains how bid synchronizes the function of a large number of discrete organelles, particularly in mitochondria-rich liver or muscle cells. here we showed that tbid ( . - nm) elicited progressive omm perme- abilization and complete cyto-c release with a dose-dependent lag time and rate in h c cell populations. once started, the omm permeabilization was not pre- vented by tbid washout. in contrast, the dose-response for digitonin-induced omm permeabilization displayed quantal behavior. in single cell imaging studies, permeabilized h c and primary human cardiac cells transfected with cyto-c-gfp showed complete tbid-induced cyto-c-gfp release closely followed by mitochondrial depolarization. the cyto-c-gfp release started at discrete sites and propagated through the mitochondria with a constant velocity and a relatively stable kinetic of release in each organelle. similar tbid-induced cyto-c-gfp release wave was documented in intact h c cells transfected with tbid. the waves were not dependent on ca þ , caspase activation or permeabil- ity transition pore opening. however, treatment with mntmpyp, a ros scav- enger or overexpression of mitochondrial superoxide dismutase suppressed the coordinated cyto-c release and also inhibited tbid-induced cell death. on the other hand, both superoxide and hydrogen peroxide sensitized mitochondria to the tbid-induced permeabilization. thus, tbid engages a ros-dependent inter-mitochondrial signaling mechanism for spatial amplification of the apoptotic signal by mitochondrial waves. -pos role of milton domains in the calcium-dependent regulation of mito- chondrial motility sudipto das, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. the mammalian grif and oip , and the drosophila milton are kinesin- binding proteins that form a complex with the miro gtpase, an outer mitochon- drial membrane ef-hand protein, to support the movement of mitochondria along the microtubules. our study demonstrates that in h c cells overexpress- ing oip or grif , the basal motility of mitochondria is increased, whereas the sensitivity to calcium-induced movement inhibition is decreased. to dissect the interaction between milton, kinesin and miro, three different milton constructs were tested: milton ( - ), the soluble domain of milton; milton ( - ), lacking the kinesin heavy chain binding site and milton ( - ) that lacks additional ~ amino acid presumably containing part of the miro binding site. immunohistochemistry revealed that the overexpressed milton ( - ) was cytoplasmic, whereas the other two milton constructs showed mitochondrial localization. the basal mitochondrial motility was in- creased by milton ( - ) but was not altered by milton ( - ) or mil- ton ( - ). a plot of mitochondrial motility against slowly rising cytoplasmic [ca þ] induced by thapsigargin ( mm), shows that overexpression of milton ( - ) significantly reduced the calcium sensitivity of mitochondrial motil- ity reminiscent of oip and grif . by contrast, milton ( - ) or milton ( - ) did not have any effect. the thapsigargin-induced cytoplasmic calcium signal was not affected by any of the milton constructs. these data indicate that 	compartmentalization of bcl family proteins mediated by organelle lipid membranes 	in search of the structure of mac in the mitochondrial outer membrane 	effects of mac formation on mitochondrial morphology 	mechanism of the mitochondrial cytochrome c release wave in bid-induced apoptosis 	role of milton domains in the calcium-dependent regulation of mitochondrial motility research letter fitwits mdtm: an office-based tool and games for conversations about obesity with - to -year-old children ann l. mcgaffey, md, diane j. abatemarco, phd, msw, ilene katz jewell, mshyg, susan k. fidler, md, and kristin hughes, mfa background: physician feelings of ineffectiveness and family-related barriers hamper childhood obesity discussions. physicians desire appealing, time-efficient tools to frame and sensitively address obesity, body mass index, physical activity, nutrition, and portion size. our university design-led coalition co- developed tools and games for this purpose. methods: in this feasibility study, we evaluated physician-level counseling of - to -year-old chil- dren and their parents/caretakers using fitwits md (carnegie mellon university school of design, pitts- burgh, pa), a brief, structured intervention with flashcards and take-home games. residency-based phy- sicians in three low- to mid-level socioeconomic urban offices provided self-report data over months through surveys, comment cards, and interviews. results: we recruited physicians and preadolescents and families. child-centered key mes- sages resulted in -minute conversations, on average. for those physicians who used fitwits md, % felt improved comfort and competence and % noted barrier reduction. conclusions: fitwits md improved residency-based physician self-efficacy and emphasized important health education topics regarding office-based childhood obesity discussions with preadolescents and parents/caretakers. ( j am board fam med ; : – .) keywords: body mass index, communication, health literacy, obesity, portion size though the health dilemma of excess weight is widely known, not all physicians and families dis- cuss childhood obesity in a forthright, understand- able way. many physicians perceive the following as barriers: time pressure; insufficient training for nu- trition-based and body mass index (bmi) counsel- ing; treatment futility; home and neighborhood environments that undermine recommendations; and insufficient reimbursement, support services, and patient educational materials. clinicians under-utilize bmi. often, families do not perceive that a problem exists and may not be motivated, have low literacy and numeracy skills, or have aver- sion to the term “obesity” and to perceived criti- cism of parenting skills. – for these reasons, we co-developed counseling tools and games to com- municate weight-related concerns and health guid- ance. in june , a carnegie mellon university design team led seven physicians and two registered dietitians through a participatory design workshop. the resulting fitwits md flashcards included a this article was externally peer reviewed. submitted november ; revised march ; accepted march . from the department of behavior and community health, university of pittsburgh graduate school of public health, pittsburgh, pa (dja); the center for health pro- motion research, case western reserve university, cleve- land, oh (ikj); primary care sports medicine fellowship program, thomas jefferson university hospital, philadel- phia, pa (skf); university of pittsburgh medical center, st. margaret family medicine residency program, pitts- burgh, pa (skf, am); and carnegie mellon university school of design, pittsburgh, pa (kh). current affiliation: thomas jefferson university, school of population health, philadelphia, pa (dja); and ambler medical associates, ambler, pa (skf). funding: this study was funded by the heinz endow- ments, the st. margaret foundation, and the allegheny county medical society foundation. conflict of interest: none declared. corresponding author: ann mcgaffey, md, university of pittsburgh medical center, st. margaret bloomfield gar- field family health center, penn avenue, pittsburgh, pa (e-mail: mcgaffeyal@upmc.edu). jabfm november–december vol. no. http://www.jabfm.org o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n n o ve m b e r . d o w n lo a d e d fro m http://www.jabfm.org/ simple definition of obesity, bmi charts with fit- wits and nitwits characters and color-coded ranges, and friendly interrogatives about personal and family history. self-management cues include minutes of daily exercise, foods and beverages con- taining large amounts of sugar and fat, healthy alterna- tives, and a hand-based portion guide (figure ; http:// www.fitwits.org). in addition, we provided to families the fitwits school take-home games. methods residency-based physicians in three western penn- sylvania low- to mid-level socioeconomic urban offices provided self-report data mid-november through july . we recruited convenience samples of physicians, parents/caretakers, and - to -year-old children presenting for well child/mi- nor illness visits, regardless of bmi. the carnegie mellon university and university of pittsburgh institutional review boards approved all study pro- cedures. fitwits team residents trained physicians using flashcards, best-evidence recommendations, and games practice in a -hour training session. absent physicians were provided with one-on-one instruc- tion. participants were instructed to use fitwits md in lieu of traditional office discussions. we used a pre- and posttest observational design. be- fore training, physicians completed a -question survey with likert-scale questions and comment areas concerning comfort and competence levels, patient health education, perceived discussion length, and physician barriers. questions after the study period included percentage of intervention use; likert scale change in comfort, competence, and barrier reduction; and perceived discussion length. physicians completed open-ended com- ment cards after each office visit intervention. in- depth audio-recorded and transcribed interviews with randomly selected physicians provided addi- tional qualitative data. the comment cards and interviews were analyzed by two evaluation team coders (dja, ikj). quantitative data were analyzed using spss software, version . (spss inc., chi- cago, il). results ninety-three families participated. of eligible physicians, ( in postgraduate year , in postgraduate year , two fellows, and seven faculty) were recruited, completed the study, and eight were interviewed. at baseline, almost all physicians reported that they discussed obesity prevention ( . %), nutrition ( . %), and exercise ( . %); only . % discussed portion size. more than half of physicians reported feeling somewhat to very comfortable ( . %) and competent ( . %). all physicians identified barriers, notably time ( . %) and parent/child issues ( . %). figure . the fitwits md flashcards use simple visual representations with accompanying health terms. the cards use characters called the “fitwits and nitwits” to clarify body mass index charts, ask open-ended questions, and give self-management information. doi: . /jabfm. . . fitwits mdtm: an office-based tool and games o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n n o ve m b e r . d o w n lo a d e d fro m http://www.jabfm.org/ after the intervention (table ), . % of phy- sicians used fitwits md at half or more visits, whereas . % did not use it. physicians who used fitwits md reported increased comfort ( . %), enhanced competence ( . %), and fewer barriers ( . %). the average perceived discussion time doubled from . minutes before the intervention to . minutes using fitwits md. interviewed phy- sicians appreciated the nonjudgmental characters, visual cues, portion size demonstrations, bidirec- tional fun conversations, and the standardized in- tervention for all patients, not just obese children. ninety-three comment cards indicated children’s excitement about the games and that fitwits md facilitated discussion about fast food and soda con- sumption, family meals, activity levels, and screen (tv, video and computer) time. discussion brief tools are needed to guide childhood obesity counseling. , in this feasibility study, the fitwits md intervention improved residency-based physi- cians’ comfort and competence levels and reduced barriers. visual literacy, simplified health terms, child-centered messages, and take-home games en- couraged physicians to invest in the health of pa- tients ages to years, regardless of bmi. three built-in components emphasized important health education topics: bmi charts, the term “obesity” simply defined, and hand-based portion sizes. – limitations included some differences in survey questions before and after the intervention, some bias from leading questions, sample size, lack of validity or reliability of measures, a control group, and data from experienced clinicians. future re- search will address these limitations and assess health outcomes. we thank lindsey detwiler barton, rd, megan mcquaide montag, rd, stephen a. wilson, md, mph, and design and additional physician participants for help with developing the fitwits tool; fitwits office champion and resident teams: laura macbeth mph, ches, melissa williams, rosia l williams, rn, stacey l. brown, md, jill haltigan, md, kristen a. scopaz, md, and michelle n. stalter, do. contributions to data analysis were provided by chrissy a. lopez. amy haugh, mls, and jennifer l. middleton, md, mph, reviewed the manuscript, and paula preisach helped with manuscript prepa- ration. references . perrin em, flower kb, garrett j, ammerman as. preventing and treating obesity: pediatricians’ self-ta bl e . r es ul ts of po st in te rv en ti on ph ys ic ia n su rv ey q ue st io ns fo r w el l ch il d vi si ts w it h - to -y ea r- o ld ch il dr en (n � ) q ue st io ns r es po ns e c at eg or ie s a pp ro xi m at el y w ha t % of vi si ts di d yo u us e f it w it s? n on e � % % to % % to % % to % � % n um be r (% ) ( . ) ( . ) ( . ) ( . ) ( . ) ( . ) a ft er us in g f it w it s, ar e yo u m or e or le ss co m fo rt ab le di sc us si ng ob es it y pr ev en ti on ? n o ch an ge m uc h le ss /a lit tl e le ss co m fo rt ab le in th e m id dl e so m ew ha t m or e co m fo rt ab le m uc h m or e co m fo rt ab le n um be r (% ) ( . ) ( . ) ( . ) h as th e f it w it s of fi ce to ol im pr ov ed ho w co m pe te nt yo u fe el di sc us si ng nu tr it io n, ex er ci se , an d po rt io n he al th ed uc at io n? n o ch an ge m uc h le ss /a lit tl e le ss co m pe te nt in th e m id dl e so m ew ha t m or e co m pe te nt m uc h m or e co m pe te nt n um be r (% ) ( . ) ( . ) ( . ) w he n us in g f it w it s, ar e an y ba rr ie rs to di sc us si ng ob es it y pr ev en ti on , nu tr it io n, ex er ci se , an d po rt io ns w it h fa m ili es re du ce d? n o f ew ch an ge s in th e m id dl e so m e ch an ge s m an y ch an ge s n um be r (% ) ( . ) ( . ) ( . ) ( . ) t ot al s do no t ne ce ss ar ily eq ua l be ca us e of m is si ng in fo rm at io n. p er ce nt ag es ar e ba se d on on ly th os e re sp on de nt s w ho pr ov id ed an an sw er . jabfm november–december vol. no. http://www.jabfm.org o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n n o ve m b e r . d o w n lo a d e d fro m http://www.jabfm.org/ efficacy, barriers, resources, and advocacy. ambul pediatr ; ( ): – . . van gerwen m, franc c, rosman s, le vaillant m, pelletier-fleury n. primary care physicians’ knowl- edge, attitudes, beliefs and practices regarding child- hood obesity: a systematic review. obes rev ; : – . . sesselberg ts, klein jd, o’connor kg, johnson ms. screening and counseling for childhood obesity: results from a national survey. j am board fam med ; ( ): – . . ben-joseph ep, dowshen sa, izenberg n. do par- ents understand growth charts? a national, internet- based survey. pediatrics ; ( ): – . . barlow se and the expert committee. expert com- mittee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. pediatrics ; (suppl ):s – . . mcgaffey a, hughes k, fidler sk, d’amico fj, stalter mn. can elvis pretzley and the fitwits im- prove knowledge of obesity, nutrition, exercise, and portions in fifth graders? int j obes (lond) ; ( ): – . . woolford sj, clark sj, ahmed s, davis mm. feasibility and acceptability of a -page tool to help physicians assess and discuss obesity with parents of preschoolers. clin pediatr (phila) ; ( ): – . doi: . /jabfm. . . fitwits mdtm: an office-based tool and games o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n n o ve m b e r . d o w n lo a d e d fro m http://www.jabfm.org/ doi: . /j.bpj. . . tuesday, march , a -pos board b regulation of mitochondrial motility by milton-like proteins, oip and grif sudipto das, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. regulation of mitochondrial motility by milton-like proteins, oip and grif grif and oip are mammalian homologs of milton, a kinesin-binding protein that forms a complex with miro gtpase, an integral outer mitochon- drial membrane ef-hand protein. kinesin, milton and miro have been proposed to function together in the movement of mitochondria along the mi- crotubules. we report here the influence of overexpression of oip and grif on mitochondrial motility and its inhibition by agonist-induced cyto- plasmic [ca þ] ([ca þ]c) signals in h c cells. ha-tagged oip and grif were overexpressed at similar level and were localized to the mito- chondria as detected by immunocytochemistry. in oip and grif overex- pressing cells, elongated mitochondria with varied degree of aggregation were visualized both in live and in fixed, immunostained samples. mitochondrial motility at resting ca þ (< nm) was greatly enhanced by oip and to a lesser extent by grif ( . . and . motility units, respec- tively against a control value of . . motility units). furthermore, the ca þ-dependent inhibition of motility during stimulation by vasopressin ( nm) was suppressed by overexpressed oip ( . . %), whereas grif ( . . %) had no significant effect compared to control ( . . %). overexpression of oip or grif did not alter either basal [ca þ]c or agonist-induced [ca þ]c levels measured by fura . collectively, these data show that both oip and grif can modulate mitochondrial motility presumably, by promoting the association of mitochondria with the motor proteins. furthermore, oip seems to have greater efficacy in the control of mitochondrial movements. -pos board b mitochondrial localization and function relationship gyorgy csordas , sudipto das , peter varnai , tamas balla , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, school of medicine, budapest, hungary, nichd, nih, bethesda, md, usa. mitochondrial contribution to cell signaling and function relies on the associ- ation and local communication of mitochondria with the er and the plasma membrane (pm). we have recently shown that the local ca þ communication between er and mitochondria is supported by interorganellar tethers, and cre- ated synthetic linkers that connected the outer mitochondrial membrane (omm) to the er and sensitized mitochondria to er ca þ release. to study the kinetics and short-term effects of the linkage formation, we have now de- vised fluorescent protein pairs targeted to the omm and er or pm containing fkbp or frb domains. rapamycin causes heterodimerization of these pro- teins to form omm-er or omm-pm bridges. confocal imaging of the induc- ible fluorescent linker pairs revealed increased association of er or pm-patches with the mitochondria within minutes of rapamycin exposure. the linkage formation between the er and mitochondria was followed by a decrease in mi- tochondrial motility (> % in min) and by sensitization of mitochondria to ip receptor-mediated ca þ release. linkage formation between pm and mitochondria also suppressed mitochondrial motility. the initial kinetics and spatial distribution of linkage formation could be followed via recording fret between cfp-and yfp-containing linker partners. a longer version of the linker was found to show faster increase of the fret signal, supporting the idea that the rate of linkage formation positively correlates with the tight- ness of the er-mitochondrial contacts. currently, we are using the fret kinet- ics to visualize the areas of close er-mitochondrial interface and study its relevance in the ca þ signal propagation to the mitochondria. thus, inducible interorganellar linkers provide a tool to assess the distance between organelles in live cells, to establish rapid changes in the subcellular distribution and dynamics of the organelles and to evaluate the ensuing changes in organellar and cell function. -pos board b bak/bax-dependent apoptotic signaling in vdac -/- cells soumya sinha roy , william j. craigen , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, baylor college of medicine, houston, tx, usa. bid, a pro-apoptotic bcl- family protein, upon activation forms truncated bid (tbid) that binds to the outer mitochondrial membrane (omm) and engages bak/bax-dependent release of cytochrome c (cyto c) and other intermembrane space proteins from mitochondria to the cytosol to induce apoptosis. the volt- age-dependent anion channel (vdac) is the major permeability pathway for metabolites and ions in the omm but its role in the tbid-induced omm perme- abilization remains controversial. previously we reported that among the vdac isoform-specific knockout mouse embryonic fibroblasts (mefs), only vdac -/- mefs lack tbid induced complete cyto c release and loss of djm. here we show by single cell fluorescence imaging that permeabilized vdac -/- mefs expressing cyto c-gfp were resistant to tbid ( nm)-induced cyto c-gfp release. furthermore, by rescuing vdac -/- mefs with vdac the tbid-induced cyto c-gfp release was restored. in addition, tbid adenovirus infection caused less cell death in intact vdac -/- mefs than in wildtype (wt) mefs. it has been reported that vdac is required for proper targeting of bak in omm. indeed, bak did not appear in the membrane fraction of vdac -/- mefs. along this line we show that permeabilized bak -/- cells were more resistant to tbid induced cyto c release and loss of djm than wt and bax-/- mefs. strikingly, washout of the cytosol further desensitized the bak-/- mefs to tbid. unlike vdac -/- mefs, the bak-/- mefs constitutively overex- pressed bax that was primarily localized in the cytosol. however, recombinant bax ( nm) could induce cyto c release and depolarization in vdac -/- mefs and also supported the tbid-induced cyto c release. thus, in vdac -/- cells bak does not localize to the mitochondria and fails to interact with tbid and does not allow a compensatory increase in bax. the combination of these two mechanisms greatly attenuates tbid-induced omm permeabilization and apoptosis. -pos board b mitochondrial fusion-fission dynamics during hypoxia/reoxygenation xingguo liu, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. structural, biochemical, and functional abnormalities of mitochondria during hypoxia/reoxygenation (h/r) are widely believed to be important pathogenic factors that underlie cell injury. however, mitochondrial fusion-fission dynam- ics responses to h/r are unclear. we investigated the effect of h/r and chem- ical hypoxia evoked by kcn on cellular atp, djm, and on mitochondrial morphology and fusion. sixty min h caused cellular atp decrease to %. djm showed progressive decrease during h, gradually improved in the first minutes r and decreased again during longer r. mitochondrial fusion activity decreased to % during h and to % during r. in addition, anomalous fusion (autofusion and fusion at multiple sites among - mitochon- dria) produced donut-shaped mitochondria during r. cyclosporine a (csa), an inhibitor of the permeability transition pore (ptp) relieved the fusion inhibition ( %) and prevented donut formation during r. five mm and mm kcn could induce cellular atp decrease to % and %, and djm decrease to % and %, respectively. depolarized mitochondria were associated with donut-formation in mm kcn, and with massive swell- ing in mm kcn. fusion activity decreased to % in mm kcn and % in mm kcn, respectively. neither h nor kcn evoked cleavage of opa , the mitochondrial inner membrane fusion protein. thus, both physical and chem- ical h induced respiratory inhibition to gradually lower djm and cellular atp level, and caused fusion inhibition that was not dependent on opa cleav- age. this is sharp contrast of the uncoupler-induced fusion inhibition that has been attributed to the rapid djm dissipation-induced opa cleavage. a conse- quence of ptp opening, the matrix swelling seems to be a key to donut forma- tion since this could be evoked by both mastoparan, a potent ptp activator and by valinomycin, a potassium ionophore. -pos board b governing respiration: tubulin’s c-terminus interaction with vdac kely l. sheldon , dan l. sackett , claire monge , valdur saks , sergey m. bezrukov , tatiana k. rostovtseva . lpsb, nichd, the national institutes of health, bethesda, md, usa, limb, nichd, the national institutes of health, bethesda, md, usa, joseph fourier university, grenoble cedex , france. mitochondria have long been known to localize within and move along the tu- bulin-microtubule network. it was shown that tubulin binds to isolated mito- chondria with high-affinity and specifically associates with the mitochondrial voltage-dependent anion channel (vdac). we found that nanomolar concen- trations of dimeric tubulin vastly increase vdac sensitivity to voltage allow- ing for vdac blockage at low transmembrane potentials. tubulin interaction with vdac requires the presence of anionic c-terminal tails (ctt) on the in- tact protein. tubulin with proteolytically cleaved ctts does not block the channel. actin, also an acidic protein but lacking ctts, does not induce vdac blockage. two synthetic peptides with the sequences of mammalian a and b brain tubulin ctt do not induce detectable channel closure up to mi- cromolar concentrations. these results suggest a completely new role for 	regulation of mitochondrial motility by milton-like proteins, oip and grif 	mitochondrial localization and function relationship 	bak/bax-dependent apoptotic signaling in vdac -/- cells 	mitochondrial fusion-fission dynamics during hypoxia/reoxygenation 	governing respiration: tubulin’s c-terminus interaction with vdac doi: . /j.bpj. . . a monday, february , mechanisms through which upregulation of bcl affects earlier steps of bax- mediated apoptosis are not fully understood. we found that bax insertion into the mom was the earliest apoptotic step inhibited by bcl overexpression. paradoxically, we also found that bax translocation to the mitochondria was not inhibited but rather spontaneously increased in this same genetic context. this increase in mitochondrial associated bax required a physical interaction be- tween bax and bcl . we therefore propose that, at least when upregulated, bcl behaves as a ‘decoy receptor’ which sequestrates bax at the mitochondria but inhibits its insertion into the mom, committing the cell to survive. supported by nyu research challenge funds to ld. -pos compartmentalization of bcl family proteins mediated by organelle lipid membranes rebecca j. boohaker, ge zhang, adina loosley, kathleen nemec, annette r. khaled. university of central florida, orlando, fl, usa. cancer is defined by a pronounced inhibition of cell death. the bcl family of proteins tightly regulates the delicate balance between life and death. one method of regulation is the compartmentalization of antagonistic members. for example, bax, a pro-apoptotic member of this family, acts as the penulti- mate factor in the apoptotic cascade by releasing apoptogenic factors such as cytochrome c from the mitochondrial lumen. the normally cytosolic protein translocates from one internal compartment to another through an elusive mechanism. individual organelles are defined not only by function (mediated by specific membrane bound proteins), but by the unique composition of their phospholipid membranes. in this work, we have evaluated the contribution of organelle lipids to the localization of of bcl proteins. -pos in search of the structure of mac in the mitochondrial outer membrane pablo m. peixoto , christian renken , shefali haldar , carmen mannella , kathleen w. kinnally . new york university college of dentistry, new york, ny, usa, wadsworth center, albany, ny, usa, academy of the holy names, albany, ny, usa. several groups have tried to determine the structure of the channel (mac) formed in mitochondrial outer membranes (om) of apoptotic cells or in syn- thetic membranes by bax and related proteins/peptides, using electron micros- copy (em), atomic force microscopy and x-ray diffraction. here, pore-like structures ~ - nm were handpicked from transmission em images of ura- nyl-acetate-stained oms isolated from control and apoptotic (il -deprived) fl . cells. these ‘‘candidate pores’’ were aligned by correlation procedures, and class averages defined by principal component and k-means analyses. main differences in the class averages were ( ) the presence of one or more dark (stain-filled) pores, and ( ) the nature of white (stain excluding) features around the pores. a class average consisting of a single -nm pore with pro- nounced white rim was rotationally averaged and used as a reference for cross-correlation searches of om images from control and apoptotic cells. searches using this -nm ‘‘donut’’ motif and the same motif doubled in size ( -nm ‘‘donut’’) yielded thousands of ‘‘hits’’ in both control and apoptotic membranes, which were subsequently aligned and classified as before. the pre- dominant stain-filled structures found with both motifs were not circular but elongated (up to ~ x nm), extending away from stain-excluding crescent- shaped features. the radial anisotropy ruled out reference bias and was in- consistent with pores formed by rings of evenly spaced protein subunits. we hypothesize that the different classes of structures detected represent stages in formation of mac as an increasingly large membrane bilayer defect (or ‘‘cleft’’) induced by successive aggregation or clustering of bax/bak molecules. a progressive assembly mechanism for mac has been recently suggested by real-time monitoring of mac conductances in isolated mitochondria by patch clamping (martinez-caballero et al. j biol chem : - ). supported by nih grant gm . -pos effects of mac formation on mitochondrial morphology pablo m. peixoto, shin-young ryu, robert range, kathleen w. kinnally. new york university college of dentistry, new york, ny, usa. accumulating literature associate mitochondrial dynamics with apoptosis, since regulation of either process has reciprocal effects. these processes seem to converge in formation of the mitochondrial apoptosis induced channel, mac, which releases cytochrome c and triggers the degradation phase of apo- ptosis. while bax and bak, core components of mac, were shown to interact with fusion and fission proteins, some studies also suggest proteins from the in- termembrane space could leak to the cytosol and further promote mitochondrial fission during apoptosis. the temporal relationship between apoptosis induc- tion, mac formation and mitochondrial fragmentation was investigated by time lapse microscopy. mac function was induced through staurosporine treat- ment and microinjection of tbid or cytochrome c. mac formation and mito- chondrial dynamics under these conditions were monitored in hela cells (clone ) that stably express low levels of gfp-bax and were transiently transfected with a pdsred- plasmid. gfp-bax relocation to mitochondria only during apoptosis signals mac formation, while pdsred- expression shows mito- chondrial structure as red fluorescence. treatment with staurosporine and microinjection with tbid or cytochrome c induced relocation of bax and col- lapse of the mitochondrial network. the temporal relationship between these two events was further analyzed. interestingly, pretreatment with imac , a spe- cific mac blocker, protected against cell death and prevented mitochondrial fragmentation after tbid injection. our results suggest a link exists between mac formation and collapse of the mitochondrial network during apoptosis. supported by nih grant gm . -pos mechanism of the mitochondrial cytochrome c release wave in bid-induced apoptosis soumya sinha roy, cecilia garcia-perez, erika davies, xuena lin, györgy hajnóczky. thomas jefferson university, philadelphia, pa, usa. bid, a bh -only bcl family protein, plays a central role in apoptosis. bid is cleaved by caspase- and other enzymes forming tbid that induce mitochon- drial outer membrane (omm) permeabilization and cytochrome c (cyto-c) re- lease. however a mystery remains how bid synchronizes the function of a large number of discrete organelles, particularly in mitochondria-rich liver or muscle cells. here we showed that tbid ( . - nm) elicited progressive omm perme- abilization and complete cyto-c release with a dose-dependent lag time and rate in h c cell populations. once started, the omm permeabilization was not pre- vented by tbid washout. in contrast, the dose-response for digitonin-induced omm permeabilization displayed quantal behavior. in single cell imaging studies, permeabilized h c and primary human cardiac cells transfected with cyto-c-gfp showed complete tbid-induced cyto-c-gfp release closely followed by mitochondrial depolarization. the cyto-c-gfp release started at discrete sites and propagated through the mitochondria with a constant velocity and a relatively stable kinetic of release in each organelle. similar tbid-induced cyto-c-gfp release wave was documented in intact h c cells transfected with tbid. the waves were not dependent on ca þ , caspase activation or permeabil- ity transition pore opening. however, treatment with mntmpyp, a ros scav- enger or overexpression of mitochondrial superoxide dismutase suppressed the coordinated cyto-c release and also inhibited tbid-induced cell death. on the other hand, both superoxide and hydrogen peroxide sensitized mitochondria to the tbid-induced permeabilization. thus, tbid engages a ros-dependent inter-mitochondrial signaling mechanism for spatial amplification of the apoptotic signal by mitochondrial waves. -pos role of milton domains in the calcium-dependent regulation of mito- chondrial motility sudipto das, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. the mammalian grif and oip , and the drosophila milton are kinesin- binding proteins that form a complex with the miro gtpase, an outer mitochon- drial membrane ef-hand protein, to support the movement of mitochondria along the microtubules. our study demonstrates that in h c cells overexpress- ing oip or grif , the basal motility of mitochondria is increased, whereas the sensitivity to calcium-induced movement inhibition is decreased. to dissect the interaction between milton, kinesin and miro, three different milton constructs were tested: milton ( - ), the soluble domain of milton; milton ( - ), lacking the kinesin heavy chain binding site and milton ( - ) that lacks additional ~ amino acid presumably containing part of the miro binding site. immunohistochemistry revealed that the overexpressed milton ( - ) was cytoplasmic, whereas the other two milton constructs showed mitochondrial localization. the basal mitochondrial motility was in- creased by milton ( - ) but was not altered by milton ( - ) or mil- ton ( - ). a plot of mitochondrial motility against slowly rising cytoplasmic [ca þ] induced by thapsigargin ( mm), shows that overexpression of milton ( - ) significantly reduced the calcium sensitivity of mitochondrial motil- ity reminiscent of oip and grif . by contrast, milton ( - ) or milton ( - ) did not have any effect. the thapsigargin-induced cytoplasmic calcium signal was not affected by any of the milton constructs. these data indicate that 	compartmentalization of bcl family proteins mediated by organelle lipid membranes 	in search of the structure of mac in the mitochondrial outer membrane 	effects of mac formation on mitochondrial morphology 	mechanism of the mitochondrial cytochrome c release wave in bid-induced apoptosis 	role of milton domains in the calcium-dependent regulation of mitochondrial motility act- - -mbr-hart_ p .. integrative medicine at jefferson: leading the way with new center and cutting-edge technology jane hart, md themyrnabrindcenter of integrative medicine at jefferson university hos- pitals, thomas jefferson university, philadelphia, pennsylvania, has com- bined its expertise, expe- rience, and advanced diagnostics to serve as a leader in the field of inte- grative medicine and provide state-of-the-art care for people desiring an integrative medicine approach to their health. now, the recent award- ing of a $ million grant by the marcus founda- tion, inc., has allowed for the establishment of a new center, the brind-marcus center of integrative medicine, in villanova, pennsylvania, which opened its doors in december . the new center has enabled expansion of both clinical and research endeavors as well as cutting-edge technology, including the addition of a unique positron emis- sion tomography–magnetic resonance imaging (pet-mri) scanner. daniel a. monti, md, mba, senior vice president and the director of both centers, commented on the evolution of success of integrative medicine at thomas jefferson university: there has been a real transformation over the past decade at jefferson, where integrative medicine is now definitely part of the fabric of the enterprise and a highly featured and well-positioned department in the institution. each integrative medicine center throughout the country may be very different in terms of clinical and research offer- ings. our approach is to look through the lens of modern medicine within a holistic framework and serve as a consultation service for all. now, through the generosity of the marcus foundation, we have expanded our current capabilities with a broader geographic reach to provide expertise in therapeutic options beyond conventional medicine, such as targeted nutrition, lifestyle change, and advanced diagnostic technology. we could not be more excited about this. kathleen gallagher, executive vice president, chief oper- ating officer, and chief corporate officer of thomas jefferson university commented: “our integrative medicine initiative has been a very successful program, with excellent patient feedback, and now the demographics of having a center in a suburban setting provides more access to individuals who are looking for this type of care.” she added: “our institution fully supports the presence and expansion of integrative medicine within our centers, and we are pleased to be able to provide board-certified physicians and expert clinicians to approach our programs and expansion from an evidence-based and sci- entifically sound foundation.” expansion of services and cutting-edge technology the new , -square-feet brind-marcus center of in- tegrative medicine in villanova, pa, represents a major ex- pansion of integrative health services at jefferson, which builds upon the successful model created by their philadelphia facility, the myrna brind center of integrative medicine. the brind-marcus center of integrative medicine will provide new as well as similar services as the main campus including: one- on-one consultations with integrative medicine experts; ex- tensive integrative medicine programming; advanced diag- nostics capabilities with the new pet-mri scanner; and an infusion center. dr. monti commented: “we provide a very careful and thoughtful assessment with the patients we see, which is comprehensive and offers a lot of one-on-one physi- cian time. however, in addition to a thorough head-to-toe assessment, we also spend considerable time on stress daniel a. monti, md, mba, senior vice president and director of jef- ferson’s myrna brind center of in- tegrative medicine and brind-marcus center of integrative medicine. alternative and complementary therapies doi: . /act. . .mbr � mary ann liebert, inc. � vol. no. april management, daily intake of nutrients, and other important lifestyle variables.” featuring holistic medical and wellness services, the depth and breadth of program offerings at both the center city philadelphia and villanova centers is significant and includes: an integrative executive health program; integrative chronic illness management; integrative cardiology; a neurocognitive (executive brain health) program; micronutrient infusion therapies; natural hormone therapies; acupuncture; a smoking cessation program; a wide range of mindfulness-based stress reduction (mbsr) programs; and others. sabrina bazzan, jd, mba, administrative and operations director at the myrna brind center and at the brind-marcus center of integrative medicine stated: “our executive health program—executive great life—is a key service that is of- fered at both locations and is one of the only executive health programs in the nation that is rooted in integrative medicine.” dr. monti added: “we have an increasing number of compa- nies signing on to have their executive team[s] receive yearly physicals through this program. this has been a stand-alone service that has done very well and has raised awareness about our center and generated many referrals as well.” the mbsr program, another flagship program, is one of the largest in the country, according to dr. monti, with the ability to certify trainers in mbsr. he states: “we have a great breadth of curriculum in mindfulness that has been a core part of the center, from offering the -week standardized program, to certifying teachers, to specialized programs for mental health professionals, as well as workshops that we offer to medical students and other professionals.” advanced diagnostic technology one of the main features of the brind-marcus center of integrative medicine is the new pet-mri scanner which was also funded through the marcus foundation grant. dr. monti stated that the pet-mri scanner at the villanova center is the first in the region, making it a distinguishing feature not only for integrative medicine at thomas jefferson university, but also for the entire institution. dr. monti explained: the pet-mri scanner allows us to do pet imaging with mri instead of a [computed tomography] scan, and there are a lot of advantages to this. if we are looking at the brain, for example, we can obtain a picture of anatomy with the mri and also get a sense of functional activity with the functional mri. in addition, we can view yet another layer of functional activity with the pet scan, all in one hybrid, integrated machine without ever leaving the room. vijay m. rao, md, facr, david c. levin professor and chair, department of radiology, sidney kimmel medical college at thomas jefferson university, commented: “our new offering of the pet-mri, the latest advancement in imaging technology, furthers our commitment to innovation and an integrative approach to patient care. the pet-mri the brind-marcus center of integrative medicine, in villanova, pennsylvania. mary ann liebert, inc. � vol. no. alternative and complementary therapies � april allows a unique view of both anatomy and metabolic activity, providing a more complete investigation into our patients’ conditions. this capability increases patient access to cutting- edge technology, and the information that a pet-mri provides can also help close the gap between diagnosis and treatment.” andrew b. newberg, md, professor of emergency medi- cine and radiology and director of research at both centers commented on the new technology: “clinically, the pet- mri scanner will help us to better evaluate patients in order to determine more effective therapeutic approaches for many of the conditions we treat.” he added: “by using the pet-mri scanner, we can obtain detailed diagnostic information to help guide therapy for conditions such as chronic fatigue, chronic pain, irritable bowel syndrome, cognitive impairment or cardiovascular risk. from a research perspective, the pet- mri will truly be a game changer in terms of helping to better understand the physiological effects of integrative therapies.” dr. newberg and his colleagues are planning an aggressive research program, which will use the pet-mri scanner to help determine, for example, how proper diet and nutrition reduce inflammation; how specific supplements might im- prove cognitive function or help patients who have neuro- degenerative disorders such as parkinson’s disease; and how practices, such as meditation, acupuncture, or other mind– body approaches, work to improve patients’ health and well being. he said: “the ability to demonstrate the specific mechanisms by which these integrative approaches work will provide the necessary data to potentially shift medical atti- tudes about integrative medicine.” the brind-marcus center of integrative health will also offer a neurocognitive assessment service (executive brain health), where the technology of the pet-mri is combined with neu- rocognitive testing, autonomic nervous system testing, and a neurological examination. bazzan said, “i am very excited about our new executive brain health program, which will utilize this technology and provide the most comprehensive assessment of cognitive function and brain health available.” in terms of how these services will specifically benefit patients, dr. monti commented: “one of our goals, for example, is that if a personisrelativelyhealthy,buttheywanttomaximizecognitive reserve, then we will take an integrative approach for the path forward, utilizing a range of options from diet and targeted nutrition to stress-reduction and brain-fitness programs.” for patients with postconcussive symptoms, the pet-mri can help document areas of the brain that are abnormal in their function and then help tailor a treatment program—including diet, supplements, meditation, or other integrative approaches designed to help support brain function—according to dr. newberg. he commented: “the opportunities with the pet- andrew b. newberg, md, reviews a pet-mri scan. positron emission tomography–magnetic resonance imaging scan- ner at the brind-marcus center of integrative medicine. mary ann liebert, inc. � vol. no. alternative and complementary therapies � april mri scanner are virtually endless. every integrative approach and every disorder we treat can be evaluated using the pet-mri scanner. it will help us to better understand the underlying path- ophysiology of diseases and show how integrative medicine ap- proaches can help reduce or eliminate the effects of these diseases and improve the physical and mental health of our patients.” collaboration key to success collaboration has been critical for the success of the myrna brind center of integrative medicine and the establishment of the new brind-marcus center of integrative medicine. dr. monti stated: “it has been so important to collaborate whenever there is an opportunity to partner with other de- partments and institutions and to grow and learn as we go. this spirit of collaboration, i believe, is one of the factors that the marcus foundation found appealing about our approach. we have built a relationship with the marcus foundation over the past several years, and our current endeavor builds upon previous successes we have had with them, as well as other external funders.” he added, “bernie marcus is a great visionary who has served the local, national and even inter- national community.” initially, the myrna brind center of integrative medicine partnered with the marcus foundation on a phase trial ex- ploring the use of high-dose intravenous vitamin c with pa- tients who had pancreatic cancer. collaboration then continued around a discussion about advancing the integrative medicine model and the potential value of a second integrative medicine site. “we are starting to see the fruits of our labor across several initiatives, and having the marcus foundation as a partner is tremendous,” dr. monti said. other important elements for success in building and ex- panding the integrative medicine model have included: a pio- neering spirit; testing therapies to prove efficacy; and initiating novel endeavors, such as exploring the use of micronutrients as supportive therapies for patients. “novel endeavors such as these have raised awareness of the kind of work that we are doing here and sends a message to both patients and clinical partners that we are willing to explore whatever is necessary to help patients who are in difficult positions,” dr. monti said. conclusion in the spirit of collaboration, dr. monti stated that the structure of integrative medicine provided at the two centers is serving as a national model to help other clinicians and insti- tutions foster their own integrative medicine programming. dr. monti commented: i, along with other clinical leaders here at jefferson, am constantly involved with national meetings and symposia where we encounter people from both academic health and private centers who are trying to figure out what steps to take next and how to expand their integrative medicine models. we also publish in both the academic and lay press so that we can share what we are learning with other people in the field. people are eager to come and see what we are doing here and want to understand how to take their centers to the next level. we like being able to share that with people and will continue to serve as a model. dr. monti concluded: “our goal is to extend the bounds of good medicine, and i think that we are continually achieving that here at our centers. our biggest job now is to avoid be- coming complacent with these successes and to keep pushing the envelope for the next series of advances.” jane hart, md, is a clinical instructor in internal medicine at case western reserve university school of medicine, in cleveland, ohio. about the centers the myrna brind center of integrative medicine at jefferson health thomas jefferson university chestnut street suite philadelphia, pa phone: - - website: http://hospitals.jefferson.edu/departments-and- services/myrna-brind-center-of-integrative-medicine/ brind-marcus center of integrative medicine at jefferson health e. lancaster avenue villanova, pa phone: - -jeff-now website: www.jefferson.edu/hospitals/departments-and- services/brind-marcus-center.html for more information, contact: daniel a. monti, md, mba senior vice president and the ellen and ron caplan director & professor thomas jefferson university and jefferson health myrna brind center of integrative medicine, philadelphia, pa brind-marcus center of integrative medicine, villanova, pa phone: - - mary ann liebert, inc. � vol. no. alternative and complementary therapies � april adverts .. https://doi.org/ . /s x downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s x https://www.cambridge.org/core https://www.cambridge.org/core/terms https://doi.org/ . /s x downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, available at https://www.cambridge.org/core/terms. 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uk £ . elsewhere. institutional subscription rate, online only: us $ . in the usa, canada, and mexico; uk £ . elsewhere. institutional subscription rate, print only: us $ . in the usa. canada, and mexico; uk £ . elsewhere. individual subscription rate, print only: $ . in the usa, canada, and mexico; uk £ . elsewhere. single part, $ . in the usa, canada, and mexico; uk £ . elsewhere. prices include postage. © cambridge university press . all rights reserved. no part of this publication may be reproduced, in any form or by any means, electronic, photocopying or otherwise, without permission in writing from cambridge university press. policies, request forms, and con- tacts are available at: http://www.cambridge.org/rights/permissions/permission.htm permission to copy (for users in the u.s.a.) is available from copyright clearance center, http://www.copyright.com, email:info@copyright. com. x_ - .qxd / / : pm page https://doi.org/ . /s x downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s x https://www.cambridge.org/core https://www.cambridge.org/core/terms stu d ies in a m er ic a n p o litic a l d ev elo p m en t v o l. ,n o . ,a p ril p a g e s – studies in american political development volume , number , april articles monetary politics: origins of the federal reserve sarah binder and mark spindel the carceral state and the crucible of black politics: an urban history of the rockefeller drug laws michael javen fortner developing freedom: thomas jefferson, the state, and human capability johann n. neem the politics of party renewal: the “service party” and the origins of the post-goldwater republican right brian m. conley s t u d i e s i n a m e r i c a n p o l i t i c a l d e v e l o p m e n t v o l u m e n u m b e r a p r i l cambridge journals online for further information about this journal please go to the journal website at: journals.cambridge.org/sap x_ - .qxd / / : pm page https://doi.org/ . /s x downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, available at https://www.cambridge.org/core/terms. creo https://doi.org/ . /s x https://www.cambridge.org/core https://www.cambridge.org/core/terms slide the relationship between different types of sharps containers and c. difficile infections rates in acute care hospitals monika pogorzelska-maziarz, phd, mph college of nursing, thomas jefferson university, philadelphia, pa background sharps disposal containers are ubiquitous in healthcare facilities. however, there is paucity of data on the potential for environmental contamination of these containers and their role in transmission of pathogens. the potential for sharps containers to become a source of pathogen transmission within the healthcare setting is an issue that has been raised , but not systematically studied. this is especially important given that contamination of the hospital environment has been shown to be an important component of pathogen transmission. results support for this study was provided by becton, dickinson and company. mpm served as a consultant to becton, dickinson and company on this project. financial support and conflict of interest objectives to describe the use of different types of sharps containers in a national sample of hospitals. to assess the relationship between the use of reusable vs. single-use sharps containers and rates of c. difficile infections. methods  cross-sectional survey of , hospitals with ≥ beds conducted in december to collect data on the use of sharps disposal containers.  survey linked to medicare provider analysis and review (medpar) dataset containing facility characteristics and c. difficile infection rates as identified by icd- codes. differences in c. difficile infection rates between hospitals using reusable vs. single-use sharps containers examined using bivariate and multivariable negative binomial regression models. conclusions completed surveys received from hospitals ( % response rate).  hospitals provided data on the type of sharps containers used in fiscal year ( % response rate). participating hospitals were predominantly non-for-profit ( %) and non-teaching ( %). the majority of respondents reported their primary role was in environmental safety ( %); a third were infection preventionists ( %). the majority of hospital utilized reusable sharps containers ( %) in fy . use of single-use vs. reusable sharps containers differed significantly by region, bedsize, ownership, annual discharges and urbanicity (p-values < . ). in bivariate regression, hospitals using single use sharps containers had significantly lower rates of c. difficile infections vs. hospitals using reusable sharps containers (incidence rate ratio [irr] = . , p-value = . ). this relationship persisted in multivariable regression (irr = . , p-value = . ] after controlling for other hospital characteristics. this is the first study to show a link between the use of single-use sharps containers and lower c. difficile infection rates and further work is needed to replicate this finding.  future studies should investigate the potential for environmental contamination of reusable sharps disposal containers with c. difficile and other micro-organisms and the role that sharps containers may play in pathogen transmission. monika pogorzelska, phd, mph thomas jefferson university south th street philadelphia, pa phone #: ( ) - monika.pogorzelska@jefferson.edu results †reusable is the comparison group hospital characteristics, n = n (%) n (%) geographic region ownership status northeast ( . ) non-profit ( . ) midwest ( . ) for profit/physician owned ( . ) south ( . ) government ( . ) west ( . ) urbanicity bedsize metropolitan (≥ million) ( . ) - ( . ) metro ( k – million) ( . ) - ( . ) metro (< k) ( . ) - ( . ) non-metro ( . ) ≥ ( . ) teaching status mean (sd) major + minor ( . ) discharges (continuous) ( ) none ( . ) multivariable analysis examining relationship between type of sharps disposal container used and c. difficile infection rates coeff se p-value irr single use sharps container† - . . . . geographic region midwest . . . . south - . . . . west . . . . beds (continuous) - . . . . ownership status for profit/physician owned - . . < . . government - . . . . urbanicity metro ( k – million) - . . . . metro (< k) - . . < . . non-metro - . . . . references . neely an, maley mp, taylor gl. investigation of single-use versus reusable infectious waste containers as potential sources of microbial contamination. am j infect control ; : - . . runner jc. bacterial and viral contamination of reusable sharps containers in a community hospital setting. am j infect control ; : - . wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ jobs wanted: cancer research january   cancer discovery |  news in depth an uncertain economic climate points young scientists toward flexible career paths and cross-disciplinary skills courtney crane, phd, has landed the kind of job that many postdoctoral researchers dream about. in april, she will begin building a multidisciplinary program in immu- nologic approaches to pediatric brain cancer at the seattle children’s research institute as an assistant professor at the university of washington. but research positions like these have become increasingly rare for people with mds or phds in biologic sciences. crane and her colleagues are emerging from years of rigorous graduate and postgraduate training into a tight job market— whose demands may take unexpected twists. while crane fielded job offers, those hiring didn’t emphasize what she would have predicted. “most people mentioned the translational aspect,” she says. her postdoc- toral fellowship at the university of california, san francisco examined how to improve patients’ immune response to an experimental immunotherapy for brain cancer. high hopes, low hires overall, the employment picture is “pretty dismal,” says economist paula stephan, phd, author of how economics shapes science (harvard university press; ). only about % of people with phds in the biologic sciences hold tenure- track jobs within to years of earning their doctoral degrees, whereas fewer than % of them work in industry, she says. no national data track the careers of individuals with mds, but the “general thought is that a paucity of physician–scien- tists inhibits the advancement of research into clinical applica- tions,” says carrie wolinetz, phd, associate vice president for federal relations at the association of american universities. in spring , nih director francis collins formed a work- ing group to examine the future of the biomedical research workforce to address the positions and support needed for suc- cessful careers that will advance science and promote health. “openly talking about this is new,” comments cynthia fuhrmann, phd, program director for academic career development and assistant professor in biochemistry and biophysics at ucsf. “national policy makers at nih might be able to create a more open dialogue about career choices and place a stronger emphasis on career development in the training of phd-level scientists.” staying flexible for research young scientists “need to be thinking about career tracks, not just research directions,” advises jonathan wiest, phd, director of the national cancer institute’s center for cancer training. given the hundreds of charitable organizations and in- stitutions devoted to cancer research, scientists may have more opportunities in cancer than other fields, observes bert vogelstein, md, ludwig professor of oncology at johns hopkins university and a howard hughes medical institute (hhmi) investigator. even so, postdocs these days may spend an extra year or trying to find the right job. jobs wanted: cancer research vogelstein advises graduate students aiming for a research career to choose a postdoctoral fellowship in a different field, such as switching from biochemistry to genetics or from proteomics to microfabrication. scientific success depends in part upon creativity, “making connections between things that haven’t been connected before,” remarks vogelstein. “in order to connect ideas or experimental approaches, one has to know things.” marja nevalainen, md, phd, extends that advice to mul- tidisciplinary experience. “typically, postdoctoral training is overseen by one mentor,” says nevalainen, an associate professor of cancer biology, medical oncology, and urology, who also oversees junior faculty and graduate education at thomas jefferson university’s kimmel cancer center in philadelphia. nevalainen suggests an advisory committee of or members for each postdoctoral trainee. “if you have a strong basic scientist as one mentor, input from a physician– scientist may facilitate thinking about research designs in the lab that have translational applications,” she adds. experts emphasize that phds and mds also must keep an eye out for growing areas of research. for instance, james broach, phd, professor of molecular biology at princeton and president of the cancer biology training consortium, recommends pro- ficiency in genomic tools and potential clinical applications, such as understanding the genetic dynamics of a particular tu- mor at the same time it is being treated. craig thompson, md, president and ceo of memorial sloan-kettering cancer center in new york, suggests delving into the strong computational approach of systems biology to understand networks within and between tumor cells. “the system is changing,” sums up howard garrison, phd, public affairs director for the federation of american societies for experimental biology. “no one is sure where the funding will come from to do it all or how to prioritize the way it gets done, but there will be opportunities for very talented people who are excited about the science.” — carol cruzan morton ■ the population of college students interested in careers in health and biologic sciences continues to climb, although those who want to do research face an increasingly tight job market. so ur ce : c ou nc il of g ra du at e sc ho ol s research. on april , . © american association for cancercancerdiscovery.aacrjournals.org downloaded from published onlinefirst december , ; 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(ccc) click on "request permissions" which will take you to the copyright clearance center's .http://cancerdiscovery.aacrjournals.org/content/ / / to request permission to re-use all or part of this article, use this link research. on april , . © american association for cancercancerdiscovery.aacrjournals.org downloaded from published onlinefirst december , ; doi: . / - .cd-nd ol- http://cancerdiscovery.aacrjournals.org/lookup/doi/ . / - .cd-nd ol- http://cancerdiscovery.aacrjournals.org/cgi/alerts mailto:pubs@aacr.org http://cancerdiscovery.aacrjournals.org/content/ / / http://cancerdiscovery.aacrjournals.org/ © macmillan magazines ltd the thomas jefferson paternity case the dna analysis of y-chromosome haplo- types used by foster et al. to evaluate thomas jefferson’s alleged paternity of eston hemings jefferson, the last child of his slave sally hemings, is impressive. how- ever, the authors did not consider all the data at hand in interpreting their results. no mention was made of thomas jeffer- son’s brother randolph ( – ), or of his five sons , . sons of sally hemings con- ceived by randolph (or by one of his sons) would produce a y-chromosome analysis identical to that described by foster et al. further collaborative data (for example, the whereabouts of any of those who might have been involved at conception) are needed to confirm that jefferson did indeed father his slave’s last child, as claimed in the title. we know thomas jefferson was there, but how about randolph jefferson and his sons? david m. abbey health science center, university of colorado, teakwood court, fort collins, colorado , usa e-mail: dabbey @aol.com if the data of foster et al. are accurate, then any male ancestor in thomas jefferson’s line, white or black, could have fathered eston hemings. plantations were inbred communities, and the mixing of racial types was probably common. as slave families were passed as property to the owner’s off- spring along with land and other property, it is possible that thomas jefferson’s father, grandfather or paternal uncles fathered a male slave whose line later impregnated another slave, in this case sally hemings. sally herself was a light mulatto, known even at that time to be thomas jefferson’s wife’s half sister , . gary davis evanston hospital, ridge avenue, evanston, illinois , usa foster et al. reply — it is true that men of randolph jefferson’s family could have fathered sally hemings’ later children. space constraints prevented us from expanding on alternative interpretations of our dna analysis, including the interesting one proposed by davis. the title assigned to our study was misleading in that it repre- sented only the simplest explanation of our molecular findings: namely, that thomas jefferson, rather than one of the carr broth- ers, was likely to have been the father of eston hemings jefferson. it had been suggested to us earlier (by herbert barger, who also helped to recruit the descendants of field jefferson who par- ticipated in our study) that isham jefferson, son of thomas jefferson’s brother ran- dolph, might have been the father of one or more of sally hemings’ children. barger’s proposal was based on a statement that isham was reared by thomas jefferson; he suggested that isham could have been at monticello or at snowden (snowden was across the james river from scottsville, which is about miles from monticello) when eston hemings was conceived. but it is not known for certain that isham was at monticello at that time, whereas it is docu- mented that thomas jefferson was. from the historical knowledge we have, we can- not conclude that isham, or any other member of the jefferson family, was as likely as thomas jefferson to have fathered eston hemings. we know from the historical and the dna data that thomas jefferson can neither be definitely excluded nor solely implicated in the paternity of illegitimate children with his slave sally hemings. when we embarked on this study, we knew that the results could not be conclusive, but we hoped to obtain some objective data that would tilt the weight of evidence in one direction or another. we think we have provided such data and that the modest, probabilistic interpretations we have made are tenable at present. e. a. foster*, m. a. jobling†, p. g. taylor†, p. donnelly‡, p. de knijff§, r. mieremet§, t. zerjal¶, c. tyler-smith¶ * gildersleeve wood, charlottesville, virginia , usa e-mail: eafoster@aol.com †department of genetics, university of leicester, adrian building, university road, leicester le rh, uk ‡department of statistics, university of oxford, south parks road, oxford ox tg, uk §mgc department of human genetics, leiden university, po box , ra leiden, the netherlands ¶department of biochemistry, university of oxford, south parks road, oxford ox qu, uk . foster, e. a. et al. nature , – ( ). . mayo, b. & bear, j. a. jr thomas jefferson and his unknown brother (univ. press of virginia, charlottesville, ). . brodie, f. m. thomas jefferson: an intimate history (norton, new york, ). . randall, w. s. thomas jefferson: a life (holt, new york, ). . history of todd county, kentucky ( ). scientific correspondence nature | vol | january | www.nature.com qualitative adjustment. rhea heart mass ( grams) conforms to that predicted for a mammal of the same body size and aero- bic power. volume densities of mitochon- dria in leg muscles are similar to those of mammals of the same size and aerobic capacity, whereas those in the relatively inactive flight muscles are only half as large and correspond to values reported for less aerobic mammals (table ). given that % of the rhea’s body mass consists of leg musculature, rates of oxygen uptake by mitochondria per millilitre dur- ing locomotion at the aerobic maximum appear to fall within the range reported for mammals. capillary densities in the rhea leg and flight muscles, like the mitochon- drial volume densities, also parallel values reported for the muscles of athletic and less mobile mammals. in contrast to the apparent conservation of structure–function relationships in most of the respiratory system, our results sug- gest that there are basic differences in the performance of the lungs of birds and mammals. we could not measure the lung volumes of the rheas directly, but in birds these are normally slightly more than half of those of mammals of the same mass , . the rheas therefore achieved maximum oxygen flux rates, equal to those of the most aerobic mammals of their size, using lungs that are probably only half as large. this supports the general belief that avian lungs provide relatively more function per unit volume than mammalian lungs , . although the aerobic limits of rheas and athletic mammals are similar, the metabolic power available in practice, and their func- tional needs, are not. unlike dogs, horses and other athletic mammals that sustain high metabolic rates for hours during pre- dation and migration, rheas do little or no sustained running and are poor at dissipat- ing metabolic heat loads . rheas have apparently not been under strong selective pressures like those that promoted the aero- bic power of extant running mammals. large flightless birds lead fairly inactive lives, and may have lost the ability to fly primarily because of a lack of predation. why rheas have an aerobic power that greatly exceeds their apparent functional needs remains a puzzle. matthew w. bundle*, hans hoppeler†, ruth vock†, june m. tester*, peter g. weyand* *museum of comparative zoology, harvard university, bedford, massachusetts , usa e-mail: pweyand@oeb.harvard.edu †department of anatomy, university of bern, buhlstrasse , ch bern , switzerland . seeherman, h. j., taylor, c. r., maloiy, g. m. o. & armstrong, r. b. respir. physiol. , – ( ). . lasiewski, r. c. & dawson, w. r. condor , – ( ). . ellington, c. p. j. exp. biol. , – ( ). . brackenbury, j. h. & el-sayed, m. s. j. exp. biol. , – ( ). . kooyman, g. l. & ponganis, p. j. j. exp. biol. , – ( ). . weibel, e. r., taylor, c. r. & hoppeler, h. proc. natl acad. sci. usa , – , ( ). . maina, j. n. & king, s. a. j. anat. , – ( ). . dubach, m. respir. physiol. , – ( ). . piiper, j. & scheid, p. in comparative physiology (eds bolis, l., schmidt-nielsen, k. & maddrell, s. h. p.) – (north- holland, ). . taylor, c. r., dmi’el, r., fedak, m. & schmidt-neilsen, k. am. j. physiol. , – ( ). reply to the letter to the editor: symptomatic pulmonary embolus after joint arthroplasty: stratification of risk factors javad parvizi md, frcs, ronald huang md, ibrahim j. raphael md, william v. arnold md, phd, richard h. rothman md, phd to the editor, w e read with interest the letter from eroglu and colleagues related to our recently published article entitled ‘‘symptomatic pulmonary embolus after joint arthroplasty: stratification of risk factors’’ [ ]. eroglu and colleagues have clearly invested extensive time and exercised great intellect to propose some interest- ing and plausible mechanisms by which iron deficiency anemia could result in an increase in venous thromboembolism, an observation of our study. the explanations offered were truly insightful and will benefit the readers also. we want to thank them for sharing their knowledge and wisdom with us and other readers. reference . parvizi j, huang r, raphael ij, arnold wv, rothman rh. symptom- atic pulmonary embolus after joint arthroplasty: stratification of risk fac- tors. clin orthop relat res. ; : – . (re: parvizi j, huang r, raphael ij, arnold wv, rothman rh. symptomatic pulmonary embolus after joint arthroplasty: stratification of risk factors. clin orthop relat res. ; : – .) each author certifies that he or she, or a member of his or her immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. all icmje conflict of interest forms for authors and clinical orthopaedics and related research editors and board members are on file with the publication and can be viewed on request. the opinions expressed are those of the writers, and do not reflect the opinion or policy of corr or the association of bone and joint surgeons . j. parvizi md, frcs (&), r. huang md, w. v. arnold md, phd, r. h. rothman md, phd orthopaedic surgery at the rothman institute, thomas jefferson university hospital, s th st. ste , philadelphia, pa , usa e-mail: research@rothmaninstitute.com; parvj@aol.com i. j. raphael md orthopaedic research at the rothman institute, thomas jefferson hospital, philadelphia, pa, usa reply to the letter to the editor published online: june � the association of bone and joint surgeons clin orthop relat res ( ) : / doi . /s - - - clinical orthopaedics and related research® a publication of the association of bone and joint surgeons® 	reply to the letter to the editor: symptomatic pulmonary embolus after joint arthroplasty: stratification of risk factors 	reference revolutionary conceptions: women, fertility and family limitations in america, ÂŒ randomized controlled trial. climacteric ; : – . mastorakos g, sakkas eg, xydakis am, creatsas g. pitfalls of the whis women’s health initiative. ann ny acad sci ; : – . shapiro s. causation, bias and confounding: a hitchhiker’s guide to the epidemiological galaxy. part . principles of causality in epidemiological research: time order, specification of the study base and specificity. j fam plann reprod health care ; : – . machens k, schmidt-gollwitzer k. issues to debate on the women’s health initiative (whi) study. hormone replacement therapy: an epidemiological dilemma? hum reprod ; : – . klaiber el, vogel w, rako s. a critique of the women’s health initiative hormone therapy study. fertil steril ; ; : – . hersh al, stefanick ml, stafford rs. national use of postmenopausal hormone therapy: annual trends and response to recent evidence. jama ; : – . du y, doren m, melchert h, scheidt-nave c, knopf h. differences in menopausal hormone therapy use among women in germany between and . bmc womens health ; : . barbaglia g, macia f, comas m, sala m, del mar vernet m, casamitjana m, et al. trends in hormone therapy use before and after publication of the women’s health initiative trial: years of follow-up. menopause ; : – . guay m, dragomir a, pilon d, moride y, perreault s. changes in pattern of use, clinical characteristics and persistence rate of hormone replacement therapy among postmenopausal women after the whi publication. pharmacoepidemiol drug saf ; : – . coombs nj, boyages j. changes in ht prescriptions in australia since . aust fam physician ; : – . gayet-ageron a, amamra n, ringa v, tainturier v, berr c, clavel-chapelon f, et al. estimated numbers of postmenopausal women treated by hormone therapy in france. maturitas ; : – . townsend j, nanchahal k. hormone replacement therapy: limited response in the uk to the new evidence. br j gen pract ; : . waaseth m, bakken k, lund e. patterns of hormone therapy use in the norwegian women and cancer study (nowac) – . maturitas ; : – . us preventive services task force. postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. ann intern med ; : – . grodstein f, manson je, stampfer mj. hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. j womens health ; : – . hernan ma, alonso a, logan r, grodstein f, michels kb, willett wc, et al. observational studies analyzed like randomized experiments. an application to postmenopausal hormone therapy and coronary heart disease. epidemiology ; : – . manson je, bassuk ss. menopausal hormone therapy and the risk of coronary heart disease. does the relation vary by age or time since menopause? the monitor ; october: – . manson je, bassuk ss. invited commentary: hormone therapy and risk of coronary heart disease – why renew the focus on the early years of menopause? am j epidemiol ; : – . rossouw je, prentice rl, manson je, wu l, barad d, barnabei vm, et al. postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. jama ; : – . manson je, allison ma, rossouw je, carr jj, langer rd, hsia j, et al.; the whi and whi-cacs investigators. estrogen therapy and coronary-artery calcification. n engl j med ; : – . salpeter sr, walsh jme, greyber e, salpeter ee. brief report: coronary heart disease events associated with hormone therapy in younger and older women. j gen intern med ; : – . harman sm, naftolin f, brinton ea, judelson dr. is the estrogen controversy over? deconstructing the women’s health initiative study: a critical evaluation of the evidence. ann ny acad sci ; : – . grodstein f, clarkson tb, manson je. understanding the divergent data on postmenopausal hormone therapy. n engl j med ; : – . naftolin f, taylor hs, karas r, brinton e, newman i, clarkson tb, et al. the women’s health initiative could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. fertil steril ; : – . manson je, bassuk ss, mitchell harman s, brinton ea, cedars mi, lobo r, et al. postmenopausal hormone therapy: new questions and the case for new clinical trials. menopause ; : – . juni p, dieppe p. older people should not be prescribed ‘coxibs’ in place of conventional nsaids. age ageing ; : – . worrall j. evidence in medicine and evidence-based medicine. philosophy compass ; : – . ortiz e. market withdrawal of vioxx: is it time to rethink the use of cox- inhibitors? j manag care pharm ; : – . shapiro s. risk of cardiovascular disease in relation to the use of combined postmenopausal hormone therapy: detection bias and resolution of discrepant findings in two women’s health initiative studies. climacteric ; : – . ettinger b, grady d, tosteson ana, pressman a, macer jl. effect of the women’s health initiative on women’s decisions to discontinue postmenopausal hormone therapy. obstet gynecol ; : – . rossouw je. postmenopausal hormone therapy for disease prevention: have we learned any lessons from the past? clin pharmacol ther ; : – . michels kb. hormone replacement therapy in epidemiologic studies and randomized clinical trials – are we checkmate? epidemiology ; : – . salpeter sr, walsh jme, greyber e, ormiston tm, salpeter ee. mortality associated with hormone replacement therapy in younger and older women. j gen intern med ; : – . ©fsrh j fam plann reprod health care : ( ) goldman/book review book review revolutionary conceptions: women, fertility and family limitations in america, – . susan e. klepp. . nc, usa: the university of north carolina press. isbn- : - - - - . price: £ . . pages (hardback) this book has been published on behalf of the college of william and mary and the colonial williamsburg foundation in the usa, both of which coincidentally i came across this summer while in virginia. it is very clear that americans have a deep relationship with their colonial heritage and take huge pride in authenticating and recreating their origins, as anyone who has visited williamsburg will have witnessed. similarly, this book has been meticulously researched from a wealth of sources and challenges old assumptions on fertility and family planning in colonial times. the author’s central theory is that american women began to reject the lifetime of childbearing and started to limit births more than years in advance of western europe, with the exception of france; an alternative ‘american revolution’ that was invented and implemented by women themselves. this book is not easy bedtime reading material and has numerous footnotes with historical references. it relates to many diverse ethnic, cultural and religious groups such as quakers, the pennsylvania dutch, rural and urban populations. there are attractive illustrations of women and family groups, often portrayed with fruit and flowers as iconic props representing ‘female promise and procreation’. there is a complex association throughout with the demographics of enslaved women; i would have been interested in a chapter specifically on their lives and patterns of childbearing. thomas jefferson, the third usa president, took up with a slave, sally hemmings, after the death of his wife in . modern dna testing has suggested his lineage continues in the current african- american population although, as a consummate politician, he denied any carnal relationship with a slave at the time. the birth control chapter states that most historians conclude that contraception was not significant in colonial america. the author disputes this and found examples to the contrary, but mainly referencing herbal remedies from diaries, chemists and doctors’ notes. she found little reference to sexual abstinence other than with nursing mothers. given the lack of effective contraception from the modern perspective, it is not exactly clear what underpins the revolutionary limitation of family size. in summary, if you are writing a phd on historical patterns of fertility in north america this book will be a godsend. for the rest of us, it may become a little dusty on the bookshelf but was an interesting read over the christmas break nevertheless. reviewed by ailsa gebbie, frcog, ffsrh, consultant in community gynaecology, nhs lothian, uk o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://jfp rh c.b m j.co m / j f a m p la n n r e p ro d h e a lth c a re : first p u b lish e d a s . / o n a p ril . d o w n lo a d e d fro m http://jfprhc.bmj.com/ the papers of thomas jefferson: progress and procedures in the enterprise at princeton by lyman h. butterfield princeton university in july , five months after mr. jefferson had retiredfrom the presidency to his virginia home, a bookseller inpetersburg named john w. campbell wrote him, making what he called a "proposition," which was to publish "a complete edition of your different writings, as far as they may be designed for the public; including the 'notes on virginia.' " to this jefferson sent a very characteristic reply. he named over the several works he supposed campbell had in mind. the notes on virginia, jefferson said, he planned to revise and enlarge, but the work of revision could not be undertaken now. the summary view "was not writ- ten for publication" in the first place: i do not mention the parliamentary manual published for the use of the senate of the u. s. because it was a mere compilation, into which nothing entered of my own, but the arrangement, and a few observations necessary to explain that and some of the cases. i do not know whether your view extends to official papers of mine which have been published. many of these would be like old newspapers, materials for future historians, but no longer interesting to the readers of the day. they would consist of reports, correspondencies, messages, answers to addresses; a few of my reports while secretary of state might perhaps be read by some as essays on abstract subjects. such as the report on measures weights &c coins, on the mint, on the fisheries, on commerce, on the use of distilled sea-water &c. the correspondencies with the british & french ministers, hammond and genet, were published by congress. the messages to congress, which might have been interesting at the moment, would scarcely be read a second time, and answers to addresses are hardly read a first time. so that on a review of these various materials, i see nothing encouraging a apaper read at chapel hill, n. c, october , , at the joint annual meeting of the society of american archivists and the american association for state and local history. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril t h e a m e r i c a n a r c h i v i s t printer to a republication of them. they would probably be bought by those only who are in the habit of preserving state-papers, & who are not many. i say nothing of numerous draughts of reports, resolutions, declarations &c. drawn as a member of congress or of the legislature of virginia, such as the declaration of independance, report on the money unit of the u. s., the act for religious freedom &c. &c. these having become the acts of public bodies, there can be no personal claim to them, and they would no more find readers now than the journals & statute books in which they are deposited. i have presented this general view of the subjects which might have been within the scope of your contemplation, that they might be correctly estimated before any final decision. they belong mostly to a class of papers not calculated for popular reading, & not likely therefore to offer profit, or even indem- nification to the republisher. submitting it to your consideration i tender you my salutations & respects. negotiations went a little further but were then dropped. evi- dently jefferson, though perfectly cooperative, brought campbell round to his own view of the matter. he would willingly have seen a collection of historical records published, for he presumed there were some others besides himself interested in acquiring such rec- ords ; but he could not recommend the proposal as a money-maker, and he said so frankly. campbell's plan for an octavo volume of jefferson's writings was the first attempt at what we are hoping to do in fifty rather larger volumes. it is pleasant, if not particularly rewarding, to speculate on what jefferson would have thought of our undertaking to gather and print all of his papers. he would, i know, have been surprised. he would not, i think, have been irritated or distressed. there is abundant evidence to show that he expected to have his papers studied and used by scholars. no other president except the sec- ond roosevelt has possessed so strong an archival instinct; and however badly his papers have been manhandled since, jefferson himself left them in beautiful order. if he had had anything to keep secret, he could and presumably would have destroyed it; yet there is no evidence that he ever destroyed a scrap of paper except his correspondence with his wife. that belonged to him, but every- thing else was preserved for the public to scrutinize in the future with all the curiosity that it wished. in the princeton file there are literally hundreds of scraps of paper saved by jefferson, and among them are some of the most entertaining and occasionally significant pieces in the whole body of his archives. there are mathematical calculations; designs for machines and furniture and landscape details; recipes for macaroni and other dishes; itineraries; agricul- d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril t h e papers of thomas jefferson tural and meteorological d a t a ; tables of useful information; book lists; and notes and memoranda on an incredible variety of subjects, from the use of archimedes' screw at kew to snuff, sophocles, and specific gravity. these may be trivia; nevertheless, we owe the re- cent recovery of a fragment of the earliest text of the declaration of independence to jefferson's habit of not throwing away any- thing he had written. or, to take a less spectacular yet important and characteristic instance of his archival habits, i may mention a dossier recently found, just as jefferson left it, of material relating to his tour in the low countries and up the rhine in the spring of . t h e r e are over fifty separate pieces in the group, includ- ing a record of daily expenditures, itineraries and advice on travel conditions, a colorful group of printed and engraved tradecards from inns and shops in the towns where he stopped, and receipted bills (in four languages) for lodging, meals, coach-hire, and pur- chases along the way. dipping into the collection is as effective a means as i know of reconstructing the life of the roads and hostel- ries of x century and a half ago. t h e jefferson archives contain masses of material of this kind — social documentation, if it is to be given a colorless name. jeffer- son would have been happy to see it put to use, however surprised he would have been to learn that his papers constitute an encyclo- pedia of his times. though i am among those who find jefferson's words unfail- ingly interesting and frequently inspiring, this is a technical rather than an inspirational paper. i shall therefore pass over the early history of the enterprise: how it grew out of m r . julian p. boyd's work as historian of the jefferson bicentennial commission in ; how t h e n e w york times co., seeking an appropriate me- morial for the late adolph s. ochs, agreed to finance the editorial operations; and how the princeton university press undertook to publish the work in an estimated fifty volumes. i propose here to present a report of progress thus far, and to treat in some detail of the three major phases of the w o r k : gathering the materials, processing them, and getting them into print. ii the plan mr. boyd set forth in his report to the bicentennial commission called for the assembling of the entire jefferson docu- mentation in photofacsimile form; and the agreement with the new york times co. called for the publication of all of the papers assembled (some, to be sure, in only summary form). these two d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril the american archivist decisions placed the work on a different footing from any previous undertaking. it was to be a new and in some respects a unique com- bination of archival and editorial aims and functions. the work could not have been undertaken at all, of course, with- out the aid of the microfilm camera — an instrument which makes us all equal, in a way, with peter force or lyman draper. of al- most equal importance to us has been the continuous-process en- largement printer, familiar to everyone as the v-mail machine, which enabled us to obtain paper prints of the documents in the larger collections at a very low cost per page. in addition to econo- my, the use of photofacsimiles has certain other solid advantages. in the several editorial processes, one cannot handle an autograph document years old with the freedom one can handle a print of it. the reproduction can be cut up and distributed by date if nec- essary, as in the case of letterbooks or in the many cases we have encountered of jefferson's using a single piece of writing paper for several purposes. a reproduction can be stamped for control pur- poses; marginal notes or readings can be placed on it. and so on. at the same time dependence on photoreproductions has some grave disadvantages. in any given , microframes made from mounted or loose mss., one can always count on a few accidental omissions. when blank pages are not filmed, endorsements and docketing memoranda of consequence are sometimes overlooked, and perplexities and doubtless errors sometimes result in attempting to reconstruct the original document. reading from poor prints, or prints made from defective originals, can be among the most ex- asperating experiences of editorial life. one is forever straining to discover what was in the inner margin into which the camera did not reach, or in the outer margin obscured by the mounting sheet. for these and other reasons we are obliged, as we transcribe and edit, to bombard the custodians of the originals with queries that must tax even their notorious patience. the second decision mentioned above — that the edition was to comprehend the entire body of jefferson's papers — differenti- ated the undertaking from others of its kind in one very obvious respect: it was to be much larger than any similar publication. i t is not possible, even if it were worthwhile, to compare statistically the total bulk of the jefferson archives with the archives of other highly productive public men; but it is doubtful whether, before the advent of the typewriter, any other public figure left as many papers. franklin lived as long and had almost as wide-ranging in- d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril t h e papers of thomas jefferson terests, but he was never president. washington was president and, what is more, commander-in-chief for eight years, but his interests were narrower and his life considerably shorter. in any event, there has been no attempt at either a comprehensive franklin or a com- prehensive washington: we have only one side of their respective correspondences in print. t h e bicentennial washington, it may be pointed out, though running to thirty-seven volumes of text, con- tains only about one third the number of words ( , , ) and about one third the number of documents ( , ) that the jeffer- son is planned to embrace in fifty volumes of text. o r if we com- p a r e the jefferson with the enterprise most nearly like it in editorial form, the yale edition of h o r a c e walpole's correspondence, we find that, though the walpole is to be completed in fifty noble vol- umes, only about one quarter as many documents are being included in each of its volumes as are planned for each volume of the jeffer- son. in his introduction to young washington, mr. freeman ob- serves that "nearly as much of the life of a man is set down in the letters addressed to him as in those written by him." with jefferson this is not only true in general, but in some correspondences the in- letters are of greater value than jefferson's own. examples are his exchange of letters wih eli whitney on the cotton gin in , his exchange with d. b. lee on transportation by air in , and, still more strikingly, in his correspondence with gen. william clark in on fossil excavations at the big bone lick. jefferson had a really boyish enthusiasm for fossils. in the fall of , at his own expense, he engaged clark to conduct a thorough search of the fossil area at big bone lick in kentucky. the bones clark dug up and shipped — some — were divided between the american philosophical society and the museum d'histoire na- turelle in paris, the latter group forming the basis of baron cu- vier's fundamental studies in paleontology. the big bone lick excavations and jefferson's part in the founding of paleontological science have been exhaustively written about, but none of the learned historians of the science have, apparently, looked through the letters jefferson received. if they had, they would have come upon a twelve-page letter clark wrote to jefferson from louis- ville on nov. . this, in the opinion of experts, is one of the best reports on early paleontological research that survives, and it is at the same time, in the opinion of anyone who can read, a wonderfully entertaining document. when one begins to quote d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril t h e american archivist from it, one cannot stop, and so i must forbear altogether. i t goes without saying that letters of this caliber we plan to publish entire. but a great many of the in-letters, particularly those of a routine nature, will be summarized. t h e availability of a letter elsewhere in print will influence our decisions on this point. t h e location of the m s . and of printed texts, if any are available, will of course always be given for the documents summarized. t h e operation of gathering the materials to reconstruct the jef- ferson archives began with certain obvious steps. t h e main mass of jefferson's "official papers" (the term is a very loose one) be- came the property of the united states in and, since the be- ginning of this century, has been in the custody of the library of congress. in the library was in the process of recataloguing and microfilming its jefferson collection and was gathering in, as well, microcopies of other major jefferson collections. w e became the library's collaborators in the latter operation, and by the be- ginning of had received and processed prints of some , jefferson documents in the l.c., the massachusetts historical so- ciety, and the historical society of pennsylvania; during about , further documents were added from several large virginia repositories, the new-york historical society, the amer- ican philosophical society, the huntington library, the new york public, and the pierpont morgan libraries. in and the large holdings of the missouri state historical society, the vir- ginia state library (a second crop), and several large private re- positories were rounded up. a systematic search at t h e national archives was begun before the end of but was interrupted and has not yet been completed. soon after our operations started, the inflow of material from smaller repositories and private col- lections began. though at times it has shrunk to a trickle, it has never dried up. nearly eighty documents a month were accessioned during . w e have done everything we could within reason — and some- times perhaps without much reason, though with definite advan- tages — to stimulate and maintain the flow. in a sense we have been concerned more, as in the scriptural story, with the fugitive one than with the dutiful ninety-nine. a case in point is the mission to the otoe indian reservation in to obtain a photostat of one of jefferson's addresses to a delegation of indian chiefs. this was the only such paper known to survive in the custody of any tribe that had received messages from jefferson, and so was of some d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril •*. < • * * *•>.-"". •• ~ ..-:, ? a'mt^n ' '^"'^ - ., * , . - -̂ j " - y ' - " . ' • , . / ; ' rt.. a page from jefferson's index to letters written and received (epistolary record), containing the entries for november- december . original in the library of congress. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril m d. •'•-' i ft •>• ^ i - n , (j - , ;j^j ; ., ̂ \ y \ a page from jefferson's alphabetical index to his epistolary record while minister to france. original in the library of congress. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril the papers of thomas jefferson sentimental interest. furthermore it was owned communally by the whole tribe, and its custody had become a warm political issue with- in the tribe. like conrad weiser or sir william johnson in another age, we found it worthwhile to subscribe to the indians' deep sense of protocol. and i may add that, upon our return to our desks, we found that a dozen or so other jefferson documents had emerged from their hiding places as a result of the publicity attendant on our otoe mission. besides publicity, both grave and gay, we have sent out many hundreds of direct-mail appeals to likely quarters — to librarians, patriotic societies, dealers, collectors, descendants of jefferson and of his correspondents. leads have come from all directions, and we have chased many a will-o-the-wisp with as much vigor as if it were a bundle of love letters exchanged by thomas jefferson and martha wayles skelton. friends of jefferson and friends of ours, some of whom never become known to us by name, prod others who own jefferson autographs to send us photostats. they also write us about jeffersonian utterances and allusions in out-of-the-way printed sources: in the minneapolis journal for february ; in a german broadside found in the hessian archives in marburg; in abolitionist periodicals and pamphlets; in travel books; and so on. we welcome information of this kind with the warmest feelings of gratitude. a fifty-first volume may have to be devoted to ac- knowledgments to our many collaborators, but the preceding fifty will be immeasurably richer for their efforts. printed bibliographies, guides (such as the carnegie series on foreign archives), catalogues of manuscript collections, bookseller's catalogues, and auction records have likewise furnished grist to our mill. the jefferson checklist at the university of virginia, an annotated card catalogue of both published and unpublished writ- ings, has proved inestimably helpful. everyone who has worked with jefferson knows of the unique aid he himself left in the form of a register of all his correspondence. this "epistolary record" becomes reliable at the time jefferson succeeded franklin as our minister in france and continues in an unbroken series of entries until ten days before he died. the period covered is over forty years; the entries for twenty-four of these years are indexed al- phabetically by correspondent; and the whole document extends to pages. the epistolary record is useful to us in important ways besides telling us what we must hunt for; it is, for example, an almost magical means of establishing the dates of undated or muti- lated letters. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril t h e american archivist finally, we go out and sniff the air and hunt for jefferson docu- ments. in jeremy belknap wrote his friend ebenezer h a z a r d about his recent trip to connecticut to gather in the great collec- tion of trumbull papers now reposing in the massachusetts his- torical society. h e expected, he said, to get some other papers from governor hancock's estate, "and when our old patriot s[am] a [ d a m s ] ' s head is laid, we hope to get more. there is nothing like having a good repository, and keeping a good look-out, not wait- ing at home for things to fall into the lap, but prowling about like a wolf for the prey." this is as sound a working principle now as it was then. t h e search so far has netted just over , separate docu- ments. this seemed a good point at which to make an analysis of our record of sources, the results of which i am pleased to present. these , pieces have been drawn from different sources, namely private owners (including dealers) and institu- tional owners (including clubs, banks, commercial firms, and schools, besides institutions primarily devoted to the preservation of historical materials). the private owners have contributed about documents as compared with about , from insti- tutional sources. a breakdown according to size of contribution shows that private and institutional sources have contributed only a single document apiece; have contributed from to documents; have contributed from to ; have contributed from to ; have contributed from to . at this point the private contributors drop out. five institutions have contrib- uted between and documents; have contributed from to ; and have contributed more than documents. t h e geographical distribution of our sources in the continental united states is shown in the following table. i. from to documents have been located in alabama louisiana oregon colorado minnesota vermont florida mississippi washington iowa nebraska wyoming kansas oklahoma west virginia i i . from to documents have been located in delaware georgia indiana kentucky maine new hampshire north carolina ohio rhode island wisconsin south carolina tennessee texas d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril t h e papers o f t h o m a s jefferson i i i . from to documents have been located in connecticut maryland new jersey illinois michigan iv. from to iooo documents have been located in missouri v. from to documents have been located in california new york pennsylvania vi. more than documents have been located in district of columbia virginia massachusetts among the states (including the district of columbia) where jeffersonian material has been located, six have contributed a single document each, while the district of columbia alone has contrib- uted over half of our total holdings, specifically , documents. we are not wholly satisfied with the situation that this table re- flects. the concentration of sources in the east was predictable from historical causes, but it is unquestionably exaggerated by the fact that the eastern territory has been more thoroughly scoured. it is hardly credible, for example, that there are no jefferson pa- pers at all in several states through which lewis and clark trav- eled, or that in the great state of texas there is only one owner of jefferson autograph material. an additional word should be said about sources outside the continental united states. two territories (hawaii and puerto rico) have contributed to our file; also canada, australia, and seven countries in europe. the european countries have contrib- uted about in proportion as they have been scoured; thus france, holland, and switzerland, where mr. howard c. rice has per- sonally searched, have made substantial contributions, but our ef- forts to work by remote control, as in the british isles, have been relatively unfruitful. this brings me to a consideration of the searching that remains to be done. the figures given in my analysis above are bound to be altered substantially very soon by the accession of a very large body of material from the national archives which has been located and filmed but which, on account of our lack of shelf-space before moving into the firestone memorial library, has not been acces- sioned. an estimated , jefferson documents have been located there, the great bulk of them in the general records of the de- partment of state, and especially in the miscellaneous letters and diplomatic and consular correspondence. important groups and d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril i o t h e a m e r i c a n a r c h i v i s t estrays have also been drawn from the national resources records and the war records in the archives. we anticipate another , or so documents, principally from the appointment and pardon papers in the state department records and from the senate and house of representatives files in the legislative records. there is besides, as we are acutely but at the moment helplessly aware, a good deal of searching yet to be done among the holdings of the division of manuscripts in the library of congress. be- tween thirty and forty of the l. c. collections, some of them run- ning to many thousand pieces, have been listed for examination as known or likely sources of jefferson material. we have had, mean- while, the inestimable benefit of mrs. vincent eaton's help in fur- nishing us with lists of the jefferson items in several of the major l. c. collections, most notably in the washington and madison papers. only a beginning has been made on the great l. c. collec- tion of manuscripts reproduced from foreign archives relating to american history. the coordination of this search with direct searches of the foreign depositories is a large problem so far only partially worked out. it will appear from this that the staff of three editors has its hands full and its work laid out. it will also perhaps help explain why copy has not reached the press and the volumes have not reached the public any faster. i turn now to a brief account of our handling of the material when it reaches us in the form of photofacsimiles. i l l our processing is extremely simple. a yellow control slip, per- forated in triplicate, is typed for each document and carries on it the date, the name of the writer (and recipient, if the document is a letter), the number of pages (exposures), the source, and the accession number. the accession number is stamped on the back of each page of the document facsimile. the document — and from this point i drop the term facsimile — is placed in a manila envelope marked with the same data. the perforated control slips are then separated and distributed in three files: a chronological file, an alphabetical file (letters being filed under the name of the writer or recipient other than jefferson), and an accession file. into the envelopes, which are filed on open shelves in chrono- logical order, go the transcripts and other editorial matter perti- nent to a given document, and also variant or duplicate copies of d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril j u r& r ,'* t 'ff c' t v < ,' /w l> , jf f/ g * i in < •• •! // i- j /• < • & .j » f t i 'l / - f t o j -f •, ' l , // • »\ «. ^ a . ^ •n -e ** ' «^ «y ia m . & *~ & u * f ci 'f •' < et £ e* ? * & - s. t. t? $. s . j* . t ,j < j. i . a« #. f .s .s a a .\ a. t .a - ? • t f . r . & .$ f ro m j ef fe rs on 's le tt er to r ob er t r . l iv in gs to n, a p ri l . t h e se m i- le gi bl e pr es s co py r et ai ne d by j ef fe rs on . o ri g in al in t he l ib ra ry o f f ro m t he r ec ip ie nt 's c op y of j ef fe rs on 's l et te r to l iv in gs to n. t h e co de c an no w b e re ad . o ri g in al i n th e m us eu m o f th e c it v of n ew y or k. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril the papers of thomas jefferson the document itself. for the letters jefferson himself wrote, the theoretical expectation is to find two facsimiles in our file — one being the copy he retained, and the other the copy he sent. the recipient's copy is usually the more desirable on two counts: first, because press copies are often only semi-legible (though the poly- graph, which replaced the letterpress in , made perfect cop- ies), and, second, because the recipient's copy bears a direction, postal markings, endorsement, etc. the copies sent are of course more difficult to obtain, because they must be picked up individually or in small groups all over the map. in some instances we cannot transcribe a letter until we locate the copy sent. a spectacular ex- ample is jefferson's letter to robert r. livingston of april , instructing him, as minister to france, to acquire new or- leans for the united states. the text of this momentous document has often been printed but never in full, because the press copy in the library of congress is not completely legible. recently the museum of the city of new york acquired from a descendant of livingston the original copy sent. readers who compare the initial pages of the two texts, as reproduced in the accompanying illus- tration, will understand why our search continues. to record missing documents we have used blue slips perforated in triplicate like the yellow ones. (a "missing" document is any jefferson paper whose existence is verified but which has not yet been found in manuscript form.) the blue slips bear as much data as we can obtain on the fugitive item. our principal sources of in- formation about missing items are the epistolary record, auction records, and printed works, such as the great documentary collec- tions like force, contemporary newspapers, and the memoirs and writings of jefferson's contemporaries. a continuous search through the whole body of printed source materials, from jefferson's time to ours, goes on in our office. it has produced some surprises — including the ferreting out of one group of autograph letters in private hands — and it is an absorbing if interminable task. the printings of documents discovered in the course of the search are recorded on the control cards in the chronological file. this infor- mation is often useful in annotating a given document; sometimes it provides a printed text that is more satisfactory than the original manuscript itself, because prepared before the original had deterio- rated. an important subsidiary file in the jefferson office is the bibli- ography of publications by and about jefferson and his contempo- d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril t h e american archivist raries. this is kept on cards, of which there are now over , , and the entries under jefferson as subject are classified under such appropriate heads and sub-heads as "agriculture — plows," "cam- paign literature," "jews, relations with," "medicine — vaccina- tion," "portraits," "visitors," and so on. we are always eager to enlarge our file of allusions to jefferson in both published and unpublished writings of his day, and have supplemented our main document file with a considerable body of typescripts and photo- duplicates of material under the rubric of "contemporary com- ment." iv a brief account of the plan of the edition will conclude this paper. about four-fifths of the material to be printed will be arranged in a single chronological sequence, making up volumes to and embracing all the correspondence, all messages, reports, bills, and dated and datable memoranda. the remaining fifth of the material is being gradually segregated for printing in a classified series, as- sumed to be volumes to , which will embrace, first, jeffer- son's larger published and unpublished writings and papers (the notes on virginia, parliamentary manual, autobiography, anas, "life and morals of jesus," the anglo-saxon grammar, account books, farm and garden books, etc.), and, second, such other papers as can be most satisfactorily used and edited in classified groups, e.g., the legal papers, the architectural drawings, and the maps and surveys. for the three groups of papers last men- tioned, arrangements have been made for more or less independent editing by specialists. a separate supplementary volume is planned as a biographical register or dictionary for the entire work. it will contain concise sketches of all of jefferson's correspondents and of other persons mentioned in the work who had significant or continuing relations with jefferson. in treating well-known figures (say madison or vergennes), emphasis will be placed upon their connection with jefferson; for obscurer figures (jefferson's french cook, or the brazilian adventurer jose da maia), an effort will be made to be more exhaustive. the advantages to readers in having a separate volume, in which they can readily find the master footnote on any given person, are obvious. the advantage to the editors is likewise obvious, for the editorial notes will by this device be relieved of a great deal of matter, much of it repetitive. plans for indexing call tentatively for a throw-away index for d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril t h e papers of thomas jefferson every five volumes of text, with a cumulative index in the required number of volumes at the end. as for annotation, we have arrived after a good deal of thought and experimenting at the conclusion that exhaustive annotation of such a large mass of documents is not feasible, even if it were de- sirable. w e have stated that our purpose in annotating is to pro- vide information essential to understanding each document pre- sented. ideally considered, such a purpose would frequently entail a prodigious amount of research in order to set forth the archival and bibliographical history of each document and assess its his- torical significance; to identify or explain all persons, events, and places, and to point out jefferson's relationship therewith; to sep- arate fact from rumor; to explain obsolete, technical, and regional t e r m s ; to trace literary quotations to their sources; to furnish ref- erences to the pertinent literature; and so on. all this and more is "essential to understanding the document" in the fullest sense of the term. yet to place no restriction on such a purpose would con- fuse the functions, on the one hand, of biographers and historians and, on the other, of editors. i t would not infrequently produce explanatory material well in excess of the documents explained, and it would add to the considerable task of the editor a burden greater than that even assumed by the biographer or historian, since they can and must select, whereas the editor cannot do so. t h e providing of "information essential to understanding the document" does not, according to our interpretation, oblige us to explain those common allusions to person, events, places, and terms which the specialist may be presumed to know or which he may find in sources or reference works as readily accessible to him as to the editors. notes on these topics will, however, be furnished when the editors find themselves in possession of new facts gath- ered in the ordinary editorial process or when they have necessarily explored sources not readily accessible. furthermore, routine stand- ards will not be applied in annotating documents that are of special importance or that present unusual features or problems. in other words, we shall try, in our capacity as editors, to solve such prob- lems as we can and to show the way toward the solution of as many others as we can. in so doing we hope to improve upon our prede- cessors, most of whom have been conspicuously irresponsible in these matters, and to approach the stature of the late and very great editor edmund c. burnett. but we do not propose to arro- d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril t h e american archivist gate to ourselves the whole vast scholarly province of jefferson and his times. the form of annotation we have settled upon may sound at first as if it were more ingenious than practical; but we have found it admirably flexible, and we believe it will best suit the widely vary- ing purposes of readers. there will be a single inclusive footnote for all except very long or very special kinds of documents. i t will be printed, in double-column and in a smaller point of type, im- mediately following the document to which it pertains, not at the foot of the page. the note will always be divided into at least two, and sometimes into three, sections or paragraphs. the first section is descriptive and will furnish physical data, such as the nature of the document (whether a draft, a recipient's copy, etc), the loca- tion of the original and of other copies if known, the address and endorsement, notation of enclosures, comment (when called for) on the handwriting or the condition of the manuscript, and the like. the second section (or paragraph) of the inclusive note is ex- planatory. within the limitations stated above, it will be a com- bined commentary and series of explanations of particular topics in the document. the key words of the topics annotated will be printed in small capitals in the note, so that the eye may readily travel from an allusion in the text to the point where it is treated in the note. the source of each item of information will follow that item parenthetically in the explanatory note. for this purpose short titles will be employed for all works commonly cited. a list of these, with their expanded forms, will be printed periodically, probably with each installment of the index, and the cumulative bibliography at the end of the work will constitute a union list of all short titles used. a third section (or paragraph) will appear in the inclusive note only when a document presents special problems, such as variations between a draft and a fair copy, matter lined out that deserves to be recorded, and the like. these textual notes will be keyed to the text by means of superscript numerals. except in the case of docu- ments of special literary or historical significance (such as the notes on virginia and the great state papers), we have not committed ourselves to recording every textual variation between extant copies. our decisions on presenting the texts themselves are the product of much thought and conscience-searching on our part, together with an abundance of advice and admonition from without. w e have recognized from the outset what some editors have never d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril • * c - z *l < j? j > w ,? d ra ft o f le tt er t o m ay o r w ei g h ti n an o f w as h in g to n , j u n e . il lu s- tr at in g je ff er so n' s ha bi ts of co m po si tio n an d th e im po rt an ce of co ll at in g dr af ts w it h fa ir co pi es . o ri g in al in t he m as sa ch us et ts h is to ri ca l s oc ie ty . f ai r co py o f th e le tt er t o w ei g h tm an , m ad e on j ef fe rs on 's po ly gr ap h an d re ta in ed b y hi m . t h is l et te r w as s en t te n da ys b ef or e je ff er so n di ed . o ri g - in al in th e l ib ra ry of c on gr es s. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril t h e papers o f t h o m a s j e f f e r s o n s been willing t o recognize, namely, t h a t type cannot simulate manu- script, for we h o l d t h a t t h e first duty of an e d i t o r is t o p r e s e n t a text t h a t can be read, not a set of t y p o g r a p h i c a l a n d e d i t o r i a l h i e r o - glyphics. briefly, we h a v e d e t e r m i n e d t o r e t a i n faithfully t h e spell- ing, g r a m m a r , capitalization, a n d punctuation of t h e m a n u s c r i p t s , t h o u g h we shall r e g u l a r l y capitalize t h e first w o r d s of sentences a n d shall clarify p u n c t u a t i o n w h e n it is confusing. e x c e p t w h e n they a r e p r o p e r n a m e s , obscure a n d a w k w a r d contractions will be expanded, b u t t h e y will be r e t a i n e d in t h e date-line a n d compli- m e n t a r y close of l e t t e r s a n d in business p a p e r s a n d t a b u l a r docu- m e n t s of all k i n d s . d o c u m e n t s of g r e a t t e x t u a l significance a n d complexity will n o t be subject t o these g e n e r a l rules of n o r m a l i z a - tion. i h a v e given h e r e only a sampling of t h e e d i t o r i a l p r o b l e m s t h a t h a v e d e m a n d e d t e n t a t i v e solutions b e f o r e sending off copy of t h e first t h o u s a n d of t h e , documents c o n f r o n t i n g u s . i n g r a p - pling daily w i t h these p r o b l e m s , we find ourselves r e p e a t e d l y a m a z e d by t h e lack of reliable i n f o r m a t i o n on m a n y p h a s e s of jef- ferson's c a r e e r . r e s o r t t o the entries in our distended bibliographi- cal file is fruitless n o t only fo r answers t o m y r i a d s of small ques- tions of b i o g r a p h i c a l i m p o r t , but, w o r s e t h a n this, it is impossible t o find full a n d reliable accounts of such capital m a t t e r s as the re- vision of the v i r g i n i a laws, t h e h i s t o r y of t h e democratic-republi- can p a r t y , jefferson's a p p o i n t m e n t s as p r e s i d e n t , his i n d i a n lin- guistic studies, his i n d i a n policy as p r e s i d e n t , a n d his introduction of anglo-saxon into the a m e r i c a n college curriculum. t h e docu- m e n t a t i o n t o be p r e s e n t e d in t h e p a p e r s of t h o m a s jefferson will t h r o w light on all these and a host of o t h e r imperfectly c h a r t e d or quite u n c h a r t e d a r e a s in our political a n d cultural h i s t o r y . f r o m this point of view we can r e g a r d ourselves as pathfinders. i n t h e same b r e a t h i must a d d t h a t editing jefferson's p a p e r s is an efficacious m e a n s of cultivating humility. t o d o t h e j o b p r o p e r l y we should be jeffersons. t h e acute a n d ever-present sense of h o w far we fall below t h a t s t a n d a r d is humbling. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .h g by c arnegie m ellon u niversity user on a pril [pdf] steroids in patients with septic shock. | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /chest. - corpus id: steroids in patients with septic shock. @article{sprung steroidsip, title={steroids in patients with septic shock.}, author={c. sprung and d. annane and m. singer and b. cuthbertson and j. briegel}, journal={chest}, year={ }, volume={ }, pages={ - } } 	c. sprung, d. annane, + authors j. briegel 	published 	medicine 	chest the authors have reported to the accp that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. reproduction of this article is prohibited without written permission from the american college of chest physicians (www.chestjournal. org/site/misc/reprints.xhtml). correspondence to: emilio bouza, md, phd, hospital gregorio maranon, clinical microbiology and infectious diseases, dr esquerdo , madrid , spain… expand view on pubmed journal.publications.chestnet.org save to library create alert cite launch research feed share this paper citationsbackground citations view all topics from this paper 	steroids 	septic shock 	digital object identifier 	 -iodo- , -dimethoxyphenylisopropylamine 	anacardium occidentale 	email 	ephrin type-b receptor , human citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency corticoides para mejorar la mortalidad en choque séptico : revisión narrativa con rigor metodológico 	cristian sanctus angeluz beltran lopez, william fernando gonzales dagua 	medicine 	 	view excerpt, cites background save alert research feed clinical course of sepsis in children with acute leukemia admitted to the pediatric intensive care unit* 	k. singer, p. subbaiah, r. hutchinson, f. odetola, t. shanley 	medicine 	pediatric critical care medicine : a journal of the society of critical care medicine and the world federation of pediatric intensive and critical care societies 	 	 	pdf 	view excerpt, cites background save alert research feed references showing - of references sort byrelevance most influenced papers recency corticosteroids for septic shock 	d. annane 	medicine 	critical care medicine 	 	 	pdf save alert research feed critical illness-related corticosteroid insufficiency. 	p. marik 	medicine 	chest 	 	 save alert research feed recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the american college of critical care medicine 	p. marik, s. pastores, + authors m. vogeser 	medicine 	critical care medicine 	 	 	pdf save alert research feed hydrocortisone therapy for patients with septic shock. 	c. sprung, d. annane, + authors j. briegel 	medicine 	the new england journal of medicine 	 	 , 	pdf save alert research feed effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. 	d. annane, v. sébille, + authors É. bellissant 	medicine 	jama 	 	 	pdf save alert research feed surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 	r. dellinger, m. levy, + authors j. vincent 	medicine 	critical care medicine 	 	 , 	pdf save alert research feed in patients undergoing cardiac surgery, thoracic epidural analgesia combined with general anaesthesia results in faster recovery and fewer complications but does not affect length of hospital stay. 	a. ronald, k. abdulaziz, t. day, m. scott 	medicine 	interactive cardiovascular and thoracic surgery 	 	 	pdf save alert research feed intensive insulin therapy in critically ill patients. 	j. mazuski, j. bailey, m. shapiro 	medicine 	the new england journal of medicine 	 	 , 	pdf save alert research feed thoracic epidural anesthesia for cardiac surgery 	j. p. williams 	medicine 	 	 	pdf save alert research feed why have new effective therapies for sepsis not been developed? 	l. eidelman, c. sprung 	medicine 	critical care medicine 	 	 save alert research feed ... ... related papers 	abstract 	topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue the distillery scibx: science–business exchange copyright © nature publishing group this week in techniques approach summary licensing status publication and contact information disease models mouse model for collagen type vi a (col a )- related muscular dystrophies a mouse model for col a -related muscular dystrophies could help identify new treatments. in mice, a col a mutation that caused low expression of a nonfunctional collagen chain variant resulted in collagen vi microfibril deficiency, and led to decreased muscle mass and contractions compared with what was seen in wild-type mice. in the mouse model, the collagen vi pathology was specific to tendons. next steps include identifying signaling pathways altered in the mutant mice. scibx ( ); doi: . /scibx. . published online april , findings unpatented; frozen sperm and breeding pairs of the mutant mice available for licensing pan, t.-c. et al. j. biol. chem.; published online april , ; doi: . /jbc.m . contact: mon-li chu, thomas jefferson university, philadelphia, pa. e-mail: mon-li.chu@jefferson.edu http://www.biocentury.com/targets/collagen_type_vi_alpha_ ?utm_source=nature http://www.biocentury.com/targets/collagen_type_vi_alpha_ ?utm_source=nature http://www.biocentury.com/targets/col a ?utm_source=nature mailto:mon-li.chu@jefferson.edu mailto:mon-li.chu@jefferson.edu 	mouse model for collagen type vi α (col a )-related muscular dystrophies 	summary 	licensing status 	references which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c release? a wednesday, february , voltage-dependent anion channel isoform (vdac ). here, we show that hcc induced by carcinogenic compounds, aflatoxin or den is highly sensi- tized to tbid-induced omm permeabilization and cyto c release when com- pared to normal liver. expression levels of vdac and bak were also higher in hcc than in control liver. the role of the vdac -bak pathway in the differential tbid sensitivity was validated by overexpression of vdac in primary hepatocytes. in hcc cells, elevation of bak was also associated with an increased level of mcl- , an inhibitor of bak. furthermore, both constitutive and drug-induced genetic deletion of mcl- in mouse embryonic fibroblasts caused sensitization to tbid-induced omm permeabilization in the absence of a change in bcl-xl or bax . based on these results, we are evaluating the possibility of selective killing of hcc cells by the combination of a bak activator and an mcl- inhibitor. -pos board b which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c release? shamim naghdi , peter varnai , soumya sinha roy , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadlephia, pa, usa, semmelweis university, budapest, hungary. vdac proteins represent a main component of the outer mitochondrial membrane (omm). the vdac family is composed of isoforms with more than percent similarity. although their primary role was known to be in ion and metabolite transport between mitochondria and cytosol, it has been dis- covered that vdacs are also involved in apoptotic pathways. we have recently found that specifically the vdac isoform is needed for tbid-induced cyto- chrome c release, due to its role in supporting bak insertion to the omm (roy et al. . embo rep. : - ). to determine the domain(s) of vdac which supports bak insertion, vdac and vdac amino acid composition compared and the unique attributes of vdac sequencewereconsideredformutationalanalysis.totestfunctionalsig- nificance of the changes in vdac or vdac , vdac -/- mef cells that are resistant to tbid, were transfected with the mutants and insertion of bak to the omm and cytochrome c release were monitored in permeabilized cells by immunoblotting. previously, we showed that the vdac -specific n terminal tail and cysteins are dispensable for tbid-induced omm permeabilization. to approach the remaining differences four chimeras were prepared: vdac ( - )vdac ( - ), vdac ( - )vdac ( - )vdac ( - ), vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ). these studies revealed that tbid dependent omm permeabilization is only sup- ported by vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ), indicating that the first two third of vdac is required and sufficient for bak targeting to the omm and tbid induced cytochrome c release. -pos board b outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion david weaver , xingguo liu , veronica eisner , peter varnai , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary. cells and tissues deficient in mitochondrial fusion have been shown to have defects linked to the exchange of inner membrane (imm) and matrix compo- nents, particularly mitochondrial dna. outer membrane (omm) constituents originate in the cytoplasm, thus the role of intermitochondrial transfer of omm components by fusion remained unexplored. here we show that fibro- blasts lacking the gtpases responsible for omm fusion, mfn / , have a more heterogeneous distribution of omm proteins than wild-type cells, and in partic- ular that heterogeneity of pro-apoptotic bak leads to dysregulation of bid- dependent apoptotic signaling. homogeneous distribution of bak is partially rescued by introduction of mfn into mfn / -/- cells. furthermore, fusions be- tween mitochondria lacking and containing bak result in hybrids sensitive to bid. proteins with different modes of omm association display varying degrees of heterogeneity in mfn / /- cells and different kinetics of transfer during fusion in fusion-competent cells. efficient coupling of omm to imm fusion depends on the presence of both mfn isoforms and is antagonized by the mitochondrial fission protein, drp . thus, omm function depends on mitochondrial fusion and is a locus of dysfunction in conditions of fusion deficiency. -pos board b mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat veronica eisner , guy lenaers , gyorgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, inserm u- , institut des neurosciences de montpellier, montpellier, france. mitochondria are highly mobile and dynamic organelles in many cell types. however, in the muscle, mitochondria are crammed into the narrow space among the myofilaments. until now, it remained unclear if mitochondrial fusion occurs in and supports the contractile activity of skeletal muscle (sm). here we applied mitochondria matrix-targeted dsred and photoactiv- able gfp to study mitochondrial fusion in rat fdb sm fibers. in vivo electro- porated fibers were imaged by confocal microscopy. when we tagged the mitochondria in ~ % of cell area with twophoton photoactivation of gfp, rapid spreading of fluorescence showed subsets of interconnected mitochondria, mostly in longitudinal direction. matrix fusion occurred with a rate of . and . events/min in adult fibers and skeletal myotubes, respectively. expres- sion of autosomal dominant optical atrophy-causing mutants of the fusion protein opa or ethanol exposure caused suppression of fusion, which is fol- lowed by mitochondrial dysfunction and late onset myopathies. when chal- lenged by repetitive tetanic stimulation, ethanol exposed cells displayed intracellular ca þ dysregulation, appearing as a fatigue pattern. ethanol also induced a decrease in mfn protein levels, without significantly altering mfn , opa or deltapsi. depletion of mfn alone was sufficient to suppress mi- tochondrial fusion in fdb fibers. fusion inhibition was apparent before any cell dysfunction, suggesting that suppression of fusion is not secondary to other problems in the cells. to directly test the role of mfn in ca þ regulation, ryr -transfected control and mfn ko mefs were stimulated with caffeine. mfn ko cells showed oscillatory ca þ transients that decayed faster than that in the control. thus, fusion dynamically connects skeletal muscle mito- chondria and serves as a target mechanism of both mutations and environmen- tal cues to cause impaired excitation-contraction coupling. -pos board b bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action katarina stroffekova, lucia balogová, mária maslaňáková, lenka dzurová, pavol mi�skovský mi�skovský. safarik university, kosice, slovakia. apoptosis is a key process in the development and maintenance of tissue homeostasis. this process of controlled cell death is tightly regulated by a balance between cell survival and damage signals. we focused our attention towards the intrinsic mitochondrial apoptotic pathway, where bcl- family of proteins plays the major role. we were particularly interested in two pro- apoptotic players bak and bax. here we investigated their role in apoptosis triggered by photodynamic action. we show the localization of bax and bak in u- mg human glioma cells incubated with photosensitizer hypericin (hyp) before and after photodynamic action. apoptotic stimulus by hyp photodynamic action caused bax translocation into mitochondria. however our results suggest that under these condi- tions there are two populations of mito- chondria: one which contains bax and bak simultaneously, and is almost exclu- sively localized near the plasma mem- brane; the other which contains bax only and is distributed throughout the cell. the different protein content and spatial distri- bution of these two populations suggest that they can play different roles in re- sponse to apoptotic stimuli. -pos board b stimulation of bax mitochondrial localization by bcl-xl thibaud renault , oscar teijido , gisele velours , yogesh tengarai ganesan , florent missire , nadine camougrand , bruno antonsson , laurent dejean , stephen manon . ibgc-cnrs, bordeaux, france, nyu college of dentistry, new york, ny, usa, merck-serono sa, geneva research center, geneva, switzerland, california state university of fresno, fresno, ca, usa. cytochrome c release, the commitment step of apoptosis, is regulated at the mitochondria through protein-protein interactions between the bcl- family proteins. an imbalance of this interaction network due to the up-regulation of the proto-oncogenes bcl- and/or bcl-xl lead to a resistance to apoptosis and is associated with tumor formation. bcl-xl overexpression act at the level of the mitochondrial outer membrane (mom) by inhibiting bax-mediated apoptosis; more particularly mac formation and cytochrome c release. how- ever, the molecular mechanisms through which bcl-xl affect earlier steps of bax-mediated apoptosis are not fully understood. surprisingly, we found that mitochondrial bax redistribution and change of conformation were not inhibited but rather spontaneously increased in response of bcl-xl overexpres- sion. in order to further investigate the molecular mechanisms involved in this 	which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c re ... 	outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion 	mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat 	bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action 	stimulation of bax mitochondrial localization by bcl-xl t h e american archivist volume i v january to october, published quarterly by t h e society of american archivists d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .p m x by c arnegie m ellon u niversity user on a pril t h e society of american archivists officers waldo gifford leland, president philip coolidge brooks, secretary herbert a. kellar, vice -president julian parks boyd, treasurer council members robert digges wimberly connor margaret cross norton william d. mccain morris l. radoff lawrence counselman wroth t h e american archivist editorial board christopher bush coleman edna louise jacobsen luther harris evans herbert ingram priestley theodore calvin pease, managing editor t h e university of illinois, sponsor the american archivist is published quarterly in the months of january, april, july, and october by the society of american archivists at ahnaip street, menasha, wisconsin. subscription price five dollars per year. entered as second-class matter february j, , at the post office at menasha, wisconsin, under the act of march , . all contributions should be addressed to the editor, lincoln hall, urbana, illinois. sub- scriptions and communications should be sent to ahnaip street, menasha, wisconsin, or the secretary, box , washington, d.c. d ow 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january, published quarterly by the society of american archivists d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .p m x by c arnegie m ellon u niversity user on a pril the society of american archivists officers w a l d o gifford leland, fresident p h i l i p coolidge brooks, secretary h e r b e r t a. kellar, vice fresident j u l i a n parks boyd, treasurer council members robert digges w i m b e r l y connor margart cross norton w i l l i a m d . m c c a i n morris l. radoff lawrence counselman w r o t h t h e american archivist editorial board christopher bush coleman edna louise jacobsen l u t h e r harris evans h e r b e r t ingram priestley theodore calvin pease, managing editor t h e university of illinois, sponsor the american archivist is published quarterly in the months of january, april, july, and october by the society of american archivists at ahnaip street, menasha, wisconsin. subscription price five dollars per year. entered as second-class matter february , , at the post office at menasha, wisconsin, under the act of march , . all contributions should be addressed to the editor, lincoln hall, urbana, illinois. sub- scriptions and communications should be sent to ahnaip street, menasha, wisconsin, or the secretary, box , washington, d.c. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .p m x by c arnegie m ellon u niversity user on a pril the american archivist january, volume iv number i published quarterly by the society of american archivists d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .p m x by c arnegie m ellon u niversity user on a pril contents the archivist in times of emergency . . . . w a l d o g. leland i t h e fourth annual meeting of the society of american archi- vists lester j. cappon european experiences in training archivists ernst posner reviews of books guide to the material in the national archives waldo g. leland wpa projects, ship registers of massachusetts: district of barnstable, - ^ ; dighton-fall river, - ; district of new bedford, - ; district of newburyport, - ; district of plymouth, - ; hamer, philip m., instructions for the compila- tion of ship registers and enrollments forrest r. holdcamper the business historical society, the preservation of business records william d. overman eduardo mujica farias, el arte de organizar bibliotecas, archivos y reparticiones en general almon r. wright meddelanden fran svenska riksarkivet for -ar harold larson rapport de varchiviste de la province de quebec pour - ; pierre-georges roy, archives de la province de quebec. inventaire des papiers de lery conserves aux archives de la province de quebec edward f. rowse shorter notices news notes abstracts of archive publications: western europe lester k. born iii d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .p m x by c arnegie m ellon u niversity user on a pril türk kütüphaneciliği , ( ), - z \ konuk yazar / guest author sosyal bilgiler eğitiminde İyi bir Örnek: abd kongre kütüphanesinin amerikan hafıza projesi a good example of social studies education: the american memory project from the library of congress bahri ata* Öz dijitalleşen bir dünyada, dünyayı ve problemlerini sınıfın dört duvarı arasında bir temel ders kitabına dayalı olarak öğrenmek genç nesiller için hoşnut edici midir? İnternet ve web siteleri yaşamımızı bütün boyutlarıyla derinliğine etkilemektedir. bu yenilikler modern sınıflarda öğretmenlerin davranışlarını ve öğretim tekniklerini de etkilemektedir. 'lardan sonra kongre kütüphanesi'nin amerikan hafıza projesinin sunduğu birincil ve ikincil kaynaklar, hem abd'de hem de diğer ülkelerde sosyal bilgiler eğitimini oldukça etkilemeye başlamıştır. bu makalenin amacı kongre kütüphanesi tarafından yürütülen amerikan hafıza projesi ve sosyal bilgiler eğitimine etkisini tanıtmaktır. bunun için, doküman analiz yöntemini kullandım. Özet olarak, bu proje, . yüzyılda sosyal bilgiler ve tarih'i öğretmede türk kütüphane ve okullarına ortaklık yolunda iyi bir örnek olabilir. anahtar sözcükler: sosyal bilgiler eğitimi, tarih eğitimi, kongre kütüphanesi, amerikan hafıza projesi abstract in the digitalized world, is it satisfactory for younger generations to learn world and its problems on the basis of a basal textbook among four walls of their classrooms? the internet and web sites are affecting all dimensions of our life very deeply. these innovations has changed the teacher's professional behaviors and instructional doç. dr., gazi Üniversitesi gazi eğitim fakültesi Öğretim Üyesi. e-posta: bahriata@gazi.edu.tr mailto:bahriata@gazi.edu.tr | konuk yazar / guest author bahri ata techniques in the modern classroom. after 's, the american memory project by the library of congress with its huge sources of primary and secondary materials began to affect the social studies education on both usa and other countries. the aim of this article is to introduce the american memory project conducted by the library of congress and its influence on social studies education. for this, i used document analysis method. in sum, this project can be a good example for turkish libraries and schools on the way of partnership to teach social studies and history in the st century. keywords: social studies education, history education, the library of congress, american memory project giriş dünyanın, dijital bir ortama dönüşmeye başladığı günümüzde teknoloji, pek çok geleneksel kurumu etkilemekte okul ve kütüphaneler de bunlardan payını almaktadır. günümüzde okullardaki genç nesillerin, sınıfın dört duvarı arasında tek bir ders kitabına bağlı kalarak dünya ve sorunları konusunda eğitim almaktan memnuniyet duymayacakları aşikârdır. buna bağlı olarak, teknolojinin kullanıldığı modern sınıflarda öğretmenin meslek davranışları ve öğretim yöntemleri de derinden etkilenmeye başlamıştır. bilindiği gibi kütüphaneler bir kurum olarak, sosyal bilgiler eğitiminin çok önemli bir bilgi kapısı görevini üstlenmektedir. sosyal bilgiler eğitimi çerçevesinde gerek öğretmen adaylarına gerekse öğrencilere kütüphanede araştırma yapma becerisi kazandırmanın önemi ortadadır. türkiye'de yılında hazırlanan ilköğretim programları, kütüphane kullanma becerisinin gelişimine ve araştırmacı öğrenci yetiştirmeye özellikle önem vermiştir. teknolojideki değişim rüzgârları kütüphaneleri de etkilemektedir. böylece “dijital kütüphane” ya da “karma (hybrid) kütüphane” denilen bir tür ortaya çıkmıştır (afzali, ). abd'deki kongre kütüphanesinin, bu tür kütüphanecilik anlayışında öncü bir rol oynadığı dikkati çekmektedir. diğer yandan küreselleşmenin etkisinin en şiddetli biçimde yaşandığı günümüzde pek çok ülke, hafıza mekânlarını dijital kütüphanelere aktararak koruma ve eğitim amaçlı olarak kullanma yarışı içine girmiştir. hiçbir ülke de bu yarışta geride kalmak istememektedir. bu tür dijital kütüphaneler, oluşturmacı sosyal bilgiler eğitimini sınıf ortamında daha mümkün kılmakta ve kolaylaştırmaktadır. sosyal bilgiler eğitimini, oluşturmacı sosyal bilgiler eğitiminde İyi bir Örnek: abd kongre kütüphanesinin amerikan hafıza projesi a good example of social studies education: the american memory project from the library of congress | (konstrüktivist) anlayışa uygun olarak gerçekleştirebilmek, öğrencilerin birinci elden kaynaklarla haşır neşir olmasını gerekli kılmaktadır. aslında tarih eğitiminde birinci kaynaklarla ders yapmak fikri çok eski olup kökenleri alman pedagoglar tarafından 'lere dayandırılan “kaynak yöntemi” (source method) düşüncesine kadar gitmektedir. İngiltere'de ise kaynaklarla tarih öğretimi konusunda ile arasında ilk coşku dalgası yaşanmış ve oxford Üniversitesinde çalışan eğitimci m. w. keatinge'in önemli katkıları olmuştur (osborne, , s. ). esasen on yıl önceki yazılarımda amerikan hafıza projesi'nden (bk. http://memory.loc.gov/ammem/index.html) kısaca söz etmiştim. daha sonra meslektaşlarım doğan ile dinç ( ) ve doğan ( ) da çalışmalarında amerikan kongre kütüphanesinin “amerikan hafıza” sitesinde yer alan, derslerde birincil kaynakları kullanma yaklaşımına ve gerekçeleri konusuna yer verdiler. aslında abd'de çevrim içi birinci elden kaynak hizmeti veren pek çok kurum bulunmaktadır. Örneğin ulusal arşiv ve kayıtlar yönetimi (nara), yale, northwestern, cornell, mississippi state, virginia Üniversiteleri, vassar koleji, franklin ve eleanor roosevelt enstitüsü gibi pek çok kurum birinci elden kaynak veri tabanına sahiptir. 'da abd'de bulunduğum sırada yaptığım okul gezilerindeki gözlemlerim ve kongre kütüphanesindeki incelemelerim sırasında bu projenin ve sosyal bilgiler eğitimine etkisinin çok daha detaylı bir çalışmayı gerektirdiğini fark ettim. bu proje, gerçekten eğitimde çok çağdaş ve iyi bir örnektir. genelde her eğitimcinin özelde de sosyal bilgiler eğitimcilerinin yurt dışındaki bu türden projelerden haberdar olması gerektiğini düşünmekteyim. Öğretmenlerden gelecek bir talep üzerine, ülkemizdeki ilgili kurumların benzer ve daha iyi projeler yapmasını sağlayacağına gönülden inanıyorum. bu makalenin kaleme alınma amacı, söz konusu projenin nasıl başladığını, nasıl geliştiğini, sosyal bilgiler eğitimine etkisini ortaya koymak ve türkiye'deki sosyal bilgiler eğitimcilerine tanıtmaktır. böylece yakın gelecekte türkiye'de de buna benzer ulusal projeler için felsefi ve pedagojik bir çerçeve oluşturmak amaçlanmaktadır. projeye ve etkilerine geçmeden önce abd kongre kütüphanesinin tarihçesinden kısaca söz etmek yerinde olacaktır. abd kongre kütüphanesinin Önemi bu kütüphane, 'de washington, dc.'de amerikan ulusal yasama organı mensuplarının ihtiyaçlarını karşılamak üzere küçük bir araştırma kütüphanesi olarak http://memory.loc.gov/ammem/index.html | konuk yazar / guest author bahri ata kurulmuştur. kütüphane, zaman içinde eğitim ve akademik amaçlarla tarihsel ve kültürel materyalleri korumayı amaç edinmiştir (hubbell, ). 'te britanya askerleri kongrenin küçük hukuk kitapları koleksiyonunu yakmışlardır. 'te thomas jefferson, kitaptan oluşan kendi özel kitap koleksiyonunu kongre kütüphanesine vererek buranın yeniden kurulmasını sağladı. yangınında bu kitapların üçte ikisi yanmıştır. 'ten sonra kütüphane, aynı zamanda birleşik devletler telif hakları ofisinin mekânı oldu. 'de kütüphane bugün thomas jefferson binası olarak adlandırılan İtalyan rönesans stilindeki binasına geçti. 'da hemen arka tarafına adams binası inşa edildi. 'de madison binası yapıldı. bu binaları yeraltından geniş tünel geçitler de birbirine bağlamıştır. thomas jefferson binası, 'de büyük bir restorasyona tabi tutularak 'de tekrar açıldı. abd kongre kütüphanesi, milyon ürünü ile günümüzde dünyanın en zengin kütüphanelerinden biridir. turistler tarafından en çok ziyaret edilen yapılardan biridir. Örneğin 'de milyon bin kişi burayı ziyaret etmiştir (anonim, ). kongre kütüphanesi, farklı hizmet vermekte olup “dünya dijital kütüphanesi, myloc.gov, veterans (gaziler) tarih projesi, Öğretmenler, ziyaretçiler, araştırmacılar, kütüphaneciler-arşivciler, Çocuklar ve aileleri” sayfaları hemen dikkati çekmektedir (bk. http://www.loc.gov/index.html). verilen hizmetlerin içinde üç hizmetin, doğrudan öğretmenlere ve öğrencilere yönelik olarak eğitim amaçlı kurulduğu görülmektedir. bunlar; “amerikan hafızası, myloc.gov, Öğretmenler sayfası”dır. makalemi daha çok dijital tarih ve kültür materyallerini içeren amerikan hafızası projesi ile sınırlamaya çalıştım. aslında bir başka çalışmada da diğer projeleri ele almak mümkündür. amerikan hafızası projesi nedir? amerikan hafıza projesi ile doküman, gazete makalesi, yazma, nadir eser, kitap, görüntü, harita, karikatür, film, fotoğraf ve ses ve müzik kayıtlarından oluşan . milyon birinci elden tarihsel kaynak dijital ortama aktarılarak arşivlenmiş ve bir arama motoru oluşturulmuştur. bunlara ilişkin olarak öğretmenlerin sınıf içinde kullanabileceği ders materyalleri de geliştirilmiştir. amerikan hafızası projesi esas olarak . yüzyıla kadar dokümanlar içermekle birlikte, ve . yüzyıla ait amerikan yaşamının değişik boyutlarına ilişkin binlerce kanıt sunmaktadır. afzali'ye myloc.gov http://www.loc.gov/index.html myloc.gov sosyal bilgiler eğitiminde İyi bir Örnek: abd kongre kütüphanesinin amerikan hafıza projesi a good example of social studies education: the american memory project from the library of congress | göre ( , s. ) bu proje, dijital kütüphaneciliğin ilk örneği olarak da kabul edilmektedir. bu proje, pilot program olarak 'da başlamış olup 'e kadar sürdü. okul ve kütüphane pilot projenin bir parçası olarak bu materyalleri içeren cd-rom'ları aldılar. ortaokul ve lise öğrencileri, bu pilot uygulama sırasında daha fazla dijital kaynak istediklerini belirtmişlerdir. 'te kütüphane, “ulusal dijital kütüphane programı”nı kurmak için milyon dolarlık bir bağış bulduğunda, amerikan hafızası projesi bu programın bir tür amiral gemisi oldu. bu projenin toplam masrafı yaklaşık milyon dolar olup kısmen birleşik devletler kongresi tarafından, büyük oranda da özel sektör tarafından karşılanmıştır. Örneğin kongre, bu proje için milyon dolarlık federal yardım yapmıştır. w.k. kellogg vakfı, 'te milyon dolar bağış yapmıştır . bu vakıf, kurulmuş olup amacı cinsiyet, ırk, inanç, milliyet farkları gözetmeksizin çocukların ve gençlerin doğrudan ya da dolaylı olarak sağlık, konfor, eğitim, beslenme, giyinme, barınma ve korunması için gerekli fonların yönetimi için kurulmuştur (w.k. kellogg foundation, ). 'de . yüzyıldan . yüzyıla doküman, arkasından “amerikan tarihinde sözler ve eylemler koleksiyonu, panoramik fotoğraflar ( - ), kadın oy hakkı mücadelesi fotoğrafları ( - )” ilk olarak çevrim içi (online) aktarılan koleksiyonlardandır. 'de harvard Üniversitesi tasarım okulundaki frances loeb kütüphanesi de amerikan hafıza web sitesine dâhil edildi. böylece ortaya “amerikan manzara ve mimari tasarım ( - )” web sunumu ortaya çıktı. bu sunum, fotoğraflarla birlikte, planlar, haritalar ve modeller içermektedir. 'de İspanya-amerika savaşı'nı gösteren hareketli resimler koleksiyonu çevrim içine eklendi. eğitimde müziğin kullanılmasının yaygınlaşmasına odaklanmış olan texaco kuruluşu da bu programa katkıda bulundu. amerikan halk yaşam merkezinin tarihli koleksiyonları da bunlara eklendi. bunların arasında - yılları arasında “yorganlar ve yorgancılık” ile ilgili bir koleksiyon da bulunmaktadır. 'da kongre kütüphanesi, amerikan hafızası web sitesine “aleksander graham bell'in aile belgeleri, efemera, güney teksas sınırını gösteren görsel kaynaklar ( - ), kuzey rio grande'nin hispanik müziği ve kültürü” gibi | konuk yazar / guest author bahri ata koleksiyonları dijital ortama aktarmıştır. bu tarihe kadar 'den fazla koleksiyon çevrim içi ortama aktarılmış oldu (balas, , s. ). 'da social studies (sosyal bilgiler) dergisinde sosyal bilimler eğitimi konsorsiyumunun yöneticilerinden ve bu sitedeki pek çok ders planını geliştirenlerden laurel r. singleton ve james r. giese tarafından öğrencilerle birinci elden doküman kullanmanın çerçevesinin anlatıldığı bir makale kaleme alındı. söz konusu makalede, sınıfta birinci elden kaynak kullanmanın mantığı ve nasıl yapılacağı konusu özetlenmiştir (singleton ve giese, ). 'te “thomas jefferson doküman koleksiyonu” da amerikan hafıza web sitesine aktarıldı. böylece washington, lincoln ve jefferson gibi amerikan başkanları ile ilgili materyaller çevrim içi ortama aktarılmış oluyordu. 'da son yapılan değişikliklerle birlikte amerikan hafızası projesi sayfasında şu linkler vardır: “başlıklarına göre koleksiyonlar, koleksiyonlarla İlgili İlginç noktalar, tarihte bugün, Öğretmenler, kütüphaneciye sorun”. aynı yıl koleksiyon sayısı 'u bulmuştur. koleksiyonlar; başlıklarına, dönemlerine, içerdikleri materyalin türüne (harita, yazma, müzik, fotoğraf, hareketli film gibi) ve ait oldukları bölgelere göre sınıflandırılmıştır. başlıklar; “reklamcılık, afrikalı-amerikalıların tarihi, mimarlık-manzara, Şehirler-kasabalar, kültür-halk yaşamı, Çevre-koruma, hükümet-kanun, göç-amerikan genişlemesi, edebiyat, haritalar, yerli amerikalılar tarihi, performans sanatları, müzik, başkanlar, din, spor ve rekreasyon, teknoloji ve endüstri, savaş askerlik, kadın tarihi” isimlerini taşımaktadır. yıllara göre baktığımızda temmuz verilerine göre, - arası için koleksiyon, - dönemiyle ilgili koleksiyon bulunmaktadır. ile günümüze ait koleksiyon bulunmaktadır. bu projenin ve . yüzyıl amerikan tarihi ve kültürü açısından oldukça zengin malzemeye sahip olduğu anlaşılmaktadır. “koleksiyonlarla İlgili İlginç noktalar” ise “uygulamalı diller merkezinin amerikan İngilizcesi diyalektleri ile alfred whital stern'in lincoln koleksiyonu”nu içermektedir. “tarihte bugün” sayfasında da “kaynaklar, arşiv ve bugün” linkleri bulunmaktadır. “Öğretmenler” sayfası; “sınıf materyalleri, mesleki gelişim, tps partnerleri, birincil kaynakları kullanma, haberler ve olaylar, ek kaynaklar ve faks” gibi kısımları içermektedir. sosyal bilgiler eğitiminde İyi bir Örnek: abd kongre kütüphanesinin amerikan hafıza projesi a good example of social studies education: the american memory project from the library of congress | “sınıf materyalleri” de “ders planları, tematik kaynaklar, birincil kaynaklar seti, sunu ve etkinlikler, koleksiyon bağlantılarını içermektedir. kısaca bu web sayfalarında öğretmenin sınıf içinde birinci elden her türlü kaynağı nasıl kullanması gerektiği ile ilgili örneklerle zenginleştirilmiş bilgiler bulunmaktadır. amerikan hafızası projesi'nin sosyal bilgiler eğitimine yansımaları nelerdir? 'den sonra amerikan hafıza projesi'nin sosyal bilgilere etkileri üç alanda kendini hissettirmeye başladı. bunlar öğretim materyallerinin hazırlanması, öğretmene hizmet içi eğitim ve uzaktan eğitimdir. Öğretmenler açısından karşılaşılan en büyük problem ders işleniş sürecini, bu çok sayıdaki kaynağı kullanarak tasarlamak ve bunları derste uygulamak olmuştur. bu problemle başa çıkmak için kongre kütüphanesi, deneyimli öğretmenlerle birlikte ulusal öğretim programı standartlarını da göz önüne alarak “öğretmen kaynakları modülü” nü hazırladı. bu modül; ayrıntılı ders planlarını, uygulamaya yönelik iyi hazırlanmış yönergeleri, performans değerlendirme ölçeklerini (rubrik) içermektedir. modül aynı zamanda birinci elden kaynakların sınıfta nasıl kullanılacağı, doküman, harita ve fotoğrafların bilgi ve tarihsel kanıt için nasıl değerlendirileceği konusunda eğitimcilere bilgi sağlamaktadır. İşte bu materyallerle öğretmenler sınıflarında kolayca oluşturmacı öğrenme ortamı oluşturabilmektedir. böylece öğrenci, bir sosyal bilimci ve tarihçi gibi kaynakların üzerinde kendi çalışabilir. bu malzemeleri kullanarak kendi sunusunu hazırlayabilir ve kendi sonucuna ulaşabilir. Örneğin, birinci dünya savaşı ile ilgili her türlü kaynağı inceleyen ve bu kaynakların nasıl ve niçin üretildiği üzerine kafa yoran öğrenciler, bir sonraki derste amerikan liderlerinin kendi dönemlerinde yaptıkları konuşmalarını dinlemişler, tarihsel olgu ile tarihsel yorumu birbirinden ayırmanın mümkün olup olamayacağını tartışmışlardır. Üçüncü derste öğrenciler amerika'nın savaşa katılımı ile ilgili “microsoft publisher” programını kullanarak farklı görüşleri yansıtan ve gazete personeli olarak kendi aralarında iş bölümü yaptıkları iki farklı gazete hazırlamışlardır (lincoln, ). kongre kütüphanesi, - arasında amerikan hafıza bursiyer (fellows) programı adı altında öğretmenler için hizmet içi eğitim programları da uyguladı. 'da kongre kütüphanesi, öğretmenlerin “amerikan hafızası tarihsel | konuk yazar / guest author bahri ata koleksiyonu”nun sınıf içinde kullanılmasında öğretmenleri eğitmek için madison binası'nda ulusal dijital kütüphane merkezini kurdu. microsoft da yardımları ile merkezin yenileşmesine önemli katkı sağladı. Çalıştaylarda öğretmenler, kütüphane personeli ile birlikte çalıştılar. Öğretim programı boyunca on-line tartışma programlarına da katıldılar. - yılları arasında bu programlara öğretmen katıldı. 'den sonra program, “eğitim sosyal yardım programı” adını aldı (veccia, ). bu tarihten sonra amerikan hafıza bursiyer (fellow) enstitüsü washington'da kütüphanecilerin, medya uzmanlarının ve öğretmenlerin katıldığı burs programları için altı günlük iki oturumdan oluşan çalıştaylar düzenlemeye devam etti. pek çok eyalette sosyal bilgiler ve tarih öğretmenlerine yönelik birinci ve ikinci elden kaynakların nasıl kullanılacağı ile ilgili hizmet içi eğitim kapsamında kurslar da düzenlenmiştir. hazırlanan materyaller, kongre kütüphanesinin “Öğrenme sayfası'na” konuldu. bu materyaller . sınıftan . sınıfa kadar ders planlarını, kaynakları, sunuları, amerikan tarihi ile ilgili etkinlikleri kapsamaktadır. oluşturmacı sosyal bilgiler ya da tarih dersleri için lise düzeyinin beklenmediği, ilköğretim için de benzer materyallerin hazırlandığı dikkati çekmektedir. bu materyaller kolayca ulaşılabilir olmasının yanı sıra, sürekli güncellenmektedir ve parasızdır. kütüphane ayrıca kitaplar ve cdrom'lar da yayınladı. 'de sosyal bilgiler programının kimlik, güç, çevre ve kültür gibi temalarının etrafında sosyal bilgiler üniteleri hazırlayarak bunları bir cd'de topladı. yine aynı yıl birinci dünya savaşı gibi pek çok konuya ilişkin üniteler tasarlanarak özellikle eğitimciler için kütüphanenin öğrenme sayfasına konuldu. sınıf içinde kullanılan etkileşimli (interaktif) akıllı tahtalar da dijital kaynaklardan yararlanmayı daha fazla kolaylaştırıyordu. bununla beraber elektronik ortamda birinci elden kaynakları kullanmanın öğrencilerin tarihsel anlayışlarının gelişimine ilişkin pek çok kaynak olmakla beraber, doğrudan amerikan hafıza projesi'nin öğrencilerin tarihsel anlayışlarının gelişimine etkisi ile ilgili amprik bir çalışmaların yapılmış olabileceğini düşünüyorum. ancak henüz bu tür çalışmalara ulaşamadım. sonuç ve tartışma kongre kütüphanesi, her türlü tarihsel dokümanın koruma ve eğitim amacıyla sanal ortama aktarılması olarak özetlenebilecek olan amerikan hafıza projesi ile önemli bir sosyal bilgiler eğitiminde İyi bir Örnek: abd kongre kütüphanesinin amerikan hafıza projesi a good example of social studies education: the american memory project from the library of congress | rol oynamıştır. 'den beri kongre kütüphanesi hizmet içi eğitimlerle ve uzaktan eğitim materyalleri ile bu projenin çıktılarının ülke çapında yaygınlaştırılması için çaba sarf etmektedir. amerikan hafızası projesi, abd kongre kütüphanesinin, unesco ve diğer kütüphanelerle birlikte 'da başladığı “dünya dijital kütüphanesi” adındaki bir başka proje için de bir model olmuştur. Özel sektör, İnternet arama şirketleri ile kütüphaneler arasındaki bu girişim örnekleri, türkiye için de iyi birer örnek oluşturmaktadır. hafıza mekânlarını aktarma projesi, ülkemiz gibi pek çok ülkeye tarihsel dokümanları gelecek nesillere aktarmak ve eğitim amaçlı kullanmak için sanal ortama transfer etmede ilham vermektedir. Ülkemizde de kongre kütüphanesine benzer bir şekilde, millî kütüphane, meclis kütüphanesi, türk tarih kurumu kütüphanesi, devlet arşivleri genel müdürlüğü ve talim ve terbiye kurulu başkanlığı gibi kurumlar ayrı ayrı koleksiyonlarını sanal ortama aktarmalıdır. Örneğin devlet arşivleri genel müdürlüğü gibi kurumlar bu işte oldukça yol kat etmişlerdir. Özellikle bu kurumlar hafıza mekânlarımızı oluşturan kaynakların toplanması, sınıflanması ve sanal ortama aktarılması konusunda iş birliği yapabilmelidirler. elbette tarihle ilgili çevrim içi veri tabanlarının artması durumu tarihçilerin de bilgi arama davranışlarını etkileyecektir. bununla beraber, birinci'nin ( , s. ) de belirttiği gibi teknoloji ne kadar gelişirse gelişsin, tarihçilerin arşiv kaynaklarının daima orijinalini tercih edecekleri söylenebilir. bu işlemlerle eş zamanlı olarak bu materyallerin eğitim amaçlı kullanılması üzerinde de çalışmalar yapılmalıdır. millî eğitim bakanlığı tarafından deneyimli sosyal bilgiler ve tarih öğretmenlerine dersin öğretim programları göz önünde bulundurularak örnek etkinlikler içeren cdrom'lar, kitaplar ya da internet sayfaları hazırlatılabilir. daha sonra bunları türkiye çapında öğretmenler arasında yaygınlaştırmak aşaması gelmektedir. bunun için de millî eğitim bakanlığı ile iş birliği içinde hizmet içi eğitim seminerleri düzenlenmesi gereklidir. bu çerçevede talim ve terbiye kurulu eski başkanı prof. dr. ziya selçuk döneminde talim ve terbiye kurulu başkanlığı'nın öğretmenler için hazırlamaya başladığı “etkinlikler havuzuna” (portal) işlevsellik kazandırılabilir. | konuk yazar / guest author bahri ata bütün bunlar yapılırken çözülmesi gereken en önemli sorunlardan biri de telif hakları sorunudur. tabii bu arada çocuklarımız ve öğrencilerimiz, internet kullanımı ile de daha da yaygınlaşan kes-yapıştıra dayalı tarih ödevleri hazırlama anlayışından uzak tutulmalıdır. onlara başkalarının emeklerine saygı göstermeyi öğrenme konusunda yardımcı olmalıyız. onları, intihal (plagiarism) konusunda da aydınlatmayı bir görev bilmeliyiz. teşekkür notu: georgia state Üniversitesi kütüphane uzmanı sayın tricia clayton'a teşekkürü bir borç bilirim. pek çok yayına onun yardımlarıyla ulaşabildim. kaynakça afzali, m. ( ). karma kütüphane: dijital ve geleneksel kütüphanelerin ortak noktası. kurbanoğlu, y. tonta ve u. ai (yay. haz.) değişen dünyada bilgi yönetimi sempozyumu içinde (ss. - ). ankara: hacettepe Üniversitesi bilgi ve belge yönetimi bölümü. anonim ( ) kongre kütüphanesi tanıtım broşürü. balas, j. l. ( ). digital bringing library collections online. computers in libraries ( ), - . birinci, h. g. ( ). tarihçilerin bilgi arama davranışları. türk kütüphaneciliği, ( ), - . brisco, s. ( ). digital resources; loc teachers page put to the test. school library journal, ( ) , - . doğan, y. ( ). birinci elden kaynakları sınıfta etkin kullanmanın yolları. bilim ve aklın aydınlığında eğitim, ( ), - . doğan, y. ve e. dinç ( ). birinci elden tarih kaynaklarının sosyal bilgiler ve tarih derslerinde internet üzerinden kullanımı: abd ve İngiltere'den uygulama örnekleri. tsa, ( ), - . hubbell, f. ( ). american memory a primary source, library and information science community. nisan tarihinde http://www.thefreelibrary.com/american+memory+a+primary+source- a adresinden erişildi. lincoln, m. ( ). constructivist learning primary sources, the book report. (nov- dec), . osborne, k. ( ). m.w. keatinge: a british approach to teaching history through sources. canadian social studies, ( ), - . singleton, l. r. ve j. r. giese ( ). using online primary sources with students. social studies, ( ) , - . veccia, s. ( ). a lasting memory. nisan tarihinde http://www.loc.gov/loc/lcib/ /alfp.html adresinden erişildi. http://www.thefreelibrary.com/american+memory+a+primary+source-a http://www.loc.gov/loc/lcib/ /alfp.html bibliography of published works relating to the upper canada rebellion, - copyright © the ontario historical society, ce document est protégé par la loi sur le droit d’auteur. l’utilisation des services d’Érudit (y compris la reproduction) est assujettie à sa politique d’utilisation que vous pouvez consulter en ligne. https://apropos.erudit.org/fr/usagers/politique-dutilisation/ cet article est diffusé et préservé par Érudit. Érudit est un consortium interuniversitaire sans but lucratif composé de l’université de montréal, l’université laval et l’université du québec à montréal. il a pour mission la promotion et la valorisation de la recherche. https://www.erudit.org/fr/ document généré le avr. : ontario history bibliography of published works relating to the upper canada rebellion, - chris raible consequences of rebellious acts: the & rebellions volume , numéro , fall uri : https://id.erudit.org/iderudit/ ar doi : https://doi.org/ . / ar aller au sommaire du numéro Éditeur(s) the ontario historical society issn - (imprimé) - (numérique) découvrir la revue citer ce document raible, c. ( ). bibliography of published works relating to the upper canada rebellion, - . ontario history, ( ), – . https://doi.org/ . / ar https://apropos.erudit.org/fr/usagers/politique-dutilisation/ https://www.erudit.org/fr/ https://www.erudit.org/fr/ https://www.erudit.org/fr/revues/onhistory/ https://id.erudit.org/iderudit/ ar https://doi.org/ . / ar https://www.erudit.org/fr/revues/onhistory/ -v -n -onhistory / https://www.erudit.org/fr/revues/onhistory/ ontario history the only published comprehensive bibliography of works related to the canadian rebellions of - was issued more than eighty years ago: public library of toronto. the rebellion of - : a bibliography of sources of in- formation in the public reference library of the city of toronto, canada (toronto: public library of toronto, ). broad though it was, that bibliogra- phy was restricted to works held by the library. it covered the rebellions of both lower and upper canada and included manuscripts and published material. it also dealt with the clerg y reserves and other political controversies that prompt- ed the rebellions as well as the aftermath, including the durham report of , the union of the canadas of , and the rebellion losses controversy of . the only published substantial survey of the historiography of the up- per canadian rebellion is also now very dated: j. e. rae, “rebellion in upper canada. ,” transactions of the his- torical scientific society of manitoba, se- ries , ( - ). rae evaluated major works, from the narratives of mackenzie ( ) and francis bond head ( ) to kilbourn’s biography ( ) and craig’s provincial history ( ). this bibliography, compiled from a great variety of sources, focuses on works specifically on upper canada. it lists, but does not attempt to evaluate, more than published writings and commentar- ies. undoubtedly there are many more, its last section ( ) lists a number of un- published graduate theses on rebellion related topics—again, there are surely others. thus additions and corrections are eagerly solicited and gratefully re- ceived (chrisraible@georgian.net). no attempt was made to list in- ternet websites—valuable as they are, they are both vast and ephemeral—and the search engines make them readily available. for example, a google search ( january ) for “’upper canada’ rebellion ” produced , pages, while “’patriot war’ ” produced , pages and ‘patriots’ war’ ” some , more. the bibliography is compiled in nine sections: bibliography of published works relating to the upper canada rebellion, - compiled by chris raible (with thanks to john carter, patricia kennedy, stuart scott and many others) “r eb el s m ar ch in g” b y c .w . j eff er ys . . . prior to bell, andrew. history of canada from the time of its discovery till the union year � -� , book (montreal: john lovell, ). chapman, henry samuel. an impartial account of the civil war in the canadas (london: j. saunders jr., ). chisholm, david. annals of canada for - , n.p., n.d. coventry, george. “a contemporary account of the rebellion in upper canada, ,” ontario historical society papers and records, ( ). davis, robert. the canadian farmer’s travels in the united states of america: in which remarks are made on the arbitrary colonial policy practised in canada and the free and equal rights and happy effects of the liberal institutions and astonishing enterprise of the united states (buffalo: steele’s press, ). elliott, thomas frederick. the canadian controversy: its origin, nature and merits (london: longman, orme, brown, green, & longmans, ). gore, montague. observations on the disturbances in canada (london: saunders & otley, ). head, francis bond. a narrative (london: john murray, – abridged and reprinted: s. f. wise, editor. toronto: mcclelland and stewart, ). head, francis bond. chapters viii-xvi of the emigrant (london: john murray, ). mackenzie, william lyon. the caroline almanack and american freeman’s chronicle for � (rochester: mackenzie’s gazette office, ). mackenzie, william lyon. mackenzie’s own narrative of the late rebellion with illustrations and notes, critical and explanatory: exhibiting the only true account of what took place at the memorable siege of toronto (first published all works are categorized according to the year written rather than the year published. . general & preliminary works . . prior to . . - . . - . border incidents & patriot hunters . . prior to . . - . . - . trials & transportation . . prior to . . . narratives by transported prisoners . . - . . - . individual & regional studies . . prior to . . - . . - . specialized studies . . prior to . . - . . - . aftermath & reflections . . prior to . . - . . - . lower canada—works of particular relevance to upper canada . . prior to . . - . . - . fiction . . prior to . . - . . - . theses . general & preliminary works ontario history [watertown, new york] jeffersonian, january – republished with critical notes by charles fothergill and an appendix by john powell (toronto: palladian office, ). mackenzie, w. l. “short letter from w. l. mackenzie to the editors of the buffalo whig and journal, informing them that the reformers of upper canada have taken up arms in defence of the principles of independence of european domination, stating ‘we are in arms near the city of toronto, ½ miles distant,’” quebec gazette ( december ). m’leod, d. brief review of the settlement of upper canada (cleveland: f. b. penniman, – republished belleville, ontario: mika publishing, ). m’mullen, john. chapter xxi of the history of canada from its first discovery to the present time (brockville: j. m’mullen, ). miller, h. orlo, editor. “the letters of rebels and loyalists,” canadian science digest, ( ). n.a. “account of the attack on toronto,” cobourg star ( december ). n.a. “account of the rebellion at toronto, upper canada,” montreal transcript ( & december ). n.a. “the affairs of canada: a review and criticism,” quarterly review, ( ). n.a. “british policy in canada, ,” quarterly review, ( ). n.a. “canada” army and navy chronicle, , ( november ). n.a. “canada: false principals of government the cause of it sufferings,” the colonial magazine & commercial maritime journal, ( january-april ). n.a. “the canada question,” blackwood’s edinburgh magazine, ( ). n.a. “the canada question,” the united states democratic review, , ( january ). n.a. “the canada question, a review,” dublin review, ( ). n.a. “a canadian,” the affairs of the canadas in a series of letters (london: j. king, ). n.a. “ canadian affairs,” fraser’s magazine, ( ). n.a. “the canadian revolt: a short review of its causes, progress and probable consequences,” united service journal and naval and military magazine, ( june ). n.a. “causes of the rebellion in canada,” dublin university magazine, ( ). n.a. “the causes of the revolution in canada,” the [toronto] mirror ( december ). n.a. “colonial discontent – lower canada – upper canada,” blackwood’s edinburgh magazine, ( ). n.a. “dr. horne’s narrative of the burning of his house, toronto, th december, ,” the [toronto] patriot ( january ). n.a. “the execution in canada,” the united states democratic review, , (march ). n.a. “gentlemen settlers in canada,” the colonial magazine and east india review, , (august ). n.a. “history of the recent insurrection in the canadas,” monthly historical register, (march-june ). n.a. “history of the recent insurrection in the canadas - part first,” the united states democratic review, , (march-june, ). n.a. “history of the recent insurrection in the canadas - part second,” the united states democratic review, , (march-june, ). n.a. “narrative of the attack on toronto by mackenzie,” the albion ( december ). n.a. “official correspondence and relation of incidents in connection with the rebellion in upper and lower canada,” quebec gazette ( december ). n.a. “opinions of the american press on canadian affairs,” cobourg star ( december ). n.a. “ministerial policy in the canadas…,” blackwood’s edinburgh magazine, ( ). n.a. “political history of upper canada to ,” colonial magazine and commercial- maritime journal, ( ). n.a. “the rebellion in lower and upper canada,” annual register ( - ). n.a. “a sketch of the canadas,” blackwood’s edinburgh magazine, , (february ). n.a. “war in canada, its causes and consequences,” eclectic review, ( ). preston, t.r. “incidents of the insurrection of and ,” chapters iii-v of three years’ residence in canada, from - , vol. (london: richard bentley, . reed, t. a. “extracts from the diary of a loyalist of ,” york pioneer and historical association report ( ). ryerson, egerton. the affairs of the canadas, in a series of letter by a canadian (london: j. king, ). rolph, thomas. “political history of upper canada,” colonial magazine and commercial-maritime journal (may-august ). rolph, thomas. “rebellion in upper canada and invasion of the americans,” colonial magazine and commercial-maritime journal (may-august ). strickland, samuel. chapter xvi, volume ii of twenty-seven years in canada west, or the experience of an early settler (london: – republished edmonton: m.g. hurtig, ). wells, william benjamin. canadiana, containing sketches of upper canada and the crisis in its political affairs (london: c & w. reynell, ), see also issues – december through � – of the albion, the cobourg star, the quebec gazette, the [toronto] mirror, and the [toronto] patriot as listed in public library of toronto, the rebellion of - : a bibliography of sources of information in the public reference library of the city of toronto, canada (toronto: public library of toronto, ), pages - . warburton, g. d. “historical sketch of canada,” chapter iii of hochelaga, or england in the new world, vol. (london: h. colburn, ). . . - bryce, george. “the canadian rebellion, ,” in rossiter johnson, editor. great events by famous historians, volume � (new york: national alumni, ). caniff, william. “the rebellion of in upper canada,” chapter of hopkins, j. c., editor, canada: an encyclopaedia, vol. (toronto: linscott pub. co., - ) – see also “constitutional development and the rebellion; editorial notes,” and “the rebellion of and the united states,” chapters of the same volume. carnochan, janet. “a wife’s devotion; a canadian heroine of sixty years ago; the story of maria wait, the wife of benjamin wait, the exile,” niagara historical society papers, ( ). clark, s.d. chapters - of movements of political protest in canada, �� - � (toronto: university of toronto press, ). cockburn, a.p. chapters vii-viii of political annals of canada (toronto: w/ briggs, ). conant, thomas. “incidents of the rebellion of - ,” chapter vi of upper canada sketches (toronto: w. briggs, ) conant. thomas. “the canadian rebellion of b�bl�ography of the upper canada rebell�on ontario history - and the causes that led to it. chapter vii of life in canada (toronto: w. briggs, ). croil. james. “the rebellion of upper and lower canada,” chapter v of dundas; or a sketch of canadian history (dundas: b. dawson & son, ). corey, albert b. the crisis of - � in canadian-american relations (new haven: yale university press, ). craig, gerald. “the american impact on the upper canadian reform movement before ,” canadian historical review, , (december ). craig, gerald m. “mackenzie and the grievances of upper canada,” “conservatives and rebels, - ,” and “an end and a beginning, - ,” chapters of upper canada: the formative years, �- � (toronto: mcclelland and stewart, ). creighton, d. g. “the economic background of the rebellions of eighteen thirty-seven,” canadian journal of economics and political science, � ( ). dent, john charles. the story of the upper canada rebellion (toronto: c. blackett robinson, ). dunham, aileen. political unrest in upper canada �- � (london: longmans green, – republished toronto: mcclelland & stewart, ). earl, david w. l. the family compact: aristocracy or oligarchy? (toronto: copp clark, ). ermatinger, c.o. “political affairs of the province,” “duncombe rising and flight,” invasion of western frontier,” and “port stanley threatened,” chapters xxvi- xxix of the talbot régime (st. thomas: municipal world, ). guillet, edwin c. the lives and times of the patriots: an account of the rebellion in upper canada, - and of the patriot agitation in the united states, - � (toronto: thomas nelson, – republished toronto: university of toronto press, ). hoolden, j. rose. “rebellion of - ,” journal & transactions of the wentworth historical society, ( ). hopkins, j. castel. chapters x-xii of in progress of canada in the nineteenth century (london & edinburgh: w. & r. chambers, ). jackson, eric. “the organization of the upper canadian reformers, – ,” ontario history, liii, ( june ). king, john. the other side of the “story”(toronto: james murray, ). kingsford, william. history of canada, volume (toronto and london: rowsell & hutchison – republished new york: ams press, ). landon, fred. western ontario and the american frontier (toronto: ryerson press & new haven: yale university press, – republished toronto: mcclelland & stewart, ). lindsey, charles. the life and times of william lyon mackenzie, volume (toronto: p.r. randall – republished toronto: coles publishing, ). lizars, robina and kathleen. humours of ‘ grave, gay and grim: rebellion times in the canadas (toronto: william briggs, ). manning, helen taft. “the colonial policy of the whig ministers, - ,” canadian historical review, xxxviii, & ( ). mcarthur, duncan. “the canadian rebellions of ,” in shortt, adam and a. g. doughty. editors. canada and its provinces, vol. (toronto: t. & a. constable at the edinburgh university press for the publishers’ association of canada limited, n.d.). mcdougall, d. j. “lord john ruddell and the canadian crisis - ,” canadian historical review, xxii, (december b�bl�ography of the upper canada rebell�on ). mcmaster, john bach. “the patriot war in canada,” chapter xlvi of history of the people of the united states, vol, � (new york: d. appleton, ). mcmullen, john. “rebellion of - ,” chapters i-v of history of canada, vol. (brockville, ontario: mcmullen, - ). middleton, jesse edgar and fred landon. “the mackenzie rebellion,” chapter x of the province of ontario: a history, � �- (toronto: dominion publishing, ). munro, w. bennett. “canada and british north america,” chapters xiv-xvi of history of north america volume xi canada and british north america (philadelphia: george barrie & sons, ). oberlander, alexander (translated by marie l. bishop). “the patriots’ war ,” in geschichte der deutschen in syracuse and onondaga county, (syracuse: public library, local history department, ). ormsby, william, editor. crisis in the canadas - : the grey journals and letters (toronto: macmillan of canada, ). ouellet, fernand. “the rebellions of / ” in j.m. bumstead, editor. interpreting canada’s past, vol. i (toronto: oxford university press, ). parks, malcolm g. the rebellions of in upper and lower canada (toronto: imperial oil limited, n.d.). public library of toronto. the rebellion of - : a bibliography of the sources of information in the public reference library of the city of toronto, canada (toronto: public library of toronto, ). rea, j.e. “rebellion in upper canada, ,” transactions of the historical and scientific society of manitoba, , ( - ). read, d. b. the canadian rebellion of (toronto: c. blackett robinson, ). roger, charles. chapter iv of the rise of canada from barbarism to wealth and civilization, vol. (montreal; h. ramsey and b. dawson, ). ryerson, stanley b. the birth of canadian democracy (toronto: francis white publishers, ). terrill, f. w. “chronolog y of the rebellion in lower and upper canada, - ,”chapter of chronolog y of montreal and of canada (montreal; j. lovell, ). tracy, frank basil. “the uprising in upper canada,” chapter of the tercentenary history of canada: from champlain to laurier, mdcviii-mcmviii (new york & toronto: p. f. collier & son, ). tuttle, charles r. “rebellion of - ,” chapters lxxv-lxxxii,xci-xcii in popular history of the dominion of canada (boston: tuttle & downie, ). sullivan, john d. “the canadian rebellion of - ,” essex historical society papers and addresses, vol. ii (windsor, ontario: essex historical society, ). wallace, w. stewart. the family compact: a chronicle of the rebellion in upper canada (toronto: glasgow brook & co., ). withrow, w. h. “rebellion of - ,” chapters xxiii-xxvi of history of canada (toronto; w. briggs, ). . . - beer, donald r. “toryism in transition: upper canadian conservative leaders, - ,” ontario history, lxxx, (september ). benn, carl. “fort york and the yonge street rebellion,” historic toronto, (spring- summer ). benn, carl. “yonge street rebellion,” in the simcoe legacy: the life and times of yonge street (toronto: ontario historical society, ). bishop, olga bernice. publications of the province of upper canada and of great britain relating to upper canada - � (toronto: ontario ministry of ontario history citizenship and culture, ). bull, stewart. “the queen’s rangers in the rebellion of ,” york pioneer, ( ) burroughs, peter. british attitudes towards canada, - � (toronto: prentice hall of canada, ). burroughs, peter. the canadian crisis and british colonial policy, - � (toronto: macmillan of canada, ). burroughs, peter. “the canadian rebellions in british politics,” in john e. flint and glyndwn williams, editors. perspectives on empire: essays presented to gerald s. graham (london: longman group, ). cadigan, sean t. “paternalism and politics: sir francis bond head, the orange order, and the election of ,” canadian historical review, lxxii, ( ). carter, terry. “rebel country: the th anniversary of the yonge street rebellion,” newmarket historical society occasional papers, , ( ). champion, isabel. “tories, reformers and rebels,” chapter of markham - (markham, ontario: markham historical society, ). craig, gerald, editor. discontent in upper canada (toronto: copp clark, ). creighton, donald g. “the rebellions of ,” in canadian viewpoints - an antholog y of canadian writing (victoria: british columbia ministry of education, ). cross, michael s. “’the laws are like cobwebs’: popular resistance to authority in mid-nineteenth century british north america,” in peter waite, sandra oxner and thomas barnet, editors. law in a colonial society: the nova scotia experience (toronto: carswell co., ). duffy, john j. and h. nicholas muller, iii. an anxious democracy: aspects of the s (westport, connecticut: greenwood press, ). francis, r. douglas, richard jones and donald smith. “upper canada, - ,” chapter of origins: canadian history to confederation (toronto: holt, rinehart and winston of canada, ). frank, mark. rebellion: a tour of toronto and nearby places (toronto: red robin press, ). fryer, mary beacock. volunteers & redcoats, raiders & rebels: a military history of the rebellions in upper canada (toronto: dundurn press for the canadian war museum, ). keilty, greg, editor. : revolution in the canadas as told william lyon mackenzie (toronto: n.c press, ). macdonald, mary lu. “present politics and past history,” chapter of literature and society in the canadas - � (lewiston, new york & queenston, ontario: edwin mellen press, ). mackay, claire. “rise of the rebel,” chapter of the toronto story (toronto: annick press, ). mallon, mary frances. “mackenzie, economics, and the rebellion of ,” york pioneer, ( ). mann, michael. a particular duty: the canadian rebellions - (salisbury: michael russell, ). morton, desmond. “the rebellion in upper canada,” chapter of rebellions in canada (toronto: grolier, ). ontario historical society. rebellion remembered: papers presented at the rebellion remembered conference (willowdale, ontario: ontario historical society, ). read, colin. “conflict to consensus: the political culture of upper canada,” acadiensis , (spring ). read, colin. “the duncombe rising, its aftermath, anti-americanism and sectarianism,” histoire sociale/social history, (may ). read, colin. the rising in western upper canada - : the duncombe revolt b�bl�ography of the upper canada rebell�on and after (toronto: university of toronto press, ) read, colin. “steadfast in their allegiance,” chapter of loyal she remains (toronto: loyalist press, ). read, colin & ronald j. stagg, editors. the rebellion of in upper canada (ottawa: carleton university press for the champlain society, ). ryerson, stanley b. “revolt against colonialism,” part of unequal union: confederation and the roots of conflict in the canadas, �- (toronto: progress books, ). salutin, rick and theatre passe muraille. , william lyon mackenzie and the canadian revolution (toronto: james lorimer, ). stagg, ronald. “the upper canadian rebels of ,” in rebellion remembered (willowdale, ontario: ontario historical society, ). stagg, ronald. “ revisited,” york pioneer, ( ). stuart, reginald c. “the provincial rebellions,” chapter of united states expansionism and british north america, �- (chapel hill, north carolina: university of north carolina press, ). thomas, mary. turning point: the story of anna jameson - and the rebellion in upper canada (belleville, ontario: epic press, ). . border incidents & patriot hunters . . prior to gavin, russell. thoughts and sentiments connected with the invasion of upper canada by a band of lawless and unprincipled men from the united states in november : a poem (montreal: campbell & becket, ), mackenzie, william lyon. “winter wanderings sixteen years since being a narrative of remarkable adventures during a five days journey between toronto and buffalo’ undertaken under peculiar circumstances, in december, ,” mackenzie’s gazette, ( & september ), maitland, james. ““glorious action on the western frontier: - the brigands driven from point pele island,” reported (among other newspapers) in bytown gazette & ottawa advertiser ( march ). morgan, scott, editor. “the battle of the windmill revisited: as recounted by lieutenant andrew agnew, rd highland regiment of foot, december ,” canadian military history, , (autumn ). n.a. “account of the attack upon the steamboat ‘united states’ and the engagement at prescott, in a letter to the editor of the argus, by a passenger who was on board the vessel,” niles’ national register ( november ). n.a. “account of the destruction of the steamboat ‘sir robert peel,’while in american waters,” niles’ national register ( may ). n.a. “account of the escape of theller and dodge from the citadel of quebec,” niles’ national register ( october ). n.a. “the affair of alexander m’leod,” the monthly chronicle of events, discoveries, improvements, and opinions, (may ). n.a. “attack on point au pelee island, in upper canada, by part of h. m. nd regiment,” united service journal and naval and military magazine, part ( july ). n.a. “canadian affairs – great meeting at the court-house,” [watertown, new york] jeffersonian ( december ). ontario history n.a. “case of alexander mcleod, the decision of the supreme court of new york,” law reporter, , ( ). n.a. “discussion in the house of representatives, washington, on the disturbances in canada, and the outrage on the steamboat caroline,” niles’ national register ( january ). n.a. “foreign news – canada,” gentleman’s magazine, (may ). n.a. “good news” report windmill prisoners’ release, unidentified newspaper (n.d. ca april ).clipping # , mackenzie-lindsey papers, archives of ontario. n.a. “invasions of upper canada from the united states – battle of point au pelee,” the colonial magazine and commercial- maritime journal, , ( ). n.a. “is it lawful to aid the canadians? – opinion of the judges,” [watertown, new york] jeffersonian ( february ). n.a. list of “american citizens now at van damien’s [sic] land,” (utica, new york) daily gazette, may . n.a. “list of persons who participated in the canadian disturbance in and were sent to van dieman’s land,” albany (new york) evening journal, may – reprinted from the madisonian. n.a. [ogle gowan?] “memoirs of the rebellions in canada, in and ,” chapter xix, kingston statesman ( october ), clipping # , mackenzie-lindsey papers, archives of ontario. n.a. “rebellion in upper canada and invasion of the americans,” the colonial magazine & commercial-maritime journal, , ( ). n.a. “salinians aided in canadian revolt,” syracuse (new york) journal, march . n.a. “the wind mill prisoners,” (lowville, new york) northern journal, october . nichols, thomas l. address delivered at niagara falls on the evening of the twenty-ninth of december, , the anniversary of the burning of the caroline (buffalo: charles faxon, ). preston, t.r. “hunter lodges in - ,” chapter iv of three years’ residence in canada, from - , vol. (london: richard bentley, – republished buffalo: buffalo historical society, ). rolph, thomas. “invasions of upper canada from the united states - battle of point au pelee,” colonial magazine and commercial- maritime journal, iv, january-april ). rolph, thomas. “rebellion in upper canada and invasion of the americans,” colonial magazine and commercial-maritime journal, ii, (may-august ). sprague, (no first name cited). “the la manche: case no , district court d, massachusetts” f, cas. , law rep, ; sprague ( june ). williams, nathan. “the prescott expedition,” [watertown, new york] jeffersonian ( january ) – reprinted from the oswego palladium). see also articles and commentary in issues of the freeman’s advocate published in lockport, new york october to march and mackenzie’s gazette published in new york and rochester may to december � . see also articles cited in december through � issues of the albion, the cobourg star, the quebec gazette, the [toronto] mirror, and the [toronto] patriot in public library of toronto. the rebellion of - : a bibliography of sources of information in the public reference library of the city of toronto, canada (toronto: public library of toronto, ). pages - . . . - alexander, edward p. “the hunters’ lodges of – documents,” new york history, ( ). bierce, l.v. “biographical sketch,” in historical reminiscences of summit county (akron, ohio: t & h.g. canfield, ). b�bl�ography of the upper canada rebell�on bishop, levi. “recollections of the ‘patriot war’ of - , on this frontier,” michigan pioneer collections, pioneer society of michigan, ( ). bonham, milledge l. “alexander mcleod: bone of contention,” new york history, , ( ). bonney, catharine van rensselaer, compiler/ arranger. chapters iv and v of a legacy of historical gleanings (albany, new york: j. munsell, ). brook, michael. “lawrence pitkethely, dr. smyles, and canadian revolutionaries in the united states, ,” ontario history, lvii, , ( june ). colquhoun, a. h. u. “the arrest and trial in of alexander mcleod for murder in connection with the burning of the steamer caroline,” the canadian magazine, , ( ). colquhoun a.h.u.. editor. the niagara frontier in - : papers from the hamilton correspondence (niagara-on-the-lake: niagara historical society, ). comins, ethel. “he dieth in full strength - job - : december , watertown new york,” bulletin of the jefferson county historical society, , (october ). comins, ethel. “hickory island fiasco,” bulletin of the jefferson county historical society, , (october ). cook, ernest g. articles about william d. sweet in watertown (new york) daily times (april & may, ). cross, d. w. “the canadian rebellion of ,” magazine of western history, , & (february & march, ). cruickshank, e. a. “a twice-told tale (the insurrection in the short hills in ),” ontario historical society papers and records, ( ). cruickshank, e. a. “the insurrection in the short hills in ,” ontario historical society papers and records, ( ). cruickshank, e. a. “the invasion of navy island in - ,” ontario historical society papers and records, ( ). denison, george taylor. “the burning of the ‘caroline’,” canadian monthly national review, ( ). dougall, james. “that windsor battle: the account of it from a canadian standpoint,” michigan pioneer collections, pioneer society of michigan, ( ). drew, andrew and judge woods. the burning of the caroline and other reminiscences of (chatham: banner printing company ). duff, louis blake. “samuel chandler of st. johns,” welland county historical society papers & records, ( ). fuller, l.n. “ patriot war,” watertown daily times, (march, april & may, ). gates, lillian f. “a note on dr. john smyles,” ontario history, lvii, (december ). gray, john morgan. “the life and death of ‘general’ william putnam,” ontario history, xlvi, (winter ). green, ernest, editor. “the song of the battle of the windmill,” ontario historical society papers and records, ( ). green, ernest. “upper canada’s black defenders,” ontario historical society papers and records, ( ). group. thetis, chapter on the patriot’s war, the liverpool legend (onondaga, new york: n.p., ). haddock, j.a. “the ‘patriot’ war,” chapter of the thousand islands of the st. lawrence river (albany, new york: weed-parsons, ). hand, augustus n. “local incidents of the papineau rebellion,” new york history, , ( ). harden, h. s. scott. “convict prisons of van dieman’s land,” canadian magazine, xxx, (november ). harmon, john h. “battle of windsor: john h. harmon’s story of the last fight in the ontario history patriot war,” detroit free press (december ) – republished in essex county historical society papers and addresses, ( ). heinmiller, gary l “recollections of patriot’s war participants,” liverpool (new york) telegraph ( january-april, ). hemans, lawton t. “the patriot war,” chapter xvii of life and times of stevens thomson mason (lansing : michigan historical commission, ). holden, j. rose. “some incidents of the rebellion in upper canada,” journal & transactions of the wentworth historical society, , ( ). hough, f. b. “the patriot war; events of - 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(chicago: j.h. beers, ). martyn, j.p. “the patriot invasion of pelee island,” ontario history, , (september ). m’farlan, robert. “the ‘patriot war’ the battle of fighting island,” michigan pioneer collections, pioneer society of michigan, ( ). mccrae, john. “battle of fighting island, february, ,” essex historical society papers & addresses, ( ). mccrae, john. “battle of windsor, canada, december th, ,” ontario historical society papers and records, ( ). mcinnis, edgar w. “the uneasy border,” chapter of the unguarded frontier: a history of american-canadian relations (garden city, new york: doubleday, doran, ). merriam, justice. “a brief outline of the history of the merriam family originally written by johnston merriam about the year ,” (re-written – n.p., ). moir, john s.. “mr. mackenzie’s secret reporter,” ontario history, lv, (december ). n.a. “the affair of alexander m’leod,” monthly chronicle of events, discoveries, improvements and opinions (may ). n.a. “george h.kimball: death of the last survivor, but one, of the ‘patriot war’ in canada in ,” (lowville, new york) journal and republican ( december ). n.a. “historical society now has document of the patriot war,” watertown (new york) daily times ( april ). b�bl�ography of the upper canada rebell�on n.a. “an interesting relic, history of the fight of found in st. thomas,” michigan pioneer collections, pioneer society of michigan, ( ). n.a. “incidents of the patriot war,” chapter xxvi of history of niagara county new york (lockport, new york: ). n.a. “last of the ‘patriots’,” watertown (new york) herald ( january ). n.a. “patriot’s war: a tale of unknown heroes and a battle forgotten by history,” watertown (new york) herald ( august ). n.a. “patriot’s war: local annals with all the charm of fanciful romance,” watertown (new york) herald ( july ). n.a. “patriots war: the tragic final chapter of the struggle for canadian freedom,” watertown (new york) herald ( august ). n.a. “salinians aided canadian ‘revolt’,” syracuse (new york) journal ( march ). n.a, “stories of – thrilling experiences of john stewart,” [toronto] globe. ( may ). n.a. “uncle david house: death of a soldier of the patriot war,” watertown (new york) herald ( august ). nattress, thomas. “fort malden and old fort days,” essex historical society papers & addresses, ( ). northman, john. “how a stone mills girl, teacher in gananoque nearly years ago, brought the warning across the ice that saved that village from capture by the patriots,” watertown (new york) daily times ( october ) – reprinted from the canadian magazine. overman, william d. “a sidelight on the hunters’ lodges of : documents,” canadian historical review, ( ). palmer, friend. “battle of windsor,” extract of francis cleary, early days in detroit, in essex historical society papers and addresses, vol. ii (windsor, ontario: essex historical society, ). parker, jenny m. “the patriot war,” chapter xvii of rochester: a story historical (rochester, new york; scranton, wetmore, ). prucha, francis paul. “reports of general brady on the patriot war,” canadian historical review, xxxi, (march ). riddell, w. r. “a contemporary account of the navy island episode, ,” royal society of canada, proceedings and transactions, rd series, , ( ). riddell, william renwick. “a patriot general,” the canadian magazine, , ( ). riddell, william renwick. “another patriot general,” the canadian magazine, , , ( ). ross, robert. “the patriot war,” michigan pioneer collections, pioneer society of michigan, ( ). shortridge, wilson porter. “the canadian- american frontier during the rebellion of - ,” canadian historical review, ( ). smith, h. perry, editor. “the patriot war,” chapter xxii of history of the city of buffalo and erie county.(buffalo: n.p., n.d.). stacey, c. p., editor. “an american account of the prescott raid of ,” canadian defence quarterly, ix, (april ). stacey, c. p., “a private report of general winfield scott on the border situation in ,” canadian historical review, , ( ). stanley, george f. “the battle of the windmill,” historic kingston, ( ). stanley, george f.g. “invasion: ,” ontario history, , (december ). stanley, george f. “william johnston: pirate or patriot?,” historic kingston, ( ). struthers, irving e. “the trial of niles von schoultz,” canadian magazine, ( ). ontario history sumner, elsie graham. “activities of canadian patriots in the rochester district, - ,” ontario historical society papers and records, , ( ). tiffany, orrin edward. the canadian rebellion of - (buffalo: buffalo historical society, – republished toronto: coles publishing, ). waterbury, edwin m. “oswego county during the patriot war,” papers of the oswego historical society (oswego: ). watt, alastair. “the case of alexander mcleod,” canadian historical review, ( ). watt, r. c. “the political prisoners in upper canada, - ,” english historical review, (october ). wella, george c. “the battle of windmill point: an incident of the rebellion of ’ ,” canadian magazine, ( ). williams, fred. “mackenzie’s escape to navy island,” [toronto] globe ( december ). wittke, carl. “ohioans and the canadian- american crisis of - ,” ohio archaeological and historical quarterly, lviii ( january ). . . - antal, sandy and kevin r. shackleton. “the patriot war of ,” chapter of duty nobly done: the official history of the essex and kent scottish regiment (windsor: the scottish borderers foundation, ). bederman, david j. “the cautionary tale of alexander mcleod: superior orders and the american writ of habeas corpus,” emory law journal (spring ). bedford, john w. journal entry xvii re border incidents and us politics, – long beach, california, private publication by clarence e. king, n.d. (ca. ). bonthius, andrew. “the patriot war of - : locofocoism with a gun?,” labour/le travail, # (fall ). brook, michael. “lawrence pitkethely, dr. smyles, and canadian revolutionaries in the united states, ” ontario history, , , ( june ). carter, george e. “daniel webster and the canadian rebellions - ,” canadian historical association papers ( ). carter, john c. “events in the western district, : the other rebellion,” in rebellion remembered (willowdale, ontario: ontario historical society, ). carter, john c. “patriot wars: blazing saga of discontent,” windsor star ( january ). carter, john c. “patriot wars: rout at fighting island,” windsor star ( april ). carter, john c. “the battle of pelee island: third patriot attempt at bloody confrontation,” windsor star ( april ). carter, john c. “the battle of windsor: last chapter in the patriot wars,” windsor star ( july ). carter, john c. “rebellious acts in the western district of upper canada: precursor to transportation to van diemen’s land,” australian canadian studies journal, & , ( & ). carter-edwards, dennis. “bound in honour … to maintain’: the defence of the western district during the border crisis of - ,” unpublished paper, presented to the canadian historical association, june . carter-edwards, dennis. “the frontier under attack - ,” “the frontier defended (part i) ,” and “the frontier defended (part ii) - ” sections in “the defended border: fort malden, - ,” research bulletin no. , national historic parks & sites branch, parks canada (october, ). carter-edwards, dennis. “fort malden: a structural narrative history - , vol. ,” parks canada manuscript reports, b�bl�ography of the upper canada rebell�on ( ). crawford, irene. “captain andrew drew,” oxford historical society, ( ). douglas, r. alan. “the battle of windsor,” ontario history, , ( ). douglas, r. alan. “communities,” “rebels and yankees” and “men in capital,” chapters - of uppermost canada (detroit: wayne state university press, ). dunley, ruth. “the canadian president: in a radical group of americans elected a president of canada, his name was a.d. smith,” ottawa citizen ( july ). dunley, ruth. “on the trail of the mysterious mr. smith,” ottawa citizen ( july ). dunning, thomas p. “the adventures of patriot hunters: danger, memory, place and virtue at the windmill,” canadian review of american studies. . ( ). dunning. thomas p. “convict bodies in van diemen’s land: the north american experience,” australian studies, , ( ). dunning, thomas p. “canadian rebellions of - : an episode in northern borderland history,” australian journal of american studies, , (december ). fraser. chad, “the battle of pelee island: the upper canadian rebellion of ,” chapter of lake erie stories: struggle and survival on a freshwater ocean (toronto: dundurn press, ). graves, donald e. guns across the river: the battle of the windmill, (toronto: robin brass studio, ). greer, allan. “rebels and prisoners: the canadian insurrections of - ,” acadiensis, xiv, (autumn ). hice, john r. “the detroit arsenal at dearborneville and the patriot war: ” the dearborn historian, , (winter ). hitsman, j. mackay. “border problems,” chapter of safeguarding canada � - , (toronto: university of toronto press, ). johnson, arthur l. “the new york state press and the canadian rebellions, - ,” american review of canadian studies, xiv, ( ). jones, howard and donald a rakestraw. “freedom awakened:remember the caroline!,” and “mother country at bay: the strange case of alexander mcleod,” chapters of prologue to manifest destiny: anglo-american relations in the � s (wilmington, delaware: s r books, ). kenny, stephen. “stranger’s sojourn: canadian journalists in exile, - 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the man they had to hang,” historic kingston, ( ). polebaum, beth m. “national self-defense in international law: an emerging standard for a nuclear age,” new york university law review (april ). raible, chris. “james mackenzie, advocate for canadian freedom,” australasian canadian studies, , ( ). read, colin. “edward alexander theller, the ‘supreme vagabond’ – ‘courageous, honest, and true’?,” ontario history, , (march ). read, colin. “the short hills raid of june, , and its aftermath,” ontario history, lxviii, ( june ). rosen, max. “state prisoner use of federal habeas corpus procedures: the great writ - a reflection of societal change,” ohio state law journal, , ( ). rosentreter, roger l. “brigands or paragons: michigan officials during the patriot war, - ,” michigan history magazine (september-october ). scott, k.f. prescott’s famous battle of the windmill, november - , (prescott, ontario: st. lawrence printing, ). scott, stuart d. “the patriot game: new yorkers and the canadian rebellion of - ,” new york history. , , ( july ). seible, george a. “the mackenzie rebellion and navy island,” chapter of ontario’s niagara parks years: a history (niagara falls, ontario: niagara parks commission, ), sillanpaa, lennard, “death of a liberator, ,” the beaver, (feb-march ), stevens, kenneth r. border diplomacy: the caroline and mcleod affairs in anglo-american-canadian relations, - � (tuscaloosa, alabama: university of alabama press, ). stevens, kenneth r. “james grogan and the crisis in canadian-american relations, - ,” vermont history, (fall ). . . prior to adams, zadock and n. e. murdock. “public meeting in behalf of the captive patriots” held in plymouth, new york april , unidentified newspaper (n.d. ca. may ), clipping # , mackenzie-lindsey papers, archives of ontario. aislabie, w.j. “remarks on transportation to australia,” the colonial magazine and india review, , (april ). burn, david. “sketches of van diemen’s land,” colonial magazine, ( - ). burn, david. vindication of van diemen’s land (london: w. w. southgate, ). chapin, roswell and nathaniel agustin. “public meeting in behalf of the captive patriots,” ( october ), unidentified buffalo newspaper (n.d. ca. november ), clipping # , mackenzie-lindsey papers, archives of ontario. douglas, r. alan, editor. john prince, a collection of documents – ontario series xi (toronto: champlain society, ). dwyer, c.p and e. scoville. “meeting in behalf of the american captives”’ held in rochester, february , rochester democrat (n.d.. ca. february ) clipping # , mackenzie-lindsey papers, archives of ontario. forster, john. “notes of a residence in van dieman’s land in - ,” simmond’s colonial magazine, , ( january ); , (may ); and , (september ). fry, alfred a. report of the case of the canadian prisoners; with an introduction on the writ of habeas corpus (london: a. maxwell, . prisoners, trials and transportation b�bl�ography of the upper canada rebell�on ). gould, marcus t. c. “trial of alexander mcleod for the murder of amos durfee,” gould’s stenographic reporter, ii, - (washington, d.c. ). hume, joseph. “the soldiers of freedom places in chain gangs with thieves, felons, murders and forgers – english faith in !!” letter dated november unidentified newspaper (n.d. ca. february ), clipping # , mackenzie-lindsey papers, archives of ontario. jackson, j. a. “the regeneration of van diemen’s land,” simmond’s colonial magazine, , ( january ). mackenzie, william lyon. “more escapes from van dieman’s land,” (new york) daily plebian (n.d. ca july ), clipping # , mackenzie-lindsey papers, archives of ontario. meredith, louisa ann. my home in tasmania, or nine years in australia (new york: bruce & brother, ). miller, linus. “letter from mr. miller, late from van dieman’s land,” dated january , (new york) express, (n.d. ca. january - republished lowville, n.y. northern journal, february ), clipping # , mackenzie-lindsey papers, archives of ontario. n.a. “american citizen in exile at van dieman’s land,” report of u.s. congressional debate, unidentified newspaper (n.d. ca. july ), clipping # , mackenzie-lindsey papers, archives of ontario. n.a. “american prisoners at van dieman’s land,” lists prisoners as of january , unidentified newspaper (n.d. ca ), clipping # , mackenzie-lindsey papers, archives of ontario. n.a. “letter from the citizens of oswego to colonel w. j. worth, commandant of the unites states army at sackett’s harbour, asking for his intercession with the military authorities in the province of upper canada in behalf of the unfortunate young men captured at prescott, oswego, november th, ,” the church ( december ). n.a. [british sympathizer] “letter from london to sutherland,” dated october , unidentified newspaper (n.d. ca november ), clipping # , mackenzie-lindsey papers, archives of ontario. n.a. “meeting in behalf of the captive patriots at van dieman’s land,” held in newark, new jersey, june , unidentified newspaper (n.d. ca. june .clipping # , mackenzie-lindsey papers, archives of ontario. n.a. “our banished countrymen,” albany (new york) evening journal ( december ) – reprinted from the jefferson county carthagenian. n.a. “the patriot prisoners,” letter to albany argus (n.d. ca september ). n.a. “release of american prisoners on van dieman’s land,” auburn (new york) christian advocate (october ). n.a. reports of state trials, news series, vol. viii, - � (london: eyre and spottiswoode, ). n.a. “resolution on american prisoners,” new york assembly, unidentified newspaper (n.d. ca ), clipping # , mackenzie- lindsey papers, archives of ontario. n.a. “van dieman’s land prisoners,” report u.s. arrival nine prisoners, unidentified newspaper reprinting utica gazette (n.d. ca ), clipping # , mackenzie-lindsey papers, archives of ontario. n.a. “a voice fro the living dead,” report of a meeting “in behalf of american citizens now prisoners at van diemen’s land” july , unidentified newspaper (ca july ). pocock, zachary pearce. transportation and the convict discipline considered (london: simmonds & co., ). robinson, john beverley. charge of the honorable john b. robinson, chief justice of ontario history upper canada to the grand jury at toronto (toronto: r. stanton, ). sutherland, thomas jefferson. “american prisoners at van dieman’s land,” albany [new york] arbus, (n.d. ca. july ), clipping # , mackenzie-lindsey papers, archives of ontario. sutherland, thomas jefferson. “american prisoners at van dieman’s land,” new-york tribune, n.d.. 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(ca. feb. ), clipping # , mackenzie-lindsey papers, archives of ontario. sutherland, thomas jefferson. “the case of the captives,” unidentified newspaper ( november ), clipping # , mackenzie-lindsey papers, archives of ontario. sutherland, thomas jefferson. a letter to her majesty the british queen, with letters to lord durham, lord glenelg and sir george arthur: to which is added an appendix embracing a report of the testimony taken on the trial of the writer by a court martial at toronto in upper canada (albany, new york: n.p., ). sutherland, thomas jefferson. a letter to lord brougham, in behalf of the captive patriots to which is annexed a list of their names (new york: n.p., ). sutherland, thomas jefferson. “letter about american captives,” new-york tribune (n.d, ca ) clipping # , mackenzie- lindsey papers, archives of ontario. sutherland, thomas jefferson. loose leaves, from the port folio of a late patriot prisoner in canada (new york: william h. colyer, ). sutherland, thomas jefferson. “sublime patriot,” letter and petition, unidentified newspaper (n.d. ca november ), clipping # , mackenzie-lindsey papers, archives of ontario. sutherland. thomas jefferson, “to the friends of the american prisoners at van diemen’s land,” report and letter, unidentified newspaper quoting the buffalo commercial advertiser (n.d. ca july ). clipping # , mackenzie-lindsey papers, archives of ontario. sutherland, thomas jefferson. “to the friends of the american prisoners at van diemen’s land,” letter ( october ) and report, albany argus,(n.d. ca november ), clipping # , mackenzie-lindsey papers., archives of ontario. syme, james. nine years in van diemen’s land (dundee: n.p., ). theller, e, a. canada in - , showing by historical facts, the causes of the late attempted revolution, and of its failure… (philadelphia: henry f. anners, ). tyler, john, et al. “american citizens - prisoners in van dieman’s land,” document no. , th congress, st session.” united states congress ( july ), clipping # , mackenzie-lindsey papers, archives of ontario. waite, benjamin. “extract of a letter received in new york from the canada state prisoners, dated newgate prison, london, march ,” unidentified newspaper, (n.d. ca. june ), clipping # . mackenzie-lindsey papers, archives of ontario. wright, s. s. and aaron dresser. letter: “americans in van dieman’s land,” new york daily tribune ( february ), clipping # , mackenzie-lindsey papers, archives of ontario. . . . narratives by transported prisoners (upper and lower canada) ducharme, leon (léandre), translated by b�bl�ography of the upper canada rebell�on george mackaness. journal of a political exile in australia (sydney: d. s. ford, – first published in french ). gates, william. recollections of life in van diemen’s land, (lockport, ny: d. s. crandall, - republished george mackaness ed. sydney: d. s. ford, ). gemmell, james. “two years in van diemen’s land,” the [new york] plebian ( & june ) – republished by chris raible, editor. “two years in van diemen’s land: the personal experiences of a transported canadian rebel,” york pioneer, ( ). gilman, john. letter dated february , albany [new york] argus, n.d., clipping # . mackenzie-lindsey papers, archives of ontario – republished by chris raible, editor. york pioneer, ( ). heustis, daniel d. a narrative of the adventures and sufferings of captain daniel heustis (boston: redding, ). marsh, robert. seven years of my life, or a narrative of patriot exile (buffalo: faxon & stevens, ). miller, linus. notes of an exile in van diemen’s land (fredonia, new york: w. mckinstry, ). monroe, mitchell. letter to his brother, [columbus, ohio] statesman, n.d., clipping # , mackenzie-lindsey papers, archives of ontario – republished by chris raible, editor, york pioneer, ( ). morrison, thomas david. trial of dr. morrison, m.p.p. for high treason at toronto on wednesday, april �, (toronto: donlevy & mctavey, ). prieur, françois xavior, translated by george mackness. notes of a convict of (sydney: d. s. ford, – first published in french ). sweet, alvin b. letter to his parents, [albany, new york] evening journal n.d., clipping # , mackenzie-lindsey papers, archives of ontario – republished by chris raible, editor, york pioneer, ( ). snow, samuel. an exiles return or narrative of samuel snow (cleveland: smead and cowes, ). stevens, elizur. letter to isaac & persis phelps, clipping # , mackenzie-lindsey papers, archives of ontario – republished by chris raible, editor, york pioneer, ( ). wait, benjamin. letters from van diemen’s land written during four years imprisonment for political offences committed in upper canada (buffalo – see also extracts in the wait letters (erin, ontario: porcépic press, ). woodman, elijah. letters edited by fred landon in an exile from canada to van diemen’s land (toronto: longmans, green, ). wright, stephen s. 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:e . doi: . /nxi. correspondence dr. rostami a.m.rostami@jefferson.edu abstract objective to study the immunomodulatory effect of dimethyl fumarate (df) on granulocyte macro- phage colony-stimulating factor (gm-csf) production in cd + t cells in experimental au- toimmune encephalomyelitis (eae) and human peripheral blood mononuclear cells (pbmcs). methods we collected splenocytes and cd + t cells from c bl/ wild-type and interferon (ifn)- γ–deficient mice. for human pbmcs, venous blood was collected from healthy donors, and pbmcs were collected using the percoll gradient method. cells were cultured with anti-cd / in the presence/absence of df for to days. cells were stained and analyzed by flow cytometry. cytokines were measured by elisa in cell supernatants. for in vivo experiments, eae was induced by myelin oligodendrocyte glycoprotein – and mice were treated with oral df or vehicle daily. results df acts directly on cd + t cells and suppresses gm-csf–producing th not th or single gm-csf+ t cells in eae. in addition, gm-csf suppression depends on the ifn-γ pathway. we also show that df specifically suppresses th and gm-csf–producing th cells in pbmcs from healthy donors. conclusions we suggest that df exclusively suppresses gm-csf–producing th cells in both animal and human cd + t cells through an ifn-γ–dependent pathway. these findings indicate that df has a better therapeutic effect on patients with th -dominant immunophenotype. however, future longitudinal study to validate this finding in ms is needed. from the department of neurology (f.s., r.t., z.l., g.-x.z., a.r.), thomas jefferson university, philadelphia, pa. dr. safavi is now at national institute of health, ninds, bethesda, md. go to neurology.org/nn for full disclosures. funding information is provided at the end of the article. the article processing charge was funded by r ai and r ns from the national institutes of health. this is an open access article distributed under the terms of the creative commons attribution-noncommercial-noderivatives license . (cc by-nc-nd), which permits downloading and sharing the work provided it is properly cited. the work cannot be changed in any way or used commercially without permission from the journal. copyright © the author(s). published by wolters kluwer health, inc. on behalf of the american academy of neurology. http://dx.doi.org/ . /nxi. mailto:a.m.rostami@jefferson.edu https://nn.neurology.org/content/ / /e /tab-article-info http://creativecommons.org/licenses/by-nc-nd/ . / ms, the leading cause of disability in young adults, is an in- flammatory demyelinating disease with axonal injury in the cns. the rapidly growing number of diagnosed cases and available immune-modifying therapies in recent years is mo- tivating scientists and clinicians to further study the mecha- nism of action of currently approved medications to discover novel underlying pathways that can be targeted to develop new and more efficient treatments for ms. patients with relapsing-remitting ms (rrms) patients are trea- ted with oral dimethyl fumarate (df) since in the united states, and df is added to the armamentarium of disease- modifying therapies for ms. in terms of an underlying mecha- nism of action, df inhibits interleukin (il)- p and il- p transcription in dendritic cells. this leads to the generation of type- dendritic cells, which indirectly increases il- + th cells in both experimental autoimmune encephalomyelitis (eae) and human cells and ameliorates inflammatory responses. , in ad- dition, eae mice treated with df show a significant reduction in thetotal numberof interferon (ifn)-γ–, il- –, andgranulocyte macrophage colony-stimulating factor (gm-csf)–producing cd + t cells among cns-infiltrating cells. these findings add to the role of df in decreasing the inflammatory profile of t cells indirectly by changing the phenotype of antigen presenting cells, but the direct effect of df on pathogenic t-cell subtypes has not been adequately studied. among the various types of immune cells involved in the pathogenesis of eae, t cells have been the main focus of research because of their pathogenic role in animal models of demyelination and the abundance of t cells in active de- myelinating brain lesions in patients with ms. , th and th cells are considered the main culprits in eae pathogenicity, , and their signature cytokines, ifn-γ and il- , playaroleindiseasepathogenesis. , lackofifn-γ leadstomore severe eae, and the absence of il- does not affect eae development. , given that neither th (ifn-γ) nor th (il- )signaturecytokinesarerequired forthedevelopmentofeae, we and others have shown that gm-csf is an essential cytokine for eae induction. gm-csf–producing cd + t cells can effec- tively induce eae by passive transfer, and lack of gm-csf in th or th cells abrogates their encephalitogenicity. in addition, gm- csf–deficient mice are resistant to eae induction. , here, we studied the direct effect of df on cd + t cells and their cytokine profiles. we demonstrate that df significantly decreases gm-csf in cd + t cells in vitro and in vivo. further evaluation showed that the decrease in gm-csf is more prominent in th than that in th or single gm- csf+cd + t cells. in addition, the suppressive effect of df on gm-csf was abrogated by the lack of ifn-γ. we also evaluated the effect of df on human pbmcs and confirmed that df significantly decreases gm-csf in th cells. methods mice female c bl/ mice, – weeks old, were obtained from jackson laboratory (bar harbor, me). mice were housed at animal facility at thomas jefferson university with water and food ad libitum. all experimental procedures were approved by the institutional animal care and use committee. eae induction and clinical evaluation mice were immunized subcutaneously with μg of myelin oligodendrocyte glycoprotein (mog) – (genscript, piscat- away, nj) emulsified in complete freund’s adjuvant (difco laboratories) containing mycobacterium tuberculosis h ra ( mg/ml; difco laboratories, detroit, mi). in addition, mice were intraperitoneally injected with ng of pertussis toxin at and hours after immunization. clinical eae was assessed daily in a blind fashion using the clinical scoring system from : normal to : death as described previously. df treatment df (sigma-aldrich, st. louis, mo) was used in an emulsion of . % methylcellulose. for in vivo treatment, df solution was ad- ministered by oral gavage twice daily ( μg for g mice in μl volume), starting the day of eae induction until termination (day post immunization). the solution was prepared early everyday and stored at °c. mice receiving vehicle were used as controls. isolation of cns-infiltrating mononuclear cells and splenocytes to collect mononuclear cells (mncs), mice were extensively perfused at day post immunization with ice-cold phosphate buffered saline. for spleen cells, spleens were collected and dis- rupted in μm cell strainer before rbc lysis. to collect cns- infiltrating cells, brains and spinal cords were removed, thinly minced in liberase tl (roche, indianapolis, in), and incubated at °c for minutes. then, the cns was strained through a μm cell strainer, and mncs were enriched by centrifugation on a / percoll gradient for minutes at , rpm. splenocyte and lymphocyte culture and elisa experiments spleen cells were cultured in iscove modified dulbecco medium (gibco, gaithersburg, md) supplemented with % fetal bovine glossary df = dimethyl fumarate; eae = experimental autoimmune encephalomyelitis; gm-csf = granulocyte macrophage colony- stimulating factor; mnc = mononuclear cell; rrms = relapsing-remitting ms; wt = wild type. neurology: neuroimmunology & neuroinflammation | volume , number | july neurology.org/nn http://neurology.org/nn serum (gibco), % l-glutamine (gibco), % penicillin/ streptomycin (gibco), and β-mercaptoethanol (sigma). spleen cells were stimulated with μg/ml anti-cd /cd agonistic antibodies for hours at °c, % co . for antigen-specific recall response, cns-infiltrating cells from eae mice, at a con- centration of × cells/ml, were stimulated with μg/ml mog – at °c, % co . at the indicated time points, supernatants were collected and centrifuged to eliminate cellular debris. cytokine levels in supernatants were measured by elisa. we analyzed the following cytokines: gm-csf (r&d systems, minneapolis, mn, dy ), human gm-csf (r&d systems dy ), ifn-γ (r&d systems dy ), human ifn-γ (r&d systems dy ), il- (r&d systems dy ), and human il- (r&d systems dy ). purification of cd + t cells mncs from spleens were subjected to positive selection according to the manufacturer’s recommendation (cd microbeads; miltenyi biotec, auburn, ca, - - ). proliferation assay splenocytes were cultured in -well plates at a concentration of × cells/ml and stimulated with anti-cd / ( μg/ ml each) for hours. cells were pulsed with . μci of h- thymidine for the last hours. thymidine incorporation was measured using a scintillation counter. human blood samples and cell culture all subjects provided informed consent before their participa- tion in the current study. all human studies were approved by the thomas jefferson university institutional review board. blood was obtained from healthy donors at the department of neurology, thomas jefferson university. pbmcs were collected by ficoll-paque plus density gradient centrifugation. pbmcs were washed and cultured at a density of × cells/ ml in x-vivo serum-free medium. cells were stimulated with μg/ml of anti-cd (hit a; bd biosciences, san jose, ca) and μg/ml anti-cd (cd . ; bd biosciences) for hours in the presence of . μg/ml of df (sigma-aldrich). flow cytometry experiments for analysis of surface markers, mncs were surface stained in flow cytometry (facs) buffer (phosphate buffered saline containing % fetal bovine serum and . % nan ) with fluorescence antibodies for minutes at °c. for analysis of cytokine production, mncs were activated with phorbol - myristate -acetate ( ng/ml), ionomycin ( ng/ml), and golgi-stop ( μg/ml) for hours. then, cells were surface stained as mentioned previously, before being fixed and per- meabilized with buffers (fix/perm; thermofisher, frederick, md). finally, cells were incubated with cytokine-specific antibodies for minutes at °c. all antibodies and reagents used in this section were purchased from bd biosciences, ex- cept for phorbol -myristate -acetate and ionomycin (both from sigma-aldrich). samples were acquired on an facs aria equipment (bd biosciences). analyses were performed with flowjo software (tree star, ashland, or). statistical analysis data are presented as mean ± standard error of the mean. statistical analysis was performed using one-way analysis of variance or the kruskal-wallis test (all analyses performed with graphpad prism software, san diego, ca). a probability level (p value) of *: p < . , **: p < . , and ***: p < . was statistically significant for all tests. all error bars represent standard error of the mean. for human results, we used pre- treatment and posttreatment paired t test analysis. data availability raw facs and elisa files are not included in this article. any unpublished and anonymized data will be shared upon re- quest from a qualified investigator. results df acts directly on cd + t cells and decreases gm-csf production to evaluate the role of df on gm-csf production in t cells, we first collected splenocytes from b wild-type (wt) mice and cultured them with anti-cd /cd in the presence and absence of df ( μg/ml) for hours. we found that gm- csf in culture supernatants was significantly lower in df-treated cells compared with controls (figure a). facs analysis of the same cells showed a significant reduction of gm- csf in both cd + and cd + t cells (figure b). as previously shown in several studies, df induces t-cell lymphopenia in patients with ms. to confirm that the effect of df on the t-cell cytokine profile is not dependent on its lymphopenic effect, we performed a proliferation assay on activated spleno- cytes with anti-cd /cd in the presence or absence of varying doses of df. administration of df at a dose of μg/ml, which we used in all our in vitro experiments, did not show a significant suppressive effect on splenocyte proliferation (figure c). following the above-mentioned experiment, we studied how df directly affects purified cd + t cells from mice. cd + t cells were isolated and cultured with anti-cd /cd abs with or without df for hours. we measured ifn-γ, gm-csf, and il- in the supernatant after the incubation period. we found that df significantly decreased gm-csf and ifn-γ, but not il- , in purified cd + t cells compared with controls (figure d). in addition, facs analysis of the same cells demonstrated that df decreased gm-csf in ifn-γ+cd + t (th ) cells (figure e). df treatment significantly decreased gm-csf+ th cells in cns-infiltrating cells to analyze the immunomodulatory effect of df treatment in eae, we first immunized all mice and then treated half of them with oral df in an emulsion of . % methylcellulose (df group) and the other half with a similar volume of . % methylcellulose vehicle (control group). mice in the control group developed eae, with an average severity of around . in scoring (score range from . to with a median score of . ). by contrast, df-treated mice showed very mild clinical neurology.org/nn neurology: neuroimmunology & neuroinflammation | volume , number | july http://neurology.org/nn figure df decreases gm-csf production and gm-csf+th cells in mouse splenocytes splenocytes from wild-type (wt) mice were stimulated with μg/ml of anti-cd / antibody in the presence or absence of df ( μg/ml) for hours. (a) gm- csf levels in culture supernatants were determined by elisa. data are representative of experiments (mean ± sem; n = replicates per group). (b) cells were stimulated with ionomycin/pma and golgiplug in the last hours of culture. after intracellular staining for gm-csf, flow cytometry analysis of gated cd + and cd + t cells showed that df administration decreased gm-csf production in both cd + and cd + t cells. (c) proliferation assay on splenocytes treated with different df doses. df did not affect proliferation of splenocytes at a dosage of μg/ml. (d) cd + t cells were purified from wt spleen cells and stimulated with anti-cd / in the presence or absence of df. il- , ifn-γ, and gm-csf were measured in cell supernatants. df decreased ifn-γ and gm-csf, but not il- . (e) flow cytometry analysis demonstrated that df significantly reduced gm-csf production in ifn-γ–producing cd + (th ) cells. df = dimethyl fumarate; gm-csf = granulocyte macrophage colony-stimulating factor; ifn = interferon; il = interleukin; pma = phorbol -myristate -acetate; sem = standard error of the mean. ***p < . . neurology: neuroimmunology & neuroinflammation | volume , number | july neurology.org/nn http://neurology.org/nn signs with an average clinical score of ≤ (score range from to . with a median score of . ) (figure a). we killed the mice at disease peak (day ) and assessed the number of infiltrating mncs in the cns of both df-treated and control groups. in addition to counting the total number of in- filtrating cells, we evaluated the immunophenotype of those cells by flow cytometry. the total number of cd + t cells and gm- csf+cd + t cells was dramatically decreased in the cns of the df-treated group (figure b).wealso looked at ifn-γ and il- incns-infiltratingcd + t cells and, interestingly, foundthatdf decreases gm-csf+cd + cells that coproduce ifn-γ, but not il- (figure c), given that df has a greater suppressive effect in vivo on gm-csf–producing th cells than that on th cells. splenocytes from treated and control mice were isolated, cultured, andstimulatedwithmog – for hours.gm-csf,ifn-γ,and il- were measured in culture supernatants by elisa. as shown in figure d, splenocytes from df-treated mice produced a sig- nificantlydecreasedamountofgm-csfandifn-γ,butnotil- . df requires an intact ifn-γ pathway to suppress gm-csf in cd + t cells based on the observation that df suppresses gm-csf pre- dominantly in th cells, and to further evaluate the underlying mechanism of the suppressive effect of df on gm-csf, we investigated whether ifn-γ plays a role in this phenomenon. wt and ifn-γ–deficient splenocytes were cultured and stim- ulated with anti-cd / in the presence or absence of df. although df suppressed gm-csf–producing cd + t cells and gm-csf cytokines in the supernatant of wt splenocytes, the lack of ifn-γ abrogated the effect of df on gm-csf in cd + t cells. this finding implies that ifn-γ plays a crucial role in the suppressive effect of df on gm-csf (figure , a and b). df decreases th and gm-csf–producing th cells in human pbmcs to determine the best dosage of df in human in vitro experi- ments, we performed a proliferation assay and treated cells with , , and . μg/ml of df as described previously. based on our result, . μg/ml df had the least toxic effects on human pbmcs (data not shown). to evaluate the effect of df on human pbmcs, we cultured and stimulated pbmcs from healthy donors with human anti-cd / with or without df ( . μg/ml) for hours. cells were analyzed with flow cytometry after days, and multiple cytokines were measured by elisa in cell supernatants. for statistical analysis, we used the paired t test to compare pretreatment and posttreatment results. df treatment significantly reduced ifn-γ+cd + (th ) t cells, and elisa analysis of pbmc culture supernatants demon- strated that df significantly decreased ifn-γ production (figure c). in terms of gm-csf–producing cd + t cells, df sig- nificantly decreased gm-csf+ th cells with no effect on total gm-csf–producing cd + t cells, implying that the suppres- sive effect of df on gm-csf is mostly on th cells (figure d). discussion df was approved by the food and drug administration for the treatment of ms in , and its efficacy has been well demon- strated. during years of treatment, df reduced clinical relapse and lesion frequency while improving health-related quality of life in adults with rrms. , however, the underlying therapeutic mechanism of df is still under investigation. df has neuro- protective effects, , , including reducing spinal cord in- flammation and protecting myelin and neurons. , also, researchers who have studied the nrf transcriptional pathway and oxidative stress that df modulates , , found that both df and its active metabolite, monomethyl fumarate, induce the re- active oxygen species scavenger glutathione in oligodendrocytes, astrocytes, and hippocampal cells. , , other pathways have also been reported, including the hydroxycarboxylic acid receptor pathway and nuclear factor kappa-light-chain-enhancer of acti- vated b cells. , , df has been shown to promote th cytokine profiles, , , and transferring df-induced il‐ alowifn‐γlowil‐ +cd + t cells has demonstrated its therapeutic effect in eae. in patients with rrms after months of df treatment, the proportion of th cells was increased among memory t cells but with a decrease in the proportion of th and with no change in th cell proportion among memory t cells. another study, however, showed a decrease in cd + t cells producing ifn-γ, il- , and gm-csf, with no significant change in il- and il- after months. we also found that directadministration ofdf decreased proinflammatory cytokine production in the super- natant of human pbmcs obtained from healthy subjects. when we took a closer look at cd + t-cell subsets, df suppressed only gm-csf+th cells, but not gm-csf+th or gm-csfonly cd + t cells. one limitation of our study is that the human data are based on very small number of samples from healthy donors. further studies are necessary to confirm the effect of df on gm- csf–producing cells from patients with ms. although il- and ifn-γ are implicated in ms, mice still develop eae even in the absence of these cytokines. , pre- vious studies have shown that gm-csf secreted by cns- infiltrating t helper cells is essential for eae, even more so than il- or ifn-γ. lack of gm-csf or gm-csf receptor abrogates eae development, and adoptively transferred gm- csf–deficient th or th cells do not induce eae. we showed that df caused a decrease in gm-csf+ th cells in both the periphery and cns-infiltrating cells during eae, and given the fact that gm-csf–expressing cells are the crucial determinant of eae susceptibility and progression, one of the underlying therapeutic mechanisms of df appears to be through suppression of gm-csf+ th cells. in a variety of t helper cell populations, different transcription factors, including bhlhe , rorγt, t-bet, gata- , and stat , – are active at multiple time points. it has been reported that il- –activated stat promotes gm-csf gen- eration of cd + t cells, which differ from rorγt-, t-bet–, and gata- –promoted gm-csf–producing cd + t cells (sheng neurology.org/nn neurology: neuroimmunology & neuroinflammation | volume , number | july http://neurology.org/nn figure df ameliorates experimental autoimmune encephalomyelitis and suppresses gm-csf–producing th cells in the cns (a) wild-type b mice were immunized with μg of mog – and were treated with df (treatment group) or placebo (control group) by oral administration starting on the day of immunization. clinical signs were scored daily following a – scale. data represent of experiments and the mean clinical scores ± sem (n = each group). (b) cns-infiltrating cells from df-treated and control mice were isolated on day of disease. df treatment significantly decreased total cd + t cells and gm- csf–producing cd + t cells among cns-infiltrating cells. (c) cells were stained with gm-csf, ifn-γ, and il- a antibodies and analyzed by flow cytometry. we found that gm-csf was decreased in th cells, but not th cells, after df treatment. (d) splenocytes from both treated and control groups were collected and cultured/ stimulated with μg/ml mog – for hours. concentrations of gm-csf, ifn-γ, and il- a in culture supernatants were measured by elisa. there was significantly less gm-csf and ifn-γ in treated mice compared with controls. **p < . ; and ***p < . . one of experiments is shown. df = dimethyl fumarate; gm- csf = granulocyte macrophage colony-stimulating factor; il = interleukin; mog = myelin oligodendrocyte glycoprotein; sem = standard error of the mean. neurology: neuroimmunology & neuroinflammation | volume , number | july neurology.org/nn http://neurology.org/nn figure the suppressive effect of df on gm-csf depends on ifn-γ in murine cells (a)splenocyteswereisolatedfromwild-type(wt)andifn-γ−/− mouseandstimulatedwith μg/mlofanti-cd / antibodiesinthepresenceorabsenceofdf( μg/ml)for hours. df treatment significantly decreased gm-csf in cd + t cellsfromwtbut not cd + t cells from ifn-γ−/− mice. (b)measurement ofgm-csf in cell supernatantsby elisa confirmed the samefinding.data are mean ± sem and representativeof of experiments. dfreducedgm-csfproduction and gm-csf+th cellsinhuman pbmcs. pbmcs fromhealthydonors(n= )werestimulatedwith μg/mlofanti-cd /anti-cd antibodyinthepresenceorabsenceofdf( . μg/ml)for hours.(c)cellswerestimulated withpma/ionomycinandgolgipluginthelast hoursofculture.flowcytometryanalysisshowedthatdftreatmentdecreasedifn-γ+cd + (th )cells.measurementofifn-γ in cell supernatants confirmed that df reduced ifn-γ in human pbmc culture. (d) df treatment did not affect the total percentage of gmcsf+cd + t cells but significantly decreasedgm-csf–producingth cells.apairedttestwasusedforthestatisticalanalysisofhumanpbmcresultsbeforeandaftertreatment.df= dimethylfumarate;gm-csf = granulocyte macrophage colony-stimulating factor; pma = phorbol -myristate -acetate; sem = standard error of the mean. *p < . ; **p < . , and ***p < . . neurology.org/nn neurology: neuroimmunology & neuroinflammation | volume , number | july http://neurology.org/nn et al., ). assay for transposase-accessible chromatin using sequencing analysis of gm-csf–expressing cells showed an open ifn-γ locus in both gm-csf– and ex-gm-csf– expressing cells, and single-cell rna-sequencing showed that pathogenic th cells gain th -like characteristics once they enter the mouse-inflamed cns. , on the epigenetic basis, gm-csf–producing t cells are also more related to ifn-γ+ t cells. here, we show that df affects only gm-csf+ifn- γ+cd + t cells, and its gm-csf suppressive effect relies on an intact ifn-γ pathway. determining whether df affects one or several transcription factors in this pathogenic t-cell subset could provide insights into its precise therapeutic mechanisms in ms. future research on df should focus on the molecular pathway of gm-csf and ifn-γ generation after df treatment. in conclusion, we evaluated the role of df on cd + t cells and its effects on gm-csf production. for mouse splenocyte experiments, gm-csf–producing th t cells were reduced, but other gm-csf–producing t cells were not. for eae model experiments, df decreased the percentage of gm-csf+ th cells in the cns. in human ex vivo experiments, gm-csf+ th cells were reduced in healthy donor pbmcs after df treatment; however, a larger study in patients before and after df treatment is needed to validate current findings in ms. we also demon- strated that the suppressive effect of gm-csf is through the ifn- γ pathway. the molecular basis of the effects of df on gm- csf–producing t cells is unknown and merits further study. acknowledgment the authors thank katherine regan for substantive editing of the manuscript. study funding this work was supported by grants r ai and r ns from the nih. disclosure f. safavi, r. thome, z. li, g.-x. zhang, and a. rostami report no disclosures relevant to the manuscript. go to neurology. org/nn for full disclosures. publication history received by neurology: neuroimmunology & neuroinflammation november , . accepted in final form march , . references . herrero-herranz e, pardo la, gold r, linker ra. pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encepha- lomyelitis: implications for multiple sclerosis. neurobiol dis ; 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: – . . nakamura y, christodoulopoulos p, cameron l, et al. upregulation of the tran- scription factor gata- in upper airway mucosa after in vivo and in vitro allergen challenge. j allergy clin immunol ; : – . . gaublomme jt, yosef n, lee y, et al. single-cell genomics unveils critical regulators of th cell pathogenicity. cell ; : – . neurology.org/nn neurology: neuroimmunology & neuroinflammation | volume , number | july https://nn.neurology.org/content/ / /e /tab-article-info http://neurology.org/nn doi . /nxi. ; ; neurol neuroimmunol neuroinflamm farinaz safavi, rodolfo thome, zichen li, et al. producing th cells in cns neuroinflammation −dimethyl fumarate suppresses granulocyte macrophage colony-stimulating factor this information is current as of may , services updated information & http://nn.neurology.org/content/ / /e .full.html including high resolution figures, can be found at: references http://nn.neurology.org/content/ / /e .full.html##ref-list- this article cites articles, of which you can access for free at: subspecialty collections http://nn.neurology.org//cgi/collection/multiple_sclerosis multiple sclerosis http://nn.neurology.org//cgi/collection/autoimmune_diseases autoimmune diseases following collection(s): this article, along with others on similar topics, appears in the permissions & licensing http://nn.neurology.org/misc/about.xhtml#permissions its entirety can be found online at: information about reproducing this article in parts (figures,tables) or in reprints http://nn.neurology.org/misc/addir.xhtml#reprintsus information about ordering reprints can be found online: academy of neurology.. all rights reserved. online issn: - . copyright © the author(s). published by wolters kluwer health, inc. on behalf of the american published since april , it is an open-access, online-only, continuous publication journal. copyright is an official journal of the american academy of neurology.neurol neuroimmunol neuroinflamm http://nn.neurology.org/content/ / /e .full.html http://nn.neurology.org/content/ / /e .full.html##ref-list- http://nn.neurology.org//cgi/collection/autoimmune_diseases http://nn.neurology.org//cgi/collection/multiple_sclerosis http://nn.neurology.org/misc/about.xhtml#permissions http://nn.neurology.org/misc/addir.xhtml#reprintsus nakladatelství karolinum univerzita karlova - karolinum 		 		 		 		 			 				 						nakladatelství karolinum 				 				 					 					menu 				 				 					 						 						 					 				 				 						Česky / english 				 				 	 	 							knihy 								novinky 	témata 	edice 						 	 		Časopisy 				 						o časopisech 					 	 						open access 					 	 						předplatné 					 	 						kontakty 					 	 	 		informace a služby 				 						o nás 					 	 						informace a opatření 					 	 						katalogy 					 	 						e-knihy 					 	 						open access 					 	 						pro média 					 	 						distribuce 					 	 						tiskárna a dtp 					 	 	 		pro autory 				 						informace pro autory 					 	 						formuláře a návody ke stažení 					 	 	kontakt 	 								english 						 	 			 		 	 		 			 				 					 					 					 						 							historie 							jaroslav Čechura 							historik jaroslav Čechura se v předkládané monografii zaměřuje na období třicetileté války. turbulentní události z všednodennosti sedláků a selek na gruntech třeboňského panství popisuje autor díky práci s několikerým typem pramenů, pozemkovými a jiterními knihami, poddanskými soupisy, matrikami, populačními seznamy, výhosty, urbáři, egodokumenty či robotními seznamy. 							přečíst 						 					 							 				 					 					 						 							historie 							mniši, dvořané, literáti 							v knize naleznete několik studií, které se věnují různým aspektům cisterciáckého řádu (například vizitacím, medicíně, politickým aktivitám) a prostředí panovnického dvora krále václava ii. ( – ), mimo jiné pozapomenuté osobnosti jana z ostrova. obě témata se prolínají v závěrečné části věnované kronice chronicon aulae regiae. 							přečíst 						 					 							 				 					 					 					 						 							katalog 							katalog jaro 							připravovaná kniha karla hvížďaly a jiřího přibáně, františka Šmahela, filipa lába, či mařatkova gastroenterologie a mnoho dalších! novinky nakladatelství karolinum na období jaro/léto naleznete v našem novém katalogu. 							přečíst 						 					 							 				 					 					 					 						 							filozofie 							k jubileu miroslava petříčka 							studenti a kolegové miroslava petříčka vydali u příležitosti jeho životního jubilea počet z vlastního myšlení a bádání, které se po jeho vzoru pouští do této riskantní oblasti. mimořádně silná sestava autorů několika generací má široký záběr: od astronomie po animovaný film, od prousta po hraničáře.  							přečíst 						 					 							 			 		 	 	 		 			 				knihy 				 					novinky 					témata 					edice 				 			 			 			 	 		 			 		 		mniši, dvořané, literáti 	 	 		charvátová, kateřina 	 	 		 			 		 		příběh školní šikany 	 	 		zvírotský, michal 		bendl, stanislav 		richterová, magdalena 	 	 		 			 		 		neklidné století 	 	 		Čechura, jaroslav 	 	 		 			 		 		světla a stíny husitství (události – osobnosti – texty – tradice) 	 	 		Čornej, petr 	 	 		 			 		 		mezi zdarem a zmarem 	 	 		payne, jan 	 	 		 			 		 		nástroj prospěšný, či vražedný? 	 	 		gecko, tomáš 	 	 		 			 		 		fašismus 	 	 		griffin, roger 	 	 		 			 		 		jak vzpomínáme na normalizaci 	 	 		pinkas, jaroslav 	 	 		 			 		 		blood and blood components, hematopoiesis, selected methods used in cytology, histology and hematology 	 	 		křížková, věra 	 	 		 			 		 		spielräume der modernen linguistischen forschung 	 	 		kloudová, věra 		Šemelík, martin 		racochová, alžběta 		koptík, tomáš 	 	 		 			 		 		myšlení hranice / hranice myšlení 	 	 		prášek, petr 		roreitnerová, alena 	 	 		 			 		 		o službě slova, víře a spasení 	 	 		landová, tabita 	 	 		 			 		 		chlap kousl psa 	 	 		koukolík, františek 	 	 		 			 		 		chci studovat němčinu na vysoké škole! 	 	 		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	 	 		 			 		 		prague medical report 		ročník: Číslo: 	 	 		 			 		 		auc philologica 		ročník: Číslo: 	 	 		 			 		 		prÁvnĚhistorickÉ studie 		ročník: Číslo: 	 	 		 			 		 		auc interpretationes 		ročník: Číslo: 	 	 		 			 		 		historickÁ sociologie 		ročník: Číslo: 	 	 		 			 		 		auc studia territorialia 		ročník: Číslo: 	 	 		 			 		 		orbis scholae 		ročník: Číslo: 	 	 		 			 		 		orbis scholae 		ročník: Číslo: 	 	 		 			 		 		auc geographica 		ročník: Číslo: 	 	 		 			 		 		auc philologica 		ročník: Číslo: 	 	 		 			 		 		prague medical report 		ročník: Číslo: 	 	 		 			 		 		central european journal for contemporary religion 		ročník: Číslo: 	 	 		 			 		 		acta medica 		ročník: Číslo: 	 	 		 			 		 		reflexe 		ročník: Číslo: 	 	 		 			 		 		auc theologica 		ročník: Číslo: 	 	 		 			 		 		auc philosophica et historica 		ročník: Číslo: 	 	 		 			 		 		auc iuridica 		ročník: Číslo: 	 	 		 			 		 		acta medica 		ročník: Číslo: 	 	 		 			 		 		ibero-americana pragensia 		ročník: Číslo: 	 	 		 			 		 		prÁvnĚhistorickÉ studie 		ročník: Číslo: 	 	 		 			 		 		auc iuridica 		ročník: Číslo: 	 	 		 			 		 		auc interpretationes 		ročník: Číslo: 	 	 		 			 		 		auc kinanthropologica 		ročník: Číslo: 	 	 		 			 		 		european journal of environmental sciences 		ročník: Číslo: 	 	 		 			 		 		auc theologica 		ročník: Číslo: 	 	 		 			 		 		prague medical report 		ročník: Číslo: 	 	 		 			 		 		auc geographica 		ročník: Číslo: 	 	 		 			 		 		auc philologica 		ročník: Číslo: 	 	 		 			 		 		acta medica 		ročník: Číslo: 	 	 		 			 		 		historickÁ sociologie 		ročník: Číslo: 	 	 		 			 		 		auc historia universitatis carolinae pragensis 		ročník: Číslo: 	 			 			 		 	 	 		 			 				kalendář akcí 				 					novinky z karolina 					informace o akcích a nových titulech nakladatelství. 					 						 						přihlásit se k odběru 					 				 			 			 				blog 				 					 					fašismus podle rogera griffina 					 . . 					v edici politeia vychází již druhá kniha jednoho z největších 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assessing patients with ankylosing spondylitis? abstracts a symptom). the health assessment questionnaire (haq) was used to measure func- tional status (scores – ). qol was measured by the mental (mcs) and physical (pcs) component summary scores of the short form- (sf- ). work/productivity loss was measured by the work productivity and activity impairment (wpai) instrument. comparisons were made between patients who currently use sc biologics versus those who discontinued treatment. results: of the , survey respondents ( % female; average age . years), ( . %) used sc biologics. the average dura- tion of ra was . years, with % reporting severe disease. the patient-reported mean scores were: morning stiffness . , fatigue . , pain . , haq . , mcs . and pcs . . patients reported . % work impairment and . % impairments in daily activity. patients who had discontinued sc biologic therapy (n , . %) reported signifi cantly worse scores in morning stiffness, fatigue, pain, and pcs (all p . ) versus patients currently treated with sc biologics (n , . %). patients who discontinued therapy had more work/activity loss; only activity impair- ment was statistically signifi cant (p . ). there was no signifi cant difference in haq scores between groups. conclusions: ra patients using current sc biolog- ics still suffer from serious impairments in symptoms, functional status, qol, and work/productivity. however, patients who discontinued sc biologic therapy have sig- nifi cantly worse symptom scores, physical functioning, and activity impairment com- pared with those currently being treated. both fi ndings indicate there is still an unmet medical need in ra patients. pms utility and quality of life of patients with osteoarthritis treated with the cyclooxygenase inhibiting nitric oxide donator (cinod) naproxcinod jonsson b , pfi ster p , holmstrom s , kobelt g uppsala university, uppsala, sweden, nicox, sophia antipolis cedex, france, nicox, sophia antipolis, france, european health economics, speracedes, france objectives: to estimate changes in quality of life (sf ) and utility (sf ) in patients treated with naproxcinod, naproxen or placebo for weeks, and to explore the effect of different disease measures on utility. methods: sf was available from international ph clinical trials in patients with knee or hip osteoarthritis comparing doses of naproxcinod ( and mg bid) to naproxen ( mg bid) and placebo. effi cacy was based on the pain, function and composite scales of the womac™ osteoarthritis index. co-morbidity measures included hypertension (ht) which increases with nsaid therapy, body mass index (bmi) and diabetes. changes in sf and individual sf domains were compared between the groups using anova and dunett’s -sided test. the effect of the womac™ indices, bp, bmi and diabetes on utility scores was explored using multiple regression analysis. results: all sf subscales except mental health as well as utility changed signifi cantly from baseline for all groups, and were correlated with changes in the womac™ indices (p . ). the change in the active groups was signifi cantly better than placebo for pain and physical function ( . ), but not signifi cantly different between treatments. however, absolute changes in utility, pain, physical function and general health were generally larger for naproxcinod mg than naproxen mg by around %. utility scores correlated signifi cantly with womac™, and patients with high bmi and bp or diabetes had lower utility scores and worse womac™ indices. increase in utilities were larger for patients with mg naproxcinod than for the other groups. conclusions: the slightly larger utility and quality of life changes with naprox- cinod mg despite a similar effect as naproxen on womac™ may be explained by a different side-effect profi le and a neutral blood pressure effect. pms an assessment of self reported outcomes in a nationally representative sample of elderly person diagnosed with rheumatoid arthritis rajpura jrjp j st. john’s university, fresh meadows, ny, usa objectives: to utilize webtv technology as a tool to measure hrqol in elderly persons having rheumatoid arthritis (ra) in a nationally representative sample and to describe their socio-demographic characteristics, medication use and other treat- ment choices. methods: a cross- sectional online survey research design. random digit dialing (rdd) survey procedures were used to draw a sample of elderly arthritic individuals from us households across states. a subsample of individu- als previously diagnosed with ra completed sf- v survey, as part of a larger study. eight sf- domain scores and physical and mental component summary (pcs and mcs) scores were computed and compared with cross-sectional norms for general us population. results: compared to the general population, our study sample per- formed poorly with respect to all the sf- domains except mental health (mh) and social functioning (sf) domains. ra is more prevalent in whites ( %) and males reported higher scores for all the eight sf- domains than females. about % of the sample reported the use of at least one available otc arthritic medication; % of the sample was taking prescription drugs, while about % reported having used natural/herbal remedies for arthritis. a signifi cant difference (p . ) was found between males and females with respect to only pcs scores. age was found to correlate negatively (p . ) with pcs and mcs summary measures, particularly for indi- viduals years and older. conclusions: webtv is an effective survey administra- tion tool for measuring hrqol. as expected, elderly perform poorly on three of the sf- domains (pf, rp, bp) having the most physical factor content. prescription drug use is fairly prevalent and use of otc medications and other forms of treatment is popular in the population under study. pms the effect of lifestyle choices on the risk of impairment in rheumatoid arthritis patients: an analysis of aerobic exercise and cigarette smoking shah a , plumb j , brawer r , tang b thomas jefferson university, philadelphia, pa, usa, centocor ortho biotech, inc, horsham, pa, usa objectives: through data analysis we will examine and identify the lifestyle factors that impact clinical outcomes of rheumatoid arthritis (ra) patients. methods: patients’ self-reported data was collected from the ra patient survey, an internet survey of ra patients. we studied the effects of aerobic exercise ( minutes a day per month), and cigarette smoking on ra patients. sign and symptom scores for morning stiffness, fatigue, and pain are defi ned from (no symptom) to (severe symptom) within the survey. the health assessment questionnaire (haq) was used to measure functional status scores ( – ). quality of life was measured by the mental component score (mcs) and physical component score (pcs) of the short-form (sf- ). productivity was measured by the work productivity and activity impairment (wpai) scale. there were no non-ra controls included in the study. results: a total of respondents were included in the analysis patients exercised and patients smoked cigarettes. the average age was . years and average ra duration was . years. patients’ mean mcs and pcs scores in the exercise ( . , . ) and non-smoking groups ( . , . ) were signifi cantly higher, than in the non- exercise ( . , . ) and smoking groups ( . , . ). overall work and productivity impairment was . % (exercise) versus . % (non-exercise), and . % (smoking) versus . % (non-smoking). signs, symptoms, and haq scores were signifi cantly better in the exercise and non-smoking groups (all p . ). conclusions: ra patients who exercise regularly have higher quality of life scores and clinical outcomes. those that smoke cigarettes have lower quality of life scores and higher symptom/ haq scores suggesting that this habit may be detrimental to their clinical outcomes. these results suggest that these lifestyle choices infl uence the overall risk of impairment in ra patients. pms is the health utilities index valid and responsive in assessing patients with ankylosing spondylitis? gooch k , feeny dh , wong r , pangan a , revicki d , van der heijde d abbott laboratories, abbott park, il, usa, kaiser permanente center for health research, portland, or, usa, abbott laboratories, parsippany, nj, usa, united biosource corporation, bethesda, md, usa, leiden university medical center, leiden, netherlands objectives: qalys are an important outcome used in cost-effectiveness analysis. the health utilities index mark (hui- ) is a self-reported measure covering attri- butes of health status. our objective was to assess construct validity and responsiveness of hui- in ankylosing spondylitis (as). methods: data were derived from the adalimumab trial evaluating long-term effi cacy and safety in as (atlas). we speci- fi ed a priori hypotheses regarding the direction and magnitude of associations expected between overall and single-attribute hui- scores and other health status and quality of life measures—sf- , asqol, bath as functional index (basfi), bath as disease activity index (basdai), and patient’s global assessment (pga). using baseline data, we calculated correlation coeffi cients and interpreted them via guidelines suggested by guyatt for negligible, weak, moderate, and strong associations. responsiveness was assessed by calculating standardized response means (srms) of hui- scores from baseline to week for patients meeting the minimum clinically important differences (mcid) for the asqol ( . ). responsiveness analysis was limited to patients with -week hui- scores. results: a total of of the patients enrolled in atlas were included in the analysis. mean age was years, . % were male, and mean duration of as was years. correlation coeffi cients between hui- scores and other instruments confi rmed . % of the a priori hypothesis, with an additional . % being under- or over-estimated by only one category. results of responsiveness analysis demonstrated that there were signifi cant differences in overall hui- (srm . ) and most single-attribute change scores for patients whose changes were greater than the asqol mcid vs. those whose changes were mcid. conclusions: these results suggest that hui- constructs are related to similar constructs in other measures, as expected. this study provides evidence of cross-sectional and longitudinal construct validity of the hui- for deriving utility scores for as patients. pms validation of the multi-attribute health utility (mahu) derived from a computer adaptive instrument, cat- d-qol, in osteoarthritis kang wg , sayre ec , steininger g , doerfl ing p , ratzlaff c , esdaile j , kopec j university of british columbia, vancouver, bc, canada, arthritis research centre of canada and simon fraser university, vancouver, bc, canada, arthritis research centre of canada, vancouver, bc, canada objectives: we aimed to validate the multi-attribute health utility (mahu) derived from the cat- d-qol, a computer-adaptive instrument composed of domains (walking, handling objects, daily activities, pain/discomfort, and feelings) in people with self-reported osteoarthritis (oa), and to compare it with womac_hui , the utility derived from the standard disease-specifi c measure in oa. methods: data were collected from participants (age ) who completed questionnaires cat- d- qol in two waves and womac in one wave of a canada-wide online survey. to assess construct validity, we used multivariable regression to examine the associations the poetry of mathematics, and other essays. by d. e. smith. pp. v, . paper, cents; cloth, cents. . scripta mathematica library, ( scripta mathematica , new york) | the mathematical gazette | cambridge core skip to main content accessibility help we use cookies to distinguish you from other users and to provide you with a better experience on our websites. close this message to accept cookies or find out how to manage your cookie 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spouses or partners. yes no more information * please enter details of the conflict of interest or select 'no'.   please tick the box to confirm you agree to our terms of use. * please accept terms of use.   please tick the box to confirm you agree that your name, comment and conflicts of interest (if accepted) will be visible on the website and your comment may be printed in the journal at the editor’s discretion. * please confirm you agree that your details will be displayed. cb conservation biology, pages – volume , no. , december the tyranny of population growth daniel h. pletscher* and michael k. schwartz wildlife biology program, school of forestry, the university of montana, missoula, mt – , u.s.a. the proximate cause behind the decline of biodiversity is most often reduction or change of habitat and isola- tion of wildlife populations. in the western united states, as in much of the world, these problems can ultimately be attributed to increases in human population and per- capita consumption. this journal has published several articles concerning the burdens of human population growth (e.g., meffe ; gehrt ); indeed, we have not met many conservation biologists who are not firmly aboard the malthusian ship. we argue that population growth also burdens personal liberty by creating a need for greater regulation. parsons ( ) discussed the rela- tionship between population and liberty; we extend that argument to conservation. people unmoved on the pop- ulation issue with conservation arguments may be moved by our regulation argument. the problems faced by conservationists have changed. one hundred years ago, the predominant problem facing wildlife in north america was overexploitation. water- fowl, forest carnivores, and ungulates were exploited, largely for market, and were minimally regulated, to the point where most were near extinction. deer ( odocoileus virginianus ) populations were especially depleted and heading toward extirpation throughout the eastern united states. the american colonies began limiting hunting methods, seasons, and equipment in the mid- s to deal with overexploitation (trefethen ). passage of the lace act of , which made it a federal offense to trans- port illegally killed wildlife across state borders, further defined the public right to wildlife and helped curb over- exploitation. these regulations marked the beginning of the end of wildlife populations being considered unpro- tected public property. unregulated taking had exacted a lasting toll on some north american wildlife. for ex- ample, the passenger pigeon ( ectopistes migratorius ), which once flew in flocks of billions, was extinct by , largely because of unregulated taking of pigeons for mar- ket (blockstein & tordoff ). at about the same time, carnivores such as lynx ( lynx canadensis ) and moun- tain lions ( puma concolor ) were exploited to local ex- tinction in the northeastern united states (godin ). as the human population grew, wildlife conservation and management developed as an applied scientific disci- pline with a focus on reducing or controlling consump- tion by humans and increasing production of wildlife. specifically, the works of aldo leopold, particularly game management (leopold ) and “the upshot” (in a sand county almanac , leopold ), focused our attention on wildlife as a renewable but finite resource and halted our illusion of boundless wildlife populations. as conservationists we can be proud of our many suc- cesses. game species have rebounded, and predators— long maligned for their way of life—are making tremen- dous comebacks. mountain lions have returned to much of their former range in the western united states and are slowly returning in the east. the wolf ( canis lupus ) has gradually returned to the rocky mountains, and there is even an active campaign to reintroduce the grizzly bear ( ursus arctos horribilis ) to parts of its former range. the u.s. public has demonstrated through laws, regulation, and private actions that it values these species and their habitats, at least in certain places and times, more than competing human uses. our glaring failure, however, has been in treating the symptoms of wildlife conservation problems rather than their root causes. the world’s human population, currently approxi- mately billion, is growing ( births minus deaths) at a rate of people per second, or approximately , people each day (united nations ). natural resource managers must deal with this growth, and plant and ani- mal life must adapt or perish. what happens when we compromise in the conflict between wildlife habitat and the demands of more people? the trade-offs almost al- ways mean a net increase in the proportion of earth’s productivity allocated to human use and a net decrease in the proportion allocated to wild areas and wild life. the effect of humans on our environment is a func- tion of per capita consumption of resources times the number of people consuming those resources. in some cases we have done a fair job of convincing people to re- duce consumption and protect some habitat. if, how- ever, we reduce per capita consumption but the num- * email pletsch@forestry.umt.edu paper submitted january , ; revised manuscript accepted may , . conservation biology volume , no. , december pletscher & schwartz population growth ber of humans increases by similar or higher rates, what have we gained? in addition, if we protect some habitat but the human population increases by higher rates, what have we gained? we argue that we have lost: space per individual, wild species, and wild areas. in addition, by ignoring the population problem, we lose individual freedoms because of the need for increased regulation. for example, years ago, people in the western united states could harvest bison at any rate they wished. with an increased market and more harvesters, laws and regulations were enacted to stop overharvest (trefethen ). at the turn of the last century, people could dump their wastes into rivers with little noticeable effect. now, with an in- creased number of residents and more wastes per capita, laws and regulations are in place to maintain water quality. we examined the montana laws restricting fishing, hunting, and access to lands for these activities and found that in the general laws required only sections of code and pages of text (montana territorial legislature ; montana legislature ). today, montana has sections of code spanning pages of text (montana legislature ). population growth is not the only fac- tor causing increases in regulations, but we believe it to be the primary and most overlooked, factor. we continue to pass more laws and regulations to control both supply and demand in an over-taxed system; thus, our individual free- doms are inversely proportional to our population. one of our most basic freedoms is our reproductive freedom, but uncontrolled population growth leads to a reduction in all other freedoms, a tyranny of population growth. despite this tyranny, taking away reproductive freedom is not morally acceptable, socially feasible, or politically possible. what we can do, quite easily, is raise awareness that human population growth is the cause of most of our environmental ills and leads to increased regulation. few conservation issues are unaffected by human population pressures, and we must demonstrate these relationships. for instance, when talking about the effects of subdivided land on biodiversity, we can point out the root of the problem. when talking about problems of access on pri- vate lands or the institution of recreation fees, we can in- dicate why they are occurring. and when we discuss air- quality regulations that prevent open burning or require tougher industrial standards, we should discuss the ulti- mate root of the problem. the tradeoffs should be identi- fied explicitly. increased human population equals in- creased pressure for regulation. furthermore, we must not only preach to the converted. these messages should be delivered to groups outside the society for conserva- tion biology, especially to those people who traditionally are uninterested in the outdoors but who have an interest in seeing government reduced. in other words, if popula- tion growth is the primary culprit hindering the conserva- tion of biodiversity, we should not stop short of enlisting political groups who are interested for different reasons. let conservation make strange bedfellows. we must continue to encourage a reduction in con- sumption and work on increasing efficiency on those lands producing goods and services. we must also con- tinue to encourage shared uses of our wild lands and nat- ural resources. but if this is all we do, we will continue to tinker while our wildlife legacy is lost. we must point out to anyone who will listen—and to recognize ourselves— that human population growth is a grave threat to indi- vidual freedom and to all that we as conservationists hold dear. there are no easy answers, but education is a start. thomas jefferson, the third american president and framer of the u.s. constitution, argued that it is the re- sponsibility of the current generation to undertake ac- tions that will maintain the freedom of the next genera- tion. by ignoring the population issue, we not only lose our valuable wild areas and wild life, but we infringe on the freedoms of the next generation. the earth belongs to each of these generations during its course, fully and in its own right. the second generation receives it clear of the debts and encumbrances of the first, the third of the second, and so on. for if the first could charge it with a debt, then the earth would belong to the dead and not to the living generation. thomas jefferson ( ) ( foner : ) acknowledgments we thank j. w. thomas, g. schildwachter, j. belsky, j. burchfield, and two anonymous reviewers for comment- ing on an early draft of this essay. literature cited blockstein, d. e., and h. b. tordoff. . gone forever: a contempo- rary look at the extinction of the passenger pigeon. american birds : – . foner, p. s., editor. . letter from thomas jefferson to james madi- son. pages – in basic writings of thomas jefferson. willey book company, new york. gehrt, s. d. . the human population problem: educating and changing behavior. conservation biology : – . godin, a. j. . wild mammals of new england. johns hopkins uni- versity press, baltimore. leopold, a. . game management. scribner’s sons, new york. leopold, a. . a sand county almanac and sketches here and there. oxford university press, new york. meffe, g. k. . human population control: the missing awareness. conservation biology : – . montana legislature. . montana codes annotated. montana legis- lative services division, helena. montana legislature. . montana codes annotated. montana legis- lative services division, helena. montana territorial legislature. . revised statutes of montana. george e. boos, helena. parsons, j. . population versus liberty. pemberton books, london. trefethen, j. b. . an american crusade for wildlife: highlights in con- servation progress. the telegraph press, harrisburg, pennsylvania. united nations. . department of economic and social affairs, pop- ulation division. world population . publication st/esa/ser.a/ , no. e. . . . united nations, new york. sixth annual becton, dickinson and company oscar schwidetzky... : anesthesia & analgesia you may be trying to access this site from a secured browser on the server. please enable scripts and reload this page. 	 log in your account has been temporarily locked your account has been temporarily locked due to incorrect sign in attempts and will be automatically unlocked in mins. for immediate assistance, contact customer service: - - (within usa), - - (international) [email protected] invalid username or password. try again or register an account. default message login no user account? 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	legal disclaimer 	terms of use 	open access policy 	 feedback 	 rss feeds 	 lww journals 	copyright ©  	international anesthesia research society this website uses cookies. by continuing to use this website you are giving consent to cookies being used. for information on cookies and how you can disable them visit our privacy and cookie policy. got it, thanks! 	 received / / review began / / review ended / / published / / © copyright rodriguez et al. this is an open access article distributed under the terms of the creative commons attribution license cc-by . ., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. an evaluation of risk attitudes and risk tolerance in emergency medicine residents carlos rodriguez , nishad a. rahman , kory london , robin naples , simran buttar , xiao chi zhang , hyunjoo lee , joshua rudner , dimitrios papanagnou . emergency medicine, thomas jefferson university, philadelphia, usa . emergency medicine, sidney kimmel medical college, thomas jefferson university, philadelphia, usa . emergency medicine, thomas jefferson university hospital, philadelphia, usa . emergency medicine, thomas jefferson university, glenside, usa . emergency medicine, maimonides medical center, commack, usa . emergency medicine, stony brook university hospital, stony brook, usa  corresponding author: carlos rodriguez, carlos.rodriguez@jefferson.edu disclosures can be found in additional information at the end of the article abstract introduction previous studies have shown that risk attitudes and tolerance for uncertainty are significant factors in clinical decision-making, particularly in the practice of defensive medicine. these attributes have also been linked with rates of physician burnout. to date, the risk profile of emergency medicine (em) physicians has not yet been described. our goal was to examine the risk profile of em residents using a widely available risk tolerance and attitude assessment tool. methods first-, second-, and third-year residents of thomas jefferson university hospital’s em residency program completed the commercially available, unmodified risk type compass, a validated instrument offered by multi-health systems (mhs inc, new york, usa). scored reports included information on residents’ risk type (one of eight personality types that reflect their temperament and disposition); risk attitudes (domains where residents are more likely to engage in risky behaviors); and an overall risk tolerance indicator (rti) (a numerical estimate of risk tolerance). rti scores are reported as means with % confidence intervals (cis). results there was no significant change in rti scores in residents across different years of their post- graduate year (pgy) training. pgy-one residents trended towards risk aversion; pgy-two residents were more risk-taking; and pgy-three residents scored in the middle. conclusion our pilot assessment of risk types in em residents highlighted shifts across the years of training. variations between members of each pgy cohort outweighed any outright differences between classes with regards to absolute risk tolerance. there was an increase in the frequency of health and safety risk-taking attitude with higher pgy class, and this was also the risk attitude that was the prominent domain for resident risk tolerance. the study was limited by sample size and single cross-sectional evaluation. categories: emergency medicine, medical education, other open access original article doi: . /cureus. how to cite this article rodriguez c, rahman n a, london k, et al. (april , ) an evaluation of risk attitudes and risk tolerance in emergency medicine residents. cureus ( ): e . doi . /cureus. https://www.cureus.com/users/ -carlos-rodriguez https://www.cureus.com/users/ -nishad-a-rahman https://www.cureus.com/users/ -kory-london https://www.cureus.com/users/ -robin-naples https://www.cureus.com/users/ -simran-buttar https://www.cureus.com/users/ -xiao-chi-zhang https://www.cureus.com/users/ -hyunjoo-lee https://www.cureus.com/users/ -joshua-rudner https://www.cureus.com/users/ -dimitrios-papanagnou- keywords: risk, risk tolerance, wellness, risk attitude, risk type, emergency medicine, graduate medical education introduction despite significant advances, healthcare remains a field steeped in uncertainty and ambiguity. there are intrinsic risks whenever any management plan is executed. these risks pose even graver challenges in emergency medicine (em), where uncertainty intersects with patient acuity and patient volume. while high-risk decisions and management are replete in the practice of em, the risk profiles of em providers, particularly those in training, have not been assessed by prior studies. knowledge of risk-taking tendencies may be critical in advising and developing physicians in training. em providers with substantial risk aversion may subject their patients to unnecessary testing, such as advanced diagnostic imaging [ ]. these providers may also be more likely to admit their patients or highly utilize observation units [ ]. in addition, cognitive biases and personality traits (i.e., omission bias, tolerance to risk, and/or overconfidence) may lead to diagnostic inaccuracies and medical errors resulting in mismanagement or inadequate resource utilization [ ]. it is imperative that providers reflect on their individual risk tolerances. given there is no clear understanding of what ideal risk aversion or risk tolerance should be in em residents, it is prudent to first identify a baseline risk profile for this group. while several studies have identified methodologies for assessing risk-taking behaviors and attitudes, they are not specific to em physicians. to date, previous studies in this area have not utilized standardized assessments; consequently, cross-study comparisons still remain a difficult challenge. the solution may be found by seeking guidance from other disciplines. studies have demonstrated improved attitudes toward team building, communication, and adverse event recognition after having clinical teams from various disciplines (i.e., em, surgery, nursing) complete coursework in crew resource management (crm) [ - ]. crm can easily be applied to em providers, as they naturally work in teams immersed in high-stakes situations while managing fatigue, communication, and decision-making. risk tolerance has been heavily studied in business, where risk attitudes are essential to employee recruitment, coaching, and strategic planning. risk attitudes and their subsequent effects on entrepreneurship [ - ], small businesses [ ], investments [ ], and role conflict [ ] have also been studied. using a validated risk assessment tool can be of potential benefit when assessing professionals across various fields and specializations. the risk type compass (rtc), created in by the psychological consultancy ltd (tunbridge wells, united kingdom), provides multiple modes of risk assessment [ ]. our pilot study aimed to describe the risk type and risk tolerance of em residents in our three post-graduate year (pgy) cohorts. we hypothesized that em residents would tend to have a higher risk tolerance when compared to the general population, in line with existing ‘cowgirl’ and ‘cowboy’ stereotypes. additionally, we hypothesized that risk tolerance would increase with the increasing pgy. materials and methods study instrument the rtc is a commercially available psychometrically validated assessment tool (multi-health systems, new york, usa, ). the standard rtc questionnaire, which consists of two parts, is a -item assessment: items that determine risk type, items that determine risk attitude, and items for validity. it includes a self-report with a six-point likert scale for part rodriguez et al. cureus ( ): e . doi . /cureus. of one, and a three-point rank ordering for part two. for this pilot, the complete version of the questionnaire was used with official individualized scoring from rtc through multi-health systems (mhs) in the form of a personal report. the rtc uses a normative sample of , adults ( sample). this particular evaluation has proven to have notable internal consistency, with α values greater than . . total rtc scores were computed by mhs software. for this pilot study, we used the rtc-generated personal report, which is not professional- or industry-specific. the rtc offers several measures. ‘risk type’, analogous to the eight personality types, is one such measure. risk types include: wary (i.e., self-disciplined and cautious), prudent (i.e., self- controlled and detailed), deliberate (i.e., systematic and compliant), composed (i.e., cool- headed and optimistic), adventurous (i.e., impulsive and fearless), carefree (i.e., spontaneous and unconventional), excitable (i.e., uninhibited and excitable), and intense (i.e., pessimistic and self-critical). risk type correlates to a spectrum for one’s relationship with risk, from risk- averse (i.e., wary) to risk-tolerant (i.e., adventurous). the second measure is the ‘risk attitude’, which includes five sub-scales of risk tolerance across the different domains of one’s life. risk attitudes include: financial (i.e., willingness to take financial risk), social (i.e., risk of embarrassing oneself or others and risking disapproval), health and safety (i.e., being alert to dangers that may impact one’s current or future health state), recreational (i.e., possibility of physical danger and its influence on decisions regarding recreational activities one engages in), and reputational (i.e., morality and a readiness to live life according to accepted principles). finally, the risk tolerance index (rti), an overall numerical estimate of tolerance for risk based on risk type and risk attitude, is calculated by combining the two measures. rti ranges from zero (low risk tolerance) to (high risk tolerance). study design and participants this cross-sectional investigation was conducted at an urban em residency training program. study recruitment included em residents ( pgy-one, pgy-two, and pgy-three residents) at a single academic medical institution, thomas jefferson university hospital in philadelphia, pennsylvania. there were no exclusion criteria for participation. the rtc was deployed electronically in august . residents completed an electronic consent form followed by a demographics questionnaire including age, gender, and level of residency training. rti scores are reported as means with % cis. differences in risk tolerance based on pgy- training level were assessed. an analysis of variance (anova) was used to evaluate differences across means. study investigator dp has had exposure to mhs products through graduate-level doctoral studies, and primarily assisted with rtc score interpretation. this study was previously presented as a poster at a local symposium (poster: rahman n, papanagnou d. an evaluation of risk attitudes and risk tolerance in emergency medicine. college within the college (cwic) posters; november , ). the study was reviewed and received approval from the institutional review board of thomas jefferson university (# e. ). results pgy-one em residents gravitated towards the risk averse part of the spectrum. pgy-two and pgy-three residents were noted to cluster at both (i.e., risk-averse and risk-tolerant) ends of the risk-type spectrum (figure ). rodriguez et al. cureus ( ): e . doi . /cureus. of figure : risk type compass: risk types of (a) pgy-one, (b) pgy-two, and (c) pgy-three residents. rtc: risk type compass pgy: post-graduate year when it comes to risk attitudes, pgy-one residents were most risk tolerant with regards to the recreational aspects of their lives. pgy-two residents were most risk tolerant with regards to their own health and safety, as well as their reputation. pgy-three residents were most risk tolerant when it came to their own health and safety (figure ) figure : risk type compass: risk attitudes of pgy-one (a), pgy-two (b), and pgy-three (c) residents. pgy: post-graduate year em: emergency medicine rtc: risk type compass rti scores from the rtc assessment were compared across pgy levels (table ). rti scores decreased as year of training increased, suggesting decreasing risk tolerance over training. statistically significant differences in rti means, however, were not observed across pgy resident groups (one-way anova: f-ratio= . , p= . ). rodriguez et al. cureus ( ): e . doi . /cureus. of https://assets.cureus.com/uploads/figure/file/ /lightbox_ f e df e a fa f c f -lightbox_ c c a e e f aef -image .png https://assets.cureus.com/uploads/figure/file/ /lightbox_ a e b d b c d -lightbox_ affde a e bffacf fd ffe-image .png total rti per pgy-year pgy-year n mean std. dev. % confidence interval pgy-one . . . [ . - . ] pgy-two . . . [ . - . ] pgy-three . . . [ . - . ] table : risk tolerance index (rti) for residents per post-graduate year. n: total number rti: risk type index std. dev.: standard deviation pgy: post-graduate year discussion the aim of this article was to describe the risk type and risk tolerance of em residents by using the risk type compass, a commercially available risk tolerance assessment tool. the rtc tool specifically focused on differences in how individuals perceive, react to, and manage risk, as well as how they make decisions when risk is involved [ ]. a significant difference in rti scores across years in training was not observed. while there were noted preferences for risk type by pgy class in our cohort, however, rti, as a measure for risk tolerance, cannot be used to fully appreciate the nuances in changes in risk type across residents. examination of resident risk attitudes is useful for identifying in which domains residents were more comfortable with risk-taking behaviors. this was most distinctive amongst pgy-three residents, who were most risk tolerant when it came to their own health and safety. furthermore, ‘health and safety’ was one of the most commonly delineated risk attitudes for the highest risk tolerance, with increasing frequency from pgy-one to pgy-three residents. while definitive conclusions are limited in our study, the evaluation of one's relationship with risk and tolerance for uncertainty in the clinical setting has the potential to offer valuable insight into trainee performance. previous studies have linked tolerance for uncertainty with burnout in both emergency medicine physicians and residents. kuhn et al. reported that poor tolerance for uncertainty, secondary to concerns for bad outcomes, is strongly correlated with emotional exhaustion and/or burnout in em physicians [ ]. another study by takeyesu et al. found that residents with higher levels of burnout were significantly less tolerant of uncertainty when it came to clinical decision-making. the authors also reported that uncertainty may serve as a source of anxiety and psychological stress, which may ultimately negatively affect clinical performance and delay informational recall, which collectively can inhibit optimal learning [ ]. in light of these findings, directly addressing areas of uncertainty during residency training may be helpful in supporting em residents as they build their clinical skills and develop their rodriguez et al. cureus ( ): e . doi . /cureus. of resilience to protect them from burnout. additional studies applying the rtc risk assessment may be of use, especially when applied to cohorts longitudinally to assess potential shifts in risk tolerance over the course of their residency training. such findings would offer insight into interventions that can impact education and training; wellness and burnout; and clinical decision-making. a potential opportunity for further investigation would be to include an objective measure for burnout, such as the physicians’ reaction to uncertainty (pru) scale [ ], to draw conclusions about the relationship between risk tolerance and burnout in specific cohorts of trainees. while our study suggests several trends, it was hindered by the small sample size of only em residents from a single institution. subsequent follow-up studies to this pilot should be adequately powered to note any differences in risk patterns. the study also represents a single snapshot of residents over the course of their training. it is possible that randomness in recruitment may impact trends between classes, where findings may actually represent differences in individual personalities, rather than effects based on training level. moving forward, our study should be replicated with more em residents across multiple institutions and repeated over the course of their training, in order to build a more robust and actionable risk profile. conclusions risk type and tolerance inevitably affect patient care in the em setting. further research is needed to determine the ideal risk profile that allows for reduction in wasteful expenditures and defensive medicine without negatively impacting patient care. this data could also help inform curricular training and identify residents who may benefit from targeted wellness interventions. our pilot study supports the notion that risk type and risk tolerance are aspects of provider personality worthy of additional scholarship. additional information disclosures human subjects: consent was obtained by all participants in this study. thomas jefferson university issued approval # e. . this study received approval from the institutional review board at thomas jefferson university. animal subjects: all authors have confirmed that this study did not involve animal subjects or tissue. conf licts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. references . pines jm, hollander je, isserman ja, et al.: the association between physician risk tolerance and imaging use in abdominal pain. am j emerg med. , : - . . pines jm, isserman ja, szyld d, dean aj, mccusker cm, hollander je: the effect of physician risk tolerance and the presence of an observation unit on decision making for ed patients with chest pain. am j emerg med. , : - . . /j.ajem. . . . saposnik g, redelmeier d, ruff c, tobler p: cognitive biases associated with medical decisions: a systematic review. bmc. , : . . /s - - - . sexton jb, thomas ej, helmreich rl: error, stress, and teamwork in medicine and aviation: cross sectional surveys. bmj. , : - . . /bmj. . . rodriguez et al. cureus ( ): e . doi . /cureus. of https://www.ncbi.nlm.nih.gov/pubmed/ https://dx.doi.org/ . /j.ajem. . . https://dx.doi.org/ . /j.ajem. . . https://dx.doi.org/ . /s - - - https://dx.doi.org/ . /s - - - https://dx.doi.org/ . /bmj. . . https://dx.doi.org/ . /bmj. . . . grogan el: the impact of aviation-based teamwork training on the attitudes of health-care professionals. j am coll surg. , : - . . /j.jamcollsurg. . . . mcculloch p, mishra a, handa a, dale t, hirst g, catchpole k: the effects of aviation-style non-technical skills training on technical performance and outcome in the operating theatre. qual saf health care. , : - . . /qshc. . . segal g, borgia d, schoenfeld j: the motivation to become an entrepreneur . ijebr. , : - . . begley tm, boyd dp: psychological characteristics associated with performance in entrepreneurial firms and smaller businesses. j bus ventur. , : - . . / - ( ) - . pak o, mahmood m: impact of personality on risk tolerance and investment decisions: a study on potential investors of kazakhstan. int j commerce manag. , : - . . /ijcoma- - - . teoh hy, foo sl: moderating effects of tolerance for ambiguity and risk taking propensity on the role conflict-perceived performance relationship: evidence from singaporean entrepreneurs. j bus ventur. , : - . . /s - ( ) - . risk type compass . accessed: march , : http://www.psychological- consultancy.com/products/risk-type-compass/. . kuhn g, goldberg r, compton s: tolerance for uncertainty, burnout, and satisfaction with the career of emergency medicine. ann emerg med. , : - . . /j.annemergmed. . . . jk takayesu, e ramoska, t clark, et al.: factors associated with burnout during emergency medicine residency. acad emerg med. , : - . . /acem. . gerrity m, white k, devellis r, dittus r: physicians' reactions to uncertainty: refining the constructs and scales. motiv emot. , : - . . /bf rodriguez et al. cureus ( ): e . doi . /cureus. of https://dx.doi.org/ . /j.jamcollsurg. . . https://dx.doi.org/ . /j.jamcollsurg. . . https://dx.doi.org/ . /qshc. . https://dx.doi.org/ . /qshc. . https://www.emeraldinsight.com/doi/abs/ . / https://dx.doi.org/ . / - ( ) - https://dx.doi.org/ . / - ( ) - https://dx.doi.org/ . /ijcoma- - - https://dx.doi.org/ . /ijcoma- - - https://dx.doi.org/ . /s - ( ) - https://dx.doi.org/ . /s - ( ) - http://www.psychological-consultancy.com/products/risk-type-compass/ http://www.psychological-consultancy.com/products/risk-type-compass/ https://dx.doi.org/ . /j.annemergmed. . . https://dx.doi.org/ . /j.annemergmed. . . https://dx.doi.org/ . /acem. https://dx.doi.org/ . /acem. https://dx.doi.org/ . /bf https://dx.doi.org/ . /bf 	an evaluation of risk attitudes and risk tolerance in emergency medicine residents 	abstract 	introduction 	methods 	results 	conclusion 	introduction 	materials and methods 	study instrument 	study design and participants 	results 	figure : risk type compass: risk types of (a) pgy-one, (b) pgy-two, and (c) pgy-three residents. 	figure : risk type compass: risk attitudes of pgy-one (a), pgy-two (b), and pgy-three (c) residents. 	table : risk tolerance index (rti) for residents per post-graduate year. 	discussion 	conclusions 	additional information 	disclosures 	references php a comparative analysis of the financing, pricing and reimbursement systems for prescription drugs in the nordic countries a abstracts php a comparative analysis of the financing, pricing and reimbursement systems for prescription drugs in the nordic countries kristensen fko, sverre jm, holm lb pharmecon as, asker, norway objectives: to elicit similarities and differences in the poli- cies and practices for financing, pricing and reimbursing pre- scription drugs in the often perceived similar nordic countries of denmark (d), finland (f), norway (n) and sweden (s). methods: a review of the four countries’ authorities’ stated policies and practices on the matter were performed through a search of the literature and of the respective authorities’ home- pages. the information was validated through interviews with key personnel of the reimbursement agencies in each country, and the final study reports for the respective countries were reviewed by the same persons. results: all countries have a national health care system financed by taxation. there are dif- ferences in the reliance upon patient co-payment (n %, others – %) and whether financing is a county (s) or national (others) responsibility. all have regulated prices for reimbursed drugs; based either upon international comparisons (n, d) or country-specific decisions (s, f). the criteria used for deciding to reimburse a drug vary between the countries, and reimbursement is practiced differently in several other dimensions: mandatory requirement for pharmacoeconomic analysis (f, n, s), the existence of patient-specific reimbursement systems (d, f, n), product- (s) or indication-based (others) reimbursement, use of graded (f), conditional (n, s) or temporary (s) reimbursement, use of reimbursement contracts (n), and different processes for handling disagreement about decisions. conclusion: the nordic countries all have a national health care system financed by taxation and encompassing prescription drugs, but differ in a number of other dimensions with respect to financing, pricing and reimbursing such drugs. php a systematic review of the european pharmaceutical market and the impact of european union regulation and jurisdiction van ginneken ej, schreyögg j, gericke ca, busse r berlin university of technology, berlin, germany objectives: to examine the impact of the increasing role of the european union (eu) on the european pharmaceutical market, focusing on industry and national policies. to give a sys- tematic overview of the current state of the european pharma- ceutical market as a whole. methods: systematic literature review for the years – , including “grey” sources of information, online databases, european commission docu- ments and european court of justice rulings, relevant journals and systematically tracing back relevant references. results: the eu attempts to liberalise the pharmaceutical market and the realisation of a single european market (sem) came to a stand- still, after some considerable achievements (e.g. marketing authorisation). instead, the eu seems to concentrate on coor- dination of results through the adoption of the so-called g recommendations. eu member states successfully—and inten- tionally—kept control on the issues of pricing, reimbursement, pharmacies and prescribing. over the last years they adapted increasingly convergent measures to cope with rising pharma- ceutical expenditures, without long-lasting cost containment effects. however, recent european case law might prove to have far reaching consequences on the provision of medicines. the european pharmaceutical industry—although profitable—is underperforming compared to the usa, which is blamed on restrictive regulatory frameworks in the member states. con- clusions: the future of the actors in the european pharma- ceutical market is not clear. will it bring more european influence or a strengthening of national influence? in the short term, major change towards a sem seems unlikely, but in the longer term european history showed that major change is pos- sible. it seems clear that much depends on the attitude of member states towards the new approach and the interpretation and influence of european case law. for the european industry, adoption and implementation of g recommendations is of great importance for future competition with us-based companies. php using an italian population database to profile prevalence and costs of chronic conditions yuen ej, maio v, louis dz, rabinowitz c, robeson m, smith kd jefferson medical college, thomas jefferson university, philadelphia, pa, usa objective: individuals with chronic medical illness may have multiple health problems, and are often costly and difficult to manage. this study identifies those with highly prevalent chronic conditions and assesses related health service use and costs in the population of emilia romagna (rer), a large northern italian region. methods: pharmaceutical, hospital, and demographic data from and have been assembled for the entire population of rer ( million). pharmaceutical and hospital tariffs were a proxy for costs. pharmacy and hospital records were used to identify individual morbidity. data included demo- graphic and geographic information, encounter dates, diagno- sis/procedure codes, pharmaceutical information, and health care costs. individuals were classified as having a chronic condi- tion in , and we examined pharmacy and hospital use/costs in . descriptive analyses compared mean and total costs, as well as proportions within the population. results: we iden- tified five highly prevalent chronic conditions: cardiovascular dis- eases (n = , , . % of the population); rheumatologic conditions (n = , , . %); gastric acid disorders (n = , , . %); chronic respiratory illnesses (n = , , . %); and psychiatric disorders ( , , . %). . % of the population had one or more of these five chronic conditions, and these individuals accounted for . % of the pharmacy costs and . % of the hospital costs in the following year. for persons with these five conditions, we also described use and costs by age and gender, residence, and income. conclusions: interest- ingly, one-fourth of the population with selected chronic condi- tions accounted for large proportions of cost and use of health services. the ability to identify those with chronic conditions would help planners and governmental agencies to address health care needs, increase quality of care, avoid unnecessary hospitalizations, and save costs. these types of data can be used to estimate health care financing and risk adjustment models, and profile specific clinical, demographic or geographic sub-groups. php adherence index of performance—a new method and tool for ongoing evaluation of medication adherence improvement initiatives day d pfizer, new york, ny, usa objectives: to develop a standardized means for measuring the impact of medication adherence improvement initiatives in disparate pharmacy claims databases over sequentially overlap- ping periods of time. methods: the adherence index of elsevier forest ecology and management ( ) - pores;i;ology management the effects of population growth on timber management and inventories in virginia david n. wear”>*, rei liub, j. michael foremanc, raymond m. sheffieldd “usda forest service, economics of forest protection and management, po. box , research triangle park nc , usa bsenior gis analyst, commonwealth of virginia, department of forestry, charlottesville va, usa ‘chiej forest resources utilization, commonwealth virginia, department of forestry, charlottesville va, usa ‘usda forest service, forest inventory and analysis, asheville nc, usa received february ; accepted october abstract expanding human populations may have important effects on the availability of timber from private lands in the south. to examine the effects of development on timber supply, we compared the density of populations and various site variables with expert opinions on the future location of commercial timberland for a study site in virginia. population density is a significant predictor of commercial timberland and resulting probability equations provide a method for adjusting timber inventories. findings indicate that the transition between rural and urban land use occurs where population density is between and people per square mile. population effects reduce commercial inventories between and % in the study area. elsevier science b.v. all rights reserved. . introduction an expanding human population may have impor- tant implications for forest resources in the united states. as domestic and global populations grow, so grows demands for resource products and natural s e t t i n g s . i n c r e a s i n g p r o d u c t i o n , i n t u r n , m a y a d v e r s e l y affect the environmental and aesthetic quality of for- e s t s . a t t h e s a m e t i m e , t h e e x p a n s i o n o f r e s i d e n t i a l a n d u r b a n a r e a s w i l l l i k e l y r e d u c e t h e a m o u n t o f r e s o u r c e s available for the production of goods and services (marcin, ; harris and deforest, ). over time, *corresponding author. tel.: +l- - - ; fax: + - - - . these concurrent impacts on both timber demand and timber supply could result in increasing market scar- c i t y a n d c o n t i n u e d u p w a r d p r e s s u r e o n t i m b e r p r i c e s . additionally, expanding ‘urban-rural interfaces,’ as they are sometimes called, may hold implications for other resource values (shands, ). for example, wildlife habitat may become more fragmented and otherwise less effective as an area becomes more populated. managing forest fuel loads may also become increasingly problematic and forest fires are likely to be more difficult to fight and more costly as p o p u l a t i o n d e n s i t y i n c r e a s e s . t h i s s t u d y e x a m i n e s t h e p o t e n t i a l e f f e c t s o f p o p u l a - tion growth on timber supply. in particular, we exam- ine how expanding populations in a part of western % / /$ - see front matter elsevier science b.v. all rights reserved. pii: so - ( ) - d.n. wear et al/forest ecology and management i ( ) - v i r g i n i a m a y i n f l u e n c e t h e m a n a g e m e n t o f f o r e s t s a n d the eventual supply of timber from forest lands. we p o s i t t h a t i n c r e a s i n g p o p u l a t i o n d e n s i t y a f f e c t s t i m b e r s u p p l y i n t w o d i f f e r e n t w a y s . o n e i s t h e c o n v e r s i o n o f forests from a timber-growing use to a residential or urban use. when this occurs, land will no longer be a v a i l a b l e f o r t i m b e r h a r v e s t o r t i m b e r g r o w i n g , t h o u g h the transition may be coincident with some timber h a r v e s t i n g - s o c a l l e d ‘ r e a l e s t a t e c u t s ’ . a m o r e s u b t l e effect may be the reduced investment in timber pro- duction in areas of moderate population density as l a n d o w n e r s a n t i c i p a t e c o n t i n u e d p o p u l a t i o n g r o w t h a n d c h a n g e s i n l a n d u s e s . t h i s p e r c e i v e d i m p e r m a n e n c e o f land use may discourage active investment in timber production, thereby reducing future timber supply. in this study, we examine the potential effects of population growth on timber production using a two- step approach. first, we compare expert opinions on where forests will not be managed as commercial timberland with population density in these areas, and test for a relationship between the two. then, we use the relationship between population density and likely timber management to adjust timber inven- tories for population effects. the study provides i n s i g h t s i n t o t h e s e i m p o r t a n t i s s u e s b u t , p e r h a p s m o r e importantly, offers some practical methods for asses- sing the effects of population growth on estimates of timberland area and timber inventories. . study site o u r s t u d y s i t e i s v i r g i n i a ’ s t h o m a s j e f f e r s o n p l a n - ning district shown in fig. . this area is defined by five counties in the general vicinity of the city of charlottesville: albemarle, fluvanna, louisa, greene, and nelson. the area has the hilly topography char- acteristic of the piedmont of the appalachian blue ridge and a variety of forest types. the oak-hickory type predominates but significant areas of loblolly- shortleaf pine and oak-pine types are also present (thompson, ). accordingly, hard hardwoods c o m p r i s e t h e l a r g e s t s h a r e o f g r o w i n g s t o c k v o l u m e s , b u t s o f t h a r d w o o d s a n d p i n e a l s o r e p r e s e n t s i g n i f i c a n t c o m p o n e n t s o f i n v e n t o r y . . methods . . r e l a t i o n s h i p b e t w e e n p o p u l a t i o n d e n s i t y a n d c o m m e r c i a l f o r e s t r y physical measures of timberland may provide lim- ited insights into whether or not forest land will actually be used for timber production. the first step of our analysis was therefore to define where lands were indeed likely to be managed for timber produc- t i o n . w e a s k e d c o u n t y f o r e s t e r s f a m i l i a r w i t h t h e s t u d y fig. . map of the study area d . n . w e a r e t al./forest e c o l o g y a n d m a n a g e m e n t ( ) - s i t e t o m a p t h e i r o p i n i o n o f w h e r e c o m m e r c i a l f o r e s t r y w o u l d a n d w h e r e i t w o u l d n o t l i k e l y b e p r a c t i c e d i n t h e future. they further identified those areas that would not be managed due to some special site feature (not necessarily related to population and land use pres- sures) such as critical species habitats, proximity to water, or buffers. these maps were drawn at a : scale and were digitized and entered as a gis map layer. w e t h e n t e s t e d t h e r e l a t i o n s h i p b e t w e e n t h i s e x p e r t classification of potential commercial timberland (pct) and several factors describing the accessibility and operability of the site and the population density of the area. that is, we posited that the probability of land (l) being labeled as pct is given as: pr(l = pct) =f(xi) = - f(g[x]) ( ) where f is a cumulative distribution function which depends on a function (g) of a vector of explanatory variables (x). we assumed that f had a logistic form which is a close approximation to the normal distribu- tion. the resulting ‘logit’ model has the following form: pr(l = pctix) = - f(g[x]) = eitcxj ( ) the vector x includes the following variables: the p o p u l a t i o n d e n s i t y o f t h e a r e a ( p o p , p e o p l e p e r s q u a r e mile), site index (si, height. at age ), slope ( s l o p e % ) , a n d t w o d u m m y v a r i a b l e s t h a t d e f i n e e a s e of access to the site (ac-easy and ac-hard). ac- e a s y i s e q u a l t o w h e r e s u r v e y c r e w s i n d i c a t e d t h a t , while roads did not exist, they could be easily built; equal to zero otherwise. ac-hard is equal to if roads were deemed difficult or very difficult to build. t h e n u l l c a s e i s d e f i n e d w h e r e r o a d s t o t h e s i t e a l r e a d y exist. taken together, these variables describe the comparative advantage of each site for various land uses. to estimate the model, we define the functional form of g as follows: g(x) = a + bl i’!? +b (s-: +b slype + b x - -easy + b i + -hard ( ) where the signs in parentheses indicate our expecta- t i o n s r e g a r d i n g t h e e f f e c t o f t h e r e f e r e n c e d v a r i a b l e o n t h e p r o b a b i l i t y o f f o r e s t c o v e r . w e e x p e c t t h a t increas- ing population density increases demand for non- forest land uses, that ease of operability (i.e., low s l o p e s ) a l s o r e d u c e s t h e l i k e l i h o o d o f f o r e s t c o v e r , a n d t h a t l e s s a c c e s s i b l e s i t e s a r e m o r e l i k e l y t o b e f o r e s t e d . w e e x p e c t t h e e f f e c t o f s i t e i n d e x t o b e n e g a t i v e g i v e n t h a t h i g h e r q u a l i t y l a n d m a y h a v e c o m p a r a t i v e a d v a n - tage for use in agriculture. p r e v i o u s s t u d i e s h a v e u s e d s i m i l a r m o d e l s t o e x a m - i n e t h e h a r v e s t c h o i c e s o f i n d i v i d u a l l a n d o w n e r s . t h e earliest application (binkley, ) addresses the effects of income, price, education, and costs on the decision to harvest timber. subsequent studies (e.g., d e n n i s , ; k u u l u v a i n e n a n d s a l o , ) h a v e u s e d d i s c r e t e c h o i c e m e t h o d s t o s i m u l t a n e o u s l y a d d r e s s t h e d e c i s i o n t o h a r v e s t a n d t h e q u a n t i t y o f t h e h a r v e s t . t h e p r e s e n t s t u d y i s p e r h a p s m o s t c l o s e l y r e l a t e d t o w e a r and flamm’s ( ) cross-sectional model of harvest choice in a single watershed. their analysis uses site f e a t u r e s ( a s s u m i n g c o n s t a n t d e l i v e r e d p r i c e s ) t o p r o x y f o r t h e c o s t s o f h a r v e s t i n g . t h e p r e s e n t s t u d y i s d i s t i n c t by virtue of its independent variable. the use of an expected land-use is an attempt to address long-run resource allocation. to test this relationship, we examined the land use classification for us forest service permanent inven- t o r y p l o t s l o c a t e d i n t h e s t u d y a r e a . u s i n g t h e s e p l o t s gave us access to several other descriptive variables and allowed us to subsequently estimate the implica- tions of population density on standard measures of timberland area and timber inventories. we overlaid t h e p l o t l o c a t i o n s t h r o u g h t h e g i s t o a s s i g n a p o p u l a - t i o n d e n s i t y t o e a c h p l o t . w e t h e n s c r e e n e d t h e p l o t s t o define the subset of forest plots in private ownership without the aforementioned special features defined b y l o c a l e x p e r t s . w e t h e n d e f i n e d l a s a b i n a r y v a r i a b l e where those plots that were classified as pct were a s s i g n e d l=l; o t h e r w i s e t h e y w e r e a s s i g n e d l=o. plot observations were then used to estimate the logit model defined by eq. ( ) using standard max- imum likelihood estimation applied to individual sur- vey plots.’ to test for the effect of the independent ‘this involves constructing the likelihood function based on the probabilities defined by eqs. ( ) and ( ) and solving for coefficients that yield the highest likelihood that the model generated the data. we used the statistical package limdep (greene, ). techniques are described in detail in maddala ( ). d.n. wear et al./forest ecology and management ( ) - variables on probability that land would be commer- c i a l t i m b e r l a n d w e t e s t t h e s i g n i f i c a n c e o f t h e m o d e l a s a whole using log likelihood ratio tests and for the s i g n i f i c a n c e o f c o e f f i c i e n t s u s i n g t - s t a t i s t i c s . . . estimating the effects of population on forest a r e a a n d t i m b e r i n v e n t o r i e s e q . ( ), i n a d d i t i o n t o b e i n g u s e d t o t e s t o u r h y p o t h - e s i s a b o u t t h e e f f e c t o f p o p u l a t i o n o n t h e p o t e n t i a l f o r c o m m e r c i a l f o r e s t r y , a l s o p r o v i d e s a w a y t o p r e d i c t t h e probability of commercial forestry as a function of p o p u l a t i o n d e n s i t y a n d o t h e r v a r i a b l e s a t a n y l o c a t i o n within the study area. given that the fit of eq. ( ) is s i g n i f i c a n t , t h e n c o e f f i c i e n t e s t i m a t e s a n d m e a s u r e s o f t h e i n d e p e n d e n t v a r i a b l e s c a n b e u s e d t o e s t i m a t e t h e probability that land will be commercial timberland. this estimated probability also defines the share of t h e f o r e s t a r e a w i t h t h i s p o p u l a t i o n d e n s i t y t h a t w o u l d be expected to be commercial forest. to estimate the total effect of population density on timberland area then, we apply the probability of commercial forestry to the area represented by each permanent inventory p l o t i n t h e s t u d y a r e a u s i n g m e t h o d s d e f i n e d b y h a r d i e and parks ( ). in equation form: e(cf) = &&f(x) ( ) i=l where e(cf) is the expected total area of commercial f o r e s t i n t h e s t u d y a r e a , ai t h e a r e a e x p a n s i o n f a c t o r f o r plot i, xi the population density at plot i, and n the n u m b e r o f p l o t s i n t h e a r e a . w e a p p l y t h e s e e s t i m a t e s to all plots in the five-county study area to estimate total effects and calculate effects on a county by c o u n t y b a s i s a s w e l l . w e u s e d t h e s a m e a p p r o a c h w i t h inventory expansion factors to estimate the effect of p o p u l a t i o n d e n s i t y o n g r o w i n g s t o c k i n v e n t o r i e s i n t h e area. . data t h e m e t h o d s d e f i n e d a b o v e r e q u i r e o v e r l a y i n g f o u r sets of spatially referenced data: ( ) expert opinion maps of where forests will and will not likely be managed as commercial forests; ( ) us census data on population density recorded at the block level; ( ) u s f o r e s t s e r v i c e i n v e n t o r y p l o t s a n d t h e i r a s s o c i a t e d data; and ( ) usgs land use categories. . . expert opinion maps expert opinions were developed by the field fores- t e r s a t t h e c o u n t y l e v e l w h o h a v e c o n s i d e r a b l e k n o w l - edge of forest ownership and production. experts mapped their opinions directly onto maps at a : scale for albemarle, greene and nelson c o u n t i e s . b o u n d a r i e s w e r e t h e n d i g i t i z e d a n d s t o r e d a s a map layer in the arc-info geographic information s y s t e m . . . us census population census tiger files were used to map population d e n s i t y ( p e o p l e p e r s q u a r e m i l e ) . d e n s i t y i s d e f i n e d f o r u s c e n s u s b l o c k s . b l o c k s a r e t h e s m a l l e s t g e o g r a p h i c u n i t s t h a t t h e c e n s u s c a l c u l a t e s s t a t i s t i c s f o r . . . f o r e s t i n v e n t o r y d a t a forest inventory plots measured in (thomp- son, ; u.s.d.a. forest service, ) were then overlaid within the gis. we recorded volume esti- m a t e s a n d a r e a a n d v o l u m e e x p a n s i o n f a c t o r s f r o m t h e i n v e n t o r y p l o t d a t a b a s e . w e a l s o r e c o r d e d s l o p e , s i t e index, and access categories for each plot. expert opinion observations and population density could t h e n b e a s s i g n e d t o e a c h i n v e n t o r y p l o t b y o v e r l a y i n g map layers. . . land use w e a l s o u s e d l a n d u s e c l a s s i f i c a t i o n m a p s f r o m t h e u s g s t o i d e n t i f y t h o s e p l o t s t h a t a r e i n b u i l t - u p u r b a n a r e a s . . results the logit model defined by eqs. ( ) and ( ) was estimated using forest survey plots. of these plots, were identified as potential commercial forest. coefficient estimates and standard error ( t a b l e ) i n d i c a t e t h a t p o p u l a t i o n d e n s i t y i s n e g a t i v e l y related to the probability of commercial forest t a b l e coefficient estimates of the logit model defined by eqs. ( ) and ( ), using data from albemarle, greene, and nelson counties. an asterisk indicates significance at the % level. the log likelihood ratio (llr) for testing the overall significance of the model is also reported coefficient intercept pop slope site ac-easy ac-hard llr n= estimate . - . . . - . . . * s e . . * . . . . (throughout this paper significance was tested at p=o.o ). however, all other variables (slope, site index, and access categories) have insignificant coef- f i c i e n t s . w e a l s o t e s t e d t h e s i g n i f i c a n c e o f p o p u l a t i o n density by estimating the logit model without the variable and constructing the log likelihood ratio statistic for the constrained model (chi-squared dis- tribution with one degree of freedom). the calculated statistic ( . ) is greater than the critical value ( . ), so we again reject that the variable has no e f f e c t . a s a l l o t h e r v a r i a b l e s a r e i n s i g n i f i c a n t , w e e s t i m a t e d a c o n d e n s e d m o d e l w i t h o n l y p o p u l a t i o n d e n s i t y a s a n e x p l a n a t o r y v a r i a b l e t o a p p l y t h e p r o b a b i l i t y m o d e l t o area and volume expansion factors using eq. ( ). for this model, the intercept was . , the population density coefficient was - . , and both coefficients were significant. we tested the overall significance of both the original model and the condensed model using a log likelihood ratio test (chi-squared distribu- tion, with degrees of freedom equal to the number of explanatory variables). for both models we reject no explanatory power (see table ). t o f u r t h e r e x a m i n e t h e e f f e c t s o f p o p u l a t i o n d e n s i t y on timber production, we plotted the probability of forest being commercial timberland as a function of p o p u l a t i o n d e n s i t y . f i g . s h o w s t h e e x p e c t e d i n v e r s e r e l a t i o n s h i p b e t w e e n p o p u l a t i o n d e n s i t y a n d p c t . a t a p o p u l a t i o n d e n s i t y o f , t h e p r o b a b i l i t y o f p c t i s . . the probability declines as population density increases and approaches zero as density reaches ca. people per square mile (psm). the odds of d . n . w e a r e t al./forest e c o l o g y a n d m a n a g e m e n t ( ) - population density fig. . the predicted probability that forest is commercial timberland as a function of population density. being commercial forest land are roughly : at a population density of people psm and the prob- ability of commercial forestry is > . at ca. people p s m . the next step in the analysis was to estimate the predicted probability of commercial forestry for all s u r v e y p l o t s i n t h e p l a n n i n g d i s t r i c t a s a w h o l e . f i g . s h o w s t h e d i s t r i b u t i o n o f p l o t s b y p r o b a b i l i t y v a l u e s . thirty percent of the plots have probability values of . or greater and % have probability values of . o r g r e a t e r . h o w e v e r , % o f t h e p l o t s h a v e p r o b a b i l i t y values that are ~ . , indicating a ~ : chance of commercial forestry. area and volume expansion factors for all plots were then used to calculate the expected commercial g - e c. ) ge - in - a ij ‘lo- (. ) e ) . ( . ) o- i i % b b p !! b a x a prob (commercial forest) ) ~ o! .- a .? fig. . number (proportion) of inventory plots by the predicted probability that forest is commercial timberland. d . n . w e a r e t &./forest e c o l o g y a n d m a n a g e m e n t ( ) - table area of timberland in the study area for the survey. subsequent columns show the effects of ( ) removing lands in public ownership, ( ) removing lands classified as urban, and ( ) reducing availability related to increasing population density area land area survey acres minus public minus urban minus pop. effect t o t a l albemarle fluvanna greene louisa nelson forest area and associated growing stock inventories f o r e a c h c o u n t y i n t h e s t u d y a r e a . p r o j e c t i o n s o f f o r e s t area are shown in table . the first column in table lists the total forest area estimated by forest survey p l o t s i n t h e p l a n n i n g d i s t r i c t ( . a c r e s ) . w e n e x t subtract the public lands from the area. this reduces total acreage by ca. . % to a total of acres. n e l s o n c o u n t y h a s a d i s p r o p o r t i o n a t e l y l a r g e s h a r e o f the public forest land (ca. . %) while fluvanna has very little public forest land (ca. . %). the area of land in urban land uses (usgs codes - ) is then excluded, removing another % of the forest area and leaving acres. we then applied eq. ( ) to t h e s e r e m a i n i n g a c r e s t o c a l c u l a t e t h e e f f e c t s o f p o p u - lation density on the availability of rural private timberland. comparing columns three and four in table s h o w s t h e t o t a l e f f e c t o f p o p u l a t i o n d e n s i t y o n f o r e s t land availability. these are also charted in fig. . population effects reduce by an additional % the estimate of available forest land in the thomas jef- ferson planning district . removing urban and public lands and adjusting forest area for population effects results in a total reduction of available forest area by %. the effects are highest in percentage terms for fluvanna and greene counties (- . and - . %, respectively) and least for nelson county (- . %). t h e e f f e c t s o n g r o w i n g s t o c k i n v e n t o r i e s a r e s h o w n i n table and are similar to effects found for timberland area. pine volume is reduced by the greatest amount ( %). the growing stock inventory of other soft- woods is reduced by % from forest inventory v a l u e s . , ; ua u c i f minus public minus urban minus pop. effect scenario b . l a n d a r e a b y c o u n t y z; u !! oe albemarle fllwaillla gv.?elle louisa ndsoll county fig. . total timberland in the thomas jefferson planning district: ( ) defined by the inventory; ( ) after screening public lands; ( ) additional screening of urban lands; and ( ) additional screening based on the predicted probability of commercial timberland. d . n . w e a r e t al/forest e c o l o g y a n d m a n a g e m e n t ( ) - table growing stock volumes in the study area for the survey. subsequent columns show the effects of ( ) removing lands in public ownership, ( ) removing lands classified as urban, and ( ) reducing availability related to increasing population density (a) pine volume survey minus public minus urban minus pop. effect thousand cubic feet t o t a l albemarle fluvanna greene louisa nelson (b) other softwood volume t o t a l albemarle pluvanna greene louisa nelson (c) soft hardwood volume t o t a l albemarle fluvanna greene louisa nelson (d) hard hardwood volume total albemarle fluvanna greene louisa nelson . future population growth density areas. we did not attempt to develop and apply a sophisticated model of urban and suburban populations will likely continue to expand in the expansion for this exercise; rather, we examined a thomas jefferson planning district. to examine the simple model that expanded populations by an equal p o t e n t i a l e f f e c t s o n f o r e s t s w e e s t i m a t e d t h e n e t e f f e c t p r o p o r t i o n a c r o s s t h e e n t i r e s t u d y a r e a . t h e s e projec- t h a t v a r i o u s l e v e l s o f p o p u l a t i o n g r o w t h m i g h t h a v e o n t i o n s t h e r e f o r e d o n o t r e p r e s e n t f o r e c a s t s , b u t t h e y d o commercial forest area using the methods developed allow for a qualitative examination of the conse- here. we increased the population density for indivi- quences of population growth. dual plots and recalculated the probability of com- r e s u l t s o f t h e p o p u l a t i o n s i m u l a t i o n s a r e c h a r t e d i n mercial timberland using eq. ( ). these values were fig. , with timberland plotted against population then used to screen the survey data using eq. ( ). (both are charted in terms of percentage change from population growth is a spatially defined process their present values). the results show an approxi- with growth concentrated at the periphery of high m a t e l y l i n e a r r e l a t i o n s h i p b e t w e e n p o p u l a t i o n g r o w t h d.n. wear et al/forest ecology and management ( ) - percent of population fig. . percent change in timberland as a function of change in population density. and timberland declines in timberland area. for each % increment in population, timberland area drops by roughly %. as fig. indicates, a large share of timberland is in areas with a very low population density (the two right-most bars in fig. ). there is relatively little timberland area in the transition popu- lation densities of - psm. as a result, the existing estimate of timberland area may be fairly robust to moderate expansion in population density. . conclusion population growth may influence forests and for- estry in several direct and indirect ways. we have examined the net effect that population density may have on the availability of forests for timber produc- t i o n . w h i l e p e r h a p s o n l y a f i r s t a p p r o x i m a t i o n o f t h e s e e f f e c t s , o u r r e s u l t s i n d i c a t e t h a t c h a n g e s a t t h e urban- rural interface may have important influence on the future supply of timber. because population data are so readily available in spatially referenced form (i.e. t h r o u g h t h e u s c e n s u s t i g e r / l i n e f i l e s ) , t h i s a p p r o a c h may prove especially useful for examining the effects o f s u b u r b a n i z a t i o n o n t i m b e r p r o d u c t i o n o v e r b r o a d e r a r e a s . we have tested for and estimated the relationship between population density and the potential for c o m m e r c i a l f o r e s t r y . t h e r e s u l t s i n d i c a t e a c o n t i n u o u s r e l a t i o n s h i p , b u t a l s o s u g g e s t s s o m e i m p o r t a n t t h r e s h - o l d s . o n e i s t h a t t h e p r o b a b i l i t y o f f o r e s t m a n a g e m e n t approaches zero at ca. people psm. at psm there is a % chance of commercial forestry. at ca. psm the odds are : that commercial forestry w i l l b e p r a c t i c e d a n d a t p s m t h e r e i s a % c h a n c e . the implication is that a transition between rural and urban use of forests occurs between and psm, s u g g e s t i n g t h a t f u t u r e r e s e a r c h s h o u l d f o c u s o n u n d e r - s t a n d i n g l a n d u s e d y n a m i c s a n d r e s o u r c e m a n a g e m e n t in this zone. t h e r e s u l t s o f t h i s s t u d y i n d i c a t e t h a t r a w e s t i m a t e s of timberland -based on physical criteria alone - may substantially overstate the availability of timber. we estimated that population effects reduced timberland a r e a a n d g r o w i n g s t o c k v o l u m e s b y r o u g h l y % f r o m their measured values. while only a first approxima- t i o n o f t h e e f f e c t s o f p o p u l a t i o n g r o w t h o n f o r e s t l a n d s , t h e s e r e s u l t s i n d i c a t e t h a t t h e e f f e c t s c a n b e s u b s t a n - tial. of course these results are developed for only a small area and would therefore benefit from replica- t i o n i n o t h e r a r e a s . i t w o u l d b e u s e f u l t o k n o w w h e t h e r t h e s e r e l a t i o n s h i p s h o l d g e n e r a l l y . d o t h e y , f o r exam- d.n. wear et al./forest ecology and management ( ) - ple, differ in areas with different topography, land- ownership pattern, or relative resource values? the study also illustrates the value of linking bio- physical forest inventories with social data. this l i n k a g e c o u l d b e i m p r o v e d b y r e c o r d i n g c e n s u s b l o c k i d e n t i f i e r s f o r e a c h p l o t i n a f o r e s t s u r v e y . t h i s w o u l d b o t h i m p r o v e t h e p r e c i s i o n o f s u b s e q u e n t a n a l y s e s a n d allow for direct screening of inventories without link- age to a gis. more extensive study in this area could l e a d t o s i g n i f i c a n t i m p r o v e m e n t s i n o u r u n d e r s t a n d i n g of timber supply from private lands and the general expression of social phenomena on forested land- s c a p e s . references binkley, c.s., . timber supply from nonindustrial forests. bulletin no. , yale university, school of forestry and environmental studies, new haven, connecticut. dennis, d.f., . a profit analysis of the harvest discussion using pooled time series and cross-sectional data. journal of environmental economics and management , - . greene, w.h., . limdep user’s manual and reference guide (version . ). econometric software, inc., bellport, ny. hardie, i.w., parks, p.j., . individual choice and regional acreage response to cost-sharing in the south, - . forest science (l), - . harris, t., deforest, c., . policy implications of timberland loss, fragmentation, and urbanization in georgia and the southeast. in: wear, d.n., talmon, j. (ed.), policy and forestry: design, evaluation and spillovers. proceedings of the southern forest economics workshop. duke university, durham, nc, pp. - . kuuluvainen, j., salo, j., . timber supply and life cycle harvest of nonindustrial private forest owners: an empirical analysis of the finnish case. forest science ( ), l- . maddala, g.s., . limited dependent and qualitative variables in econometrics. cambridge university press, new york. marcin, t.c., . demographic change: implications for forest management. journal of forestry ( l), . shands, w.e., . problems and prospects at the urban-forest interface. journal of forestry ( ), - . thompson, m.t., . forest statistics for the northern piedmont of virginia. resource bulletin se- , usda forest service, southeastern forest experiment station, asheville, nc, . wear, d.n., flamm, r.o., . public and private forest disturbance regimes in the southern appalachians. natural resource modeling ( ), - . u.s.d.a. forest service, field instructions for the southeast. usda forest service, southeastern forest experiment station, forest inventory and analysis work unit, asheville, nc, . www.ajog.org smfm abstracts transvaginal ultrasound findings and mode of delivery in placenta previa patrizia vergani , ilaria pozzi , sara ornaghi , massimiliano greco , francesca maria russo , ilaria follesa , university of milano-bicocca, depart- ment of obstetrics and gynecology, monza, milan, italy objective: there is consensus that a placenta previa that totally or partially overlies the internal os requires delivery by caesarean, however the mode of delivery when the placenta lies in proximity to the internal os is more controversial. three retrospective studies concluded that a placental edge-os distance greater than mm permitted a safe vaginal delivery. conversely there is no concordance about the treatment of women with a placental edge-os distance between and mm. we have related transvaginal ultrasound findings with mode of delivery and outcomes in cases of complete or partial placenta previa. study design: retrospective review of consecutive singleton pregnancies with placenta previa confirmed by a transvaginal ultrasound performed at � days of delivery. excluded were cases with a placental-to-internal os distance of - mm (n� ). cases in which the placental edge overlapped the internal cervical (n� ) underwent cesarean section (cs). the other cases were allowed to labor and included group (n� ) with a placental edge-to-internal os distance of - mm and group (n� ) with a distance of - mm. likelihood of cs and other obstetric variables were compared using chi-square and one-way anova where appropriate. results: mean scan-to-delivery interval was days. the group and dif- fered for maternal age ( � vs � years, p� . ) but had similar rates of nulliparity ( % vs %). rates of cs ( % vs %, or� . , % ci - ) and rates of bleeding before labor ( % vs %, or� . , % ci . - . ) were sig- nificantly higher in group than group . blood loss at delivery ( � vs � ml, p� . ) and rate of severe postpartum hemorrhage ( % vs %, or � . , % ci . - . ) were similar in the groups. conclusion: patients with marginal placenta previa and a placental edge- to-os distance � mm should be allowed to labor as more than two-thirds will deliver vaginally without increased risk of hemorrhage. - /$ - see front matter doi: . /j.ajog. . . umbilical cord gases and neuro-developmental disability in very preterm births alan tita , joseph biggio , suzanne p. p. cliver , fred biasini , richard rector , william andrews , university of alabama at birming- ham, obstetrics and gynecology, birmingham, alabama, university of alabama at birmingham, psychology, birmingham, alabama objective: to assess the relationship between umbilical artery acid-base sta- tus and major neurodevelopmental disability at age years among very preterm births (vptb). study design: secondary analysis of a prospective cohort of vptbs be- tween and weeks= from - . arterial cord gas parameters � th %tile for ph (� . ), base excess (� � . meq/l), bicarbonate (� meq/l), po (� mm hg) and � th percentile for pco (� mm hg) were considered abnor- mal. neurodevelopmental disability was defined as iq � , or the composite of iq� , cerebral palsy, blindness, deafness or other major deficits (abnormal bal- ance, impaired coordination, dystonia and seizure disorder). logistic regression was used to adjust for race and parental iq and (in additional analyses) for gesta- tional age (ga). results: of survivors with mean ga of . weeks were evaluated at mean age of . years. in unadjusted analyses, ga (inversely) and abnormal ph, base excess and pc , but not bicarbonate or po , were associated with long-term disability. multivariable analyses with and without adjustment for ga (as a contin- uous variable) are presented in the table. not shown, each week increase in ga, was associated with a - % significant decrease in adjusted risks of iq� and composite major disability. children with cord gas abnormalities had higher rates of disability within sub-groups of earlier and later ga. conclusion: the risk of long-term major neurodevelopmental disability as- sociated with abnormal cord ph and base excess remains considerably increased (over -fold) after accounting for the strong association with ga. however, a much larger cohort would be needed to conclusively assert the suggested association be- tween cord gas abnormalities and long-term disability. - /$ - see front matter doi: . /j.ajog. . . suppleme polysubstance abuse by women in a methadone treatment program increases the risk for preterm birth christopher almario , neil seligman , edward hayes , kevin dysart , vincenzo berghella , jason baxter , thomas jefferson university, obstetrics and gynecology, philadelphia, pennsyl- vania, thomas jefferson university/nemours foundation, neonatology, phila- delphia, pennsylvania objective: to determine whether the increased rate of preterm birth (ptb) among women in a methadone treatment program is associated with supplemen- tation of methadone with additional substances. study design: case-control study of opiate-addicted gravid women in a methadone treatment program. we defined cases and controls as those with a preterm or term delivery, respectively. women who delivered a live-born neonate between - were included. we defined “supplements to methadone” to include alcohol (by self report) and any illicit drugs, except marijuana, found on a urine drug screen within two weeks of delivery. odds ratio (or) and % confi- dence interval (ci) for ptb were calculated for each substance individually and multiple substances used together. results: we analyzed opiate-addicted gravid women on methadone. the rate of ptb was . %. the most commonly used “supplements” to methadone were opiates ( . %), cocaine ( . %), benzodiazepines ( . %), alcohol ( . %), and barbiturates ( . %). we found no elevated risk for ptb in women who solely supplemented methadone with the above individual substances when compared to those not supplementing. those using methadone with two or more “supplements” near the time of delivery were at increased risk for ptb, and there appeared to be an additive effect (table). tobacco use was high ( . %) and therefore not included as a “supplement” in our model. conclusion: opiate-addicted gravid women on methadone treatment who supplement with illicit drugs or alcohol are at increased risk for ptb, and the risk is dependent on the number of “supplements” used. no. of “supplements” to methadone preterm birth or ( % ci) . ( . - . ) . ( . - . ) � . ( . - . ) - /$ - see front matter doi: . /j.ajog. . . is there any relation between development of non reassuring fetal heart rate pattern and acutely increased uterine artery vascular flow resistance during dinoprostone use in postterm pregnancies? deniz karcaaltincaba , derya akdag , omer kandemir , seda guvendag-guven , serdar yalvac , ali haberal , etlik women’s hospital, ankara, turkey objective: development of non reassuring fetal heart rate pattern(nrfhrp) during labour is common indication for emergency cesarian section. sustained release form of dinoprostone is frequently used for induction of labour in posterm pregnancies. in this prospective cohort study we aimed to investigate relation be- tween development of nrfhrp and changes in doppler parameters of fetal and uterine arteries during induction of labor with vaginal dinoporostone . study design: totally postterm pregnancies(who completed gesta- tional weeks) were included. patients(n� ) who had successful spontaneous vaginal delivery were recruited as control group and patients( n� ) who under- went c sections due to nrfhrp were recruited as study group. remaining patients who underwent cesarian section because of other causes were excluded from final analysis. associated risk factors were recorded. doppler param- eters(ri,pi, s/d) of umbilical, middle cerebral and uterine arteries were measured before and - hours after dinoprostone application during relaxation period of contractions. results: there was no statiscal difference with regard to age and gestational week between study and control groups. results of basal doppler analysis of uterine and fetal arteries were not statistically different. after vaginal dinoprostone appli- cation there was statistically significant increase in uterine arteryri(uari) in study group( . ) compared to control group( . ) (p� . ). receiveroperatingchar- acteristic(roc) curve identified an uari increase value of . as optimal threshold for prediction of nrfhrp with . %sensitivity and . %specificity. logistic regression analysis demonstrated that increase of uari was predictive for nrfhr- p(odds ratio(ci) . ( . - . )) conclusion: increased uari more than . after sustained release of dino- prostone in postterm pregnancies may allow earlier prediction of development of nrfhrp. increased uari associated with dinoprostone use may lead poor perfu- sion of fetoplasental unit during labour which may be possible cause of emergency cesarean section. - /$ - see front matter doi: . /j.ajog. . . nt to december american journal of obstetrics & gynecology s sara_ornaghi highlight policy brief a small percentage of family physicians report time devoted to research jennifer r. voorhees, md, imam m. xierali, phd, andrew w. bazemore, md, mph, robert l. phillips, jr., md, msph, carlos r. jaén, md, phd, and james c. puffer, md despite calls by family medicine organizations to build research capacity within the discipline, few fam- ily physicians report research activity. policy that supports efforts in family medicine research and in- creases awareness of opportunities for primary care research in the practice setting is essential for fam- ily medicine to expand its scholarly foundations. ( j am board fam med ; : – .) for decades, family medicine professional organi- zations have called for increasing the discipline’s capacity for research and scholarly work. , there is widespread recognition of the need for relevant research in the primary care setting to improve patient and population outcomes, and family physicians are uniquely poised to conduct such research because they provide the largest volume of health care of any single specialty (nearly million patient visits annually). despite this acute awareness and need, research remains a particular challenge to the profession, and family physicians are minimally involved with the na- tional institutes health compared with other specialties. , of american board of family medicine main- tenance of certification examination candidates from to (n � , ), . % reported spending any time on research, with . % spending � % of their time, . % spending � % but � %, and . % spending � % of their time on research (figure ). urban family physicians were more likely to do research compared with rural physicians ( . % vs . %, respectively). men were more likely to report any research activity ( . % vs . %), but women who performed research were this article was externally peer reviewed. from thomas jefferson university, philadelphia, pa (jrv); association of american medical colleges (aamc), washington, dc (imx); the robert graham center for policy studies in family medicine and primary care, washington, dc (awb, rlp); and the american board of family medicine, lex- ington, ky (crj, jcp). funding: support was provided by the american board of family medicine, which contracts annually for health poli- cy/health services research conducted by the robert gra- ham center for studies related to maintenance of certifica- tion and quality. conflict of interest: none declared. corresponding author: andrew w. bazemore, md, mph, the robert graham center for policy studies in family medicine and primary care, connecticut avenue, nw suite , washington, dc (e-mail: abazemore@aafp.org). the paper was submitted for publication while dr. xierali was at the american academy of family physicians. he is currently manager for public health and diversity data ini- tiatives at the association of american medical colleges. figure . percentage of family physicians reporting time devoted to research in – . doi: . /jabfm. . . policy brief o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n ja n u a ry . d o w n lo a d e d fro m http://www.jabfm.org/ more likely than men to report devoting � % of their time ( % vs %). thirty-one percent of full-time faculty and % of part-time faculty mem- bers participated in research, compared with . % of nonfaculty members. participation was relatively equal across ages. the effort to promote translation of research into primary care requires more family physi- cians to be trained as researchers and translators. family medicine organizations should renew support to build research capacity and push fam- ily physicians to incorporate scholarly activity into their practice behavior through targeted continuing medical education/maintenance of certification activities and through assistance with federally mandated quality improvement initiatives. research advocates and governmental organizations, particularly the national institutes of health, should increase the funds available to support a primary care research agenda to enable broader participation of family physicians dedicating sufficient time to im- portant research endeavors. references . dickinson wp, stange kc, ebell mh, ewigman bg, green la. involving all family physicians and family medicine faculty members in the use and generation of new knowledge. fam med ; : – . . what does it mean to build research capacity? fam med ; : – . . hsiao cj, cherry dk, beatty pc, rechtsteiner ea. national ambulatory medical care survey: summary. natl health stat report ;( ): – . . lucan sc, phillips rl jr, bazemore aw. off the roadmap? family medicine’s grant funding and com- mittee representation at nih. ann fam med ; : – . . ley tj, rosenberg le. the physician-scientist career pipeline in : build it, and they will come. jama ; : – . jabfm january–february vol. no. http://www.jabfm.org o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n ja n u a ry . d o w n lo a d e d fro m http://www.jabfm.org/ biographical feature eileen l. randall, ph.d. alexander j. mcadam, editor, journal of clinical microbiology department of laboratory medicine, boston children’s hospital, boston, massachusetts, usa dr. eileen l. randall was an accomplished clinical microbiol-ogist when the field was still developing its identity. as her colleague and friend dr. josephine morello recently said, “eileen randall was a distinguished clinical microbiologist even before most microbiologists knew what clinical microbiology was. she was in the forefront of this nascent field, widely imparting her vast knowledge of infectious microorganisms.” her contributions in- cluded research in bacteriology, the clinical care that her labora- tories performed, and, perhaps foremost, her educational work and mentorship of clinical microbiologists. dr. randall received her b.s. in medical technology from ohio state university in . she attended graduate school in micro- biology at the jefferson medical college in philadelphia, pa. her master’s dissertation was titled “studies on the morphology, phys- iology, and immunology of endamoeba histolytica, endamoeba coli, and endamoeba invadens.” her ph.d. work was done with the guidance of dr. henry stempen. dr. randall turned from parasi- tology to bacteriology, which remained her primary area of re- search throughout her life. she completed her ph.d. in , on “studies on mima-like and herellea-like organisms.” after her studies, dr. randall became director of the microbi- ology laboratory at thomas jefferson university hospital and was appointed in the departments of microbiology and pathology. in , she became director of the microbiology laboratory at evanston hospital. she rose to become professor of pathology at the northwestern university feinberg school of medicine and senior attending in medicine at evanston hospital. mr. richard gottschall, who was manager of microbiology at evanston hospi- tal, said “because she started as a bench-level technologist, she always had a profound understanding of the issues facing the techs published ahead of print august copyright © , american society for microbiology. all rights reserved. doi: . /jcm. - jcm.asm.org journal of clinical microbiology p. – november volume number o n a p ril , a t c a r n e g ie m e l l o n u n iv l ib r h ttp ://jcm .a sm .o rg / d o w n lo a d e d fro m http://dx.doi.org/ . /jcm. - http://jcm.asm.org http://jcm.asm.org/ in the lab every day and for that she was respected and appreci- ated.” dr. randall was a leader in the national and local asm. she was chair of the asm clinical division from to and served on several committees, including the american board of medical mi- crobiology, the board of education and training, and the foun- dation for microbiology lecturer series ( ). dr. randall was the secretary of the eastern pennsylvania branch of the asm from to , and she was on the steering committee in when the clinical microbiology section was formed in the eastern penn- sylvania branch ( ). she directed and participated in many work- shops and symposia in the clinical microbiology branch. dr. ran- dall was also the president of the illinois society for microbiology. chief among dr. randall’s contributions were those in educa- tion. she started a master’s degree program in clinical microbiol- ogy in philadelphia, pa. dr. james poupard recalls, “she applied all her talents of persuasion to convince faculty and administra- tion of the thomas jefferson university graduate school to estab- lish a program. it was a big struggle on her part, but she finally got approval in august of , just month before classes were to start. the program was a complete success and had a significant effect on the quality of clinical microbiology in philadelphia.” dr. randall and dr. morello taught a traveling workshop on staphy- lococci and streptococci sponsored by the asm, and dr. morello recalls, “many times. . . the days would be prolonged, because she invariably got caught up in answering questions about any topic of diagnostic microbiology raised by the attendees.” dr. randall was a mentor to those interested in clinical micro- biology. dr. gary doern recalls that when he knew her, early in his career, “she was not only an extraordinarily gifted clinical micro- biologist; she was generous in spirit, full of enthusiasm and a truly wonderful teacher. indeed, i cannot remember a single instance when we were together that she didn’t teach me something.” dr. paul schreckenberger says, “dr. randall befriended me when i first arrived to work at the university of illinois chicago in . she encouraged me (actually pushed me) to go back to graduate school and get my ph.d. degree because she always felt that i had the calling to be a laboratory director. eileen was proud as a parent when i fulfilled my dream of becoming a laboratory director.” dr. randall published over articles, mainly in clinical bac- teriology. her early work included extensive analyses of the bio- chemical characteristics of clinical isolates of members of the mi- mae tribe (now reclassified), which included bacteria that mimic the morphology of neisseria in clinical specimens. biochemical identification of organisms was a lasting interest, and one of her later publications is an evaluation of a system for identifying en- terococcus. dr. randall published a series of studies on improving and validating methods of blood culture and articles on detection of pharyngeal streptococcus pyogenes. these papers emphasize the clinical utility of the methods, but they are also striking for their careful analysis of laboratory concerns, including ease of use, workflow, and instrument requirements. her achievements and contributions were recognized with sev- eral awards ( ). she received the distinguished alumni award from thomas jefferson university, graduate school of biomedi- cal sciences, in . this award “focuses on the professional ac- complishments of alumni and helps to foster communication be- tween current and former graduate students.” her professional accomplishments were recognized with the significant contribu- tors to clinical microbiology award from the south central as- sociation for clinical microbiology in and the pasteur award from the illinois society of microbiology in . dr. randall was an important voice in shaping the field of clinical microbiology. dr. randall passed away on december , , after a long illness that she met with courage. her early death was a great loss to her colleagues, friends, and family. she left an important legacy through her impact on our field. dr. tom thompson, who was a student and friend of dr. randall, said, “the commitment and passion that we in clinical microbiology have today has flowed, in large part, from dr. randall’s career and life. she was smart, compassionate, unselfish, fair, loyal and fiercely dedicated. when i look at our profession today, that is what i see.” acknowledgments dr. tom thompson generously provided biographical information about dr. randall and the photograph of her and also made many helpful sug- gestions about sources of information. dr. james a. poupard provided biographical information about dr. randall and her role in the history of the eastern pennsylvania branch of the asm. those who provided their memories of dr. randall that are quoted above are also gratefully ac- knowledged. references . morello ja, fernandes p. . obituary of eileen l. randall. asm news : . . poupard ja. . a history of microbiology in philadelphia: to , st ed. xlibris corporation, bloomington, in. selected bibliography sanders e, sweeney fj, friedman ea, boring jr, randall el, pold ld. . an outbreak of hospital-associatd infections due to salmonella derby. jama : – . prince ln, randall el, lentz jw, shapiro lh. . the evaluation of oxytetracycline in the treatment of gonorrhea in the prenatal patient, a pre- liminary report. am. j. obstet. gynecol. : – . randall el, linegar e. . isolates of members of the mimeae tribe. ann. n. y. acad. sci. : – . randall el. . increasing incidence of fungal infections. del. med. j. : – . salventi jf, davies ta, randall el, whitaker s, waters jr. . effect of blood dilution on recovery of organisms from clinical blood cultures in me- dium containing sodium polyanethol sulfonate. j. clin. microbiol. : – . schwabe ld, small mt, randall el. . comparison of testpack strep a test kit with culture technique for detection of group a streptococci. j. clin. microbiol. : – . kim mj, gottschall rl, schwabe ld, randall el. . effect of agitation and frequent subculturing on recovery of aerobic and facultative pathogens by roche septi-chek and bactec blood culture systems. j. clin. microbiol. : – . kim mj, weiser m, gottschall s, randall el. . identification of strep- tococcus faecalis and streptococcus faecium and susceptibility studies with newly developed antimicrobial agents. j. clin. microbiol. : – . schwabe ld, randall el, miller-catchpole r, squires ci, gottschall rl. . a comparison of oxoid signal with nonradiometric bactec nr- for detection of bacteremia. diagn. microbiol. infect. dis. : – . schwabe ld, gobbo af, gottschall rl, randall el. . comparison of testpack plus strep a with selective and nonselective culture media for detec- tion of group-a streptococci. diagn. microbiol. infect. dis. : – . biographical feature november volume number jcm.asm.org o n a p ril , a t c a r n e g ie m e l l o n u n iv l ib r h ttp ://jcm .a sm .o rg / d o w n lo a d e d fro m http://jcm.asm.org http://jcm.asm.org/ 	biographical feature 	acknowledgments 	references © macmillan magazines ltd the thomas jefferson paternity case the dna analysis of y-chromosome haplo- types used by foster et al. to evaluate thomas jefferson’s alleged paternity of eston hemings jefferson, the last child of his slave sally hemings, is impressive. how- ever, the authors did not consider all the data at hand in interpreting their results. no mention was made of thomas jeffer- son’s brother randolph ( – ), or of his five sons , . sons of sally hemings con- ceived by randolph (or by one of his sons) would produce a y-chromosome analysis identical to that described by foster et al. further collaborative data (for example, the whereabouts of any of those who might have been involved at conception) are needed to confirm that jefferson did indeed father his slave’s last child, as claimed in the title. we know thomas jefferson was there, but how about randolph jefferson and his sons? david m. abbey health science center, university of colorado, teakwood court, fort collins, colorado , usa e-mail: dabbey @aol.com if the data of foster et al. are accurate, then any male ancestor in thomas jefferson’s line, white or black, could have fathered eston hemings. plantations were inbred communities, and the mixing of racial types was probably common. as slave families were passed as property to the owner’s off- spring along with land and other property, it is possible that thomas jefferson’s father, grandfather or paternal uncles fathered a male slave whose line later impregnated another slave, in this case sally hemings. sally herself was a light mulatto, known even at that time to be thomas jefferson’s wife’s half sister , . gary davis evanston hospital, ridge avenue, evanston, illinois , usa foster et al. reply — it is true that men of randolph jefferson’s family could have fathered sally hemings’ later children. space constraints prevented us from expanding on alternative interpretations of our dna analysis, including the interesting one proposed by davis. the title assigned to our study was misleading in that it repre- sented only the simplest explanation of our molecular findings: namely, that thomas jefferson, rather than one of the carr broth- ers, was likely to have been the father of eston hemings jefferson. it had been suggested to us earlier (by herbert barger, who also helped to recruit the descendants of field jefferson who par- ticipated in our study) that isham jefferson, son of thomas jefferson’s brother ran- dolph, might have been the father of one or more of sally hemings’ children. barger’s proposal was based on a statement that isham was reared by thomas jefferson; he suggested that isham could have been at monticello or at snowden (snowden was across the james river from scottsville, which is about miles from monticello) when eston hemings was conceived. but it is not known for certain that isham was at monticello at that time, whereas it is docu- mented that thomas jefferson was. from the historical knowledge we have, we can- not conclude that isham, or any other member of the jefferson family, was as likely as thomas jefferson to have fathered eston hemings. we know from the historical and the dna data that thomas jefferson can neither be definitely excluded nor solely implicated in the paternity of illegitimate children with his slave sally hemings. when we embarked on this study, we knew that the results could not be conclusive, but we hoped to obtain some objective data that would tilt the weight of evidence in one direction or another. we think we have provided such data and that the modest, probabilistic interpretations we have made are tenable at present. e. a. foster*, m. a. jobling†, p. g. taylor†, p. donnelly‡, p. de knijff§, r. mieremet§, t. zerjal¶, c. tyler-smith¶ * gildersleeve wood, charlottesville, virginia , usa e-mail: eafoster@aol.com †department of genetics, university of leicester, adrian building, university road, leicester le rh, uk ‡department of statistics, university of oxford, south parks road, oxford ox tg, uk §mgc department of human genetics, leiden university, po box , ra leiden, the netherlands ¶department of biochemistry, university of oxford, south parks road, oxford ox qu, uk . foster, e. a. et al. nature , – ( ). . mayo, b. & bear, j. a. jr thomas jefferson and his unknown brother (univ. press of virginia, charlottesville, ). . brodie, f. m. thomas jefferson: an intimate history (norton, new york, ). . randall, w. s. thomas jefferson: a life (holt, new york, ). . history of todd county, kentucky ( ). scientific correspondence nature | vol | january | www.nature.com qualitative adjustment. rhea heart mass ( grams) conforms to that predicted for a mammal of the same body size and aero- bic power. volume densities of mitochon- dria in leg muscles are similar to those of mammals of the same size and aerobic capacity, whereas those in the relatively inactive flight muscles are only half as large and correspond to values reported for less aerobic mammals (table ). given that % of the rhea’s body mass consists of leg musculature, rates of oxygen uptake by mitochondria per millilitre dur- ing locomotion at the aerobic maximum appear to fall within the range reported for mammals. capillary densities in the rhea leg and flight muscles, like the mitochon- drial volume densities, also parallel values reported for the muscles of athletic and less mobile mammals. in contrast to the apparent conservation of structure–function relationships in most of the respiratory system, our results sug- gest that there are basic differences in the performance of the lungs of birds and mammals. we could not measure the lung volumes of the rheas directly, but in birds these are normally slightly more than half of those of mammals of the same mass , . the rheas therefore achieved maximum oxygen flux rates, equal to those of the most aerobic mammals of their size, using lungs that are probably only half as large. this supports the general belief that avian lungs provide relatively more function per unit volume than mammalian lungs , . although the aerobic limits of rheas and athletic mammals are similar, the metabolic power available in practice, and their func- tional needs, are not. unlike dogs, horses and other athletic mammals that sustain high metabolic rates for hours during pre- dation and migration, rheas do little or no sustained running and are poor at dissipat- ing metabolic heat loads . rheas have apparently not been under strong selective pressures like those that promoted the aero- bic power of extant running mammals. large flightless birds lead fairly inactive lives, and may have lost the ability to fly primarily because of a lack of predation. why rheas have an aerobic power that greatly exceeds their apparent functional needs remains a puzzle. matthew w. bundle*, hans hoppeler†, ruth vock†, june m. tester*, peter g. weyand* *museum of comparative zoology, harvard university, bedford, massachusetts , usa e-mail: pweyand@oeb.harvard.edu †department of anatomy, university of bern, buhlstrasse , ch bern , switzerland . seeherman, h. j., taylor, c. r., maloiy, g. m. o. & armstrong, r. b. respir. physiol. , – ( ). . lasiewski, r. c. & dawson, w. r. condor , – ( ). . ellington, c. p. j. exp. biol. , – ( ). . brackenbury, j. h. & el-sayed, m. s. j. exp. biol. , – ( ). . kooyman, g. l. & ponganis, p. j. j. exp. biol. , – ( ). . weibel, e. r., taylor, c. r. & hoppeler, h. proc. natl acad. sci. usa , – , ( ). . maina, j. n. & king, s. a. j. anat. , – ( ). . dubach, m. respir. physiol. , – ( ). . piiper, j. & scheid, p. in comparative physiology (eds bolis, l., schmidt-nielsen, k. & maddrell, s. h. p.) – (north- holland, ). . taylor, c. r., dmi’el, r., fedak, m. & schmidt-neilsen, k. am. j. physiol. , – ( ). a key gating charge interaction required for slow inactivation of the navab bacterial sodium channel a sunday, february , core metadata, citation and similar papers at core.ac.uk provided by elsevier - publisher connector stabilized by surrounding hydrophobic residues. we propose that mutations of the asparagines affect activation-inactivation of the channels and drug action through destabilizing the open state. diversity of h-bonding partners explains different effects of mutations of individual asparagines on the channel activa- tion, inactivation, and drug sensitivity. supported by nserc grant to bsz, the ras program ‘‘molecular and cell biology’’ to dbt, and cihr award to ib. -pos board b binding of isoflurane to a bacterial voltage-gated sodium channel: structure and accessibility of distinct interaction sites srinivasa g. raju , vincenzo carnevale , david n. lebard , annika f. barber , michael l. klein . temple university, philadelphia, pa, usa, yeshiva university, new york, ny, usa, thomas jefferson university, philadelphia, pa, usa. the most likely targets for volatile anesthetics (va) are ion channels. the mechanism of volatile anesthetic action is not completely understood. identify- ing the molecular pathway for drug binding is crucial to understand the effect of va on voltage gated sodium channels. we use molecular dynamics simula- tions to identify the binding sites for a hydrophobic general anesthetic isoflur- ane, on voltage gated bacterial sodium channel nachbac. apart from the voltage sensing domain (s -s ), linker and the pore domain (s -s ), bacterial sodium channels also have fenestrations, which provide a hydrophobic tunnel through the lipid-embedded portion of the channel to the central cavity, where the known local anesthetic site is located. unbiased ‘‘flooding’’ simulations were performed on the activated open confirmation of nachbac. we per- formed a cluster analysis to identify all the possible binding sites of isoflurane. the three most important ones among them are: a region near the selectivity filter, called the extracellular site, a region near the s -s linker, called the linker site, and a region within the cavity, called the cavity site. the most important observation is that isoflurane enters the central cavity through the fenestrations. free energy perturbation method was employed to calculate the binding affinities of isoflurane for each of these sites. we also studied the interactions between isoflurane and the amino acids in these three binding sites. -pos board b a key gating charge interaction required for slow inactivation of the navab bacterial sodium channel tamer m. gamal el-din, todd scheuer, william a. catterall. university of washington, seattle, wa, usa. bacterial voltage-gated sodium (nav) channels are considered an ideal model for structure-function studies. the elucidation of the crystal structure of the bacterial channel navab (payandeh et al., nature , - , ) opened an avenue to understand electrical signaling in excitable cells at the structural level. navab expressed in hi insect cells as for structural studies has unusually negative voltage-dependent activation (va ~ mv). navab also has three phases of inactivation, a biphasic early inactivation process (t ~ ms, t ~ . s, at � mv) followed by an unusually strong and use-dependent slow-inactivation process. to search for the molecular basis for negative activation and slow inactivation of navab, we mutated the outer- most gating charge partner in the s segment, asn , to lys. this mutation shifted the activation curve ~ mv toward more positive potentials. surpris- ingly, it also completely abolished use-dependent slow inactivation. we showed previously that the equivalent residue in nachbac (asp ) interacts with the r gating charge in the s segment during activation using the disul- fide locking method (decaen et al, pnas ( ) - ). to test whether this interaction between r and n was critical for slow inactivation, we mutated navab r to cys. the resulting mutant navab_r c also had positively shifted channel activation (þ mv) and no use-dependent slow inactivation. the fact that these reciprocal mutations have the same functional effects suggests that interaction between r in the s segment and n in the s segment is an important link that stabilizes the activated state of the voltage sensor and triggers the slow inactivation process. -pos board b computational study of the prokaryotic sodium channel karen m. callahan, benoit roux. university of chicago, chicago, il, usa. ion-selective voltage-gated ion channels allow ions of a specific element or set of elements to pass, but exclude other ions. recently, the crystal structure of navab was published (payandeh et al ( ) nature , ), giving an un- ambiguous picture of the structure of the sodium channel selectivity filter (sf) of the prokaryote arcobacter butzleri. the filter is much wider than that of the narrow, carbonyl-lined potassium channels, allowing ions to penetrate with minimal dehydration, multiple pathways, and even to pass each other. previous computational studies have attempted to explain sodium selectivity, and claimed consensus (corry and thomas ( ) jacs , , furini and domene ( ) plos , e ). experimental ion selectivity determina- tion from pore-only constructs of a sodium channel with the same sf sequence shows stronger ion selectivity from reversal potential than from the ratio of the fluxes of sodium and potassium (shaya et al ( ) pnas , ), but selectivity, na þ/kþ, was still less than five. simulations based upon the closed-pore crystal structure could not determine selectivity directly from con- duction. to investigate this issue, we first calculated multi-ion potentials of mean force in the selectivity filter of pore-domain-only navab with an ex- tended equilibration period, and a replica-exchange molecular dynamics scheme, which allows for improved sampling. we then explored the non- equilibrium conduction of sodium and potassium in the presence of an applied electric field through a model navab pore truncated to mimic the conformation of the open pore. we also present multi-ion pmf calculations to illustrate similarities and differences between this model and the intact pore. when taken together, these two methods provide complementary views of ion selectivity and conduction based upon the conformation of the navab crystal structure of payandeh et al ( ). -pos board b volatile general anesthetic interactions with a bacterial sodium channel annika f. barber , srinivas g. raju , david lebard , vincenzo carnevale , michael l. klein , manuel covarrubias . thomas jefferson university, philadelphia, pa, usa, temple university, philadelphia, pa, usa. general anesthesia results from complex interactions involving ion channels in the brain. voltage-gated ion channels are modulated by halogenated inhaled general anesthetics, however the drug-channel interactions are generally believed to be non-specific making it difficult to investigate the molecular mechanisms of anesthetic action. we find, however, that the bacterial sodium channel nachbac exhibits differential regulation by different general anes- thetics, suggesting that there may be specific interactions. molecular dynamics (md) simulations have identified several possible binding sites for isoflurane in the nachbac channel structure. here, we have characterized the affinity, occu- pancy and hydrogen bonding for these sites and identified key interactions. in addition, experimental evidence suggests that both isoflurane and sevoflurane have dual actions on nachbac, possibly involving action at two different sites. consistent with pore block, sevoflurane accelerates the decay of the current ( % faster at . mm sevoflurane) but, at the same time, increases the peak current ( % increase with . mm sevoflurane), which argues against the blocking mechanism. we hypothesize that an additional mechanism involving a distinct site is necessary to explain the latter effect. we are currently employ- ing md simulation and structural modeling combined with mutagenesis and electrophysiology to test this two-site hypothesis and investigate the molecular mechanisms of these opposing effects. supported by ninds f ns (afb) and nigms p gm (mlk). -pos board b polymodal, high affinity actions of m-conotoxins on a bacterial voltage- gated sodium channel rocio k. finol-urdaneta , robert glavica , jeff r. mcarthur , robert j. french . university of calgary, calgary, ab, canada, rmit, melbourne, australia. m-conotoxins (mctxs) are potent blockers of eukaryotic sodium channels, and individual members of the mctx family are highly specific for particular nav isoforms. we have begun to explore mctx interactions with nachbac, a pro- karyotic nav channel closely related to navab, whose crystal structure was re- cently determined (payandeh et al, , nature : ). our data reveal actions on both ion conduction and gating, consistent with polymodal actions on the pore domain. under voltage clamp, whole-cell currents from nachbac expressed in tsa- cells were reduced, up to nearly complete block, by concentrations in the pm to mm range, for wildtype toxins and derivatives of mctx piiia and kiiia. for wildtype piiia, dose-response data ( . - , nm) yielded the following: ic = . nm; maximal fraction of current blocked = . ; hill coefficient = . . chen & chung ( , biophys. j. : ) predicted an ic of . nm for piiia when the navab channel is occupied by sodium ions. even at very low [piiia] ( pm), the unblocked currents showed increasing rates of inactivation as the peptides were washed in, suggesting a gating mod- ulation, that was not tightly associated with pore block. for mctx piiia ( . nm), or kiiia ( nm), inactivation accelerated by ~ -fold. substitution of key basic residues (piiia-r a and kiiia-k a) reduced blocking potency and decreased the speeding of inactivation to less than -fold. given the remarkably high selectivity and affinity that mctxs show for certain eukaryotic nav channels with highly asymmetric pores, it may seem surprising that they bind to symmetric bacterial nav channels with such high affinity. https://core.ac.uk/display/ ?utm_source=pdf&utm_medium=banner&utm_campaign=pdf-decoration-v 	binding of isoflurane to a bacterial voltage-gated sodium channel: structure and accessibility of distinct interaction sites 	a key gating charge interaction required for slow inactivation of the navab bacterial sodium channel 	computational study of the prokaryotic sodium channel 	volatile general anesthetic interactions with a bacterial sodium channel 	polymodal, high affinity actions of μ-conotoxins on a bacterial voltage-gated sodium channel  increased pd-l tumor expression correlates with high rate of response to pd- inhibitors in patients with unresectable, recurrent, and metastatic cutaneous squamous cell carcinoma methods we reviewed the medical records of patients with nsclc receiving immunotherapy as between july and june . progression-free survival and overall survival was calculated using kaplan-meier curve. results the average age of patients was years (range: – years), with a male predominance ( %). majority of the patients were caucasian ( %), followed by african-american ( %), and asian ( %). most of the patients were former smoker ( %), followed by current smoker ( %) and never smoker ( %). adenocarcinoma and squamous cell carcinoma was diagnosed in ( %) patients and ( %) patients, respectively. the ecog-ps was , , and in ( %), ( %), ( %) and ( %), respectively. four differ- ent immunotherapies were used, namely atezolizumab in ( %), durvalumab in ( %), nivolumab in ( %) and pembrolizumab in ( %) patients. average number of cycles of atezolizumab received by the patient was (range – cycles), durvalumab (range – cycles), nivolumab (range – cycles), and pembrolizumab (range – cycles). patients were grouped in good performance status (ecog – ) and poor performance status (ecog � ). the median progression free survival (pfs) was months ( % ci . – . ) in patients with good ps and months ( % ci . – . ) in patients with poor performance status (p< . ). the median overall survival (os) for patients with good per- formance status was months ( % ci . – . ) and months ( % ci . – . ) in patients with poor ps (figure ). adverse effects were recorded in a total of ( %) patients, ( %) patients had ecog-ps , ( %) patients had ecog-ps , ( %) patients had ecog-ps and ( %) patients had ecog-ps of . most common adverse effects were pneumonitis ( %), diarrhea ( %) and hypothyroidism ( %). abstract figure progression free survival (pfs) and overall survival (os) in patients with good performance status (ecos ps – ) and poor performance status (ecog � ) treated with immunotherapy in nsclc conclusions our data suggests that while the patients with poor ps tolerated the immunotherapy. however, poor ps was associated with significantly lower pfs and os. further studies are required to evaluate the effect of ps on survival in front- line immunotherapy. acknowledgements we thank dr. saqib abbasi for helpful discussions. trial registration n/a ethics approval the study was approved by the institution review board at kumc, #cr . references n/a http://dx.doi.org/ . /jitc- -sitc . increased pd-l tumor expression correlates with high rate of response to pd- inhibitors in patients with unresectable, recurrent, and metastatic cutaneous squamous cell carcinoma nate bowers*, kimberly burcher, jess savas, phillip williford, laura doerfler, hafiz shabbir patwa, joshua waltonen, christopher sullivan, james brown, mercedes porosnicu. wake forest, winston salem, nc, usa background pd- inhibitors were approved for locally advanced and metastatic cutaneous squamous cell carcinoma (cscc) in . the identification of tumor characteristics that predict potential responders to immune checkpoint inhibi- tors (ici) is an area of ongoing research. here we present a series of consecutive patients with locally advanced, recurrent, or metastatic cscc treated with pd- inhibitors and analyze tumor and blood genomics as well as pd-l expression with the aim of correlating with treatment response. methods we analyzed cases of cscc treated with single agent pd- inhibitors in the last years at wake forest. demo- graphic and outcome data were collected. tumor tissue, when- ever available, was tested for pd-l , tmb, msi, and genetic mutations. blood was tested for circulating tumor at the beginning of treatment and at the time of maximum response. results fourteen patients with cscc treated with pd- ici were included in this study. six had locally advanced disease, seven had recurrent locally advanced disease, and one had metastatic disease. four patients received treatment for > months and all had complete response (cr). five patients had – months of treatment and all had near cr (pending imaging studies and ctdna to confirm). three patients had < months of treatment and had partial response (pr). two of the patients had progressive disease, although one with pos- sible pseudoprogression based on review of post-treatment sur- gical pathology specimen. treatment was well tolerated with no immune related side-effects except one case of grade i hypothyroidism. eleven patients had sufficient tumor tissue for genomic and pd-l testing. initial blood genomic testing was performed in of patients and in follow up in patients who achieved maximum response. patients with cr had pd- l of at least %. the additional tested patients had pd-l above %. the most frequently mutated gene was tp present in tumor in all tested patients and in blood in patients, followed by notch / detected in the tumor of of patients tested. tmb was intermediate/high in tested patients except in the only patient who presented clear tumor progression. conclusions treatment of locally advanced, recurrent, and metastatic cscc with ici led to a dramatic change in the management and prognosis of cscc. our series of patients with cscc had a higher than reported rate of response. this corresponded with high tp alterations, notch / altera- tions, high/intermediate tmb, and high level of expression of pd-l . pd-l rates were higher than previously published. abstracts a j immunother cancer ; (suppl ):a –a o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://jitc.b m j.co m / j im m u n o th e r c a n ce r: first p u b lish e d a s . /jitc- -s it c . o n n o ve m b e r . d o w n lo a d e d fro m http://jitc.bmj.com/ ethics approval the study was approved by wake forest uni- versity institution’s ethics board, approval number irb . references . migden mr, rischin d, schmults cd, guminski a, hauschild a, lewis kd, et al. pd- blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. n engl j med. ; : – . . garcia-pedrero jm, martinez-camblor p, diaz-coto s, et al. tumor programmed cell death ligand expression correlates with nodal metastasis in patients with cutaneous squamous cell carcinoma of the head and neck. j am acad dermatol ; ( ): – . http://dx.doi.org/ . /jitc- -sitc . racial differences in outcomes for metastatic renal cell carcinoma (mrcc) patients managed on immune-checkpoint inhibitor (ici) therapy t anders olsen*, dylan martini, subir goyal, yuan liu, sean evans, benjamin magod, jacqueline brown, lauren yantorni, greta russler, sarah caulfield, jamie goldman, bassel nazha, wayne harris, viraj master, omer kucuk, bradley carthon, mehmet bilen. emory university school of medicine, atlanta, ga, usa; emory university, atlanta, ga, usa; winship cancer institute of emory university, atlanta, ga, usa background immune checkpoint inhibitors (icis) have increased in prevalence for the treatment of metastatic clear- cell renal cell carcinoma (mccrcc) in recent years given their efficacy and favorable toxicity profile. however, there has been insufficient investigation in the literature of how clinical outcomes differ on the basis of race. in this paper, we investi- gated differences in clinical outcomes between african ameri- can (aa) and caucasian mrcc patients treated with ici therapy. methods we performed a retrospective study of patients with mrcc who received ici at the emory winship cancer institute from – . clinical outcomes were measured by overall survival (os), progression-free survival (pfs), and clinical benefit (cb). os and pfs were calculated from ici- initiation to date of death and radiographic or clinical pro- gression, respectively. cb was defined as a best radiographic response of complete response, partial response, or stable dis- ease maintained for at least months per response evaluation criteria in solid tumors version . . the association of self- identified race with os and pfs was generally modeled by cox proportional hazards model. univariable and multivariable logistic regression models were used for binary outcomes of cb. the univariate association of immune-related adverse events (iraes) and non-clear-cell rcc (nccrcc) with race was assessed using chi-square test. results our cohort was made up of aa ( %) and caucasian ( %) patients. most of the patients were diag- nosed with ccrcc ( %) and more than half received pd- monotherapy ( %). most patients were international mrcc database consortium (imdc) intermediate ( %) or poor-risk ( %) groups. aa patients displayed significantly shorter pfs (hr= . , % ci: . – . , p= . ) and trended towards decreased cb (or= . , % ci: . – . , p= . ) in mva (table ). there was no difference in os (hr= . , % ci: . – . , p= . ) between the two racial groups in mva (table ). on kaplan-meier method, aa patients had shorter median os ( vs months, p= . ) and median pfs ( . vs . months, p= . ) relative to caucasian patients (figure ). additionally, aa patients more commonly had nccrcc compared to caucasian patients ( . % vs . % nccrcc, p- . ). aa patients also trended towards a lower incidence of iraes compared to caucasian patients in uva ( . % vs . %, p= . ). abstract table *mva controlled for age, race, gender, imdc risk group, number of prior lines of therapy, pd- monotherapy, and ccrcc **statistical significance at alpha < . abstract figure african-american (black) and caucasian (white) for os (left panel) and pfs (right panel) conclusions in this group of mrcc patients treated with ici, african american patients had significantly shorter pfs com- pared to caucasian patients. these findings suggest race could play a role in the management of late-stage mrcc. larger, prospective studies are needed to validate these findings. acknowledgements research reported in this publication was supported in part by the breen foundation and the biostatis- tics shared resource of winship cancer institute of emory university and nih/nci under award number p ca . the content is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health. trial registration not applicable. ethics approval this retrospective study was approved by the emory university institutional review board. consent not applicable. references not applicable http://dx.doi.org/ . /jitc- -sitc . outcomes of stage iv melanoma in the era of immunotherapy: a national cancer database (ncdb) analysis tamara sussman*, wei wei, pauline funchain, brian gastman. cleveland clinic foundation, cleveland, oh, usa background immunotherapy (io) has revolutionized the treat- ment landscape for metastatic melanoma and is now the main- stay of treatment since the approval of ipilimumab in and anti-pd- therapies (nivolumab and pembrolizumab) in . the majority of data stems from trials that have abstracts j immunother cancer ; (suppl ):a –a a o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://jitc.b m j.co m / j im m u n o th e r c a n ce r: first p u b lish e d a s . /jitc- -s it c . o n n o ve m b e r . d o w n lo a d e d fro m http://jitc.bmj.com/ 한국조경학회지� ( ):� ~ ,� .� .� j.� kila� vol.� ,� no.� ,� pp.� ~ ,� june,� pissn - eissn - https://doi.org/ . /kila. . . . 한국조경학회지� 제� 권� 호( 년� 월)� � †: 이 논문은 년 월 미국 버지니아주에 위치한 robert h. smith international center for jefferson studies로부터 단기 연 구비(short-term fellowship)를 지원 받아 수행한 연구의 결과임. corresponding author: jung-hwa kim, postdoctoral fellow, institute for advanced studies in the humanities, university of edinburgh, edinburgh eh nw, united kingdom, tel.: + - - - , e-mail: junghwa @gmail.com 토머스 제퍼슨의 버지니아대학교 식물원 구상 배경과 내용† 김정화 에든버러대학교 고등인문연구소 박사후연구원 the background and content of thomas jefferson's plan for a botanical garden for the university of virginia kim, jung-hwa postdoctoral fellow, institute for advanced studies in the humanities, university of edinburgh abstract this paper examines the background and content of thomas jefferson’s botanical garden plan for the university of virginia. when jefferson promoted the establishment of a botanical garden, european botanical gardens were evolving from physic gardens, and american botanical gardens were in their infancy. accordingly, this paper compares the botanical garden plan for the university of virginia with contemporary botanical gardens. this is examined by outlining the trends of botanical gardens in europe and the united states around the nineteenth century, analyzing their function and spatial structure. also, jefferson’s perspective on botany, his plan, and botanical gardens are reviewed. this study found that jefferson’s project had its background in the social recognition of the importance of botany as a practical science, advancing the national economy, which was a prominent goal in late eighteenth-century europe, and in developing networks of exchanging plants and information concerning botany and botanical gardens. based on the botanist correia’s opinion on the role of a public botanical garden, the botanical garden plan for the university of virginia was developed by jefferson as an action plan, including its site creation, space organization, and supplying of plants. compared to the other contemporary botanical gardens, the university of virginia’s botanical garden plan has the following characteristics. first, like european gardens in the late eighteenth century, it evolved from being a physic garden to a botanical one. as such, it emphasized botanical research and education over medicine, creating a tree garden and a plant garden. second, it differed from many european and american botanical gardens in that it rejected decorative elements, refused to install a greenhouse, and attempted to spread practical overseas plants suitable to the local climate. this study contributes to broadening the history of botanical gardens at the turn of the nineteenth century. key words: botany, harvard botanical garden, united states botanic garden, physic garden journal of the korean institute of landscape architecture 김정화 한국조경학회지� 제� 권� 호( 년� 월) 국문초록 본 연구는 토머스 제퍼슨의 버지니아대학교 식물원 구상의 배경과 내용을 고찰한다. 제퍼슨이 식물원 설립을 추진했 던 시기가 유럽에서 식물원이 약용 식물원에서 진화한 때이자 미국에서 여러 식물원이 설립된 초창기라는 사실에 주목하 여 동시대 식물원과 비교하여 버지니아대학교 식물원 구상의 특징을 짚어내고자 하였다. 이를 위해 세기 전후 구미 주요 식물원의 역할과 공간 구조를 분석하여 경향을 파악하였다. 이와 함께 식물학과 식물원에 대한 제퍼슨의 관점과 식물원 구상안을 검토하며 버지니아대학교 식물원을 당대 사례와 비교 검토하였다. 연구 결과 그 배경은 세기 후반 유럽에서 두드러지게 나타난 국가 경제를 견인하는 실용 과학으로서 식물 교육과 연구의 중요성에 대한 사회 인식, 그리고 식물학과 식물원에 대한 정보와 식물을 교환하는 네트워크에서 찾을 수 있다. 버지니아대학교 식물원 구상은 공공 식물원의 역할에 대한 식물학자 코레아의 의견이 바탕이 되어 제퍼슨에 의해 부지 조성과 개략적인 공간 구성, 식물 수급 방안을 포함한 실행 전략으로 발전되었다. 동시대 식물원 사이에서 버지니아대학교 식물원 구상이 지니는 특징은 다음과 같다. 첫째, 초본 이외에 교목 정원을 별도로 구성하고 의학이 아닌 식물학 연구와 교육을 강조했던 측면에 서 세기 후반 유럽 식물원의 약용 식물원에서 식물원으로의 진화와 같은 경향을 보인다. 둘째, 장식적 요소를 배제하고 온실 설치를 거부하며 지역 기후에 적합한 해외 실용 식물을 확산시키려 했다는 점에서 유럽과 미국의 많은 식물원과 다르다. 본 연구는 버지니아대학교 식물원 구상을 사례로 세기 전후 식물원의 역사와 문화에 대한 이해의 폭을 넓히는 데 기여한다는 점에서 의의를 지닌다. 주제어: 식물학, 하버드대학교 식물원, 미국립식물원, 약용 식물원 figure . portrait of thomas jefferson by rembrandt peale, source: wikimedia commons Ⅰ. 서론 . 연구 배경과 목적 최근 몇 년 새 국내에서 식물원 조성 소식이 이어지고 있다. 국립백두대간수목원과 서울식물원이 문을 열었으며, 이 외에도 여러 식물원이 계획 혹은 조성 단계에 있다. 바야흐로 식물원 의 르네상스를 맞이하고 있다. 식물원의 존재 의의를 재고하고 미래 방향을 모색하기 위해 식물원의 역사를 되짚어보는 일이 더욱 필요한 시점이다. 본 연구는 미국의 제 대 대통령이었던 thomas jefferson ( ~ , figure 참조)이 년에 착수했던 버지니아대 학교 식물원 조성 계획을 살핀다. 비록 완성되지 못했으나, 다음 과 같은 사실을 고려할 때 이 식물원 계획은 주목을 요한다. 첫 째, 세기 후반부터 세기 초에 이르는 시기는 유럽의 식물 원들이 약용 식물원에서 식물원으로 진화한 때인데(o'malley, ; johnson, ; hickman, ), 당시 제퍼슨은 변화가 지속되고 있었던 파리 왕립식물원과 밀접한 관계를 맺고 있었 다(spary, ). 둘째, 세기 초는 미국에서 공공식물원 조성 이 본격화된 여명기였으며, 제퍼슨은 이러한 움직임을 이끈 주 요 인물이었다(o'malley, ). 미국립식물원(united states botanic garden) 설립을 추진한 사람 중 한 명이었고(o'malley, ), 뉴욕식물원의 전신인 엘긴식물원(elgin botanic garden) 과 하버드대학교 식물원 등에 씨앗과 식물을 제공하며 그 탄 생에 기여하였다(fox-bruguiere, ). 이러한 점을 고려할 때 제퍼슨의 버지니아대학교 식물원 계획은 세기 전후 미국 과 유럽 식물원의 동향에 대한 이해의 폭을 넓히는 적절한 사 례이다. 본 연구는 다음과 같은 질문에 대한 답을 구하고자 한다. 제 토머스� 제퍼슨의� 버지니아대학교� 식물원� 구상� 배경과� 내용 journal of the korean institute of landscape architecture 한국조경학회지� 제� 권� 호( 년� 월)� � 퍼슨이 버지니아대학교에 식물원을 조성하려 했던 배경은 무 엇인가? 제퍼슨이 구상했던 버지니아대학교 식물원의 모습은 어떠했나? 버지니아대학교 식물원 구상과 세기 전후 유럽과 미국의 식물원의 유사점과 차이점은 무엇인가? . 연구사 검토 토머스 제퍼슨이 버지니아대학교에 식물원을 설립하려 했다 는 사실은 그간 큰 조명을 받지 못했다. 단적인 예로 토머스 제 퍼슨의 조경가로서의 면모를 밝힌nichols and griswold( ) 의 thomas jefferson, landscape architect와 버지니아대학교 캠퍼스 계획을 소개한 thomas jefferson's academical village 은 식물원 계획을 다루지 않고 있다. 그러나 버지니아대학교의 식물원 계획이 전혀 언급되지 않 았던 것은 아니다. 세기 말에서 세기 초 유럽과 미국 내 식 물원을 과학 탐구와 픽처레스크 미학의 융합으로 논한 o'malley ( )의 연구에서 간략히 소개된 바 있다. o'malley( : - )는 제퍼슨의 식물원 계획을 과학과 자연식 정원에 대한 미 적 관점이 동시에 반영된 세기 초 미국의 여러 식물원과 같 은 경향을 지닌 사례로 규정했다 ). 그러나 제퍼슨의 글을 짧게 인용하는데 그치고 있어 동시대 식물원과 버지니아대학교 식 물원 계획의 유사성을 주장하기에 한계를 보였다. 버지니아대학교 식물원 계획은 fox-bruguiere( ; ) 의 연구를 통해 자세히 밝혀졌다. 그는 제퍼슨의 식물학과 식 물원에 대한 관심과 관련활동을 검토하며 식물원의 계획 배경 을 고찰하고, 년대에 작성된 버지니아대학교 식물원 구상 안 문서와 제퍼슨의 편지를 살펴 식물원 계획 내용을 드러냈다. 또한 년 제퍼슨의 서신을 조사하여 식물원 조성 과정을 정리하였다. 그는 식물원 설립 배경이 식물학 교육과 연구가 과학 수준을 앞당기고 국가의 진보를 견인하는 열쇠라는 제퍼 슨의 생각에 뿌리를 두고 있다고 주장했다. 이와 함께 제퍼슨이 저명한 식물학자 josé correia da serra( ~ )에게 요 청하여 식물원 구상안을 마련하였고, 박물학 교수 john patton emmet( ~ )를 통해 구상을 실현하려 했다는 등의 사 실을 밝히며 미완의 유산을 이해할 수 있는 토대를 구축했다. 그러나 그는 제퍼슨의 식물원 계획을 제퍼슨의 식물학에 대 한 관심과 활동 속에서 살폈을 뿐, 동시대 유럽과 미국의 식물 원의 경향과 비교하지 않았다. 또한 계획 수립 과정에서 조경 가로서 제퍼슨의 역할을 다루지 않았다. 버지니아대학교 식물원 계획을 “독창적이지도 특별하지도 않다(fox-bruguiere, : )”라고 평하며, 버지니아대학교 설립과 국가 진보에 대한 제퍼슨의 교육적․경제적․국가적 관점을 이해할 수 있는 수 단에 한정했다. 본 연구는 세기 전후 유럽과 미국의 식물원 동향을 고찰하 여 버지니아대학교 식물원이 동시대 식물원사에서 지니는 특 징을 드러내고, 코레아와 제퍼슨의 식물원 구상안을 비교하여 버지니아대학교 식물원 계획에 담긴 제퍼슨의 역할을 조명한 다는 점에서 앞선 연구와 차별성을 갖는다. . 연구 과정과 방법 연구 과정과 방법은 다음과 같다. 첫째, 제퍼슨의 버지니아 대학교 식물원이 동시대 식물원사에서 지니는 의미를 찾을 수 있는 토대를 마련하였다. 이를 위해 세기 후반에서 세기 초반 유럽과 미국의 식물원 동향을 개괄하였다. 특히 주요 식 물원을 중심으로 역할과 공간 구성 방식의 변화와 특징을 파악 하였다. 유럽 사례 중 제퍼슨이 크게 영향을 받았던 파리식물 원과 세기 후반 유럽 식물원의 진화를 잘 보여주는 사례인 에든버러식물원을 검토하였고, 미국 사례 중 초기 계획안과 식 물 목록이 전해지며 제퍼슨이 식물을 제공하기도 했던 하버드 대학교 식물원을 검토하였다. 둘째, 버지니아대학교 식물원의 특징을 이해하기 위하여 식물학 및 식물원에 대한 제퍼슨의 생 각과 입장을 파악하였다. 토머스 제퍼슨의 도서 목록(catalogue of the library of thomas jefferson) )에 기록된 식물학 관련 서적과 그의 버지니아 주에 대한 비망록(notes on the state of virginia) ) 중 식물에 대한 서술과 제퍼슨이 지인과 주고받 은 서신 중 식물원이 언급된 자료를 검토하였다. 이와 함께 본 연구는 fox-bruguiere( )가 다루지 않은 제퍼슨과 임용 담 당자 francis walker gilmer( ~ ) )가 주고받은 서신을 분석하며 차후 식물원 조성책임을 맡는 박물학 교수 임용 과정 을 조사하였다. 셋째, 버지니아대학교 식물원 구상 내용에서 공 간적 특징을 파악하였다. 이를 위해 버지니아대학교 도서관에 소장된 코레아의 식물원 구상안 )과 미국회도서관에 소장된 년 월 일 제퍼슨이 작성한 식물원 설립 제안 서신 )을 살펴, 같은 시기 유럽과 미국의 식물원과 유사점 및 차이점을 찾고자 하였다. Ⅱ. ~ 세기 식물원의 동향 . 유럽의 식물원 년에 설립된 피사대학교의 식물원을 시작으로 ~ 세 기 유럽의 여러 의과대학은 약물학(materia medica) 연구와 교육을 위해 약용 식물원을 조성하였다(johnson, ; hunt, ). 그러나 세기에 이르러 다음과 같이 식물원에 변화를 일으킬저변이 형성되었다. 사탕수수, 담배, 커피등 실용 식물 의 발견과 유입으로 식물 수집 대상이 약용 식물에서 실용 작 물로 확장되었으며, 년 린네의 식물철학(philosophia bo- tanica) 발표 이후 식물 탐구는 의약학에서 박물학 혹은 식물 journal of the korean institute of landscape architecture 김정화 한국조경학회지� 제� 권� 호( 년� 월) a: plan of jardin du roi, b: plan of jardin du roi, c: plan of jardin du roi by gabriel thouin, figure . changes in plans of the botanic garden edinburgh source: a, b: http://www.ctgpublishing.com, c: wikimedia commons 학으로 분리 발전되었다(findlen, ). 이러한 변화는 영국의 여러 식물원에서도 발견된다. 예컨대 에든버러 식물원은 년 에든버러대학교의 의학교수이자 왕 의 식물학자로 부임한 john hope( ~ )의 주도 아래 새 식물원을 계획하고 조성했다. 의과대학 옆 기하학적 구조로 이 루어진 개의 직사각형 토지에 종과 속 그리고 알파벳 순서에 따라 식물을 배열했던 이전의 약용 식물원(doyle, )과 달 리, 호프는 약용 식물 교육 공간(schola botanica)은 작게 구성 함과 동시에 교목 연구와 교육 공간(sylva botanica)을 크게 마 련하고 온실을 건축했다. 특히 당대 픽처레스크 미학에 영향을 받은 그는 교목 정원을 곡선형길과 비정형적인 소정원들로 이 루어진 공간으로 계획하였다(lausen-higgins, ). 케임브리 지대학교 식물원도 년에 부임한 john stevens henslow ( ~ ) 교수를 중심으로 약용 식물원에서 식물원으로 거듭나기 위한 계획을 수립했다. 교목을 적극적으로 도입했던 헨슬로우 역시 정원을 곡선형의 유기적 형태로 계획하며 당대 정원 미학을 반영했다(parker, ). 파리의 약용 식물원(jardin du roi) 역시 세기를 지나는 동안 변화를 도모했다. 먼저 년 박물학자 georges louis leclerc de buffon( ~ )이 원장으로 임명되면서 식물원 의 주 관심사가 약용 식물에서 교목, 특히 프랑스 기후에 적용 할 수 있는 북미 교목으로 이동하였다. 그 결과, 년에 이르 러 식물원에서 가장 큰 부분을 차지하는 공간은 교목 재배지가 되었다(spary, : - ; figure -a, -b 참조). 이러한 변화는 프랑스 혁명 후에도 지속되어 andré thouin( ~ ) 이 원장으로 임명된 시기에는 투인과 그의 형제이자 조경가였 던 gabriel thouin( ~ )에 의해 확장 계획이 수립되었 고(figure -c 참조), 식물학, 광물학, 동물학을 아우르는 대표 적인 자연과학 기관으로 거듭났다(petersen, ). . 미국의 식물원 세기 초 미국의 식물학 연구는 시작 단계에 있었다. 년 미국에 첫 발을 들인 코레아는 미국의 식물학 연구 수준을 다음과 같이 묘사했다. 미국의 식물학은 아직까지 초기 단계로, 일부 아마추어들이 대륙 전체에 흩어져 있고 일부 유럽인들은 식물학자라기보다 여행하는 정원가로서 돈 많은 유럽 사람의 정원이나 식물 재배지를 위해 식 물, 관목, 나무를 수집하고 있다 ). 년 이전까지 미국의 식물 수집과 탐구를 주도한 집단은 학자가 아닌 식물 애호가들이었다(hedrick, ). 식물원을 조 성한 사람들 역시 개인적인 관심 혹은 원예 사업차‘신세계’ 미 국을 탐험하며 식물을 채집하던 이들이었다. 예를 들어 년 필라델피아에 조성된 미국의 첫 식물원은 평생 미국을 여 행하며 식물을 수집하고 여 년간 첼시 약용 식물원의 peter collinson( ~ )과 서신과 씨앗을 주고받았던 식물 애호가 john bartram( ~ )의 정원이었다(hill, ; bailey, ). 미국의 식물 수집과 탐구는 년대에 이르러 활발해지기 토머스� 제퍼슨의� 버지니아대학교� 식물원� 구상� 배경과� 내용 journal of the korean institute of landscape architecture 한국조경학회지� 제� 권� 호( 년� 월)� � figure . undated plan of the botanic garden at cambridge, harvard college source: courtesy of the botany libraries, harvard university 시작했다. 이때부터 년대까지 상당량의 이국 식물이 미국 으로 유입되면서 많은 식물원이 설립되었다(hedrick, ). 특 히 식물학이 미 대륙 내 실용 작물을 발견하여 국가 경제와 과 학 발전에 이바지하고 동시에 유럽에 대한 미 대륙 자연의 풍 부함을 드러낼 수 있다는 미 건국기 사회 리더들의 생각은 공 립 식물원 탄생의 원동력이 되었다(o'malley, ). 신호탄은 미국의 초대 대통령 george washington( ~ )이 년 에 작성한 청원서로, 그는 워싱턴dc 도시계획에 식물원을 포함 할 것을 요청하며 미국립식물원 설립의 기초를 닦았다(solit, ; fallen, ). 세기 초에는 여러 대학기관도 식물원 설립에 관심을 두기 시작해 첫 여 년 동안 하버드, 예일, 프린스턴, 사우스 캐롤리 나, 펜실베이니아대학교 등이 부설 식물원을 설치했다(o'malley, ). 이 중 년에 식물원을 조성한 하버드대학교의 사례 를 살펴보면 식물원 둘레로 곡선형의 동선을 따라 교목과 관목 전시 공간이 배치되었고, 중심에 온실과 교육 공간(garden of arrangement on botanic school)이 기하학적 구조로 배치되었 다(figure 참조). 년에 발간된 식물목록에 따르면 하버 드대학교 식물원은 국내외에서 수집한 실용 식물과 약용 식물 을 비롯해 장식용 식물까지 수집하여 총 , 종에 이르는 식 물을 보유하고 있었다 ). 정리하면, 제퍼슨이 버지니아대학교 식물원 설립에 착수하던 시기 전후로 유럽과 미국의 식물원들은 각각 전환기와 여명기 에 놓여 있었다. 세기 말 유럽의 식물원들은 의학 탐구 정원 에서 식물학 연구 기관으로 진화하면서 실용 식물, 특히 교목 을 적극 수집하고 배열하였고, 세기 초 미국의 식물원들은 의 학과 박물학의 경계에서 식물학 연구와 교육을 시작하며 대학 의 부설 기관으로 출발했다. Ⅲ. 제퍼슨의 식물학과 식물원에 대한 관점 . 식물학에 대한 관심 제퍼슨은 식물학에 깊은 관심을 두었다. 그의 정원과 philip miller( ~ )의 정원사의 사전(gardener's dictionary), 그리고린네의책등은 그의 식물학 지식의 원천이 되었다(ewan, ). 토머스 제퍼슨의 도서 목록 중 식물학 관련 서적은 pedanius dioskorides, jean jacques rousseau, erasmus darwin, mark catesby, carl von linnaeus 등이 저술한 총 권으로, 제퍼슨은 고대 그리스의 약학서부터 동시대 저명한 학자의 박 물학서까지 소장하고 있었다 ). 그의 식물학 지식은 호기심을 넘어 상당한 수준에 이르렀던 것으로 알려져 있다. 버지니아 주에 대한 비망록에서 학명을 사용해 버지니아의 식물을 나열하는 것에서 그의 박물학, 식물 학 지식수준을엿볼수 있다 ). 이외에도bernard jussieu( ~ )의 분류 체계보다 린네의 식물 분류법이 보다 합리적인 이유를 설명한 그의 편지(ewan, ), 미국의 첫 식물학 교과 서 저자 benjamin smith barton( ~ )이 제퍼슨의 박물 학 지식을 높이 평가하며, 새로 발견한 식물에 그의 이름을 붙 인 이야기(betts, : - ) 등 제퍼슨의 식물학 수준의 깊 이를 보여주는 여러 가지 일화가 전해진다. 년부터 년까지 외교관으로서 프랑스에 거주하며 쌓 은 유럽 식물학자들과의 친교 관계는 제퍼슨이 세기 전후 세 계 식물 네트워크의 주요 인물로 자리매김하는 토대가 되었다 (rice, ). 년 저명한 과학자 alexander von humboldt ( ~ )는 버지니아 산 담배 씨앗과 메릴랜드 산 담배를 요청하기 위해 제퍼슨에게 서신을 보냈으며(andress, ), 파리 왕립식물원 원장 투인과 제퍼슨의 관계는 곧 미국과 프랑 스 간 식물 교환 통로로 작용했다(spary, ). 제퍼슨에게 식물학은 개인의 지적 호기심이나 취미 활동 이 상의 의미를 지녔다. 미 건국기의 사회 리더로서 그는 식물학 을 “가장 귀중한 과학” ) 혹은 국가에 대한 “가장 위대한 일” ) 로 규정했다. 이러한 태도는 제퍼슨이 조지 워싱턴과 같이 실 용성에 주목하여 식물학이 국가 발전을 견인할 수 있는 중요한 과학 분야라고 생각하고 있었음을 보여주는 것이자 공공의 자 원으로서 식물원 설립의 필요성을 인식하고 있었음을 내포하 는 것이다. . 식물원에 대한 관점 식물학 네트워크의 주요 인물 중 한 사람이었던 만큼 제퍼슨 은 국외 주요 식물원을 방문하거나 소식을 접했다. 특히 년부터 년까지 프랑스 공사로서 파리에 거주하던 때에는 뷔퐁의 감독 아래 교목 수집과 공간 확장 등의 변화를 추구하 journal of the korean institute of landscape architecture 김정화 한국조경학회지� 제� 권� 호( 년� 월) 고 있던 파리식물원과 긴밀한 네트워크를 쌓았으며, 미국으로 돌아간 후에도 꾸준히 파리식물원으로부터 씨앗을 전해 받았 다(spary, ). 년에는 당시 갓 개원한 리버풀식물원의 연설문(address at the opening of the botanic garden of liverpool)과 식물 목록(a catalogue of plants in the botanic garden, at liverpool)을 전해 받기도 했다(ewan, ). 이외 에도 제퍼슨은 파리에 거주하던 시기 옥스퍼드와 큐를 비롯한 영국의 여러 도시와 정원을 여행했는데, 그가 남긴 글에서 식 물원에 대한 의견은 보이지 않는다. 큐 정원을 방문하기는 했 으나 그는 식물원이 아닌 물을 적극활용한 정원으로 인식했다 (wilson and stanton, : - ). 이러한 일련의 예들은 그 가 식물원을 해외 식물을 확보할 수 있는 장소로 여기고 있었 으며, 여러 식물원들 중에서도 영국의 식물원들보다 파리식물 원으로부터 강한 영향을 받았음을 가리킨다. 식물원의 방향성에 대한 제퍼슨의 생각은 앞서 살핀 세 기 말영국과 프랑스 등지에서 일어난 식물원의 변신, 약용 식 물원에서 자연과학 기관으로의 발전과 접점을 이루고 있었다. 버지니아 주에 대한 비망록에서 나타난 식물 구분법을 보아 도 기본적으로 그는 식물을 약용에 한정하지 않고, 약용, 식용, 장식용, 실용 식물로 구분했다 ). 차후 식물원 조성책임을 맡는 박물학 교수를 임용하는 과정에서도 이러한 태도가 엿보인다. 제퍼슨이 자신을 대신하여 버지니아대학교 교수 채용을 담당 했던 길머와 주고받은 서신에서 의학과 박물학(natural history) 각각 교수를 채용하려 했던 사실은 그가 이 둘을 별개의 학문 으로 규정하고 있었고 ), 박물학을 화학을 비롯해 지질학, 동물 학, 식물학을 아우르는 자연과학으로 인식하고 있었음을 알려 준다 ). Ⅳ. 버지니아대학교 식물원의 계획과 추진 과정 . 식물원 조성 계획 제퍼슨은 년 박물학자 john bradbury( ~ )의 워싱턴시 식물원 설립 소식에 대한 편지에 “과학에 흥미를 지 닌 자라면 누구나 바라는 일” )이라고 답하며, 식물원 설립에 뜻이 있음을 간접적으로 내비쳤다. 그러나 그가 버지니아대학 교 식물원 설립에 착수한 때는 년대에 들어서였다. ) 년 손턴의 식물원 설립 제안 년 제퍼슨의 버지니아대학교 식물원 구상을 논하기에 앞서 세 건의 문서를 살펴볼 필요가 있다. 이미 년과 년 그리고 년경, 각자 다른 세 사람이 제퍼슨에게 버지니 아대학교 내에 식물원을 조성할 것을 권했기 때문이다. 모두 계획도면이 없는 서신에 불과하지만, 그들의 제안은 시기적으 로 제퍼슨의 식물원 계획에 앞서기에 차후 그의 계획안에 일정 한 영향을 미쳤을 가능성을 배제할 수 없다. 년 제퍼슨의벗이자 미국회의사당건축가로알려진 william thornton( ~ )이 대학교 내 식물원 조성을 제안하였다. 손턴은 그 이전에도 제퍼슨과 워싱턴의 국립식물원 설립에 관 해 몇 차례 서신을 주고받으며 공공 식물원에 대한 남다른 관 심을 표했던 인물이다(fox-bruguiere, ). 년 당시 손 턴은 제퍼슨과 아카데미컬 빌리지와 파빌리온 구상에 대한 의 견을 주고받고 있었는데, 당해 월 일의 편지에서 파빌리온 설계에 대한 의견을 서술한 뒤, 분수, 숲, 운동 공간 등 학교에 필요한 몇 가지 시설을 추가로 제시하며, “식물원이 있어야 한 다” )고 말했다. 그러나 손턴의 식물원 조성 제안에 대한 제퍼 슨의 답장은 확인되지 않는다. ) 년 쿠퍼의 식물원 설립 제안 년 월, 버지니아대학교의 아카데미컬빌리지 건설이 착 수되고 마당(lawn)과 정원 계획이 본격화되던 때(wilson et al., ), 제퍼슨은 또 다른 이로부터 식물원 조성 제안을 받 았다. 버지니아대학교의 화학 및광물학 담당 교수로 예정되었 던 thomas cooper( ~ )였다. 월 일 쿠퍼는 제퍼슨 에게 보낸 편지에서 학과 운영에 대한 몇 가지 생각을 밝히며, 파리식물원에서 매년 보내는 씨앗을 직접 탐구할 수 있도록 식 물원을 설립하자고 제안하고 식물학자를 추천하기까지 했다 ). 이에 대한 제퍼슨의 답장에서 쿠퍼가 추천한 식물학자에 대한 관심은 보이나, 식물원에 대한 의견은 보이지 않는다 ). 이후 쿠퍼가 버지니아대학교에 임용되지 못하였고, 이와 함께 그의 제안도 구체화되지 못했다. ) 년경 코레아의 식물원 구상안 버지니아대학교 도서관에 소장된 문서 가장 실용적이며 저 렴한, 공립학교를 위한 식물원 계획(plan for a botanic garden for a public school, on the most useful, and least expensive plan) 은 작성일 미상이다. 그러나 fox-bruguiere( )는 년 코레아가 미국을 떠나기 전 제퍼슨의 몬티첼로를 방문했을 때 제퍼슨의 요청으로 이 문서를 작성한 것으로 추정한다. 이러한 경위로 미루어 보아 제퍼슨은 쿠퍼가 식물원 설립을 제안한 때 부터 코레아가 몬티첼로에 방문했던 시기 사이에 버지니아대 학교 내 식물원 설립을 고려하기 시작한 것으로 판단된다. 내용은 다음과 같은 세 가지로 구성되어 있다. 첫째, 식물원 의 역할이다. 식물 목록 증대와 수집 자체에 혈안이 된 동시대 식물원을 비판하며, 코레아는 식물원의 초점은 식물 교육이어 야 한다고 강조하였다. 둘째, 이어서 그는 식물원의 교육과 연구 방향을 제시하였다. 구체적으로는 과학으로서 식물 해부학 및 생리학, 린네의 분류 체계를 따른 식물 분류학(distinguishing 토머스� 제퍼슨의� 버지니아대학교� 식물원� 구상� 배경과� 내용 journal of the korean institute of landscape architecture 한국조경학회지� 제� 권� 호( 년� 월)� � a: serpentine wall at the campus b: jefferson's sketch of serpentine walls for the academical village, about - figure . serpentine wall source: a: photo by author in march , b: nichols, , p. plants), 프랑스 혁명 정신과 상통하는 진정한 과학으로서 식물 체계화(grouping), 가장 유용한 학문으로서 식물 활용 연구 그 리고 식물 문헌학 등 다섯 가지였다. 셋째, 식물 유형으로 그는 교육과 연구 취지에 적합한 식물을 도입할 것을 권하였다. , 종의 식물로 이루어진 에이커 규모의 정원과 교목으로 이루어진 에이커규모의 부지를 설정하고, 미국 내 식물 확산 을 위해 식물원의 식물과 교목은 모두 버지니아 비자생종이어 야 한다고 주장하였다 ). 정리하면, 식물원의 부지 규모를 언급한 것 이외 공간 계획 에 관한 생각이 엿보이지 않기에 그의 구상안은 식물원의 비전 과 미션 제시에 초점을 둔 제안서라 할 수 있다. 제안 방향은 자연과학 교육에 충실한 식물학 수업의 실습장이자 미국에 유 용한 식물을 확산시키기 위한 일종의 시험장을 설립하는 것이 었다. ) 년 제퍼슨의 식물원 구상안 제퍼슨이 버지니아대학교 식물원 설립에 본격적으로 착수한 때는 년이다. 제퍼슨은 사망하기 몇 달 전인 월 일 버지 니아대학교의 박물학장 에머트에게 식물원 설립 계획을 전하 는 편지를 보냈다. 버지니아대학교가 개원한 지 년이 되어 가 는 때이자, 에머트가 교수로 부임한 지 년이 되는 때였다 ). 편지는 크게 네 가지 내용으로 이루어져 있다. 첫 번째는 식 물원 설립에 착수하길 요청하는 내용으로, 바로 “이제 우리 대 학에 식물학과의 도입을 생각할 때” )라는 문장으로 시작한다. 두 번째는 코레아의 식물원 구상안 소개로, 구상안 요청 배경 과 요청 내용도 함께 설명하였다. 세 번째는 식물원 설립을 위 한 네 가지 과제로, 그는 번호를 붙여가며 부지 선정, 담장 조 성, 지형 그리고 식물 목록에 대한 의견을 제시하였다. 네 번째 로 식물 종류와 수급 방안을 서술하였다. 제퍼슨은 코레아의 교육과 연구 기능에 충실한 온실 도입을 배제하고, 탐닉적이지 않은 ‘절제적인 관점'에 만족감을 표하며 ), 코레아의 제안 대부분을 수용했다. 코레아의 제안대로 식물 로 이루어진 에이커의 정원과 교목으로 구성된 에이커 규모 의 식물원을 구상했고, 식물 종류에 있어서도 코레아의 의견대 로 식물학 탐구에 충실한 식물을 수급하고, 국가에 이익이 되 는 비자생 교목을 도입할 것을 강조하였다 ). 물론 제퍼슨이 코레아의 제안을 절대적으로 따르기는 했으 나, 에머트에게 제시한 네 가지 과제를 살펴보면 건축과 조경 에 대한 자신의 지식과 경험을 바탕으로 코레아의 제안을 실행 하기 위한 보다 구체적인 구상안을 마련하였음을 알 수 있다. 코레아가 제시한 규모 이외에 토양, 급수, 거리 등을 종합적으 로 고려하여 캠퍼스 상단 도로변 토지를 식물원 부지로 선정하 였다. 아카데미컬빌리지에 구현한 바 있는 구불구불한 벽돌담 (serpentine wall; figure 참조)을 쌓아 공간을 위요시키려는 구상은 오로지 그의 생각으로, 제퍼슨은 담장의 높이, 벽돌의 양과 재료비까지 언급하였다. 이외에도 경사진 언덕을 화단과 소로로 이루어진 테라스 지형으로 조성할 것을 제시한 부분에 서 토목 계획을 엿볼 수 있다. 이외에도 파리식물원의 씨앗을 식물 수급 방안으로 언급하거나, 도입할 교목으로 낙엽송․굴 참나무․마로니에 등 특정 수종을 열거하고, 각 수종을 구할 수 있는 경로를 제시하는 등 제퍼슨은 자신의 식물학 네트워크와 지식을 바탕으로 실행 가능한 식물 수집 방안을 모색하였다 ). 이러한 내용은 제퍼슨이 답사, 실측, 계산 등의 과정을 통해 현 장에 구상안을 앉히기 위해 노력하였음을 가리킨다. 에머트에게 보낸 제퍼슨의 서신은 식물원에 대한 기초 구상 으로, 공간 구조에 대한 상세한 생각이나 식물 배열 방안에 대 한 의견은 담겨있지 않다. 초본과 교목 정원을 구분하여 각각 평지와 언덕에 배치하고, 언덕은 화단과 소로를 계획할 수 있 도록 계단 형태로 만들 것을 제시하는 수준에 그쳤다 ). 이처 럼 초본과 교목을 각각 별도로 배열하는 방식은 제퍼슨의 파리 거주 시절 보았던 파리식물원 그리고 비슷한 시기에 조성된 하 버드대학교 식물원에서 공통적으로 발견된다. 그러나 주어진 자료만으로는 여기서 더 나아가 하버드대학교 식물원을 비롯 해 세기 후반부터 세기 초반 자연풍경식 정원 양식에 영향 을 받은 유럽과 미국의 여러 식물원들에서 나타나는 구불구불 한 길과 비정형적인 정원 구조(o'malley, ; johnson, ) journal of the korean institute of landscape architecture 김정화 한국조경학회지� 제� 권� 호( 년� 월) figure . view of site proposed for a botanical garden at university of virginia source: photo by author in march 는 확인할 수 없다. . 식물원 조성 추진 과정 제퍼슨으로부터 서신을 받은 바로 다음 날인 년 월 일 에머트는 그에게 식물원 조성 제안에 동의하지만, 식물학이 자신의 주 전공분야가 아님을 강조하면서 감독직에 대한 책임 을 완곡히 거절하는 답변 )을 보냈다. 에머트가 ‘마지못해’ 식물원 조성 감독직을 담당하는 동안, 제 퍼슨은 특히 년 월 한 달 동안 다음과 같이 식물원 설립 을 위해 주변 여건을 마련하였다. 첫째, 그는 주변의 벗과 전문 가로부터 조언과 도움을 구하였다. 미국 네 번째 대통령이자 지역 농업협회장을 역임했던 자신의 벗 james madison( ~ )과 학교 설립 지원자 중 한 사람인 john hartwell cocke ( ~ )에게 식물원 설립에 대한 조언을 요청했고 ), 둘 째, 앙드레 투인의 사망 후 그간 파리식물원의 씨앗이 버지니 아 지역 농업협회로 전달되었음을 알게 된 제퍼슨 )은 농업협 회장 james barbour( ~ )에게 서신을 보내 씨앗의 신 속한 배송을 요청했다 ). 이외에도 버지니아대학교 조성공사 감 독인 arthur brockenbrough( ~ )에게 모든 여유시간 동안 식물원 조성에 힘을 쏟을 것을 주문하는 작업 지시 노트 를 보냈다 ). 그러나 제퍼슨이 사망하고 몇 달 뒤인 월 일, 에머트는 이사회에 보낸 서신 )에서 다시 한 번 식물학이 자신의 주 전 공분야가 아님을 강조하면서 사임의 뜻을 밝히고 자리에서 물 러났다. fox-bruguiere( )의 연구에 따르면 이후 대학교 이 사회는 년 월 다시 식물원을 조성할 계획을 세웠으나, 이 역시 실현되지 못했다. 식물원 계획이 수립되었던 부지는 오늘 날 테니스장과 잔디마당으로 활용되고 있다(figure 참조). Ⅴ. 결론 제퍼슨의 버지니아대학교를 위한 식물원 계획 배경은 연구 결과 다음과 같은 두 가지로 요약된다. 첫째, 세기 후반부터 유럽에서 대두된 자연과학으로서 식물학의 중요성에 대한 인 식과 국가에 경제적 이익을 가져오는 식물학의 효용성에 대한 동시대 미국에서의 믿음이다. 둘째, 제퍼슨의 식물학 및 식물 네트워크이다. 여러 식물학자와 탐험대로부터 수집한 식물과 씨앗은 버지니아대학교 식물원 설립의 당위성과 실현 가능성 으로 작용하였다. 특히 제퍼슨이 주변 인물들의 제안 후에 학 교 내 식물원 설립을 구상하기 시작한 사실과 식물원의 방향에 대한 코레아의 생각을 수용한 것으로 보아, 그의 식물학 네트 워크가 버지니아대학교 식물원 조성 착수에 결정적인 역할을 한 것으로 판단된다. 동시대 구미에서 식물학의 사회적 위상과 제퍼슨의 네트워 크와 같은 조건이 버지니아대학교 식물원 설립의 배경이었다 하더라도, 계획 실행은 제퍼슨이 있었기에 가능했다. 에머트에 게 보낸 서신에서 드러나듯, 현장답사와 측량, 재료 계산, 공간 구상, 식물 수급 계획 등을 수립하고 실시한 자는 제퍼슨이었 다. 제퍼슨이 년 월 한 달 동안 추진력을 보일 수 있었던 이유는 세기 초 유럽과 미국 사회에서 식물학의 가치를 읽어 내는 통찰력, 식물학에 대한 개인적인 관심과 열정, 네트워크 그리고 정원에 대한 그의 경험과 지식이 밑바탕에 있었기 때문 이다. 담장으로 식물원을 위요한다거나, 비탈진 언덕을 계단형 으로 조성하려는 생각, 부지 선정 시 거리와 물 공급을 고려하 는 부분이 이를 뒷받침한다. 세기 전후 유럽과 미국의 주요 식물원들과 비교해볼 때 버 지니아대학교 식물원 구상이 보이는 특징은 다음과 같다. 첫째, 초본 이외에 교목 정원을 별도로 구성하고 의학이 아닌 박물학 토머스� 제퍼슨의� 버지니아대학교� 식물원� 구상� 배경과� 내용 journal of the korean institute of landscape architecture 한국조경학회지� 제� 권� 호( 년� 월)� � 의 일부분으로서 식물학 연구와 교육을 강조했던 측면에서 세기 후반 유럽 식물원들이 약용 식물원에서 식물원으로 발전 한 흐름과 같은 경향을 보인다. 둘째, 코레아와 제퍼슨은 호기 심이나 장식적 요소를 배제하며 온실 설치를 거부하였고, 버지 니아대학교 식물원을 지역 기후에 적합한 해외 수종을 도입하 고 확산시키기 위한 실용 식물 연구 장소로 계획했다. 이러한 방향성은 온실을 설치했던 유럽과 미국의 많은 식물원과 다른 부분으로, 특히 온실을 건축하고 실용 식물 이외에 약용 식물 과 장식용 식물까지 두루 수집했으며 국내외 수종을 가리지 않 았던 하버드대학교 식물원과 대조를 이룬다. 본 연구는 코레아와 제퍼슨의 버지니아대학교 식물원 조성 배경과 구상 내용을 당시 유럽과 미국의 식물원과 비교함으로 써 그 특징을 드러냈다는 데 의의를 지닌다. 버지니아대학교 식 물원 구상은 세기 전후 유럽 식물원의 진화 방향을 반영하면 서도, 동시에 다른 식물원과 달리 장식적 요소를 배제하고 실 용 식물 연구와 확산을 추구한, 공공성을 강력하게 띄었던 사 례이다. 따라서 제퍼슨의 버지니아대학교 식물원 조성 계획은 미국 초창기 식물원의 파리를 중심으로 한 유럽 식물학계 및 식물원과의 관계, 그리고 식물원의 사회적 역할과 공공성에 대 한 국가 리더의 생각이 반영된 독특한 사례이다. 현재까지 드러난 자료만으로는 미완에 그친 버지니아대학교 식물원의 공간 구조와 식물 전시 방식을 구체적으로 파악하기 어렵다. 이에 따라 본 연구는 버지니아대학교 식물원 구상에서 세기 전후 구미의 식물원에서 나타나는 비정형적인 공간 구 조와 같은 정원 양식의 변화를 논하지 못한 한계를 지닌다. ------------------------------------- 주 . o'malley( : - )는 제퍼슨과 그의 동료들이 원 서식지를 모사한 자연 풍경 속에서 식물을 관찰하는 것이 식물 과학과 교육 기능에 적합하다고 생각했다고 주장하였으나, 이를 뒷받침하는 인 용 부분은 식물 생리학 교육과 연구 장소로서 식물원의 기능을 강 조하는 글로, 자연식 풍경이나 미적 측면에 대한 생각이 보이지 않 는다. o'malley의 버지니아대학교 식물원에 대한 해석은 재고될 필 요가 있다. 주 . 미국의회도서관의 서지학자 emily millicent sowerby( ~ ) 가 년에 시작해 년에 완성한 토머스 제퍼슨의 도서 목록이 다. 토머스 제퍼슨의 년 도서 목록과 년 미국의회도서관에 판매된 도서 목록을 바탕으로 작성되었는데, 총 권 중 권의 쪽 부터 쪽에서 식물학 관련 도서 목록을 확인할 수 있다(http:// hdl.loc.gov/loc.rbc/jeffcat. ). 주 . 프랑스 외교관의 미국에 대한 질문에 대한 제퍼슨의 답으로 구성된 책으로, 버지니아 주의 지형, 자원, 동물과 식물, 역사 등이 기술되 어 있다. 주 . 길머는 버지니아 출신의 법률가로, 버지니아대학교 초대 법학 교수 로 임용될 예정이었으나 사망으로 인해 자리에 오르지 못했다. 어 린 시절 제퍼슨을 통해 소개 받은 코레아와 식물 조사 여행을 다녔 고, 장 자크 루소의 글 중 식물학의 즐거움에 관한 부분을 영문으로 번역할 만큼 식물학에 깊은 관심과 지식을 보였다(davis, ). 주 . 가장 실용적이며 저렴한, 공립학교를 위한 식물원 계획(plan for a botanic garden for a public school, on the most useful, and least expensive plan) . papers concerning the establishment and construction of the university of virginia, - . accession # -b, at the special collections, university of virginia library. 주 . letter form thomas jefferson to john patton emmet, april , , in the thomas jefferson papers, - at the library of congress. 주 . “botany is still in her infancy in america; some amateurs are scattered throughout this continent, and some european rather traveling gardeners than real botanist, are collecting plants and shrubs and trees for the gardens of european rich men, or for the nurseries. (letter from correia da serra to james smith, november , , as cited in davis, : ).” 주 . “the botanic garden at cambridge was intended for the cultivation of plants from various parts of the world, to facilitate the acquisition of botanical knowledge. it was also intended to receive all such indigenous trees, shrubs, and herbaceous plants, as are worthy of attention, as being useful in domestic economy, in the arts, or in medicine. …… they are objects rather of study than of culture; but whoever studies botany for the love of it, will find his patient and laborious investigation of these admirable productions of almighty wisdom, amply rewarded by the entertainment and gratification they will afford (peck, : ⅲ-ⅳ).” 주 . http://hdl.loc.gov/loc.rbc/jeffcat. 주 . “i will sketch out those which would principally attract notice, … adding the linnaean to the popular names, … . senna -cassia ligustrina. arsmart -polygonum sagittatum. clivers, or goose grass -galium spurium. … (jefferson, : )." 주 . “botany i rank with the most valuable sciences … (letter from thomas jefferson to thomas cooper, october , , in the thomas jefferson papers, - ).” 주 . “the greatest service which can be rendered any country is to add an useful plant to its culture (ford, - : ).” 주 . “a complete catalogue of the trees, plants, fruits, &c., is probably not desired. i will sketch out those which would principally attract notice, as being medicinal; esculent; ornamental; or, useful for fabrication … (jefferson, : )." 주 . “the professors of natural philosophy & of natural history, still re- main to be procured. i despair of finding chemistry with natural history. it may go with natural philosophy, especially as the mathematician can take astronomy, or it may belong [to] dr. dunglison, who is very desirous of having it with his department (letter from gilmer to jefferson, september , , as cited in davis, : ).” 주 . “the next best person i can hear of, and undoubtedly superior to any i saw in g. b. is dr. j. p. emmet, son of the eminent counsel of newyork. ... he is an excellent chemist, mineralogist, geologist, & pretty well informed in zoology, & botany. i doubt if we can procure a more fit person (letter from gilmer to jefferson, december , , as cited in davis, : ).” 주 . “no doubt it is desired by every friend of science, … (letter form thomas jefferson to john bradbury, march , , in the thomas jefferson papers, - ).” 주 . “there ought also to be a botanic garden, …. (letter from william thornton to thomas jefferson, may , , in the thomas jefferson papers, - ).” 주 . “has m. correa de serra, written to you concerning mr nuttal as botanist? i am sure we can get none better, …… i wish a botanical garden was established, for it grieves me to see the annual present of seeds from the jardin des plantes to the agricultural society here, so negligently thrown away (letter from thomas cooper to thomas jefferson, june , , in the jefferson papers of the university of virginia at the special collections, university of virginia library).” journal of the korean institute of landscape architecture 김정화 한국조경학회지� 제� 권� 호( 년� 월) 주 . “i would add to these four acres, two more for a grove of trees, none of them of virginia, but either from other states of the union, or from other countries of temperate climates, that could grow here (letter from thomas jefferson to thomas cooper, july , in the jefferson papers of the university of virginia).” 주 . plan for a botanic garden for a public school, on the most useful, and least expensive plan. 주 . 버지니아대학교는 년 월 일 첫 강의를 열었고, 에머트는 년 봄에 부임했다(https://www.encyclopediavirginia.org/). 주 . “it is time to think of the introduction of the school of botany into our institution (letter form thomas jefferson to john patton emmet, april , , in the thomas jefferson papers, - )." 주 . “… restrained altogether to objects of use, and indulging not at all in things of mere curiosity, and especially not yet thinking of a hothouse or even a green-house. i inclose you a copy of his paper, which was the more satisfactory to me, as it coincided with the moderate views … (letter from jefferson to emmet, april , )." 주 . “make out a list of the plants thought necessary and sufficient for botanical purposes, and of the trees we propose to introduce, … (letter from jefferson to emmet, april , )." 주 . “as to the seeds of plants, much may be obtained from the gardeners of our own country. …… the seed of the larch can be obtained from a tree at monticello, cones of the cedar of libanus are in most of our seed shops, … (letter from jefferson to emmet, april , )." 주 . “the bottom ground would suit for the garden of plants, the hillsides for the trees. … form all the hill sides into level terraces of convenient breadth curving with the hills, and the level ground into beds and allies (letter from jefferson to emmet, april , ).” 주 . letter from john patton emmet to thomas jefferson, april , , in thomas jefferson collection, - , at the huntington library. 주 . letter from thomas jefferson to james madison, may , , in the thomas jefferson papers, - ; letter from thomas jefferson to john hartwell cocke, may , , in the jefferson papers of the university of virginia at the special collections, university of virginia library. 주 . letter from james madison to thomas jefferson, may , , in the james madison papers at the library of congress. 주 . letter from thomas jefferson to james barbour, may , , in coolidge collection of thomas jefferson manuscripts at massachusetts historical society (as cited in fox-bruguiere, : ). 주 . letter from thomas jefferson to arthur brockenbrough, may , in the jefferson papers of the university of virginia. 주 . letter from john patton emmet to the board of visitors, october , # , the special collections, university of virginia library. references . andress, r.( ) a short letter by humboldt to jefferson. early american studies ( ): - . . bailey, l. h.( ) the standard cyclopedia of horticulture. new york: the macmillan company. . betts, e. m. ed.( ) thomas jefferson's garden book. charlottesville: thomas jefferson memorial foundation. . davis, r. b. ed.( ) correspondence of thomas jefferson and francis walker gilmer - . columbia: university of south carolina press. . davis, r. b.( ) forgotten scientists in old virginia. the virginia magazine of history and biography ( ): - . . davis, r. b.( ) the abbé correa in america, - : the contributions of the diplomat and natural philosopher to the foun- dations of our national life. philadelphia: american philosophical society. . doyle, d.( ) edinburgh doctors and their physic gardens. the journal of the royal college of physicians of edinburgh : - . . ewan, j.( ) how many botany books did thomas jefferson own? missouri botanical garden bulletin: - . . fallen, a. c.( ) a botanic garden for the nation: the united states botanic garden. washington, d.c.: us government printing office. . findlen, p.( ) possessing nature: museums, collecting, and scien- tific culture in early modern italy. berkeley: university of california press. . ford, p. l. ed.( - ) the works of thomas jefferson, vol. . new york: g. p. putnam’s son. . fox-bruguiere, l.( ) an uncultivated legacy: jefferson's bo- tanical garden at the university of virginia. master’s thesis. uni- versity of virginia. . fox-bruguiere, l.( ) ‘to be pursued at all spare times’: thomas jefferson's botanical garden at the university of virginia. studies in the history of gardens & designed landscapes ( ): - . . hedrick, u. p.( ) a history of horticulture in america to . portland, or.: timber press. . hickman, c.( ) curiosity and instruction: british and irish botanic gardens and their audiences, - . environment and history : - . . hill, a. w.( ) the history and functions of botanic gardens. annals of the missouri botanical garden ( / ): - . . hunt, j. d.( ) the botanical garden, the arboretum and the cabinet of curiosities. in a world of gardens. london: reaktion books. pp. - . . jefferson, t.( ) notes on the state of virginia. richmond, va.: j. w. randolph. . johnson, n. c.( ) nature displaced, nature displayed: order and beauty in botanical gardens. london; new york: i.b. tauris. . lausen-higgins, j.( ) "sylva botanica": evaluation of the lost eighteenth-century leith walk botanic garden edinburgh. garden history ( ): - . . nichols, f. d. and r. e. griswold( ) thomas jefferson landscape architect. charlottesville: university press of virginia. . nichols, f. d.( ) thomas jefferson's architectural drawings. charlottesville, va.: thomas jefferson memorial foundation. . o'malley, t.( ) art and science in the design of botanic gardens, - . in j. d. hunt, ed. garden history: issues, approaches, methods. washington, d.c.: dumbarton oaks research library and collection. pp. - . . o'malley, t.( ) “your garden must be a museum to you": early american botanic gardens. huntington library quarterly ( / ): - . . parker, j.( ) the development of the cambridge university botanic garden. curtis's botanical magazine : - . . peck, w. d.( ) a catalogue of american and foreign plants cultivated in the botanic garden, cambridge, massachusetts. cam- bridge, mass.; hilliard and metcalf at the university press. 토머스� 제퍼슨의� 버지니아대학교� 식물원� 구상� 배경과� 내용 journal of the korean institute of landscape architecture 한국조경학회지� 제� 권� 호( 년� 월)� � . petersen, r. h.( ) new world botany: columbus to darwin. ruggell [liechtenstein]: a. r. g. gantner verlag. . rice, h. c., jr.( ) thomas jefferson's paris. princeton, n. j.: princeton university press. . solit, k. d.( ) history of the united states botanic garden: - . us government printing office, washington, dc. . spary, e. c.( ) utopia's garden: french natural history from old regime to revolution. chicago: university of chicago press. . wilson, d. and l. stanton( ) jefferson abroad. newyork: modern library. . wilson, r. g., j. m. lasala and p. c. sherwood( ) thomas jefferson's academical village: the creation of an architectural masterpiece. charlottesville: university of virginia press. . papers concerning the establishment and construction of the uni- versity of virginia, - , at the special collections, university of virginia library. . the james madison papers at the library of congress. . the jefferson papers of the university of virginia at the special collections, university of virginia library. . the thomas jefferson papers, - at the library of congress. . thomas jefferson collection, - , at the huntington library. . http://hdl.loc.gov/loc.rbc/jeffcat. (catalogue of the library of thomas jefferson) . http://www.ctgpublishing.com . https://commons.wikimedia.org . https://www.encyclopediavirginia.org received revised accepted 인익명� 심사필 : : : � december,� � january,� � may,� � may,� ( st) ( nd) wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ doi: . /j.bpj. . . monday, february , a the c terminus of milton is an important regulator of the mitochondria associated motors and is involved in conferring the calcium sensitivity from miro to the motors. milton - is sufficient for the mitochondrial binding, whereas the - amino acids are critical for the control of calcium sensitivity of mi- tochondrial motility. -pos biophysical properties of mitochondria undergoing fusion xingguo liu , orian shirihai , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, boston university, boston, ma, usa. emerging evidence shows the importance of genes controlling mitochondrial fusion in physiology and their deregulation in neurodegenerative and metabolic disorders. however, apart from djm, the biophysical properties of the fusion- competent mitochondria remain elusive. to evaluate the conditions of contact formation and fusion, we used organelle-targeted fluorescent proteins, includ- ing photoactivatable gfp, which allow tracking of individual mitochondria. in h c cells, almost every mitochondrion is aligned with microtubules that pro- vide the primary tracks for mitochondrial movement. our results show that ~ % of fusion events involve moving mitochondria. however, fusion occurs irrespective of mitochondrial speed. furthermore, ~ % of fusion events in- volve the tip portion of the mitochondrion, whereas only ~ % of these events involve organelle side. nocodazol, a microtubule disrupting agent that inhibits mitochondrial movements decreases the fusion frequency and changes mito- chondrial fusion sites. strikingly, - % of the physical contacts between ad- jacent mitochondria did not result in fusion events. to evaluate whether the fu- sion efficacy depends on the spacing between the outer and inner mitochondrial membranes we used drugs that alter the matrix volume. valinomycin, a k þ ion- ophore that induces matrix swelling evoked a decrease in mitochondrial motil- ity leading to fewer contacts among mitochondria but the number of fusion events was maintained, indicating an increase in fusion efficacy. this change occurred at a low valinomycin concentration ( . nm) that did not affect djm or opa cleavage. nigericin ( . mm), a k þ /h þ ionophore that induces shrinkage of the matrix elicited fusion inhibition and mitochondrial aggrega- tion. importantly, no motility inhibition or opa cleavage occurred at the same time and the djm was increased. these results suggest that mitochon- drial fusion is facilitated by mitochondrial motility, the key determinant of the inter-mitochondrial encounter numbers and preferentially involves the front-tip of the moving organelle. in addition, fusion efficacy depends on the mitochondrial matrix volume. -pos mitochondrial fusion dynamics in human skeletal muscle-derived cells veronica eisner, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. mitochondria have a fundamental role in both muscle physiology and pathol- ogy. mitochondrial fusion and fission are important for energy metabolism, calcium homeostasis and cell death. however, the mechanisms underlying mitochondrial dynamics are poorly understood, especially in physiological models such as skeletal muscle. here we evaluated mitochondrial fusion dy- namics in human skeletal muscle cells (husmc). skeletal muscle satellite cells were isolated from human muscle biopsies and were maintained and dif- ferentiated in cell culture. mitochondrial fusion events were evaluated by con- focal imaging of cells expressing mitochondria matrix targeted dsred and matrix targeted or outer mitochondrial membrane (omm) targeted photoacti- vatable-gfp. when we tagged the mitochondria in ~ % of total cellular area with photoactivated-gfp, we found those mitochondria undergoing matrix fusion with a frequency of . . events/min/cell (n= ). among the fusion events, % led to complete fusion and only % was followed by separation at the apparent fusion site within to seconds. both complete and transient fusion events resulted mostly from longitudinal mergers, involving end to end interaction or from mergers of adjacent mitochondria in side to side orien- tation. furthermore, we found that omm and matrix fusion are sequential and separable steps, displaying . seconds gap (n= ). finally, we evaluated the mitochondrial fusion dynamics in husmc derived from both normal and malignant hyperthermia susceptible individuals. at resting state, no significant differences were found in the number of events or in their characteristics. thus, mitochondrial fusion commonly occurs in husmc, and enables mixing of both soluble and integral membrane factors. this process would help to maintain the stability of mitochondrial metabolism. the relatively low frequency of the tran- sient fusion is probably due to the parallel organization of the cytoskeletal tracks for mitochondria and to the limited mitochondrial motility. -pos imaging interorganelle contacts and local calcium dynamics at the er-mitochondrial interface györgy csordás , péter várnai , tünde golenár , swati roy , george purkins , tamás balla , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary, national institutes of child health and human development, bethesda, md, usa. the local coupling between er and mitochondria is essential for proper cell function. a main role of the er-mitochondrial junctions is to provide a local calcium signaling domain that is important both for keeping energy production in line with demand and for the control of apoptotic mechanisms. so far it has not been possible to visualize the tiny er-mitochondrial contact points in living cells or to monitor the localized [ca þ] changes in the narrow space between er and mitochondria ([ca þ]er-mt). here, we exploited rapamycin-mediated heterodimerization of fkbp and frb domains of fluorescent protein constructs respectively targeted to the outer mitochondrial membrane and the er as drug-inducible inter-organelle linkers to identify er-mitochondrial contacts and to measure the [ca þ ]er-mt. high- resolution fluorescence imaging and d reconstruction revealed rapamycin-in- duced clustering of the er-targeted fluorescent linker-half to the contact areas with the mitochondria without major changes in the spatial arrangement of the er. essentially all mitochondria displayed contacts with the er in both rbl- h and h c cells. plasma membrane-mitochondrial contacts were less frequent with er stacks being inserted between the two organelles. single mitochondria display discrete patches of er contacts as well as continuous as- sociations. cytoplasmic and mitochondrial matrix [ca þ] showed robust er-mitochondrial ca þ transfer with considerable heterogeneity even among adjacent mitochondria. pericam-containing linkers revealed ip -induced [ca þ ]er-mt signals that were resistant to buffering bulk cytosolic [ca þ ]c in- creases and exceeded um. the largest [ca þ ]er-mt signals did not occur at the tightest associations, indicating space requirements for the ca þ transfer machinery and functional diversity among er-mitochondrial junctions. these studies provide direct evidence for the existence of high ca þ microdo- mains between the er and mitochondria in living cells, and open new possibil- ities to probe the functional importance of this specialized compartment. -pos dependence of er-mitochondria calcium transfer on different ip receptor isoforms tunde golenar , szava bansaghi , gyorgy csordas , david i. yule , suresh k. joseph , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, university of rochester medical center, rochester, ny, usa. ip receptors (ip rs) release ca þ from the er, which is locally relayed to the mitochondria to control several aspects of mitochondrial function. recent stud- ies have suggested that type ip rs (ip r ) are particularly important for me- diating the ca þ transfer at the er-mitochondrial interface. we set out to sys- tematically evaluate the respective role of each ip r isoform in chicken dt cell lines that express only one ip r isoform (double-knockout, dko , dko and dko ) or provide a null-background (triple-knockout, tko) for analysis of mammalian ip rs and their mutants. simultaneous imaging of cytoplasmic and mitochondrial matrix [ca þ] ([ca þ]c and [ca þ]m) was performed in either permeabilized cells chal- lenged with ip or in muscarinic receptor overexpressing intact cells stimulated with carbachol (cch), an ip -linked agonist. saturating ip evoked complete discharge of er calcium and resulted in comparable [ca þ]m increases in each dko. furthermore, the cch-induced [ca þ]c spike was closely followed by a [ca þ]m rise in each dko. when tko cells were rescued with rat ip r or ip r , the latter mediated a larger [ca þ]c transient but the [ca þ]m increases were very similar for both isoforms. the relationship between the [ca þ]c peak and the corresponding [ca þ]m response was also very similar for ip r and ip r . to assess the impact of the release kinetic through ip r in the mitochondrial ca þ transfer we used two point mutants of the ip r , which display either enhanced inhibition by ca þ (d n) or are relatively insensitive to ca þ inhibition (d n). d n showed dampened [ca þ]m signal and [ca þ]m vs. [ca þ]c relationship, whereas d n displayed a steeper [ca þ]m vs. [ca þ]c relationship than the wild type ip r . thus, each ip r isoform can support local er-mitochondrial ca þ transfer and their competence to activate mitochondrial ca þ uptake depends on their deactiva- tion kinetic. 	biophysical properties of mitochondria undergoing fusion 	mitochondrial fusion dynamics in human skeletal muscle-derived cells 	imaging interorganelle contacts and local calcium dynamics at the er-mitochondrial interface 	dependence of er-mitochondria calcium transfer on different ip receptor isoforms a scoring system predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leukemia poster session i s conclusion: our results indicate an increased risk of acute gvhd in association with dpb mismatch regardless of the tce classifica- tion. tce classification did not correlate with any transplant out- come considered in our cohort. this analysis does not support the clinical relevance of ranking dpb mismatches based on the tce algorithm. a scoring system predicting outcome after unrelated donor stem cell transplantation in primary refractory acute mye- loid leukemia craddock, c.f. , labopin, m. , schmid, c. , mohty, m. , rocha, v. queen elizabeth hospital, birmingham, united kingdom; faculte de medecine st-antoine, paris, france; klinikum augsburg, germany; nantes hospital, nantes, france; hopital st louis, paris, france treatment options for adults with primary refractory aml (pref aml) are extremely limited. whilst sibling allogeneic stem cell transplantation can result in long term survival most pa- tients lack a matched family donor and are destined to die of refrac- tory disease. greater availability of unrelated donors and improvements in supportive care have increased the proportion of patients with pref aml in whom allografting is technically fea- sible but the outcome of unrelated donor transplantation in this population has not been extensively studied. we therefore analysed overall survival in patients with pref aml who underwent unrelated donor transplantation between and with a me- dian follow-up of months ( - ). patients received three or more courses of induction chemotherapy. the median percentage of bone marrow (bm) blasts at transplant was %. the -year overall survival for the whole group was %. in multivariate anal- ysis, fewer than three courses of induction chemotherapy, a lower percentage of bm blasts at transplant and patient cmv seropositiv- ity were associated with improved survival. we used the prognostic factors identified in multivariate analysis to develop a scoring sys- tem. this allowed the delineation of four prognostic groups with survival rates ranging between % and %. this study dem- onstrates an important role for unrelated donor transplantation in the management of selected patients with pref aml and confirms the importance of initiating an urgent unrelated donor search in pa- tients with no matched sibling donor who fail to respond to induc- tion chemotherapy. pre-transplant factors allow the identification of patients with pref aml who are likely to benefit from unre- lated donor transplantation. hla disparity and rapid immune reconstitution do not over- come propensity to relapse in patients undergoing haploi- dentical hematopoietic stem cell transplant (hsct) with persistent disease at the time of transplant grosso, d. , alpdogan, o. , carabasi, m. , colombe, b. , cornett farley, p. , filicko-o’hara, j. , flomenberg, p. , gitelson, e. , kasner, m. , martinez-outschoorn, u. , o’hara, w. , wagner, j.l. , weiss, m. , werner-wasik, m. , flomenberg, n. thomas jefferson university kimmel cancer center, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa while increasing hla disparity is known to be associated with increased risk of significant graft versus host disease (gvhd), there is less data as to whether increasing hla disparity is corre- lated with stronger, clinically significant graft versus leukemia ef- fects. we examined a group of patients with acute leukemia undergoing haploidentical hsct to assess whether ) there was a marked difference in relapse rates based on the degree of hla mismatch and ) if early recovery of donor lymphoid subpopula- tions was associated with less relapse after hla mismatched hsct. thirty-four adult patients with aml ( ) and all ( ) underwent haploidentical hsct between and using a step process which separates the infusion of the lymphoid and myeloid portions of the graft while attempting to render the lymphocytes tolerant utilizing cyclophosphamide. the patients re- ceived x e /kg donor cd cells (dli) after conditioning with either tbi gy (n ) or fludarabine mg/m � , thiotepa mg/m � , and tbi gy (n ). two days after the dli, all patients received cyclophosphamide (cy) mg/kg � followed by a cd selected donor product. the tbi based regimen was given to % of patients with all and % with aml. we exam- ined relapse rates based on the number of antigen mismatches at a, b, cw, and drb in the gvh direction. there were no discern- able differences based on degree of hla disparity with even the most haplodisparate group exhibiting high rates of relapse when disease was present at hsct. in contrast, the presence of active leukemia at the time of hsct had far more impact on subsequent relapse rates (see table). table . outcomes based on degree of hla disparity antigen antigen antigen antigen mismatch mismatch mismatch mismatch number of patients relapsed/ total relapsed/ total relapsed/ total relapsed/ total active disease at hsct ( %) / ( %) / ( %) / ( %) n/a cr at hsct ( %) / ( %) / ( %) n/a / ( %) total / ( %) / ( %) / ( %) / ( %) we also examined the impact of immune recovery on relapse. ab- solute numbers of nk, and cd and cd t cells were examined in the first months post hsct. t cell, mnc, and total chimerism was greater than % donor-derived at the time of the assessment. for patients who did or did not relapse post hsct the median numbers of lymphoid subsets (cells/ul) were: nk ( - ) vs ( - ), cd ( - ) vs ( - ), and cd ( - ) vs ( - ) respectively. in this small series of patients treated with the step transplant method, relapse was associated more with the presence of disease at hsct than with any discern- able trend in degree of hla disparity or early immunologic recov- ery. other approaches to treat resistant leukemia are required to substantially improve disease free survival in these high risk patients. anti-hla antibodies predict graft failure, time to engraft- ment and umbilical cord unit dominance in double umbilical cord blood transplantation cutler, c. , kim, h.t. , sun, l. , sese, d. , kao, g. , vasquez, m. , armand, p. , koreth, j. , ho, v.t. , alyea, e. , soiffer, r.j. , ballen, k. , ritz, j. , milford, e. , antin, j.h. dana-farber cancer institute, boston, ma; dana-farber cancer institute, boston, ma; brigham and women’s hospital, boston, ma anti-hla antibodies (hla-ab) predict graft failure in unrelated donor and single umbilical cord blood (ucb) transplantation. we measured hla-ab in double ucb transplantation (ducbt) with the hypothesis that hla-ab would predict time to engraftment, graft failure and ucb unit dominance. methods: patients with banked pre-transplant sera who under- went ducbt using / or better allelic hla-matched ucb units ( - ) were studied. labscreen (one lambda inc.) was used to capture class i/ii hla-ab and the luminex is system was used to detect fluorescent tagged binding of human igg. visual software was used to normalize results and to deter- mine the presence of mixed class i/ii hla-ab. positive samples were tested using single antigen-coated microbeads. beads with a mean fluorescent intensity above baseline were considered positive. chimerism was measured using str typing of informa- tive alleles. graft failure was defined as the absence of neutrophil engraftment days from ducbt or loss of ucb chimerism by day without malignant relapse. ucb dominance was defined as . % contribution to hematopoiesis by a single ucb unit at day . 	a scoring system predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leu ... 	hla disparity and rapid immune reconstitution do not overcome propensity to relapse in patients undergoing haploidentical h ... 	anti-hla antibodies predict graft failure, time to engraftment and umbilical cord unit dominance in double umbilical cord b ... php using an italian population database to profile prevalence and costs of chronic conditions a abstracts php a comparative analysis of the financing, pricing and reimbursement systems for prescription drugs in the nordic countries kristensen fko, sverre jm, holm lb pharmecon as, asker, norway objectives: to elicit similarities and differences in the poli- cies and practices for financing, pricing and reimbursing pre- scription drugs in the often perceived similar nordic countries of denmark (d), finland (f), norway (n) and sweden (s). methods: a review of the four countries’ authorities’ stated policies and practices on the matter were performed through a search of the literature and of the respective authorities’ home- pages. the information was validated through interviews with key personnel of the reimbursement agencies in each country, and the final study reports for the respective countries were reviewed by the same persons. results: all countries have a national health care system financed by taxation. there are dif- ferences in the reliance upon patient co-payment (n %, others – %) and whether financing is a county (s) or national (others) responsibility. all have regulated prices for reimbursed drugs; based either upon international comparisons (n, d) or country-specific decisions (s, f). the criteria used for deciding to reimburse a drug vary between the countries, and reimbursement is practiced differently in several other dimensions: mandatory requirement for pharmacoeconomic analysis (f, n, s), the existence of patient-specific reimbursement systems (d, f, n), product- (s) or indication-based (others) reimbursement, use of graded (f), conditional (n, s) or temporary (s) reimbursement, use of reimbursement contracts (n), and different processes for handling disagreement about decisions. conclusion: the nordic countries all have a national health care system financed by taxation and encompassing prescription drugs, but differ in a number of other dimensions with respect to financing, pricing and reimbursing such drugs. php a systematic review of the european pharmaceutical market and the impact of european union regulation and jurisdiction van ginneken ej, schreyögg j, gericke ca, busse r berlin university of technology, berlin, germany objectives: to examine the impact of the increasing role of the european union (eu) on the european pharmaceutical market, focusing on industry and national policies. to give a sys- tematic overview of the current state of the european pharma- ceutical market as a whole. methods: systematic literature review for the years – , including “grey” sources of information, online databases, european commission docu- ments and european court of justice rulings, relevant journals and systematically tracing back relevant references. results: the eu attempts to liberalise the pharmaceutical market and the realisation of a single european market (sem) came to a stand- still, after some considerable achievements (e.g. marketing authorisation). instead, the eu seems to concentrate on coor- dination of results through the adoption of the so-called g recommendations. eu member states successfully—and inten- tionally—kept control on the issues of pricing, reimbursement, pharmacies and prescribing. over the last years they adapted increasingly convergent measures to cope with rising pharma- ceutical expenditures, without long-lasting cost containment effects. however, recent european case law might prove to have far reaching consequences on the provision of medicines. the european pharmaceutical industry—although profitable—is underperforming compared to the usa, which is blamed on restrictive regulatory frameworks in the member states. con- clusions: the future of the actors in the european pharma- ceutical market is not clear. will it bring more european influence or a strengthening of national influence? in the short term, major change towards a sem seems unlikely, but in the longer term european history showed that major change is pos- sible. it seems clear that much depends on the attitude of member states towards the new approach and the interpretation and influence of european case law. for the european industry, adoption and implementation of g recommendations is of great importance for future competition with us-based companies. php using an italian population database to profile prevalence and costs of chronic conditions yuen ej, maio v, louis dz, rabinowitz c, robeson m, smith kd jefferson medical college, thomas jefferson university, philadelphia, pa, usa objective: individuals with chronic medical illness may have multiple health problems, and are often costly and difficult to manage. this study identifies those with highly prevalent chronic conditions and assesses related health service use and costs in the population of emilia romagna (rer), a large northern italian region. methods: pharmaceutical, hospital, and demographic data from and have been assembled for the entire population of rer ( million). pharmaceutical and hospital tariffs were a proxy for costs. pharmacy and hospital records were used to identify individual morbidity. data included demo- graphic and geographic information, encounter dates, diagno- sis/procedure codes, pharmaceutical information, and health care costs. individuals were classified as having a chronic condi- tion in , and we examined pharmacy and hospital use/costs in . descriptive analyses compared mean and total costs, as well as proportions within the population. results: we iden- tified five highly prevalent chronic conditions: cardiovascular dis- eases (n = , , . % of the population); rheumatologic conditions (n = , , . %); gastric acid disorders (n = , , . %); chronic respiratory illnesses (n = , , . %); and psychiatric disorders ( , , . %). . % of the population had one or more of these five chronic conditions, and these individuals accounted for . % of the pharmacy costs and . % of the hospital costs in the following year. for persons with these five conditions, we also described use and costs by age and gender, residence, and income. conclusions: interest- ingly, one-fourth of the population with selected chronic condi- tions accounted for large proportions of cost and use of health services. the ability to identify those with chronic conditions would help planners and governmental agencies to address health care needs, increase quality of care, avoid unnecessary hospitalizations, and save costs. these types of data can be used to estimate health care financing and risk adjustment models, and profile specific clinical, demographic or geographic sub-groups. php adherence index of performance—a new method and tool for ongoing evaluation of medication adherence improvement initiatives day d pfizer, new york, ny, usa objectives: to develop a standardized means for measuring the impact of medication adherence improvement initiatives in disparate pharmacy claims databases over sequentially overlap- ping periods of time. methods: the adherence index of untitled research report dendrochronological dating of two tulip poplars on the west lawn of monticello daniel l. druckenbrod* and nicole chakowski department of geological, environmental, and marine sciences, rider university, lawrenceville road, lawrenceville, nj, , usa abstract two tulip poplars (liriodendron tulipifera l.) growing at monticello, the home of thomas jefferson, were recently removed because of potential damage to the house; however, their ages were uncertain. jefferson’s writings express his interest in tulip poplars and suggest that he may have planted at least one, but his documents are not conclusive. after the thomas jefferson foundation purchased the property in a.d. , expert opinions on the ages of these trees were divided. this study investigated the ages of both trees (referred to as northwest and southwest). even though the southwest tree’s bole was hollow and decay was present in the northwest tree, usable cross-sections were obtained. the southwest tree’s cross-section was from an upper branch, whereas upper and lower cross-sections were extracted from the bole of the northwest tree. ring widths were crossdated and statistically verified using an oak chronology from monticello. the innermost rings of the southwest tree dated to a.d. and those of the upper and lower sections of the northwest tree dated to and , respectively. these dendrochronological analyses in combination with historical photographs support the conclusion that the northwest tree and likely the southwest tree were jefferson era, but the evidence for the southwest tree is less certain. keywords: monticello, thomas jefferson, liriodendron tulipifera, garden history, southeastern us, agricultural plantation. introduction monticello, located in the virginia piedmont, was the plantation home of thomas jefferson, who in his own words sought to be remembered as the ‘‘author of the declaration of american independence, of the statute of virginia for religious freedom, and father of the university of virginia’’ (jefferson : ). monticello is now classified as a national historic landmark as well as a unesco world heritage site. in , jefferson cleared and leveled the site for mon- ticello and began construction in . jefferson moved into the house in , but continued to build and remodel other parts of the house through (nichols and bear ). he lived there until his death in . while jefferson lived at monticello, he took an active interest in planning the grounds surrounding monticello, notably with the plantings of gardens in as he neared the end of his second term as president (betts and perkins ). using tree-ring dating, the objective of this study is to determine whether two large tulip poplar trees recently removed from the west lawn of monticello date to the jefferson era. these tulip poplars are referred to as southwest and northwest (figure ) following jefferson’s designations for the four shrub circles placed around the main house (jefferson ). jefferson’s own writings attest to his interest in native trees – tulip poplars particularly. in an letter to madame de tessé, jefferson exclaims that only the white oak (quercus alba l.) ‘‘disputes for pre-eminence with the lirioden- dron,’’ calling the white oak the jupiter and the tulip poplar ‘‘the juno of our groves’’ (jefferson : – ). as he planned changes to his west*corresponding author: ddruckenbrod@rider.edu tree-ring research, vol. ( ), , pp. – doi: http://dx.doi.org/ . / - - . . copyright ’ by the tree-ring society lawn gardens, on april , , jefferson states that he planted ‘‘ . laurodendron in margin of s. w. [shrub circle] from the nursery’’ (jefferson : ). this entry has led to a historical interpretation that the southwest tree is likely a jefferson-era tree, but no direct link has shown that either tree dates to that time. other contem- porary references to the natural establishment of tulip poplars in the soil at monticello exist in a letter from thomas mann randolph, jr., lamenting the rapid ability of tulip poplars to establish in monticello’s plantation fields and an letter from cornelia j. randolph who mentions the weeding of young poplars from the yard at monticello; however, her letter may refer instead to populus (l.) species that were planted at monticello (jefferson ). tulip poplar seed- lings are still common today in fields adjacent to monticello at montalto where an annual mowing is used to prevent the re-establishment of forests in historically open areas. across their wide range in eastern north america from new york to florida, tulip poplars grow best in deep, moist loam soils within coves or lower slopes and are common on the ultisol soils of the virginia piedmont (burns and honkala ). although originally considered an early successional species, tulip poplars can attain ages of more than years and may be a component of late successional forests as well (skeen et al. ; pederson ). materials and methods the growth of trees in the virginia piedmont can be explained largely as a function of precipi- tation and available solar radiation passing through a forest canopy to a tree (kozlowski ; druckenbrod et al. ). thus, a component of the annual growth of these trees is a common climate signal, typically spring or summer precip- itation (e.g. druckenbrod et al. ). the samples from these two trees are compared to a well- replicated oak chronology extending back to a.d. at monticello with many of the trees growing nearby on the western slopes of monticello. the southwest tree was felled in and the northwest tree in . five radii of tree-ring widths from three cross-sections were analyzed in this study. two radii from an upper cross-section of the southwest tree, one radius from an upper cross- section on the northwest tree, and two radii from a lower cross-section of the northwest tree at ca. m (stump height). the diameter of the northwest tree at stump height was ca. . m (inside bark), noticeably smaller than the diameter of the southwest tree. crossdating using skeleton plots (stokes and smiley ) and ring-width measure- ments was conducted using a dissecting stereo microscope. ring widths were measured using a velmex ta system to a -micron precision (as described in speer ) and the j x measurement program. cofecha was used to verify the visual crossdating of the ring-width data by generating correlations for each sample in -year moving windows (holmes ). samples with poor statis- tical correlation in cofecha were compared with figure . southwest tulip poplar (with cables) in foreground and northwest tulip poplar in background. photograph was taken the day before the removal of the southwest tree (june , ). northwest tree was removed in june . [credit: thomas jefferson foundation, inc. at monticello]. druckenbrod and chakowski skeleton plots to confirm the most accurate possible dating. ring-width measurements from each tulip poplar were converted into separate standard chronologies using the program arstan (cook and krusic ). cores were detrended using either a negative exponential or linear regression fit (with a positive or negative slope) and a -year cubic spline. these chronologies enabled a final correlation of each tree’s average tree-ring indices with a master oak (quercus l.) chronology (n trees) from forests surrounding monticello dating back to a.d. using the spearman rank correlation, a nonparametric measure of similarity between the two chronologies through time. results for each of the five ring-width series (figure ), cofecha generated positive correlations across all -year sample windows; however, the southwest tree had lower correlations than the northwest tree (table ). the earliest ring of the upper section of the northwest tree crossdated to , but the lower radii crossdated to . the upper branch of the southwest tree crossdated to ; however, some of the moving window correlations for these series were low, below a commonly accepted threshold of . for individual series. similarly, an averaged growth chronology of ring-width series from the northwest tree correlated significantly with the local oak chronology (figure a) with a correlation of . (p , . ). the averaged growth chronology from the southwest tree again exhibited a lower, but still highly significant, correlation (figure b) of . (p , . ). as an additional verification, the northwest tree chronology was compared with an independently dated chronology of tulip poplars from an old stand near buena vista, virginia, collected by dr. neil pederson (unpublished data). the correlation between these two chronologies was . (p , . ), even with a large distance between these sites extending into the blue ridge mountains physiographic province. discussion these results clearly evidence that the north- west tree and likely the southwest tree began growing well before jefferson’s death in . although the southwest tree did not crossdate as strongly as the northwest tree, the dendrochrono- logical dating of both trees is extremely unlikely to have resulted from chance. several factors could explain the variation in magnitude of these correlations with the local oak chronology across series and through time. first, the oak species present at monticello are generally more drought tolerant during the growing season and may not respond to interannual climate variation in the same manner as tulip poplars. second, these oaks grew in a closed-canopy forest environment, whereas the two tulip poplars were likely in open canopy conditions and maintained as part of the formal gardens for at least their latter years. finally, perhaps most importantly the southwest poplar’s correlations are particularly low during the early to mid s. this tree was topped around and heavily pruned during the s (thomas jefferson foundation, inc. ). these actions may have induced other interannual growth trends in this tree obscuring the climate forcing on its growth through the mid-twentieth century. independent verification of the age of these two trees was also considered through a compar- ison of photographs, paintings, maps, and letters depicting the conditions of the west lawn of monticello from to the present. to assist in approximating the size of these two trees through time, beck ( ) provides a site index curve for tulip poplars by age in different soil fertilities. the curve shows the range in tree heights for forest- grown, dominant or co-dominant tulip poplars through time based on sites in the virginia and north carolina piedmont. extrapolating from the range of soils on this site index curve, a typical tulip poplar would have grown taller than the top of monticello (ca. . m) by years of age, even on the lowest quality site. most tulip poplars would be taller than m by twenty years of age. the tulip poplars at monticello were growing in largely open conditions, which could reduce the rate of height growth relative to trees in a forest. these two tulip poplars may also be growing on a site that wouldn’t naturally feature this species in a forest. even though tulip poplars readily establish tulip poplars at thomas jefferson’s monticello in the soils as seedlings at monticello, their distribu- tion is limited to largely the north and east slopes of the site. oaks and other species dominate the forests on the south and west slopes of the site. the soils on the top of the site would not have as much soil moisture as those on the north and east slopes and could result in a slower rate of growth for these poplars. two documentary records from the early to mid- th century provide conflicting interpretations of the ages of these two trees. a map of the garden restoration undertaken by the garden club of virginia between – (betts and perkins ; p. – ) labels both of these tulip poplars as original to jefferson’s time (figure ), but earlier in the s an arborist and architect both concluded that these trees post-dated jefferson (thomas jefferson foundation, inc. ). an analysis of photographs of the west lawn of monticello during the th and late th centuries consistently shows these two tulip poplars in their present locations. notably in the early th century, an oblique aerial of the west lawn in the winter of – shows both trees at that time (figure ). at the turn of the th century, these trees remain visible in a holsinger studio collection photograph of the east front of the house taken between and (figure ). the two trees are clearly taller than the house in this image, and the diameter of the northwest tree remains noticeable smaller than the southwest tree even at this early date. this east front perspective is similar to one of the oldest images of the house taken by william roads in (held by the albert and shirley small special collections library, university of virginia). the southwest figure . crossdated ring-width measurements from northwest and southwest tulip poplars sampled in this study. a and b are lower radii and c is an upper radius from the northwest tree, and d and e are upper radii from the southwest tree. druckenbrod and chakowski tree and the faint outline of the northwest tree are also apparent in this image. again, both trees are taller than the house in this image. using the lower cross-section of the north- west tree, one can estimate the size of this tree through time. by the end of , the year of jefferson’s death, the diameter of the tree (as averaged from the two measured radii) inside the bark would have been ca. . cm. by the end of , the year of the roads photograph, the diameter inside the bark would have been . cm. an estimation of the tree’s height in is also possible with an allometric equation. a parabolic equation (h + b d + b d ) from ker and smith ( ) for forest grown trees (see druckenbrod et al. ) requires the tree’s figure . comparison of the northwest tree (a) and southwest tree (b) chronologies (dashed lines) with a local monticello oak chronology (bold line). table . -year moving window correlations for each ring-width series compared against the other four ring-width series from the northwest and southwest tulip poplars growing on the west lawn at monticello. tree series time span – – – – – – – – northwest a – . . . . . . . . northwest b – . . . . . . . . northwest c – . . . . . . . . southwest a – . . . . . . southwest b – . . . . . . tulip poplars at thomas jefferson’s monticello figure . plan of monticello garden restored by the garden club of virginia between and labeling both the northwest and southwest trees as original to jefferson. flower beds and shrub circles are shown in gray, trees with black dots, and original trees are labeled ‘‘ ’’. [credit: thomas jefferson foundation, inc. at monticello]. figure . oblique aerial photograph of the west lawn at monticello in – showing the northwest and southwest tulip poplars adjacent to the house. [credit: thomas jefferson foundation, inc. at monticello]. figure . east front of monticello showing the northwest and southwest tulip poplars adjacent to the house between and . [credit: holsinger studio collection – , albert and shirley small special collections library, university of virginia, charlottesville]. druckenbrod and chakowski diameter including its bark (assuming additional cm) as well as estimates of maximum height and diameter for tulip poplars. because these param- eters are imperfectly known, this height determi- nation is approximate at best, but this equation suggests that the tree would have been ca. m at the end of . this result agrees with the interpretation of these early photographs in that even the northwest tree would have been notice- ably taller than the house by the time of the roads and holsinger photographs. thus, these photo- graphs provide a consistent documentary record of what appears to be the northwest and southwest trees back to the late s when both trees were still taller than the house. because the southwest tree was hollow at the base, we were limited to sampling a cross-section from an upper branch (with a cable wire attached). comparing its size to the northwest tree and knowing that the branch position was at least as high as the house, it seems likely that the southwest tree is substantially older than the date determined from the upper cross- section. potentially, the greater size of the southwest tree could have also resulted from a more productive soil beneath its position on the west lawn. archaeological analyses of the west lawn suggest that prior to the construction of the house the site was leveled by transferring the a and a portion of the b soil horizons from the northern part of the west lawn (where the northwest tree was growing) to the southern portion (where the southwest tree was growing) (f. neiman, director of archaeology, monticello, personal communication), potentially improving the soil fertility for the southwest tulip poplar at the expense of the northwest tree. the preponderance of the evidence suggests that the northwest tree and the southwest tree likely established during the time that jefferson planned his formal gardens on the west lawn of monticello. no documentary record exists to support the interpretation that jefferson intention- ally planted the northwest tree, as tulip poplars readily establish on mineral soil and documentary evidence suggests that their establishment was pervasive at monticello. regardless of the tree’s origins, jefferson was clearly fond of tulip poplars and appears to have incorporated this tree into his west lawn plan. although dendrochronological dating cannot confirm that the southwest tree is the same as the one mentioned by jefferson in his april , , garden book entry, its size and presence in early photographs also suggest that it was also jefferson era. acknowledgments we thank the thomas jefferson foundation for the opportunity to crossdate these two tulip poplars. we are grateful for the assistance of peggy cornett, peter hatch, gabriele rausse, robert self, william beiswanger, jack robertson, leah stearns, fraser neiman, and others from the thomas jefferson foundation in providing these samples and early photographs. we are also grateful to frederick williamson for cutting the samples for the northwest tree and neil pederson for sharing a tulip poplar chronology. ed cook, michael mann, david richardson, and the archaeology staff and field school students at monticello all assisted in collecting samples for the master oak chronology. nicole chakowski was supported by a grant from bristol-myers squibb to rider university. references cited beck, d. e., . yellow poplar site index curves. usfs southeastern forest experiment station research note , asheville; pp. betts, e. m., and h. b. perkins, . thomas jefferson’s flower garden at monticello. university of virginia press, charlottesville. burns, r. m., and b. h. honkala, tech. coords, . silvics of north america: . conifers; . hardwoods. agriculture handbook . us department of agriculture, forest service, washington, dc, : p. http://www.na.fs.fed.us/ pubs/silvics_manual/volume_ /liriodendron/tulipifera.htm. ac- cessed september, . cook, e. r., and p. j. krusic, . arstan ver. d. http:// www.ldeo.columbia.edu/tree-ring-laboratory/resources/software. accessed september, . druckenbrod, d. l., m. e. mann, d. w. stahle, m. k. cleaveland, m. d. therrell, and h. h. shugart, . late- eighteenth-century precipitation reconstructions from james madison’s montpelier plantation. bulletin of the american meteorological society : – . druckenbrod, d. l., h. h. shugart, and i. davies, . spatial pattern and process in forest stands within the virginia piedmont. journal of vegetation science : – . tulip poplars at thomas jefferson’s monticello holmes, r. l., . computer assisted quality control in tree- ring dating and measurement. tree-ring bulletin : – . jefferson, t., . thomas jefferson’s garden book, - , with relevant extracts from his other writings. annotated by e. m. betts. introduction by p. j. hatch. thomas jefferson memorial foundation, charlottesville. ———, . the papers of thomas jefferson, digital edition, edited by b. b. oberg, and j. j. looney, university of virginia press, charlottesville. ker, j. w., and j. h. g. smith, . advantages of the parabolic expression of height diameter relationships. the forestry chronicle : – . kozlowski, t. t., . light and water in relation to growth and competition of piedmont forest tree species. ecological monographs : – . nichols, f. d., and j. a. bear, jr., . monticello. thomas jefferson memorial foundation, monticello, virginia. pederson, n., . eastern old list. http://www.ldeo.columbia. edu/,adk/oldlisteast/. accessed july, . skeen, j. n., m. e. b. carter, and h. l. ragsdale, . yellow-poplar: the piedmont case. bulletin of the torrey botanical club : – . speer, j. h., . fundamentals of tree-ring research. the university of arizona press, tucson, arizona. stokes, m. a., and t. l. smiley, . an introduction to tree- ring dating. university of chicago press, chicago. thomas jefferson foundation, inc, . ‘‘tulip poplar tree.’’ the thomas jefferson foundation, inc. http:// www.monticello.org//and-gardens/poplar-tree. accessed june, . received october ; accepted september . druckenbrod and chakowski << /ascii encodepages false /allowtransparency false /autopositionepsfiles true /autorotatepages /none /binding /left /calgrayprofile (dot gain %) /calrgbprofile (none) /calcmykprofile (u.s. sheetfed coated v ) /srgbprofile (srgb iec - . ) /cannotembedfontpolicy /error /compatibilitylevel . /compressobjects /off /compresspages true /convertimagestoindexed false /passthroughjpegimages true /createjobticket false /defaultrenderingintent /default /detectblends true /detectcurves . /colorconversionstrategy /leavecolorunchanged /dothumbnails false /embedallfonts true /embedopentype false /parseiccprofilesincomments true /embedjoboptions true /dscreportinglevel /emitdscwarnings false /endpage - /imagememory /lockdistillerparams false /maxsubsetpct 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anion channel isoform (vdac ). here, we show that hcc induced by carcinogenic compounds, aflatoxin or den is highly sensi- tized to tbid-induced omm permeabilization and cyto c release when com- pared to normal liver. expression levels of vdac and bak were also higher in hcc than in control liver. the role of the vdac -bak pathway in the differential tbid sensitivity was validated by overexpression of vdac in primary hepatocytes. in hcc cells, elevation of bak was also associated with an increased level of mcl- , an inhibitor of bak. furthermore, both constitutive and drug-induced genetic deletion of mcl- in mouse embryonic fibroblasts caused sensitization to tbid-induced omm permeabilization in the absence of a change in bcl-xl or bax . based on these results, we are evaluating the possibility of selective killing of hcc cells by the combination of a bak activator and an mcl- inhibitor. -pos board b which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c release? shamim naghdi , peter varnai , soumya sinha roy , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadlephia, pa, usa, semmelweis university, budapest, hungary. vdac proteins represent a main component of the outer mitochondrial membrane (omm). the vdac family is composed of isoforms with more than percent similarity. although their primary role was known to be in ion and metabolite transport between mitochondria and cytosol, it has been dis- covered that vdacs are also involved in apoptotic pathways. we have recently found that specifically the vdac isoform is needed for tbid-induced cyto- chrome c release, due to its role in supporting bak insertion to the omm (roy et al. . embo rep. : - ). to determine the domain(s) of vdac which supports bak insertion, vdac and vdac amino acid composition compared and the unique attributes of vdac sequencewereconsideredformutationalanalysis.totestfunctionalsig- nificance of the changes in vdac or vdac , vdac -/- mef cells that are resistant to tbid, were transfected with the mutants and insertion of bak to the omm and cytochrome c release were monitored in permeabilized cells by immunoblotting. previously, we showed that the vdac -specific n terminal tail and cysteins are dispensable for tbid-induced omm permeabilization. to approach the remaining differences four chimeras were prepared: vdac ( - )vdac ( - ), vdac ( - )vdac ( - )vdac ( - ), vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ). these studies revealed that tbid dependent omm permeabilization is only sup- ported by vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ), indicating that the first two third of vdac is required and sufficient for bak targeting to the omm and tbid induced cytochrome c release. -pos board b outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion david weaver , xingguo liu , veronica eisner , peter varnai , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary. cells and tissues deficient in mitochondrial fusion have been shown to have defects linked to the exchange of inner membrane (imm) and matrix compo- nents, particularly mitochondrial dna. outer membrane (omm) constituents originate in the cytoplasm, thus the role of intermitochondrial transfer of omm components by fusion remained unexplored. here we show that fibro- blasts lacking the gtpases responsible for omm fusion, mfn / , have a more heterogeneous distribution of omm proteins than wild-type cells, and in partic- ular that heterogeneity of pro-apoptotic bak leads to dysregulation of bid- dependent apoptotic signaling. homogeneous distribution of bak is partially rescued by introduction of mfn into mfn / -/- cells. furthermore, fusions be- tween mitochondria lacking and containing bak result in hybrids sensitive to bid. proteins with different modes of omm association display varying degrees of heterogeneity in mfn / /- cells and different kinetics of transfer during fusion in fusion-competent cells. efficient coupling of omm to imm fusion depends on the presence of both mfn isoforms and is antagonized by the mitochondrial fission protein, drp . thus, omm function depends on mitochondrial fusion and is a locus of dysfunction in conditions of fusion deficiency. -pos board b mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat veronica eisner , guy lenaers , gyorgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, inserm u- , institut des neurosciences de montpellier, montpellier, france. mitochondria are highly mobile and dynamic organelles in many cell types. however, in the muscle, mitochondria are crammed into the narrow space among the myofilaments. until now, it remained unclear if mitochondrial fusion occurs in and supports the contractile activity of skeletal muscle (sm). here we applied mitochondria matrix-targeted dsred and photoactiv- able gfp to study mitochondrial fusion in rat fdb sm fibers. in vivo electro- porated fibers were imaged by confocal microscopy. when we tagged the mitochondria in ~ % of cell area with twophoton photoactivation of gfp, rapid spreading of fluorescence showed subsets of interconnected mitochondria, mostly in longitudinal direction. matrix fusion occurred with a rate of . and . events/min in adult fibers and skeletal myotubes, respectively. expres- sion of autosomal dominant optical atrophy-causing mutants of the fusion protein opa or ethanol exposure caused suppression of fusion, which is fol- lowed by mitochondrial dysfunction and late onset myopathies. when chal- lenged by repetitive tetanic stimulation, ethanol exposed cells displayed intracellular ca þ dysregulation, appearing as a fatigue pattern. ethanol also induced a decrease in mfn protein levels, without significantly altering mfn , opa or deltapsi. depletion of mfn alone was sufficient to suppress mi- tochondrial fusion in fdb fibers. fusion inhibition was apparent before any cell dysfunction, suggesting that suppression of fusion is not secondary to other problems in the cells. to directly test the role of mfn in ca þ regulation, ryr -transfected control and mfn ko mefs were stimulated with caffeine. mfn ko cells showed oscillatory ca þ transients that decayed faster than that in the control. thus, fusion dynamically connects skeletal muscle mito- chondria and serves as a target mechanism of both mutations and environmen- tal cues to cause impaired excitation-contraction coupling. -pos board b bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action katarina stroffekova, lucia balogová, mária maslaňáková, lenka dzurová, pavol mi�skovský mi�skovský. safarik university, kosice, slovakia. apoptosis is a key process in the development and maintenance of tissue homeostasis. this process of controlled cell death is tightly regulated by a balance between cell survival and damage signals. we focused our attention towards the intrinsic mitochondrial apoptotic pathway, where bcl- family of proteins plays the major role. we were particularly interested in two pro- apoptotic players bak and bax. here we investigated their role in apoptosis triggered by photodynamic action. we show the localization of bax and bak in u- mg human glioma cells incubated with photosensitizer hypericin (hyp) before and after photodynamic action. apoptotic stimulus by hyp photodynamic action caused bax translocation into mitochondria. however our results suggest that under these condi- tions there are two populations of mito- chondria: one which contains bax and bak simultaneously, and is almost exclu- sively localized near the plasma mem- brane; the other which contains bax only and is distributed throughout the cell. the different protein content and spatial distri- bution of these two populations suggest that they can play different roles in re- sponse to apoptotic stimuli. -pos board b stimulation of bax mitochondrial localization by bcl-xl thibaud renault , oscar teijido , gisele velours , yogesh tengarai ganesan , florent missire , nadine camougrand , bruno antonsson , laurent dejean , stephen manon . ibgc-cnrs, bordeaux, france, nyu college of dentistry, new york, ny, usa, merck-serono sa, geneva research center, geneva, switzerland, california state university of fresno, fresno, ca, usa. cytochrome c release, the commitment step of apoptosis, is regulated at the mitochondria through protein-protein interactions between the bcl- family proteins. an imbalance of this interaction network due to the up-regulation of the proto-oncogenes bcl- and/or bcl-xl lead to a resistance to apoptosis and is associated with tumor formation. bcl-xl overexpression act at the level of the mitochondrial outer membrane (mom) by inhibiting bax-mediated apoptosis; more particularly mac formation and cytochrome c release. how- ever, the molecular mechanisms through which bcl-xl affect earlier steps of bax-mediated apoptosis are not fully understood. surprisingly, we found that mitochondrial bax redistribution and change of conformation were not inhibited but rather spontaneously increased in response of bcl-xl overexpres- sion. in order to further investigate the molecular mechanisms involved in this wednesday, february , a effect, different bax and bcl-xl mutants were co-expressed in yeast. we found that wild-type bcl-xl increased the mitochondrial localization of bax; but that this effect was lost when bcl-xl mutants unable to physically interact with bax were expressed instead of wild-type bcl-xl. also, bax retrotranslocation from mitochondria to cytosol was also increased; suggesting that both translocation and retrotranslocation events were differentially stimulated by the expression of wild-type bcl-xl. further, a c-terminally truncated mutant of bcl-xl, that lost its capacity to relocate to mitochondria, still increased the mitochondrial localization of and cytochrome c release activity of wild-type bax. finally, wild-type bcl-xl protected activated bax against proteolytic degradation. these data suggest that bcl-xl, by acting as a modulator of mitochondrial bax localization, may play an active role along the pathway leading to bax activation. -pos board b mitochondrial dna nucleoid redistribution after mitochondrial network fragmentation as visualized by d super-resolution biplane fpalm microscopy andrea dlaskova , tomas spacek , jan tauber , lukas alan , jitka santorova , katarina smolkova , jaroslav zelenka , zdenek svindrych , joerg bewersdorf , petr jezek . institute of physiology, prague, czech republic, department of cell biology, yale university, new haven, ct, usa. mitochondrial (mt) network undergoes locally frequent fragmentation and fusion events. when integrated over time, its basic morphology encompasses highly interconnected mt reticulum, a single mitochondrion within the cell ( ). upon certain insults and/or pathological states fragmented network persists. mtdna is organized in nucleoids containing assessor proteins and recruited proteins of mt replication/ transcription machinery. it is debated on their uniform size and whether a single nucleoid contains a single mtdna mol- ecule or up to average mtdna molecules. to image nucleoid distribution within mt network, we employed d super-resolution fluorescent photactivable localization microscopy of biplane schema ( ). mt network of hepatocellular carcinoma hepg cells was imaged first by its matrix space using mteos or as outer mitochondrial membrane contour using eos -conjugates of truncated fis protein (not inducing massive fission, eos -fis tr). resulting d images confirm the existence of highly-connected mt network and unlike conventional confocal microscopy, d biplanefpalm distinguished a hollow character of mt reticulum tubules when visualized by eos -fis tr. upon network fragmen- tation, hollow max ~ micrometer spheres occurred. imaging of mt nucleoids confirmed the existence of ~ nucleoids per cell with size distribution from nm to nm. optimized dual transfection strategy had to be em- ployed for simultaneous imaging of network (mteos or eos -fis tr) and nucle- oids (mtssb-pscfp ). images revealed an equidistant nucleoid distribution of an average distance of ~ micrometer between nucleoids. fragmentation by different agents led to observations of clusters of mt nucleoids within the spher- ical fragmented objects thus formed. supported by grants p / / , p / /p and p / / of gacr and me (czech ministry of education); and r gm - (nih). ( ) mlodzianoski mj, schreiner jm, callahan sp, smolková k, dlasková a, �santorová j, je�zek p, bewersdorf j. opt express ; : – . -pos board b integrating mitochondrial energetics, redox and ros metabolic networks: a two-compartment model jackelyn m. kembro, miguel a. aon, raimond l. winslow, brian o’rourke, sonia cortassa. johns hopkins university, baltimore, md, usa. to understand the mechanisms involved in the control and regulation of mito- chondrial reactive oxygen species (ros) levels, a two-compartment computa- tional mitochondrial energetic-redox (me-r) model accounting for energetic, redox and ros metabolisms is presented. the me-r model incorporates four main redox couples (nadh/nad þ, nadph/nadpþ, gsh/gssg, trx(sh) / trxss). main scavenging systems - glutathione, thioredoxin, superoxide dis- mutase, catalase - are distributed in mitochondrial matrix and extra-matrix compartments, and transport between compartments of ros species (superox- ide: o .- , hydrogen peroxide: h o ), and gsh is also taken into account. model simulations are compared with experimental data obtained from isolated heart mitochondria. the me-r model is able to simulate: i) the shape and order of magnitude of h o emission and dose-response kinetics observed after treatment with inhibitors of the gsh or trx scavenging systems; and ii) steady and transient behavior of djm and nadh after single or repetitive pulses of substrate- or uncoupler-elicited energetic-redox transitions. the dynamics of the redox environment in both compartments is analyzed with the model fol- lowing substrate addition. the me-r model represents a useful computational tool for exploring ros dynamics, the role of compartmentation in the redox environment modulation, and the role of redox regulation in the control of mi- tochondrial function. -pos board b dj regulates neuronal mitochondrial bioenergetic efficiency elizabeth a. jonas, emma lazrove, panah nabili, kambiz n. alavian. yale university, new haven, ct, usa. the progressive loss of midbrain dopaminergic neurons is the hallmark of parkinson’s disease (pd). defects in mitochondrial electron transport and mitochondrial dna replication predispose to the onset of pd. the protein products of several pd genes, including parkin, pink and dj are known to localize to mitochondria; pathological mutations in these genes may disrupt mitochondrial function. in a previous study we found that the anti-apoptotic pro- tein bcl-xl enhances the efficiency of neuronal energy metabolism by increasing total cellular atp levels while decreasing cellular oxygen use. bcl-xl produces this effect in part through a direct interaction with the beta sub- unit of the f fo atp synthase. the interaction causes a decrease in leak of hþ ions across the mitochondrial inner membrane, correlated with an increase in coupling of oxidative phosphorylation. we now show that the parkinson’s dis- ease gene-encoded protein, dj (park ), is also associated with the atp syn- thase complex and has a similar regulatory effect on enzymatic activity of the synthase and on the coupling of oxidation to phosphorylation. pathological mutations of dj may disrupt mitochondrial efficiency leading to neurodegen- eration of mesencephalic dopaminergic neurons. the exact site of the leak inhibited by bcl-xl and dj is now being determined, but likely resides in or adjacent to the c-subunit ring of the atp synthase fo. improved mitochondrial metabolic efficiency that accompanies decreases in h þ leak may result in long lasting changes in synaptic efficacy and survival in both healthy and at-risk neu- rons, suggesting a role for leak regulation in future therapeutic interventions. -pos board b identification of mitochondrial proteins regulated during activation of gper -leading to cardioprotection jean chrisostome bopassa , rong lu , harpreet singh , bjorn olde , l.m. fredrik leeb-lundberg , ligia toro , enrico stefani . university of california los angeles, la, ca, usa, lund university, lund, sweden. several studies have demonstrated that g-protein coupled estrogen receptor (gper ) can directly bind to estrogen and mediate its action. we previously demonstrated that gper activation with g , a specific agonist is cardioprotec- tive in wild-type (wt) mice subjected to ischemia/reperfusion injury. here, we identified regulatedmitochondrial proteinsassociated with gper activationby estrogen treatment in wt and gper -/- mouse hearts after ischemia/reperfu- sion. isolated hearts from male wt (c bl/ ncrl) or gper -/- mice were perfused using the langendorff technique with krebs henseleit buffer, with and without (control) the addition of estrogen ( nm). hearts were subjected to min global ischemia followed by min reperfusion. mitochondria were isolated, and d-dige followed by mass spectrometry was performed. proteins of interest were the ones (up-or down- regulated)in wtþe vs. wt-controlthat remained unchanged in gper-/-þestrogen vs. gper-/–control and wt-control vs. gper-/–control.robustchangesofproteinswereobservedin spots,outof which were down regulated and up regulated. in these spots, unique proteins were identified. among the proteins identified, estrogen treatment in- duced the regulation of enzymes mostly involved in electron transfer chain and atp production. estrogen action involved the down-regulation of filament proteins(filamina,b,c),the up-regulationofproteinsthatactivatetranscription, and proteins involved in the contractile system (tropomyosin and myosin). further, estrogen treatment is associated with regulation of proteins acting in stress (stress- protein, and kda heat shock protein), in cell communication (glial fibrillary acidic protein), and in signaling pathways (membrane-associated phosphatidylinositol transfer protein). finally, estrogen down-regulated the mitochondrial inner membrane protein, this protein controls mitochondrial cris- tae morphology. in conclusion, rapid estrogen effects through gper activation are associated with the down- or up-regulation of mitochondrial and non- mitochondrial proteins likely in close contact to mitochondria. -pos board b adrenergic stimulation accelerates mitochondrial ca d uptake by pyk -dependent phosphorylation of mitochondrial ca d uniporter in cardiac h c cells jin o-uchi, bong sook jhun, shey-shing sheu. jefferson medical college, thomas jefferson university, philadelphia, pa, usa. background: recent break-through discovery in the molecular identity of mitochondrial ca þ uniporter (mcu) opens the new possibilities for applying 	which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c re ... 	outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion 	mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat 	bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action 	stimulation of bax mitochondrial localization by bcl-xl 	mitochondrial dna nucleoid redistribution after mitochondrial network fragmentation as visualized by d super-resolution bi ... 	integrating mitochondrial energetics, redox and ros metabolic networks: a two-compartment model 	dj regulates neuronal mitochondrial bioenergetic efficiency 	identification of mitochondrial proteins regulated during activation of gper -leading to cardioprotection 	adrenergic stimulation accelerates mitochondrial ca + uptake by pyk -dependent phosphorylation of mitochondrial ca + unipor ... editorial reviews in neuroimmunology robert s. fujinami received: december /accepted: december /published online: february # journal of neurovirology, inc. this special issue highlights young investigators in the area of neurovirology. they represent a new wave of researchers who will carry the field into the future. we are delighted to feature some of their works in this special issue. the work spans a wide range of virus-cns-host interactions, and they represent the field well. aaron johnson is at the mayo clinic and provides us with insights into antiviral cd + t cells and the disruption of the blood brain barrier (bbb). he spent most of his early training at the mayo graduate school and received his phd there in biomedical science. his postdoctoral training was at the mayo clinic and at the university of washington. brenda fredericksen is at the university of maryland. she studies models of flavivirus pathogenesis. she received her phd at the university of tennessee health science center and re- ceived additional training at washington university. she provides us with an excellent review of west nile virus pathogenesis. jayasri das sarma received her early training in india and much of her scientific career in philadelphia. she is currently at the thomas jefferson university in philadelphia. jayasri provides an interesting look at microglial cells and interactions with mouse hepatitis virus. her work shows that microglial cells can amplify the virus-induced disease. jennifer gordon spent her education and training in penn- sylvania. she received her phd from drexel (mcp hahne- mann) school of medicine and postdoctoral fellowship at temple. she is at temple university. one of her areas of expertise is human jc virus (jcv). she provides an excellent review of the contributions of the immune response to jcv and how immunomodulatory therapies can lead to the devel- opment of progressive multifocal leukoencephalopathy. julie olson is at the university of minnesota. she received her phd from the university of iowa college of medicine. julie spent additional training at northwestern university. she provides a review about the innate immune response to viral infection and contribution to demyelinating disease. karin peterson is at the rocky mountain laboratories (rml) in hamilton, montana. karin received her phd from the university of missouri medical school. she then went to rml as a postdoctoral fellow, studying retrovirus pathogen- esis in the cns. she started out as faculty at lsu and later returned to rml. karin provides a review of la crosse virus pathogenesis in the cns and innate contributions to disease. maria nagel received her ms from the university of illi- nois and took additional training at the university of colorado school of medicine where she is now on the faculty. she provides new findings on varicella zoster virus (vzv) vascu- lopathy. this is a newly appreciated area of exploration in vsv pathogenesis. mineki saito is at the kawasaki medical school where he studies htlv- pathogenesis. he provides a review of adult t cell leukemia/lymphoma (atl) and htlv- associated myelopathy/tropical spastic paraparesis (ham/tsp). various r. s. fujinami (*) university of utah, salt lake city, ut, usa e-mail: robert.fujinami@hsc.utah.edu j. neurovirol. ( ) : – doi . /s - - - aspects of the innate and adaptive immune response to the virus contribute to the pathogenesis. pooja jain is at the drexel institute for biotechnology and virology research. she received her phd from the central drug research institute in india. she, with shilpa buch who is at the nebraska medical center in omaha, provides new and exciting work on the role of dendritic cells in the pathogenesis of neuroaids. xuebin qin received his md at the wannan medical college in wuhu china and phd at the peking union medical college and chinese academy of medical sciences in bejing, china. after obtaining additional training in boston at tufts university and harvard medical school, he is now at temple university. part of his research is study- ing cd and hiv lysis. this review summarizes some of this work. j. neurovirol. ( ) : – 	reviews in neuroimmunology pancan- - -ver -rogers_ p .. case report open access pancreatic endocrine neoplasm concomitant with a complicated endocrine history: a case report and literature review amelia rogers,* christine lotto, and charles j. yeo abstract background: pancreatic neuroendocrine tumors (pnets) are rare, and metastases when present are most com- monly found in the liver or the peripancreatic lymph nodes. in this study, we present a patient who developed a metastatic pnet in the liver in the setting of multiple concomitant autoimmune disorders, including pernicious anemia and atrophic gastritis with hypergastrinemia. case presentation: the patient is a -year-old woman with a history of hashimoto’s thyroiditis, thymoma, gas- tric carcinoid tumors, and autoimmune atrophic gastritis with pernicious anemia. she was found to have a cm mass in the pancreaticoduodenal groove originating from the pancreas. a preoperative endoscopic ultrasound with fine-needle aspiration showed a well-differentiated pnet. during surgery, she was found to have multiple subcentimeter liver lesions, which on frozen section were shown to be a metastatic neuroendocrine tumor. after surgical resection, final pathology revealed a pnet with metastases to the liver. the metastatic lesions stained positive for gastrin. conclusion: we were only able to find one other example in the literature of a pnet occurring in association with pernicious anemia. our patient developed a metastatic pnet in the setting of multiple autoimmune disor- ders, including pernicious anemia. keywords: atrophic gastritis; gastric carcinoid syndrome; hypergastrinemia; pancreatic neuroendocrine tumor; pernicious anemia introduction and background pancreatic neuroendocrine tumors (pnets) are rare, accounting for < % to % of all pancreatic masses. in this study, we present a patient who developed a metastatic pnet. she had a history of several other concomitant and rare autoimmune disorders, includ- ing autoimmune atrophic gastritis and pernicious anemia. it is known that gastric carcinoid tumors are associated with pernicious anemia, likely stimu- lated by the associated hypergastrinemia. our pa- tient additionally had a history of gastric carcinoid tumors. case presentation a young-appearing -year-old woman presented with a mass in the head of her pancreas in the setting of multiple known autoimmune diseases. she had a long-standing history of hashimoto’s thyroiditis and a prior thymoma resection. she also had a history of hypergastrinemia and atrophic gastritis, both of which were manifestations of pernicious anemia, as evidenced by anemia associated with a low serum b level of pg/ml (normal: – pg/ml), an equivocal intrinsic factor blocking ab assay, and an elevated gastric parietal cell antibody titer of . department of surgery, sidney kimmel medical college, thomas jefferson university, philadelphia, pennsylvania. *address correspondence to: amelia rogers, ms iv, department of surgery, sidney kimmel medical college, thomas jefferson university, walnut street, suite curtis building, philadelphia, pa , e-mail: amelia.rogers@jefferson.edu ª amelia rogers et al. ; published by mary ann liebert, inc. this open access article is distributed under the terms of the creative commons license (http://creativecommons.org/licenses/by/ . ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. journal of pancreatic cancer volume . , doi: . /pancan. . journal of pancreatic cancer (positive > ). because of this, and her lack of any his- tory of peptic ulcer disease, the patient was not thought to have had hypergastrinemia because of the zollinger– ellison syndrome. her pernicious anemia required monthly vitamin b injections. she also had several small, gastric fundal polyps followed yearly with esoph- agogastroduodenoscopy, and she had a history of en- doscopic resection of these gastric carcinoid tumors arising in the polyps. owing to some vague abdominal pain, she under- went a computed tomography scan that showed a cm mass extending extrinsically from the pancreatico- duodenal groove (fig. ). an endoscopic ultrasound confirmed a mm well-circumscribed, hypoechoic mass within the head of the pancreas. fine-needle aspi- ration demonstrated a well-differentiated pnet. upon presentation, she was asymptomatic, without signs of obstructive jaundice or weight loss. preoperative labo- ratory results included a chromogranin a level of ng/l (ref < ng/l) and a markedly elevated gastrin level of pg/ml (ref. < pg/ml). exploration of the abdomen revealed a marble-sized mass just inferior to d in the superior head of the pan- creas. the remainder of the pancreas was firm and the duodenum was not involved. assessment of the liver demonstrated myriad pale blue-colored, subcentime- ter, cystic-appearing lesions. a frozen section from these lesions in the liver showed metastatic neuroendo- crine tumor. the lesion in the superior aspect of the pancreatic head was then dissected and found to be fairly deep in the gland. with distant disease and being wary of the proximity of the mass to the main pancreatic duct, a partial enucleation of the primary pancreatic mass was performed. she did well postoper- atively and was discharged home on postoperative day . her further recovery was uneventful. final pathology confirmed metastatic neuroendo- crine tumor in the liver and a primary pnet. the pan- creatic tumor stained positive for synaptophysin and cd , with a ki proliferation index of %. owing to the degree of necrosis of the primary pancreatic tumor, immunohistochemistry staining for gastrin was nonspecific. the liver biopsy showed features sim- ilar to the pnet and stained positive by immunohisto- chemistry for gastrin (fig. ). discussion carcinoid tumors are relatively rare, with reports describing an annual incidence of . – . out of , patients. , gastric carcinoid tumors are well-differentiated neuroendocrine tumors that arise from the enterochromaffin-like (ecl) cells of the di- gestive tract. gastrin, released by antral g cells of the stomach, stimulates the ecl cells to secrete histamine, which acts on parietal cells to secrete hydrogen ions (acid) to lower the ph of the gastric secretions. gastrin also directly stimulates acid secretion by parietal cells. repeated overstimulation of gastric ecl cells by a hypergastrinemic state is the presumed pathogenesis of gastric carcinoid tumor formation. pernicious ane- mia and the resulting achlorhydria and hypergastrine- mia are one such cause for the development of g cell hyperplasia and elevated gastrin levels. at the time of presentation, our patient had a serum gastrin level of pg/ml (ref. < pg/ml), in retrospect perhaps because of both her achlorhydria and her metastatic pnet, and gastrin positive in the liver. such patients may also have other associated endocrinopathies such as hypothyroidism, diabetes, and hypoadrenocoricoid- ism. our patient had a history of thymoma and hypo- thyroidism from hashimoto’s thyroiditis. there are many conditions that may cause a patient to have an increase in fasting gastrin level and it can be dif- ficult to distinguish benign causes from the gastrinomas. two-thirds of patients with gastrinomas had < -fold increase in gastrin, which overlaps with more common fig. . computed tomography scan showing a cm mass (arrow) in the pancreaticoduodenal groove near d –d . rogers, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . conditions, and < % have a very high (> -fold in- crease) in gastrin. it must be differentiated whether the hypergastrinemia is associated with a hypo- or achlorhy- dic state, such as pernicious anemia, atrophic gastritis, gas- tric cancer, postvagotomy, or antisecretory drug induced, as compared with a hyperchlorhydria, as in helicobacter pylori infection, peptic ulcer disease with obstruction, antral g-cell hyperplasia, renal failure, short bowel syn- drome, or zollinger–ellison syndrome. in addition, a gas- trin provocation test with secretin has a high sensitivity and specificity for diagnosing patients with gastrinomas. our patient had a high gastrin level and did not undergo a gastrin provocation test. she unfortunately likely has both a metastatic gastrinoma and achlorhydic hypergastrine- mia because of pernicious anemia. pnets arise from islet cells. up to – % of these tumors are nonfunctioning and do not secrete the hor- mones of their cells or origin. they have a low annual incidence, < out of , , and comprise only about % to % of all pancreatic tumors. although they tend to have a more favorable prognosis than exocrine pan- creas cancer, hepatic metastases are observed in more than % of patients with pnets. the -year overall survival for patients with pnets is reported to be – % for stage i and % for stage iv disease, depending on the staging system utilized. without a strong index of suspicion, it would be easy for a physi- cian to contribute the sole cause of a patient’s hypergas- trinemia to his or her underlying autoimmune and endocrinopathies. in doing so, they could miss a poten- tially more aggressive pancreatic exocrine cancer. upon our review of the literature, we found only a single case report of a woman with gastric carcinoid tumors in the setting of atrophic gastritis, who subse- quently developed a pancreatic endocrine neoplasm. in this study, we present a patient with a similar history who was found to have a primary pnet with hepatic metastatic disease, in the setting of pernicious anemia, autoimmune atrophic gastritis, and gastric carcinoid tumors. she has been referred to medical oncology and is receiving treatment with small molecule therapy and depo-octreotide, now months postresection. fig. . (a) h + e stain of the well-differentiated pancreatic neuroendocrine tumor at · power; (b) h + e stain of liver metastasis at · power; and (c) gastrin stain (+) liver metastasis at · power. h+e, hematoxylin and eosin stain. rogers, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . author disclosure statement no competing financial interests exist. references . ikezawa k, uehara h, sakai a, et al. risk of peritoneal carcinomatosis by endoscopic ultrasound-guided fine needle aspiration for pancreatic can- cer. j gastroenterol. ; : – . . strosberg j. clinical characteristics of carcinoid tumors. uptodate, may , . . hemminki k, li x. incidence trends and risk factors of carcinoid tumors. cancer. ; : – . . yao jc, hassan m, phan a, et al. one hundred years after ‘‘carcinoid’’: epidemiology of and prognostic factors for neuroendocrine tumors in , cases in the united states. j clin oncol. ; : – . . vakil n. physiology of gastric acid secretion. uptodate, april , . . berna mj, hoffmann km, serrano j, et al. serum gastrin in zollinger-ellison syndrome. medicine. ; : – . . strosberg j. classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine tumors (islet-cell tumors). uptodate, january , . . strosberg jr, cheema a. prognostic validity of a novel american joint committee on cancer staging classification for pancreatic neuroendocrine tumors. j clin oncol ; : – . . caggiano a, adams d, metcalf j, et al. neuroendocrine tumor of the pancreas in a patient with pernicious anemia. am surg. ; : – . cite this article as: rogers a, lotto c, yeo cj ( ) pancreatic en- docrine neoplasm concomitant with a complicated endocrine history: a case report and literature review, journal of pancreatic cancer : , – , doi: . /pancan. . . abbreviations used pnet ¼ pancreatic neuroendocrine tumor ecl ¼ enterochromaffin-like publish in journal of pancreatic cancer - immediate, unrestricted online access - rigorous peer review - compliance with open access mandates - authors retain copyright - highly indexed - targeted email marketing liebertpub.com/pancan rogers, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . http://www.liebertpub.com/pancan#utm_campaign=pancan&utm_medium=article&utm_source=advert department of medicine, thomas jefferson university hospital, philadelphia pa, the united states; office of the deputy health commissioner, philadelphia department of public health, philadelphia, pa, the united states. conflict-of-interest statement: the authors declare that there is no conflict of interest regarding the publication of this paper. open-access: this article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. it is distributed in accordance with the creative com- mons attribution non commercial (cc by-nc . ) license, which permits others to distribute, remix, adapt, build upon this work non- commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non- commercial. see: http://creativecommons.org/licenses/by-nc/ . / correspondence to: brenda french, md, market st, suite , philadelphia, pa , the united states. email: brenda.french@jefferson.edu telephone: + - - - received: septmber , revised: septmber , accepted: septmber , published online: october , abstract aim: lower gastrointestinal hemorrhage in a patient presenting with diverticulitis shifts the diagnosis from uncomplicated to complicated diverticulitis leading to more aggressive treatment measures. this study sought to determine the demographic characteristics of patients hospitalized with diverticular bleeding and diverticulitis with a focus on identifying factors that predispose to hemorrhage. we aim to use demographic information to elucidate whether hemorrhage in the setting of diverticulitis is more similar mechanistically to diverticular bleeding or diverticulitis. materials and methods: inpatient data collected by the pennsylvania health care cost containment council was used to analyze , hospitalizations spanning from to at phila- delphia healthcare institutions where the primary diagnosis for admis- sion was diverticulitis or diverticular bleeding. age, race, and gender were collected for patients hospitalized with diverticular bleeding, di- verticulitis, and diverticulitis complications. demographic data from the us census was used for comparison. results: diverticulitis (n = , ) disproportionately affects white individuals (p < . ) while diverticular bleeding (n = , ) disproportionately affects black individuals (p < . ). of all di- verticulitis complications, hemorrhage (n = , ) had the highest proportion of black individuals. patients admitted for diverticular bleeding tend to be older ( . ± . ) than patients admitted for diverticulitis ( . ± . ; p < . ). among those with compli- cated diverticulitis, patients with hemorrhage are the oldest ( . ± . ). conclusion: patients admitted with diverticulitis complicated by hemorrhage were more similar demographically to patients admit- ted with diverticular bleeding than those admitted with other forms of diverticulitis. reframing diverticulitis complicated by hemorrhage as uncomplicated diverticulitis with diverticular bleeding could prompt more appropriate treatment with avoidance of potentially unneces- sary antibiotics and imaging. synopsis: an epidemiological assessment of diverticular bleeding and diverticulitis found that patients admitted with diverticulitis complicated by hemorrhage were more similar demographically to patients admitted with diverticular bleeding than those admitted with other forms of diverticulitis. because prior studies have suggested that demographic differences between diverticular bleeding and di- verticulitis suggest distinct etiologies, we conclude that hemorrhage in the setting of diverticulitis should be treated as a diverticular bleed and not as a complication of diverticulitis itself. key words: diverticular disease; diverticulitis; diverticular bleeding; hemorrhage © the authors. published by act publishing group ltd. all rights reserved. french b, johnson c. redefining hemorrhage in diverticulitis: complicated diverticulitis or exacerbation of diverticular bleeding? journal of gastroenterology and hepatology research ; ( ): - available from: url: http://www.ghrnet.org/index.php/ joghr/article/view/ introduction although diverticular bleeding is only the second most common original article redefining hemorrhage in diverticulitis: complicated diverticulitis or exacerbation of diverticular bleeding? brenda french , md; caroline johnson , md journal of ghr october ; ( ): - issn - (print) issn - (online) online submissions: http: //www.ghrnet.org/index./joghr/ doi: . /j.issn. - . . . journal of gastroenterology and hepatology research extraction and analysis. hospitalizations with diverticular bleeding or diverticulitis as the primary diagnosis were identified using inter- national classification of disease (icd) and icd codes. from the admissions for diverticulitis, complications were identified from primary or secondary diagnosis fields containing icd and codes for diverticular abscess, perforation, hemorrhage, obstruction, and fistula. patient population inclusion criteria for this study were all patients years or older with a philadelphia zip code admitted to an acute care hospital in philadelphia with primary diagnosis of diverticular bleeding or diver- ticulitis. demographic parameters interrogated included patient age, gender, zip code, race, and ethnicity. race and ethnicity categories in- cluded asian, white (non-hispanic), black (non-hispanic), hispanic, and other (american indian, alaskan native, native hawaiian/pacific islander, and two or more race groups). patients with unknown race (n = ) were excluded from statistical analysis of race composition. us census data from was used for demographic comparison of patient data to the general philadelphia population. statistical analysis basic descriptive statistics and figures were used to summarize data. one-way analysis of variance with tukey’s test for post hoc analysis was used to determine differences between mean age of patients with diverticular bleeding, diverticulitis, and diverticulitis complications. chi square tests with calculation of odds ratios were used to deter- mine racial and gender differences between patients with diverticular bleeding, diverticulitis, or diverticular complications and the general philadelphia population. results between and , there have been , recorded hospital- izations for diverticulitis and , hospitalizations for diverticu- lar bleeding. of the , diverticulitis admissions, nearly % (n= ) were from complicated diverticulitis of which , were complicated by hemorrhage (table ). race diverticulitis disproportionately affects white individuals whom comprise . % of admissions compared to . % of the philadel- phia population (or = . ; % ci = . - . ; p < . ). how- ever, diverticular bleeding (n= ) disproportionately affects black individuals whom account for . % of admissions compared to . % of the general population of philadelphia (or = . ; % ci = . - . ; p < . ) (figure ) (table ). although all complica- tions of diverticulitis appear to preferentially affect white individuals more than black individuals, this trend is least pronounced with hem- orrhage in the setting of diverticulitis (figure ) (table ). in other words, hemorrhage had the highest proportion of black individuals of all diverticulitis complications at . % which is significantly higher than the general population of philadelphia (or = . ; % ci = . - . ; p < . ). age and gender patients admitted for diverticular bleeding tend to be older ( . ± . ) than patients admitted for diverticulitis ( . ± . ; p < . ). among those with complicated diverticulitis, patients with hemorrhage are the oldest ( . ± . ) by at least years (average age of . ± . years for obstruction) and at most years (average cause of hospitalization for diverticular disease[ ], it accounts for up to % of lower gastrointestinal bleeds requiring hospital admission[ ]. unlike diverticulitis, diverticular bleeding is typically not associated with inflammation. instead, diverticular bleeding is likely due to a combination of thinning of the colonic wall increasing the proximity of vessels to the colonic lumen as well as inherent segmental weak- ness in arteries supplying diverticula secondary to structural changes associated with the development of diverticulosis[ ]. this can lead to spontaneous rupture of arteries supplying a diverticulum producing a painless, often self-limiting hematochezia[ ]. though bleeding re- solves in - % of patients without intervention[ , ], bleeding which does not resolve may require endoscopic, endovascular, or surgical correction to prevent complications[ , ]. even for those for which bleeding resolves spontaneously, there is still up to a % chance of rebleeding[ ]. other than recurrent bleeds and potential need for intervention during episodes, diverticular bleeding is typically not as- sociated with long-term complications which often manifest in other forms of diverticular disease, such as diverticulitis. diverticulitis itself has many complications which make it the most severe and life-threatening form of diverticular disease[ , ]. acute diverticulitis is thought to be caused by microperforations in diverticula producing diverticular inflammation which presents as se- vere abdominal pain most commonly localized in the left lower quad- rant[ , ]. the most common complication of acute diverticulitis is ab- scess formation caused by the walling off of material which egressed from diverticular microperforations into adjacent pericolonic fat and mesentery[ , ]. the inflammation of diverticula and pericolonic tis- sue can additionally produce partial obstruction through ileus and colonic narrowing as well as fistulas between the colon and adjacent organs[ ]. lastly, while diverticular bleeding is a separate disease process from diverticulitis, complicated diverticulitis can present with hemorrhage due to irritation of surrounding microvasculature in the area of inflammation[ ]. lower gastrointestinal hemorrhage in a patient presenting with diverticulitis is a defining symptom that shifts the diagnosis from un- complicated diverticulitis to complicated diverticulitis[ ]. because of higher mortality risks associated with complicated diverticulitis and the need for closer monitoring, this shift could mean the difference between conservative outpatient management with little to no antibi- otics and inpatient admission with more aggressive treatment involv- ing intravenous antibiotics and expensive imaging[ ]. the pathophys- iological basis of diverticulitis and diverticular bleeding is not well understood and controversy remains regarding their etiology. this study sought to determine the demographic characteristics of patient populations hospitalized with diverticular bleeding and complicated diverticulitis with a focus on a distinction between hemorrhage in the setting of diverticulitis and diverticular bleeding. methods design a retrospective cross-sectional study was used to determine patterns of hospital admissions for diverticular disease, diverticulitis, and di- verticulitis complications in philadelphia between january and december . data was obtained from the pennsylvania health care cost containment council which collects more than . million inpatient discharge records each year from pennsylvania hospitals. the dataset includes admission characteristics with one primary and up to eighteen secondary diagnosis codes as well as patient charac- teristics including age, gender, zip code, race, and ethnicity. approval was obtained from the institutional review board prior to data french b et al . redefining hemorrhage in diverticulitis abscess perforation hemorrhage obstruction fistula us census philadelphia diverticular bleeding diverticulitis uncomplicated diverticulitis complicated diverticulitis us census philadelphia age of . ± . years for abscess). there was no significant dif- ference in gender distribution between diverticular bleeding and di- verticulitis or any of its complications, all of which showed a female predominance (table ). discussion it is well documented that of the manifestations of diverticular dis- ease, those presenting with diverticular bleeding tend to be older than those with diverticulitis[ , ]. while the peak age for diverticulitis in our data is around years of age, there are almost no cases of diver- french b et al . redefining hemorrhage in diverticulitis table total number, average age (+/- s.d.), and number/percentage f e m a l e g e n d e r o f h o s p i t a l i z a t i o n s w i t h d i v e r t i c u l a r b l e e d i n g , diverticulitis, and diverticulitis complications in philadelphia from - . admission diagnosis n average age female gender (n [%]) diverticular bleeding . ± . ( . %) diverticulitis . ± . ( . %) uncomplicated diverticulitis . ± . ( . %) complicated diverticulitis . ± . ( . %) abscess . ± . ( . %) perforation . ± . ( . %) hemorrhage . ± . ( . %) obstruction . ± . ( . %) fistula . ± . ( . %) table total number and race composition (n, %) of hospitalizations with diverticular bleeding, diverticulitis, and diverticulitis complications in philadelphia from - compared to philadelphia census data. patients with unknown race were excluded. admission diagnosis n asian (n [%]) black, non- hispanic (n [%]) white, non- hispanic (n [%]) hispanic (n [%]) other (n [%]) excluded (n) diverticular bleeding ( . %) ( . %) ( . %) ( . %) ( . %) diverticulitis ( . %) ( . %) ( . %) ( . %) ( . %) uncomplicated diverticulitis ( . %) ( . %) ( . %) ( . %) ( . %) complicated diverticulitis: ( . %) ( . %) ( . %) ( . %) ( . %) abscess ( . %) ( . %) ( . %) ( . %) ( . %) perforation ( . %) ( . %) ( . %) ( . %) ( . %) hemorrhage ( . %) ( . %) ( . %) ( . %) ( . %) obstruction ( . %) ( . %) ( . %) ( . %) ( . %) fistula ( . %) ( . %) ( . %) ( . %) ( . %) census data, philadelphia ( . %) ( . %) ( . %) ( . %) ( . %) figure percent race composition of hospitalizations with diverticular disease, diverticular bleeding, diverticulitis, uncomplicated diverticulitis, and complicated diverticulitis in philadelphia from - compared to philadelphia census data. figure percent race composition of hospitalizations with diverticulitis complicated by abscess, perforation, hemorrhage, obstruction, and fistula in philadelphia from - compared to philadelphia census data. figure number of patients hospitalized with diverticular bleeding, d i v e r t i c u l i t i s , a n d d i v e r t i c u l i t i s c o m p l i c a t e d b y h e m o r r h a g e i n philadelphia from - , categorized by age. pe rc en ta ge o f p at ie nt p op ul at io n( % ) asia black, non-hispanic white, non-hispanic hispanic pe rc en ta ge o f p at ie nt p op ul at io n( % ) asia black, non-hispanic white, non-hispanic hispanic n um be r of p at ie nt s ho sp it al iz ed w it h d iv er ti cu la r d is ea se age ticular bleeding in patients years or younger (figure ). not only is age vastly different between diverticulitis and diver- ticular bleeding, racial composition also was distinctly different for the two forms of disease. the difference between diverticulitis and diverticular bleeding in terms of patient demographics further ce- ments the idea that these two manifestations of diverticular disease have vastly different mechanisms of development and are discreet en- tities within the realm of diverticular disease. however, bleeding can occur as a complication of diverticulitis. hemorrhage in complicated diverticulitis has unique features compared to all other complications including an older age and tendency to occur in black individuals. french b et al . redefining hemorrhage in diverticulitis the demographics associated with diverticulitis complicated by hemorrhage more closely mirror those found in diverticular bleeding than other forms of diverticulitis suggesting that hemorrhage in the setting of diverticulitis is more similar mechanistically to diverticular bleeding than diverticulitis. in fact, this may suggest that rather than a complication of diverticulitis, hemorrhage during acute diverticulitis may be an exacerbation of diverticular bleeding. in other words, the strong overlap in patients susceptible to hemorrhage in the setting of diverticulitis and diverticular bleeding indicates that the etiology of these two manifestations of bleeding are the same or at least similar. this is also important because identifying susceptible populations aids physicians in recognizing patients that may be at higher risk for hemorrhage during an episode of acute diverticulitis. one explanation for the elevated risk of hemorrhage in black and older individuals may be the increased usage of anticoagulant and antiplatelet medications in these populations which have been shown to predispose to diverticular bleeding[ - ]. especially in philadelphia where profound racial healthcare inequality exists, black individu- als are more likely to be on long-term anticoagulation or aspirin due to the increased disease burden including hypertension, dvts/pes, and diabetes disproportionately affecting this segment of the popula- tion[ - ]. similarly, patients > years old are more likely to be using antithrombotic medication as older age is a risk factor for almost all vascular disease manifestations[ , ]. this consideration is important for a physician to bear in mind when treating patients with concurrent coagulopathies and diverticular disease so as to minimize the risk of hemorrhage while maximizing the anticoagulation effects. with shifts towards conservative outpatient management of un- complicated diverticulitis, there is a widening gap between the level of treatment administered for uncomplicated and complicated di- verticulitis cases[ ]. many uncomplicated diverticulitis episodes are treated outpatient with physicians forgoing antibiotics and imaging in favor of reducing the cost burden associated with this disease[ - ]. by classifying hemorrhage as a complication of diverticulitis, patients are exposed to potentially unnecessary antibiotics and imaging that they otherwise might not receive. the results of our study suggest hemorrhage in the setting of diverticulitis is more likely to be closer in etiology to diverticular bleeding than diverticulitis based on patient demographics and therefore should prompt changes in treatment para- digms surrounding this clinical presentation. by prioritizing treatment protocols for diverticular bleeding rather than complicated diverticu- litis, patients may receive more appropriate treatment while avoiding extraneous tests and medications for what would otherwise be consid- ered uncomplicated diverticulitis. in this way, a reclassification of di- verticulitis complicated by hemorrhage as uncomplicated diverticulitis with superimposed diverticular bleeding may reduce the cost burden associated with this disease as well as prevent potentially harmful ef- fects of unnecessary broad-spectrum antibiotics and imaging. overall, patients admitted with diverticulitis complicated by hemorrhage are more similar demographically to patients admitted with diverticular bleeding than those admitted with other forms of diverticulitis. because prior studies have suggested that demographic differences between diverticular bleeding and diverticulitis suggest distinct etiologies, we conclude that hemorrhage in the setting of di- verticulitis should be treated as a diverticular bleed and not as a com- plication of diverticulitis itself. if these patients were diagnosed with uncomplicated diverticulitis with diverticular bleeding instead, this could lead to a reduction in length of stay and prompt more appropri- ate treatment with greater focus on hemodynamic stability, a higher threshold for administering antibiotics, and avoidance of unnecessary imaging. references . milenkovic m, russo ca, elixhauser a. hospital stays for gas- trointestinal diseases, : statistical brief # . sep. in: healthcare cost and utilization project (hcup) statistical briefs [internet]. rockville (md): agency for healthcare research and quality (us); feb. 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[doi: . / .cd .pub ]; [pmid: ] re: evaluation of an ongoing diabetes group medical visit in a family medicine practice correspondence re: evaluation of an ongoing diabetes group medical visit in a family medicine practice to the editor: we want to share our experience with a similar patient demographic using diabetes shared med- ical appointments (smas). the report, by cunningham et al. , describes a series of four -hour sessions. one hour is dedicated to a traditional one-on-one medical appointment with additional time for goal setting, while hour two is group diabetes self-management education. these are two different components, not an sma. the traditional one-on-one medical visit does not work for the care of chronic medical conditions, as exemplified by the low number of people with diabetes meeting goals for hba c, blood pressure, and lipids. our group has previously described a multidisciplinary sma model that incorporates medical care (directed by an endocrinologist), patient support, and interactive group education with improved access to care and lower hba c levels. the value of an sma lies in patient education, empowerment, and engagement. the tagline for every sma should be, “what happens in the group is good for everyone in the group.” over time, patients build relationships with staff and other patients that would be challenging to develop in a limited number of sessions. we appreciate the work our colleagues across the delaware river have done to improve the care of patients with diabetes. we would encourage them to continue their work while changing the model to promote more sharing of patient experiences. we call for changes on a national level to develop sma best practices to aid in further evaluation of this innovative care model, develop a national working group to share sma models and experiences across disease states, and for medical associations to designate time at national conferences to new models of care delivery. valerie s. ganetsky, pharmd, bcps, associate professor of clinical pharmacy, university of the sciences, philadelphia college of pharmacy, research fellow, university of pennsylvania perelman school of medicine; steven kaufman, md, associate professor of medicine, cooper medical school of rowan university., medical director, urban health institute, division head, endocrinology and metabolism references . cunningham, at, delgado, dj, jackson, jd et al. evalua- tion of an ongoing diabetes group medical visit in a family medicine practice. j am board fam med. ; : – . . ganetsky, v, adams, r, coolman, t, brenner, j, kaufman, s. specialty diabetes group medical visits improve access to care and clinical outcomes at lower cost in an underserved patient population. diabetes jun; (supplement ): -pub; . doi: . /jabfm. . . the above letter was referred to the author of the article in question, who offers the following reply. response: re: evaluation of an ongoing diabetes group medical visit in a family medicine practice to the editor: we thank steven kaufman, md; and valerie s. ganetsky, pharmd, bcps and for their re- sponse to our article evaluating a diabetes group medical visit (gmv) and for sharing their experience implement- ing a diabetes shared medical appointment (sma). we applaud their implementation of an ongoing diabetes sma. as the authors illustrate, the terminology for these types of group visits (gmv vs sma) varies. however, the terms are ultimately interchangeable; both refer to group visits that incorporate medical care and group self-man- agement education. , while our program has a different structure than that of drs. kaufman and ganetsky, we do want to clarify that our participants have opportunities to interact and support another during the diabetes self- management education component of our gmv. in fact, an earlier study of our diabetes gmv, consisting of interviews with former participants, showed that a sub- stantial proportion of participants found that the pro- gram offered peer support and important opportunities to learn about diabetes self-management from their peers. in addition, we agree with the authors’ call for na- tional best practices for group visits, a national working group, and national conferences focused on group visits and other care delivery innovations. while diabetes group visits hold promise as a patient-centered approach to chronic disease management, more research is needed to identify the optimal group visit size, frequency, struc- ture, and payment mechanisms that will make these visits effective and sustainable in primary care practices. amy t. cunningham, phd, mph department of family and community medicine, thomas jefferson university, philadelphia, pa to see this article online, please go to: http://jabfm.org/content/ / / .full. references . cunningham at, delgado dj, jackson jd, et al. evaluation of an ongoing diabetes group medical visit in a family medicine practice. the journal of the american board of family medicine. ; : – . jabfm september–october vol. no. http://www.jabfm.org co p yrig h t. o n a p ril b y g u e st. p ro te cte d b y h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n s e p te m b e r . d o w n lo a d e d fro m http://jabfm.org/content/ / / .full http://jabfm.org/content/ / / .full http://www.jabfm.org/ comment open access father figures mark a jobling show a portrait of thomas jefferson ( - ), third us president, to a room full of brits, and no-one ever knows who he is. but if there is an american there, it’s a different matter. they always recognise him: maybe not from his appearance on the two-dollar bill (a balti- more resident was briefly incarcerated for proffering a wad of these rarities in a car radio shop), but more likely from the ubiquitous nickel, or from high school history lessons. i know this because of the talks i give to the general public. speaking to non-scientists about science is fun (as well as part of our solemn duty to obey our munifi- cent funders) and the jefferson story is a good one to tell, with its ingredients of sex, race, slavery and genet- ics. thomas’s wife martha predeceased him by years, and thomas was true to his word never to marry again. but it was alleged that he had a relationship with one of his slaves, sally hemings, and may have been the father of her six children [ ]. genetics entered the picture in when eugene foster, a retired virginia pathologist, realised that y- chromosome testing might be able to shed light on the controversy. he traced living male-line descendants of sally’s first and last children, tom and eston, and to provide a comparative sample carrying the ‘jefferson’ y chromosome recruited male-line descendants of tho- mas’s paternal uncle field jefferson, since thomas had no acknowledged sons of his own. the notion was to compare y chromosomes, and ask if there was a match between sally’s and thomas’s descendants. we and our colleagues analysed y-chromosomal mar- kers (snps, strs and a minisatellite) in these samples [ ], and showed that eston’s descendant, john weekes jefferson, did indeed carry the same y-type as the field jefferson descendants. this finding supported the belief that thomas fathered sally’s last child. the evidence is strengthened by the great rarity of the y chromosome, now known to belong to haplogroup t a* [ ] - the sharing is unlikely to be a coincidence. of course, a weakness of any such y-chromosome analysis is that any other man in thomas’s patriline (his brother ran- dolph, for instance) would have carried the same y, and the two possible fathers cannot be formally distin- guished by dna analysis. however, historians helped here, by providing the telling circumstantial evidence that thomas and sally were together at monticello nine months before the birth of each of her children. but what of the descendants of tom, sally’s first son? here, there were more twists to the tale: the family had a cherished and widely believed oral history of their des- cent from the president, and this was dashed when the results were published [ ], showing that they do not carry the jefferson lineage. another unwelcome revela- tion was the fact that one of the tested descendants car- ried a different y-chromosome type from his putative first cousin - so a recent non-paternity had occurred. these painful findings illustrate two of the potential pit- falls of genealogical analysis, made worse by the fact that they were communicated to the family not through a confidential discussion, but in a phone call from us news and world report, thanks to the hasty publication of the paper. the indecent rush was due to the topical and (to some) seemingly parallel presidential saga of bill clinton and monica lewinsky. bill’s middle name, inci- dentally, is jefferson. whoever said that scientific jour- nals were only interested in science? although it revealed a non-paternity event, the success of the jefferson study relied upon non-paternity being rare - if it had been much more common than the event in transmissions observed (~ . % per genera- tion), then no reliable conclusions could have been reached. yet there is a wide perception that the fre- quency is indeed much higher than this, and an ‘urban mythical’ figure of % is commonplace [ ]. genetic stu- dies in western europe contradict this high value: swiss pedigrees show < % [ ], and data from uk cystic fibro- sis screening show . % [ ]. hollingsworth’s examina- tion of the genealogies of the british peerage between and [ ] counted , legitimate sons and male ‘bastards’ - ~ . % overall. there is much varia- tion around this average, with the prolific first earl correspondence: maj @le.ac.uk department of genetics, university of leicester, university road, leicester le rh, uk jobling investigative genetics , : http://www.investigativegenetics.com/content/ / / © jobling; licensee biomed central ltd. this is an open access article distributed under the terms of the creative commons attribution license (http://creativecommons.org/licenses/by/ . ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. mailto:maj @le.ac.uk http://creativecommons.org/licenses/by/ . ferrers ( - ) siring bastards among his off- spring. but frequencies also vary greatly from place to place, depending on customs and socioeconomic cir- cumstances. for example, among the himba, a semi- nomadic people in northwest namibia, . % of all chil- dren born within marriage were not fathered by the husband [ ]. dna analysis, typically using the same autosomal strs as are used in individual identification, generally provides a straightforward answer to any question about paternity when the child, mother and putative father are analysed. the paternity testing industry is large - ~ , tests were done in the usa in - and pro- vides much interesting data for the curious geneticist, including fabulously detailed information about allele- and sex-specific mutation rates of strs. but what pater- nity testing data cannot provide is a useful estimate of the non-paternity frequency; when a test is done, there’s often a prior reason to suspect some irregularity, and published frequencies from these sources range from % to over % [ ]. dna-based kinship analysis is also used in the contro- versial practice of familial searching, where a crime- scene dna profile is used to search a database for pro- files sufficiently similar to derive from close relatives; siblings, for example, are expected to share on average half of their dna by descent. familial searching has been most used in the uk, and has had some famous successes. craig harman was convicted of manslaughter after his profile on a brick led police to his brother, and thence to him. serial rapist david lloyd’s dna profile picked out that of his sister, who entered the national dna database following a driving offence. ethical objections have been raised, because familial searching increases police interest in individuals based purely on their relatives’ previous contact with the criminal justice system, but nonetheless the method seems to be catch- ing on [ ]. we proposed another controversial way of discovering suspects from crime-scene dna, by predicting their sur- names from a large database of y-str profiles and asso- ciated names [ ]. forensic databases of this kind do not yet exist, but genetic genealogy companies maintain publicly accessible databases with many tens of thou- sands of entries (e.g. http://www.ysearch.org). how well it would work would depend on the simplicity of the link between ancestral founders of heritable surnames and their modern descendants. for some rare surnames, among them attenborough, it is simple - over % of apparently unrelated attenborough men share a y hap- logroup, and a set of closely related y-str haplotypes [ ]. if we assume that the common y type descends from the original mr attenborough when the name was founded about years ago, and that the other y lineages are due to non-paternity events, then this allows us to calculate an average non-paternity fre- quency of - % per generation. jeffersons, however, are not like this. among unre- lated men with this surname there are many different y chromosome types, reflecting as many as different possible founders. but much to their surprise, two unre- lated english jeffersons share the rare hg t a* haplotype with the president [ ]. luckily, these distant relatives link thomas jefferson to britain within the last few cen- turies, rather than to the heartland of haplogroup t, the middle east, thus defusing yet another possible mystery story about the celebrated figure on the $ bill. received: october accepted: october published: october references . gordon-reed a: thomas jefferson and sally hemings: an american controversy. charlottesville, va: university press of virginia; . . foster ea, jobling ma, taylor pg, donnelly p, de knijff p, mieremet r, zerjal t, tyler-smith c: jefferson fathered slave’s last child. nature , : - . . mendez fl, karafet tm, krahn t, ostrer h, soodyall h, hammer mf: increased resolution of y chromosome haplogroup t defines relationships among populations of the near east, europe, and africa. hum biol , : - . . williams sr: genetic genealogy: the woodson family’s experience. cult med psychiatr , : - . . macintyre s, sooman a: non-paternity and prenatal genetic screening. lancet , : - . . sasse g, muller h, chakraborty r, ott j: estimating the frequency of non- paternity in switzerland. hum hered , : - . . brock djh, shrimpton ae: non-paternity and prenatal genetic screening. lancet , : . . hollingsworth th: the demography of the british peerage. pop studies , :, suppl: - . . scelza ba: female choice and extra-pair paternity in a traditional human population. biol letters . . anderson kg: how well does paternity confidence match actual paternity? evidence from worldwide nonpaternity rates. curr anthropol , : - . . gershaw cj, schweighardt aj, rourke lc, wallace mm: forensic utilization of familial searches in dna databases. forensic sci internat genet , : - . . king te, ballereau sj, schürer k, jobling ma: genetic signatures of coancestry within surnames. curr biol , : - . . king te, jobling ma: founders, drift and infidelity: the relationship between y chromosome diversity and patrilineal surnames. mol biol evol , : - . . king te, bowden gr, balaresque pl, adams sm, shanks me, jobling ma: thomas jefferson’s y chromosome belongs to a rare european lineage. am j phys anthropol , : - . doi: . / - - - cite this article as: jobling: father figures. investigative genetics : . jobling investigative genetics , : http://www.investigativegenetics.com/content/ / / page of http://www.ysearch.org http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract http://www.ncbi.nlm.nih.gov/pubmed/ ?dopt=abstract 	references the american archivist / vol. , no. / winter views in review: a historiographical perspective on historical editing fredrika j. teute in a letter of march james madison commented to edward ever- ett, on reviewing my political papers & correspondence, i find much that may deserve to be put into a proper state for preservation; and some things that may not in equal amplitude be found elsewhere. the case is doubtless the same with other individuals whose public lives have extended thro' the same long & pregnant period. it has been the misfortune of history, that a personal knowledge and an impartial judgment of things rarely meet in the historian. the best history of our country therefore must be the fruit of contributions bequeathed by contem- porary actors & witnesses, to succes- sors who will make an unbiassed use of them. and if the abundance & au- thenticity of the materials which still exist in the private as well as public re- positories among us shd. descend to hands capable of doing justice to them, the[n] american history may be ex- pected to contain more truth, and les- sons, certainly not less valuable, than that of any country or age. significantly, the last sentence from this madison quotation appeared on the title page of the national historical publications commission's re- port. implied was that the commission considered itself the beneficiary and executor of madison's trust and that it shared madison's faith in the para- mount value and instructive power of american history. the same sense of historical self-importance and special mission of spreading the "truth" has descended from madison's time to our own. as jesse lemisch pointed out eight years ago, the inception of the current program of modern, scholarly historical editing projects in the early gaillard hunt, ed., the writings of james madison, vols. (new york: g. p. putnam's sons, - ), : - . the projects considered in this paper include those which have been underway for some time and have published at least one volume that has been reviewed in scholarly history journals. the projects are: adams family; john c. calhoun; john carroll; henry clay; jefferson davis; benjamin franklin; ulysses s. grant; nathanael greene; alexander hamilton; joseph henry; james iredell; john jay; thomas jefferson; andrew johnson; henry laurens; james madison; john marshall; george mason; robert morris; james k. polk; booker t. washington; george washington; daniel webster; and woodrow wilson. the institutional projects under consideration are: documentary history of the first federal congress; documentary history of the first federal flections; documentary history of the ratification of the constitution; and letters of delegates to congress, - . microfilm projects have not been included. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril t h e american archivist/ winter s was colored with the political overtones of the cold war era. in the commission's r e p o r t of , the opinion was expressed that publication of the papers of the na- tion's leaders, even in a critical period of international crisis, would be evi- dence both at home and abroad of an abiding faith in the future of the na- tion. in times like these when the democratic world is seriously threat- ened by enemies within and without its borders, they believe that an un- derstanding of the american heritage and of the ideas and ideals upon which it rests is vitally important. . . . the publication of well-edited primary sources is an investment in the future. . . . they will . . . yield year after year national and international benefits of enduring character. a decade later, reflecting the inter- national political situation of the early s, the commission was promoting these projects with the claim that "only a free people could dare reveal the whole of its past triumphs and failures . . . [which required] no manipulated or authoritarian pattern of interpreta- tion." t h e preservation and publi- < cation of presidential papers as a sym- bol of the openness of american society was made explicit by one of the editors of these projects at about the same time as the commission report. lyman h. butter field wrote that these activities will guarantee historians the means of re-creating whole men and essential keys to the whole truth about their periods of activity on the american scene. i know comparatively little about librar- ies and archives in soviet russia, but i have not heard of a library built to house the papers of joseph stalin and to make them available in orderly stages to scholarly investigators. nor would i be inclined to trust any com- pilation of his papers or biographical or monographic work on stalin until these things are done. such expressions reflect madison's assumption that later generations of historians, because of their detach- ment, would write "impartial" and "unbiassed" history based on the manuscripts of public men such as himself. t h e conviction that "the whole truth" could be derived from such sources paralleled madison's belief that the american history written from these materials would contain great truths and lessons. t h e self-conscious preservation and transferral to poster- ity of their papers by the public "actors & witnesses" of madison's genera- tion were indicative of a keen appreci- ation of their own historical impor- tance. this emphasis on individuals jesse lemisch, "the american revolution bicentennial and the papers of great white men," aha newsletter (nov. ): - , passim. national historical publications commission, a national program for the publication of historical doc- uments: a report to the president by the national historical publications commission (nhpc: washington, d.c., ), p. . see also lester j. cappon's review of volume ofthe papers ofthomas jefferson, in the journal of southern history (hereafter cited asjsh). cappon says: "national and world-wide issues of the mid-twentieth century have reawakened an appreciation of his [jefferson's] kinship with free men in their struggle against bigotry and tyranny in many forms." (jsh [ ]: .) national historical publications commission, a report to the president containing a proposal by the national historical publications commission to meet existing and anticipated needs over the next ten years under a national program for the collection, preservation, and publication, or dissemination by other means, of the documentary sources of american history (nhpc: washington, d.c., ), p. . lyman h. butterfield, " t h e recent past," in l. h. butterfield and julian p. boyd, eds., historical editing in the united states: papers read at the th annual meeting of the american antiquarian society (worcester, mass.: american antiquarian society, , reprint, ), p. . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril historical editing prominent in history has continued down to our own day and is reflected in the current editions of papers which are a part of and contribute toward partial history, rather than the whole of our past aimed at by both madison and the national historical publica- tions and records commission. largely owing to madison's self- awareness, and that of other public fig- ures, we do have a rich heritage of doc- uments worth preserving. but the commission's assertion that "it does not directly promote the study of his- tory or concern itself with the writing of history" is insupportable; and its belief that "these editions will endure because they are above suspicion of partisanship and because in their in- clusiveness they anticipate the chang- ing interests of future historians" is highly questionable. not the commis- sion itself so much, but its expression of a widely held assumption that these projects are value-free and exist out- side of the continuum of american historiography deserves scrutiny. of course the commission's activities and the editing of these volumes promote the study of history, and a particular kind of history, usually centered around a single figure of public prom- inence. as one reviewer has said, "the enormous investment of professional financial resources in such projects is a continuing reaffirmation of belief, even faith, in the towering importance of bi- ographical study in the pursuit of un- derstanding of the past." involved also is the writing of his- tory; hardly any of these editions claim to be publishing volumes devoid of his- torical interpretation. and the history written in them has at times revealed limited perspective, outdated histo- riography, or careless scholarship of the editors. the papers of james iredell, particularly, has come under heavy at- tack for poor editing, inaccurate texts, and outmoded and superficial, or else silent, treatment of issues of current historiographical interest. such criticism points to one of the distinguishing characteristics of these modern editions: the historical notes written around the documents. these emendations have come to be expected in the editions, but have also become a focal point of controversy about them. almost thirty years ago, with his review of the first volume of the papers of thomas jefferson, lester cap- pon heralded the beginning of the era of comprehensive, scholarly editions. he singled out as particularly notewor- thy julian boyd's editorial notes for being "gems of historical criticism, as interesting and provocative as the n h p c , a report to the president, p . . ibid., p . . t h o m a s b. alexander, review of the papers of andrew johnson, vol. , in jsh ( ): . reviews of the papers of james iredell, vols. - , by philander d. chase, in american historical review (hereafter cited as ahr) ( ): ; by charles cullen, in journal of american history (hereafter cited as jah) ( ): - ; and by marvin l. michael kay, in william and mary quarterly (here- after cited as wmq) , d series ( ): - . for similar criticism of other projects, see edwin a. miles, review of the papers of james k. polk, vol. , in jsh ( ): - ; forrest mcdonald, review of the papers of alexander hamilton, vols. - and - , in wmq , d series ( ): - and wmq , d series ( ): ; john tracy ellis, review of the john carroll papers, vols. - , in ahr ( ): - ; seward w. livermore, review of the papers ofwoodrow wilson, vols. - , in ahr ( ): - ; and david ammer- man, review of letters of delegates to congress, - , vols. - , injah ( - ): - . many reviews of the editions reveal implicitly and explicitly this expectation. see, for instance, brooke hindle, review of the papers of benjamin franklin, vol. , in mississippi valley historical review d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril the american archivist/ winter manuscripts to which they pertain." far more than cappon could have an- ticipated at the time, julian boyd, by his methods of historical and textual criticism, established new standards for historical editing. fifteen years after his initial review, cappon conse- quently put forth "a rationale for his- torical editing past and present," in which he defined the new breed of "scholar-editors" as historians whose responsibility lay "in transmitting au- thentic and accurate texts . . . and . . . in making these texts more intelligi- ble." to achieve the latter he advo- cated the boydian method of relating the particular documents of the man to the larger body of records of the age. part of the editor's function was to provide interpretative and critical commentary. cappon asserted that "if research has provided the hard core of his editing, there is no sound reason why he should not write history from the documents at his command." such justification of historical editing is indicative of the concern, expressed then and since, that the historical profession has not accorded editors proper recognition and status as seri- ous historians and scholars. at the same time, however, their vol- umes have been promoted as defini- tive—a status that may be claimed for a conventional work of history, but that rarely proves to be so. modern scholar-editors have wanted it both ways: that they be considered practic- ing historians, but that their product be considered beyond the reach of time. the admonishment of charles beard seems appropriate here: every student of history knows that his colleagues have been influenced in their selection and ordering of mate- (hereafter cited as mvhr) ( - ): ; jack c. barnes, review of the papers of benjamin frank- lin, vol. , injsh ( ): ; lester j. cappon, review of the papers of thomas jefferson, vols. - , in jsh ( ): ; brooke hindle, review of the papers of benjamin franklin, vols. - , in mvhr ( - ): ; e.james ferguson, review of the papers of alexander hamilton, vols. - , in ibid.: - ; charles sellers, review of the papers of henry clay, vol. , injsh ( ): ; cecelia kenyon, review of the papers of benjamin franklin, vols. - , in wmq , d series ( ): - ; noble e. cunningham, review of the papers of alexander hamilton, vols. - , in jsh ( ): ; forrest mcdonald, review ofthe papers of alexander hamilton, vols. - , in wmq , d series ( ): ; dewey w. grantham, review of the papers of woodrow wilson, vols. - , in jah ( - ): ; norman k. risjord, review of the papers of george mason, vols. - , in jah ( - ): ; joseph a. ernst, review of the papers of robert morns, vol. , in wmq , d series ( ): - ; edmund s. morgan, review ofthe adams family correspondence, vols. — , inahr ( ): - ; kent newmyer, review of the papers of john marshall, vol. , injah ( - ): - ; ludwell h. johnson iii, review of the papers of jefferson davis, vol. , in jsh ( ): - ; philander d. chase, review ofthe papers ofjames iredell, vols. \- ,\nahr ( ): ; and warren w. hassler, jr., review of the papers of ulysses s. grant, vol. , in jsh ( ): - . jsh ( ): . see also david potter's prescient review of the first volume, in mvhr ( - ): - . see leonard w. levy, review of the papers of james madison, vol. , inmvhr ( - ): ; joseph a. ernst, review of the papers of robert morris, vol. , in wmq , d series ( ): - ; merrill d. peterson, review of the papers of thomas jefferson, vols. - , in wmq , d series ( ): - . uwmq , d series ( ): . ibid., p. . see, for instance, julian p. boyd, "the next stage," in butterfield and boyd, eds., historical editing in the united states, pp. - , passim; and stanley j. idzerda, "the editor's training and status in the historical profession," in leslie w. dunlap and fred shelley, eds., the publication of american historical manuscripts (iowa city: university of iowa libraries, ), pp. — . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril historical editing rials by their biases, prejudices, be- liefs, affections . . . and if he has a sense of propriety, to say nothing of humor, he applies the canon to him- self, leaving no exceptions to the rule. the pallor of waning time, if not of death, rests upon the latest volume of history, fresh from the roaring press. the editors and volumes of the cur- rent papers projects are not exempt from this injunction. historian-editors have their biases like other historians, but they can hide them behind the duality of their function. aileen krad- itor, in a review essay, pointed out the possibilities of prejudicing the per- spective through the editor's role in selecting the documents. she convinc- ingly demonstrated "that different ed- itorial frameworks and the decisions made within them affect the reader's picture of the subject to a far greater degree than he probably imagines." the criteria of selection "can be inter- preted differently by different editors and by the historians who use the vol- umes. especially is this true now, when historians are reexamining the rela- tionship between individual psychol- ogy and group activity." a fine balance must be sought be- tween inclusiveness and selectivity. some historians have viewed the com- prehensiveness of the modern editions as embodying a "distracting dispropor- tion" by which important documents are engulfed by a horde of minutiae. yet other scholars have lamented the omission of any document and be- lieved the inclusion of routine items may yield "otherwise elusive informa- tion." that the interests of historians change, making what may once have seemed trivial significant, is an argu- ment used for including all apparently relevant material. ultimately the choice lies with the editor, and concealed within the editor is the historian with his notions of sig- nificance and his conscious and uncon- scious historical values. on the other hand, the historian can use his role as editor to legitimize the researching, writing, and publishing of historical monographs within the volumes of ed- ited papers. an extensive investigation of the hamilton-beckwith affair was justified by julian boyd as "obligatory in view of the fact that the documents tracing the evolution of jefferson's policy cannot be understood unless the validity of those to which in some de- gree they are a response is assessed." charles a. beard, "written history as an act of faith," in hans meyerhof, ed., the philosophy of history in our time (garden city, n.y.: doubleday & co., ), p. . aileen kraditor, "editing the abolitionists," in reviews in american history ( ): . ibid., p. . reviews of the papers of john marshall, vol. , by robert k. faulkner, in wmq , d series ( ): - , and by maxwell bloomfield, inahr ( ): ; and review by david herbert donald, of the papers of jefferson davis, vol. , in ahr ( ): - . forrest mcdonald, review ot the papers of alexander hamilton, vols. - , in wmq , d series ( ): . robert m. weir, review of the papers of henry laurens, vols. — , in wmq , d series ( ): . for instance, robert a. rutland implicitly criticized merrill jensen for incorporating his bias to- ward the confederation period in vol. of the documentary history of the ratification of the constitution by allotting a major portion of the space to documents relating to the articles of confederation. but, said rutland, "every historical editor has a frame of reference." (rutland's review is in wmq , d series [ ]: - .) julian p. boyd, ed., the papers of thomas jefferson, vols. to date (princeton: princeton university press, -), : . see the critical reviews of this volume by dumas malone innew york times book review, sept. , pp. - ; and by merrill d. peterson in wmq , d series ( ): - . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril the american archivist / winter the example set by boyd has been followed in varying degrees by other editors. reviewers of the papers of jef- ferson davis have found the editing "prolix," "excessive," "irrelevant." laudatory of the editors' efforts, lud- well h. johnson found the annotation so "extensive" and "exhaustive" (but at times irrelevant) that investigators of collateral subjects would find the davis volumes exceedingly helpful. david herbert donald commented that a biographer would need look no fur- ther for any material he might want to consult. donald urged the editors to follow robert a. rutland's injunction: "footnotes rarely endure and may serve an editor's vanity more than a scholar's needs. thus we would do well to check our impulses, annotate sparingly, and leave the scholar free to make his own interpretations of clio's wanderings." is it really appropri- ate for the editor to aggrandize his function to the extent of usurping the historian's task? such massive collecting of docu- ments and comprehensive annotating may be a boon to investigators who cannot afford the time and money for research as thorough, but there may be negative effects for the historians using these volumes. noble e. cun- ningham, in reviewing the impressive array of documents gathered by the documentary history of the first federal elections, - , said, " f u t u r e his- torians of these elections will miss the excitement of doing their own re- search, but they can be reasonably con- fident that, when this series is com- plete, they will have the full evidentiary record before them when they begin to write." this statement is arresting in its implications. that historians will no longer need to do their own re- search raises serious questions about the future quality of their work. the inclusiveness and convenience of these modern editing projects could well in- hibit rather than encourage the writ- ing of good history. the very process of independent research is the source of that inspiration which provides new insights and original interpretations. eliminating the excitement from the historian's job may produce very dull history indeed. there is also a danger in being lulled into believing that the evidence is com- plete, accurate, and objective as it is presented in the modern, "complete" editions. almost every project reaches a point at which it becomes necessary to omit some documents. the issues of how much has been omitted, and what the criteria were in choosing, are not always carefully delineated or applied consistently in the volumes. the user may unquestioningly assume he has all the relevant or significant material be- fore him when in fact he may not. r e v i e w s o f v o l . oithe papers of jefferson davis, b y l u d w e l l h . j o h n s o n i i i injsh ( ) : - ; by charles p. roland mjah ( - ): - ; and by david herbert donald in ahr ( ): - . the documentary history of the first federal elections, - , v o l . , r e v i e w e d b y n o b l e e . c u n - ningham in wmq , d series ( ): . see also the review of vol. by john s. pancake in which he comments that the "reader feels positively pampered." (pancake's review is in jsh [ ]: .) see dewey w. grantham, review of the papers of woodrow wilson, vols. - , in jah ( - ): ; and forrest mcdonald, review of the papers of alexander hamilton, vols. - , in wmq , d series ( ): . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril historical editing the collateral questions not only of a text's accuracy but of which text is used, although raised by a few review- ers, are not so frequently asked by historians or by historical editors as a recent literary critic thought essential. g. thomas tanselle has faulted histor- ical editors for their superficial and in- consistent approach to textual mat- ters. but his advocacy of applying the standards of the center for scholarly editions (cse) to historical editions tended to obscure the differences in the uses made of literary and historical documents. that the eclectic approach sponsored by the cse is a matter of debate within the literary profession went unnoted. as peter shaw pointed out, the historical editor treats the doc- ument as a fact. while perhaps slight- ing the nuances which literary editors appreciate, he does not produce bowd- lerized versions claiming to represent the author's true, though unex- pressed, intent. tanselle may be jus- tified in attacking the "partial modern- izations" of historical editions as inconsistent and insensitive to the au- thor's style and language, but the ec- lectic texts of the literary editions are no less subjective and oblivious of his- torical context. the attempt by the editor of which- ever profession to clarify the author's intentions is a risky business better left to the reader. when the editor pre- sents an interpretation of the author's character and motives, he may seri- ously mislead the reader. even the way in which the documents are organized in the volumes can create an inaccu- rate impression. james h. hutson has criticized the adams family project for the decision to publish the various pa- pers in separate series. the predomi- nantly political writings in the general correspondence of the papers of john adams gives the effect of "disembodied intellectualism, of ideas wrenched from their social context." to the extent that the editor's particular perspective informs his decision concerning the organizing and grouping of docu- ments, the impressions created by the sequence of materials are a result of his historical values. in reviewing the papers of benjamin franklin, brooke hindle explored the potential for distortion in the presen- tation and interpretation of docu- ments by the historian-editor. hindle raised the question of "whether the ed- itor's vantage point and the image he holds of franklin influences his edit- ing . . . . any interpretive essay must distort by generalizing upon the pa- pers contained; this one distorts by overemphasizing english politics and franklin's own activities—which are, in some instances, not much reflected j . a . l e o l e m a y , r e v i e w o f the papers of benjamin franklin, v o l . , in ahr ( ) : ; c h a r l e s c r o w e , r e v i e w o f t h e s a m e , vols. - , in wmq_ , d s e r i e s ( ) : - ; a n d w i l l i a m l. j o y c e , r e v i e w of the papers of john adams, vols. - , in american archivist ( ) : . g. t h o m a s t a n s e l l e , " t h e e d i t i n g o f h i s t o r i c a l d o c u m e n t s , " in studies in bibliography ( ) : - , - , , . see peter shaw, "the american heritage and its guardians," in american scholar ( - ): - . review of the papers of john adams, series iii, general correspondence, vols. - , in wmq , d series ( ): - . on the same point, see christopher collier's review of the papers, of robert morris, vol. , for limiting the publication to morris's public papers as superintendent of finance. collier argues that since the most controversial aspect of morris's career was the combining of his private with his public business, the editors ought to be inclusive so that the reader may come to his own conclusions (ahr [ ]: - ). see also donald roper, review ofjohn jay: the making of a revolutionary, i: unpublished papers, - (wmq , d series [ ]: - ). d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril the american archivist/ winter in the papers." in a subsequent re- view hindle expanded upon his objec- tions to the editorial concentration on franklin's role in imperial politics at the expense of colonial political, cul- tural, and scientific matters. he postu- lated the conclusion "that the project has become unworkable. the satura- tion scholarship pioneered by julian p. boyd may have led historical editors down a blind alley, and it may be time to confess the crisis." hindle's as- sessment of the situation appeared on the crest of a wave of increasingly crit- ical commentary upon the priorities of these long-term editorial endeavors. the attack essentially has been three- pronged. the question raised earliest has also recurred more recently, al- though with a somewhat different em- phasis: who deserves to be edited and published in letterpress volumes? charles sellers, in a review in of the first volume of the papers of henry clay, doubted the utility of extending such "comprehensive publication" to secondary historical figures and sug- gested that the resources be put into collecting the documents into one dep- ository and making them available on microfilm. such a policy in fact has been instituted by some of the newer projects, in conjunction with a selected edition of published papers. yet there are a number of "second- ary" figures whose papers are being published in comprehensive editions. these men are not the founding fa- thers but the next generation of prom- inent american politicians, who tended not to be as historically minded or catholic in their interests and intellects as the revolutionary set. by general re- port, their letters, what there are of them, make tedious reading. many of these men did not write much or well and did not bother to save what was written. these circumstances have led reviewers to look forward to future volumes perhaps containing more, and more important, letters of the subject. reviewers have commented also that the editing of the documents is supe- rior in quality to the documents them- selves. this seems an inversion of the editorial purpose; the notes should ex- plicate the documents, not improve upon them. brooke hindle, review of the papers of benjamin franklin, vols. - , injah ( - ): - . william b. willcox, the editor, has been roundly criticized on all of the points mentioned in the preceding paragraph. j. a. leo lemay, in his review of vol. , said that "at its worst, it is a deliberately selected edition, rather than a complete one, of unsound texts, full of officious editorializing" (ahr [ ]: ). see also david ammerman, review of vol. of the same, in ahr ( ): - . brooke hindle, review of the papers of benjamin franklin, vols. - , injah ( - ): . /sh ( ): . most notably, the papers of daniel webster. see reviews by maurice g. baxter, of vol. , in jah ( - ): ; of vol. , injah ( - ): - ; and by norman d. brown, of vol. , mjsh ( ): . also, about the papers of joseph henry, see n. , below. those who have borne the brunt of such commentary are james k. polk, andrew johnson, and, to a lesser degree, john c. calhoun. robert v. remini said of polk that he has been "fantastically lucky" and well served both then and now. the implication is that polk has gotten better than he deserved both in charles seller's "fine" biography and in the "superbly yet unobtrusively edited" papers (review of the correspondence of james k. polk, vol. , in jah [ - ] : ). see also reviews of vol. , by the same, in jah ( - ): - ; and by edwin a. miles, in jsh ( ): . in regard to the papers of andrew johnson, j. h. parks, in commenting on the paucity of andrew johnson items, said that "the serious student may find the editors' notes more interesting and valuable than the letters reproduced" (review of vol. , in jah [ - ]: ). see also his reviews of vols. and , injah ( - ): - ; and ( - ): ; and thomas b. alexander, reviews of vols. and , injsh ( ): - , and ( ): . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril historical editing such projects may well serve to in- flate the stature and importance of certain personages in our past and to allocate time and money that could better be expended elsewhere. in his november aha newsletter article, "the american revolution bicenten- nial and the papers of great white men," jesse lemisch probed this question further. he argued that the publications program had been ex- cluding "those who were not great, not white, not men." he has since con- tended that history in america in the s encompasses a broader defini- tion than that of "notable," "distin- guished" people and has urged that the national historical publications and records commission redirect its think- ing and support toward assembling and publishing records of the "inarticulate." interrelated with the question of whom to publish is the question of amount of time and money spent. criticism on these grounds in- creased as publication schedules and costs were steadily revised upward. concomitantly, the issue of detailed annotation and "editorial im- perialism" came to the fore as the pace of publication in many of the projects slowed down and the editorial apparatus burgeoned. indicative of the situation is that the quotation given at the beginning of this article was taken from an edition of madison's writings published seventy years ago; the current madison project has to publish almost thirty-five years of his life before it reaches this letter. to varying degrees many of the projects are in a similar state of arrears. as put by leonard levy, "these volumes are being edited for posterity, and their publication will probably continue un- til their audience arrives." this wave of condemnation against the elaborateness and costliness of the projects had reached its peak by . the protest markedly subsided there- after. extensive editorial apparatus be- gan to be praised again and little com- for the papers of john c. calhoun, see john a. munroe's comment that calhoun "remains a non- person, an office," in his review of vol. , in jah ( - ): . see also his reviews of vols. and - , in mvhr ( - ): , and jah ( - ): ; and harry ammons, review of vol. , injsh ( ): - . jesse lemisch, "the papers of great white men"; and "the papers of a few great black men and a few great white women," in the maryland historian ( ): , and - . sellers raised the question of time and money in his review of the papers of henry clay, vol. , in jsh ( ): . leonard levy was one of the first to attack extensive annotation, and did so in his reviews of the papers of james madison, vols. - , in mvhr ( - ): - , and of vol. in jah ( — ): - . critical reviews on both of these points became more frequent in the latter part of the s and may be linked with the appearance of vol. of the jefferson papers in , which contained a disproportionate number of editorial notes and was not published until four years after the preceding volume. criticism seems to have been spurred on after lemisch's attack in . it had reached a crescendo around the time of hindle's review in . see, for instance, dumas malone, review of the papers of thomas jefferson, vol. , in new york times book review, sept. , pp. - ; merrill d. peterson, review of the papers of thomas jefferson, vol. , in wmq , d series ( ): - ; john howe, review of the earliest diary of john adams, in ibid.: ; w. w. abbot, review of the papers of james madison, vol. , in ahr ( - ): ; leonard w. levy, review of the papers of james madison, vols. - , injah ( - ): - ; robert mccolley, reviews of the papers of thomas jefferson, vol. , injsh ( ): - , and of vol. , in jsh ( ): ; brooke hindle, reviews of the papers of benjamin franklin, vols. - , injah ( - ): - , and vols. - , in ibid.: - ; e.james ferguson, review of the papers of alexander hamilton, vols. - , in ibid.: - ; glyndon van deusen, review ot the papers of henry clay, vol. , in ibid.: ; donald fleming, review of the papers of joseph henry, vol. , in ibid.: ; and joseph ernst, review of the papers of robert morris, vol. , in wmq , d series ( ): . review of the papers of james madison, vols. - , in jah ( - ): . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril the american archivist/ winter ment was made about the rate at which volumes were published. on the other hand, projects which seemed to have responded to earlier criticism and to economic pressures by limiting edito- rial notes, abstracting some documents and leaving out others, have recently come under attack for these now per- ceived sins of omission. the shifts in the attitudes of reviewers toward these papers projects have root in contem- porary historical developments. in his important article "the american her- itage and its guardians," peter shaw noted edmund wilson's suggestion of similarities in the s between the vietnam war and the center for edi- tions of american authors (ceaa, subsequently cse). they both "lacked modesty of scale." the goal of being error-free and definitive had "an in- nocently millenarian, american flavor to it." as pointed out in the begin- ning of this article, the modern histor- ical editions and nhpc partook of this millenarianism. the majority of his- torians who reviewed the volumes in the s tended to share in the zeal- otry of american idealism and pride, which had its political counterpart in our involvement in vietnam. as countervailing currents of pro- test overwhelmed the war effort and engendered distrust of many tradi- tional aspects of american society, so did historians come to question the utility and lavishness of the publication of america's national political heroes of the past. involved in their attack were the dissolution of consensus about america's past, and present, and the division among historians over the kind of history to be written. the self-ex- amination of the early s infected the nhprc, editors, and reviewers alike. the scrutiny brought about a diversification as well as a defense of historical editing projects. see, for instance, kent newmyer, review of the papers of john marshall, vol. , injah ( - ): - ; merrill d. peterson, review of the papers of thomas jefferson, vols. - , in wmq , d series ( ): - ; brooke hindle, review of the papers of benjamin franklin, vols. - , in jah ( - ): - ; e.james ferguson, reviews of the papers of alexander hamilton, vols. - and - , mjah ( - ): - and ( - ): - ; george m. curtis iii, review of the diaries of george washington, vols. - , in ahr ( ): ; lowell h. harrison, review of the same, in jsh ( ): ; philander d. chase, review of the papers of james iredell, vols. - , in ahr ( ): ; and warren w. hassler, jr., review of the papers of ulysses s. grant, vol. , in jsh ( ): - . among these reviewers are merrill d. peterson, brooke hindle, and e.james ferguson, all of whom had criticized, in previous reviews, the use of space, time, and money. in comparison to the scholarly contributions made by the editors in their explanatory notes and essays, these reviewers seemed no longer to mind the inefficiencies of the editorial apparatus. see robert g. sherer, review of the booker t. washington papers, vol. , in ahr ( ): ; dewey w. grantham, review of the papers ofwoodrow wilson, vols. - , mjah ( - ): ; hugh hawkins, review of the same, vols. - , mahr ( ): ; paul w. brewer, review of the documentary history of the first federal elections, - , vol. , in ibid.: ; steven r. boyd, review ofthe papers of james madison, vol. , in ibid.: ; winton u. solberg, review ofthe docu- mentary history of the ratification of the constitution, vols. - , inysh ( ): ; donald roper, review of john jay: the making of a revolutionary, i: unpublished papers, - , in wmq , d series ( ): - ; linda grant depauw, review of the papers of robert morris, vol. , in which she does take cognizance of the necessity for economizing, but suggests that microform production is preferable to limiting the editorial apparatus (ahr [ ]: - ); noble e. cunningham, review of the papers of alexander hamilton, vol. , in jsh ( ): - ; and charles royster, review of the letters of delegates to congress, - , vols. - , in wmq , d series ( ): . peter shaw, "the american heritage and its guardians," american scholar ( - ): . ibid., p. . ibid. shaw would agree with this. e. berkeley tompkins, "the nhprc in perspective," in dunlap and shelley, eds., the publica- tion of american historical manuscripts, pp. - . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril historical editing in the late s, opposition to the modern editions dwindled, just as na- tionally the capacity for critical ap- praisal became exhausted. the relapse into quiescence has helped legitimize what has by now become the tradi- tional approach in modern historical editing initiated by boyd over thirty years ago. the bicentennial gave a big boost to the reversal in attitude. "a marked renaissance of interest in history, and especially in historical sources" has been announced. the papers projects could be promoted as popular reading. they were hailed "as monuments to the two hundredth an- niversary of independence"; they would remain "long after the lesser and grosser aspects of the bicentennial are deservedly forgotten." the view of the modern historical editions as monuments which would last for generations has recurred with the birthday of the revolution which projected the authors of these docu- ments into fame and history. but the current complacency with the course pursued by most editing projects ig- nores the "crisis" which hindle and others perceived in the early s. the problems, however, remain unre- solved. as peter shaw said, "the guard- ians of our tradition have succeeded in keeping it out of print." that this is so can be traced back to madison's be- quest. modern "scholar-editors" seem to continue to feel that madison's trust has descended directly on them, that they are executing the charge of un- biased use of the documents and of purveying the truth. in the process of doing justice to our documentary in- heritance, ever more money, more time, and more detailed historical exe- gesis of the texts has been rationalized. it is time to stop, as hindle urged, and, further, to recognize that these proj- ects are not like the great cathedrals. not only should they not take centu- ries to be completed, but also they may not and perhaps should not endure that long. george m. curtis iii, in his review oithe diaries of george washington, vols. - , praised them "as a monument to creative editing." he acknowledged that "the new washington project is vulnerable to criticism from those seeking greater economies in publication or heavier emphasis upon lesser known figures." however, curtis appeared to think it inconsequential that thousands of dollars and a decade of effort were spent to publish two volumes of washington's diaries which had been pro- duced in a complete and unbowdlerized edition fifty years before (ahr [ ]: ). for a critical review of the same on these issues, see mary beth norton in jah ( ): - . her review, which would have been unexceptionable a few years ago, stands out among current reviews for its hostile stance toward the new edition. the recent increase in laudatory reviews may be partly attributable to the numbers of reviewers who are themselves editors. with a few exceptions, rather than being more exacting of colleagues in their own field, they are less so than historians generally. perhaps this is because historical editors are still on the defensive within the historical profession and prefer not to bring adverse attention to historical editing. among the reviewers cited here, philander d. chase, charles cullen, george m. curtis iii, e.james ferguson, don higginbotham, james h. hutson, merrill jensen, ralph l. ket- cham, and robert a. rutland all have been or are historical editors. the author of this article also must be counted among them. several reviewers have welcomed the publication of first volumes of the newer projects as auspi- cious events of the bicentennial. see for instance, j. edwin hendricks, review of the letters of delegates to congress, - , vols. - , injsh ( ): - ; don higginbotham, review of the papers ofnathanael greene, vol. , in jah ( - ): ; donald o. dewey, review of the documentary history of the ratification of the constitution, v o l s . — , i n i b i d . , p . . john s. pancake, review of the papers of alexander hamilton, vols. - , in ahr ( ): - . merrill jensen, "the bicentennial and afterwards," in dunlap and shelley, eds., the publication of american historical manuscripts, p . . peter shaw, "the american heritage and its guardians," american scholar ( - ): . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril the american archivist/ winter at one point within our generation, max farrand's records of the federal convention and edmund c. burnett's letters of members of the continental con- gress were considered to be acceptable by the standards of modern editing. yet it has recently been found neces- sary to redo completely burnett's work, and the madison papers have under consideration the prospect of a new edition of the notes on the consti- tutional convention. the writings of george washington, edited by j o h n c. fitzpatrick some forty-five years ago and published in thirty-nine volumes at public expense, is now considered inadequate. rather than remedying the omissions of fitzpatrick, the current editors are redoing washington's pa- pers in their entirety. how secure are any of these projects against some fu- ture school of revisionist editors? and the more history that is written in these volumes, the more vulnerable they are. is it inconceivable that some edi- tor will find unacceptable julian boyd's anti-hamilton history con- tained in the most recent volumes of the papers of thomas jefferson, and find imperative a new edition free of such editorializing? or will someone de- cide that the imperial political empha- sis in the papers of benjamin franklin must be corrected? there appears to be only one way out: to deescalate the claims and ex- pectations of these projects; to con- sider them, like any other work of his- tory, as a project of a particular generation out of whose values they evolved. a number of alternatives have been suggested or are being tried. sev- eral approaches seem viable. one would be to follow the suggestion of hindle and the practice of the papers of joseph henry and the papers of daniel webster: publish an exhaustive micro- film edition of the papers accom- panied by selective, extensively anno- tated, topical, letterpress volumes. another would be, as proposed by charles sellers and joseph ernst, to collect copies of all the manuscripts in one place and produce a well-indexed and complete microfilm publication of the documents. another idea, ap- butterfield and boyd, eds., historical editing in the united states, pp. - , - , and ; lester j. cappon, "a rationale for historical editing past and present," wmq , d series ( ): - . in fact, the papers of james madison has been criticized for not including all of madison's speeches in the federal convention. steven r. boyd has asserted that if the speeches are not included later, it will make the edition less than definitive (review of vol. in ahr [ ]: ). the decisions of the editors of the papers of benjamin franklin to print summaries of letters to and from franklin and to omit the first part of the autobiography in its proper chronological sequence have been called unjustified. the edition is thereby incomplete (david ammerman, review of vol. , in ahr [ ]: - ; j. a. leo lemay, review of vol. , in ahr [ ]: ). an opposing view has been taken by linda k. kerber in her review of the papers of james madison, vols. - . she rejected the editor's reasons for omitting interpretative essays as "misguided worries." she thought the costs of the editing projects small in comparison to many other expenditures in our society. wondering whether any editor really believed his edition would not be subjected to historio- graphical reappraisal, she suggested editors should embrace the chance to stamp their character on their work. her main concern was that inexpensive editions be made available to a wider audience. she did not discuss whether that goal is compatible with her other contentions (wmq , d series [ ]: - ). s e e r o b e r t m c c o l l e y , r e v i e w s o f the papers of thomas jefferson, v o l . , injsh ( ) : - ; and of vol. , injsh ( ): - . brooke hindle, review of the papers of benjamin franklin, vols. - , injah ( - ): ; donald fleming, review of the papers of joseph henry, vol. , in ibid., p. ; and i. bernhard cohen, review of the same, in ahr ( ): - . see n. , above. charles sellers, review of the papers of henry clay, vol. , injsh ( ): ; and joseph ernst, review of the papers of robert morris, vol. , in wmq , d series ( ): . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril historical editing proached tentatively by the papers of james madison, broached by e. james ferguson, and strongly urged by linda k. kerber is to omit documents which have been published with reasonable competency elsewhere. this could eliminate much duplication of effort, duplication sometimes with little im- provement in accuracy. one of the fallacies upon which these modern edi- tions are based is that the texts are vir- tually error-free and supersede, in terms of completeness and expertise, all that has gone before. it is quite likely that substantive mistakes can be found in every volume. some former editions such as gaillard hunt's of james madison and edmund c. bur- nett's of the members of the conti- nental congress, although lacking in completeness, attain a very acceptable standard of accuracy. the elusive goal of perfection and the deceptive lure of immortality have led the historical ed- iting profession into an exaggerated view of its importance and of its func- tion. comprehensive letterpress edi- tions of the documents of preeminent americans have preempted most of the energy and resources; the stand- ard, once set, has become increasingly difficult to depart from. the distorted perception of priorities has inhibited the trial of divergent methods and di- verse types of projects. attention and money ought to be diverted to the preservation of records which are in danger of perishing altogether. the aim should be to make available in one form or another, to a wider audience, authentic and inexpensive reproduc- tions of as great a variety of manu- script collections as possible. more imagination and effort should be devoted to new kinds of projects. for instance, many state archives con- tain large bodies of petitions which could be grouped chronologically and topically. they would provide a mar- velous source of social and political his- tory and a means of getting at the "in- articulate" of our past. another see robert a. rutland, et al., eds., the papers of james madison, vols. to date (chicago: univer- sity of chicago press, -), : n., n., and : - nn., , - , ; e. james ferguson, review of the papers of alexander hamilton, vols. - , in jah ( - ): - ; and linda k. kerber, review of the papers of james madison, vols. - , in wmq , d series ( ): - . see on this point william l. joyce, review of the papers of john adams, vols. - , in american archivist ( ): . these goals have also been emphasized by peter shaw, in "the american heritage and its guard- ians," in american scholar ( - ): ; and by linda k. kerber (see n. , above). in recent years, nhprc has broadened its scope. the commission responded to criticism by new left historians, of the elitism of the original editing projects and to the increased interest in pluralism in the american past. the redefinition of nhprc's mandate, from the publication of the papers of america's great statesmen to the preservation and publication of records and papers of a wider range of subjects, reflected the change in political climate and the shift of interests in the scholarly world. by the expansion in the types of projects, the records and publications programs have come to include women, blacks, other ethnic minorities, reform and labor movements, as well as men notable in polit- ical, scientific, or cultural realms. but when the lists of projects are scrutinized, the numbers and appropriations are still heavily weighted in favor of exceptional individuals or groups, and prominent institutions. the commission's support for the preservation and cataloging of local and state records is com- mendable; let us hope that more money and imagination will be expended in developing other and less accessible records concerning common people and less well-known institutions. the other impor- tant shift in nhprc's emphasis has been to projects more modest in scale and expense. the most impressive fact still remains that the bulk of nhprc's support has gone to the "great, comprehensive historical enterprises" which continue to consume disproportionate time and money in ratio to their productivity and utility (see national historical records and publications commission, report to the president [nhprc: washington, d.c., ], pp. i, v-vi, - , and - , passim). d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril the american archivist/ winter source, fast disappearing, are the retir- ing railwaymen who have worked on this country's railroads for the last forty or fifty years. a wealth of docu- mentation could be provided through the collection and preservation of oral histories of the men and of the institu- tional records of the companies and unions. the ongoing projects ought to devote more energy to publishing the documents and less to the writing of history in the form of annotation. as expressed by e. james ferguson and robert mccolley, there seems to be in operation "some undiscovered law about historical editing that would re- late the duration of the project to the growth of editorial apparatus," which in turn takes over the project and all but submerges the actual pa- pers from view. if the effect of this law is not reversed, these projects will be consigned to the fate described by tristram shandy: when a man sits down to write a his- tory, . . . if he is a man of the least spirit, he will have fifty deviations from a straight line to make with this or that party as he goes along, which he can no ways avoid. he will have views and prospects to himself perpetually solic- iting his eye, which he can no more help standing still to look at than he can fly; he will moreover have various accounts to pick up: inscriptions to make out: stories to weave in: tradi- tions to sift: personages to call upon: panegyricks to paste up at this door: pasquinades at that: . . . to sum up all; there are archives at every stage to be look'd into, and rolls, records, documents, and endless genealogies, which justice ever and anon calls him back to stay the reading of:—in short, there is no end of it. . . , e. james ferguson, review of the papers of alexander hamilton, vols. - , injah ( - ): . robert mccolley, review of the papers of thomas jefferson, vol. , injsh ( ): . laurence sterne, the life and opinions of tristram shandy, gentleman (new york: the odyssey press, ), pp. - . the passage is quoted also by merrill d. peterson in his review otthe papers of thomas jefferson, vol. , in wmq , d series ( ): . fredrika j. teute formerly served as associate editor of the papers of james madison. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u hh by c arnegie m ellon u niversity user on a pril wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); 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civil rights, women’s suffrage and reform movements; the world war ii home front; and labor history. the politi- cal history collection includes some of the country’s most important national treasures, including the small portable desk on which thomas jefferson wrote the declaration of independence, the top hat president abraham lincoln wore the night he was assas- sinated, small metal buttons made to celebrate george washington’s inauguration in and items from recent presidential elections. through incomparable collections, rigor- ous research, and dynamic public outreach, the national museum of american history explores the infinite richness and complexity of american history. it helps people under- stand the past in order to make sense of the present and shape a more humane future. the museum is continuing to renovate its west exhibition wing, developing galleries on democracy, immigration and migration, and culture. visiting the museum for more information, visit http://ameri- canhistory.si.edu. the museum is located on constitution avenue, between th and th streets nw, and is open daily from am to : pm (closed december ). admission is free. for smithsonian information, the public may call ( ) - . ■ the exhibit includes election-related pieces of history like this automatic voting machine with privacy curtain, invented in iowa, . this ballot box, on display, was used in the northeast united states during the s. election signs for candidates still in the race are displayed at the museum’s constitution avenue, surrounded by historic voting machines and ballot boxes. (all photos courtesy of the national museum of american history, smithsonian institution) http://americanhistory.si.edu http://americanhistory.si.edu microsoft word - thakur_tonmedj the open nuclear medicine journal, , volume dedication - x/ bentham open open access dedication wolfgang becker ( - ) it is hard to believe that, by the time this journal started, it is years since wolfgang becker md, phd, passed away. he was only years old. however, in such a relatively short life span, he had accomplished so much both in his personal and professional life that speaks for him everyday and keeps him alive, in a way, even after his death. he was born in , in uffenheim, mittelfranken, germany. in , he obtained his md degree from the university of würzburg. he then served in german army and began his nuclear medicine career in at the university of würzburg. while working there, he developed interest in then a relatively new field of imaging infection with in- -oxine and used his clinical findings for his phd degree which he obtained in . in , he moved to the university of nürnberg-erlangen as a professor of nuclear medicine and then in to the university of göttingen as the chair of the department of nuclear medicine. he worked at göttingen until his demise. his interest in in- labeled white blood cells and their continued innovative applications in patients, mark one of his major contributions to clinical science in nuclear medicine. he gave several presentations on this topic in national and international gatherings, wrote more than original papers and numerous review articles. he was certainly among the few who have helped to establish the art of infection imaging using radiolabeled white blood cells. he was one of the participants at the north atlantic treaty organization’s advanced study institute that i, as the inventor of in- -oxine labeled white blood cells, with my colleague and friend dr. john mcafee, had directed in in maratea, italy. that was my first encounter with wolfgang, which led to a deep friendship bonded by common scientific interest, common ideology, and warm respect for each other. his qualities in life, creativity, and hard work to accomplish his goals, brought him many more friends and admirers. for the - term, he was elected as the president of european association of nuclear medicine (eanm), the challenge he sought to serve nuclear medicine community and the field, beyond his own university and country. despite his illness during the same time, he served the association with vision and vigor. he passed away before his term was over but during that time, he had proved to be an excellent leader. he deeply cared for issues that confronted the field, fought battles, yet made no enemies. he was persuasive and decisive. he worked with his counterparts in other nuclear medicine organizations and worked with them for common goals. he worked long hours professionally but did not neglect his family which he loved dearly. as a man he was calm, pleasant, and a good listener. as a friend, he was supportive and warm. as a scientist, he was creative and conclusive, and as a leader, he was persuasive and decisive. it were these qualities that brought him the friends and the fame, all in less than years of his life span. i am glad that the editor-in-chief prof. helmut sinzinger has chosen to dedicate this journal to wolfgang. although these words are only a few, these will revive the memory of many of those who had worked with prof. wolfgang becker, known him as a friend, witnessed him as a leader, and heard him as a scientist. i am grateful to dr. sinzinger for giving me the opportunity to pay my respect, once again, to wolfgang becker, md, phd. mathew l. thakur laboratories of radiopharmaceutical research and molecular imaging radiology & radiation oncology thomas jefferson university philadelphia pa usa past president of snm e-mail: mathew.thakur@jefferson.edu © mathew l. thakur; licensee bentham open. this is an open access article licensed under the terms of the creative commons attribution non-commercial license (http: //creativecommons.org/licenses/by-nc/ . /) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited. microsoft word - gilder_hagger hypercultura biannual journal of the department of letters and foreign languages, hyperion university, romania electronic issn: - , issn-l - vol , no / cultural and institutional memory as (a) means of progress (part i) ………………………………………………………………………………………………………... mervyn hagger eric gilder the british interregnum: a yesterday that never happened ……………………………………………………………………………………………………… recommended citation: hagger, mervyn and eric gilder. “the british interregnum: a yesterday that never happened”. hypercultura . ( ) mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page mervyn hagger independent scholar (the john lilburne research institute for constitutional studies) eric gilder papua new guinea university of technology in lae, papua new guinea and “c. peter magrath” center for international academic cooperation, “lucian blaga” university of sibiu (romania) the british interregnum: a yesterday that never happened abstract three hundred years before george orwell wrote his novel nineteen eighty four (edition ), th century events referred to as the ‘interregnum’, could have served as one source for his inspiration. several themes run through orwell’s musings, and one pertains to the compilation of a dictionary scheduled for publication by the year . the purpose of orwell’s lexicon is to document the finality of a process achieved through ‘extirpation by redaction’. by intentionally reversing common definitions of specific words, and then interjecting those alternative renditions into common usage, they eventually lose their original meanings, and those words can then be removed from the dictionary. orwell explained that it is part of a process to control human memory: “you are unable to remember real events and you persuade yourself that you remember other events which never happened” ( ). today, each time the word ‘interregnum’ is substituted for events which took place between the years to , the process of ‘extirpation by redaction’ is being employed. keywords: interregnum; orwell; cromwell; lilburne; charles ii. introduction during april , in a lonely farmhouse on the bleak outer scottish island of jura , george orwell commenced work on a novel containing several themes which collectively became known as nineteen eighty four ( ). one theme or ‘thread’ pertains to the compilation of a new dictionary scheduled for completion by the year (nef ). its purpose is to document by publication, the finality of a process which has achieved ‘extirpation by redaction’. by means of intentionally reversing common definitions of targeted words, and then interjecting those corrupted definitions into common usage, they eventually lose their original meaning. once that occurs, those words can be removed from the dictionary, while new words that describe the corrupted rendition, can be supplemented in their place. orwell explained that it is all part of a process to control human memory so that: “you are unable to remember real events and you persuade yourself that you remember other events which never happened (nef )”. three hundred years before orwell wrote his novel, the raison d’être behind his dictionary had already been invented in order to obliterate real events that took place between the years of and on the island of great britain. this is a geographical reference to the british isles where the main events described herein, took place. in orwell’s novel he uses the word ‘remember’ over times; ‘memory’ times; ‘memories’ times; ‘recall’ times a scottish island located in the inner hebrides and off the northwest coast of the main island of great britain. see note mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page a clanton conundrum if cultural memory is one of many ways to remember the past, then what is a life lived, if it is based upon distorted recollections of past events? how much of a false cultural memory can be incorporated into a single life lived, before a corrupted cultural memory seriously distorts the past to the point where it is safe to say that the life lived was a living lie, because the past, as remembered, never happened. judgments made today, which are based upon such distorted recollections of yesterday, merely add to the mass-distortion of cultural memory that will be recalled by other lives tomorrow. when cultural decisions made today require the addition of foundational legal precedent, a conundrum is created. the past so-called, then becomes a phantasmal illusory mental image which has been conjured-up by words and pictures, rather than by a truly recalled transcribed memory reflecting an actual event which once occurred in the space of time and place. cultural memories are layered, one on top of another, generation after generation. today’s corrupted precedents merely add to the distortion of tomorrow’s recalled record of unreality. it is in our mind that we could recall that ‘swamp-pop’ nasal recording of jimmy clanton as he describes his own cultural nightmare: “just a dream, just a dream, all our plans and our all schemes, how could think you'd be mine, the lies i'd tell myself each time” (“jimmy clanton lyrics - just a dream”). immortal memory the mournful lyrics of clanton’s ballad tell of attempts to drown-out thoughts regarding an impossible relationship, along with counter-thoughts suggesting impractical romanticism. orwell’s sub-plot involving the creation of a dictionary is about redacting words so that they cannot be used to establish a true account of the past. the word ‘interregnum’, when applied to actual events that took place in the british isles between the years to , creates a spurious alternative romantic account of monarchical lives lived, and it was invented to support a manipulative political agenda which resonates into political lives lived, today. when used in this context, the word ‘interregnum’ might be better suited to the title of a novel, or even to the lyrics of a pop song in which “any resemblance to real persons, living or dead is purely coincidental ”. if lives lived are rooted in the oxymoron of ‘corrupted factuality’, then it is no wonder that life on this planet seems to be a game of chance where nothing is certain, because nothing can ever be certain concerning all of the events of today which are in turn based upon events that took place yesterday. as individuals, we are limited in our first-hand observations, and what we perceive may not be a true interpretation of an actual event. distortions abound when we as individuals have to rely upon the recall of others, if their observations are preserved in the written word (nef ) . in a legal setting, even first-hand observations are not necessarily reliable guides to what a person may think they have just observed . however, the laws which govern society today are all rooted in past precedents which have all been “written down” (nef ) . therefore, it is well to recall emerson’s observations about the past: "all history becomes subjective; in other words, there is properly no history; only biography" (“history”). but if history is biography, then history is really the corrupted collective record of faux lives lived. standard legal disclaimer as used in novels. nineteen eighty-four: p. : “does the past exist concretely, in space? is there somewhere or other a place, a world of solid objects, where the past is still happening?'” (italics added.) see: res gestae - the whole thing that happened. margaret l. ross and james p. chalmers, “hearsay”. walker and walker: the law of evidence in scotland, rd edition. practical law . . http://uk.practicallaw.com/books/ /chapter (accessed november, ). nineteen eighty-four: p. : “…where does the past exist, if at all?” asked o’brien, to which winston replied: “in records. it is written down” (italics added). mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page if we, as individuals, continually attempt to reassert our own individuality by referring back to our own corrupted cultural memories, then we as individuals are lost before we start: because we are looking for memories born within corrupted cultural files. we again recall orwell’s words: “you are unable to remember real events and you persuade yourself that you remember other events which never happened”. that orwellian scenario also depicts one of the basic flaws built into wikipedia, because its policy controllers forbid the entry of what they call ‘original research’ and, therefore, wikipedia relies upon information which has already been widely disseminated. but if that existing information is in error because it has been drawn from corrupted sources, it reinforces the caveat that anyone undertaking serious research should not rely upon wikipedia, and yet it is surprising how many official sources currently link to wikipedia as their source of information (see “what's wrong with wikipedia?”). corrupted memory recall in court cases human memory is known to be a most unreliable source of information (see engelhardt - ); yet a hysterical wave of human memory recall is now being fostered in the united kingdom to send individuals to prison on the basis of memory recall . even when eye- witnesses to an event have reduced their observed experience to writing, they have subjected that redaction to orwell’s mantra that: “who controls the past controls the future: who controls the present controls the past” (nef ). while “a camera may not lie ”, its human operator can selectively record some images while not capturing others, and thus distort the representation of a past event perceived by viewers at a later time. almost as soon as it became possible to make copies of documents, enforced licensing by governing bodies formed the foundation for institutionalized censorship , and by content expurgation, overseers controlled all potential influence those documents might have on the public at large. sometimes complete works were removed from general circulation, but quite often redacted versions containing intentionally corrupted information were also put into wide circulation (see gilder and hagger - ). in many instances, with the passage of time, the propaganda value emitted by such corrupted texts has become the accepted version of particular events, because they have drowned out all pointers to the existence of alternative renditions. to make matters worse, the chief proponents of mass learning - mass-redaction and mass-propaganda - have often been religious organizations masquerading as the official voice of the source of all that exists, or will ever exist. they thereby impose nonsense by means of fear, in a similar manner to the scenario described in orwell’s ‘room ’ (nef ). primarily due to the efforts of mark williams-thomas, a student-lecturer at (uk) birmingham university, the name of deceased uk radio and tv personality jimmy saville has become a rallying call for ‘sex-crime’ investigations which have resulted in lurid headlines and prison sentences for a number of well-known individuals. these alleged offences stretch back into the s and they are all based upon memory-recall by alleged victims who appeared in court decades after the claimed events occurred. see: mark williams-thomas webpage http://www.bcu.ac.uk/social-sciences/criminology/employability/mark-williams-thomas and: jane mathews, “operation yewtree investigating new suspects including police officers and politicians” express online, october , – http://www.express.co.uk/news/uk/ /operation-yewtree- -new-suspects-police-officers-politicians (accessed november ). an interesting essay on this subject is available at: photographic fictions, “the camera does not lie”. the american museum of photography http://www.photographymuseum.com/phofictionsreading.html (accessed november ). historical overview of book censorship. http://viking.coe.uh.edu/~wmasterson/cuin /history.htm (accessed november ). mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page the vanishing act three hundred years before orwell wrote his seminal work, an interlocking series of civil wars took place on the british isles archipelago. on the main island of great britain between the years and , a republican form of government was introduced, but its official memory was later expunged by employing the highly subjective and suggestive label of ‘interregnum’. this closed cultural laboratory by ‘time-branding’ has resulted in the implantation of an alternative, but bogus chronology, wherein the reign of one monarch has immediately followed another. both of them were named charles, and the second was the son of the first. however, the execution of the first king charles was followed by a unitary republic, and not by his son reigning as charles ii over his father’s two kingdoms . in , that intervening republic was terminated, and king charles ii began two new monarchies , since the original monarchies reigned over by his father had terminated with his execution in . during the creation period of those two new monarchies of king charles ii, his henchmen manufactured a faux timeline by making it illegal to refer to past events . when samuel pepys was a - year - old schoolboy, he was present at the execution of charles i. eleven years later pepys was desperate that his youthful desire to obliterate the king’s memory should itself be forgotten. fortunately, he had not only chance, but the law, on his side. forgetting was officially sanctioned: the act of indemnity and oblivion banned “any name or names, or other words of reproach tending to revive the memory of late differences or the occasions thereof” (norbrook ). while the official website of the british monarchy of today acknowledges that there was no seamless continuation connecting the reigns of charles i and charles ii, it does misleadingly call the intervening years an ‘interregnum’ . clearly, there is no scientific evidence to show that human beings have the ability to roll back time. in this instance, however, it is as if chapter one is followed by chapter three, while pretending that chapter two had never been written. therefore, according to this alternative scenario, chapter three is really chapter two. it is a truly proto-orwellian concept. it is also a current concept, because in it could be imagined that executives at google were performing as a presley tribute act , when they told european officials that “forgetting isn't easy” . separate kingdoms of england and scotland having a shared king. same as note although the implication is that the king is also the institution of the crown, this is obviously not the case. here the word ‘crown’ has two meanings: . a type of hat; . institutions managed by a variety of people sheltering under the name of a collective umbrella. while there is a little more transparency in their actions today, the record of individual administrators has been one of political infighting gaining enough power to unseat one king and install another to their liking. it is generally conceded that without the military masterminding of major-general george monck, the creation of the new monarchies established in the name of king charles ii could not have been accomplished, although: "centuries later, historians cannot agree on whether or not the restoration of the stuarts was monck's intention..." (don jordan and michael walsh, the king's revenge. london: abacus, . . - italics added) “forgetting was officially sanctioned: the act of indemnity and oblivion banned ‘any name or names, or other words of reproach tending to revive the memory of the late differences or the occasions thereof ’ (david norbrook, “introduction: acts of oblivion and republican speech-acts”. writing the english republic: poetry, rhetoric and politics, - ). http://assets.cambridge.org/ / /excerpt/ _excerpt.pdf; “charles ii, : an act of free and general pardon indemnity and oblivion: ‘xxiv. persons, within three years, using any words tending to revive the memory of the late differences…’ http://www.british-history.ac.uk/report.aspx?compid= (accessed november ). see ‘the official website of the british monarchy’ at: http://www.royal.gov.uk/historyofthemonarchy/kingsandqueensoftheunitedkingdom/thestuarts/charlesi.aspx i forgot to remember to forget, elvis presley at mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page in the real world of , england became a republic, and then, three years later, scotland began to be folded into that same unified nation . but in , that singular republic vanished from the legislative books, and depending upon their geographical locations, its inhabitants became subjects of one of the two new kingdoms which were created to take its place. inhabitants were forbidden by law to even mention the existence of that unified republic , or to discuss the act of legal magic which pretended that in , the monarch who now reigned over both of these new kingdoms, had begun his reign back in . the truth of the matter is that in , one king had been executed, and both of the separate kingdoms over which he had ruled came to a cessation. there was no ‘interregnum’. “sing tantarara, rogues all…” the idea of intentionally removing information from public scrutiny is not a new one (gilder and hagger - ), but in this instance it served the purpose of obliterating legal precedent. this aspect of tampering with collective cultural memory is actually the result of a legal fiction derived from the ability to exercise nunc pro tunc in a most dishonest manner. by removing one document and substituting another, and then by pretending that the document substituted contains the same information as the document removed, sans inconsequential typographical-style errors, the past can be made to vanish within the twinkling of mischievous eyes. while thomas jefferson was not above interpreting past events to suit his own needs, the mocking lament he once recited in a letter to a fellow believer comes to mind: what a conspiracy this, between church and state! sing tantarara, rogues all, rogues all, sing tantarara, rogues all! silently resonating into the referendum in scotland was this mocking regale of jefferson, because, according to the standardized political parlance of today, the period of time now known as the ‘interregnum’ began on january , with the execution of king charles i of england, scotland and sundry other places . it ended on may , with a proclamation that king charles ii https://www.youtube.com/watch?v=haqjscx_ uw see: google says 'forgetting' isn't easy, as requests mount: after europe's 'right to be forgotten' ruling, the technology giant claims requests are so many, it is proving difficult to follow. the telegraph ( august ). http://www.telegraph.co.uk/technology/google/ /google-says-forgetting-isnt-easy-as-requests- mount.html (accessed november ). the process of assimilating scotland with england into a unitary republic was gradual and in april this procedure resulted in ‘an ordinance for uniting scotland into one commonwealth with england’. see: april : an ordinance for uniting scotland into one commonwealth with england. british history online. http://www.british-history.ac.uk/report.aspx?compid= (accessed november, ). see note a latin term meaning now for then which in the usa has been retroactively employed in legal practice to substitute one record for another. one such example is substituting an adopted child’s original birth certificate with a document that replaces birth name(s) with adopted name(s), but retaining other details. another example is in the revival of a business corporation wherein the name of the original founding owner is substituted for a new owner who has bought the shell corporation as a result of a bankruptcy. in both instances the actual historical record on file can be legally changed to reflect manufactured events that never happened, and only a court order can unseal the original document, which requires knowledge that the existing document is not a true historical reflection of the original events that took place. co-author mervyn hagger has personal family experience of the first example, and cites the texas legal history of the jingle company known as ‘pams’, as a second example of nunc pro tunc document substitutions for other than typographical errors. letter of reply dated june , to major john cartwright. http://www.let.rug.nl/usa/presidents/thomas-jefferson/letters-of-thomas-jefferson/jefl .php (accessed ` november ). he also claimed to be king of france. mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page had seamlessly stepped into his father’s shoes at the very moment his father died. that product of nunc pro tunc laid the foundation for yet another work of legal fiction with the proclaimed union of , which merged the kingdom of england and the kingdom of scotland, into a joint kingdom of great britain. it was from that kingdom which many in scotland wanted to secede in as a result of a referendum. however, back in , just before scotland joined england in the creation of a united republic, the same king charles ii, who in became the separate king of england and king of scotland, had already been crowned in scotland as ‘king of great britain’ . the problem with that ceremony was and is that the kingdom of great britain did not come into existence until the year . that was when the bogus kingdom of england and the equally bogus kingdom of scotland, both of which were created in with charles ii as their shared but individual monarchs, formed the kingdom of great britain after the separate parliament at edinburgh was folded into a single parliament at westminster . in order to deal with this glitch in the thread of the historical timeline, many records falsely claim that the son of king charles i was actually crowned “king of scots", which of course, he was not . he was falsely crowned ‘king of great britain’. independence: from what? on july , , which was a mere years after the creation of the kingdom of great britain in , colonies united in a north american confederacy and it became known as the ‘united states of america’ (“primary documents in american history”). this confederacy of colonies issued their own unilateral divorce decree from the kingdom of great britain, and they called their act of disconnection a ‘declaration of independence’. those former british colonies replaced the institution of the british crown with an undefined ‘supreme creator’, although this source of their ultimate authority was further specified as being ‘nature’s god’, author of ‘nature’s laws’. as we shall see, it was by referring to this higher power that these confederated former colonies overcame the legal fiction that jefferson later drew attention to in his letter to major cartwright . while a supreme creator was immediately declared to be the ultimate source of all authority in the confederated united states of america, when the usa became a federal nation in , its founding laws were set forth in a written constitution which named ‘the people’ as its authors. however, ‘the people’ retained in their laws this same unspecified deity as their ultimate source for of all that exists. the institution known as the british crown is in law defined as a corporation sole (maitland - ) which, because it is an artificial creation, outlives its monarchical representatives who wave to citizen-subjects in much the same way that mickey and minnie mouse wave to disneyland tourists. it gives rise to the sloganeering chant that “the king is dead. long live the king! ”. it is this institution which holds the real power in today’s united kingdom of england, scotland and northern great britain is the largest island among thousands of islands which form the archipelago of the british isles, including the island of ireland. at that time, ‘great britain’ was limited to a geographical description of an island comprising most of the territory of two independent political sovereign nations called england and scotland. queen anne became the last monarch in line from charles ii, to rule separately over england and scotland, and the first queen of the kingdom of great britain. ireland would not be added to this mix for almost another hundred years in . several preceding monarchs beginning with james vi of scotland, who subsequently also became james i of england, tried to imply that their ‘union of crowns’ was their authority to claim title as ‘king of great britain’, but the validity of those claims was not accepted by either the ruling elite in england or scotland. the usa did not become a federal nation under its present constitution until june , with george washington as its first president who held that office from april , to march , . see note a cliché with both secular and religious claimed origins; in this instance it indicates continuity of office (crown), not current office holder (or current monarch representing the crown.) mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page ireland. it is to the british crown that the military swears its allegiance, and it is in its name that british courts administer their version of justice, and hold prisoners, and most importantly, it is by means of this institution that the wealth of the nation is controlled. during the recently failed referendum regarding the question of whether scotland should be an independent country , the hope of the ‘yes’ vote was to merely untangle the union of . voters on both sides remained silent about the bogus coronation of when some in scotland had crowned charles ii as “king of great britain”. they also remained silent on the subject of the republic which had united scotland with england. therefore, it was not surprising that both sides in the referendum debate remained silent about the true status of the currency presently in use by the united kingdom; yet both sides danced around this currency maypole while chanting questions about ownership of the currency. however, neither side really wanted to answer that question because it was a conundrum from which neither side had an escape plan. neither side wanted to tell the truth regarding the fraudulent way in which the governance of great britain has been conducted since ; nor the manner in which its bogus history has been promulgated to the masses. the reason for their silence is easy to explain: the crown is a subject that remains ‘off limits’ because it is founded upon a fraudulent series of events, and it is controlled by operatives who remain hidden within the shadows of privy council secrecy . the identity of the crown cannot be partially unraveled without taking events back to , and that is why the term ‘interregnum’ has always been used to prevent that from happening. jefferson’s personal links when jefferson wrote to cartwright on june , , his letter of was penned a mere years after jefferson had helped to write the ‘declaration of independence’ on behalf of the usa confederacy, and it was only years since the usa had been transformed into a federal nation. but in-between those two events, connecticut’s danbury baptist association had written to jefferson on october , and they were complaining that their state legislature did not believe that the first amendment to the u.s. constitution applied to their state. in reply to this baptist organization on january , , jefferson who was president at that time, wrote in part: “believing with you that religion is a matter which lies solely between man and his god the whole american people declared that their legislature would ‘make no law respecting an establishment of religion, or scotland’s referendum. the scottish government. http://www.scotreferendum.com (accessed november ). as of january , the united kingdom of great britain and northern ireland is comprised of england, scotland, wales, and northern ireland. england absorbed the area known as wales beginning in . according to the official nunc pro tunc version of current history, scotland politically united with england in . ireland was absorbed into the uk during , but in , subsequent losses of territory on the island of ireland, shrank uk territorial claims on that island to its north-eastern sector, which approximated the territory of an ancient kingdom called ulster. it is interesting to note that the official parliamentary explanation refers to the secret nature of the privy council while ‘the official website of the british monarchy’ pretends that today there is nothing secret about it. see: oonagh gay and anwen rees, the privy council: standard note: sn/pc/ ( july ). http://www.parliament.uk/documents/commons/lib/research/briefings/snpc- .pdf and queen and privy council. the official website of the british monarchy. http://www.royal.gov.uk/monarchuk/queenandgovernment/queenandprivycouncil.aspx (accessed november ). cartwright had attempted to foster republican ideals by establishing ‘hampden clubs’ in england and scotland, which were named after john hampden who helped to trigger the first of the civil wars. in glasgow the famous hampden stadium still celebrates the lead-in to the ‘interregnum’. march , to march , . mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page prohibiting the free exercise thereof’, thus building a wall of separation between church and state ”. three years before the u.s. adopted its federal constitution in , thomas jefferson toured some of the civil war battle sites of england with his friend and traveling companion, john adams. in , both men had been instrumental in creating the ‘declaration of independence’; but instead of visiting a nation where all previous ill-feeling about that document was forgotten and forgiven, a few years after their visit, british warships fired upon the usa during the war of , giving rise to events described in its national anthem ‘the star spangled banner’. it was also during that time that british troops invaded washington, dc and set fire to both the white house and the library of congress. the british waited to invade new orleans after that phase of hostilities had nominally come to an end . even before the creation of the confederated united states of america in , political and religious refugees had struggled to reach america’s shores. on board the mayflower, which had sailed years earlier in , there were passengers with neo-anabaptist beliefs .their tormentors included officials in control of the state church of england, which specifically named anabaptists as enemies . all of this was more than mere national history to jefferson, because it was specifically a part of his family history. in , which was years after the mayflower sailed for north america, king charles i was executed and the era of republic began in england. unfortunately, the departed king’s son decided to fight on until he was finally defeated at worcester. jefferson had reason to know the intimate details of the royalist defeat, because royalist reinforcements were cut-off before they reached worcester by an army led by colonel robert lilburne. he was a baptist fighting for issues with which jefferson identified . unfortunately there is no historical collection of baptist archives, as such. see: american baptist historical society. http://abcconn.org/history/index.php?title=american_baptist_historical_society (accessed november ). “the american baptist historical society (abhs) is the oldest baptist historical society in the united states… it was established in … destruction of archives in … when a fire destroyed the abhs collection”. the collection was reassembled from other sources after this date, such as: james hutson, 'a wall of separation'. fbi helps restore jefferson's obliterated draft. library of congress. http://www.loc.gov/loc/lcib/ /danbury.html and jefferson’s letter to the danbury baptists ( january ). http://www.heritage.org/initiatives/first-principles/primary-sources/jefferson-s-letter-to-the-danbury-baptists (accessed november ). in the ‘battle of new orleans’ became a hit for singer johnny horton. http://www.youtube.com/watch?v=nfesmrwhcmc (accessed november ). the history of the anabaptists is both complicated and lengthy and beyond the scope of this article. therefore as a means of linkage only, we offer this basic explanation: on the island of great britain anabaptists eventually became known simply as ‘baptists’. they were divided theologically into two distinct groups identified as being ‘general’ (arminian) or ‘particular’ (calvinistic). http://www.abc-usa.org/what_we_believe/our-history (accessed november ). many on board the mayflower adhered to “the believers baptism’ (submersion of adults instead of sprinkling upon infants), and concurred that: “…all that believed were together, and had all things common”. cited: book of acts : , king james version. see: e. belfort bax, rise and fall of the anabaptists. new york: american scholar publications, ( ). print. page supra “here was buried thomas jefferson - author of the declaration of american independence of the statute of virginia for religious freedom and father of the university of virginia”. jefferson's grave. the jefferson monticello. mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page the first amendment to the federal u.s. constitution specifically forbids the federal government from interfering with the free exercise of religion: it can neither assist, nor resist religious worship . while this was a doctrine that jefferson agreed with, it also provided another reason why there was more than a genealogical bond between the lilburne and jefferson families. when thomas jefferson arrived as a tourist accompanied by his on-again, off-again, on-again friend john adams, both men were well aware of the lilburne name. it was no coincidence that the virginia house thomas jefferson was born in was called ‘shadwell’, because it had been named after a parish east of the city of london where his grandfather isham randolph on his maternal line, had married jane lilburne. but when the shadwell family home burned down, thomas’ father moved his family into a house name edge hill , and that is where thomas grew up. thomas jefferson’s mother was the daughter of jane lilburne, who came from a line stretching back to an uncle of robert and john. jane married twice, and as jane rogers, she married isham randolph. this couple produced jefferson’s mother, who gave birth to his sister named lucy. she married charles lilburne lewis, who gave one of her sons the first name of lilburne. thomas’ brother randolph also gave one of his children the first name of lilburne. john adams’ speech at worcester, england colonel robert lilburne was only one of several in the lilburne family who played important parts during the civil wars. after his army caused the final collapse of the royalist military cause at worcester, robert lilburne was sent to scotland to maintain martial law from a headquarters at dalkeith , and that is where he became acting commander of all military forces on land. it was because robert was in command, that he was able to throw open the doors to the founding of both baptist and quaker congregations in scotland. however, post-‘interregnum’ accounts of baptist congregations in scotland are a prime example of orwellian expurgation at work. in this instance its victims are ‘unable to remember real events’, because the history of the baptist church in scotland just vanishes from the scene once the republic is overthrown. the baptist union of scotland reports that many of robert lilburne’s men were “baptist soldiers who used their influence to establish small churches in leith, perth, cupar, ayr and aberdeen ”. when general george monck took over from lilburne about a year later, he turned back the hands of time by re-imposing religious intolerance once more . consequently, baptist congregations http://www.monticello.org/site/research-and-collections/jeffersons-gravestone (accessed november ). see: first amendment. legal information institute. http://www.law.cornell.edu/wex/first_amendment (accessed november ). named after the first major battle of the civil wars. near edinburgh, see retrieval: https://www.google.com/maps/place/dalkeith,+midlothian,+uk/data=! m ! m ! s x b df ee db : x b fa a acb a ?sa=x&ei=msrrvp rl jqakuxglgb&ved= ciabepibmas (accessed november, ). about us: the baptist union of scotland today – scan down to ‘history’. http://www.scottishbaptist.org.uk/about-us (accessed november, ). ibid. monck became a failed mentor to general benedict arnold, who adopted the code name of ‘monck’ during the u.s. revolutionary war, when he switched sides as monck had done, because arnold thought that the british would win. while it worked well for monck, arnold’s side lost and he went down in history as being a byword for traitor. http://clements.umich.edu/exhibits/online/spies/stories-arnold- .html (accessed november ). ‘monk, indeed, did all he could to repress them’. david douglas, history of the baptist churches in the north of england from to . london: houlston and stoneman, . print. mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page disappeared for the next one hundred years, and during that time “baptist life in scotland ceased to exist ”. in april , while jefferson and adams were on their tour of england, they arrived at fort royal hill in worcester. that is where the royalist dream had been finally terminated on september , , with the essential assistance of robert lilburne’s troops. the former battlefield was not far from edgehill where the first battle in a series of civil wars had begun at, during . but it was in worcester that adams delivered a speech which he noted in his diary: at worcester that i was provoked and asked, “and do englishmen so soon forget the ground where liberty was fought for? tell your neighbors and your children that this is holy ground, much holier than that on which your churches stand. all england should come in pilgrimage to this hill, once a year". this animated them, and they seemed much edgehill and worcester were curious and interesting to us, as scaenes where freemen had fought for their rights. the people in the neighborhood, appeared so ignorant and careless pleased with it. perhaps their aukwardness [sic] before might arise from their uncertainty of our sentiments concerning the civil wars . adams asked in amazement: ‘and do englishmen so soon forget the ground where liberty was fought for?’ his answer would have to wait until it arrived in the form of a novel explanation hundreds of years later, during april . that is when it was penned by george orwell in that lonely farmhouse on the bleak scottish island of jura. orwell might well have re-written his answer as “they are unable to remember real events and they persuade themselves that they remember other events which never happened”. however, by it was not only a case of englishmen at worcester forgetting about “the ground where liberty was fought for”, or scots who forgot to ask the real question about their union with england during their failed referendum of . americans have seemingly joined the ranks of the forgetful and adopted the attitude that jefferson and adams must have dreamed-up, a concept of individual rights when they wrote the ‘declaration of independence’. although jefferson did not acknowledge his real sources of inspiration, a united states supreme court justice undertook that task for him, albeit about years after jefferson’s death (gilder and hagger “the pedigree” - ). the supreme court remembers while robert was a baptist, his brother john had drifted from puritan to quaker (feuer ) by the time he died. ‘freeborn john’ was more-or-less led by the circumstances in which he found himself, and this is how he developed his skills as both a writer and orator. his fiery legal career began with a landmark trial , in , when he established his right to remain silent, and he made it clear that he would be a slave to none. that star chamber court hearing took place during the reign of charles i, and its importance was later noted by u.s. supreme court justice hugo black. beginning in , black began to footnote see note john adams diary , march - july : adams family papers. massachusetts historical society. http://www.masshist.org/digitaladams/archive/doc?id=d (accessed november, ). ‘some of the lines of the original diary are preceded by what appear to be quotation marks’, and highlighted above with italics. (john adams’ original handwritten pages are also reproduced on this site). february , . court of star chamber. british history online. http://www.british-history.ac.uk/report.aspx?compid= &strquery=john% lilburne (accessed november ). mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page the works of john lilburne in several of his written opinions , and he also cited them as being a precursor to the u.s. bill of rights (black - ; gilder and hagger - ). he was joined by fellow justice william o. douglas and chief justice earl warren, who also noted the contributions made by john lilburne. but it was warren who delivered the majority opinion in that landmark case of miranda vs. arizona , and supported his opinion with references to john lilburne. however, on october , , newsweek magazine ran a major article, “loss of liberties, britain’s war on terror”, which began with these words: “in john lilburne fought a charge of high treason in a london court by claiming that ‘the good old laws of england’ permitted silence on questions ‘against or concerning myself’. last week the lilburne principle fell victim to london’s stepped-up war against irish republican army terrorism” ( ). the visit by jefferson and adams during took place a mere ten years after they crafted the declaration of independence, and noted that the reigning king george iii of great britain had created “a history of repeated injuries and usurpations, all having in direct object the establishment of an absolute tyranny over these states”. however, jefferson remained politically quiet during his visit, and his own notes were made as a tourist about the architectural, botanical and scientific information that he stumbled across during his vacation . obfuscating the issues several decades ago on november , , roy hattersley , then deputy leader of the british labor party, appeared on cspan television in the usa. mervyn hagger had the chance to ask him why a written constitution does not govern the affairs of the people in the british isles. a portion of his response in the context of this article is quite illuminating, and therefore it is worth repeating here. hattersley replied: “…why don’t we have a written constitution?…. it doesn’t fit our parliamentary system of government. if we incorporated a written constitution into our processes, any government could overturn it in a single line bill ”. the parliament to which roy hattersley referred is the parliament in london, of which only the house of commons. hattersley used to sit in that house as an elected member of parliament, but not anymore. he is now a member of the unelected house of lords and a member of the secretive privy council . hattersley has for years claimed to be a republican , and therefore on paper, against a monarchical form of government. although he said that a written constitution “doesn’t fit our parliamentary system of government”, it is because the crown occupies the same spot that would adamson v. california, u.s. ( ); dissent: hugo l. black. http://www.law.cornell.edu/supremecourt/text/ / #writing-ussc_cr_ _ _zd (accessed november ). miranda v. arizona. legal information institute. http://www.law.cornell.edu/supremecourt/text/ / (accessed november ). notes on a tour of english country seats, &c., with thomas jefferson, – ? april . founders online, the national archives http://founders.archives.gov/documents/adams/ - - - - - (accessed november ). lord hattersley http://www.parliament.uk/biographies/lords/lord-hattersley/ (accessed november ). cspan, november , , brian lamb book review program: with printed words as transcribed by mervyn hagger from a recording of this broadcast. see note “as an anti-monarchist...” and “if monarchists condescended to argue with republicans like me…” excerpts from roy hattersley. the queen can help free ireland from history. the times (london); may , . http://www.thetimes.co.uk/tto/opinion/columnists/article .ece (accessed november ). mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page be occupied by a written constitution, that it “doesn’t fit our parliamentary system of government”. that is the reason why parliament has limited powers that would enable a written constitution introduced by parliament at a level beneath the crown, to be overturned by parliament “in a single line bill”. hattersley admitted that this was true, but said that ‘the people’ liked it this way: “the tradition of great britain, the spirit of great britain, the feelings of the people of great britain is that we run by individual items of legislation and you can’t superimpose a written constitution onto a system where people are expecting and reacting and supporting something quite different ”. then hattersley claimed that: “a declaration, …a statement, …a constitution is putting the interpretation of those powers into the hands of the courts, and in our experience, the sort of freedoms that we want to see, the sort of extensions of liberties are not best interpreted by courts, but by politically motivated, intentionally motivated parliaments… ”. in other words, hattersley believes that a “one man show” that can dictate to ‘the people’, is what ‘the people’ want. this was the basis upon which the autocratic bbc was originally formed, because it bowed to the will of john reith, and john reith was quite specific about why the bbc was formed and what it intended to do. his reasoning was that ‘the people’ did not know what they wanted, and so he would tell them, while making sure that his view about what was good and what was bad, was imposed upon them, for their own good (gilder and hagger “john reith” - ). it was this dictatorial approach that allowed oliver cromwell to become ‘the protector’ of the new republic that was created following the abolition of the monarchy, because while cromwell executed a man, he did not destroy the institution of the crown. the north american colonies did that with their ‘declaration of independence’, but cromwell’s cronies even offered him the title of ‘king’ , if he wanted it, because they had retained the very institution that was the cause of the problem, no matter who was the monarch, or what title that person was known by. cromwell presided over a faux republic. john lilburne repeatedly clashed with oliver cromwell on the issue of the nation’s sovereignty, because lilburne was pushing for the adoption in england of a written constitution called ‘an agreement of the free people of england’ . if such a document had replaced the institution of the crown, then the people of scotland would have been free to decide upon their own legal framework for governance. the result of lilburne’s continual confrontations with cromwell’s supporters was resolved by imprisoning him for the remainder of his life in dover castle . extirpation by redaction it is only necessary to see what happened after charles ii died on february , to understand the modus operandi of both the english and scottish crown institutions at work. his successor was see note see note the interchangeability of the words ‘monarch’, ‘king’ and ‘queen’ with ‘crown’, when talking about the representative of the crown as an institution, can lead to confusion, which may or may not be intentional. it is another example of words losing their ability to communicate in an orwellian manner. see: “in february , a group of mps headed by lord broghill presented a new constitution known as the humble petition and advice under which cromwell was formally offered the crown”. (oliver cromwell, - . bcw project) http://bcw-project.org/biography/oliver-cromwell (accessed november ). see details of various editions at an agreement of the people. bcw project. http://bcw-project.org/church-and-state/second-civil-war/agreement-of-the-people (accessed november ). see details of his imprisonment through letters to his wife, the resurrection of john lilburne, now a prisoner in dover-castle. street corner society. http://www.strecorsoc.org/docs/resurrection .html (accessed november ). mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page james ii in england and james vii in scotland (and a list of other titles). but he did not last long, because the movers and shakers who controlled both the crown corporation sole in england and scotland, deposed him. then they ran him out of the county when he would not abide by their wishes . the next move by these people behind the scenes was to invite a dutch prince to take over the vacancy left by the king who had just been forced out, and that is when william of orange was installed with his wife mary as co-monarch. they arrived with enough foreign troops to make sure that their coup would not be overturned by supporters of the king, who had been thrown off his throne. with a flourish of orwellian irony, their supporters branded the arrival of this pair as the ‘glorious revolution’ . after william and mary came anne, and it was during her reign as the separate queen of england and queen of scotland that the controlling agents in england blackmailed their counterparts in scotland into accepting a financial bail-out for their failed south american colony of darien . that was to be the price paid for shutting down their scottish parliament. thus, in , the kingdom of great britain finally came to life with the same queen anne as its first monarch . from here the story of the kingdom of great britain switches to a line of german kings who led the way to king george iii. about this king, jefferson wrote in the u.s. declaration of independence: “a prince whose character is thus marked by every act which may define a tyrant, is unfit to be the ruler of a free people”. the north american colonists decided that the only way to free themselves from the british crown was to issue a declaration of independence. their declaration was not accepted at face value by the british crown, which then turned to german mercenaries in order to wage war on the renegade colonists. by , this lesson had been lost on the scots who in turn lost their referendum seeking independence. debates surrounding the issue of scottish independence were redacted in order to prevent the issue of the crown from being discussed. therefore, since the crown holds the finality of power governing today’s united kingdom, by not discussing crown sovereignty, both sides of the issue failed to discuss whether scotland should be an independent country, with the corporation sole which currently holds that sovereignty. king james ii ( - ). royal family history http://www.britroyals.com/kings.asp?id=james (accessed november ). “revolutionaries…. hope to recast popular memory to justify the new order”. see: melinda zook, “the bloody azzines: whig martyrdom and memory after the glorious revolution”. albion. vol. , no. (autumn, ), pp. - . http://www.jstor.org/stable/ (accessed november, ) and: the glorious revolution. http://www.parliament.uk/about/living-heritage/evolutionofparliament/parliamentaryauthority/revolution (accessed november ). see map and other details in richard cavendish, “founding of the darien colony”. http://www.historytoday.com/richard-cavendish/founding-darien-colony (accessed november ). robert burns penned his poem marking this episode with the title: ‘such a parcel of rogues in a nation’. burns country. http://www.robertburns.org/works/ .shtml (accessed november ). anne (r. - ). the official website of the british monarchy. http://www.royal.gov.uk/historyofthemonarchy/scottish% monarchs( ad- )/thestewarts/anne.aspx (accessed november ). hessians. chronicle of the revolution. liberty! the american revolution. http://www.pbs.org/ktca/liberty/popup_hessians.html (accessed november ). mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page conclusions after reviewing the record of actual events which have taken place, it becomes readily apparent why orwell could write: you are unable to remember real events and you persuade yourself that you remember other events which never happened. therefore, we should try to discover what it is that we should collectively remember, but which we have collectively forgotten. it is the opposite of the lines sung by elvis: i forgot to remember to forget her…, because we have remembered something that never was, and in doing so, we have thus forgotten to remember something that did happen. we have forgotten why in john adams attributed so much importance to the events which had taken place in at fort royal hill, just outside of worcester in england, and we have forgotten to remember why thomas jefferson would have immediately picked up on adams’ reference to edgehill. if civil war reenactments have not buried the real story by diverting our attention to battles over shed blood, instead of considering the spilled ink that has blotted out the basic question of individual human rights, then obfuscation by glorification of the present queen elizabeth, surely has. but even here obfuscation is at work. there has only been one queen elizabeth in scotland, and that is the present monarch. the ‘other’ queen elizabeth was a product of english monarchical madness that had nothing to do with the scots. yet we persist in calling the current queen, ‘elizabeth ii’. this is part of the transfer of terminology whereby the word ‘british’ has come to mean ‘english’, as though the scots do not exist. it is the equivalent of describing all americans as californians. but this process of obfuscation does not stop there. the world of anniversaries is now about to once again celebrate ‘magna carta’ of , ignoring the fact that there were several of these documents. the celebrations also ignore the fact that the edition was annulled by the pope, one month after it had been signed by king john of england . but what did king john or his magna carta have to do with the kingdom of scotland? the answer is nothing, nothing at all, because john was not the king of scotland . but this will not deter the many engaged in obfuscation as a means of selling a fantasy version of history to tourists as ‘british’ history. while critics may laugh at the idea of an australian reenacting the life of william wallace and events that never happened, while at the same time ignoring many events that did happen during the actual life of this man, the movie braveheart has been taken to heart by the promoters of scottish tourism as a useful tool to rid visitors of their ‘spare change’. therefore, we should also remember that orwell wrote his tale about a dictionary while huddling from the cold on that bleak scottish isle. unlike the title of his novel, the publication date of that dictionary is still in the future, because the work of ridding our collective lives-lived of reality by means of obfuscation through redaction is still a work in progress. best of all for the scriptwriters, it is also a process that seems to be both entertaining and one that makes money. perhaps one day we will all come to love ‘big brother’. there is still time, because is still well into the future, our future, the future of us all . “his conflict with the church led to his excommunication. the annulment of magna carta by pope innocent iii in august , at john’s request, led to a renewal of the baronial revolt which was still raging when john died in october ”. magna carta: people and society. magna carta. british library. http://www.bl.uk/magna-carta/articles/magna-carta-people-and-society (accessed november ). after king james vi of scotland who was king james i of england, references were made to the king ruling over territory, and not people. “critics consensus: distractingly violent and historically dodgy”. braveheart ( ). http://www.rottentomatoes.com/m/ -braveheart (accessed november ). “…the struggle was finished. ….he loved big brother”. the concluding words in orwell’s novel nineteen eighty-four: p. . mervyn hagger and eric gilder, “the british interregnum: a yesterday that never happened”. cultural and institutional memory as (a) means of progress (part i) hypercultura, vol , no / page works cited “adams family papers”. massachusetts historical society. web. nov. . “adamson v. california, u.s. 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(autumn, ): - . print. web. nov. . http://www.jstor.org/stable/ authors meryn hagger is an independent scholar whose work is closely associated with dr. eric gilder and the john lilburne research institute (for constitutional studies). since , gilder and hagger have collaborated upon a series of academic articles arising out of a study of the history of publishing and broadcasting, and their relationship to the acts of governmental licensing as a means of political censorship. contact: mervynhagger@hotmail.com eric gilder is a professor in the department of communication and development studies at the papua new guinea university of technology in lae, papua new guinea. he also holds (on leave) the post of university professor and fellow of the “c. peter magrath” center for international academic cooperation at the “lucian blaga” university of sibiu (romania). with mr. hagger, he had published a series of articles on comparative broadcasting history and legal history since . contact: egilder @yahoo.com doi: . /j.bpj. . . a monday, february , mechanisms through which upregulation of bcl affects earlier steps of bax- mediated apoptosis are not fully understood. we found that bax insertion into the mom was the earliest apoptotic step inhibited by bcl overexpression. paradoxically, we also found that bax translocation to the mitochondria was not inhibited but rather spontaneously increased in this same genetic context. this increase in mitochondrial associated bax required a physical interaction be- tween bax and bcl . we therefore propose that, at least when upregulated, bcl behaves as a ‘decoy receptor’ which sequestrates bax at the mitochondria but inhibits its insertion into the mom, committing the cell to survive. supported by nyu research challenge funds to ld. -pos compartmentalization of bcl family proteins mediated by organelle lipid membranes rebecca j. boohaker, ge zhang, adina loosley, kathleen nemec, annette r. khaled. university of central florida, orlando, fl, usa. cancer is defined by a pronounced inhibition of cell death. the bcl family of proteins tightly regulates the delicate balance between life and death. one method of regulation is the compartmentalization of antagonistic members. for example, bax, a pro-apoptotic member of this family, acts as the penulti- mate factor in the apoptotic cascade by releasing apoptogenic factors such as cytochrome c from the mitochondrial lumen. the normally cytosolic protein translocates from one internal compartment to another through an elusive mechanism. individual organelles are defined not only by function (mediated by specific membrane bound proteins), but by the unique composition of their phospholipid membranes. in this work, we have evaluated the contribution of organelle lipids to the localization of of bcl proteins. -pos in search of the structure of mac in the mitochondrial outer membrane pablo m. peixoto , christian renken , shefali haldar , carmen mannella , kathleen w. kinnally . new york university college of dentistry, new york, ny, usa, wadsworth center, albany, ny, usa, academy of the holy names, albany, ny, usa. several groups have tried to determine the structure of the channel (mac) formed in mitochondrial outer membranes (om) of apoptotic cells or in syn- thetic membranes by bax and related proteins/peptides, using electron micros- copy (em), atomic force microscopy and x-ray diffraction. here, pore-like structures ~ - nm were handpicked from transmission em images of ura- nyl-acetate-stained oms isolated from control and apoptotic (il -deprived) fl . cells. these ‘‘candidate pores’’ were aligned by correlation procedures, and class averages defined by principal component and k-means analyses. main differences in the class averages were ( ) the presence of one or more dark (stain-filled) pores, and ( ) the nature of white (stain excluding) features around the pores. a class average consisting of a single -nm pore with pro- nounced white rim was rotationally averaged and used as a reference for cross-correlation searches of om images from control and apoptotic cells. searches using this -nm ‘‘donut’’ motif and the same motif doubled in size ( -nm ‘‘donut’’) yielded thousands of ‘‘hits’’ in both control and apoptotic membranes, which were subsequently aligned and classified as before. the pre- dominant stain-filled structures found with both motifs were not circular but elongated (up to ~ x nm), extending away from stain-excluding crescent- shaped features. the radial anisotropy ruled out reference bias and was in- consistent with pores formed by rings of evenly spaced protein subunits. we hypothesize that the different classes of structures detected represent stages in formation of mac as an increasingly large membrane bilayer defect (or ‘‘cleft’’) induced by successive aggregation or clustering of bax/bak molecules. a progressive assembly mechanism for mac has been recently suggested by real-time monitoring of mac conductances in isolated mitochondria by patch clamping (martinez-caballero et al. j biol chem : - ). supported by nih grant gm . -pos effects of mac formation on mitochondrial morphology pablo m. peixoto, shin-young ryu, robert range, kathleen w. kinnally. new york university college of dentistry, new york, ny, usa. accumulating literature associate mitochondrial dynamics with apoptosis, since regulation of either process has reciprocal effects. these processes seem to converge in formation of the mitochondrial apoptosis induced channel, mac, which releases cytochrome c and triggers the degradation phase of apo- ptosis. while bax and bak, core components of mac, were shown to interact with fusion and fission proteins, some studies also suggest proteins from the in- termembrane space could leak to the cytosol and further promote mitochondrial fission during apoptosis. the temporal relationship between apoptosis induc- tion, mac formation and mitochondrial fragmentation was investigated by time lapse microscopy. mac function was induced through staurosporine treat- ment and microinjection of tbid or cytochrome c. mac formation and mito- chondrial dynamics under these conditions were monitored in hela cells (clone ) that stably express low levels of gfp-bax and were transiently transfected with a pdsred- plasmid. gfp-bax relocation to mitochondria only during apoptosis signals mac formation, while pdsred- expression shows mito- chondrial structure as red fluorescence. treatment with staurosporine and microinjection with tbid or cytochrome c induced relocation of bax and col- lapse of the mitochondrial network. the temporal relationship between these two events was further analyzed. interestingly, pretreatment with imac , a spe- cific mac blocker, protected against cell death and prevented mitochondrial fragmentation after tbid injection. our results suggest a link exists between mac formation and collapse of the mitochondrial network during apoptosis. supported by nih grant gm . -pos mechanism of the mitochondrial cytochrome c release wave in bid-induced apoptosis soumya sinha roy, cecilia garcia-perez, erika davies, xuena lin, györgy hajnóczky. thomas jefferson university, philadelphia, pa, usa. bid, a bh -only bcl family protein, plays a central role in apoptosis. bid is cleaved by caspase- and other enzymes forming tbid that induce mitochon- drial outer membrane (omm) permeabilization and cytochrome c (cyto-c) re- lease. however a mystery remains how bid synchronizes the function of a large number of discrete organelles, particularly in mitochondria-rich liver or muscle cells. here we showed that tbid ( . - nm) elicited progressive omm perme- abilization and complete cyto-c release with a dose-dependent lag time and rate in h c cell populations. once started, the omm permeabilization was not pre- vented by tbid washout. in contrast, the dose-response for digitonin-induced omm permeabilization displayed quantal behavior. in single cell imaging studies, permeabilized h c and primary human cardiac cells transfected with cyto-c-gfp showed complete tbid-induced cyto-c-gfp release closely followed by mitochondrial depolarization. the cyto-c-gfp release started at discrete sites and propagated through the mitochondria with a constant velocity and a relatively stable kinetic of release in each organelle. similar tbid-induced cyto-c-gfp release wave was documented in intact h c cells transfected with tbid. the waves were not dependent on ca þ , caspase activation or permeabil- ity transition pore opening. however, treatment with mntmpyp, a ros scav- enger or overexpression of mitochondrial superoxide dismutase suppressed the coordinated cyto-c release and also inhibited tbid-induced cell death. on the other hand, both superoxide and hydrogen peroxide sensitized mitochondria to the tbid-induced permeabilization. thus, tbid engages a ros-dependent inter-mitochondrial signaling mechanism for spatial amplification of the apoptotic signal by mitochondrial waves. -pos role of milton domains in the calcium-dependent regulation of mito- chondrial motility sudipto das, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. the mammalian grif and oip , and the drosophila milton are kinesin- binding proteins that form a complex with the miro gtpase, an outer mitochon- drial membrane ef-hand protein, to support the movement of mitochondria along the microtubules. our study demonstrates that in h c cells overexpress- ing oip or grif , the basal motility of mitochondria is increased, whereas the sensitivity to calcium-induced movement inhibition is decreased. to dissect the interaction between milton, kinesin and miro, three different milton constructs were tested: milton ( - ), the soluble domain of milton; milton ( - ), lacking the kinesin heavy chain binding site and milton ( - ) that lacks additional ~ amino acid presumably containing part of the miro binding site. immunohistochemistry revealed that the overexpressed milton ( - ) was cytoplasmic, whereas the other two milton constructs showed mitochondrial localization. the basal mitochondrial motility was in- creased by milton ( - ) but was not altered by milton ( - ) or mil- ton ( - ). a plot of mitochondrial motility against slowly rising cytoplasmic [ca þ] induced by thapsigargin ( mm), shows that overexpression of milton ( - ) significantly reduced the calcium sensitivity of mitochondrial motil- ity reminiscent of oip and grif . by contrast, milton ( - ) or milton ( - ) did not have any effect. the thapsigargin-induced cytoplasmic calcium signal was not affected by any of the milton constructs. these data indicate that monday, february , a the c terminus of milton is an important regulator of the mitochondria associated motors and is involved in conferring the calcium sensitivity from miro to the motors. milton - is sufficient for the mitochondrial binding, whereas the - amino acids are critical for the control of calcium sensitivity of mi- tochondrial motility. -pos biophysical properties of mitochondria undergoing fusion xingguo liu , orian shirihai , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, boston university, boston, ma, usa. emerging evidence shows the importance of genes controlling mitochondrial fusion in physiology and their deregulation in neurodegenerative and metabolic disorders. however, apart from djm, the biophysical properties of the fusion- competent mitochondria remain elusive. to evaluate the conditions of contact formation and fusion, we used organelle-targeted fluorescent proteins, includ- ing photoactivatable gfp, which allow tracking of individual mitochondria. in h c cells, almost every mitochondrion is aligned with microtubules that pro- vide the primary tracks for mitochondrial movement. our results show that ~ % of fusion events involve moving mitochondria. however, fusion occurs irrespective of mitochondrial speed. furthermore, ~ % of fusion events in- volve the tip portion of the mitochondrion, whereas only ~ % of these events involve organelle side. nocodazol, a microtubule disrupting agent that inhibits mitochondrial movements decreases the fusion frequency and changes mito- chondrial fusion sites. strikingly, - % of the physical contacts between ad- jacent mitochondria did not result in fusion events. to evaluate whether the fu- sion efficacy depends on the spacing between the outer and inner mitochondrial membranes we used drugs that alter the matrix volume. valinomycin, a k þ ion- ophore that induces matrix swelling evoked a decrease in mitochondrial motil- ity leading to fewer contacts among mitochondria but the number of fusion events was maintained, indicating an increase in fusion efficacy. this change occurred at a low valinomycin concentration ( . nm) that did not affect djm or opa cleavage. nigericin ( . mm), a k þ /h þ ionophore that induces shrinkage of the matrix elicited fusion inhibition and mitochondrial aggrega- tion. importantly, no motility inhibition or opa cleavage occurred at the same time and the djm was increased. these results suggest that mitochon- drial fusion is facilitated by mitochondrial motility, the key determinant of the inter-mitochondrial encounter numbers and preferentially involves the front-tip of the moving organelle. in addition, fusion efficacy depends on the mitochondrial matrix volume. -pos mitochondrial fusion dynamics in human skeletal muscle-derived cells veronica eisner, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. mitochondria have a fundamental role in both muscle physiology and pathol- ogy. mitochondrial fusion and fission are important for energy metabolism, calcium homeostasis and cell death. however, the mechanisms underlying mitochondrial dynamics are poorly understood, especially in physiological models such as skeletal muscle. here we evaluated mitochondrial fusion dy- namics in human skeletal muscle cells (husmc). skeletal muscle satellite cells were isolated from human muscle biopsies and were maintained and dif- ferentiated in cell culture. mitochondrial fusion events were evaluated by con- focal imaging of cells expressing mitochondria matrix targeted dsred and matrix targeted or outer mitochondrial membrane (omm) targeted photoacti- vatable-gfp. when we tagged the mitochondria in ~ % of total cellular area with photoactivated-gfp, we found those mitochondria undergoing matrix fusion with a frequency of . . events/min/cell (n= ). among the fusion events, % led to complete fusion and only % was followed by separation at the apparent fusion site within to seconds. both complete and transient fusion events resulted mostly from longitudinal mergers, involving end to end interaction or from mergers of adjacent mitochondria in side to side orien- tation. furthermore, we found that omm and matrix fusion are sequential and separable steps, displaying . seconds gap (n= ). finally, we evaluated the mitochondrial fusion dynamics in husmc derived from both normal and malignant hyperthermia susceptible individuals. at resting state, no significant differences were found in the number of events or in their characteristics. thus, mitochondrial fusion commonly occurs in husmc, and enables mixing of both soluble and integral membrane factors. this process would help to maintain the stability of mitochondrial metabolism. the relatively low frequency of the tran- sient fusion is probably due to the parallel organization of the cytoskeletal tracks for mitochondria and to the limited mitochondrial motility. -pos imaging interorganelle contacts and local calcium dynamics at the er-mitochondrial interface györgy csordás , péter várnai , tünde golenár , swati roy , george purkins , tamás balla , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary, national institutes of child health and human development, bethesda, md, usa. the local coupling between er and mitochondria is essential for proper cell function. a main role of the er-mitochondrial junctions is to provide a local calcium signaling domain that is important both for keeping energy production in line with demand and for the control of apoptotic mechanisms. so far it has not been possible to visualize the tiny er-mitochondrial contact points in living cells or to monitor the localized [ca þ] changes in the narrow space between er and mitochondria ([ca þ]er-mt). here, we exploited rapamycin-mediated heterodimerization of fkbp and frb domains of fluorescent protein constructs respectively targeted to the outer mitochondrial membrane and the er as drug-inducible inter-organelle linkers to identify er-mitochondrial contacts and to measure the [ca þ ]er-mt. high- resolution fluorescence imaging and d reconstruction revealed rapamycin-in- duced clustering of the er-targeted fluorescent linker-half to the contact areas with the mitochondria without major changes in the spatial arrangement of the er. essentially all mitochondria displayed contacts with the er in both rbl- h and h c cells. plasma membrane-mitochondrial contacts were less frequent with er stacks being inserted between the two organelles. single mitochondria display discrete patches of er contacts as well as continuous as- sociations. cytoplasmic and mitochondrial matrix [ca þ] showed robust er-mitochondrial ca þ transfer with considerable heterogeneity even among adjacent mitochondria. pericam-containing linkers revealed ip -induced [ca þ ]er-mt signals that were resistant to buffering bulk cytosolic [ca þ ]c in- creases and exceeded um. the largest [ca þ ]er-mt signals did not occur at the tightest associations, indicating space requirements for the ca þ transfer machinery and functional diversity among er-mitochondrial junctions. these studies provide direct evidence for the existence of high ca þ microdo- mains between the er and mitochondria in living cells, and open new possibil- ities to probe the functional importance of this specialized compartment. -pos dependence of er-mitochondria calcium transfer on different ip receptor isoforms tunde golenar , szava bansaghi , gyorgy csordas , david i. yule , suresh k. joseph , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, university of rochester medical center, rochester, ny, usa. ip receptors (ip rs) release ca þ from the er, which is locally relayed to the mitochondria to control several aspects of mitochondrial function. recent stud- ies have suggested that type ip rs (ip r ) are particularly important for me- diating the ca þ transfer at the er-mitochondrial interface. we set out to sys- tematically evaluate the respective role of each ip r isoform in chicken dt cell lines that express only one ip r isoform (double-knockout, dko , dko and dko ) or provide a null-background (triple-knockout, tko) for analysis of mammalian ip rs and their mutants. simultaneous imaging of cytoplasmic and mitochondrial matrix [ca þ] ([ca þ]c and [ca þ]m) was performed in either permeabilized cells chal- lenged with ip or in muscarinic receptor overexpressing intact cells stimulated with carbachol (cch), an ip -linked agonist. saturating ip evoked complete discharge of er calcium and resulted in comparable [ca þ]m increases in each dko. furthermore, the cch-induced [ca þ]c spike was closely followed by a [ca þ]m rise in each dko. when tko cells were rescued with rat ip r or ip r , the latter mediated a larger [ca þ]c transient but the [ca þ]m increases were very similar for both isoforms. the relationship between the [ca þ]c peak and the corresponding [ca þ]m response was also very similar for ip r and ip r . to assess the impact of the release kinetic through ip r in the mitochondrial ca þ transfer we used two point mutants of the ip r , which display either enhanced inhibition by ca þ (d n) or are relatively insensitive to ca þ inhibition (d n). d n showed dampened [ca þ]m signal and [ca þ]m vs. [ca þ]c relationship, whereas d n displayed a steeper [ca þ]m vs. [ca þ]c relationship than the wild type ip r . thus, each ip r isoform can support local er-mitochondrial ca þ transfer and their competence to activate mitochondrial ca þ uptake depends on their deactiva- tion kinetic. 	compartmentalization of bcl family proteins mediated by organelle lipid membranes 	in search of the structure of mac in the mitochondrial outer membrane 	effects of mac formation on mitochondrial morphology 	mechanism of the mitochondrial cytochrome c release wave in bid-induced apoptosis 	role of milton domains in the calcium-dependent regulation of mitochondrial motility 	biophysical properties of mitochondria undergoing fusion 	mitochondrial fusion dynamics in human skeletal muscle-derived cells 	imaging interorganelle contacts and local calcium dynamics at the er-mitochondrial interface 	dependence of er-mitochondria calcium transfer on different ip receptor isoforms [pdf] a randomized controlled comparison of flushing protocols in home care patients with peripherally inserted central catheters | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /nan. corpus id: a randomized controlled comparison of flushing protocols in home care patients with peripherally inserted central catheters @article{lyons arc, title={a randomized controlled comparison of flushing protocols in home care patients with peripherally inserted central catheters}, author={m. lyons and a. phalen}, journal={journal of infusion nursing}, year={ }, volume={ }, pages={ – } } 	m. lyons, a. phalen 	published 	medicine 	journal of infusion nursing introduction/significance/population: research has failed to demonstrate an optimal flushing solution or frequency for central catheters. in a study of home care patients, catheter dysfunction with loss of patency was the most common complication and occurred in % of the peripherally inserted central catheters (piccs) tracked. with the advent of the affordable care act and the promise of expanded home care services, this study offers evidence as to a preferred flushing protocol to… expand view on wolters kluwer download.lww.com save to library create alert cite launch research feed share this paper citationshighly influential citations background citations methods citations view all topics from this paper 	flushing 	heparin 	alteplase 	cns disorder 	home care of patient 	protocols documentation 	neoplasms 	confidence intervals 	heparin-induced thrombocytopenia 	drug allergy 	sample variance 	anticoagulants 	clinical act of insertion 	laboratory procedures 	exclusion 	excretory function citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency obstruction of peripherally inserted central catheters in newborns: prevention is the best intervention 	m. l. g. pedreira 	medicine 	revista paulista de pediatria : orgao oficial da sociedade de pediatria de sao paulo 	 	 	pdf save alert research feed quality improvement initiative reduces the occurrence of complications in peripherally inserted central catheters 	b. walters, chelsey price 	medicine 	journal of infusion nursing : the official publication of the infusion nurses society 	 	 save alert research feed heparin flush vs. normal saline flush to maintain the patency of central venous catheter among adult patients: a systematic review and meta-analysis 	s. sharma, s. mudgal, rakhi gaur, rrk sharma, maneesh sharma, k. thakur 	medicine 	journal of family medicine and primary care 	 	 	view excerpt save alert research feed normal saline versus heparin for patency of central venous catheters in adult patients - a systematic review and meta-analysis 	l. zhong, h. wang, + authors zhan-sheng hu 	medicine 	critical care 	 	 	highly influenced 	 	view excerpts, cites background save alert research feed flushing and locking of venous catheters: available evidence and evidence deficit 	g. goossens 	medicine 	nursing research and practice 	 	 	pdf 	view excerpts, cites methods save alert research feed heparin versus . % sodium chloride locking for prevention of occlusion in central venous catheters in adults. 	e. lópez-briz, v. ruíz garcía, j. cabello, s. bort-martí, rafael carbonell sanchis, a. burls 	medicine 	the cochrane database of systematic reviews 	 	 	 save alert research feed right management and flushing 	c. cullinane 	medicine 	 	pdf save alert research feed comparison between saline solution containing heparin versus saline solution in the lock of totally implantable catheters. 	antonio rafael de oliveira brito, k. nishinari, + authors bruno leonardo de freitas soares 	medicine 	annals of vascular surgery 	 	 save alert research feed randomized controlled trials in central vascular access devices: a scoping review 	mari takashima, gillian ray-barruel, a. ullman, s. keogh, c. rickard 	medicine 	plos one 	 	 	pdf save alert research feed evidence-based criteria for the choice and the clinical use of the most appropriate lock solutions for central venous catheters (excluding dialysis catheters): a gavecelt consensus 	m. pittiruti, s. bertoglio, + authors enrico delutio 	medicine 	the journal of vascular access 	 	 	highly influenced 	pdf 	view excerpts, cites background save alert research feed ... ... references showing - of references sort byrelevance most influenced papers recency central venous catheters in home infusion care: outcomes analysis in , patients. 	n. moureau, s. poole, m. murdock, s. gray, c. semba 	medicine 	journal of vascular and interventional radiology : jvir 	 	 save alert research feed efficacy of normal saline solution versus heparin solution for maintaining patency of peripheral intravenous catheters in children. 	k. leduc 	medicine 	journal of emergency nursing: jen : official publication of the emergency department nurses association 	 	 save alert research feed the impact of needleless connector device design on central venous catheter occlusion in children: a prospective, controlled trial. 	s. schilling, d. doellman, n. hutchinson, b. jacobs 	medicine 	jpen. journal of parenteral and enteral nutrition 	 	 	pdf save alert research feed does low-dose heparin maintain central venous access device patency?: a comparison of heparin versus saline during a period of heparin shortage. 	m. jonker, kurt osterby, l. vermeulen, susan m kleppin, k. kudsk 	medicine 	jpen. journal of parenteral and enteral nutrition 	 	 save alert research feed comparison of occlusion rates by flushing solutions for peripherally inserted central catheters with positive pressure luer‐activated devices 	l. bowers, k. speroni, louann jones, m. atherton 	medicine 	journal of infusion nursing : the official publication of the infusion nurses society 	 	 save alert research feed guidelines on the insertion and management of central venous access devices in adults 	l. bishop, l. dougherty, + authors j. treleaven 	medicine 	international journal of laboratory hematology 	 	 	pdf save alert research feed management of occlusion and thrombosis associated with long-term indwelling central venous catheters 	j. baskin, c. pui, u. reiss, j. wilimas, s. howard 	medicine 	the lancet 	 	 	pdf save alert research feed the risk of bloodstream infection associated with peripherally inserted central catheters compared with central venous catheters in adults: a systematic review and meta-analysis 	v. chopra, j. c. o’horo, m. rogers, d. maki, n. safdar 	medicine 	infection control &#x ; hospital epidemiology 	 	 	pdf save alert research feed safe and cost effective use of alteplase for the clearance of occluded central venous access devices. 	j. timoney, m. malkin, + authors l. saltz 	medicine 	journal of clinical oncology : official journal of the american society of clinical oncology 	 	 save alert research feed peripherally inserted central catheters and midline catheters for the homecare nurse 	l. gorski, l. m. czaplewski 	medicine 	journal of infusion nursing : the official publication of the infusion nurses society 	 	 save alert research feed ... ... related papers 	abstract 	topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue p el lugar (ii) cpa_ dos modos de situarse en el lugar monticello de thomas jefferson y taliesin de f. lloyd wright juan antonio cortés pride of place es la historia del modo en que una joven nación ha construido su país... en amé- rica, hemos tenido no sólo que fabricar nuestro mundo en un vasto continente no construido, sino también fabricarnos nuestra propia historia. nuestros edificios cuentan la historia de la gran energía que tenemos que dedicar a inventar y reinventar nuestro pasado. en el país del hom- bre hecho a sí mismo, hay grandes aspiraciones a reinventar tanto la historia personal como la nacional. la historia de nuestra arquitectura, pues, es también en gran medida la historia de las personas, de los clientes apasionados y de los arquitectos individuales con visiones particulares. cada obra de arquitectura está coloreada por los sueños y las experiencias de sus creadores.n robert a. m. stern gran parte de la obra de jefferson debería ver- se, hablando metafóricamente, como una lu- cha entre el pasado fijo europeo y el futuro móvil americano, entre palladio y frank lloyd wright, entre el deseo de una geometría con- tenida, clásica, y el instinto de extenderse hori- zontalmente sobre la superficie del terreno. n vincent scully n robert a. m. stern. pride of place. building the ame- rican dream. boston y nueva york, , p. . n vincent scully. american architecture and urbanism. praeger publishers, nueva york y washington, , p. . n ibídem, p. . n véase william howard adams. jefferson’s monticello. abbe- ville press, nueva york, , pp. , y . two ways of situating ourselves within a place: monticello by thomas jefferson and taliesin by frank lloyd wright this article consists of a comparative description of two buildings: monticello, thomas jefferson’s residence which he built for himself in virginia, and taliesin, the studio and home of frank lloyd wright in wisconsin. first, the text studies the architectural references and evolution of the project for monticello, in order to later focus on the taliesin´s explanation. there is a certain similarity in the way that monticello and wright’s houses (especially the ward willits house) extend horizontally across the land. the thesis of this article is that both jefferson’s and wright’s residences rest upon a hill, but monticello crowns the top while taliesin borders it, like an eyebrow. in conclusion, we can say that taliesin is a “natural house”, which manages to fully integrate its architecture with nature. palabras clave palabras clave: casa, proyecto, evolución, corona, natural keywords house, design, development, crown, natural dos modos de situarse en el lugar j.a.cortés cpa .indd / / : p el lugar (ii) cpa_ en su libro pride of place: building the american dream, robert stern narra, entre otras muchas historias de la arquitectura norteamericana, la de dos edificios, monticello —la casa que thomas je- fferson construyó para sí mismo en virginia— y ta- liesin —la casa y estudio de frank lloyd wright en wisconsin—. jefferson eligió como emplazamiento la cima de una colina próxima a la plantación de su padre y lugar de su nacimiento, al otro lado del río rivanna, y dirigió su edificio hacia el oeste, mi- rando hacia el territorio indio que se extendía más allá de los pies de la colina. la decisión de cons- truir encima de una colina, a pesar de los numero- sos problemas prácticos que esto suponía, incluida la escasez de agua, reflejaba las altas miras de je- fferson al planear su casa, su fe en las casi ilimita- das posibilidades inherentes a la vasta expansión continental. la posición dominante de la casa per- mitía una vista sobre el paisaje lejano, un paisaje que para jefferson “era un jardín continental sin paralelo en su belleza y como tierra de promisión”. n desde el punto de vista práctico, su interven- ción en la colina consistía en su aterrazamiento y la subsiguiente plantación de jardines y huertas, que contrastaban con el bosque circundante y que su- pusieron la creación de un verdadero asentamien- to para él, su familia y todo el personal a su servi- cio. monticello era el centro de una plantación de hectáreas, en gran medida autosuficiente y que incluía cuatro granjas. la casa estaba rodeada por huertas y distintos tipos de jardines, en con- creto jardines de flores, de verduras y de frutales, de modo que los terrenos alrededor del edificio se convirtieron en una especie de laboratorio vivo dos modos de situarse en el lugar j.a.cortés f monticello. vista aérea desde el oeste (william howard adams. jefferson’s monticello. abbeville press, nueva york, , ó vincent scully. american architecture and urbanism. praeger publishers, nueva york y washington, ) f monticello. plano general de la propiedad, (william howard adams. jefferson’s monticello. abbeville press, nueva york, ) f monticello. plano de emplazamiento, (frederick doveton nichols, ed. thomas jefferson’s architectural drawings. t. j. memorial foundation, charlottesville, ) cpa .indd / / : el lugar (ii) cpa_ p para el estudio de plantas útiles y ornamentales procedentes de diversos lugares del mundo. decisiones fundamentales para la creación de monti- cello fueron la elección del lugar exacto de implanta- ción de la casa y la orientación de la misma. un plano de jefferson de toda la propiedad dibujado en muestra la localización de los terrenos en relación con el río rivanna y la carretera larga y serpenteante que conduce a la casa desde el este. es especialmen- te significativo que, dada la escala del plano, no se dibuja la planta de la casa, pero sí se marcan los dos ejes de la misma. en otro plano, de y a escala mayor, se dibuja esa planta y el nivel horizontal de forma oval y plantado de césped en el que la casa se asienta. se dibuja también el paseo recto al sur de la casa —en el que se localizaban los distintos talleres con que contaba la propiedad— y los cuatro caminos de circunvalación que rodean la colina de monticello a distintos niveles, estableciendo un orden concéntri- co alrededor de la casa. en otro plano dibujado por jefferson a partir de , éste señala las distintas es- pecies vegetales que proyecta plantar alrededor de la casa, lo cual muestra la importancia que para él tenía esta cuestión.n pocas casas en los estados unidos de américa refle- jan más claramente la personalidad de su dueño que el monticello de jefferson. su proyecto, construcción y remodelación se extendieron a lo largo de más de cuarenta años. jefferson empezó a edificar monti- cello en —cuando tenía veinticuatro años de edad— y, como la construcción avanzó lentamente, la primera casa estaba aún sin terminar cuando en partió para francia en misión diplomática. des- pués de su regreso de europa en y de sus cuatro años como ministro de estado, jefferson comenzó a rediseñar monticello agrandando la casa por el pro- cedimiento de duplicar casi simétricamente las anti- guas habitaciones respecto a un nuevo eje formado por pasillo, escaleras y recintos de servicio. cuando, al final de su segundo mandato como presidente, je- fferson se retiró de la vida pública en , la casa estaba prácticamente acabada y amueblada. como sigue señalando stern, el nombre italiano que jefferson eligió para su casa y plantación —monti- cello— y también en cierta medida su localización constituían un homenaje a palladio, el cual señalaba como segundo emplazamiento recomendable para una casa un lugar “elevado y alegre”.n jefferson, que había estudiado atentamente los cuatro libros de ar- quitectura, había constatado con consternación la divergencia entre los modelos originales y no sólo las copias coloniales, sino también los más importantes ejemplos ingleses. este deseo de vuelta a una arqui- tectura más fielmente palladiana mostraba el desa- grado de jefferson con la arquitectura colonial típica de las plantaciones de virginia, una arquitectura que seguía los modelos georgianos. durante su estancia en francia, jefferson pudo co- nocer de primera mano algunos ejemplos de arqui- tectura romana, inspiradora en gran medida de la del propio palladio. a su vuelta, decidió reconstruir monticello como un símbolo de la nación americana. surgió así un edificio en forma de templo clásico, con un pórtico con frontón en cada fachada y una cúpula algo incongruente rematando el conjunto. dos largas alas en l, casi enterradas en la ladera, se proyectan desde la casa y abrazan un espacio en u. con sus cu- biertas planas, forman pasarelas que conducen a los cuerpos extremos, los cuales se perciben como pa- bellones aislados en medio de una gran extensión de césped.n en varias de sus obras, vincent scully señala, con su poética manera de expresarse, la singularidad y el significado de algún modo heroico de la relación entre monticello y su emplazamiento: “su colina, monticello, es un montículo perfecto, como un to- los regio, hinchado en su perfil y lo suficientemente pequeño para que la compacta casa pueda ahuecar debidamente su cima y completar la forma de la co- lina mediante su cúpula. colinas más altas se elevan como olas a su alrededor, y la cadena de montañas blue ridge se levanta hacia el oeste con el vasto de- safío de la frontera”.n sin embargo, el mismo scully dos modos de situarse en el lugar j.a.cortés n el emplazamiento recomen- dado en primer lugar era la orilla de un río. n véase stern, op. cit., p. . n vincent scully. american architecture and urbanism, cit., p. . f planta de robert morris y primeras plantas de monticello (vincent scully. american architecture and urbanism. praeger publishers, nueva york y washington, ) f planta de monticello. cuarta solución, - (vincent scully. american architecture and urbanism. praeger publishers, nueva york y washington, ) f y ’. monticello. planta baja, (frederick doveton nichols, ed. thomas jefferson’s architectural drawings. t. j. memorial foundation, charlottesville, , ó william howard adams. jefferson’s monticello. abbeville press, nueva york, ) f monticello. planta de la versión final (vincent scully. american architecture and urbanism. praeger publishers, nueva york y washington, ) cpa .indd / / : p el lugar (ii) cpa_ dos modos de situarse en el lugar j.a.cortés n véase scully. architecture. the natural and the manma- de. st. martin’s press, nueva york, , p. . n véase scully. american ar- chitecture and urbanism, cit., pp. - . n ibídem, p. . n véase scully, ibídem, p. , y “american houses: tho- mas jefferson to frank lloyd wright”. en aa.vv. the rise of an american architecture. pall mall press, londres, , pp. y . n scully. the rise of an american architecture, cit., p. . n ibídem, p. . n stern, op. cit., p. . n wright decidió entonces abandonar a su mujer catheri- ne, y a sus seis hijos en oak park para empezar una nueva vida con mamah borwick cheney, la mujer de un vecino y anti- guo cliente. n ibídem, p. . n véase ibídem, p. . n ibídem, p. . señala que la obsesión de jefferson por poner todo lo que conoce en un sólo edificio hace que éste parez- ca destartalado en comparación con la serena sen- cillez de la villa rotonda de palladio, majestuosa en su asentamiento sobre la colina. pero en monticello puede también detectarse una tensión entre la retó- rica clásica y las tradiciones vernáculas, de modo que el edificio expresa el intento de expandir las fronte- ras existentes, extendiéndose lateralmente, lo que se convertiría posteriormente en algo característica- mente americano.n a pesar de la clara influencia de palladio en este edificio de jefferson, hay que tener en cuenta que las formas palladianas se habían fil- trado a inglaterra y a américa a través de la visión pintoresca del paisajismo inglés, por lo que sus deri- vados tenían menos consistencia arquitectónica que los originales del maestro del véneto. además de la influencia general de palladio, scully se- ñala como fuente específica para los proyectos origi- narios de monticello una planta tomada del libro del inglés robert morris selected architecture, en la que el bloque central de la planta se proyecta ligeramente hacia delante y hacia atrás respecto a los dos laterales. en sus primeras plantas, jefferson hace más gruesa la masa de las chimeneas y adelgaza en cambio las pa- redes, de acuerdo con lo que eran las casas coloniales típicas. al mismo tiempo, cambia las proporciones de los bloques laterales, de modo que tanto ellos como el central se proyectan según los dos ejes. de hecho, el prisma que aún constituía el proyecto de morris des- aparece; en su lugar, empieza a definirse un esquema cruciforme. a continuación, jefferson clarifica este esquema de dos ejes que se cruzan al dar continui- dad transversalmente al espacio interior y al extender el eje de acceso hacia afuera mediante la adición de lo que parece que hubiera sido una loggia con arcos. pero no se detiene ahí; extiende más los dos ejes, si- tuando habitaciones poligonales en tres de los lados y prolongando los dos extremos del eje de entrada mediante porches con columnas. además, de acuerdo con las villas palladianas, el eje de entrada ha quedado libre como eje visual y de recorrido que atraviesa la casa, para lo que las chimeneas se sitúan sólo en las paredes laterales del bloque central. cpa .indd / / : el lugar (ii) cpa_ p lograda la extensión según los dos ejes horizontales, jefferson desea también darle a la casa un eje vertical —al menos exteriormente— que lo fije a su empla- zamiento. para ello recurre al tambor y la cúpula así como al frontón del pórtico —que engloba dos plantas en la apariencia de una—, tomados todos ellos de la tradición que procede de la villa rotonda de palladio y pasa por la villa chiswick de lord burlington. pero, a diferencia de la rotonda, e incluso de chiswick, la cúpula de monticello no funciona interiormente como culminación de la sala que está debajo; en su interior sólo hay una habitación de ático. no existe un espa- cio vertical que se contraponga a los ejes horizontales, que son los que caracterizan la organización de la villa; un potente eje conduce al interior de la casa desde la pendiente de la colina y de nuevo al exterior de la cima allanada.n las alas típicas de la tradición de las villas palladianas —no de la rotonda— “son apartadas del uso que esa tradición hace de ellas como un elemento humanista que abraza al que va a entrar y son empu- jadas bajo tierra para abrazar, en cambio, a la propia colina bajo su cima”.n según scully, la planta de monticello prefigura la de la casa ward willitts de frank lloyd wright. la liber- tad respecto a las restricciones antiguas es el tema común de ambos arquitectos, los dos se fijaron el mismo problema: cómo hacer estallar la caja. si en aquélla los ejes tratan de romper la caja compacta y extenderse libremente, en ésta lo llevan a cabo final- mente. si en el edificio de jefferson el volumen del edificio está encerrado en un tenso combate entre la vertical autocontenida y la horizontal expansiva, con la cúpula y las alas pugnando fieramente, en el de wright todo cede ante la extensión horizontal de los planos de cubierta. además, la casa retoma un com- ponente abandonado por jefferson en el desarrollo del proyecto de monticello: la chimenea colonial situada en el centro de la planta y desde la que se proyectan los ejes en cruz.n dos modos de situarse en el lugar j.a.cortés n véase ibídem, pp. - . n neil levine. the architec- ture of frank lloyd wright. nueva york, . cap. iv. “the story of taliesin”, p. . n ibídem, p. . n como señala stern, “ta- liesin tiene una historia de pasiones heroicas, tanto arquitectónicas como perso- nales” (op. cit., p. ), una historia que incluye dos destrucciones por incendio y dos consiguientes reconstruc- ciones. n véase levine, op. cit., pp. y . f monticello. alzado occidental de la versión final (frederick doveton nichols, ed. thomas jefferson’s architectural drawings. t. j. memorial foundation, charlottesville, ) f monticello desde el oeste (william howard adams. jefferson’s monticello. abbeville press, nueva york, ) f monticello. pabellón sur (william howard adams. jefferson’s monticello. abbeville press, nueva york, ) cpa .indd / / : p el lugar (ii) cpa_ además del tema de la libertad respecto a las ata- duras del pasado y, en concreto, respecto a la caja cerrada del edificio tradicional —y de ahí la expan- sión horizontal—, el otro tema que ya se plantea en monticello es el del control de la naturaleza, el de la posesión de la tierra por el hombre: “la casa coro- na la colina cónica, la controla, como la tumba de un héroe”.n esta casa para una sola familia encarna el instinto de posesión de una extensión de terre- no, de dominio sobre el mismo. y es precisamente esta relación de la casa con la naturaleza en general y, en concreto, con el terreno en el que se asienta la que diferencia monticello de otra casa, el taliesin de wright. “a diferencia de la de jefferson, la casa de wright trata de abrazarse a la colina en vez de coro- narla; éste construyó para sí mismo no un panteón sino una cueva y una tienda en su seno”.n robert stern desarrolla esta idea sobre taliesin en su libro antes mencionado y lo pone también en para- lelo con monticello: “la obra de frank lloyd wright en la casa-estudio a la que llamó taliesin, en spring green, wisconsin, trató de rivalizar con el monticello de jefferson como autobiografía y como modelo para el destino arquitectónico y cultural de américa.”n después de haber abandonado en oak park — un suburbio de chicago en el que había vivido duran- te más de veinte años n — y de pasar un año en europa—, wright volvió en el otoño de para establecerse a finales del año siguiente en el campo de wisconsin donde había crecido y empezar allí una nueva vida. pero la valoración que wright hacía de la situación era menos optimista que la de jefferson: “desanimado por mucho de lo que vio en el mundo industrializado, se retiró a la naturaleza. anidó su casa en la colina y le dio el nombre —topográficamente explícito— de taliesin, que significa ‘borde resplan- deciente’ en galés. taliesin era también el nombre de un legendario poeta galés del siglo quinto, una identificación que expresaba la tendencia anticlási- ca de wright.” n a pesar de las coincidencias con monticello, en el sentido de una vuelta a la tierra, la relación con ésta es distinta en ambos casos. para je- fferson, el diálogo entre el hombre y la naturaleza era mutuamente edificante, mientras que para wright la naturaleza ocupaba el primer lugar. n por ello, taliesin fue construida con fachadas de pie- dra local cortada toscamente, cubiertas bajas y una horizontalidad insistente que hace que el edificio parezca parte del paisaje. “taliesin era una obra de integración ambiental, que deliberadamente borra- ba la separación entre lo hecho por el hombre y lo natural”.n como señala stern, cada elemento del diseño de wright corresponde al paisaje circundan- te. la piedra amarilla a las colinas locales; el acabado de la madera a los troncos grises de los árboles; las paredes revocadas a los bancos de arena del río. así, taliesin fue el primer edificio americano que estaba completamente en paz con el continente. sin em- bargo, las fuentes en las que se inspiró no eran sola- mente americanas. mantuvo la gran chimenea como corazón sólido de la casa y con su sentido primario de protección según la tradición doméstica colonial. pero el sentido de vinculación con la tierra, los teja- dos bajos que se proyectan hacia el suelo y el patio suavemente perfilado y puntuado por estatuas sugie- ren las villas campesinas italianas que wright conocía dos modos de situarse en el lugar j.a.cortés n frank lloyd wright. auto- biografía. - . el cro- quis editorial, madrid, , p. . n cit. en levine, op. cit., p. . n la “habitación de trabajo” tenía aproximadamente treinta y cuatro pies de largo por diecisiete de ancho. (véase levine, op. cit., p. ). n wright. an autobiography. duell, sloan and pearce, nueva york, , p. . n wright. autobiografía. - , cit., p. . n el esquema en l, primero, y en u, después, con que hemos descrito la planta de taliesin podría entenderse más bien como interpenetración en cruz de esquemas lineales. la parte residencial, en concreto, es el resultado de la interpenetra- ción del cuerpo de habitaciones con una banda perpendicular de espacios abiertos —la loggia, su terraza, el recinto que antecede la entrada y, al otro lado del comedor, la terraza hacia el valle—. significati- vamente, wright repite este mecanismo compositivo de pro- longar más allá de la esquina los dos cuerpos perpendicula- res entre sí en el otro ángulo del conjunto, aunque aquí sin consecuencias espaciales ni visuales. n wright, op. cit., p. . n véase levine, op. cit., p. . levine da como referen- cias posibles la villa medici f taliesin desde el lago, finales de la década de (neil levine. the architecture of frank lloyd wright. princeton university press, ) cpa .indd / / : el lugar (ii) cpa_ p mente por debajo de su cima. la casa se convirtió, como wright escribió luego, en “la ‘ceja’ o borde de la colina”. n los primeros planos para taliesin, de abril de , muestran un edificio en forma de l integra- do por un ala de estancia y por otro ala constituida por una “habitación de trabajo”, o estudio, y por una generosa loggia abierta y una terraza que conecta ambas áreas. n siguiendo el contorno de la colina, un ala se extiende paralela al recodo del río en direc- ción noroeste-sudeste mientras que la otra apunta aguas arriba hacia el nordeste. las caras exteriores del diedro formado por la casa se orientan así hacia las dos vistas más despejadas, el curso alto del río y el valle. la planta de junio del mismo año duplica el esquema inicial formando una u, con lo que queda definido un patio cerrado por tres de sus lados; este patio está separado de la cima de la colina por un muro de contención recto que forma su cuarto lado y formaliza el desnivel entre ambos. de sus viajes por la toscana. por su parte, los espacios abiertos y fluidos estaban en parte inspirados por su admiración por la arquitectura de japón, que había visitado en . n en cualquier caso, la íntima relación de taliesin con el marco paisajístico era enteramente nueva en la obra de wright. el mundo propio de las ‘casas de la pradera’ quedó atrás, de modo que, al liberarse de chicago como centro político y cultural, “la naturale- za ahora reemplazó a la cultura como fuente directa de las ideas arquitectónicas de wright”. n taliesin fue diseñado como un ‘refugio’ y un ‘retiro’; había de ser un hogar para él y su nueva mujer así como un estudio desde el que acometería su renovada prácti- ca profesional y, finalmente, sería también la escuela en la que propagaría sus nuevas ideas. como sigue señalando neil levine, taliesin no fue nunca sólo una casa, ni siquiera un mero edificio, sino una propiedad en el campo: “a la vez casa, granja, estudio, taller, es- cuela y morada familiar, es una completa expresión de la integración que wright lleva a cabo de la arqui- tectura y la naturaleza”. n algo que se mantendrá a lo largo de su tormentosa historia. n desarrollemos, siguiendo el texto de levine, esta idea de la integración que se logra en taliesin entre arqui- tectura y naturaleza. la elección de su emplazamien- to fue una primera decisión fundamental. se sitúa en el estado de wisconsin, a cuarenta millas al oeste de la ciudad de madison, en el lugar denominado hillsi- de en el helena valley (también denominado jones valley), donde sus abuelo materno, richard lloyd jo- nes, se había establecido a principio de la década de . está separado de la localidad de spring green, a unas dos millas al norte, por el río wisconsin, que en ese área fluye de este a oeste. la colina en la que se emplaza taliesin está al oeste del valle, en el punto en que éste se abre y el río forma un pronunciado recodo. desde la colina, por tanto, se domina toda la profundidad del valle hasta las pendientes arboladas distantes y también el cauce del río curso arriba. n en su autobiografía, wright explica que amaba esa colina por su sentido liberador del espacio y la vista, que comparaba con la experiencia de mirar la super- ficie del suelo desde un avión: “cuando se está en la cima de la pequeña colina, se tiene la impresión de estar en el aire, como balanceándose en un aeropla- no,... (divisando) las copas de los árboles.” n como dice levine, antes incluso de ser una casa, taliesin era una colina. una vez decidido a construir en esa colina, wright tomó otra decisión fundamental, referente a su modo de asentarse, una decisión que da la clave para entender el significado de taliesin y subraya otros de sus aspectos. para aprovechar la vista panorámica sin comprometer la integridad de la colina, wright no construyó sobre su cima, sino que rodeó con las alas de la casa sus dos flancos prominentes, pero clara- dos modos de situarse en el lugar j.a.cortés f spring green y helena valley, wisconsin (neil levine. the architecture of frank lloyd wright. princeton university press, ) en fiesole, la villa d’este en tivoli, la villa lante en bagnaia y, como más probables, las villas aldobrandini y tor- lonia en frascati. n una denominación que wright aplicará luego a las casas usonianas. n levine, op. cit., p. . n véase ibídem, pp. - . n wright, autobiografía. - , cit., p. . n véase levine, op. cit., p. . cpa .indd / / : p el lugar (ii) cpa_ dos modos de situarse en el lugar j.a.cortés con esta disposición, wright evitó ocupar la propia cima con la casa, pero ésta no le da la espalda, sino que establece una estrecha conexión con ella por medio del patio. aunque desde puntos algo distintos, tanto en el proyecto de abril como en el definitivo de junio la entrada a la casa se realiza desde atrás, a tra- vés del patio, dándole así una condición de espacio delantero: “no hay patio trasero. taliesin es todo él patio delantero”. n en efecto, como observa levi- ne, wright volvió del revés el modelo de la ‘casa de la pradera’. en vez de rodear a un elemento interior, como el núcleo de la chimenea típico de ésta, talie- sin se organiza alrededor de un elemento exterior del paisaje natural. el patio se convirtió en el núcleo de un diseño global en el que wright comenzó a liberar- se de la dependencia respecto a los patrones clásicos de simetría y axialidad que aún habían sido tan bási- cos en su obra anterior y que conferían a la casa de la pradera una cierta formalidad. tanto la planta como el uso de los materiales enfatizan la informalidad del edificio, su irregularidad y su íntima relación con el entorno natural, ya que “debía ser de la colina, per- tenecer a ella... como los árboles y las rocas”, a la vez que “era impensable, intolerable, que cualquier casa fuera puesta encima de aquella amada colina”. n se podría decir que el patio extiende su dominio a través de la casa y se asoma al paisaje desde la loggia y las terrazas. n desde la entrada al patio por la por- te-cochère, la vista está ya canalizada hacia la aper- tura al río, enmarcada por la loggia. pero el patio es también un espacio encerrado en sí mismo y con un tratamiento paisajístico propio, aunque relacionado con otras plantaciones que se extienden más allá de la casa. el jardín incluido en el patio es un jardín for- mal, al que wright denominaba un “jardín de flores” y que estaba diseñado según el modelo de giardino segreto propio de las villas italianas del renacimien- to. en la ladera sur de la colina, a lo largo del camino de acceso, creó a un lado un “jardín aterrazado” que prolongaba el “jardín de flores” más allá de la porte- cochère, y al otro lado un jardín de verduras. delante f taliesin. plano de la propiedad, finales de la década de (kathryn smith. frank lloyd wright’s taliesin and taliesin west. harry n. abrams, nueva cork, ) f taliesin. esquema en planta y sección (eduardo sacriste. “usonia”, aspectos de la obra de wright. librería técnica cp , buenos aires, ) f taliesin. planta, (bruce brooks pfeiffer, texto, y yukio futagawa, fotografías. ga. frank lloyd wright. taliesin. taliesin west. a.d.a edita, tokio, ) cpa .indd / / : el lugar (ii) cpa_ p de la casa, hacia las vistas del río y del valle, se exten- día lo que llamaba un “jardín silvestre” o bosquecillo y, al otro lado de la cima de la colina, había viñedos y huertas. muy importante paisajísticamente y desde el punto de vista práctico del riego era la manipula- ción que hizo wright del elemento del agua. represó un arroyo que corría a los pies de la colina para crear un “jardín de agua”, “un estanque al pie de la colina que elevaba el nivel del agua en el valle hasta que pudiera verse desde taliesin”.n como sigue señalando levine, la implantación en la colina, el aterrazamiento, el jardín de flores ence- rrado, la torre-belvedere en el otro extremo de la u (respecto a la porte-cochère), el asiento de piedra y la exedra en la cima de la colina, la estatua y, espe- cialmente, las fuentes, estanques y el uso controla- do del agua son todos reminiscentes de ejemplos de villas italianas que wright conocía por publica- ciones o directamente durante su reciente estancia en fiesole. n entre villa y casa de labranza, parece en cualquier caso innegable la influencia de la cam- piña de la toscana o del lacio en taliesin. wright describió taliesin como la primera “casa na- tural”, n ya que consideraba que en su arquitectu- ra había alcanzado un equivalente de la naturaleza. en este sentido, deseaba que la casa pareciese lite- ralmente parte de la colina: “la relación con la na- turaleza no era ya una de analogía, mediada por las convenciones históricamente determinadas del tipo, sino una de homología”. n frente a la idea de una casa que se añade a un paisaje, taliesin era una par- te integral de ese paisaje, de modo que la naturaleza —la colina— venía primero y la casa después, no al revés. la casa no era algo con identidad propia aun- que cualificado por la naturaleza, sino que ésta era modificada para convertirse en una casa. n en efec- to, a diferencia de la típica ‘casa de la pradera’ —que afirmaba sus propios límites y bordes para condensar la imagen del paisaje en sí misma—, en taliesin se bo- rró deliberadamente la línea divisoria entre edificio y paisaje de modo que “no fuese fácil decir dónde aca- baban los pavimentos y paredes y dónde comenzaba la tierra”.n aunque esto es así y, además, las vistas desde le patio y desde la casa se extienden más allá de los confines de la misma y relacionan el interior y el exterior como si se tratase de un único espacio continuo, n lo cierto es que, junto a esta condi- ción extrovertida, taliesin tenía que cumplir tam- bién una condición introvertida. tenía que ser un refugio, tanto en los sentidos habituales de refu- gio frente al clima y frente a las intrusiones a la privacidad como en los sentidos derivados de la situación particular de wright en ese momento, que se sentía tratado hostilmente por la sociedad y personalmente desorientado. n por eso no es de extrañar que los símbolos y los requisitos del refugio dominen en taliesin. la casa se construyó rodeando la ladera de la colina, con su parte de atrás contra el muro; su imagen dominante siem- pre ha sido la de sus tejados protectores, tejados que emergen al azar de la vegetación y que tie- nen la pendiente de la propia colina; la línea de los aleros es continua y está muy próxima al suelo en el lado hacia donde sube la pendiente. los únicos rasgos que competían con la horizontalidad de los tejados eran las masas verticales de las chimeneas de piedra, que, al señalar los lugares de reunión del interior, reforzaban el simbolismo de refugio. n en relación con esto, thomas beeby enumera una serie de elementos de taliesin que sugieren un dolmen, desde los tejados de la secuencia de en- trada, apoyados en pilares de piedra, hasta las pro- pias chimeneas, con su dintel también de piedra. en definitiva, considera que toda la casa es análo- ga a un dolmen, “la primera construcción espacial del hombre, una cueva fabricada”. n f taliesin. patio jardín, mirando al sudeste desde el puente de los establos hacia el ala de vivienda, c. (neil levine. the architecture of frank lloyd wright. princeton university press, ) f taliesin. patio jardín (kathryn smith. frank lloyd wright’s taliesin and taliesin west. harry n. abrams, nueva cork, ) f taliesin. planta, (bruce brooks pfeiffer, text, y yukio futagawa, photographs. ga. frank lloyd wright. taliesin. taliesin west. a.d.a edita, tokio, ) f taliesin. sala de estar, mirando al este, finales de la década de (neil levine. the architecture of frank lloyd wright. princeton university press, ) n véase grant hildebrand. the wright space. pattern & meaning in frank lloyd wright’s houses. university of washington press, seattle, , pp. - . n véase ibídem, p. . n thomas beeby. “the song of taliesin”. modulus. the uni- versity of virginia school of architecture review, - , p. . (cit. en hildebrand, op. cit., p. ). n stern, op. cit., p. . dos modos de situarse en el lugar j.a.cortés cpa .indd / / : p el lugar (ii) cpa_ juan antonio cortÉs arquitecto catedrático de la etsa de valladolid en , a la edad de sesenta y cinco años y en ple- na depresión económica, en un momento en que su actividad profesional y sus finanzas atravesaban un punto muy bajo, wright concibió la idea de transfor- mar taliesin en una escuela para arquitectos, crean- do la denominada ‘taliesin fellowship’. como señala stern oportunamente, aunque forzando un tanto la comparación: “al sustituir a los esclavos de la plan- tación de jefferson por los aspirantes a arquitectos y al ponerles a trabajar en las tareas domésticas y en la granja, wright extendió al siglo xx la arcádica visión de jefferson. su comunidad fue, en cierto sen- tido, una expresión de la idealización por wright de la experiencia de los pioneros americanos”. n en cualquier caso, podemos afirmar para concluir que si el político profesional y arquitecto aficionado tho- mas jefferson había orientado al oeste su vivienda en virginia —aunque volviendo la vista al clasicismo europeo para las referencias arquitectónicas—, el arquitecto frank lloyd wright, por su parte, avanzó físicamente hacia el oeste y creó una verdadera inte- gración paisajística, genuinamente americana, entre arquitectura y naturaleza al construir en el campo de wisconsin su nueva casa-estudio. dos modos de situarse en el lugar j.a.cortés cpa .indd / / : volume number april the american archivist published quarterly by the society of american archivists d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .t t w by c arnegie m ellon u niversity user on a pril the american archivist c. f. w. coker, editor douglas penn stickley, jr., assistant editor department editors maygene daniels, reviews f. p. dowling, news notes elizabeth t. edelglass, bibliography frank b. evans, the international scene milton o. gustafson, the 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minnesota is conduct- ing a nationwide survey of more than , archives and manuscripts repositories for sources documenting the history of women in the united states from the colonial period to the present. the results of this survey will be published as a multivolume guide designed to serve scholars in women's history, women's stud- ies, and a variety of other fields in the humanities and social sciences. the women's history sources survey, which is funded by a $ , grant from the national endowment for the humanities and the university of minnesota, has been formally endorsed by the executive council of the society of american archi- vists. it has also received support from the american historical association, regional organizations of archivists and historians, and many individuals in the archives, library, and history professions. at this time approximately , repositories are participating in the survey; many of them are reporting dozens—or hundreds—of collections which fall within 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american life." because work on the survey will continue through , there is still ample time for interested archivists and manuscripts curators to report collections. those who wish to do so are invited to write to: clarke a. chambers and andrea hinding, co- directors, women's history sources survey, social welfare history archives, uni- versity of minnesota, minneapolis, minnesota . andrea hinding the american archivist the american archivist: index to volumes - ( - ) index to volumes - ( - ) mary jane dowd, compiler $ members $ others $ members $ others the american archivist ( - ) $ roll, $ set members mm. microfilm, rolls $ roll, $ set others add $ postage and handling charge on orders under $ not prepaid. society of american archivists the library university of illinois at chicago circle box , chicago, illinois d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .t t w by c arnegie m ellon u niversity user on a pril ppn : development of an instrument to capture ease-ofcare outcomes in patients treated with pca delivery systems abstracts treatment among occupational injury cases. methods: an analysis of a state-based worker’s compensation claims data captured prescription reimbursement information of all injuries that occurred between january , and december , . payment information was followed over a -month period fol- lowing date of injury. a prescription sequence analysis was carried out to estimate treatment incidence rates of potential addiction due to narcotic analgesic use. results: of the , occupational injury cases, about % (n = ) received at least narcotic analgesic (therapeutic class h a). average length of therapy was days, with % of patients receiving nar- cotic analgesics for greater than days. the majority of nar- cotic prescriptions were for hydrocodone ( %). nine percent of patients received less than four different types of narcotic anal- gesics. from the prescription sequence analysis, we identified cases who received either methadone or clonidine, medications indicated for addiction treatment or detoxification. the inci- dence rate of receiving treatment for narcotic withdrawal or detoxification was per patients on narcotic analgesic therapy ( % ci: . , . ). among patients who received potential detoxification treatment, the median duration from ini- tiation of narcotic analgesic therapy to need for withdrawal or detoxification therapy was days. a cox proportional hazards model identified greater risk of suspected methadone use in oxycontin treated patients compared to other narcotic treated patients (p < . ). conclusions: to our knowledge, this is the first study that estimated the incidence rates of sus- pected addiction treatment due to narcotic analgesics used in the worker’s compensation population using sequential prescription analysis. the study has implications for developing strategies to manage narcotic analgesic prescribing practices and reduce the risk of addiction among injured workers who are narcotic anal- gesic users. pain pain—methods and concepts ppn development of an instrument to capture ease-of- care outcomes in patients treated with pca delivery systems harding g , vallow s , leidy nk , zhang m , olson w , hewitt d , viscusi e medtap international inc, bethesda, md, usa; janssen medical affairs, l.l.c, titusville, nj, afghanistan; ortho-mcneil pharmaceutical inc, raritan, nj, usa; ortho-mcneil pharmaceutical inc; thomas jefferson university department of anesthesiology patient controlled analgesia (pca) is a common method of post- surgical pain management. the extent to which this method is optimal in terms of overall convenience, ease of use, and effec- tiveness of managing pain from a patient’s perspective has not been determined. objectives: to develop a questionnaire to measure “ease-of-care” outcomes from the perspective of patients who use pca delivery systems for post-operative pain management. methods: we conducted qualitative interviews among a convenience sample of patients who had undergone hip or lower abdominal surgery and who received intravenous (iv) pca for their post-operative pain at thomas jefferson uni- versity medical center during june . a content analysis approach was used to identify domains of relevance and gener- ate an item pool. content validation of the draft “ease of care” questionnaire was performed by subjects who participated in the initial interviews. subjects were asked to rate the relevancy of each item on a scale of zero (not at all relevant) to four (highly relevant). each item was assessed for clarity and relevance, and revised as appropriate. cognitive debriefing interviews to evalu- ate patient experiences completing the instrument were conducted with a separate sample of patients from the same institution who completed the questionnaire approximately – hours post-surgery. results: the final patient ease-of-care ques- tionnaire consists of items and covers seven aspects associated with acute care pain management systems: control/self-efficacy, device function, mobility, quality of pain control, confidence, knowledge/understanding, and satisfaction. all items are scored on a -point likert scale. conclusion: we developed an instrument to capture “ease-of-care” outcomes among patients who use pca delivery systems for the management of their acute pain. the instrument is currently being used in clinical trials com- paring two pca delivery systems. psychometric properties of the instrument are currently being evaluated. ppn development of two instruments to capture ease-of-care outcomes in health-care providers who care for patients treated with pca delivery systems harding g , vallow s , leidy nk , zhang m , olson w , hewitt d , polomano r medtap international inc, bethesda, md, usa; janssen medical affairs, l.l.c; ortho-mcneil pharmaceutical, inc; pennsylvania state college of medicine objectives: to develop questionnaires to measure “ease-of- care” outcomes from the perspective of nurses and physical ther- apists who manage the care of patients treated for acute pain with pca delivery systems. methods: we conducted four focus group sessions of – participants to explore nurses’ and physical therapists’ experiences with patients using intravenous (iv) pca during july . a content analysis approach was used to identify general themes and specific issues and concerns associated with “ease of care” using the iv-pca. two item pools were generated for the development of two draft questionnaires, one from the perspective of nurses’ and the other from physical therapists, to address clinical and practical problems encoun- tered in routine care. items were selected based on relevance to the underlying concepts, clarity of item, and the overall flow and comprehensiveness of the instruments. subjects who participated in the focus group sessions also participated in a cognitive debriefing of the draft questionnaires. results: the final nurse and physical therapist ease-of-care questionnaires each consist of items that capture aspects of care delivery associated with acute care pain management systems. all items are scored on a -point likert scale. conclusion: we developed two instru- ments to capture “ease-of-care” outcomes among health-care providers to be used in upcoming studies of alternative pca delivery systems for the management of post-operative pain. the instruments are currently being used in clinical trials comparing two pca delivery systems. results will be used to examine the instruments’ psychometric properties. respiratory diseases/disorders respiratory diseases/disorders—clinical outcomes studies prs evaluation of monotherapy and combination antibiotic treatment regimens for pseudomonas aeruginosa pneumonia angalakuditi m, coley k, rea r university of pittsburgh, pittsburgh, pa, usa a step approach to myeloablative haploidentical hematopoietic stem cell transplanation (hsct): report of a phase ii trial with months of follow-up for all patients oral presentations s ) at least one / hr matched donor exists on btmr ) no potential / hr donors exist ) potential / hr donors exist pp searches falling into category (accrued until n per race) then had an hla search strategy expert rank potential donors within btmrinorder oftheirmatchinglikelihood.previouslystoreddonor samples were hr hla tested in order of ranking and evaluated to de- termine match status. consecutive rounds of donor sample testing were performed until either an / matched donor was identified or no potential donors with stored samples remained. results: the table below shows the / hr match rate of cases to be % for cau, % for his, % for api, and % for afa. careful review of the cases ‘‘pending further testing; no stored sample’’ sug- gests that few additional cases would yield / hr matches. cau pp his pp api pp afa pp / hr matched ( %) ( %) ( %) ( %) pending further testing; no stored sample ( %) ( %) ( %) ( %) no / hr match ( %) ( %) ( %) ( %) total conclusions: thisstudyprovidesatrue / hrmatchrateestimatefor cau, his, api, and afa patients through btmr, which has not been accomplished previously. these results demonstrate the racial disparity in hla match rates and can be used to inform patients searching btmr.thisstudyalsoprovidesvitalinformationfordonorrecruitment and availability efforts. results provide a baseline match rate that can be further supplemented using the additional worldwide urd inventory. a step approach to myeloablative haploidentical hemato- poietic stem cell transplanation (hsct): report of a phase ii trial with months of follow-up for all patients grosso, d. , carabasi, m. , colombe, b. , cornett farley, p. , flomenberg, p. , filicko-o’hara, j. , kasner, m. , o’hara, w. , wagner, j.l. , weiss, m. , werner-wasik, m. , flomenberg, n. thomas jefferson kimmel cancer center, philadelphia, pa; thomas jef- ferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, phila- delphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa haploidentical hsct using post transplant cyclophosphamide (cy) for elimination of alloreactive lymphocytes has been reported as a safe option for patients lacking an hla identical donor. we re- port an alternate approach with the following salient differences: mye- loablative vs non-myeloablative conditioning, peripheral blood rather than marrow stem cell source, no exposure vs exposure of hsc to cy- clophosphamide, higher fixed number of cd cells versus a lower var- iable number of cd cells in each graft. results are reported now with a followed up of - months. table . patient characteristics- step approach age ( - ) aml remission resistant/pif biphenotypic leukemia (active disease) all cr (ph-) persistent disease (ph+) mds nhl resistant saa hla mm (gvh direction) patients received gy of total body irradiation (tbi), followed by a donor lymphocyte product (dli) containing � e cd cells/kg (step ). this large dose of haploidentical lymphocytes re- sulted in fever (median temperature . �f), diarrhea and rash. cy mg/kg was given on days - and - resulting in resolution of symp- toms. tacrolimus and mmf were begun on day- . a cd selected donor product was infused on day (step ). two of the patients died of toxicity and infection before day . of the remaining pa- tients, had complete engraftment while two with pre-existing anti-donor hla antibodies failed to engraft. only of ( %) pa- tients developed severe acute gvhd, of ( %) developed limited chronic gvhd, and no patient died of gvhd. only two of pa- tients ( %) died of infection. of disease-free patients surviving months from hsct, median cd count at day was cells/ ml (range - ). eight of ( %) patients relapsed after hsct. probability of survival (os) at and years post transplant is % and % respectively. all surviving patients are disease-free. os at years is % for patients transplanted in cr, but only % for patients transplanted with active disease. kir mismatching was not correlated with relapserates. incontrast, child tomother transplants for aml ap- pear to be relapsing at higher rates than other combinations ( % vs %). in the context of cy tolerization, a dose of � e /kg t-cells resultedinconsistentengraftment,prompt immunereconstitution,lit- tle severe gvhd, acceptable toxicity, and encouraging overall sur- vival, particularly in patients transplanted in cr. using this -step platform allows us to explore the use of alternate agents for the elimi- nationofalloreactive lymphocytes,increase the lengthoftime between dliand cy, and toemploytwo donor strategies toimprove outcomes in high risk patients. unmanipulated haploidentical stem cell transplantation using myeloablative or reduced-intensity preconditioning regimen ikegame, k., yoshihara, s., kaida, k., taniguchi, k., inoue, t., kato, r., fujioka, t., tamaki, h., okada, m., soma, t., taniguchi, y., ogawa, h. hyogo college of medicine, nishinomiya, hyogo, japan background: related haploidentical donors, as cord blood, can be alternative donor sources in stem cell transplantation (sct). severe gvhd, however, has interfered the progress of haploidentical sct (haplosct). to deal with this strong gvhd, t cell depletion has usually been used in us and european countries. in order to pursue the controllable gvl effect by t cells, we have performed unmanip- ulated haplosct using myeloablative or reduced intensity precondi- tioning regimen accompanied with intensified gvhd prophylaxis. in this meeting, we will summarize our experience of haplosct for more than ten years. patients: from august to september , we have performed cases of haplosct (all cases were hla - antigen mismatched in gvh direction). patients’ characteristics are sex: male , female , age: - years old (median ), disease: aml/mds , all , ml , others . % of cases underwent sct in non-complete remission (non-cr) state. patients under years old underwent mye- loablative preconditioning regimen consisting of flu/ca/cy/ tbi gy (haplo-full, n ), and patients over years old or with comorbidities or repetitive sct (including second to fifth sct) underwent reduced intensity preconditioning regimen consist- ing of flu/(ca)/bu/atg or flu/(ca)/mel/atg (haplo-mini, n ). high dose ara-c (ca) was optional to reduce tumor burden. as atg, atg (fresenius) mg/kg, or thymoglubulin (genzyme) - mg/kg were used. gvhd prophylaxis consisted of taclolimus (tac), methylprednisolone (mpsl) mg/kg/day, short term mtx, and mycophenolate mofetil (mmf) mg/kg/day in haplo-full, and tac, mpsl mg/kg/day in haplo-mini, respectively. for elderly pa- tients over years old in haplo-mini, mmf was added. results: hematopoietic engraftment in haplosct was as rapid as that in hla-identical sct, except ten cases of graft rejection. acute gvhd (grade ii-iv) was observed in %. overall survival in five years is % in haplo-full and % in haplo-mini, respectively. if limited to cr cases, overall survival reached over % in haplo- mini. there is no difference in survival rate among patients’ diseases. discussion: unmanipulated haplosct is feasible and effective for refractory diseases. atg dose used in haplo-mini is critical, and rather low compared with that of european cases reported so far. 	a step approach to myeloablative haploidentical hematopoietic stem cell transplanation (hsct): report of a phase ii trial ... 	unmanipulated haploidentical stem cell transplantation using myeloablative or reduced-intensity preconditioning regimen sharp increase in large-vessel stroke risk seen in young, he... : neurology today you may be trying to access this site from a secured browser on the server. please enable scripts and reload this page. journal logo 		sections	ask the ethicist 	at the bench 	best advances 	disease mechanisms 	diversity 	for your patients 	in the pipeline 	viewpoint 	neurotech 	off the 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etoc 	 	 		 			home > sharp increase in large-vessel stroke risk seen in young, he... 		 	 		 			 				 				 			 		 			 				 					 					 sharp increase in large-vessel stroke risk seen in young, healthy covid- patients 	for your patients by dan hurley may , the science explainedarticle in brief stroke neurologists at major medical centers reported an increased incidence of serious large vessel strokes in young covid- patients. not all the experts agree on the reasons why. dr. laura k. stein, in personal protective gear, worked straight -hour days in the emergency department at mount sinai hospital. a sharp increase in the incidence of serious large-vessel stroke among covid- patients under age has been reported by the largest medical system in new york city. the report, in a letter to the editor of the new england journal of medicine published on april , described a two-week period in which five patients between the ages of and presented to the mount sinai health system with new-onset symptoms of large vessel ischemic stroke. (none had serious symptoms of covid- , which was diagnosed only upon testing.) their mean score at presentation on the nih stroke scale was , which is consistent with a severe stroke. by comparison, the two-week average for such cases at mount sinai during the previous year was just . patients, according to the letter. thus, the five cases between march and april represented a seven-fold increase over the usual rate. outcomes have been serious, with two discharged to a rehabilitation facility, one still in the stroke unit, and only one having returned home. the remaining patient, described in the paper as experiencing multi-organ failure, has since died. the poorer-than-average outcomes were attributed in part to the patients' delay in seeking medical care. the youngest, a female, presented at the hospital hours after symptoms began, due to fear of covid- . another presented hours after symptom onset. two presented at eight hours. the remaining patient presented after just two hours. some stroke neurologists at other hospitals around the country told neurology today they are seeing a similar trend, consistent with an increased risk of clots forming in other organ systems; they are now recommending that all patients with covid- be treated with heparin or other therapy as a preventive measure. not all stroke neurologists, however, are convinced that the trend is real. rather than an increase, some say they are seeing a sharp decline in strokes generally, especially mild strokes or transient ischemic attacks, in keeping with a broad decline in emergency department visits of all kinds other than those involving covid- . even coauthors of the new report agreed that it's too early to be sure what the true link is between covid- and stroke. “we think there's a connection—we can't be certain, but it does seem to be real,” said stanley tuhrim, md, professor of neurology and director of the division of vascular neurology at mount sinai hospital. “and from speaking with colleagues around the country, i don't think it's an experience unique to mount sinai or even to new york city.” another report, now under review, involves a dozen stroke patients who were covid- positive and treated at thomas jefferson university hospitals in philadelphia between march and april . “these are all preliminary results,” said pascal jabbour, md, professor and chief of the division of neurovascular and endovascular neurosurgery in the department of neurological surgery at the sidney kimmel medical college at thomas jefferson university. “in general, you cannot draw conclusions from a small case series. but in pandemics like this, everything moves quickly. if we see something unusual, we need to investigate it and report it.” dr. jabbour is now in the process of collaborating with other centers in the united states and europe on a larger analysis of strokes in covid- patients, he said. nejm case the case described in greatest detail in the new england journal of medicine series from mount sinai involved a previously healthy -year-old woman who presented to the hospital with an nihss score of . she had previously developed cough, headache, and chills lasting one week, and then had dysarthria with both numbness and weakness in the left arm and left leg, which progressed for hours before she finally went to the hospital. ct and ct angiography revealed “a partial infarction of the right middle cerebral artery, with a partially occlusive thrombus in the right carotid artery at the cervical bifurcation,” the letter stated. “patchy ground-glass opacities in bilateral lung apices were seen on ct angiography, and testing to detect sars-cov- was positive. antiplatelet therapy was initiated; it was subsequently switched to anticoagulation therapy. stroke workup with echocardiography and magnetic resonance imaging of the head and neck did not reveal the source of the thrombus. repeat ct angiography on hospital day showed complete resolution of the thrombus, and the patient was discharged to a rehabilitation facility.” the letter noted that a report from wuhan, china, pre-printed in the lancet, described the incidence of stroke among hospitalized covid- patients at about percent. large-vessel stroke was also reported in association with the sars-cov- outbreak in singapore. in just the two weeks since the mount sinai letter was submitted to the new england journal of medicine, three additional cases of large-vessel stroke in young patients with covid- have presented to the hospital there, according to the letter's first author and neurologist thomas j. oxley, md, phd, an instructor and director of innovation strategy for the department of neurosurgery at mount sinai. “when young patients present with a large-vessel stroke, we would normally expect to see substantial risk factors,” he told neurology today. “most of these patients did not have any.” two of the patients had no risk factors for stroke: a -year-old man had undiagnosed diabetes and a -year-old man had a mild prior stroke and diabetes. the person who died, a -year-old man, had hyperlipidemia and hypertension. in addition to the five patients under age described in the letter, close to other patients, of all ages, both patients positive and negative for covid- , presented at mount sinai with large-vessel strokes during a recent three-week period, according to neurologists there. “it's probably close to patients in three weeks,” said laura k. stein, md, an assistant professor of neurology who serves as an attending stroke neurologist at mount sinai hospital. “a little over half were covid positive. many were young and likely don't have the same risk factor we typically see.” dr. stein expressed concern that outcomes for covid- patients appear to be worse than she would normally expect. “we give them tpa and thrombectomy but then they sometimes develop really bad swelling of the brain and a catastrophic outcome,” she said. “it's too early to tell if that's real or just an impression, but it's a concern right now that we're not seeing the same outcomes.” on the other hand, she has also seen healthy young people with covid- present with a clot in large vessel, but one that does not fully occlude. “they are treated with full-dose anticoagulation, and when we repeat the ct angiogram, we see that the clot is gone. it's quite remarkable.” to better understand what is going on, she said, “we're embarking on an ambitious effort to study what we're seeing more closely. we want to compare people with stroke and covid- to stroke without covid- . we also want to understand the difference between people who have mild or incidental covid- with stroke, and those who have really severe covid and then suffer a stroke or other thrombotic event.” dr. stein spoke on saturday, april , after completing days as the attending stroke neurologist at mount sinai hospital. “twelve straight days,” she said. “it was exhausting, but exciting. this is why i went into medicine. we were getting in at every morning; some days i didn't leave my office till : at night.” mechanisms and treatments a potential explanation for why strokes should be occurring in seemingly healthy young people was offered in a paper published ahead of print in the lancet on april . researchers based at university hospital zurich noted that the sars-cov- virus infects hosts via the angiotensin-converting enzyme (ace ) receptor, expressed not only in the lungs but also in the heart, kidney, intestine and endothelial cells. the swiss researchers described three cases in which they observed direct viral infection of the endothelial cells and diffuse endothelial inflammation. “covid- -endothelitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with covid- ,” the paper stated. “this hypothesis provides a rationale for therapies to stabilize the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ace inhibitors, and statins.” another possible mechanism behind the apparent increased risk of stroke was described by dutch researchers in a paper published online on april in the journal thrombosis research. in icu patients with proven covid- pneumonia, a composite outcome of either symptomatic acute pulmonary embolism (pe), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism was seen in percent, a figure they called “remarkably high.” at the main campus weve seen about , patients with covid- . were still collecting and analyzing our data, but it seems to be around the order of percent of them having a stroke. if you consider these are very sick people with lots of inflammation, thats not actually very high.”—dr. babak navi “our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all covid- patients admitted to the icu,” the paper concluded, “and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.” as a result of such findings, mount sinai instituted a new protocol earlier this month to raise prophylactic doses of heparin in some covid- patients to that usually given to dissolved clots, even before any such clots occur. “we expect there's a problem either with the coagulation system or the endothelial lining of their vessels,” dr. tuhrim said. “if there's a large-vessel occlusion amendable to thrombectomy, we certainly do that. in addition, we are anticoagulating these people. the hospital has developed a protocol, a very complicated algorithm, but it boils down to using anticoagulant with lovinox or one of the newer oral anticoagulants in patients we might not otherwise have treated.” while many other hospitals around the world are following a similar strategy, dr. tuhrim cautioned: “it's too soon to tell whether the strategy being deployed worldwide will turn out to be beneficial. it's a question of balancing the potential benefit against the risk of increasing hemorrhage.” steven r. levine, md, faan, distinguished professor of neurology and emergency medicine at suny downstate health sciences university and chief of neurology at university hospital of brooklyn has proposed a clinical trial to compare the approaches. “you've got every recipe in the book for preventing clotting right now,” dr. levine said. “some are giving aspirin, some are giving low-dose tpa, some are giving subcutaneous heparin. i've proposed a clinical trial with a standardized protocol of two or three treatments and an interim analysis so we can eliminate the ones that aren't working and find the optimal antithrombotic or anticoagulant.” collateral damage? whatever the cause of the increased risk of stroke associated with covid- , dr. jabbour at thomas jefferson said that both the presentation and outcome are often worse than in other strokes. “usually these covid- patients present with more than one vessel that is blocked,” he said. “we also notice that the outcome of these patients isn't so good. in our series, the mortality was around percent. despite the fact that we are opening the vessels, they end up having another major stroke. their blood keeps clotting so quickly.” aside from mechanisms directly mediated by sars-cov- virus, another factor at play is the delay in presentation seen at mount sinai and elsewhere. “we see patients presenting late,” dr. jabour said. “if they come too late, we can't help them.” babak navi, md, associate professor of neurology and neuroscience at weill cornell medicine, division chief of stroke and hospital neurology, and medical director of the weill cornell stroke center, said that he, too, has seen many strokes in people with covid- , but that most are older and already critically ill from the viral infection. “there are some younger people who have had vascular events and also tested positive for covid- ,” he said, “but that's pretty rare despite the recent interest in this area. we're in the middle of the epicenter. at the main campus we've seen about , patients with covid- . we're still collecting and analyzing our data, but it seems to be around the order of percent of them having a stroke. if you consider these are very sick people with lots of inflammation, that's not actually very high.” he agreed, however, that covid- patients who do have a stroke tend to fare poorly. “a lot of that has to do with respiratory failure and other end-organ problems,” he said. “in some cases, the strokes are the fatal event, but these are very sick people.” dr. navi called for better-designed studies to determine the true risk and best strategies for preventing and treating strokes in covid- . “i think we need high quality, rigorous studies that are well controlled,” he said. “making strong statements based on small, single center case series without comparison groups is problematic. case series are useful in raising the suspicion for a novel or unique association or risk factor, but they need to be validated in methodologically strong studies. we're not there yet.” ashutosh p. jadhav, md, phd, associate professor of neurology at the university of pittsburgh medical center, said that he is not seeing a rash of covid- patients with stroke. in fact, the number of stroke admissions across a -hospital network in the area fell by about percent in march compared to previous years, although the number of large-vessel occlusions was more or less flat. “the way i interpret that is that we are not seeing the milder strokes, but the severe strokes are still coming in,” dr. jadhav said. the likely result, he said, is that people who could benefit from treatment to prevent a second stroke are not getting it. “people are not coming in to get the medical attention they need, because they're afraid to interact with the health system,” dr. jadhav said. “i call it collateral damage. in our part of the country, that's more impactful than covid- itself. it's probably hurting more people than covid- will.” even in new york city, dr. navi agreed that patients' fear of going to the hospital is cause for concern. “i actually think that's a more concerning phenomenon,” he said. “the people with tia and minor stroke are in my experience more likely to not call and seek medical attention. those are people we could potentially intervene on with evidence-based proven strategies who now we often cannot because they present to the hospital too late.” link up for more information • oxley tj, mocco j, majidi s, et al. large vessel stroke as a presenting feature of covid- in the young https://www.nejm.org/doi/full/ . /nejmc . new engl j med ; epub apr . • li y, wang m, zhou y, et al. acute cerebrovascular disease following covid- : a single center, retrospective, observational study https://papers.ssrn.com/sol /papers.cfm?abstract_id= . lancet ; epub mar . • klok fa, kruip mjha, van der meer njm, et al. incidence of thrombotic complications in critically ill icu patients with covid- https://www.sciencedirect.com/science/article/pii/s . thromb res ; epub apr . • varga z, flammer aj, steiger p, et al. endothelial cell infection and endotheliitis in covid- https://www.thelancet.com/journals/lancet/article/piis - ( ) - /fulltext. lancet ; epub apr . 						 					 						 							 email to colleague colleague's e-mail is invalid your name: (optional) your email: colleague's email: separate multiple e-mails with a (;). message: thought you might appreciate this item(s) i saw at neurology today. send a copy to your email 						 							 your message has been successfully sent to your colleague. 						 							 some error has occurred while processing your request. please try after some time. 						 					 						 							 								 add item(s) to:   an existing folder a new folder folder name: description: 							 								 the item(s) has been successfully added to "". 							 						 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articles 				 			 		 			 				 					 						 back to top 					 				 			 		 	 	 american academy of neurology neurology today 	 current issue 	 issue archive 	 at the meetings 	 video gallery 	 contact us about 	 about neurology today 	 subscription services 	 reprints 	 rights and permissions 	 advertising 	 about the aan contact wolters kluwer health, inc. email: 	[email protected] phone: 	 - - (within the usa) 	 - - (outside of the usa) american academy of neurology 	 search 	 log in 	 facebook 	 twitter 	 youtube 	 subscribe to issue alert 	 log in/register 	 facebook 	 twitter 	 youtube 	 subscribe to issue alert copyright ©    american academy of neurology  privacy policy terms of use 	 		 	 this website uses cookies. by continuing to use this website you are giving consent to cookies being used. for information on cookies and how you can disable them visit our privacy and cookie policy. got it, thanks! doi: . /j.bpj. . . tuesday, march , a -pos board b regulation of mitochondrial motility by milton-like proteins, oip and grif sudipto das, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. regulation of mitochondrial motility by milton-like proteins, oip and grif grif and oip are mammalian homologs of milton, a kinesin-binding protein that forms a complex with miro gtpase, an integral outer mitochon- drial membrane ef-hand protein. kinesin, milton and miro have been proposed to function together in the movement of mitochondria along the mi- crotubules. we report here the influence of overexpression of oip and grif on mitochondrial motility and its inhibition by agonist-induced cyto- plasmic [ca þ] ([ca þ]c) signals in h c cells. ha-tagged oip and grif were overexpressed at similar level and were localized to the mito- chondria as detected by immunocytochemistry. in oip and grif overex- pressing cells, elongated mitochondria with varied degree of aggregation were visualized both in live and in fixed, immunostained samples. mitochondrial motility at resting ca þ (< nm) was greatly enhanced by oip and to a lesser extent by grif ( . . and . motility units, respec- tively against a control value of . . motility units). furthermore, the ca þ-dependent inhibition of motility during stimulation by vasopressin ( nm) was suppressed by overexpressed oip ( . . %), whereas grif ( . . %) had no significant effect compared to control ( . . %). overexpression of oip or grif did not alter either basal [ca þ]c or agonist-induced [ca þ]c levels measured by fura . collectively, these data show that both oip and grif can modulate mitochondrial motility presumably, by promoting the association of mitochondria with the motor proteins. furthermore, oip seems to have greater efficacy in the control of mitochondrial movements. -pos board b mitochondrial localization and function relationship gyorgy csordas , sudipto das , peter varnai , tamas balla , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, school of medicine, budapest, hungary, nichd, nih, bethesda, md, usa. mitochondrial contribution to cell signaling and function relies on the associ- ation and local communication of mitochondria with the er and the plasma membrane (pm). we have recently shown that the local ca þ communication between er and mitochondria is supported by interorganellar tethers, and cre- ated synthetic linkers that connected the outer mitochondrial membrane (omm) to the er and sensitized mitochondria to er ca þ release. to study the kinetics and short-term effects of the linkage formation, we have now de- vised fluorescent protein pairs targeted to the omm and er or pm containing fkbp or frb domains. rapamycin causes heterodimerization of these pro- teins to form omm-er or omm-pm bridges. confocal imaging of the induc- ible fluorescent linker pairs revealed increased association of er or pm-patches with the mitochondria within minutes of rapamycin exposure. the linkage formation between the er and mitochondria was followed by a decrease in mi- tochondrial motility (> % in min) and by sensitization of mitochondria to ip receptor-mediated ca þ release. linkage formation between pm and mitochondria also suppressed mitochondrial motility. the initial kinetics and spatial distribution of linkage formation could be followed via recording fret between cfp-and yfp-containing linker partners. a longer version of the linker was found to show faster increase of the fret signal, supporting the idea that the rate of linkage formation positively correlates with the tight- ness of the er-mitochondrial contacts. currently, we are using the fret kinet- ics to visualize the areas of close er-mitochondrial interface and study its relevance in the ca þ signal propagation to the mitochondria. thus, inducible interorganellar linkers provide a tool to assess the distance between organelles in live cells, to establish rapid changes in the subcellular distribution and dynamics of the organelles and to evaluate the ensuing changes in organellar and cell function. -pos board b bak/bax-dependent apoptotic signaling in vdac -/- cells soumya sinha roy , william j. craigen , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, baylor college of medicine, houston, tx, usa. bid, a pro-apoptotic bcl- family protein, upon activation forms truncated bid (tbid) that binds to the outer mitochondrial membrane (omm) and engages bak/bax-dependent release of cytochrome c (cyto c) and other intermembrane space proteins from mitochondria to the cytosol to induce apoptosis. the volt- age-dependent anion channel (vdac) is the major permeability pathway for metabolites and ions in the omm but its role in the tbid-induced omm perme- abilization remains controversial. previously we reported that among the vdac isoform-specific knockout mouse embryonic fibroblasts (mefs), only vdac -/- mefs lack tbid induced complete cyto c release and loss of djm. here we show by single cell fluorescence imaging that permeabilized vdac -/- mefs expressing cyto c-gfp were resistant to tbid ( nm)-induced cyto c-gfp release. furthermore, by rescuing vdac -/- mefs with vdac the tbid-induced cyto c-gfp release was restored. in addition, tbid adenovirus infection caused less cell death in intact vdac -/- mefs than in wildtype (wt) mefs. it has been reported that vdac is required for proper targeting of bak in omm. indeed, bak did not appear in the membrane fraction of vdac -/- mefs. along this line we show that permeabilized bak -/- cells were more resistant to tbid induced cyto c release and loss of djm than wt and bax-/- mefs. strikingly, washout of the cytosol further desensitized the bak-/- mefs to tbid. unlike vdac -/- mefs, the bak-/- mefs constitutively overex- pressed bax that was primarily localized in the cytosol. however, recombinant bax ( nm) could induce cyto c release and depolarization in vdac -/- mefs and also supported the tbid-induced cyto c release. thus, in vdac -/- cells bak does not localize to the mitochondria and fails to interact with tbid and does not allow a compensatory increase in bax. the combination of these two mechanisms greatly attenuates tbid-induced omm permeabilization and apoptosis. -pos board b mitochondrial fusion-fission dynamics during hypoxia/reoxygenation xingguo liu, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. structural, biochemical, and functional abnormalities of mitochondria during hypoxia/reoxygenation (h/r) are widely believed to be important pathogenic factors that underlie cell injury. however, mitochondrial fusion-fission dynam- ics responses to h/r are unclear. we investigated the effect of h/r and chem- ical hypoxia evoked by kcn on cellular atp, djm, and on mitochondrial morphology and fusion. sixty min h caused cellular atp decrease to %. djm showed progressive decrease during h, gradually improved in the first minutes r and decreased again during longer r. mitochondrial fusion activity decreased to % during h and to % during r. in addition, anomalous fusion (autofusion and fusion at multiple sites among - mitochon- dria) produced donut-shaped mitochondria during r. cyclosporine a (csa), an inhibitor of the permeability transition pore (ptp) relieved the fusion inhibition ( %) and prevented donut formation during r. five mm and mm kcn could induce cellular atp decrease to % and %, and djm decrease to % and %, respectively. depolarized mitochondria were associated with donut-formation in mm kcn, and with massive swell- ing in mm kcn. fusion activity decreased to % in mm kcn and % in mm kcn, respectively. neither h nor kcn evoked cleavage of opa , the mitochondrial inner membrane fusion protein. thus, both physical and chem- ical h induced respiratory inhibition to gradually lower djm and cellular atp level, and caused fusion inhibition that was not dependent on opa cleav- age. this is sharp contrast of the uncoupler-induced fusion inhibition that has been attributed to the rapid djm dissipation-induced opa cleavage. a conse- quence of ptp opening, the matrix swelling seems to be a key to donut forma- tion since this could be evoked by both mastoparan, a potent ptp activator and by valinomycin, a potassium ionophore. -pos board b governing respiration: tubulin’s c-terminus interaction with vdac kely l. sheldon , dan l. sackett , claire monge , valdur saks , sergey m. bezrukov , tatiana k. rostovtseva . lpsb, nichd, the national institutes of health, bethesda, md, usa, limb, nichd, the national institutes of health, bethesda, md, usa, joseph fourier university, grenoble cedex , france. mitochondria have long been known to localize within and move along the tu- bulin-microtubule network. it was shown that tubulin binds to isolated mito- chondria with high-affinity and specifically associates with the mitochondrial voltage-dependent anion channel (vdac). we found that nanomolar concen- trations of dimeric tubulin vastly increase vdac sensitivity to voltage allow- ing for vdac blockage at low transmembrane potentials. tubulin interaction with vdac requires the presence of anionic c-terminal tails (ctt) on the in- tact protein. tubulin with proteolytically cleaved ctts does not block the channel. actin, also an acidic protein but lacking ctts, does not induce vdac blockage. two synthetic peptides with the sequences of mammalian a and b brain tubulin ctt do not induce detectable channel closure up to mi- cromolar concentrations. these results suggest a completely new role for 	regulation of mitochondrial motility by milton-like proteins, oip and grif 	mitochondrial localization and function relationship 	bak/bax-dependent apoptotic signaling in vdac -/- cells 	mitochondrial fusion-fission dynamics during hypoxia/reoxygenation 	governing respiration: tubulin’s c-terminus interaction with vdac suttontalk_aapm _v .pptx ultrasound-mediated drug delivery for cardiovascular disease jonathan t. sutton , kirthi radhakrishnan , jason l. raymond , kenneth j. bader , guillaume bouchoux , kevin j. haworth , , gail pyne-geithman , christy k. holland , university of cincinnati; biomedical engineering program, college of engineering and applied science; cincinnati, oh usa university of cincinnati; internal medicine, division of cardiovascular diseases; cincinnati, oh usa university of cincinnati, college of medicine, department of neurosurgery; cincinnati, oh usa acknowledgements: •  nih ro hl •  nih/ninds r ns •  nih ro hl conventional drug delivery strategy: perfuse entire vasculature with drug tissue specificity systemic effects ultrasound-mediated drug delivery: .  target drug/bubbles to pathologic tissue. -  antibody conjugation -  molecular image-guidance .  trigger release & penetration -  permeabilize barriers -  drive drug penetration . induce bioeffects -  stabilize plaques -  inhibit cell proliferation -  expedite clot lysis cvd drug delivery: strategies sem: human blood clot artery cross section holzapfel and gasser, j elasticity, . sutton et al. exp. op. drug delivery, . sonothrombolysis te xa s h ea rt in st itu te , . ischemic stroke cerebral hemorrhage deep vein thrombosis myocardial infarction •  acute ischemic stroke: sudden cerebrovascular stenosis •  treatment: i.v. recombinant tissue-type plasminogen activator (rt-pa) –  – % reperfusion, - % hemorrhage, treatment window •  progress: sonothrombolysis to expedite clot lysis bubble dynamics sonothrombolysis: background roger et al., circulation. . saver et al., j thromb hemost, . datta et al. umb. enzyme penetration: rt-pa sonothrombolysis: drug penetration = lysis % c lo t m as s lo ss implement an accurate transcranial propagation numerical model. validate experimentally. –  cycle, khz sinusoidal excitation –  simulations compared with hydrophone measurements –  degassed human skulls –  – % pressure reduction (rel. ff) –  shift in peak pressure position < . mm –  homogenous acoustic pressure in mca sonothrombolysis: know thy sound field bouchoux et al. pmb. . g. bouchoux, phd research question: does clot retraction affect extent of sonothrombolysis? erythrocytotic fibrin-enriched liebeskind et al. stroke, . borosilicate strong retraction flint glass weak retraction sonothrombolysis: barrier permeability pulsatile pump membrane oxygenator afterload reservoir preload reservoir effluent pressure transducer infusion pump -khz therapy transducer . -mhz pcd acoustic absorber flow clamp sonothrombolysis: ex vivo perfusion model retracted clots unretracted clots p er ce nt m as s lo ss plasma alone 
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�������	 ���������� * * * sutton et al., umb. . retracted clots unretracted clots e,f: bar = µm a-d: bar = mm sonothrombolysis: bioeffects us: khz, . mpapk-pk, cw ex vivo thrombosis system cardiovascular drug delivery: us contrast agents te xa s h ea rt in st itu te , . drug targeting & image-guidance: elip theragnostic ultrasound contrast agents –  entrain air to confer echogenicity –  targeted to pathologic tissue: atherosclerosis, cancer, thrombosis –  drug loading proposed schematic of an echogenic liposome (elip) gas hydrophilic drug antibody hydrophobic drug j. raymond raymond et al. umb, (submitted). drug targeting & image-guidance: elip targeting to smooth muscle laing et al. j. liposome res. . neuroprotection peripheral vascular disease atherosclerosis cardiovascular drug delivery: therapeutics t hom as jefferson h ospital, . te xa s h ea rt in st itu te , . sutton et al. expert opinion in drug delivery. . pulsatile pump membrane oxygenator afterload reservoir preload reservoir effluent pressure transducer infusion pump -khz therapy transducer . -mhz pcd acoustic absorber flow clamp sonothrombolysis: ex vivo perfusion model therapy us transducer mhz bev-elip sham control bev-elip + us bioeffects: drug penetration bevacizumab (avastin) rx: anti-angiogenesis size: kda antibody form: bev-elip us: mhz, . mpapk-pk, cw bioeffects: bioactive gas delivery g blunt hypo. needle force (t) rx nitric oxide (no) size: soluble gas, da form: no liposomes mechanism: no + sm = vasodilation + permeability bioeffects: nitric oxide − − − − − − time after treatment (s) p er ce nt t en si on (r el . m ax k c l) a rt er ia l t en si on (% ) buffer nitric oxide liposomes − − − − − − time after treatment (s) p er ce nt t en si on (r el . m ax k c l) a rt er ia l t en si on (% ) buffer nitric oxide liposomes nitric oxide liposomes + us us: mhz, . mpar, cycles, % dc bioeffects: nitric oxide − − − − − − time after treatment (s) p er ce nt t en si on (r el . m ax k c l) a rt er ia l t en si on (% ) + ctrl: snp buffer nitric oxide liposomes nitric oxide liposomes + us us: mhz, . mpar, cycles, % dc bioeffects: nitric oxide goal of uc igutl: investigate possible role of ultrasound to treat cardiovascular disease –  circulatory stability of drug carriers –  ultrasound image guidance, molecular imaging –  tissue targeting –  promote bioeffects, understand mechanism current work: -  developing/assessing novel drug carrier & us contrast agent (elip) -  sonothrombolysis -  drug penetration into tissue & resulting bioeffect •  fibrinolytic enzymes, bevacizumab, nitric oxide cvd drug delivery: summary thank you questions, comments? brief report late diagnosis of early disseminated lyme disease: perplexing symptoms in a gardener brooke e. salzman, md, amber stonehouse, md, and james studdiford, md the timely diagnosis of early disseminated lyme disease presenting as multiple secondary erythema migrans lesions is sometimes delayed because this stage is infrequently encountered in a general prac- tice. we report a case of a -year-old woman whose initial complaints of an erythematous, “burning” rash and flu-like symptoms led to several laboratory tests with no specific diagnosis. the correct diag- nosis was only made after sorting through other possibilities in the differential diagnosis. by reproduc- ing the medical images and reviewing the medical literature, we underscore the importance of including lyme disease in the list of diagnoses pertaining to diffuse skin rashes in the febrile patient. ( j am board fam med ; : – .) case report a -year-old woman presented to her primary care doctor in june with a -day history of numerous, oval, diffusely erythematous patches scattered across her chest, abdomen, back, and extremities sparing her palms and soles (see figures and ). the rash, which became more prominent after a hot shower or expo- sure to a warm, ambient environment, was also de- scribed as “burning” and “hot.” further, she reported a -week history of flu-like symptoms consisting of headache, neck pain, generalized body aches, fever, chills, and malaise. she also complained that her cheeks felt unusually hot and were bright red. she denied having any associated respiratory or gastroin- testinal symptoms. the patient denied a history of a recent tick or insect bite. however, on further questioning, she de- scribed herself as an avid gardener. she lives in a rural area of new jersey where deer sightings are frequent. the patient’s bilateral facial erythema, which was reminiscent of the classic “slapped cheeks” ap- pearance of parvovirus b- prompted serologic testing for this viral agent. a complete blood count and a comprehensive metabolic panel were also performed. the results were all normal except the liver function tests, which were mildly elevated with an alanine aminotransferase of u/l, aspar- tate aminotransferase of u/l, and alkaline phos- phatase of u/l. at a follow-up visit days later, because of the persistence of numerous ery- thematous plaques accompanied by fever, myalgias, and arthralgias, lyme disease (ld) was suspected and the patient was screened for borrelia burgdorferi antibody with the standard enzyme-linked immu- nosorbent assay. this was positive with a reported value of � (� . is considered positive). west- ern blot analysis for igm was positive and negative for igg, thus confirming acute, early disseminated ld. the patient was treated with mg of doxy- cycline twice daily for a period of days with resolution of her symptoms. on further monitor- ing, her liver function tests returned to normal. discussion this case describes a patient with secondary ery- thema migrans (em) associated with early dissem- inated ld. the vast majority ( % to %) of patients in the united states who present with early ld have only a single, primary em lesion which occurs at the site of a tick bite. primary em lesions typically develop to days after a tick bite, with a reported range of to days. they are rapidly expanding, round or oval erythematous lesions that measure � cm in largest diameter, and are flat or this article was externally peer reviewed. submitted august ; revised november ; accepted november . from the department of family and community medi- cine (bes, as, js), division of geriatrics (bes), thomas jefferson university, philadelphia, pa. funding: none. conflict of interest: none declared. corresponding author: brooke e. salzman, md, depart- ment of family and community medicine, division of ge- riatrics, thomas jefferson university, philadelphia, pa (e-mail: brooke.salzman@jefferson.edu). jabfm may–june vol. no. http://www.jabfm.org o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n m a y . d o w n lo a d e d fro m http://www.jabfm.org/ slightly raised. early, untreated localized infection is often followed days to weeks later by hematog- enous dissemination of the infection to multiple sites, which may include the skin ( % to %), the nervous system ( %), the heart ( %), or the joints ( %). secondary em lesions of early disseminated ld arise at sites distant from the tick bite, indicating systemic dissemination of the spirochete borrelia burgdorferi via blood or lymph. as such, secondary lesions lack the punctum indicative of a tick bite, which can often be found in primary em lesions. the number of secondary lesions can range from to � , with a median of , often appearing in or crops of similarly sized and shaped lesions. – secondary em lesions are generally lighter, smaller, less edematous, and have less central clear- ing compared with primary ems. , typically they first become apparent or intensify with elevations of body temperature. patients with secondary em without an obvious primary lesion may lack a host immune response to the bacterial antigen. , sec- ondary em lesions can appear on the head, face, trunk, and extremities, usually sparing the palms, soles, and mucus membranes. both early localized and early disseminated ld are usually accompanied by nonspecific, flu-like symptoms including myalgias, arthralgias, fatigue, headache, neck stiffness, and sometimes fever. , patients with secondary em may have more con- stitutional symptoms than those with primary em lesions alone. upper respiratory tract and gastro- intestinal symptoms are typically absent. the dif- ferential diagnosis for a diffuse, patchy, erythema- tous rash associated with flu-like symptoms can include urticaria, secondary syphilis, parvovirus b- , lichen planus, erythema multiforme, pityria- sis rosea, lyme disease, and fixed drug eruption. urticaria would probably not be associated with myalgias and arthralgias, as seen in our patient. our patient’s rash spared the palms and soles, unlike syphilis. the rash associated with parvovirus b- generally is limited to the cheeks. erythema mul- tiforme usually is described as iris or target-like vesicular lesions and typically involves the palms and soles. our patient did not have the fine scaling papules and plaques with collarettes typically seen with pityriasis rosea. health care practitioners located in areas of en- demicity for ld should especially become familiar with these early clinical manifestations. these geo- graphic regions in the united states include areas of the northeast (massachusetts to maryland), up- per midwest (wisconsin, minnesota), northern california, and oregon. most cases of ld occur during the late spring and summer, peaking in june and july. this time frame correlates with the nymphal stage of the life cycle of the ixodes tick, which accounts for the large majority of ld trans- mission. figure . numerous oval, erythematous patches scattered across this patient’s chest, abdomen, back, and extremities sparing her palms and soles. figure . anterior view. doi: . /jabfm. . . lyme disease: perplexing symptoms o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n m a y . d o w n lo a d e d fro m http://www.jabfm.org/ the diagnosis of early ld in the acute phase is generally a clinical one, based primarily on clinical findings, including the presence of a characteristic solitary em and a history of tick exposure in an endemic area. because of the high rate of false- negative results in the acute phase of ld ( %), routine use of serologic tests in patients with em is not recommended. such patients should be diag- nosed and treated for ld without further testing. , cases in which serologic testing may provide valu- able information include patients, such as ours, with clinical findings suggestive of early dissemi- nated ld or patients with prolonged constitutional symptoms (� weeks) suggestive of early ld with- out em. , when testing is indicated, both acute- phase and convalescent-phase ( weeks after the acute phase) serum samples should be tested using a -tiered assay recommended by the centers for disease control. with the -tiered assay, a positive or indeterminate screening test (ie, enzyme-linked immunosorbent assay) is followed by a more spe- cific confirmation test (ie, western blot). additional testing that may be ordered on pa- tients such as ours may include hepatic function panels. in the case of ld these tests (specifically transaminase determinations) are nonspecific mea- sures of liver inflammation and not indicative of specific liver pathology. such liver function test abnormalities have been reported to occur in % of patients with early disseminated ld. these are most often asymptomatic and resolve after weeks of appropriate antibiotic therapy. the recommended treatment for adult pa- tients with early localized or early disseminated ld (in the absence of specific neurologic mani- festations including radiculopathy, cranial neu- ropathy, mononeuropathy multiplex, meningitis, or encephalomyelitis, or advanced atrioventricu- lar heart block) is doxycycline ( mg twice per day), amoxicillin ( mg times per day), or cefuroxime axetil ( mg twice per day) for approximately days. conclusion it is important to consider lyme disease (ld) in patients who present with unexplained flu-like symptoms during summer months, particularly in areas endemic for ld. inquire about outdoor ac- tivities and routes of exposure when ld may be suspected. clinicians should be aware that early ld may present with a diffuse rash indicating dissem- inated infection. references . steere ac, sikand vk. the presenting manifesta- tions of lyme disease and the outcomes of treat- ment. n engl j med ; : – . . smith rp, schoen rt, rahn dw, et al. clinical characteristics and treatment outcome of early lyme disease in patients with microbiologically confirmed erythema migrans. ann intern med ; : – . . wormser gp. early lyme disease. n engl j med ; : – . . mcginley-smith de, tsao ss. dermatoses from ticks. j am acad dermatol ; : – . . melski jw, reed kd, mitchell pd, barth gd. pri- mary and secondary erythema migrans in central wisconsin. arch dermatol ; : – . . malane ms, grant-kels jm, feder hm, luger sw. diagnosis of lyme disease based on dermatologic manifestations. ann intern med ; : – . . centers for disease control and prevention. lyme disease—united states, – . available at http:// www.cdc.gov/mmwr/preview/mmwrhtml/mm a . htm. accessed march , . . wormser gp, dattwyler rj, shapiro ed, et al. the clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the infec- tious diseases society of america. clin infect dis ; : – . . foy aj jr, studdiford js iii. lyme disease. clinics fam pract ; : – . . horowitz hw, dworkin b, forseter g, et al. liver function in early lyme disease. hepatology ; : – . jabfm may–june vol. no. http://www.jabfm.org o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n m a y . d o w n lo a d e d fro m http://www.jabfm.org/ revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x thomas jefferson: entre el liberalismo y el republicanismo. la posiciÓn de hannah arendt thomas jefferson: between liberalism and republicanism. the position of hannah arendt elisa goyenechea universidad católica argentina eligoye@gmail.com recibido: febrero de aceptado: abril de palabras clave: arendt, jefferson, liberalismo, republicanismo, consejos keywords: arendt, jefferson, liberalism, republicanism, wards. resumen: el trabajo examina la interpretación de hannah arendt del pen- samiento político de thomas jefferson. en primer lugar, presentamos los principales argumentos que lo ubican en el marco de las ideas del libera- lismo. al respecto, en sus escritos del período pre revolucionario jefferson alude a la antigua constitución sajona y a los derechos naturales de john locke. en segundo lugar, exponemos la posición de hannah arendt respec- to de la revolución americana como réplica del republicanismo clásico, en desmedro de la tesis prevaleciente hasta , que la ubica bajo la égida del liberalismo clásico. en este contexto, mostramos que la autora interpre- ta a t. jefferson como representante del republicanismo, destacando, en particular, su tesis sobre el sistema de consejos. abstract: the paper examines hannah arendt’s interpretation of thomas jefferson’s political thought. first, we put forward the main arguments that place him within the framework of political liberalism. in this regard, his writings of the pre-revolutionary period allude to the ancient saxon constitution and to the natural rights of john locke. second, we expose hannah arendt’s assessment of the american revolution as a replica of classical republicanism, to the detriment of the thesis prevailing until , which places it within the context of classical liberalism. we assert that she interprets t. jefferson as representative of republicanism, highlighting in particular his thesis on the council system. revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x “it has also been a great solace to me to believe that you are engaged in vindicating to posterity the course we have pursued for preserving to them, in all their purity, the blessings of self-government, which we had assisted too in acquiring for them.” (jeffer-(jeffer- son tenía años cuando, preocupado por su legado, escribió esta carta a james madi- son, el de febrero de ). “the councils say: we want to participate, we want to debate, we want to make our voi- ces heard in public, and we want to have a possibility to determine the political cour- se of our country”. (hannah arendt, crises of the republic, a harvest book. harcourt brace & company, san diego, new york, london, ; cf. p. ). este trabajo busca poner en evidencia la recepción de algunos aspectos del pensa- miento de thomas jefferson por parte de hannah arendt. en on revolution ( ), la pensadora pone en tensión las dos re- voluciones del siglo xviii, la francesa y la estadounidense. en el marco de ésta últi- ma, aborda el pensamiento de los padres fundadores y el de thomas jefferson, en particular. nos proponemos tres objeti- vos. en primer término, presentaremos las ideas políticas de t. jefferson en el marco del liberalismo y bajo la égida del second treatise on civil government , de john locke. en segundo lugar, desarrollaremos brevemente la posición de arendt sobre la revolución americana como réplica del . cf. jefferson, thomas, the works of thomas jefferson, federal edition (new york and lon- don, g. p. putnam’s sons, - ). vol. . [on- line] available from http://oll.libertyfund.org/ titles/ ; accesed / / ; internet (formato ebook); cf. p. . . �ocke, john, second treatise of government. edited, with an introduction, by c. b. macpher- son, �ackett publishing company, inc., india- napolis. cambridge, . republicanismo clásico, en desmedro de las posiciones prevalecientes hasta el que la ubican en el marco del liberalismo clásico . el republicanismo clásico y el hu- manismo cívico con sus ideas de igualdad y participación, destaca el rol central de la virtud cívica en la preservación del ideal clásico de la libertad política. como dice helena béjar, arendt es pionera al respec- to pues on revolution ( ) introduce esta novedad aportando evidencia de las ideas y convicciones afines al republica- nismo en sus padres fundadores , varios años antes de pocock en su the ma- chiavellian moment ( ), quien asume la posición de arendt sin darle el debido crédito . tercero, indagaremos particular- . el texto clásico al respecto es el de �ouis �artz, the liberal tradition in america, �ar- court brace and �orld, new york, . . para precisar la naturaleza y la procedencia del republicanismo clásico o �humanismo cívico”, véase �ans baron, in search of florentine civic humanism. essays on the transition from me-essays on the transition from me- dieval to modern thought. volume ii, princeton university press, princeton, new jersey, ; cf. pp. - . también, del mismo autor, the crisis of the early italian renaissance: civic humanism and republican liberty in an age of classicism an tyranny, princeton university press, princeton, new jersey, ; cf. pp. - . . béjar, �elena, el corazón de la república: avatares de la virtud política, paidós, barcelona, ; cf. pp. - . dice béjar: �[…] arendt co- necta ambas revoluciones con la resurrección del mundo clásico y de la república que defendían �arrington, john milton y montesquieu. con ello se adelanta en más de diez años a los his- toriadores republicanos centrales como pocock, skinner o �ood, que apenas la citan”. . en el capítulo xv, �the americanization of virtue: corruption, constitution and frontier”, de the machiavellian moment, princeton uni- versity press, princeton and oxford, , po- cock alude a on revolution (en la p. ) y a the human condition, más extensamente (en la p. ). en esta última, afi rma que ha toma-en esta última, afirma que ha toma- revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x mente la interpretación de hannah arendt del pensamiento político de t. jefferson. sostenemos que la pensadora interpreta al autor de la declaración de la independen- cia en el marco del republicanismo clásico destacando su defensa de la democracia participativa a través del sistema de conse- jos (ward system), a los que llamó “repú- blicas elementales” . entendemos que su concepción del “espíritu revolucionario” y sus nociones clave de “espacio público” y de “praxis mancomunada” son, en gran medida, deudoras de las ideas de jeffer- son. buscaremos probar nuestra posición refiriendo e interpretando los fragmentos más significativos de ambos autores en donde se evidencia la deuda. los estudios especializados sobre thomas jefferson señalan tres fuentes decisivas de su pensamiento . primero, el liberalismo clásico fundado en el second treatise… de john locke, compatible con la idea de un gobierno moderado, esencialmente limita- do de arendt la idea de homo politicus (arendt no emplea ese término. alude al �orador” y al �agente”) como tipo humano distinto del homo credens, del homo mercator y del homo faber. . jefferson emplea la expresión en la carta a jo- seph cabell del de febrero de . . arendt, �annah, on revolution (introduction by jonathan schell), penguin books, new york, ; cf. pp. , , . . arendt, �annah, the human condition (�ith an introduction by margaret canovan), the uni- versity of chicago press, chicago and �ondon, ; cf. pp. , - . . cf. idem; pp. , .. cf. idem; pp. , . . meacham, jon, . meacham, jon, thomas jefferson: the art of power, random �ouse, new york, ; cf. part i, chapter : �roots of revolution”; part ii, chapter and : �the course of �uman events”, �the pull of duty”. maier, pauline, american scripture. making the declaration of independence, random �ouse, new york, ; cf. pp. - ; - . do, cuyo fin es la protección de los indivi- duos y sus libertades garantizadas consti- tucionalmente. segundo, el republicanismo clásico, desde aristóteles hasta maquiavelo y harrington, con sus ideas de virtud cívica, libertad política y compromiso activo; teoría que incluye un fuerte contenido ético y que reclama una particular visión antropológica y de la comunidad humana, cuya fuente es aristóteles. tercero, las premisas de la ilus- tración escocesa, cuya influencia estudian gilmar ostrander en su artículo, “jefferson and the scottish culture”, y daniel robin- son en “the scottish enlightenment and the american founding” . nuestro trabajo no indagará esta tercera línea de influencia. a continuación, seguiremos el siguiente orden: primero, identificaremos los pos- tulados del liberalismo clásico en thomas jefferson, destacando los fragmentos más significativos de dos obras del período revo- lucionario: a summary view of the rights of british america ( ) y declaration of the causes and necessity of taking up arms ( ) . en particular, recalaremos en su invocación de las libertades sajonas de la ancient constitution inglesa y en su apropiación de las premisas lockeanas, en relación a su modo novedoso de concebir el imperio británico. en segundo lugar, se- ñalaremos sucintamente la interpretación que realiza hannah arendt de la revolu- ción americana, como réplica del repu- blicanismo clásico, en desmedro de la . robinson, daniel n., �the scottish en-. robinson, daniel n., �the scottish en- lightenment and the american founding”, the monist, vol. , no. ; cf. pp. - . puede consultarse también: ostrander, gilman m., �jef- ferson and scottish culture”, historical reflec- tions / réflexions historiques, vol. , no. , , pp. – . (www.jstor.org/stable/ ). . por razones de espacio, no nos referiremos a declaration of independance ( ) y al first inaugural speech ( ), en los que también se encuentra esta temática. revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x posición prevaleciente, que la alinea tras los ideales del liberalismo. en ese marco, pondremos en evidencia –en tercer lugar- los tópicos esenciales del republicanismo que ella encuentra en thomas jefferson. entendemos que la preocupación por el autogobierno, la virtud y la participación -la posición de h. arendt- se encuentra principalmente en su epistolario, y en par- ticular, en las cartas posteriores a . . thomas jefferson entre el liberalismo y el republicanismo en the political philosophy of thomas jefferson ( ), garret ward sheldon ubica a jefferson entre el liberalismo y el clasicismo . cierto es que las premisas del liberalismo y las del republicanismo predominan en períodos bien diferencia- dos, siendo lockeano durante el período revolucionario y anti-federalista, y repu- blicano durante el período de construc- ción nacional post-revolucionario. sin embargo, tras una lectura atenta, ambas vertientes atraviesan sus escritos durante su vida. en the creation of the american republic, - ( ), gordon wood defiende la tesis de una amalgama de ideas filosóficas reunidas en un todo comprehensivo y coherente. para el his- toriador, jefferson no habría considerado contradictorio defender al mismo tiempo la protección de los derechos naturales individuales y la participación popular de las repúblicas democráticas clásicas . . sheldon, garret �ard, . sheldon, garret �ard, the political philosophy of thomas jefferson, the john �opkins university press, baltimore & �ondon, ; cf. pp. - . �ood, gordon, . �ood, gordon, the creation of the american republic, - , chapel �ill, university of north carolina press, ; cf. pp. - . más aun -defiende wood- él creía que la participación asidua y comprometida de los ciudadanos funcionaría como garantía de la preservación de los derechos . en efecto, en sus obras del período revolu- cionario, t. jefferson toma una posición cercana al liberalismo lockeano, que pre- domina contra el parlamento y contra los federalistas al defender una república de legislaturas autónomas en las colonias o en los estados. al mismo tiempo, su de- fensa de la república clásica (o sea, parti- cipativa) en todos los niveles de organiza- ción política, es decir, tanto en el consejo, como en el condado, en el estado y en el gobierno nacional (propia del segun- do período), conduciría directamente a la protección de los derechos y las liber- tades individuales del gobierno tiránico. contrario a james madison, quien veía en la participación popular mayoritaria una amenaza potencial a los derechos indi- viduales , jefferson vinculaba estrecha- mente ambas circunstancias, por lo que -argumenta wood- tuvo éxito en fusionar las ideas republicanas clásicas con las li- berales lockeanas. si la lectura de gordon wood es acertada, entonces la praxis concreta de los ciuda- danos, reunida en las ideas de partici- pación popular y de compromiso activo, constituiría el medio instrumental propi- cio para el verdadero fin la política, que coincidiría con la garantía de las liberta- des civiles y la defensa de los derechos consagrados por la constitución. o sea, si seguimos esta lectura, el republicanismo de t. jefferson sería subalterno de su li- beralismo y -en los términos de arendt- la participación activa en la cosa pública se- ría el medio por el que se logran los ver- . idem, cf. pp. - . . idem, cf. pp. - . . cf. . cf. the federalist, . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x daderos fines de la vida humana, en este caso, las libertades garantizadas constitu- cionalmente. claramente, hannah arendt no comparte esta lectura de jefferson, pues conceptualiza la política como un fin en sí mismo, y entiende que esta perspec- tiva es compatible con las ideas del propio jefferson. cuando arendt cuestiona la gran tradición de pensamiento político occidental, espe- cialmente en was ist politik? ( ) y en the human condition ( ), defiende un modo de entender la política diverso del inaugurado con platón, el iniciador de la filosofía política . su posición es que desde platón la política se entendió como un medio para fines más elevados (en su caso, la paz y el orden para la actividad filosófica), todos ellos, con independen- cia de su contenido, se ubican fuera de la política . en otras palabras, a partir de la filosofía política, que platón inaugura, encontramos una versión precoz de la in- vasión de la razón instrumental, en per- juicio de la razonabilidad o la sensatez fronética. de allí el título del parágrafo de the human condition: “la tradicional substitución de actuar [acting] por hacer [making]” . fundando su interpreta- ción en poetas e historiadores previos a la escuela socrática, arendt entiende la política como un fin en sí mismo, como espacio de despliegue de la praxis con- junta (como algo distinto de la destreza técnica) y de la libertad como un hecho . arendt, �annah, �philosophy and politics”, . arendt, �annah, �philosophy and politics”, social research, vol. , no. (spring ), pp. - ; cf. pp. - , - , - . . arendt, �annah, . arendt, �annah, was ist politik? aus dem nachlass, pieper verlag, münchen, ; cf. pp. - . . arendt, �annah, . arendt, �annah, the human condition, op. cit.; cf. pp. - . . idem, cf. pp. , - .. idem, cf. pp. , - . a la vista de todos (como algo distinto del libero arbitrio) . para la pensadora, la po- lítica comprende las actividades más emi- nentes de la vita activa -praxis y lexis- por las cuales exhibimos nuestra verdadera humanidad al actuar junto a otros en be- neficio de lo que es común a todos . este modo de entender la política, más cer- cano a las notas del republicanismo que a la defensa de las libertades negativas, propio del liberalismo, es el que arendt atribuye a thomas jefferson. jefferson creció y se formó profesional-ó y se formó profesional-profesional- mente en el contexto ideológico del im- perio británico. g. sheldon esclarece este concepto asignándole la condición de imperio a la inglaterra del xviii y ca- lificándola como un dominio imperial que había asentado colonias en américa bajo un monarca absoluto . los vínculos entre ambos estaban asentados en car- tas reales y tradiciones feudales. según sheldon, las ideas revolucionarias que jefferson aprendió como estudiante de abogacía contenían los principios políti- cos generados en inglaterra en los tumul- tos entre y , año que marcó el final de la restauración estuardo y la lle- gada al trono de guillermo iii de orange, con su esposa maría ii. particularmente, . arendt, �annah, . arendt, �annah, between past and future. eight exercises in political thought, penguin books, new york, ; cf. pp. - , - . . arendt, �annah, . arendt, �annah, the human condition, op. cit.; pp. - . . sheldon, . sheldon, the political philosophy of thomas jefferson, op. cit.; pp. - . véase también carl becker, the declaraction of independence. a study in the history of political ideas, �arcourt, brace and company, new york, ; cf. cap. iii: ��istorical antecedents of the declaration. theory of the british empire”. (http://oll.liberty- fund.org/titles/becker-the-declaration-of-indepen- dence-a-study-on-the-history-of-political-ideas). revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x la invocación a la ancient constitution, a las libertades sajonas, y a los derechos naturales de locke, las armas teóricas que el parlamento había esgrimido para destituir a jacobo ii. entendemos que t. jefferson adaptó estas ideas conveniente- mente para su batalla ideológica por la in- dependencia de las colonias, inclusive al precio de caer en ambigüedades e incon- sistencias, como veremos. mostraremos, además, que empleó nociones clave del pensamiento de john locke para refor- mular, en términos modernos, la noción tradicional de imperio. . jefferson y la antigua constitución sajona jefferson transitó los años previos a la re- volución con temor, por las posibles acu- saciones de traición y la perspectiva de la muerte, y con angustia, por el corte con los lazos tradicionales con la madre pa- tria . en la declaration of independence, alude claramente al dolor de la ruptura de lazos afectivos e inclusive sanguíneos (“brethren”), pero al mismo tiempo con- signa que la medida de la opresión que las colonias están dispuestas a soportar ha sido sobrepasada y su paciencia, col- mada: “cuando la corona fue a la guerra contra las colonias [...] con mercenarios escoceses y extranjeros […] la última es-última es- es- tocada de un afecto agonizante [...] re- nuncia para siempre a estos hermanos insensibles [...] olvida nuestro antiguo amor por ellos» . . sheldon, . sheldon, the political philosophy of thomas jefferson, op. cit.;cf. pp. y . . becker, carl �otus, . becker, carl �otus, the declaration of in- dependence: a study on the history of politi- cal ideas (new york: harcourt, brace and co., ). [online] available from http://oll.liberty- desde los primeros asentamientos co- loniales con elizabeth i, inglaterra había mudado su fisonomía y estructura, has- ta convertirse en un imperio expansivo y dominante. su estructura imperial ya no respondía a los parámetros tradicionales de la monarquía feudal, ámbito en que las colonias habían sido asentadas en el xvii. esta “ideología imperial”, involucra- ba convicciones, parámetros de juicios, pre-conceptos y hábitos de pensamiento que conforman, juntos, la cosmovisión po- lítica y social de la época. con la palabra ideología, se alude a la auto-comprensión que una época tiene de sí misma y al modo en que los humanos en determinada épo- ca, se comprenden a sí mismos y actúan en consecuencia . las ideas y conceptos, fund.org/titles/ ; accessed / / ; internet. (formato ebook pdf); cf. p. . (todas las tra- ducciones son nuestras). . para el uso de la palabra ideología véase joyce appleby, �republicanism and ideolo-appleby, �republicanism and ideolo- gy”, american quaterly, vol. , n. , ; pp. - . (stable ur�: http://www.jstor.org/sta- ble/ ). appleby recala en la diferencia entre idea e ideología y afirma que las ideas no pueden orientar la praxis a menos que se hayan encarnado en una estructura social. o sea, cuan- do expresan la auto-comprensión de esa comuni- dad en una determinada etapa. appleby alude al cap. (p. ), del texto de b. bailyn, the ideo- logical origins of the american republic, donde el autor alude a la ideología como un �conmu- tador intelectual conectado de modo tal que una serie dada de acontecimientos ponía en acción un juego claro de señales”. dice appleby: �he [bai- lyn] replaced the tired old notion of intellectual influence with the exciting concept of ideology. ideas, bailyn maintained, only influence political action when they are part of a socially-created structure. the cassandras of the british oppo- sition shaped events in america because their opinions organized attitudes otherwise too vague to be acted upon, because, as he said, they crystal- lized otherwise inchoate discontent. ideas, to use bailyn’s metaphor, compose themselves into intel- revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x por sí solos, no pueden orientar la praxis a menos que estén encarnados en una es- tructura social. se vuelven ideología cuan- do expresan la auto-comprensión de una comunidad en una determinada etapa e inspiran sus acciones. la cosmovisión o ideología imperial invo- lucraba política, economía, sociedad y religión en un todo integrado y armónico gobernado por un solo soberano bajo una ley natural, cuya fuente era dios. esta vi- sión de una totalidad integrada tradicional fue trasladada a las colonias y a todo el im- perio. suponía una dependencia asentada en vínculos feudales y en la fidelidad al rey. el control de la corona sobre la política de las colonias era generalizada. la legítima posesión de las tierras era garantizada por carta real, los funcionarios, gobernadores y consejos eran nombrados por la corona; las leyes, promulgadas por asambleas pú- blicas menores, eran enviadas a londres para la aprobación real y regresaban como decretos reales. la auto-comprensión de los colonos estaba ligada a su pertenencia a esta estructura imperial feudal. tras la glorious revolution de y el act of settlement de , el paradigma de la monarquía tradicional se modifica y deja paso al establecimiento de la supre- macía parlamentaria. es decir, la soberanía se desplazó de la corona al parlamento, y el imperio británico se volvió más comer-ánico se volvió más comer-co se volvió más comer- cial pues este estamento se volvió cada vez lectual switchboards [conmutadores intelectuales] wired so that certain events almost surely will pro- voke particular reactions. the colonial elite, con- fronting the parliamentary reforms of the s, for example, was compelled to interpret the new measures as signs of a tyrannical impulse in eng- land because this unexpected exercise of power tripped existing fears about the unbalancing of the constitutional order which preserved englishmen in their liberties and estate”. más influyente en el parlamento. acaece un cambio de paradigma. los intereses mercantiles, la expansión territorial y las atribuciones desmedidas que se arrogó el parlamento primaron por sobre la antigua conducta del imperio feudal . en el lugar de una dependencia integral basada en vínculos feudales en la gran familia de es- tados o colonias, las colonias se volvieron objeto de preocupación e interés en vistas de los beneficios pecuniarios, que podían reportar al imperio (fundamentalmente para saldar deudas). ahora bien, aun si el parlamento y sus ambiciones expansio- nistas comerciales tomaron el control del imperio, este aún retenía la estructura, las ideas y pre-conceptos explicativos de la “benigna ideología real” , que en origen lo estableció. según sheldon, una conduc- ta primordialmente comercial y agresiva, pero revestida del ropaje de una cosmo- visión tradicional influyó en la confusión, abonó el resentimiento y, finalmente, activó el deseo de independencia de las colonias. la expresión teórica de ese deseo en las colonias empleó las mismas armas ideo- lógicas con las que el parlamento inglés había tumbado la monarquía, casi cien años antes. es decir, la invocación de la ancient constitution y de los derechos naturales, fueron el principal argumento usado por los colonos en américa, y por jefferson en particular, para derribar los vestigios de la supremacía real, a saber, la ideología tradicional del imperio bri- . para el tema de la . para el tema de la supremacía parlamentaria y el derecho del parlamento a imponer impuestos a las colonias, véase: reid, john phillip, consti- tutional history of the american revolution, the university of �isconsin press, �isconsin and �ondon, ; cf. chapter : �the authority to tax”, cf. pp. - . . sheldon, g. �., . sheldon, g. �., the political…, op. cit.; cf. p. . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x tánico. se trata, repetimos, de las ideas británicas del período - , que culminó con la abdicación de jacobo ii, la entronización de guillermo iii de orange, y la bill of rights (de ) . las ideas independentistas de thomas jefferson . el historiador británico y neozelandés, j. g. a. pocock, en cambio, vincula los eventos con el affair �alpole y la reacción republicana al comercialismo de - . �a diferencia de posturas no alude solamente a los treinta años que median entre ellas, sino a la verdadera fuen- te de la ideología emancipatoria en las colonias. si las ideas políticas inglesas que alimentaron la revolución en américa eran de cien años atrás (los principios que alimentaron la glorious re- volution), entonces se trata de los principios anti- monárquicos, cuya fuente es la ancient constitu- tion y el second treatise….de john �ocke. pero si eran del período posterior, cuando el poder del parlamento y la expansión comercial estaban ya bien afianzados, entonces las ideas inspiradoras de jefferson habrían provenido del republica- nismo clásico y sus ideas de virtud y frugalidad. véase, pocock, the machiavellian moment. florentine political thought and the atlantic republican tradition. (with a new afterworld by the author), princeton university press, princ- eton and oxford, ; cf. pp. - , . �a idea clave de la oposición –esclarece pocock en su �afterword” a the machiavellian moment, de , no era tanto el auge del comercio sino el crédito, y el reclamo de conducta virtuosa frente a la corrupción del clientelismo (political patro- nage). cf. idem, pp. - . pocock minimiza el papel de �ocke en la revolución y la funda- ción de los eeuu. dice en la p. : �no existe un prototipo [blueprint] de una república lockea- na, y �ocke –que estaba más interesado en el ori- gen y el fin del gobierno que en su estructura y ejercicio- se abstuvo cuidadosamente de instruir al pueblo sobre cómo reconstituir al estado, des- pués de haberlo disuelto. un orden político [po- lity] lockeano sería una comunidad de portadores de derechos, pero no dice nada sobre su forma, ni de su constitución. debemos, por lo tanto, mirar más allá de �ocke para descubrir por qué se dio por descontado que los nuevos estados indepen- dientes serían repúblicas.” fueron las proclamas compatibles con el liberalismo lockeano, anti-autoritarias y anti-monárquicas, que desembocaron en la revolución gloriosa. cuando buscaron justificar su separación de la metrópoli, los patriotas de las colonias americanas -y jefferson especialmente- insistieron en que la emancipación era el resultado de las reiteradas violaciones de los principios y tradiciones históricas por parte de la madre patria en su trato con las colonias ultramarinas, en particular en su política fiscal discriminatoria e injusta. fundaremos esta apreciación que vincu- la a thomas jefferson con las ideas del liberalismo en algunos fragmentos desta- cados de dos obras del período pre-revo- lucionario: a summary view of the rights of british america ( ) y declaration of the causes and necessity of taking up arms ( ). allí, jefferson esgrime dos justificaciones teóricas: primero, la ancient constitution como la cuna -históricamente emplazada- de las venerables libertades sajonas, el precedente fundacional para los derechos coloniales. segundo, el libe- ralismo lockeano, con su noción clave de los derechos naturales, reforzaba los recla- mos coloniales invocando una naturaleza humana supra-histórica, tan universal y abstracta, como los derechos inalienables que fundaba. además, la herencia de john locke y la deuda con el liberalismo clásico es evidente en su novedosa concepción del imperio. ambas fuentes le proveyeron los argumentos que las colonias independen- tistas necesitaban para justificar teórica- mente su desvinculación de una estructura imperial tradicional, a la que consideraban corrupta. ciertamente, jefferson denuncia abiertamente la corrupción parlamentaria y la inoperancia del rey, pero al hacerlo no invoca a la virtud republicana (como de- fiende pocock), sino que usa el lenguaje revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x de los antiguos derechos sajones. es decir, busca defender las libertades agraviadas y los derechos usurpados. adaptó a sus pro- pias circunstancias esas venerables y tradi- cionales verdades -la herencia de las liber- tades sajonas- y formuló una concepción original del imperio británico confederado. en the ideological origins of the ameri- can revolution, b. bailyn sostiene que para inglaterra la ancient constitution era considerada la “libertad perfecta”, asen- tada en principios y prácticas de gobier- no de las tribus sajonas pre-feudales. el término alude a una edad dorada en los albores de la historia inglesa, que luego sería vulnerada con la invasión normanda y su codificación (siglo xi), con las que llegaron la monarquía y la organización feudal . el paraíso perdido y mítico de la libertad inglesa previo a la incorporación de la estructura e influencias de la auto- ridad monárquica. más específicamente, esta antigua constitución sajona era el fundamento último de la salvaguarda de las libertades de los individuos para par- ticipar en políticas de gobierno que afec- taran su propiedad privada (taxation). el aspecto específico en el que jefferson recaló, era que la constitución sajona era hostil a la estructura monárquica feudal, que consideraba toda propiedad territorial como posesión y don del soberano. ade- más, el feudalismo monárquico no con- sideraba esas distintas esferas de la vida humana como espacios de libertad del individuo, sino como partes integrales de un cuerpo orgánico ordenado piramidal- mente bajo la égida de su majestad. esta peculiar constitución inglesa fue descripta por john adams como “la más . bailyn, bernard. bailyn, bernard, the ideological origins of the american revolution, belknap press, cam- bridge, massachusetts, ; cf. pp. - , - . perfecta combinación de poderes hu- manos en sociedad, que la sabiduría fi- nita ha ideado [contrieved] y puesto en práctica para la preservación de la liber- tad y la producción [production] de la felicidad” . para b. bailyn, en los años previos a la revolución, los colonos ame- ricanos no entendían la palabra constitu- ción como lo podríamos hacer nosotros, como un documento escrito, o inclusive como un diseño de gobierno no escrito, pero deliberadamente elaborado, suma- do a una especificación de los derechos, que la legislación no puede tocar. por el contrario, concebían la constitución como el “orden [arrangement] constituido –es decir, pre-existente- de instituciones gu- bernamentales, leyes y costumbres, jun- to con los principios y los fines que las animan” . ese sentido de constitución era el invocado por lo colonos, cuando reclamaban a la madre patria por sus derechos usurpados. como dice pocock, citando precisamente on revolution, de arendt: “en defensa de su virtud contra la corrupción de la tiranía de la monarquía parlamentaria, los americanos empezaron a reconstituirse a sí mismos en una con- federación de repúblicas; hasta este pun- to su revolución fue una rinnovazione” , es decir, una restauración de libertades antiguas (constitution). en suma, mien- tras que los parlamentarios, abogados y jurisconsultos ingleses habían situado su reclamo históricamente sobre bases que antecedían a la monarquía, jefferson he- . adams, john, . adams, john, the political writings of john adams (edited with an introduction by george �. carey), regnery publishing, inc., �ashing- ton, ; cf. p. . . bailyn, b, . bailyn, b, the ideological origins of the american revolution, op. cit.; cf. p. . . pocock,. pocock, j.g.a., the machiavellian moment, op. cit.; cf. p. . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x redó este concepto y lo empleó para sus propios propósitos, que comprendían, ini- cialmente, la restauración de viejas liber- tades y, finalmente, la impugnación de la monarquía feudal entendida como tiranía parlamentaria. thomas jefferson vinculó directamente el argumento histórico de la ancient consti- tution con los derechos naturales a-histó- ricos (the rights of man), combinando sin escrúpulo razón e historia, teoría y datos empíricos, o como dice gordon wood, empirismo y racionalismo . para el his- toriador estadounidense, jefferson buscó reforzar el argumento de la legitimidad histórica con el plus de los derechos na- turales de john locke. en otras palabras, derivó principios universales de los datos históricos contingentes. al respecto sos- tiene wood: “el blend de empirismo y ra- cionalismo de los americanos les concedió cierta permisividad en el uso de la historia […], a menudo parece que simplemen- te seleccionan del pasado ejemplos para reforzar generalizaciones deducidas por la pura razón. […] sus argumentaciones presentan el delicado equilibrio entre ex- periencia histórica y verdad auto-evidente. y el verdadero riesgo es que las urgencias y necesidades racionales del momento podrían dominar [overpower] la veracidad del pasado” . es decir, ante la urgencia política, jefferson que era más hombre de estado que historiador, interpretó y editó los hechos efectuando un particular “uso de la historia”. vinculó directamente la suerte de las colonias con la recuperación de las libertades sajonas, en desmedro de la herencia normanda, que introducía . �ood, gordon, . �ood, gordon, the creation of the american republic, - , the university of north carolina press, chapel �ill and �ondon, (first edition ); cf. p. . . idem, cf. pp. - .. idem, cf. pp. - . premisas inconvenientes. creemos que esta estrategia introdujo inconsistencias en el argumento de thomas jefferson. en lo que sigue, mostraremos la ambigüedad del discurso del autor en sus escritos. . perplejidades del discurso de jefferson para thomas jefferson, la metrópoli usur- pó los derechos de los colonos, expoliando riqueza de las tierras coloniales para hacer frente a la descomunal deuda pública con- traída para financiar la guerra de los siete años contra francia ( - ). dice jefferson: “ellos [el parlamento] hablan de hacer cumplir las leyes, cuando están violando la constitución […]. ¿acaso sus ministros -¡señor!- descubrieron minas de inextinguible riqueza en américa, para ex- poliar, para cancelar nuestra enorme deu- da nacional?” . la metrópoli pretendía cancelar sus deudas mediante la entrega de tierras, y la alta burguesía terratenien- te virginiana, a la que jefferson pertene- cía, quería defender su propiedad ante la amenaza de expropiación. de allí que je- fferson avale una aristocracia propietaria y terrateniente intocable. pero esta idea -admítase- responde al paradigma de la monarquía feudal, que claramente entra en colisión con su permanente invocación de los derechos sajones, como previos a (y posteriormente contaminados por) la legislación normanda. quizá jefferson era consciente de esta inconsistencia en su argumentación y, por eso, usó como prin- cipal argumento la voracidad y la extra . cf. thomas jefferson. cf. thomas jefferson the works of thomas jefferson, federal edition (new york and lon- don, g. p. putnam’s sons, - ). vol. . [on- line] available from http://oll.libertyfund.org/ titles/ ; accessed / / ; internet. véase p. . (formato ebook pdf). revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x limitación del parlamento: “mientras que cada día asistimos a un nuevo e injusti- ficado ejercicio de poder sobre sus súb- ditos del otro lado del agua [on that side the water]. […] la verdadera razón por la que declaramos estas leyes nulas es que el parlamento británico no tiene derecho a ejercer su autoridad sobre nosotros” . como destaca garret sheldon, la princi- pal perplejidad del recurso teórico a una constitución sajona para legitimar los de- seos emancipatorios de las colonias, es que la validez histórica del precedente sajón es cuestionable. la noción de una ancient constitution esgrimida por los revolucionarios es un peculiar uso de la historia: “una edad dorada, un paraíso perdido en el que los ingleses habrían go- zado de libertades que luego fueron usur- padas, y que debían ser restauradas” . es decir, un relato pergeñado durante el siglo xvii en ocasión de las luchas políti- cas entre el rey y el parlamento agravia- do. más específicamente, los parlamen- tarios que habían procurado fundar sus derechos en alguna fuente diversa de la prerrogativa real y el privilegio feudal, la hallaron en una tradición constitucional pre-feudal anterior a la corona y preser- vada en la common law. compelidos a buscar una base para sus reclamos, los constitucionalistas del xvii, “vincularon sus libertades a períodos más y más míti- cos y remotos en su esfuerzo por probar que esos derechos eran independientes de la voluntad de los reyes” . lo decisivo del asunto es que la evocación de la mí- tica constitución adolecía de rigurosidad histórica, lo cual le mermaba consistencia . ibidem.. ibidem. . sheldon, garret �., . sheldon, garret �., the political philosophy of thomas jefferson, op. cit.; cf. p. . . idem, cf. p. .. idem, cf. p. . al argumento revolucionario. glosando a pocock, sheldon sostiene que, en rigor, la tradición de la common law no alude fundamentalmente a las antiguas liber- tades sajonas con las que se pretendía fundar la supremacía parlamentaria, sino que codifica las relaciones feudales que llegaron a la isla con william the conque- ror: “la common law era ante todo, una ley reguladora de la tenencia de la tierra, la cual presuponía usos [tenures] milita- res y feudales que los normandos habían importado” . en suma, por razones de conveniencia, jefferson aludió a la constitución sajona para pasar por alto la estructura política y jurídica normanda; buscó una fuente que legitimara el derecho absoluto de los indi- viduos propietarios sobre las tierras, para prevenir expropiaciones por deudas . despachó como “excepcional” la estruc- tura feudal y los derechos de propiedad normandos, y pretendió expulsarlos de la tradición de la common law, como meras irregularidades a la norma. jefferson re- chazó el feudalismo por razones pragmá- . idem, cf. p. .. idem, cf. p. . . dice en a summary view of the rights of british america : �con el mismo espiritu de im- parcialidad e igualdad debería evaluarse la ley del parlamento aprobada durante el to año del reinado por la cual las tierras americanas quedan sujetas a las demandas de acreedores británicos, mientras que sus propias tierras en gran bretaña están excluidas. una de las conclusiones obliga- das es que la justicia no es pareja en gran breta- ña y en américa o, al menos, que los miembros del parlamento le prestan menos atención aquí que en �ondres [else that the british parliament pay less regard to it here than there].” véase jef- ferson, thomas, the works of thomas jefferson, federal edition (new york and london, g. p. putnam’s sons, - ). vol. . [online] avail- able from http://oll.libertyfund.org/titles/ ; accessed / / ; internet. cf. p. (formato e-book pdf). revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x ticas y enalteció las viejas leyes sajonas, a pesar de que su validez era cuestionable, ya que él mismo reconocía el fundamen- to real feudal, que las sustituyó. es decir, jefferson no niega que el orden feudal importado por los normandos, finalmente, prevaleció. pero advierte que el origen de ese orden fue la usurpación que sufrieron sus antepasados, que no eran “aboga- dos, sino granjeros”. en consecuencia, el axioma que dice que las tierras origina- riamente pertenecen al rey, es falso. en a summary view..., leemos: “nuestros an- cestros, sin embargo, quienes emigraron aquí, eran granjeros, no abogados. fue- ron tempranamente persuadidos a creer como verdadero, el principio ficticio que dice que originariamente todas las tierras pertenecen al rey”. y continúa diciendo: “la propiedad feudal no era sino una ex- cepción en las leyes sajonas de posesión, bajo las cuales el derecho a la tenencia de todas las tierras era absoluto. estas leyes aún forman la base, la roca fundacional de la common law, que prevalece sin im- portar las excepciones que hayan ocurri- do. américa no ha sido conquistada por william el normando, ni sus tierras han sido entregadas a él o a sus sucesores” . los colonos luchaban por sus derechos históricos, y a jorge iii no se le permitiría convertirse en otro william el normando, que impondría una regla tiránica a los emigrantes sajones en américa. jefferson concluye con una exhortación: “los reyes son los sirvientes, no los propietarios del pueblo. abra su pecho, señor, al pensa- miento liberal y expandido [liberal and ex- panded thought]. que el nombre de jorge . jefferson, thomas,. jefferson, thomas, the works of thomas jefferson, federal edition (new york and lon- don, g. p. putnam’s sons, - ). vol. . [on- line] available from http://oll.libertyfund.org/ titles/ ; accessed / / ; internet. cf. p. (formato e-book pdf). iii no sea una mancha en las páginas de la historia” . la carta a edmund pendleton del de agosto de pone en evidencia el pragmatismo de jefferson. refiriéndo- se a la ancient constitution y después de admitir la posibilidad de su invalidez, jefferson simplemente abandona el te- rreno de la justificación teórica y recurre al de la conveniencia política, declarando el asunto como meramente especulativo (“this matter is now a mere speculative point”). asimismo, exige una adhesión indeclinable al “feliz sistema de nuestros ancestros” y defiende la “restitución de las antiguas leyes sajonas”, en lugar de quedar enredados en la cuestión de su problemática validez . . dos concepciones imperiales. el imperio británico vs. el imperio moderno de jefferson continuemos ahora examinando algunos párrafos significativos de jefferson en rela- ción a estas cuestiones. con respecto a la filiación entre los ingleses (en este caso, los colonos de américa) y los sajones, sumado al derecho natural de apropiación de los bienes de la tierra , leemos en a summary view of the rights of british america: . cf. idem, pp. - .. cf. idem, pp. - . . cf. https://founders.archives.gov/documents/. cf. https://founders.archives.gov/documents/ jefferson/ - - - . no hemos hallado la carta a e. pendleton, en la biblioteca on line de liberty fund, de donde preceden todas nuestras citas referidas a los escritos de jefferson. . �ocke, john, . �ocke, john, second treatise…, op. cit.; p. . dice: �whatsoever then he removes out of the state that nature hath provided, and left it in, he hath mixed his labour with, and joined to it something that is his own, and thereby makes it his property”. revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x “nuestros ancestros, antes de su emigra- ción a américa, eran habitantes libres de los dominios británicos en europa, y po- seían un derecho que la naturaleza ha dado a todos los hombres, de partir del país en el que viven, no por elección, sino por azar, y de ir en busca de nuevas tierras, y esta- blecer nuevas sociedades, bajo las leyes y las regulaciones que mejor promuevan la felicidad pública. bajo esta ley universal, sus ancestros sajones, de la misma mane- ra, abandonaron sus bosques y sus tierras nativas en el norte de europa, y poseyeron ellos mismos la isla de bretaña, en ese en- tonces menos poblada y establecieron allí ese sistema de leyes, que ha sido, desde hace tanto tiempo, la gloria y la protección de ese país.” (jefferson, t., the works of thomas jefferson, op. cit.; cf. p. ). a renglón seguido defiende la continui- dad ininterrumpida de británicos y sajo- nes pues “no hay ninguna circunstancia que distinga materialmente la emigración británica de la sajona” . es decir, su es- trategia es evitar la mediación de los códi- ces normandos de propiedad compatibles con la organización de una estructura monárquica y feudal, en la tradición de la common law, en la que los colonos se insertaban en calidad de herederos. con el objetivo de defender los derechos de los colonos frente a una política fiscal abusiva por parte de la metrópoli, t. je- fferson formula una teoría del imperio ori- ginal y moderna, con la incorporación de premisas lockeanas. jefferson entiende el imperio británico como una federación de legislaturas iguales e independientes, . jefferson, thomas,. jefferson, thomas, the works of thomas jefferson, federal edition (new york and lon- don, g. p. putnam’s sons, - ). vol. . [on- line] available from http://oll.libertyfund.org/ titles/ ; accessed / / ; internet (formato ebook pdf). cf. p. . tanto las coloniales (la commonwealth de virginia, la de pennsylvania, etc.), como la doméstica (el parlamento en inglaterra). estos estados iguales e independientes eligen luego un rey, cuya función es la del juez, que protege los derechos de cada legislatura de toda amenaza de potencias extranjeras y que arbitra en los conflictos entre ellas. al igual que el gobierno árbitro creado por locke por individuos iguales e independientes a partir del estado de naturaleza , la corona británica, ejerce- ría -en el esquema de jefferson- un po- der delegado y estrictamente limitado a la protección de los derechos de las legisla- turas iguales e independientes que com- ponían el imperio (o sea, la idea de mild government). para john locke, abandonar el estado de naturaleza significa que cada hombre debe deponer su poder de defenderse, cuando sus derechos naturales son viola- dos. el poder de ejecutar la ley natural ya no está en sus manos, sino en la comu- nidad política. dice locke: “la sociedad política se dará allí y sólo allí donde cada uno de sus miembros se haya despojado de este poder natural, renunciando a él y poniéndolo en manos de la comunidad [...] [que] se convierte en el árbitro que [...] dictamina sobre todas las diferencias que puedan tener lugar entre los miem- bros de esa sociedad” . los atributos de la sociedad civil de locke son desplaza- dos por jefferson a la estructura imperial. así como en locke “las personas […] se unen en un cuerpo y disponen de una ley común así como de una judicatura a la que apelar, con autoridad para decidir en las controversias que surjan entre ellos y . �ocke, john. �ocke, john, second treatise.., op. cit.; cf. pp. , . (�as traducciones son nuestras). . cf. idem, p. . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x poder para castigar a los delincuentes” , en jefferson el monarca árbitro tiene el deber de intervenir cuando una de las le- gislaturas pretende usurpar los derechos de las otras. el comportamiento tiráni- co, sostiene locke, disuelve la autoridad legítima y restaura la libertad natural y la igualdad, que existe en el estado de natu- raleza . jefferson sigue a locke cuando apela a “los sagrados y soberanos dere- chos de castigar [punishment] reserva- dos en manos del pueblo en casos de emergencia” . y también cuando denun- cia que el parlamento “[your ministers] han roto las barreras legales de la consti- tución y destruido las distinciones de [po- der] del gobierno” . jefferson exhorta al rey a velar por la igualdad entre las legislaturas y a impedir que una usurpe los derechos de las otras: “por lo tanto, ahora es la gran función de su majestad, hacer ejercicio de su poder negativo [to resume exercise of his nega- tive power], y evitar que una legislatura del imperio promulgue leyes que resulten injuriosas para los derechos e intereses de otra” . el gobierno árbitro tiene un poder estrictamente limitado en natura-limitado en natura- leza y alcance: proteger a la comunidad sin interferir en la vida de los individuos. es un árbitro pasivo, que sólo interviene cuando hay disputas, de allí que jeffer- son le reclama al rey que ejerza su poder . cf. idem, p. . cf. idem, p. . cf. idem , pp. - .. cf. idem , pp. - . . jefferson, thomas,. jefferson, thomas, the works of thomas jefferson, federal edition (new york and lon- don, g. p. putnam’s sons, - ). vol. . [on- line] available from http://oll.libertyfund.org/ titles/ ; accessed / / ; internet (formato ebook pdf); véase p. . . cf. idem, p. .. cf. idem, p. . . thomas jefferson. thomas jefferson the works of thomas jef- ferson, op. cit.; cf. p. . “negativo”, como reza el fragmento ante- dicho. en locke, el poder del árbitro surge y depende del contrato que hicieron los individuos para conformar la sociedad ci- vil y política. en el esquema de jefferson, su poder es delegado y proveniente de las legislaturas que, en plano de igualdad, conformaron el imperio. al respecto, en a summary view…, designa al rey como “el vínculo central [central link] conectan- do las distintas partes del imperio, que se había de ese modo multiplicado” . jeffer- son se dirige al rey como “the chief officer of the people” , el principal funcionario del pueblo. para locke el propósito principal de la sociedad política es proteger los derechos de propiedad en sentido amplio, esto es, “la vida, la libertad y los bienes [life, liber- ty and estate]” . estos derechos existen antes de la constitución de la sociedad política e inclusive en la misma socie- dad política, de allí que, para jefferson, imponer impuestos sin el consentimiento de sus miembros, u obligar a las colonias a hacer negocios sólo con la metrópoli, supone invadir sus derechos. thomas jefferson argumenta que los derechos de los colonos a su vida, libertad y bie- nes [“liberty, fortunes and lives” ] derivan directamente de los derechos sajones, o sea, que son previos a la organización mo- nárquica y feudal de los conquistadores normandos. le advierte a jorge iii, que la ruina de las libertades de los colonos será, también, su propia perdición: “[…] podría terminar siendo la ruina de ambos: ¡usted, señor! podría perder su soberanía . cf. idem, p. . . cf. idem, p. . . cf. idem, p. .. cf. idem, p. . . �ocke, john, . �ocke, john, second treatise…, op. cit.; cf. p. . . jefferson, thomas,. jefferson, thomas, the works of thomas jef- ferson, op. cit.; cf. p. . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x y su honor; nosotros, nuestras libertades, nuestras fortunas y nuestras vidas.” en declaration of the cause and necessi- ty of taking up arms ( ), jefferson recurre claramente a john locke para teorizar sobre la nueva forma del imperio. alude a las distintas partes del imperio como “amigos vinculados por pactos” bajo un mismo rey. respecto de los an- cestros que emigraron y formaron socie- dades en américa, dice: “para continuar su vínculo con los amigos que habían dejado atrás, se organizaron por medio de convenios [charters of compact] bajo el mismo rey común, quien así completó […] el vínculo de unión entre las distintas partes del imperio” . desde el punto de vista de jefferson, la usurpación comenzó cuando una de las legislaturas del imperio confederado -el parlamento británico- se convirtió en el legislador de otras legislatu- ras libres e independientes (las colonias) y el árbitro -sólo en teoría neutral- cola- boró con los usurpadores. denuncia los intentos de “la legislatura de gran bre- taña de establecer un gobierno absoluto sobre estas colonias”; “de obtener el de- recho de legislación absoluta [unbounded . cf. ibidem . existen dos borradores del documento, que fue expedido por el segundo congreso conti- nental, en julio de para dar las razones por las que las trece colonias tomaban las armas con- tra gran bretaña. el primero, más radical en su formulación, es de jefferson, el segundo es de john dickinson, quien incorporó los argumentos y el lenguaje del primer borrador. �emos citado fragmentos de ambos. . jefferson, thomas,. jefferson, thomas, the works of thomas jefferson, federal edition (new york and lon- don, g. p. putnam’s sons, - ). vol. . [on- line] available from http://oll.libertyfund.org/ti- tles/ ; accessed / / ; internet. (formato e-book pdf). véase p. . . cf. ibidem. . cf. ibidem. legislation] sobre las colinas en america”; “de tomar nuestro dinero sin nuestro con- sentimiento” y de “cambiar la forma de gobierno de una de las colonias” (se re- fiere a massachusetts, en la que impuso la ley marcial, con las cohercitive acts en respuesta al episodio del tea party). de- nomina esta política como “despotismo de extensión ilimitada” . para jefferson es inadmisible que una de esas legisla- turas libres e independientes se arrogue la potestad de suspender o de invadir los poderes de otra y (en a summary view…) amonesta con las siguientes palabras: “invasiones y usurpaciones intentadas por la legislatura de una parte del impe- rio, sobre aquellos derechos que dios y las leyes han dado a todas ellas, iguales e independientes [those rights which god and the laws have given equally and inde- pendently to all]” . clave en su confrontación con el parla- mento son las cohercitive acts (para las colonias, “intolerable acts”) con que la corona respondió a la rebelión fiscal del suceso del tea party. jefferson defiende a quienes arrojaron millones (en té) a la bahía de boston, en protesta por las im-ston, en protesta por las im- posiciones tributarias (relativamente bajas en comparación a lo que tiraron al mar), que el parlamento imponía sobre los pro- ductos que las colonias estaban obligadas a obtener comprándole a la madre patria. leemos: “todos fueron presa de una rui- na indiscriminada, a causa de un nuevo poder ejecutivo inaudito hasta ese mo- mento, el del parlamento británico. una propiedad valuada en varios millones, fue sacrificada para vengar [revenge], no para pagar [repay], la pérdida de unos po- . cf. idem, p. .. cf. idem, p. . . cf. idem, p. .. cf. idem, p. . . cf. idem, p. .. cf. idem, p. . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x cos miles [se refiere a la carga impositiva sobre el te]. ¡esto es -verdaderamente- administrar justicia con mano dura!”. las intolerable acts, a las que llama “bloody edict”, “han suspendido los poderes de una de las legislaturas americanas […] y han declarado que pueden legislar por nosotros”. además, “tratan de rebeldes y traidores a los colonos”, e imponen “la ley marcial en una de las provincias” [en massachusetts], […] destruyendo las vida y la propiedad de sus habitantes” . resumiendo, jefferson adoptó la tesis pactista de john locke como la unión de individuos libres e independientes y la trasladó a su visión sobre lo que debería ser el imperio británico: una asociación (alianza, compact/agreement) de legis- laturas iguales e independientes, enca- bezadas por un monarca-árbitro, cuya función es mediar en los litigios, a fin de que se protejan los derechos y las liberta- des de cada una. la indeclinable defensa de los derechos de propiedad, condujo a jefferson a eludir la herencia normanda y a fundar sus argumentos en los derechos de los sajones. siguiendo a g. w. sheldon y a b. bailyn, hemos procurado mostrar que lo que habilitó este peculiar uso de la historia es una modificación de la ideolo- gía imperial, un cambio significativo en la auto-comprensión que de si mismos te- nían los colonos y los patriotas, que bus- caron justificación teórica para la inde- pendencia. dicho con otras palabras, en el marco ideológico del imperio original y tradicional (o sea, la estructura jerárquica y piramidal) gobernado por la autoridad absoluta de un monarca feudal, la disolu- ción de legislaturas menores o coloniales, no hubiera parecido fuera de lugar. pero jefferson alude a otra cosa, pues las cir- cunstancias han cambiado; el monarca . cf. idem, pp. y .. cf. idem, pp. y . ha sido suplantado por un parlamento vo- raz (una legislatura inferior) que pretende -esto es clave- gobernar las colonias como si fuera un rey. a esto llama jefferson “ti- ranía parlamentaria” y alude a las usurpa- ciones como “medidas tiránicas”. . la revolución americana y el republicanismo: la visión de hannah arendt en on revolution cuando hannah arendt teoriza sobre las revoluciones modernas, pone en tensión el evento en francia y en eeuu, y discrimi- na las bendiciones que rodearon la revo- lución en américa y las desgracias que sellaron la suerte y llevaron a su perdición a la francesa . la tesis central de on re- volution ( ) es que el acontecimiento por el que se fundó el cuerpo político de los estados unidos, fue una revolución en la que la violencia brilló por su ausencia. clave al respecto es el énfasis con que la autora distingue entre república, que es . jefferson. jefferson, thomas, the works of thomas jefferson, federal edition (new york and lon- don, g. p. putnam’s sons, - ). vol. . [on- line] available from http://oll.libertyfund.org/ti- tles/ ; accessed / / ; internet. (formato e-book pdf). véase p. . . �annah arendt no discrimina entre las dis- tintas revoluciones del continente americano y refiere la revolución de los eeuu como �the american revolution”. . para un indagación del análisis de arendt . para un indagación del análisis de arendt de las dos revoluciones, véase ingram, david, �novus ordo saeclorum: the trial of (post) mo- dernity or the tale of two revolutions”, en may, �arry and kohn, jerome (ed.), hannah arendt. twenty years later, the mit press, cambridge, massachusetts. �ondon, england, ; cf. pp. - . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x el fruto de la revolución, y gobierno limi- tado, noción distintiva del liberalismo clá- sico . arendt dedica muchas páginas de su obra en distinguir entre gobierno limi- tado y república, entre libertades civiles y libertad política o positiva, entre liberación y constitución de la libertad. en el caso de los estados unidos, el momento de libera- ción, el que usualmente llama la atención por su violencia o por su dramatismo, y ha sido considerado –erróneamente- como la condición per quam de las revoluciones, fue sucedido (sin hiato, sino con sólo con un “compás de espera”) por el momento estrictamente revolucionario que la autora identifica con la “pasión constitucionalista” o la “fiebre constitucional” en las trece co- lonias . liberación de o rebelión frente a un gobierno abusivo o colonial –esclarece arendt- remite a la necesidad de restaurar las libertades antiguas, es afín al reclamo por un gobierno limitado y no tiene nada de revolucionario, sino que puede ras- trearse hasta la carta magna y los antiguos derechos feudales: la petition of rights de , el habeas corpus de y la bill of rights de . allí, se aprecia el afán de restauración mas no de revolución, que ambiciona un cambio radical en la forma de gobierno. la idea de revolución a di- ferencia de la de restauración, contiene el elemento del nuevo origen, la discusión por la mejor forma de gobierno y el estable- cimiento de un nuevo sistema de poderes. . manent, pierre, historia del pensamiento li- beral, emecé, buenos aires, , cf. pp. - . . cf. arendt, �annah. cf. arendt, �annah, on revolution, op. cit. cf. pp. , . �as trece colonias que se invo-�as trece colonias que se invo- lucraron en la lucha por la independencia fueron, por el norte: massachusetts [nueva inglaterra], connecticut, new �ampshire, rhode island; en el centro: new jersey, new york, delaware, pen- silvania; en el sur: virginia, maryland, carolina del norte, carolina del sur y georgia. en una palabra, la noción de revolución no remite a la exención de los abusos o al control de los órganos de poder, circuns- tancia que alude a las libertades negativas (incluso el derecho a la representación para decidir sobre las cargas impositivas), sino a la libertad política y a la participación en los asuntos públicos. entre las cualidades que la pensadora resalta en el suceso americano es que la guerra de la independencia, el proceso de liberación o rebelión -consustancial a una revolución, pero no su condición suficiente- no arrojó a los colonos a un estado de naturaleza, para decirlo en pa- labras de hobbes, sino que los encontró ya organizados en “sociedades políticas” o “cuerpos políticos civiles” . tales aso- ciaciones preliminares regulaban sus asuntos con relativa autonomía y -lo que resalta arendt- recibieron la sanción de las cartas reales con posterioridad a su institución espontánea (no tutelado ni guiado por una autoridad superior); fue- ron súbditos ingleses por casi años hasta su independencia, por lo que no estaban investidos de soberanía. combi- naban, entonces, libertad y no soberanía. en on revolution, arendt interpreta la experiencia colonial y pre-colonial de los eeuu con sus propias categorías de pensamiento político, fraguadas sobre el carácter ejemplar de la polis griega y de la civitas romana. pertrechada de los ins- trumentos teóricos antedichos, la autora halla en los orígenes de su patria adoptiva una riqueza política y una experiencia re- volucionaria, que no ha sido debidamente enaltecida. animada con este espíritu, re- gistra en estas “sociedades políticas” co- loniales, en las “repúblicas elementales” . cf. idem, pp. , - , - .. cf. idem, pp. , - , - . . cf. idem, pp. , , .. cf. idem, pp. , , . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x de thomas jefferson y en el “civil body politik” de la fórmula del mayflower una réplica moderna de esas primeras institu- ciones políticas libres del mundo clásico de las que somos herederos . la guerra por la independencia, la desvin- culación de la corona inglesa, a diferencia de lo que sucedería en francia, no barrió los privilegios de los antiguos estamentos y ordenes, que -pertenecientes al antiguo régimen- constituían los patrones de una organización obsoleta; la emancipación lo fue respecto de la corona inglesa, pero no se sintieron eximidos de sus propios pactos coloniales y Órdenes fundamen- tales , en las que yacía su organización. . cf. arendt, �annah,. cf. arendt, �annah, on revolution, op. cit.; p. . �eemos: �estos cuerpos, estrictamente ha-�eemos: �estos cuerpos, estrictamente ha- blando, no eran concebidos como gobiernos; no implicaban gobierno y la división entre goberna- dos y gobernantes. […] el pueblo así constituido pudo seguir siendo súbdito real del gobierno de inglaterra, por más de ciento cincuenta años. es- tos nuevos cuerpos políticos eran verdaderamente <<sociedades políticas>> y su gran importancia para el futuro yacía en la formación de un dominio político, investido de poder y con la prerrogativa de reclamar derechos, sin poseer soberanía”. . connectituc, hoy uno de los cincuenta esta- dos de los estados unidos, fue una de las trece colonias, en origen dependientes del reino uni- do. �a región, hoy llamada connecticut, fue ex- plorada en primer lugar por colonos holandeses, que establecieron puestos comerciales, pero los primeros asentamientos permanentes se debieron a los ingleses puritanos de massachusetts, a par- tir de . �a colonia de connecticut, desde su origen, gozó de gran autonomía política y fue, en consecuencia, la primera en poseer un constitu- ción escrita, llamada fundamental orders, o first orders (mandatos fundamentales o primeras Ór- denes). fue adoptada el de enero de y pro- clama un principio de gobierno democrático ba- sado en la voluntad del pueblo. esta constitución colonial serviría de base para la redacción de la constitución estadounidense, por esa razón se lla- ma a connecticut �el estado de la constitución” en primer lugar, la suerte de los colonos americanos estuvo predeterminada por su herencia no absolutista, le hacían fren- te a un gobierno constitucional, la pro- tección de los abusos potenciales de la monarquía les estaba garantizada por el hecho de que gozaban de “los derechos de los ingleses” . es decir, el aspecto de- (�the constitution state”). para el documento de las Órdenes fundamentales de connecticut, véase grau, �uis, �istoria del constitucionalismo ame- ricano. materiales para un curso de historia de las constituciones, universidad carlos iii de madrid, madrid, , cf. pp. - . para el texto original del mandato fundamental de connecticut, véase: http://oll.libertyfund.org/pages/ -fundamen- tal-orders-of-connecticut . burke, edmund. burke, edmund, reflections on the french revolution, cf. http://oll.libertyfund.org/title/ . nos referimos a la sentencia de edmund burke, que –contra la proclamación de la revolución francesa– impugna los derechos naturales ina- lienables del �ombre y reivindica los derechos históricamente emplazados y sancionados por la tradición. edmund burke sostiene que para teorizar o reflexionar sobre la dimensión política de los hombres basta con �constatar o reflejar lo que aparece, dejando de lado la función de pe- netrar tras las apariencias positivas, forzando su sentido, mediante la aplicación de principios no visibles, que son construcciones racionales”. el pensador irlandés, define la sociedad y la historia según el modelo de la naturaleza, en la cual pue- de descubrirse cierta legalidad y constancia. �o racional en el plano social e histórico es lo que se ha comprobado como constante e inalterado, aquello que ha resistido al transcurso del tiempo. para burke, en consecuencia, la racionalidad y naturaleza del orden social se encuentra en �cier- tas constancias inalteradas por el paso del tiem- po, es decir, en la tradición”. �a tradición, enton- ces, es �el único principio legitimante del orden público”. discute toda defensa de la libertad que tenga por fundamento ideas abstractas sobre el hombre, o que se base en la naturaleza humana y defiende la índole histórica y contingente de los principios. en este caso, �el carácter convencio- nal (no natural) de todo derecho y la sola legiti- mación de éstos como derechos históricos, como revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x cisivamente revolucionario no fue el recla- mo por un gobierno limitado y su consti- tución –en consecuencia- no se basó en una enumeración de derechos. si la re- volución de los eeuu, hubiera sido sólo esto, no habría sido más que un reclamo restaurador ante la voracidad impositiva de un parlamento tiránico o la desmesu- ra de jorge iii . el aspecto decisivo de la revolución americana –consigna arendt- es que la cuestión de la revolución y fun- dación de un nuevo cuerpo político nun- ca tuvo su centro en la enumeración de derechos; es decir, en la salvaguarda de las libertades civiles, mediante garantías constitucionales. o sea, la posición de arendt es que el aspecto crucial del pro- ceso revolucionario en los eeuu no yace en la raíz liberal clásica, sino en la discu- sión por la mejor forma de gobierno o por la distribución más sabia de los poderes. veremos que su posición sobre la revolu- ción es compatible con su interpretación �herencia del pueblo inglés�”. véase, molían, tomás �burke y las concepciones conservadoras de la democracia”, crítica & utopía, latinoame- ricana de ciencias sociales, número , buenos aires, septiembre, . se consultó la versión on line publicada por la red de bibliotecas vir- tuales de ciencias sociales de américa �atina y el caribe de la red clacso: www.biblioteca- virtual.clacso.org.ar/ar/libros/criticayutopia.htm véanse especialmente pp. - . edmund burke argumenta sobre los derechos de los ingleses, es decir, los derechos y libertades que se heredan por tradición en reflections on the french revo- lution. véase, http://oll.libertyfund.org/title/ especialmente, pp. - , . en esta última leemos: “in the famous law of the rd of charles i. called the petition of right, the parliament says to the king, �your subjects have inherited this freedom», claiming their franchises, not on abstract principles as the «rights of men», but as the rights of englishmen, and as patrimony de- rived from their forefathers”. . cf. sheldon, garret, �., . cf. sheldon, garret, �., the political phi- losophy of thomas jefferson, op. cit.; pp. - , del pensamiento de thomas jefferson. dicho de otro modo, la cuestión esencial fue el establecimiento de un nuevo siste- ma de poder, o -en palabras de la pensa- dora- “la constitución de la libertad recién conquistada”. en consecuencia, la fuen- te clave fue el republicanismo clásico . “constitutio libertatis” , es el subtítulo del capítulo iv de on revolution, titulado “foundation i” . . béjar, �elena, el corazón de la república: ava- tares de la virtud política, op. cit.; cf. pp. - . . cf. arendt, �annah. cf. arendt, �annah, on revolution, op. cit.; pp. - . . �a constitución de los estados unidos fue redactada en la convención constitucional de filadelfia, en , ratificada en (the fe- deralist) y entró en vigencia en . es la cons- titución de mayor antigüedad que se encuentra, aún hoy, vigente en el mundo. sustituyó a los �artículos de la confederación y unión perpe- tua”, que eran los estatutos originales de los es- tados unidos, vigentes desde . inicialmente, la constitución definitiva de los estados unidos contenía un preámbulo y siete artículos, en los que se establece el sistema de distribución de po- der, o el diseño de las instituciones, lo que arendt denomina �constitutio libertatis”. así, consigna los principios básicos en los que se fundamenta el gobierno federal de los estados unidos y los límites a los que tal gobierno está sometido. �a mayor objeción que se le hizo a la constitución durante su proceso de ratificación fue la ausencia de una declaración de derechos fundamentales. inmediatamente después de ser distribuido el tex- to alexander �amilton publicó en los periódicos de new york un artículo con el título de �the federalist”, bajo el seudónimo publius. allí, se comprometía a resolver todas las inquietudes que suscitaba el texto de la constitución. para ello, recabó la ayuda de james madison y de john jay. entre octubre de y agosto de , los au- tores publicaron en dos periódicos de new york, setenta y siete artículos con el mismo título y bajo el mismo seudónimo. Éstos fueron publica- dos a fines de en dos volúmenes con el títu- lo �the federalist. a collection of essays writ- ten in favor of the new constitution, as agreed revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x . hannah arendt y el republicanismo de thomas jefferson: el sistema de consejos cuando interpreta la historia colonial de eeuu, hannah arendt emplea su cate- goría de praxis y destaca la potencia per- formativa de las promesas y a las alianzas. debido a su elasticidad y su operatividad hacia el futuro, no sólo obligan a los aho- ra contratantes, sino que son virtualmente extensible a las generaciones futuras. por esa razón, encuentra arendt en la capa- cidad de sellar pactos una facultad que erige mundo, suministrando durabilidad y estabilidad, en una medida humana. la medida humana de tal durabilidad garan- tiza una solidez relativa, no sólo porque las promesas pueden no ser sostenibles a perpetuidad, sino porque el embate de las nuevas generaciones que ingresan al mun- do de lo público trae consigo gestos inusi- tados de praxis y nuevos reclamos. porque traen renovación, vulneran y amenazan la upon by the federal convention, september , ”. �os ensayos más famosos son el número , en el que madison trata de cómo impedir la tiranía de la mayoría y la ventaja de un estado grande sobre varios pequeños. en el , madison describe el federalismo y en el introduce la doctrina de los �checks and balances”. el de marzo de , el congreso de los estados uni- dos aprobó doce enmiendas a la constitución y el de septiembre fueron enviadas a todos los estados para su ratificación. finalmente, el de diciembre de diez de ellas se convirtieron en el bill of rights, o carta de derechos, de la constitución de los estados unidos. �asta ahora, la constitución ha sido modificada con veinti- siete enmiendas. véase grau, �uis, historia del constitucionalismo americano. materiales para una historia de las constituciones, op. cit.; en especial pp. - , - . estabilidad del mundo . en suma, este sentido acotado de mundo como espacio público comprende toda la esfera de lo instituido, que emerge de acuerdos y de pactos. cierto es que la estabilidad es una cualidad inexcusable del espacio público, en general, y de la república, en parti- cular, pues sin ella la vida humana sería imposible. sin embargo, debe ser flexible a los cambios; se trata, entonces, de una estabilidad relativa. arendt, al igual que jefferson, destaca particularmente la in- tensidad con que las nuevas generacio- nes (“los recién llegados” ) “toman por asalto” el mundo, que los adultos les en- tregamos en custodia , y cuya solidez ha de ser lo suficientemente vigorosa para encauzar su praxis -la estabilidad relativa- al tiempo que ha de dejar espacio para cambiar los aspectos, otrora operativos y significativos, pero hoy obsoletos. la categoría clave del ámbito público y político es la acción; designada con los vocablos griegos praxis y lexis (literalmen- te: actuar y hablar), la acción responde a la condición humana de la pluralidad . hablar y actuar siempre acaece entre los hombres. por su carácter impredeci- ble e ilimitado, no podemos dominar por completo los resultados o de las conse- cuencias de la praxis, precisamente por- que es praxis mancomunada (“action in concert”) . es decir, no controlamos sus implicancias porque hablar y conversar . cf. arendt, �annah. cf. arendt, �annah, the human condition, op.cit.; p. . . cf. idem, p. .. cf. idem, p. . . cf. arendt, �annah,. cf. arendt, �annah, between past and fu- ture. eight exercise in political thought, op. cit.; p. . . cf. arendt, �annah. cf. arendt, �annah, the human condition, op.cit.; cf. pp. y . . cf. idem, pp. , . cf. arendt, . cf. idem, pp. , . cf. arendt, on revo- lution, op. cit., cf. pp. - . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x siempre impacta en una red de relaciones e interacciones humanas, imposibles de gobernar. en relación a estos atributos, arendt des- taca dos aspectos inherentes a la praxis. el primero alude a la capacidad de insti- tuir algo novedoso, de cambiar y de trans- formar un estado de cosas. creemos que arendt enaltece muy especialmente este aspecto de la acción, que podemos llamar ominoso, fatídico e ilimitado: en términos políticos, el aspecto revolucionario. el se- gundo aspecto de la acción, ineludible para la recta conceptualización del mundo público, alude a todo lo instituido por los hombres: las leyes, las constituciones, los estatutos y reglamentos, en general. toda institución demarca los límites dentro de los cuales la acción inicia sus cursos, pro- cesos –a su vez- cuyo automatismo, la misma acción interrumpirá . es decir, el segundo aspecto, al que podemos llamar conservador, circunscribe la potencial ca- pacidad de innovación de la acción a lí- mites relativamente precisos. en between past and future ( ), la autora iden- tifica estos dos rostros de la acción con dos posiciones políticas y existenciales, la conservadora y la liberal (o progresista). una, tendiente a mantener el status quo o a restaurar una circunstancia pasada deseable, la otra, proclive a la renovación y el cambio . en on revolution arendt profundiza esta postura, aseverando que lo que originariamente fueron dos caras de uno y el mismo fenómeno (el carác- ter dual de la praxis), con el tiempo se osificó en dos posiciones irreductibles: la conservadora y la liberal. conservaduris- . cf. arendt �annah, . cf. arendt �annah, the human condition, op. cit.; pp. - . . cf. arendt, �annah. cf. arendt, �annah, between past and fu- ture. eight exercises in political thought, op. cit.; cf. pp. - . mo y liberalismo, entonces, designan dos actitudes teóricas con reivindicaciones contrapuestas y en apariencia irrecon- ciliables, pero remiten a la experiencia originaria de la praxis, con sus potenciali- dades concurrentes. arendt entiende que ambos aspectos están contenidos en la experiencia revolucionaria o, en sus tér- minos, en el “espíritu revolucionario” . en otras palabras, el “espíritu de la revo- lución” une dos elementos solo en apa- riencia incompatibles. el primero es “el acto de la fundación de un nuevo cuer- po político” y remite a la experiencia de la novedad que acaece en la fundación. al mismo tiempo, tal acto “involucra la grave preocupación [grave concern] por la estabilidad y la durabilidad de la nue- va estructura” . es la “experiencia que aquellos comprometidos en esta gravosa tarea [grave business] deben tener”, a sa- ber, “la extraordinaria toma de conscien- cia [exhilarating awareness] de la capa- cidad humana de comenzar”. atrapados en el momento pasmoso de la creación, la revolución enciende “la exaltación del espíritu [high spirits] que siempre asiste al nacimiento de algo nuevo en la tierra” . para arendt, el aspecto fundacional y performativo de la praxis, que contiene el elemento del cambio y la transformación, conlleva, también, el deseo de fundar es- tructuras estables y sólidas. en suma, el espíritu revolucionario incluye tanto el jú- bilo y la euforia compatibles con los actos de derribar y construir, como también la mesura y la tranquilidad provenientes de las estructuras perdurables. . cf. arendt, �annah. cf. arendt, �annah, on revolution, op. cit.; pp. - . . cf. idem, p. . cf. idem, p. . cf. ibidem.. cf. ibidem. revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x desde el punto de vista de la categoría de poder, clave en arendt, el poder plural (diametralmente contrario a la violencia, que puede ser unipersonal) surge cuan- do muchos actúan juntos . ese poder de instituir, que emerge cuando los hombres se reúnen para actuar, es efímero e ines- table, hasta tanto sea “reificado” , es de- cir institucionalizado en leyes, estatutos, constituciones. estos dispositivos de po- der instituido establecen un espacio pú- blico duradero y sólido. en on violence, apunta la autora: “el poder surge siempre que los hombres se reúnan y actuen en concierto, (…) pero deriva su legitimi- dad de la acción conjunta inicial [from the initial getting together].” según esto, la legitimidad de dicho poder se relacio- na “con una apelación al pasado” ; sin embargo, las instituciones legítimas son “manifestaciones y materializaciones de poder; se petrifican y decaen tan pronto como el poder vivo del pueblo deja de sostenerlos” . en consecuencia, el poder no sólo se manifiesta originariamente en el momento fundacional, cuando muchos se reúnen para hablar o actuar (praxis y lexis), sino que debe perdurar activo como savia que vivifica las instituciones. dicho con arendt, el poder también es “aquello que mantiene en existencia el espacio público [public space], el espacio potencial de aparición que acaece entre los hombres, en calidad de agentes y de oradores”. el ámbito público es un es- . cf. arendt, �, . cf. arendt, �, the human condition, op. cit.; pp. - . . cf. idem, p. .. cf. idem, p. . . �annah arendt, �on violence,” in crises of the republic, �arcourt brace jovanovich. inc., new york, ; cf. p. . . cf. idem, p. .. cf. idem, p. . . cf. arendt, �annah, . cf. arendt, �annah, the human condition, op. cit, ; p. (el énfasis es añadido). pacio potencial, como señala el fragmen- to antedicho, tan potencial como el poder que generan muchos para actuar y para hablar. insistimos, ese puro poder de ins- tituir es inestable e impresiso hasta tanto no se instituya en estatuto o constitución. al mismo tiempo, debe perdurar latente y animar todas las instituciones, ya que dicho poder es el vínculo con el origen le- gitimante. vemos así, que a causa de la misma naturaleza potencial del poder , es imperativo el establecimiento de ins- tituciones o de canales sancionados por la constitución, que garanticen la acción permanente de los ciudadanos, so pena de debilitar y osificar sus instituciones. en este particular aspecto, arendt es deu- dora de jefferson y de su percepción de la indeclinable necesidad del sistema de consejos. richard bernstein denomina este aspecto equívoco de la praxis como “la paradoja de la fundación” . el propósito de una revo- lución es fundar una nueva constitución. la libertad tangible que aparece a la vista de todos en los espacios públicos recién creados es la misma actividad instituyente de la fundación, que coincide con el acto de diseñar una nueva constitución. para- dójicamente, el mayor peligro que enfren- ta una revolución es que su éxito puede echarse a perder si las instituciones crea- das ahogan el espíritu revolucionario que las originó. es decir, la paradoja consiste en que solo los fundadores parecen poder . cf. arendt, �annah, . cf. arendt, �annah, the human condition, op. cit.; p. . arendt esclarece la procedencia etimológica del término poder en alemán (die macht) para poner en evidencia su carácter po- tencial. die macht proviene de mögen y möglich (poder y posible, respectivamente). . richard bernstein, . richard bernstein, hannah arendt and the jewish question, polity press, cambridge, uk; cf. position (e-book). revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x gozar de la libertad pública y de la felici- dad pública inherentes al momento ins- tituyente. arendt sostiene que jefferson fue el único pensador político americano que “percibió mejor que nadie, con gran claridad y apasionada preocupación, esta debilidad -en apariencia inevitable- de la estructura de la república”. fue jeffer- son quien exigió la división de la república en consejos, a los que llamó “repúblicas elementales [elementary republics]” , con el fin de renovar el espíritu revolu- cionario de la generación fundadora, la savia nutriente que podía mantener viva a la república. si su proyecto de las “re- públicas elementales” se hubiese imple- mentado, consigna arendt, hubiéramos asistido a una réplica de esa forma novel de gobierno que podemos detectar en las sociedades populares de la revolución francesa y en las secciones de la comuna de parís de fines del xix, entre otros acon- tecimientos ejemplares y sobresalientes de la “tradición revolucionaria perdida”, que on revolution pone en evidencia. cuando hannah arendt examina la re- volución en los eeuu, valora las ense- ñanzas de t. jefferson y advierte que los padres fundadores “fallaron en incorpo- rar el municipio y la comuna [the town- ship and the town hall meeting] en la constitución” . los municipios (o ayun- tamientos) eran “espacios de libertad [spaces of freedom]” ; como tales eran las instituciones cruciales de la nueva re- pública. la vida del hombre libre -apunta arendt- necesita de espacios acondicio- nados para congregarse en calidad de . cf. �annah arendt, . cf. �annah arendt, on revolution, op. cit.; pp. , . . cf. idem, pp. y siguientes. . cf. idem; pp. , .. cf. idem; pp. , . . cf. idem, p. .. cf. idem, p. . ciudadanos, “el espacio específicamente político, donde los hombres de reúnen como ciudadanos, no como personas privadas” . es decir, la vida pública y la libertad pública que la acompaña, exigen foros institucionalmente reconocidos para la acción libre, en donde los ciudadanos se manifiestan unos a otros, en la acción y en la palabra. arendt insiste en la im- portancia política de “the ward system” y destaca la relevancia de estos espacios instituidos porque contribuyen a mante- ner un estilo de vida -la vida ciudadana- a la que no debemos renunciar. el aspecto clave del consejo no es tanto los procesos de decisión y el logro de objetivos concre- tos, sino que estos foros garantizan un es- pacio para que los hombres puedan com- portarse como ciudadanos, reuniéndose, discutiendo, argumentando e ilustrándose mutuamente con sus opiniones . en una palabra: poniendo en evidencia que les importa algo más que su estrecho bienes- tar privado; en esto radica -para hannah arendt- la relevancia de la praxis manco- munada como expresión más excelsa de nuestra humanidad. para hannah arendt esta actividad -esencialmente política- es un fin en sí mismo. no necesita remitirse a los propósitos y objetivos, para ser sig- nificativa. su especial interés en el jeffer- son republicano, con sus ideas sobre los municipios, la participación activa garan- tizada, y con la división de la república en consejos, no se debe a una actitud nostál- gica de las decisiones directas de las an- tiguas polis griegas, pese a su reluctancia hacia la representación política. arendt desea rescatar otra cosa. las sociedades o clubes revolucionarios en francia, y los wards virginianos no se establecieron ne- . cf. idem, p. .. cf. idem, p. . . cf. idem, p. .. cf. idem, p. . . cf. idem, p. .. cf. idem, p. . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x cesariamente para la toma de decisiones, o para las funciones ejecutivas; su obje- tivo no era solo el gobierno o la adminis- tración de un municipio, sino asegurar un ámbito para la discusión, el debate y la conversación. en on revolution, por ejemplo, arendt valora particularmente un club francés que se había impuesto a sí mismo la prohibición de tener algún tipo de influencia en la asamblea gene- ral. el club existía solamente “para con- versar sobre [los asuntos públicos] y para intercambiar opiniones, sin la necesidad de plantear propuestas, hacer peticiones, nombramientos, y cosas por el estilo” . de la misma manera, los consejos eran un espacio de libertad, un lugar donde la gente se podía reunir y discutir sobre cuestiones del día, comunes a todos. su importancia no recae -como vemos- en sus logros, o en los fines que consiguen, sino en lo que fomentan y promueven. como espacios institucionales de expe- riencia política organizada, los consejos ideados por jefferson, recreaban y fo- mentaban la emulación de las pasiones y acciones pasadas; ofrecían la experiencia de la acción libre y de la felicidad pública, que son posibles solamente en el proceso de la acción conjunta y de la conversación con otros. veamos la cuestión en los es- critos de t. jefferson. en notes on the state of virginia ( ), jefferson escribió que deseaba “dividir cada condado en pequeños distritos de cinco o seis millas cuadradas, llamados cientos [hundreds]” . un año más tar- . cf. idem, p. .. cf. idem, p. . . �hundreds” se refiere a cien varones cabe- zas de familia. en origen, la propuesta tenía fines educativos. �this bill proposes to lay off every country into small districts of five or six miles square, called hundreds and in each of them to establish a school for teaching, reading, writing, de, con la aprobación de la land act de (que establecía que una sección por municipio debería reservarse para propó- sitos educativos), la idea se convirtió en ley. treinta años más tarde, cuando las tres ramas del gobierno federal -ejecuti- vo, legislativo y judicial- habían crecido desmesuradamente en poder en relación a los gobiernos locales, jefferson insistió en la relevancia política de su idea de los wards, que combinaba todos los requisi- tos de una república en miniatura: parti- cipación y auto-gobierno en un territorio pequeño. en la carta del de enero de dirigida a joseph cabell, jefferson alude al estado de virginia y le confía su antiguo anhelo: “hace tiempo que creo que la subdivisión del condado [county] en consejos [wards] es la medida funda- mental para asegurar la continuidad del gobierno republicano” . dos años des- pués, el de febrero de , se dirigió al mismo destinatario precisando su pro- puesta en relación a la naturaleza de las funciones del consejo: “que al gobierno nacional le sea confiada la defensa de la nación y sus relaciones extranjeras y fe- derales. a los gobiernos estatales [se les confíen] los derechos civiles, las leyes, la policía y la administración de lo que le concierne generalmente al estado. a los condados les compete los asuntos [con- cerns] locales; y cada consejo dirige los and arithmetic”. véase jefferson, thomas, the works of thomas jefferson, federal edition (new york and london, g.p. putnam’s sons, - ). vol. . [online] available from http://oll.liberty- fund.org/titles/ ; accesed / / ; internet. (formato ebook pdf). cf. query , p. . . jefferson, thomas, . jefferson, thomas, the works of thomas jefferson, federal edition (new york and lon- don, g.p. putnam’s sons, - ). vol. . [on- line] available from http://oll.libertyfund.org/ titles/ ; accesed / / ; internet. (formato ebook pdf); cf. p. . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x intereses que le son pertinentes a sí mis- mos”. jefferson explica la gradación de autoridades, de abajo hacia arriba, siendo la fuente de la autoridad de toda la es- tructura de la unión, el poder que nace en los consejos. se trata, entonces, de una estructura piramidal inversa respec- to de las jerarquías tradicionales. alude a una aristocracia de virtud y mérito, cuya fuente de autoridad es la base, es decir, los municipios o los ayuntamientos: “las repúblicas elementales de los consejos, las repúblicas del condado, las repúblicas de los estados y la república de la unión, formarían una gradación de autoridades, basadas en la ley, manteniendo cada una su participación delegada de poderes” . ahora bien, ¿cuáles eran los intereses y las obligaciones de los consejos específica- mente? en una carta a samuel kercheval el de julio de esclarece los inte- reses que deben confiarse a los consejos. idealmente, estos incluían la elección, la instalación y el soporte de una amplia va- riedad de servicios, que en ese momento estaban bajo la dirección de autoridades distantes, a saber: jueces, una escuela militar para educar jóvenes, patrullas de vigilancia, equipos de mantenimiento de rutas, el cuidado de los enfermos y los po- bres. en resumen, a juicio de jefferson, los municipios debían funcionar como repúblicas en miniatura. su proyecto era dividir y subdividir las repúblicas del po- der central por medio de la subordinación a las estructuras más próximas al pueblo (o sea, la subordinación era de arriba ha- cia abajo: nación, estados, condados, . http://press-pubs.uchicago.edu/founders/do . http://press-pubs.uchicago.edu/founders/do cuments/v ch s .html. no hemos encontrado la carta del de febrero de dirigida a j. ca- bell en la biblioteca on line de liberty fund, de donde proceden el resto de las citas de las obras y cartas de t. jefferson. municipios -wards o town hall meetings-) para, finalmente, terminar en “la adminis- tración de la propia granja”, para beneficio de todos. para jefferson, el elemento de- cisivo para “cementar” el todo, es decir, la unión, era la participación en los asuntos públicos: “and the whole is cemented by giving to every citizen, personally, a part in the administration of the public affairs”. la clave, explicaba jefferson, era “asignar las tareas según las competencias de las personas” y “poner bajo su supervisión lo que puede gestionar”. de esta forma cada ciudadano se transforma en “un miembro activo del gobierno” y no en un mero vo- tante que solo ejerce su ciudadanía el día del sufragio . . conclusión en conclusión, en su obra de , on revolution, hannah arendt ha puesto en evidencia las raíces republicanas de la revolución estadounidense, en desme- dro de su interpretación habitual en el contexto de las ideas del liberalismo clá- sico. empleando sus propias categorías de pensamiento -espacio público, praxis mancomunada y poder- la autora indagó la experiencia revolucionaria y colonial estadounidense señalando allí el poder performativo de pactos y acuerdos, y la acción en concierto que elude las finali- dades particulares de los agentes, para seguir sus propia lógica estableciendo instituciones duraderas y transmisibles. pero la acción y el discurso, hemos visto, involucran también el instante inaugural . cf. jefferson, thomas, the works of thom- as jefferson, federal edition (new york and london, g.p. putnam’s sons, - ). vol. . [online] available from http://oll.libertyfund. org/titles/ ; accesed / / ; internet. (for- mato ebook pdf); cf. pp. - . revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x de la fundación. inexcusablemente, el nuevo origen que pone en existencia un nuevo cuerpo político y que es el esfuerzo conjunto de muchos, ha de pervivir intac- to alimentando y sosteniendo la vitalidad de las instituciones. esta particular con- vicción del thomas jefferson republica- no, celebrada y compartida por arendt, se evidencia en su insistencia en incorporar las unidades políticas básicas (consejos, municipios o distritos) como foros institu- cionalizados de participación ciudadana. cierto es que el padre fundador admite y, hasta cierto punto, amalgama los motivos del liberalismo (fuertemente presentes en los años previos a la revolución) y los del republicanismo. sin embargo, tras la novedosa lectura que arendt propone, la figura de thomas jefferson integra la corriente del republicanismo clásico en forma eminente. en este punto, hannah arendt desliza su propia posición sobre el concepto de lo político hacia la interpreta- ción del autor de la declaración de la in- dependencia. cuando jefferson exigió la división de los condados en distritos (con- sejos o wards, en virginia y town hall mee- tings, en new england) como enmienda constitucional -sostiene arendt- sabía que . cf, arendt, �annah, �never-before-pub-. cf, arendt, �annah, �never-before-pub- lished �annah arendt on �hat freedom and revolution really mean”, new england re- view, volume , number , . en la página , leemos : �and in part it is because nothing in the course of these revolutions is as con- spicuous and striking as the emphatic stress on novelty, repeated over and over by actors and spectators alike, in their insistence that nothing comparable in significance and grandeur had ever happened before. the crucial and difficult point is that the enormous pathos of the new era, the novus ordo seclorum, which is still inscribed on our dollar bills, came to the fore only after the actors, much against their will, had reached a point of no return”. se debían proveer canales instituciona- lizados por medio de los cuales los ciu- dadanos tendrían la oportunidad de ser republicanos, es decir, de comportarse como ciudadanos en forma permanente, y no solamente el día de la votación. en- tendemos que el enaltecimiento de la vita activa y particularmente de la praxis, ce- lebrado por arendt en the human condi- tion, encuentra su réplica en la exigencia de thomas jefferson en el compromiso sostenido y la participación vigorosa de cualquier ciudadano en los asuntos co- munes. arendt cree que esta actividad era para el tercer presidente de los eeuu un fin en sí mismo, es decir, que el valor de la acción y el discurso yace en ellos mismos, más allá de la consecución de los fines y los propósitos de los agentes. como no son meros medios instrumentales, sino el medium o el ambiente propicio para el despliegue de las actividades esencial- mente humanas (ni animales, ni divinas), entonces la política es también un fin en sí mismo. hannah arendt entiende que esta nota es esencial al republicanismo de t. jefferson y, en consecuencia, concertar voluntades, actuar junto a otros y conver- sar sobre todo lo que nos concierne como ciudadanos poseen un valor inherente y una significación propia allende los pro- pósitos estrechos de los actores. en este contexto, arendt minimiza la asombrosa posición de jefferson sobre la promisoria modalidad de las revoluciones recurrentes , que consistía en volver a foja cero cada veinte años, de manera que con cada recambio generacional, los recién llegados (los principiantes [“begin- . thomas jefferson, . thomas jefferson, the works of thomas jefferson, federal edition (new york and �on- don, g.p. putnam’s sons, - ). vol. . [on- line] available from https://oll.libertyfund.org/ titles/ ; accessed / / ; internet. revista internacional de pensamiento político - i Época - vol. - - [ - ] - issn - x ners”] de arendt ) mantuvieran vivo el espíritu revolucionario, cuyo más propio sentido coincide con la energía fundacio- nal y el poder constituyente. cierto es la que la pensadora atempera las opiniones radicales de jefferson sobre la prerroga- tiva de las generaciones de cuestionar la forma de gobierno del mundo al que ingresan y –en consecuencia- de modifi- car su constitución. sin embargo, coinci- de con el admirador de la revolución en francia, en que sin los órganos básicos que canalicen la participación ciudada- na, el pueblo –eventualmente- recurrirá a la fuerza y la rebelión para expresar su fastidio . en opinión en arendt, thomas jefferson creía que el sistema de consejos podía ofrecer: “una exacta repetición de todo el pro- ceso de acción que había acompañado el curso de la revolución [...]. y [en] sus últimos escritos estaba enteramen- te concernido por el acto de hacer una constitución y el establecimiento de un nuevo gobierno, esto es, por aquellas actividades que por sí mismas consti- tuyen el espacio de libertad [freedom]”. . cf. arendt, �annah, . cf. arendt, �annah, the human condition, op. cit.; pp. , . . en la carta del de septiembre de a su rival electoral y amigo, john adams, jefferson defiende las revoluciones, en general, y la france- sa, en particular, como el paso �del despotismo a la libertad”. �os pueblos deben aprender a ser li- bres y necesitan de varias generaciones para ins- tituir repúblicas, porque �la generación que co- mienza una revolución raramente la completa” y usualmente �[estos] terminan siendo instrumen- tos en las manos de los bonapartes, que derrotan sus derechos y propósitos”. un �primer intento de auto-gobierno puede fallar, como también un segundo y un tercer intento”, sin embargo -even- tualmente- �alguno de los intentos renovados, tendrá éxito”. véase, http://oll.libertyfund.org/ title/ ; cf. p. . (arendt, hannah, on revolution, op. cit.; cf. p. ). dicho espíritu revolucionario, que yacía en la conciencia del poder del pacto, ha- bía nutrido el país desde la época colonial e inclusive pre-colonial (si nos atenemos al ejemplo del mayflower compact, caro a arendt) y sólo podía perdurar activo “[…] si se incorporaban y se constituían debidamente, se re-fundaban las fuentes originales de su poder y de la felicidad pública” . para thomas jefferson, los consejos eran “la más sabia invención […] del ingenio humano, para el perfec- to ejercicio del auto-gobierno, y para su preservación” . . cf. arendt, �annah, . cf. arendt, �annah, on revolution, op. cit.; cf. p. . . cf. jefferson, thomas, the works of thom- as jefferson, federal edition (new york and london, g.p. putnam’s sons, - ). vol. . [online] available from http://oll.libertyfund. org/titles/ ; accesed / / ; internet. (for-(for- mato ebook pdf); cf. p. . people in political science his friends, colleagues, students, and strangers. his brilliant and productive career as a political scientist both drew upon and reinvigorated his personal and political commitment to preserv- ing and enhancing all human life. he was a man as good and kindly as his scholarship was great. he received strength from his many friends and most of all from his family. he is survived by his wife, juanita, and their children, marit, mia and helge. his presence is deeply missed. joseph fletcher alkis kontos university of toronto guy renfro donnell guy r. donnell, oklahoma state university emeritus professor of political science, , died on novem- ber . for years he taught politics to students enthralled by his quick wit and carefree cynicism. students flocked to enroll in his classes, and when the time finally came for him to retire in , he was honored with a scholarship fund from which awards are granted annually in his memory. with guy donnelps passing, another gallant witness to pioneer times in the southwest is gone. his mother, iva may, came to texas with her parents after a nine-week trip by covered wagon from illinois. she married john donnell, whose father had fought with the missis- sippi regiment in the civil war. she strongly encouraged their three chil- dren to excel in school, and between them they went on to earn seven uni- versity degrees. when guy donnell graduated from saint jo high school, montague county, he was the valedictorian of his class. he studied for one year at what was then called north texas state teach- ers college in denton, after which, at the ripe age of , he secured the first of several teaching jobs in small county schools. living frugally, he managed to squeeze in semesters at college between teaching jobs. it took him nine years to get his bachelors degree, which was awarded by the university of oklahoma, and several more years to get master's and doctoral degrees from the uni- versity of texas in austin. when world war ii broke out, donnell joined the u.s. army air corps. he served as a flight com- mander at the aviation cadet center in san antonio, which was then regarded as the elite school for army aviators. donnell abhorred pomp and pretentiousness. he had a repu- tation for being kind and considerate to cadets, who were often the butt of harsh discipline administered by younger officers with heads freshly swelled at west point. thanks to friendships formed in those days, donnell received shortly after the war a welcome invitation to join the political science faculty at oklahoma a&m in stillwater. donnell became a mainstay of the political science department, which he managed almost single-handedly while the nominal head of the de- partment busied himself with more lucrative ventures. donnell planned the class schedules, attended count- less committee meetings, advised hundreds of students, and taught three or four courses a semester, all the time delighting students with wicked anecdotes and sarcasms he found it inadvisable to repeat outside of the classroom. his familiarity with state and local politics affected both his view of human nature and his view of academic political science. he would often merrily dismiss a piece of scholarly writing by compar- ing its author's intelligence unfavor- ably to that of his cat, cochise. donnell was a great favorite of faculty members of all departments. his election to serve on the univer- sity's faculty council testified to their respect for him. he himself took special pride, however, in his service on the university's athletic cabinet, appointment to which, as the only university committee from which faculty members drew any tangible benefits, was incontroverti- ble proof he was not a chump. after his retirement from the osu faculty donnell continued to fre- quent the campus and to regale friends and colleagues with amusing stories and outrageous insights. even as he coped valiantly with the loss of his wife, sue, and three serious ill- nesses, his intelligence and sense of humor never faltered. vigorous and charming into his ninth decade, he found a new and valued friend, mary elizabeth jones, who joined him in marriage and brought him new happiness. bertil hanson oklahoma state university cecelia kenyon cecelia marie kenyon (cele as she was more generally known) died in her home in northampton on janu- ary , . she was born in gainesville, georgia, in , and received her ph.d. from radcliffe in . she had come to smith the year before as an instructor and remained a member of the smith fac- ulty until she retired in . she was named the charles n. clark profes- sor of government in . her field was european and american political theory, and most of her scholarly writing dealt with the political theoretical arguments surrounding the birth of the ameri- can republic. for a variety of reasons she did not publish much, but the articles and books she did publisli have become classics in her field to be cited, discussed, and argued about by others. this is especially true of her seminal essay, "men of little faith: the anti- federalists on the nature of repre- sentative government," which was originally published in and then, expanded to over pages, served as an introductory essay to her edited volume the anti-federal- ists, published in . in recognition of her contribution to our understanding of the founda- tions of the american political order, cele was awarded an honorary degree by rutgers university in . in the same year, she spoke before the u.s. congress at a program marking the birthday of thomas jef- ferson, one of her heroes. two years earlier, in , she had been chosen to address the united states house of representatives at a program marking the th anniversary of the first continental congress. she also served as a member of the board of trustees of oberlin college, where she had received her b.a. degree. if cele was a creative scholar, she was also a respected and revered ps: political science & politics in memoriam teacher. she worked closely with her students, going over their examina- tions or papers with a fine-tooth comb, writing pages and pages of comments and spending hours and hours of her time with them. at the peak of her career she was an impor- tant model for many government majors, partly because they knew that, while demanding, she was also supportive and fair. and while she could be very serious, she also had a rich, wry sense of humor. as one of her former students wrote recently: my most favorite memory of cecelia kenyon is the lecture she gave on thomas jefferson in which she admit- ted to stealing two bricks from monti- cello on one of her pilgrimages there. this admission she made with a con- spiratorial grin and defiant toss of her head in front of over fifty saturday morning smith students. before that moment i felt mostly awe in her pres- ence. after that moment my awe was tempered by the warmth of her admis- sion. the steel trap mind was wedded to a very human heart. cecelia ken- yon has been, and remains, my most important memory of four years at smith. her influence on my life has reached far beyond the information she imparted. cele was also a wonderful col- league. she gave freely of her time to the college, fostering that faculty self- governance which has become its hall- mark, and she was elected to many key committees by the faculty. she loved smith and, therefore, insisted that the college live up to her very high standards of fairness and jus- tice. thus, although not confronta- tional by nature, and, indeed, rather shy, she said what she believed and stuck by it. for this reason cele was sometimes regarded with trepidation and annoyance, if also respect, by her colleagues and those college pres- idents who served while cele was here. she was the sometimes lovable and sometimes not so lovable bane of their existences. cele was, to use an old-fashioned word which she liked, a lady. she was invariably courteous to her opponents and soft spoken, inter- lacing her arguments with wryly humorous remarks, which during the height of her powers, often produced peals of laughter even from those with whom she disagreed. of course, we all knew that the velvet glove covered an iron fist. cele was also an old-fashioned lib- eral democrat. she hated both richard nixon and ronald reagan with a passion, not only because of their conservative social policies, but also because both of them, she believed, had violated the rule of law and its constitutional underpinnings. on the other hand, she was not par- ticularly sympathetic to radical critics of the american system and she was not a feminist. although very sensi- tive to discrimination against women of the kind she had experienced at harvard, she was quite angered by attempts to write off political theories because they had been con- structed by men. thomas hobbes was another one of her heroes and, insofar as she had made his thought hers, his gender was, she believed, unimportant, and he could be suit- ably revised to provide support for equality of opportunity for men and women. it was equality of oppor- tunity that cele sought. she was strongly opposed to quotas or even "goals." finally, she was passionately com- mitted to freedom of expression and academic freedom. she would, indeed, have echoed the words of jefferson: "here we are not afraid to follow truth wherever it may lead, nor to tolerate any error so long as reason is left free to combat i t . " many ascribe to that view when asked, but relatively few people in this world, a saving remnant, are willing to put themselves on the line defending unpopular speech when push comes to shove. cele was a member of that saving remnant. may her spirit long be with us. stanley rothman smith college horace b. jacobini h. b. (jack) jacobini died at the age of on august , , after waging a valiant battle against cancer. he came to southern illinois university at carbondale in after teaching at the citadel, the university of alabama (huntsville center), east central state college (oklahoma), and at the university of michigan on assignment at the uni- versity of the philippines. his pri- mary teaching interests and special- ties included international law, administrative law, jurisprudence, and the government and politics of southeast asia. he served on over eighty master and ph.d. committees, directing more than his share of theses and dissertations. he traveled widely, giving lectures and conduct- ing research throughout the world. jack was the author of numerous professional articles published in the united states and abroad. he penned eight books. completed just before his death, his tome, inter- national administrative law, is scheduled for publication by oceana in . his best known works are two editions of the widely adopted book, international law: a text ( / ). his father was an italian immi- grant who taught romance languages at fort hayes kansas state college, an institution where jack received his a.b. and m.s. degrees. it is perhaps this background that helps to explain jack's interest in and intense study of modern languages. his bedtime reading often included studying one exotic language or another so that he might better understand an obscure manuscript or converse with experts in their native tongue. jack was a modest man who dis- dained those who made too much of their academic pedigree. he was the first recipient of the ph.d. degree in political science at the university of kansas ( ) and a man who marched to his own intellectual drummer. he believed that scholars should pursue their own research agendas, without respect to existing paradigms or discipline orthodoxy. a thoroughly humane individual, jack always had time for his stu- dents, colleagues, and friends. his kindness to students was well-known but it was not until his death that many of us learned that he aided political refugees from foreign lands, providing food and shelter to the less fortunate. living the life of a gentleman- scholar, jack and his wife billie occupied a fine home and ranch/ farm not too many miles from the carbondale campus. in this idyllic setting, they nurtured four successful march michaela kleppinger independent scholar orcid: - - - doi . / . . denial of consent: the modern heir of sexual violence within slavery introduction on one night in , a pregnant nineteen-year-old girl named celia was, understandably, not feeling very well. on this same night, a man entered her room, and attempted to rape her, despite her efforts to convince him to spare her. acting out of fear and desperation, celia struck the man twice, accidently causing his death. celia’s actions were a clear case of self-defense–a justifiable homicide. however, celia was a slave and the man was her owner. the sixty-year-old widower, robert newsom, had specifically purchased celia to fulfill his sexual desires and had, there- fore, been raping her regularly. celia had pleaded and warned him that she might “hurt [newsom], if he did not quit forcing [raping] her while she was sick” but he did not listen; celia was his property, to do with as he wished. ultimately, celia was executed for murder–executed for fighting back against her own rapist. the institution of slavery is a stain upon the history and the psy- che of the united states and its people. at its core, it was inherently reliant upon an imbalance of power between the enslaved subject and the slave owner. the enslaved individual’s capacity to assert their own will was virtually nonexistent, allowing white male slave owners the op- portunity to exploit this discrepancy in order to take advantage of the enslaved women and girls under their dominion. the history of slav- ery in the united states is burgeoning with stories like celia’s of sexu- al exploitation and victimization at the hands of predatory white men without a thought or care for the well-being of the women and girls they violated and abused. it is from these roots of coercion and violence that myths and stereotypes proclaiming the sexual immorality of black wilma king, “prematurely knowing of evil things: the sexual abuse of african american girls and young women in slavery and freedom,” the journal of african amer- ican history , no. (july ): . michaela kleppinger women emerged, resulting in the discrediting and discounting of their word. for centuries, white men and society at large have ignored and repressed this history in an effort to avoid blame and deny culpability, leaving black women and girls vulnerable and targets of further victim- ization—an injustice that has veritably stripped them of their right to refuse consent. sexual violence and exploitation within the institution of slavery as william wells brown establishes at the beginning of his literary work, clotel or the president’s daughter, a narrative of the life of a fictional- ized enslaved daughter of president thomas jefferson: a slave is one who is in the power of a master to whom he belongs. the mas- ter may sell him, dispose of his person, his industry, and his labour. he can do nothing, possess nothing, nor acquire anything, but what must belong to his master. the slave is entirely subject to the will of his master, who may correct and chastise him, though not with unusual rigor, or so as to maim and mutilate him, or expose him to the danger of loss of life, or to cause his death. this reality of complete subjection was even more poignant for par- ticularly vulnerable enslaved women and girls. in the united states, white male slave owners took advantage of the power discrepancy be- tween themselves and their enslaved property in order to sexually har- ass, exploit, and assault the women and girls under their charge. as mary church terrell wrote in her article “lynching from a ne- gro’s point of view”: “throughout their entire period of bondage […] colored women were debauched by their masters”. slave owners did not consider their behavior as a form of violation or a breach of christian morality. based on their southern slaveholding principles, there was no question that they were well within their rights to use these women and girls as they so desired. as james hammond, a mid-nineteenth centu- ry writer and slave owner, who engaged in a sexual relationship with both his slave sally johnson and her daughter louisa, claimed: “i do not remember that i ever intentionally did wrong, i do not think that i william wells brown, clotel; or, the president’s daughter: a narrative of slave life in the united states, ed. robert s. levine (boston: bedford / st. martin’s, ), . estelle b. freedman, “african americans redefine sexual violence,” in redefining rape (harvard university press, ), . denial of consent: the modern heir of sexual violence within slavery ever deliberately or otherwise, wronged any human being”. in her anal- ysis of hammond’s behavior and professed beliefs, wilma king, in her work “‘prematurely knowing of evil things’: the sexual abuse of afri- cans american girls and young women in slavery and freedom,” sug- gests: “hammond’s introspection gives readers pause and may explain why some enslaved people endured suffering peculiarly their own when slaveholders seemed oblivious to it all, or did not see them as equally hu- man, or had no sense of religious morality or moral center” . in essence, within the institution of slavery, the sexual exploitation and victimiza- tion of black women and girls was not only accepted but the cultural norm. beyond expectations of providing physical labor, enslaved women and girls were considered perpetually sexually available and treated as brood mares. as harriet martineau details in her work “morals of slav- ery,” following her visit to the united states in the s, on plantations, “it was understood that the female slaves were to become mothers at fifteen” –at fifteen-years-old, scarcely out of puberty and certainly not fully into womanhood. slave owners could simply rape enslaved women and then profit from the results of this assault: with the growing population of slaves in the southern states of america, there is a fearful increase of half whites, most of whose fathers are slaveo- wners, and their mothers’ slaves. society does not frown upon the man who sits with his mulatto child upon his knee, whist its mother stands a slave behind his chair. in many respects, as robert s. levine writes in his historical back- ground to brown’s text, “mastery afforded southern slave owners an ex- ploitative sexual power, and their practice of treating some of their slaves as concubines became an unspoken part of southern white culture” . by exploiting the vulnerability of enslaved women and girls, white male slave owners were able to both satisfy their “boundless licentiousness” and increase their own wealth by encouraging and personally participat- ing in the production of enslaved offspring. king, “prematurely knowing of evil things,” . ibid. harriet martineau, “morals of slavery” in clotel; or the president’s daughter, ed. robert s. levine (boston: bedford/st. martin’s, ), . brown, clotel, . robert s. levine, “thomas jefferson and sally hemings,” in clotel; or the presi- dent’s daughter (boston: bedford/st. martin’s, ), . martineau, “morals of slavery,” . michaela kleppinger other than outlawing interracial marriage, which simply penalized unions founded in affection rather than protecting women, there were no laws in place to prevent white men from abusing their slaves. en- slaved women were considered overtly sexual by nature; regardless of age, they “were assumed to be experienced without concern about whether or not they were sexually active” . even the most horrific cas- es of sexual violence committed against innocent young girls were ig- nored solely on the basis of race. for example, in , james keyton was indicted by a grand jury in tennessee for “violently feloniously and unlawfully” raping an enslaved girl named beck who was under ten- years-old at the time. witnesses testified “that keyton did “forcefully” and “wickedly” come to “carnally know and abuse” beck “against her will”. unfortunately for beck, she was not to receive justice. while the grand jury had believed her case was worthy of an indictment, jurors ul- timately rendered a verdict of “not guilty in manner and form as charged in the indictment”. the grand jury felt that they had no other choice as a result of an statute which set down that: “if any slave or free person of color, shall be guilty of the crime of rape, upon the person of any white female child, under the age of ten years, he shall suffer death for such offense, upon conviction,” meaning that because beck was not white and her assailant was not black, she was not entitled to either pro- tections or recompense under the law. keeping these ideas in mind, the sexual exploitation and victimization of enslaved women and girls is a topic that found its way into many an- ti-slavery works of the eighteenth and nineteenth century, both fictional and non-fictional in nature. william wells brown founded the basis of his literary work, clotel or the president’s daughter, on this culture of exploitation and assault. first and foremost, the title of his work refers specifically to the rumored sexual relationship between president thom- as jefferson and sally hemings, one of his female slaves. historically, “there is considerable evidence that they had seven children together, and that jefferson gave special privileges to both hemings and their chil- dren”. brown choose to root his narrative in the sexual exploitation of the fictional enslaved woman currer, an obvious stand in for hemings, by president thomas jefferson in order to represent that this attitude and corresponding belief system could be traced to the highest echelons of american society – the president of the united states. if such a man, a king, “prematurely knowing of evil things,” . ibid., . ibid., . ibid. ibid. levine, “thomas jefferson and sally hemings,” . denial of consent: the modern heir of sexual violence within slavery man who preached of liberty and equality, was susceptible to such base desires than it is not surprising his example was followed by other slave owners throughout the country. the heroines at the center of brown’s text each face sexual exploita- tion and victimization within slavery at the hands of white men. the experiences of the matriarch, currer, as has already been elaborated, allude to the sexual relationship between thomas jefferson and sally hemings. that being said, the experiences of her eldest daughter and tit- ular character, clotel, represent the southern practice, especially found in new orleans, of pairing mulatto, mixed race, girls with wealthy white gentlemen. these young girls were specifically “brought up by their mothers to be what they [had] been; the mistresses of white gentle- men” . as harriet martineau further elaborates: every young man early selects one, and establishes her in one of those pretty and peculiar houses, whole rows of which may be seen in the remparts. the connection now and then lasts for life: usually for several years. in the latter case, when the time comes for the gentleman to take a white wife, the dread- ful news reaches his quadroon partner, either by a letter entitling her to call the house and furniture her own, or by the newspaper which announces his marriage. in clotel’s case, she believes her relationship with horatio green to be one founded upon love and mutual affection. green, in essence, seduces clotel with notions of love and fidelity. however, after green purchases clotel, she has no legal protections within their self-labeled marriage. while he promises that, after purchasing her, he will “make her mis- tress of her own dwelling” , as his property, she is completely under his power. when green eventually does abandon his vows to clotel for the advantages of a politically and socially motivated marriage, she refuses to continue their sexual relationship. this choice, she admits: “would no doubt expose her to his wrath, and probably cause her to be sold”. her fears are eventually realized when she is sold first, as a maid and, second, for other, more unseemly, purposes. as brown explains: “most quadroon women who are taken to the lower countries to be sold are either pur- chased by gentlemen for their own use, or sold for waiting-maids”. in martineau, “morals of slavery,” . ibid. brown, clotel, . ibid., . ibid., . michaela kleppinger the end, after first escaping her master and then being recaptured trying to reclaim her daughter mary, clotel chooses death over a lifetime of enslavement and further abuse at the hands of white men. while her sister, althesa, is arguably the most fortunate of brown’s cast of enslaved women, her two daughters are not as lucky. after the death of althesa and her husband, it is discovered that she was once a slave, invalidat- ing their marriage. as a result, their two daughters are sold. her eldest daughter ellen makes the same choice as clotel upon realizing “for what purpose she had been bought”. ellen’s younger sister jane is similarly purchased by a wealthy young man to be sexually exploited. she, ulti- mately, dies of a broken heart. in the end, after living lives characterized by exploitation, manipulation, and assault, each of brown’s heroines dies a tragic death. turning from fictional examples of the sexual exploitation and victimization of enslaved women and girls, while frederick douglass, in his narrative of the life of frederick douglass, avoids overtly discuss- ing the practice, there is one scene which stands out as a particularly gut-wrenching example – the whipping of aunt hester. douglass’ aunt hester was a uniquely beautiful woman. as he describes: “she was a woman of noble form, and of graceful proportions, having few equals, and few superiors, in personal appearance, among the colored or white women of our neighborhood”. as a result, she unfortunately catches the attentions of their master. douglass is rather demure in elaborating upon these attentions, simply leaving his readers to intuit the facts for themselves: “why my master was so careful of her, may be safely left to conjecture”. however, it may be safely assumed that their master was sexually assaulting or harassing hester is some form, especially consid- ering how closely he policed her independent sexuality: he had ordered her not to go out evenings, and warned her that she must never let him catch her in company with a young man, who was paying at- tention to her belonging to colonel lloyd. the young man’s name was ned roberts, generally called lloyd’s ned. hester does not heed these commands and continues to visit lloyd’s ned. as a result, as douglass details, one night she “happened to be ab- sent when [their] master desired her presence” and was found with ibid., . frederick douglass, narrative of the life of frederick douglass: an american slave, written by himself (new york: simon & schuster paperbacks, ): . ibid. ibid. ibid. denial of consent: the modern heir of sexual violence within slavery ned. douglass and hester’s master is enraged, both that he was not able to satisfy his sexual desires when he wished, and because hester had the nerve to seek her own satisfaction elsewhere. what follows is a brutal scourging that is both difficult to read and difficult to imagine a woman enduring: before he commenced whipping aunt hester, he took her into the kitch- en, and stripped her from neck to waist, leaving her neck, shoulders, and back, entirely naked. he then told her to cross her hands, calling her at the same time a d–d b–h. after crossing her hands, he tied them with a strong rope, and led her to a stood under a large hook in the joist, put in for the purpose. he made her get upon the stool, and tied her hands to the hook. she now stood fair for his infernal purpose. her arms were stretched up at their full length, so that she stood upon the ends of her toes. he then said to her, “now, you d–d b–h. i’ll learn you how to disobey my orders!” and after rolling up his sleeves, he commended to lay on the heavy cowskin, and soon the warm, red blood (amid heart-rending shrieks from her, and horrid oaths from him) came dripping to the floor. this is hester’s punishment for failing to bend to her master’s every whim; for failing to allow herself to be unconditionally sexually available to him. what this scene contradicts, more than any other concept, is the absolutely ludicrous notion that enslaved women and girls were capable of consenting to sexual relationships with their masters within the in- stitution of slavery. they had no options. they had no rights or liberties. a man could rape them or brutalize them. as long as the man was their master, it was his choice – not theirs. in her fictionalized retelling of her own experiences within the institution of slavery, incidents in the life of a slave girl, through the pseudonym linda, harriet jacobs details the sexual harassment she faced at the hands of her owner, dr. flint. upon turning fifteen her life dramatically shifts as she is thrust from the meager protections of girl- hood into the almost complete vulnerability of enslaved womanhood. the slave girl is abandoned by society – abandoned by mankind – to “be- come prematurely knowing of evil things”. the slave girl quickly learns “to tremble when she hears her master’s footfall”; she quickly learns “she is no longer a child”. in jacobs’ case, flint begins to “whisper foul words in [her] ear” and fill her “young mind with unclean images” in ibid., – . harriet jacobs, “incidents in the life of a slave girl,” in the classic slave narra- tives, ed. henry louis gates, jr (new york: signet classics, ): . ibid. michaela kleppinger order to “corrupt the pure principles [her] grandmother had instilled” . jacobs does her best to combat flint’s advances; however, as she reminds her readers, as his slave she is particularly vulnerable: but he was my master. i was compelled to live under the same roof with him – where i saw a man forty years my senior daily violate the most sacred commandments of nature. he told me i was his property; that i must be subject to his will in all things. my soul revolted against the mean tyranny. but where could i turn for protection? no matter whether the slave girl be as black as ebony or as fair as her mistress. in either case, there is no shadow of law to protect her from insult, from violence, or even from death; all these inflicted by fiends who bear the shape of men. in an effort to break jacobs’ resolve, using diction reminiscent of brown’s horatio green, flint makes promises to “cherish” jacobs’ and treat her as a “lady”. he even begins building jacobs’ her own house “in a secluded place” outside of town for their sole use and privacy – effectively prom- ising to make her his mistress. jacobs escapes the clutches of dr. flint, but not before being forced by circumstance into a less detestable form of sexual exploitation at the hand of mr. sands, which produces two children. emancipation and the sedimentation of stereotypes of black female sexuality following the course of history, emancipation would, unfortunately, not save black women and girls from sexual exploitation and victimization at the hands of white men. as estelle b. freedman writes in her chap- ter “african americans redefine sexual violence” from redefining rape: “from the day they were liberated to the present time, prepossessing young colored girls have been considered the rightful prey of white gen- tlemen in the south, and they have been protected neither by public sen- timent nor by law”. as one southern african american woman wrote to a white magazine in the s, “few colored girls reach the age of sixteen without receiving advances” . while no longer subject to the same power dynamics present within the institution of slavery, with the emergence of jim crow era segregation and discrimination, black wom- jacobs, “incidents in the life of a slave girl,” . ibid. ibid., . ibid., . freedman, “african americans redefine sexual violence,” . ibid., . denial of consent: the modern heir of sexual violence within slavery en and girls continued to be left unprotected by the law and society. one educator, anna julia cooper, expressed her concerns in , by describ- ing “the promising “colored girls of the south” who lived “in the midst of pitfalls and snares, waylaid by the lower classes of white men”. espe- cially in the reconstruction years immediately following the civil war, “white men raped black women with impunity” as a means of revenge for their perceived losses. furthermore, young black girls continued to be sexually exploited within the homes of wealthy white men. activist fannie barrier williams reported receiving frantic letters from mothers desperately asking for help for their daughters “to save them from going into the homes of the south as servants, as there is nothing to save them from dishonor and degradation” . as in slavery, black women and girls continued to be targets of sexual predators. potentially the most dangerous concept that has emerged out of this history and culture of sexual exploitation and victimization is confused notions of consent. there have been considerable efforts in the post-slav- ery years to label enslaved women who had sexual relationships with their owners as mistresses. this is dangerous, simply put, because words have meaning – labels have meaning. the fifth edition of webster’s colle- giate dictionary defines a “mistress” as “a woman paramour” . the more contemporary dictionary.com similarly defines a “mistress” as “a wom- an who has a continuing, extramarital sexual relationship with one man, especially a man who, in return for an exclusive and continuing liaison, provides her with financial support” . the problem with applying this label to enslaved women is that it implies mutual consent, despite the reality that any form of sexual contact within the institution of slavery was, if not assault, at least extremely exploitative. even brown, who ef- fectively and emotionally described the sexual exploitation and victimi- zation of enslaved women and girls in clotel, voiced similar sentiments within the novel: reader, when you take into consideration the fact, that amongst the slave population no safeguard is thrown around virtue, and no inducement held out to slave women to be chaste, you will not be surprised when we tell you that immorality and vice pervade the cities of the southern states in a man- ner unknown in the cities and towns of the northern states. indeed most of ibid. ibid. freedman, “african americans redefine sexual violence,” . “mistress,” webster’s collegiate dictionary, th edition ( ): . “mistress,” dictionary.com. michaela kleppinger the slave women have no higher aspirations than that of becoming the finely dressed mistress of some white man. disproportionate power dynamics between an enslaved woman and her master rendered her incapable of consenting to a sexual relationship – any other perspective undermines the horrific reality of the trauma and abuse these women and girls experienced. looking back, specially at the case of thomas jefferson and sally hemings, many scholars and historians have desired to label hemings as jefferson’s mistress – to impose some sort of consensual and affectionate relationship upon them. however, as mentioned previously, what these romantic notions fail to consider is that, within bondage, a woman was incapable of consenting to any sort of sexual contact with the man who owned her. furthermore, regardless of the idealistic image of thomas jefferson that has been propagated throughout the united states with- in classrooms and the media at large, he unquestionably took advan- tage and exploited the young woman under his power. thomas jefferson first met sally hemings, the enslaved daughter of his father-in-law and half-sister of his deceased wife, in , when “she was fourteen and he was forty-four” . hemings was, at the time, undoubtably, still a child. calling enslaved women mistresses completely erases the reality of their victimization at the hands of white men. this victim blaming, while a rather contemporary term, is not a con- temporary idea. within the institution of slavery as well as the years following their emancipation, african american women and girls were blamed for their own violation, both by their communities and society at large. looking to mrs. flint as an example, she tells a young enslaved girl, on the brink of death following the birth of a child fathered by dr. flint: “you suffer, do you?” […] i’m glad of it. you deserve it all, and more too”. when the girl’s mother expresses a wish for her daughter and grandchild to “soon be in heaven,” mrs. flint cruelly asserts that “there is no such place for the like of her and her bastard”. mrs. flint blames this young girl for her own violation at the hands of dr. flint— as if the child courted and encouraged the predator’s attentions. there were some individuals who even believed, like mrs. flint, most notably frances kellor, that “enslavement made all black women less capable of leading moral, respectable lives”. kellor further blamed african amer- brown, clotel, – . levine, “thomas jefferson and sally hemings,” . jacobs, “incidents in the life of a slave girl,” . ibid. cheryl d. hicks, “i want to save these girls: single black women and their pro- tectors, – ,” talk with you like a woman: african american women, justice, and denial of consent: the modern heir of sexual violence within slavery ican women and girls, “without considering that women might resist harassment and rape” by stating that “negro women yield to white men quite as readily as in slavery” . it is from these roots of coercion and sexual assault that the myth of the inherently sexually immoral black female was born. instead of making an attempt to counteract these vicious stereotypes, following emancipation and into the twentieth century, many individu- als among the african american community demonized and condemned lower class black women whom they judged to be immoral. many mid- dle-class black women “who claimed their rights to sexual respectabil- ity often contrasted their own morality with that of lower class black women”. these women suggested that the “sexual behavior” of low- er-class black women “discredited the race” . in harriet jacob’s nar- rative, while her children ultimately serve as her motivation to escape from bondage, in freedom their existence labels her as sexually immoral and promiscuous – as was considered the case for many single moth- ers. when she is honest regarding the choices she was forced to make as a slave, including the conception of her children, the minister mr. durham cautions her: “your straightforward answers do you credit; but don’t answer everybody so openly. it might give some heartless people a pretext for treating you with contempt”. even prominent leaders and intellectuals, like w.e.b. du bois, “emphasized that single black women in the city jeopardized the stability of black families”. using rhetoric and ideals very similar to those espoused by actors of rape culture today, many individuals, both from within and outside of the black community, “sought to assist and instruct young black women” in how to avoid becoming victims instead of condemning their victimizers. women like jacobs, women who has escaped slavery but not without certain scars, were judged and blamed for the paths their lives had taken – for the con- sequences of their own exploitation and victimization. as a result, in contrast to the mainstream african american commu- nity, there were some outspoken activists, mainly black women, who desired to expose the hypocrisy of white male views of female virtue and chastity and combat the stereotypes that demonized black women and girls. for example, ida b. wells pointedly criticized the “southern reform in new york, – (chapel hill: university of north carolina press, ), . hicks, “i want to save these girls,” . freedman, “african americans redefine sexual violence,” . ibid., . jacobs, “incidents in the life of a slave girl,” . hicks, “i want to save these girls,” . ibid. michaela kleppinger sensitivity to women’s honor” , that led to the lynching of scores of black men as a result of accusations of raping white women, while they par- ticipated and continued to participate in the violation of black women and girls without consequences. wells acutely wrote: “virtue knows no color line, and the chivalry which depends upon complexion of skin and texture of hair can command no honest respect”. wells, and her fellow african american female activists, understood the danger that notions of black female sexual immorality could have as “reformers dedicated to protecting young women from moral dangers often found themselves characterized by black men and white society as immoral, or at least morally questionable” . wells, and other women like her, understood that all black women felt the consequences of “blanket accusations of immorality” that denied the accomplishments of, in her words: “moth- ers, wives and maidens who have attained a true, noble, and refining womanhood” . harriet jacobs was one of these mothers who had over- come adversity and societal prejudice in order to provide for her chil- dren. as she ends her narrative: “reader, my story ends with freedom; not in the usual way, with marriage. i and my children are now free!” . jacobs is acutely aware that she will always be condemned and excluded by large segments of her own community. regardless of her accomplish- ments, she will always be judged for her particular path to motherhood and the circumstances that surrounded this path. these stereotypes of black female immorality, like the jezebel, sought to undermine the credibility of black women and girls. the jezebel being “one of the most overtly sexual images of african american women to have emerged […] is often depicted as a “mulatto” woman with light skin and long hair” and “perceived as seductive, manipulative, and una- ble to control her sexual drives” . in order to combat these stereotypes, wells and other activists “employed a range of arguments to defend the respectability of black women, including an insistence that white men should be held accountable for interracial assaults” as they “agreed that white men deserved most of the blame for the sexual degradation of women of their race”. however, despite their best efforts, there con- tinued to be “cases of white men who got away with the rape of black freedman, “african americans redefine sexual violence,” . ibid. hicks, “i want to save these girls,” . freedman, “african americans redefine sexual violence,” – . jacobs, “incidents in the life of a slave girl,” . tiffany g. townsend, torsten b. neilands, anita jones thomas, and tiffany r. jackson, “i’m no jezebel; i am young, gifted and black: identity, sexuality, and black girls,” psychology of women quarterly ( ): . freedman, “african americans redefine sexual violence,” . ibid., . denial of consent: the modern heir of sexual violence within slavery women and girls”. at best these men received “light sentences” . in most cases, the perpetrator never made it to trial as grand juries refused “to indict white men for rape”. the complete lack of consequences faced by white men for raping black women and girls, and the labeling of them as inherently sexually experienced, effectively made them the perfect victims. denial of consent as manifest today looking at the treatment faced by black women and girls today, espe- cially those enmeshed in disadvantaged communities who have been virtually abandoned by the police, it is careless to ignore the reality of their risk for sexual victimization. in the lives of these women and girls “the threat of sexual violence [is] a common theme”. as one adolescent black girl named britney explained in jody miller’s sociological study getting played: african american girls urban inequality and gendered violence: we face…a lot of stuff. males, if you don’t want to give it up they’ll probably try to take it. if you walking by yourself and in the dark they’ll probably ap- proach you and want to, you know what i’m saying, do something with you. that’s why you don’t never walk by yourself after dark. approximately “ % of girls […] reported having been forced to have sexual intercourse at some time in their lives” – “african americans girls report[ing] higher rates of involuntary first intercourse than their european and latina counterparts” . as previously alluded, the great- est threat these stereotypes continue to pose is that they have “made black women more vulnerable to sexual assault”. by discounting and discrediting their word. rape culture is a concept typically roughly de- fined as “a set of values and beliefs that promote an environment condu- cive to rape”. these labels and stereotypes of black female immorality, that originated within the institution of slavery, are interwoven with rape culture; they have created “an environment conducive to rape” by ibid. ibid. ibid. jody miller, getting played: african american girls urban inequality and gen- dered violence (new york: new york university press, ), . ibid. townsend, neilands, thomas, and jackson, “i’m no jezebel,” . freedman, “african americans redefine sexual violence,” . miller, getting played, . michaela kleppinger “shap[ing societal] perceptions of black womanhood” and influencing “the way in which others value and interact with them”. it is much easier to get away with raping a woman who society already considers sexually deviant and desiring of such ill-treatment. furthermore, in a society that does not place value in the va- lidity of their word, these women and girls have been forced to remain silent. they have been forbidden to voice their traumas – forbidden to name their abusers – “lest any discussion of sexuality contribute to neg- ative depictions of their morality”. in more contemporary examples, the words of desiree washington and anita hill were both disregarded when they dared to name their assailants. instead of coming to the aid of these women, the african american community and greater society defended mike tyson and clarence thomas. tyson’s supporters claimed, “that he was being “railroaded” by a vengeful woman and a biased judi- cial system” and that her charges “were detrimental to african ameri- cans in general, and black men in particular”. the religious leaders of the national baptists convention usa even asked their congregations “to ignore washington’s allegations” . these actions and the reactions of african americans to the assault of a woman from their own commu- nity, highlight specifically how “the marginalization of african american women” has eliminated “their right to protection from sexual assault” and effectively “erased their ability to refuse consent”. as in the institu- tion of slavery, african american women and girls continue to be left to fend for themselves against a world populated by predators. conclusion in his introduction discussing thomas jefferson and sally hemings, rob- ert levine posed the question: “what sort of culture celebrated human equality and then countenanced slavery and the practice of rape?” . while levine is specially referring to the united states of the revolu- tionary era, his question still has resonance for the current state of the country. segments of white society have, since emancipation, unceasing- ly called for an end to the discussion of the institution of slavery. they believe, or would like to convince others to believe, that the institution hicks, “i want to save these girls,” . townsend, neilands, thomas, and jackson, “i’m no jezebel,” – . freedman, “african americans redefine sexual violence,” . king, “prematurely knowing of evil things,” . ibid. ibid. freedman, “african americans redefine sexual violence,” . levine, “thomas jefferson and sally hemings,” . denial of consent: the modern heir of sexual violence within slavery of slavery is no longer relevant, that it was hundreds of years ago and should be allowed to fade into the recesses of the country’s past. however, words have power. history has power. they each, in their own way, form present understandings. black women and girls continue to live with the consequences of slavery – to live with the consequences of the exploita- tion and victimization of their ancestors at the hands of white men. while simply acknowledging and recognizing the weight of these evils will not erase the dangers these women and girls face, it is a place to start. bibliography brown, william wells. clotel; or, the president’s daughter: a narrative of slave life in the united states. ed. robert s. levine. bedford / st. martin’s, . douglass, frederick. narrative of the life of frederick douglass: an american slave, written by himself. new york: simon & schuster paperbacks, . freedman, estelle b. “african americans redefine sexual violence.” redefining rape, harvard: harvard university press, , – . hicks, cheryl d. “i want to save these girls: single black women and their pro- tectors, – .” talk with you like a woman: african american women, justice, and reform in new york, – , chapel hill: university of north carolina press, , – . jacobs, harriet. “incidents in the life of a slave girl.” the classic slave narra- tives. ed. henry louis gates, jr. new york: signet classics, . – . king, wilma. “’prematurely knowing of evil things’: the sexual abuse of afri- can american girls and young women in slavery and freedom.” the journal of african american history, vol. , no. (july ): – . levine, robert s. “thomas jefferson and sally hemings.” clotel or the pres- ident’s daughter, by william wells brown, boston: bedford/st. martin’s, , – . martineau, harriet. “morals of slavery.” clotel or the president’s daughter, edit- ed by robert s. levine, boston: bedford/st. martin’s, , – . miller, jody. getting played: african american girls urban inequality and gen- dered violence. new york: new york university press, . “mistress.” dictionary.com. “mistress.” webster’s collegiate dictionary. th ed., . . townsend, tiffany g., neilands, torsten b., thomas, anita jones, & jackson, tiffany r. “i’m no jezebel; i am young, gifted and black: identity, sexuality, and black girls.” psychology of women quarterly, vol. ( ): – . michaela kleppinger odmowa zgody: współczesny spadkobierca przemocy seksualnej w obrębie niewolnictwa abstrakt instytucja niewolnictwa jest skazą na historii i psychice stanów zjednoczonych oraz ich mieszkańców. w istocie polegała ona na braku równowagi sił między zniewolonym podmiotem a właścicielem niewolnika. zdolność osoby zniewolo- nej do wyrażania własnej woli praktycznie nie istniała, co pozwalało właścicie- lom niewolników, białym mężczyznom, korzystać ze zniewolonych kobiet oraz dziewcząt. historia niewolnictwa w stanach zjednoczonych obfituje w opowie- ści o wykorzystywaniu seksualnym i wiktymizacji dokonywanych przez drapież- nych białych mężczyzn, bez namysłu czy dbania o dobro kobiet i dziewcząt, któ- re gwałcili i wykorzystywali. to właśnie z tych korzeni: przymusu i przemocy, wyłoniły się mity i stereotypy głoszące niemoralność seksualną czarnych kobiet, prowadzące do ich dyskredytowania i bagatelizowania ich woli. przez stulecia biali mężczyźni i ogół społeczeństwa ignorowali i tłumili tę historię, starając się uniknąć odpowiedzialności i odmawiając przyznania się do winy, pozostawiając czarne kobiety i dziewczęta narażone na niebezpieczeństwo i wiktymizację. to niesprawiedliwość, która w faktycznie pozbawiła je prawa do odmowy zgody. słowa kluczowe: napaść na tle seksualnym, przemoc, niewolnictwo, wykorzy- stywanie, kobiety. michaela kleppinger jest absolwentką george washington university z tytułem magistra literatury angielskiej w columbian college of arts and sciences. jej badania koncentrują się na analizowaniu przedstawień kobiet w literaturze, szerzej zaś: w kulturze, w obrębie problemów przemocy i wykorzystywania. obecnie mieszka w maryland ze swoim kotem georgie. denial of consent: the modern heir of sexual violence within slavery summary the institution of slavery is a stain upon the history and the psyche of the unit- ed states and its people. at its core, it was inherently reliant upon an imbalance of power between the enslaved subject and the slave owner. the enslaved in- dividual’s capacity to assert their own will was virtually nonexistent, allowing white male slave owners the opportunity to exploit this discrepancy in order to take advantage of the enslaved women and girls under their dominion. the his- tory of slavery in the united states is burgeoning with stories of sexual exploita- denial of consent: the modern heir of sexual violence within slavery tion and victimization at the hands of predatory white men without a thought or care for the well-being of the women and girls they violated and abused. it is from these roots of coercion and violence that myths and stereotypes proclaim- ing the sexual immorality of black women emerged, resulting in the discrediting and discounting of their word. for centuries, white men and society at large have ignored and repressed this history in an effort to avoid blame and deny culpability, leaving black women and girls vulnerable and targets of further vic- timization—an injustice that has veritably stripped them of their right to refuse consent. keywords: sexual assault, violence, slavery, exploitation, women michaela kleppinger is a recent graduate of the george washington universi- ty with a master’s in english literature from the columbian college of arts and sciences. her research centers on interrogating representations of women in liter- ature, and culture more broadly, within instances of violence and exploitation. she currently resides in maryland with her cat georgie. editorial evolution explanation of the relevance of the astonishing advances in molecular genetics to neurological practice. we hope that this series will stimulate not just interest but lively debate in our correspondence section. the neurological management series will also be published as a book in due course. these changes will not deflect the journal from its main task of publishing the best papers in clinical neuro- logical, neurosurgical, and neuropsychiatric science. previous changes have been followed by gratifying improvements in the position ofjnnp in various citation indices. if the copy of the journal that you are reading is not your own, check whether your membership of your national neurological society entitles you to an individual subscription at a discount that is almost half price. rac hughes department ofneurology, umds, guy's hospital, london sei rt, uk neurological stamp casper wistar ( - ) caspar wistar obtained his medical education at the university of the state of pennsylvania in the united states and at edinburgh university in the united kingdom, where he was twice president of a student organisation, the royal medical society. he also assisted in organising a natural history society. he returned to the united states, practised in philadelphia and, in , was appointed professor of chemistry, later professor of anatomy, surgery, and midwifery, and then professor of anatomy. wistar described the ethmoid bone. his text book a system of anatomy for the use of students of medicine (two volumes, - ) was the first such american work. he had weekly library gatherings at his home with members of the american philosophical society to which, in , he succeeded thomas jefferson as president. these famous meetings, which continued after his death, were known as wistar parties. wisteria, a high-climbing, woody vine of the pea family, native to china, japan, and eastern north america, was named after wistar by the botanist and ornithologist thomas nuttal. a japanese stamp issued in shows the wisteria vine (stanley gibbons , scott a). l f haas _w w w, w_w_w.-w w w uwiw-w p p -' k, w - .;:. ., i aban -̂ i^ ^k^ ow i a a * o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://jn n p .b m j.co m / j n e u ro l n e u ro su rg p sych ia try: first p u b lish e d a s . /jn n p . . . o n ja n u a ry . d o w n lo a d e d fro m http://jnnp.bmj.com/ evolution of hiv- resistance to a cholesterol-linked d-peptide fusion inhibitor a sunday, february , is currently unknown. in this work, we use density gradient centrifugation and liposome coflotation analysis to demonstrate that the anchoring energy of the dengue e protein in anionic membranes composed of popcþpopg is much greater than in membranes composed of popcþpope. -pos board b hiv fusion peptide perturbs membrane structure in a cholesterol dependent fashion alex liqi lai, jack h. freed. acert, cornell university, ithaca, ny, usa. the fusion between viral envelopes with host cell membranes is required for viral entry and infection, which is mediated by special glycoproteins anchored on the viral membrane. fusion peptide (fp) is the domain that initiates mem- brane fusion. however, the mechanism of membrane fusion is still unclear. we previously found that the influenza hemagglutinin fp increases the order of dmpc lipid bilayer. we hypothesize that inducing lipid ordering might be a critical step in fusion caused by a variety of fusion proteins. hiv gp fp plays a similar role as influenza ha fp. however, gp fp is polymorphic and changes from alpha helix to beta aggregation as cholesterol concentration in lipid increases. we used pc spin labels on the lipid head group and different positions on the acyl chain to detect the perturbation by gp fp to popc/ popg lipid bilayers with different cholesterol concentration ( % to %) by cw-esr. our data show that ) gp fp affects the lipid order in the same pat- tern as ha fp does, i.e., a cooperative effect vs. lipid/peptide ratio, thus sup- porting our hypothesis; ) gp fp induces membrane ordering in all tested lipid compositions, consistent with promoting membrane fusion in these com- positions; ) in the high cholesterol containing lipid bilayers, whereas gp fp is in the beta aggregation conformation, its effect on the lipid ordering reaches deeper into the bilayer, consistent with deeper membrane insertion for gp fp in this conformation. we are extending the esr studies to look for coexisting membrane microdomains induced by different conformations of fps and the fp partitioning between them and for precise separation of the effects of ordering and molecular motion. -pos board b cd binding induces an asymmetric transition of hiv- env from its native conformation into the prehairpin intermediate state mukta d. khasnis, konstantine halkidis, anshul bhardwaj, michael root. thomas jefferson university, philadelphia, pa, usa. hiv- membrane fusion is mediated by sequential binding of the viral homo- trimeric env (gp /gp ) to cellular cd and chemokine receptor (cxcr or ccr ). these binding events coordinate conformational transitions of the gp trimer from its native conformation into a prehairpin intermediate state (phi) and, subsequently, into its fusogenic trimer-of-hairpins structure (toh). in the phi, the gp trimer assumes an extended conformation that bridges the viral and cellular membranes, and exposes the n-hr and c-hr do- mains which are targeted by hiv- fusion inhibitors t and -helix, respec- tively. our previous work suggests that the phi-to-toh transition occurs in a concerted (symmetric) fashion. here, we investigate the transition from the native state to the phi using a functional complementation strategy that em- ployed heterotrimeric envs containing only one or two functional cd - and chemokine receptor-binding sites. additionally, by incorporating t - and -helix- resistance mutations into individual env protomers, we were able to interrogate exposure of discrete gp n-hr and c-hr domains. our data indicate that a single cd binding to an env trimer is sufficient to promote fusion. moreover, the first cd binding event appeared to expose only one of three possible binding sites for each fusion inhibitor, suggesting an asymmetric transition into the phi. this asymmetry was significantly more pronounced in the gp n-hr region compared to the gp c-hr region. these results can be used to explain the multiphasic titration of mutant env homotrimers that naturally form asymmetric n-hr domain structures. taken together, these data suggest that the native state-to-phi transition of env occurs in a multistep (asymmetric) fashion. -pos board b evolution of hiv- resistance to a cholesterol-linked d-peptide fusion inhibitor amanda e. siglin , nicholas francis , michael s. kay , micheal j. root . thomas jefferson university, philadelphia, pa, usa, university of utah, salt lake city, ut, usa. during hiv- entry, the n-hr and c-hr regions of the gp viral glycoprotein associate to form a trimer-of-hairpins critical for membrane fusion. the n-hr region contains a highly conserved hydrophobic pocket that is the target for a multivalent, d-peptide fusion inhibitor, pie -trimer. recently, a modified form of this inhibitor with a conjugated cholesterol (chol-pie -trimer) was shown to possess up to -fold increased potency, presumably due to mem- brane targeting. here, we determined the resistance profile of chol-pie - trimer starting from either inhibitor-naı̈ve or pie -trimer-resistant hiv- (nl - strain). viral propagation in increasing inhibitor concentrations pro- duced hiv- populations with - to -fold reduced sensitivity chol- pie -trimer. these viruses were also resistant to the parental, unconjugated inhibitor pie -trimer. using hiv- fusion inhibitors di-c and -helix, we were able to interrogate the effect of escape mutations on the exposure of the gp n-hr and c-hr regions, respectively. resistance to chol-pie - trimer resulted in a slight decrease in the temporal window of n-hr exposure, regardless of the starting viral population. exposure of the c-hr region was unchanged for resistant viruses generated from the inhibitor-naı̈ve viral pool. by contrast, the temporal window of c-hr exposure was significantly increased (> -fold) for resistant viruses that were generated from the pie -trimer-resistant viral pool. efforts to identify the mechanisms of chol- pie -trimer resistance and the decoupling of n-hr and c-hr exposure are underway. -pos board b fusogenic activity of the hiv- gp mper-tmd region: mechanism and targeting by immunogens and inhibitors jose l. nieva , beatriz apellaniz , carmen domene , nerea huarte , eneko largo . biophysics unit (csic-upv/ehu) and dept. of biochemistry, university of the basque country (upv/ehu), bilbao, spain, chemistry research laboratory, university of oxford, oxford, united kingdom. fusion of the viral envelope with the cell membrane marks the beginning of the hiv- replicative cycle. this event is targeted by inhibitors currently in clinical use and by preventive vaccines under development. antibodies e and e bind to the gp membrane proximal external region (mper)- transmembrane domain (tmd) junction and block fusion. these antibodies display the broadest viral neutralization known to date, which underscores the conservation and functionality of the mper-tmd region. in recent work, we have described that peptides representing this region have potent membrane-destabilizing effects. here, based on the outcome of vesicle assays, atomic force microscopy studies and molecular dynamics simulations, we propose a mechanism for the involvement of the mper-tmd region in hiv- fusion. in addition, we provide evidence that underpins the poten- tial use of its activity as a new target for inhibitor and immunogen development. -pos board b studies on the membrane-active behavior of outer membrane vesicles from a gram negative bacterium william bartos, rensa chen, donald y. kobayashi, paul r. meers. rutgers, the state university of new jersey, new brunswick, nj, usa. gram-negative bacteria are known to produce small ~ - nm vesicles by ‘‘blebbing’’ of their outer membranes. these outer membrane vesicles (omv) have been implicated in activities such as transmission of virulence fac- tors, horizontal gene transfer and development of biofilms. in this investigation, the interactions of omv from lysobacter enzymogenes (strain c ) with other membranes have been monitored using fluorescent assays for association and/or fusion. defined composition large unilamellar vesicles labeled with the fluorescence resonance energy transfer (fret) pair , -dipalmitoyl-sn- glycero- -phosphoethanolamine-n-( -nitro- - , -benzoxadiazol- -yl) (nbd- pe) and , -dipalmitoyl-sn-glycero- -phosphoethanolamine-n-(lissamine rho- damine b sulfonyl) (rh-pe) were incubated with isolated omv to observe the interaction via the fret ratio of donor/acceptor. omv substantially increased this ratio over the course of about an hour (t / ~ - min.) at �c, when added directly to vesicles comprising disordered or fluid lipids, such as -palmitoyl- -oleoyl-sn-glycero- -phospho-( ’-rac-glycerol) (popg), -pal- mitoyl- -oleoyl-sn-glycero- -phosphoethanolamine (pope) or -palmitoyl- - oleoyl-sn-glycero- -phosphocholine (popc). this apparent fusion was much more limited or absent with liquid ordered membranes of , -dipalmitoyl-sn- glycero- -phosphocholine/cholesterol (dppc/chol). in the case of popg/ pope / vesicles, apparent fusion was also confirmed by testing vesicles with exclusively inner monolayer fluorescent probes to diminish any fluores- cence changes from external interactions of outer monolayer fluorophores. when the omv were labeled with the fluorophore , -dioctadecyl- , , , - tetramethylindocarbocyanine, and incubated with a natural host, yeast cells (strain s ), association and/or fusion was observed by co-sedimentation of the omv label with yeast cells. these studies may help to elucidate the mech- anism of natural host-pathogen interactions and define the lipid specificity for 	hiv fusion peptide perturbs membrane structure in a cholesterol dependent fashion 	cd binding induces an asymmetric transition of hiv- env from its native conformation into the prehairpin intermediate state 	evolution of hiv- resistance to a cholesterol-linked d-peptide fusion inhibitor 	fusogenic activity of the hiv- gp mper-tmd region: mechanism and targeting by immunogens and inhibitors 	studies on the membrane-active behavior of outer membrane vesicles from a gram negative bacterium corr insights®: custom acetabular cages offer stable fixation and improved hip scores for revision tha with severe bone defects corr insights : custom acetabular cages offer stable fixation and improved hip scores for revision tha with severe bone defects thomas jefferson blumenfeld md where are we now? t he ideal reconstructive method for the severely deficient acetabulum in revision tha remains unsolved. severe acetabular deficiencies may be evaluated by the paprosky et al. [ ] grading system from which both the anticipated bony defects and the reconstruction needs may be identified. fortunately, the incidence of severe acetabular deficiency is low, with a report from the mayo clinic finding that paprosky iiib defects occurred in only . % of hips ( / ) undergoing revision acetabular surgery at that ter- tiarycarecenterbetween – [ ]. most acetabular reconstructions are performed with a large hemispherical shell with a survivorship range of % to % at mid- to long-term followup [ ]. for acetabuli with greater bony loss, porous metal augments may be added, allowing the creation of a bony and metal concavity supportive of a hemispherical shell. as the defect worsens, more-elaborate options come into the picture, perhaps including custom acetabular cages (or triflange cups), reconstruction cages, cup-cage constructs, or cup-cup constructs. surgeons must recognize the high surgical complexity when contemplat- ing using one of these approaches, as complications can be severe, and unrecognized or untreated pelvic dis- continuities can result in a high risk of failure. during more than a -year period, the authors of the current study reported the surgical treatment of patients (all with type iiib defects, four with a pelvic discontinuity) who underwent acetabular reconstruction using a grit- blasted titanium custom cage. at a mean followup of months (range, months to months) in patients only one cage was felt to be possibly loose, and the authors reported the appearance of particulate allograft incorporation in of patients. one important caveat of this study is that this was the first revision surgery for all but one patient. we can compare the results in this series to other reports about severe acetabular defects, which used other approaches, namely reconstruction cages, or custom triflange cups. in a single-surgeon series, reconstruction cages failed in % of reconstructions at mean . -year followup, with the highest failure rates occurring in hips with american academy of orthopaedic surgeons (aaos) type this corr insights is a commentary on the article ‘‘custom acetabular cages offer stable fixation and improved hip scores for revision tha with severe bone defects’’ by li and colleagues available at: doi: . /s - - - . the author certifies that he, or any member of his immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/ licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. all icmje conflict of interest forms for authors and clinical orthopaedics and related research editors and board members are on file with the publication and can be viewed on request. the opinions expressed are those of the writers, and do not reflect the opinion or policy of corr or the association of bone and joint surgeons . this corr insights comment refers to the article available at doi: . /s - - - . t. j. blumenfeld md (&) sutter medical center, k street, suite , sacramento, ca , usa e-mail: tblumenfeld @gmail.com corr insights published online: december � the association of bone and joint surgeons clin orthop relat res ( ) : – / doi . /s - - - clinical orthopaedics and related research® a publication of the association of bone and joint surgeons® http://dx.doi.org/ . /s - - - http://dx.doi.org/ . /s - - - http://dx.doi.org/ . /s - - - http://crossmark.crossref.org/dialog/?doi= . /s - - - &amp;domain=pdf http://crossmark.crossref.org/dialog/?doi= . /s - - - &amp;domain=pdf iv (pelvic discontinuity) defects [ ]. in these reconstructions, even with the use of structural allograft, three cages loosened, two flange fractured, and a pelvic dissociation remained in two reconstructions. similar results were shown by perka et al. [ ] who reported that three of revisions for grade iiib defects failed at a mean of . years. where do we need to go? these failures, in my opinion, are not secondary to the concept of spanning a deficient acetabulum with a large metal frame, but due to the loss of either ischial fixation, or malleable flange fracture, both possibly related to the use of materials of inadequate strength. material issues and fixation can be addressed by the use of a cus- tom triflange. christie et al. [ ] reported on acetabular reconstruc- tions performed with a custom triflange component of which involved an aaos type iv defect. at mid-term followup % ( / ) of the reconstructions showed healing of the pelvic discontinuity. similar results have been reported [ ] with those authors suggesting posterior column plating of the discontinuity. therefore, both the current report, and prior data, would suggest three key elements for success: material rigidity, fixation stability, and creation of a custom implant that attempts to reproduce the joint center. whether filling the acetabular defect with metal or as in the current report, allografting of the defects, will lead to improved long- evity, remains unanswered. these unique reconstruction situa- tionspointtothreeresearchneeds:( )to confirm that we are comparing apples to apples in terms of the defects being studied, ( ) to identify the implant most likely to result in a durable long-term reconstruction for type iiia and iiib defects, and ( ) to try to lower the cost when a custom implant is needed. how do we get there? regarding the first unmet need, while the paprosky classification system has concrete radiographically identifiable guidelines which allow discrimination between a type iia/b and iiia/b defect, decisions are subjective. the preoperatively identified paprosky clasification has been shown to corelate to the intraoperativley identified acetabular defect volume [ ]. a prospective study that included the preoperative paprosky defect classifi- cation, the intraoperative bony defects identified, and the implant(s) used, might allow further refinement of the classification system. although the data on the use of one or more augments and a porous metal acetabular component appear extremely promising [ ], in order to satisfy the second unmet need, we need long-term data (a minimum of years) before concluding that the majority of type iiia defects can and should be man- aged in this fashion. finally, what to do for the most-sev- ere defects remains unsolved and it remains up to the discretion of the sur- geon whether to use a reconstruction cage, the custom implant as described by li et al., or a custom triflange cup. the apparent reconstructive answer at this time is that the implant needs to be structurally rigid, and obtain bony fixa- tion. one may consider these custom implants to be analogous to ‘‘orphan drugs,’’ in that these devices are rela- tively rarely used and so there is little incentive for implant vendors to keep the prices down. the general cost from the time of ct scanning to custom implant creation is more than usd . therefore, it seems rational to try to create an off-the-shelf reconstruction cagethatincorporatesthe benefitsshown with the use of custom implants, without the need for component fabrication for individual patients. references . berry dj, lewallen dg, hanssen ad, cabanela me. pelvic discontinuity in revision total hip arthroplasty. j bone joint surg am. ; : – . blumenfeld clinical orthopaedics and related research corr insights . blumenfeld, tj. implant choices, technique, and results in revision acetabular surgery: a review. hip int. ; : – . . christie mj, barrington sa, brinson mf, ruhling me, deboer dk. bridg- ing massive acetabular defects with the triflange cup: - to - year results. clin orthop relat res. ; : – . . fernandez-fairen m, murcia a, blanco a, merono a, murcia jr a, ballester j. revision of failed total hip arthroplasty acetabular cups to porous tantalum components: a -year fol- low-up study. j arthroplasty. ; : – . . goodman s, saastamoinen h, nadav s, gross a. complications of iliois- chial reconstruction rings in revision total hip arthroplasty. j arthroplasty. ; : – . . holt ge, dennis da. use of custom triflanged acetabular components in revision total hip arthroplasty. clin orthop relat res. ; : – . . paprosky wg, perona pg, lawrence jm. acetabular defect classification and surgical reconstruction in revision arthroplasty. a -year follow-up eval- uation. j arthroplasty. ; : – . . perka c, ludwig r. reconstruction of segmental defects during revision procedures of the acetabulum with the burch-schneider anti-protrusio cage. j arthroplasty. ; : – . . yu r, hofstaetter jg, sullivan t, costi k, howie dw, solomon lb. validity and reliability of the paprosky acetabular defect classification. clin orthop relat res. ; : – . volume , number , march corr insights corr insights 	corr insightsreg: custom acetabular cages offer stable fixation and improved hip scores for revision tha with severe bone defects 	where are we now? 	where do we need to go? 	how do we get there? 	references the t-cell epitope (tce) algorithm for classifying hla-dpb mismatches does not predict clinical outcomes in hsct table . cumulative incidence (ci) of neutrophil engraftment and median day to anc > . according to day bone marrow s poster session i methods: the study cohort consists of consecutive patients ( matched siblings, unrelated and haplo) with leukemia, saa, and nhl. the median age is years ( - ). conditioning regimens: ) ara-c bucy (n ); ) ara-c buflu (n ). in addition, haplo and urd received either ) ara-c bucy atg (n ) or, ) ara-c buflu atg. (n ) followed by unma- nipulated g-csf mobilized bone marrow and/or peripheral blood (g-bmpb or g-pb). patients used other regimen. gvhd prophy- laxis: csa, mmf and short-term mtx. multiple linear regression models were used for cost analysis. variables considered were: trans- plant type (sibling vs. urd vs. haplo), quality of life (qol), d/r sex match, patient age by decade, comorbidity, diagnoses, disease status pre-transplant, conditioning regimen, graft type, mnc, cd cells, anc and platelet engraftment, agvhd and death. results: the median follow-up was days (range - ). clinical outcomes are shown in the following table. table . clinical outcomes after transplantation sibling urd haplo p composition and chimerism (n ). p value trm day ( - )% ( - )% ( - )% . day bm ci engraftment by bm characteristic for ci trm year ( - )% ( - )% ( - )% . characteristic sub-group (day anc $ . ) (rr , p value) comparison relapse day ( - )% ( - )% ( - )% . relapse year ( - )% ( - )% ( - )% . % total myeloid < % (n ) - % (n ) > % (n ) . dfs day ( - )% ( - )% ( - )% . precursors % ( days) % ( days) %( days) dfs year ( - )% ( - )% ( - )% . in aspirate (rr . , (rr . , reference survival day ( - )% ( - )% ( - )% . (n ) p . ) p . ) survival year ( - )% ( - )% ( - )% . % cellularity in core (n ) < % (n ) % ( days) (rr . , p . ) - % (n ) % ( days) (rr . , p . ) > % (n ) %( days) reference . % total donor chimerism (n ) < % (n ) % ( days) (rr . , p . ) - % (n ) % ( days) (rr . , p . ) % (n ) % ( days) reference . the overall median cost (range) within -day of transplant was , usd ( , – , ). the mean cost ( % ci) of hla matched sibling, urd and haplo was , usd ( , - , ), , usd ( , - , ) and , usd ( , - , ) (p . ), respectively. multivariate cost analysis indicated that qol # , conditioning including flu or flu atg and acute gvhd - correlated with increased cost. conclusion: these data suggest that transplant type (sibling vs. urd vs. haplo) does not significantly effect on the clinical out- comes and -day cost of transplantation. future studies with more patients and longer follow-up are warranted. total donor chimerism in the day bone marrow predicts sustained donor neutrophil engraftment following double unit cord blood transplantation (cbt) avery, s. , voss, m.h. , gonzales, a.m. , lubin, m. , castro- malaspina, h. , kernan, n.a. , scaradavou, a. , hedvat, c. , stevens, c.e. , barker, j.n. memorial sloan-kettering cancer center; memorial sloan-kettering cancer center; memorial sloan-kettering cancer center, new york, ny delayed or failed engraftment is a concern after cbt, even when using double unit grafts. therefore, we analyzed the ability of the day bone marrow (bm) composition and percent donor chimerism to predict sustained donor neutrophil engraftment in recipients of myeloablative double unit cbt. patients (median age years, range - ) were transplanted for hematological malignancies, pre- dominantly acute leukemia. units had infused cell doses of . � tnc/kg/ . � cd cells/kg for the larger unit, and . � tnc/kg/ . � cd cells/kg for the smaller unit, with a donor-recipient hla-match of / (n ), / (n ), and / (n ). the cumulative incidence (ci) of neutrophil engraft- ment was % ( % confidence interval: - ), with patients engrafting with unit and engrafting with . the percentage of to- tal myeloid precursors in the day bm aspirate (median %, range - ), and the percent cellularity in the day bm biopsy (median %, range - ), were both associated with neutrophil engraftment (table ). however, the most critical predictor of engraftment was the percent total donor chimerism (unit# unit# , median %, range - ), regardless if or units were present (table ). sustained engraftment was seen in % of the patients who were % donor at day with a median day to absolute neutrophil count (anc) $ . of days. by contrast, only % of the pa- tients \ % total donor engrafted [median day to anc $ . days with a relative risk (rr) . , p . ]. patients who were \ % donor had especially poor engraftment (table ). the asso- ciation between total donor chimerism and engraftment was inde- pendent of the percentage of myeloid precursors or bm cellularity. in patients (n ) without engraftment by day , a sub-group of particular clinical concern, day total donor chimerism was also significantly associated with subsequent engraftment success (p . ). no patient demographic was associated with total donor chimerism, and the only significant graft characteristic was the in- fused cfu dose of the engrafting unit (p . ). these findings demonstrate the critical importance of the day bm total donor chimerism and are of practical significance in the care of double unit cbt recipients. further, they give interesting insights into dou- ble unit biology and suggest that the hematopoietic potential of the engrafting unit underlies the ability to generate complete donor chi- merism. the t-cell epitope (tce) algorithm for classifying hla-dpb mismatches does not predict clinical outcomes in hsct askar, m., flanagan, p., rybicki, l., kalaycio, m., pohlman, b., andresen, s., dean, r., duong, h., copelan, e., bolwell, b., sobecks, r. cleveland clinic a number of reports suggested the relevance of hla-dpb matching for the outcomes of allogeneic hematopoietic stem cell transplantation (hsct). an algorithm for determining dpb mis- match permissiveness based on t-cell epitopes (tce) has been proposed (zino et al, blood ). according to this algorithm, all dpb alleles are categorized in (tce ) or (tce ) groups based on antigenicity. accordingly dpb mismatches are classified as permissive; non-permissive in gvhd; or non-permissive in hvg direction. objective: to determine whether tce classification is associated with hsct outcomes. the outcomes considered in this analysis are failure to engraft, acute gvhd, chronic gvhd, and overall survival. methods: we analyzed unrelated donor ($ / allele matches at a, b, c, drb ) allogeneic transplants performed in our center be- tween - . hla-dpb mismatches were assessed using both tce and tce versions of the algorithm. recursive parti- tioning analysis with a log-rank splitting method was used to catego- rize tce variables into groups that best predict each outcome. cox proportional hazards analysis was used to identify prognostic factors for each outcome. results: graft failure was significantly highest among recipient with permissive dpb mismatches (ahr . , % ci . - . , p . ) compared to recipients of zero mismatched, gvhd non-per- missive, and hvg nonpermissive dpb mismatched donors. acute gvhd was significantly higher in all dpb mismatches regardless of tce classification (ahr . , % ci . - . , p . ) com- pared zero dpb mismatch. there was no significant association be- tween tce classification and chronic gvhd, or overall survival. poster session i s conclusion: our results indicate an increased risk of acute gvhd in association with dpb mismatch regardless of the tce classifica- tion. tce classification did not correlate with any transplant out- come considered in our cohort. this analysis does not support the clinical relevance of ranking dpb mismatches based on the tce algorithm. a scoring system predicting outcome after unrelated donor stem cell transplantation in primary refractory acute mye- loid leukemia craddock, c.f. , labopin, m. , schmid, c. , mohty, m. , rocha, v. queen elizabeth hospital, birmingham, united kingdom; faculte de medecine st-antoine, paris, france; klinikum augsburg, germany; nantes hospital, nantes, france; hopital st louis, paris, france treatment options for adults with primary refractory aml (pref aml) are extremely limited. whilst sibling allogeneic stem cell transplantation can result in long term survival most pa- tients lack a matched family donor and are destined to die of refrac- tory disease. greater availability of unrelated donors and improvements in supportive care have increased the proportion of patients with pref aml in whom allografting is technically fea- sible but the outcome of unrelated donor transplantation in this population has not been extensively studied. we therefore analysed overall survival in patients with pref aml who underwent unrelated donor transplantation between and with a me- dian follow-up of months ( - ). patients received three or more courses of induction chemotherapy. the median percentage of bone marrow (bm) blasts at transplant was %. the -year overall survival for the whole group was %. in multivariate anal- ysis, fewer than three courses of induction chemotherapy, a lower percentage of bm blasts at transplant and patient cmv seropositiv- ity were associated with improved survival. we used the prognostic factors identified in multivariate analysis to develop a scoring sys- tem. this allowed the delineation of four prognostic groups with survival rates ranging between % and %. this study dem- onstrates an important role for unrelated donor transplantation in the management of selected patients with pref aml and confirms the importance of initiating an urgent unrelated donor search in pa- tients with no matched sibling donor who fail to respond to induc- tion chemotherapy. pre-transplant factors allow the identification of patients with pref aml who are likely to benefit from unre- lated donor transplantation. hla disparity and rapid immune reconstitution do not over- come propensity to relapse in patients undergoing haploi- dentical hematopoietic stem cell transplant (hsct) with persistent disease at the time of transplant grosso, d. , alpdogan, o. , carabasi, m. , colombe, b. , cornett farley, p. , filicko-o’hara, j. , flomenberg, p. , gitelson, e. , kasner, m. , martinez-outschoorn, u. , o’hara, w. , wagner, j.l. , weiss, m. , werner-wasik, m. , flomenberg, n. thomas jefferson university kimmel cancer center, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa while increasing hla disparity is known to be associated with increased risk of significant graft versus host disease (gvhd), there is less data as to whether increasing hla disparity is corre- lated with stronger, clinically significant graft versus leukemia ef- fects. we examined a group of patients with acute leukemia undergoing haploidentical hsct to assess whether ) there was a marked difference in relapse rates based on the degree of hla mismatch and ) if early recovery of donor lymphoid subpopula- tions was associated with less relapse after hla mismatched hsct. thirty-four adult patients with aml ( ) and all ( ) underwent haploidentical hsct between and using a step process which separates the infusion of the lymphoid and myeloid portions of the graft while attempting to render the lymphocytes tolerant utilizing cyclophosphamide. the patients re- ceived x e /kg donor cd cells (dli) after conditioning with either tbi gy (n ) or fludarabine mg/m � , thiotepa mg/m � , and tbi gy (n ). two days after the dli, all patients received cyclophosphamide (cy) mg/kg � followed by a cd selected donor product. the tbi based regimen was given to % of patients with all and % with aml. we exam- ined relapse rates based on the number of antigen mismatches at a, b, cw, and drb in the gvh direction. there were no discern- able differences based on degree of hla disparity with even the most haplodisparate group exhibiting high rates of relapse when disease was present at hsct. in contrast, the presence of active leukemia at the time of hsct had far more impact on subsequent relapse rates (see table). table . outcomes based on degree of hla disparity antigen antigen antigen antigen mismatch mismatch mismatch mismatch number of patients relapsed/ total relapsed/ total relapsed/ total relapsed/ total active disease at hsct ( %) / ( %) / ( %) / ( %) n/a cr at hsct ( %) / ( %) / ( %) n/a / ( %) total / ( %) / ( %) / ( %) / ( %) we also examined the impact of immune recovery on relapse. ab- solute numbers of nk, and cd and cd t cells were examined in the first months post hsct. t cell, mnc, and total chimerism was greater than % donor-derived at the time of the assessment. for patients who did or did not relapse post hsct the median numbers of lymphoid subsets (cells/ul) were: nk ( - ) vs ( - ), cd ( - ) vs ( - ), and cd ( - ) vs ( - ) respectively. in this small series of patients treated with the step transplant method, relapse was associated more with the presence of disease at hsct than with any discern- able trend in degree of hla disparity or early immunologic recov- ery. other approaches to treat resistant leukemia are required to substantially improve disease free survival in these high risk patients. anti-hla antibodies predict graft failure, time to engraft- ment and umbilical cord unit dominance in double umbilical cord blood transplantation cutler, c. , kim, h.t. , sun, l. , sese, d. , kao, g. , vasquez, m. , armand, p. , koreth, j. , ho, v.t. , alyea, e. , soiffer, r.j. , ballen, k. , ritz, j. , milford, e. , antin, j.h. dana-farber cancer institute, boston, ma; dana-farber cancer institute, boston, ma; brigham and women’s hospital, boston, ma anti-hla antibodies (hla-ab) predict graft failure in unrelated donor and single umbilical cord blood (ucb) transplantation. we measured hla-ab in double ucb transplantation (ducbt) with the hypothesis that hla-ab would predict time to engraftment, graft failure and ucb unit dominance. methods: patients with banked pre-transplant sera who under- went ducbt using / or better allelic hla-matched ucb units ( - ) were studied. labscreen (one lambda inc.) was used to capture class i/ii hla-ab and the luminex is system was used to detect fluorescent tagged binding of human igg. visual software was used to normalize results and to deter- mine the presence of mixed class i/ii hla-ab. positive samples were tested using single antigen-coated microbeads. beads with a mean fluorescent intensity above baseline were considered positive. chimerism was measured using str typing of informa- tive alleles. graft failure was defined as the absence of neutrophil engraftment days from ducbt or loss of ucb chimerism by day without malignant relapse. ucb dominance was defined as . % contribution to hematopoiesis by a single ucb unit at day . 	total donor chimerism in the day bone marrow predicts sustained donor neutrophil engraftment following double unit cord ... 	the t-cell epitope (tce) algorithm for classifying hla-dpb mismatches does not predict clinical outcomes in hsct 	a scoring system predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leu ... 	hla disparity and rapid immune reconstitution do not overcome propensity to relapse in patients undergoing haploidentical h ... 	anti-hla antibodies predict graft failure, time to engraftment and umbilical cord unit dominance in double umbilical cord b ... a novel biosimulation task trainer for the deliberate practice of resuscitative hysterotomy innovation open access a novel biosimulation task trainer for the deliberate practice of resuscitative hysterotomy lawrence lau , dimitrios papanagnou , , elaine smith , crystal waters , elizabeth teixeira and xiao chi zhang * abstract resuscitative hysterotomy is a daunting and rarely performed procedure in the emergency department (ed). given the paucity of clinical exposure to this intervention, resuscitative hysterotomy is an ideal opportunity for simulation- mediated deliberate practice. the authors propose a novel training program using a homegrown, realistic, simulation device as a means to practice resuscitative hysterotomy. two high-fidelity, tissue-based task-trainer models were constructed and tested on a convenience sample of emergency medicine (em) residents. the simulated human placenta, bladder, amniotic sac, and uterus were constructed through the use of porcine skin, porcine stomach, transparent plastic bag, foley tubing, and squid mantle, all secured with nylon sutures. a gaumard s articulating newborn was inserted in the simulated uterus, and the entire model was placed into a gaumard s childbirth simulator. each model required less than h for assembly. emergent hysterotomy was first demonstrated by an em faculty facilitator, followed by hands-on deliberate practice. formal feedback on the learners’ self-reported confidence and satisfaction levels was solicited at the end of the workshop through a survey previously cited for use with a low-fidelity resuscitative hysterotomy. quantitative evaluation of the simulated training session was extracted through a -item questionnaire using a -point likert-type scale (i.e., from , strongly disagree, to , strongly agree). item scores were added for a cumulative total score, with a possible maximum score of and minimum score of . responses were overwhelmingly positive [ . (± . )]. qualitative feedback was extracted from the survey through open-ended questions; these responses highlighted learners’ appreciation for hands-on practice and the development of a novel, tissue-based simulation task trainer. all participants recommended the training session be available to future learners. resuscitative hysterotomy is a high-stakes, low- frequency procedure that demands provider practice and confidence. our hybrid, tissue-based hysterotomy model represents a feasible opportunity for training. the model is cost conscious, easily reproducible, and portable and allows for ample deliberate practice. keywords: resuscitation, resuscitative hysterotomy, c-section, emergency medicine, rapid cycle deliberate practice, task trainer, education introduction the perimortem cesarean section, rebranded in recent years as the “resuscitative hysterotomy,” is perhaps the most daunting and infrequently performed procedure by emergency physicians, necessitating the frequent review of indications, techniques, and pitfalls to ensure the best possible outcome for mother and baby. this procedure is indicated within min of maternal cardiac arrest with a uterine fundus above the umbilicus (indicating a gesta- tion of > weeks) to maximize the probability of favor- able maternal neurologic outcome and the secondary goal of fetal survival [ – ]. despite the importance of re- suscitative hysterotomy, the exact circumstances in which this procedure is to be performed are seldom en- countered. given the paucity of clinical exposure to this intervention, resuscitative hysterotomy is an ideal candi- date for simulation-mediated deliberate practice. * correspondence: xzhang @gmail.com department of emergency medicine, thomas jefferson university, sansom st., thompson bldg, suite , philadelphia, pa, usa full list of author information is available at the end of the article © the author(s). open access this article is distributed under the terms of the creative commons attribution . international license (http://creativecommons.org/licenses/by/ . /), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the creative commons public domain dedication waiver (http://creativecommons.org/publicdomain/zero/ . /) applies to the data made available in this article, unless otherwise stated. lau et al. advances in simulation ( ) : https://doi.org/ . /s - - - http://crossmark.crossref.org/dialog/?doi= . /s - - - &domain=pdf http://orcid.org/ - - - mailto:xzhang @gmail.com http://creativecommons.org/licenses/by/ . / http://creativecommons.org/publicdomain/zero/ . / to date, there are only a few commercially manufac- tured resuscitative hysterotomy task trainers available for training, further complicated by costly components, maintenance costs, and task trainer availability [ – ]. to address these issues, the authors propose a novel train- ing program using a homegrown, high-realism, task trainer that can be easily inserted into an inexpensive childbirth simulator to teach emergency medicine (em) residents resuscitative hysterotomy. to further augment the realism of this model, the authors chose to design a lifelike task trainer that provided learners with the realis- tic feel of organic tissue. through this program innovation, the authors sought to ( ) enhance proced- ural training of resuscitative hysterotomies; ( ) integrate a realistic simulation model for hands-on, rapid cycle de- liberate practice (rcdp) with em residents; and ( ) compare the efficacy of our task trainer with similar hys- terotomy models for resident learners. rcdp represents a conceptual model for skill acquisition that provides for timely and focused education [ ]. simulation training of high-stakes, low-frequency procedures, combined with rcdp, offers a ripe opportunity for the development of “muscle memory” and enhanced confidence during highly stressful conditions [ ]. through the use of a sur- vey previously cited in the simulation literature [ ], the authors aimed to specifically measure the following: preference of instructional delivery with regard to hys- terotomy training, appreciation for human anatomic representation, applicability to clinical practice, comfort with performing resuscitative hysterotomy, and familiar- ity with the procedure. these were each captured through items on the survey. method for this training program innovation, two identical high-fidelity, tissue-based task-trainer models were con- structed and tested on a convenience sample of em residents at the thomas jefferson university, a -year em residency program in philadelphia, pa, usa. partici- pant breakdown included five post-graduate-year (pgy)- residents, six pgy- residents, and three pgy- residents. the training for simulation delivery for em residents took place at a monthly journal club literature review session, which was held in a classroom on the medical school campus. two identical task trainers were implemented to allow for simultaneous procedural learning among the learners for the training program. simulated human placentas, bladders, and uteri were constructed through the use of porcine skin, porcine stomach, and a squid mantle, re- spectively, which were secured in place with nylon su- tures. the amniotic sac was created through the use of a transparent plastic bag that contained a gaumard s articulating newborn and was filled with warm water (i.e., the amniotic fluid) through a foley catheter. each task trainer model was placed into a gaumard s childbirth simulator with an overlying porcine belly to simulate the gravid abdomen. once the aforementioned models were created, they were mounted on a plastic dolly cart that allowed for ease of transport across pre-clinical environments. each model required less than h for assembly (fig. ) and cost $ . to construct (excluding expired hospital supplies and existing gaumard s task trainers, provided in kind by the in- stitutional simulation center) (table ). a detailed step-by-step construction guide for the biosimulated re- suscitative hysterotomy can be found in additional file : appendix . emergent hysterotomy was first demonstrated by the content expert (i.e., em faculty facilitator) and followed by immediate hands-on deliberate practice. errors in technique were immediately corrected at each step, and the preceding steps were reviewed prior to continuing the procedure. learners were cycled twice through both simulators with rapid cycle feedback, utilizing the micro-debriefing format (i.e., feedback was delivered im- mediately as each step in the procedure was performed) [ ]. residents who were not performing the hysterotomy watched their peers, and questions were encouraged. residents were divided into pairs, and each pair had the opportunity to perform the procedure. the biosimula- tion models were reset between procedures via reim- plantation of the fetus model with placenta inside new plastic bags with all previous lacerations repaired with nylon suture. formal feedback on the learners’ self-reported confidence and satisfaction levels was soli- cited at the end of the workshop through the use of sur- vey that was previously used specifically for low-fidelity resuscitative hysterotomy [ ]. quantitative evaluation of the simulated training session was extracted through a -item questionnaire using a -point likert-type scale (i.e., from , strongly disagree, to , strongly agree). item scores were added for a cumulative total score, with a possible maximum total score of and a minimum total score of . this study was exempt from review by the thomas jefferson university institutional review board (irb), as the resident workshop was part of the em residency cur- riculum. participants provided verbal consent for their anonymous responses to be collected. results the response rate from resident participants was %. responses were overwhelmingly positive [ . (± . )]. nearly all residents indicated the model was a good rep- resentation of human anatomy [ . (± . )] and helped them become more familiar [ . (± . )] and prepared [ . (± . )] to perform resuscitative hysterotomy. lau et al. advances in simulation ( ) : page of table biosimulation resuscitative hysterotomy model materials and cost item cost ($) pork belly lbs at . /lb (on sale) = pig skin lbs at . /lb = . squid whole squid = . pig stomach of adult size, multiple at . /lb = clear plastic grocery bags free from grocery store foley catheter × expired supply (ed) -l water tap gaumard s original childbirth simulator (includes non-articulating simulation baby fetus) loan from the rector clinical skills and simulation center gaumard s articulating newborn loan from the rector clinical skills and simulation center suction tubing expired supply (ed) umbilical cord tubing from foley catheter expired supply (ed) suture ( - to - nylon, any type) expired supply (or) laceration tray expired supply (ed) gloves expired supply (or) blunt scissors loan from ed scalpel blade expired supply (ed) absorbent floor mats expired supply (ed) ppe (mask, gown, boots) expired supply (ed) ed emergency department, or operating room fig. condensed instruction guide for the hybrid biosimulation model for resuscitative hysterotomy lau et al. advances in simulation ( ) : page of residents reported that knowledge gained would be dir- ectly applicable to future clinical shifts [ . (± . )]. participants using the current study model gave over- all more positive feedback than the model utilized by sampson et al.; however, the small sample size ( in present study and for sampson et al.) is insufficient to achieve the appropriate level of statistical power for comparison via student’s t tests (fig. ). enthusi- asm for the course was evaluated using a -point scale. ratings at the time of initial registration indicate medium interest with wide variability [ . ( . )]. at the conclusion of the course, all participants rated their inter- est in the course as high [ . ( . )]. ratings for enthusi- asm post-course were not significantly higher than pre-course (t = . × − , p = . ). all participants ( %) recommended the training session be available for future emergency medicine residents. qualitative feedback from self-written responses highlighted the learners’ appreciation for hands-on prac- tice ( % of resident responses), practice-changing man- agement towards resuscitative hysterotomy ( % of resident responses), and the realistic nature of the tissue-based simulation task trainer ( % of resident re- sponses). areas for improvement included ( ) additional models to allow for repeated practice (i.e., more than two times), ( ) ongoing cardiopulmonary resuscitation (cpr) during the procedure to further increase realism, and ( ) visual printout of the procedural steps with the model. discussion creating an inexpensive, lifelike, simulation training model with tactile realism was a primary goal of this innovative workshop. previously attempted models have relied on ex- pensive simulation equipment as the basis for their models. one model in the literature [ ] is based on the gaumard noelle unit, which costs $ at the time of this paper alone (http://www.gaumard.com/s ). by con- trast, the simulation pelvis used in this study was much cheaper ($ ), including the simulation baby (http:// www.gaumard.com/s ), and could be used several times for multiple learners. though the equipment could theor- etically be borrowed from a university simulation center, not all residency programs have access to expensive high-realism simulation models or access to a simulation center for this purpose. even without the simulated pelvis, this model could easily have been placed in a simple plas- tic wash basin commonly found in the ed, and the pro- cedure could still have been performed in its entirety. this in turn supports the portability of the model to many dif- ferent clinical and pre-clinical environments for training. in addition, the entire cost of the disposable materials in this model was $ . for two high-fidelity tissue models. though this at a glance is more expensive than the materials used in prior attempts ($ for seven models [ ] or $ – for one model [ ]), the subtle benefit of incorporating animal tissue models is the abil- ity to suture the tissue together post procedure and re-arranging the tissue for the next participant, allowing for the creation of multiple fresh models to allow partic- ipants experience the procedure in an rcdp style repeti- tion several times. in a technological age where anatomy labs are becoming more expensive to upkeep and digital applications are taking over standard pedagogy, tactile learning and experience are somewhat lost. as a further attribute, a tissue-based model allows the learner to feel the different layers of anatomy during incision, a sensa- tion that cannot be reproduced with commercial and/or gelatin products. as a final benefit of the present model, the creation of two models took the study investigators less than h each to construct from start to finish. one model de- scribed in the literature [ ] requires latex to dry over- night as a single step, in addition to having gelatin set for h at a time. other published studies [ , ] do not specify a construction time. the study investigators propose that the quick production and rapid portability across different learning spaces make this an efficacious model for learning resuscitative hysterotomy. when considering other cesarean simulators currently available on the market or those that allow for such modifications (table ), some important key issues arise. though the other models listed are serviceable for edu- cating general procedure and anatomy, the disadvantage lies in their higher cost and expenditure. in our opinion, only one model is debatably comparable in realism, but is extreme in cost (operative experience’s c-celia - ob- stetric simulator for fetal extractions at cesarean deliv- eries, ranging from $ , to $ , ). combining bio tissue or moulage materials with these simulators can re- sult in damage to electronic components, some which may be difficult to sterilize. the current chosen model was easy to outfit with the aforementioned tissue and decontaminate after the session, making it more effica- cious in cost, durability, and realism. the model’s structural advantages were mirrored by the overwhelmingly positive feedback by the em learner-participants in familiarizing and preparing them for future performance. this study employed the same assessment scale as previously described by sampson et al.’s [ ] low-fidelity resuscitative hysterotomy model, with resounding success. the cumulative satisfaction scores between our model and sampson’s model were . and . , respectively. the data from both studies show a preference of hands-on simulation above trad- itional lectures and reading alone, the improvement in procedural competency, and usefulness for future emer- gency department shifts. the use of animal tissue also offers both cost-effective and high-fidelity advantage in lau et al. advances in simulation ( ) : page of http://www.gaumard.com/s http://www.gaumard.com/s http://www.gaumard.com/s fig. evaluation of simulation model. all survey questions ( – ) were adapted from sampson et al.’s [ ] survey analysis of a low-fidelity resuscitative hysterotomy model, using a -point likert-type scale lau et al. advances in simulation ( ) : page of preparing participants for the techniques necessary in dissecting through actual tissue layers. furthermore, the rcdp style training was well-received by all participants by allowing them to improve upon their previous mis- takes in real time, be offered feedback on their technical skills, and review critical actions before progression. this simulation can be combined with cpr as described by nadir et al. to further increase the fidelity [ ]. with respect to the accreditation council for gradu- ate medical education (acgme) milestones for resident competency, this high-realism task trainer, if fully imple- mented with the use of high-fidelity simulation tech- niques (i.e., incorporating confederate actors or environmental props), has the potential to enhance fu- ture patient care with respect to the following: emer- gency stabilization (patient care ), diagnosis (patient care ), general approach to procedures (patient care ), medical knowledge, and team management (inter- personal and communication skills ) [ ]. residents are challenged to recognize the critical situation of a pregnant mother in extremis; understand the indications to perform the resuscitative hysterotomy; communicate with staff and preceptors about their intent, equipment, and personnel required; and physically perform the pro- cedure in a safe clinical environment. the challenges of this simulation reflect sufficiently the skills needed, stress level, and mental capacity required to manage crit- ical illness under duress. limitations the study was limited in power due to being at a single center and including a small sample size of em learners. despite using an assessment from a previous study, we were unable to determine a statistical significance due to the small sample sizes. though the results promisingly suggest that a tactile, tissue-based, rcdp simulation can stimulate learner knowledge and enhance practice pat- terns, more study is needed to adequately demonstrate that this particular format is superior to traditional simulation-based learning and journal club experiences. conclusion resuscitative hysterotomy is a high-stakes, low-frequency procedure that demands provider practice and confidence. review of procedural steps, indications, and materials needed is imperative to the success of this procedure in pregnant patients in extremis. our hybrid, tissue-based hysterotomy model shows promise in adding the next level of realism for deliberate procedural practice while of- fering additional utility in cost, reproducibility, and port- ability to learners of various abilities. future studies can explore learning benefit differences between using cheaper table currently commercially available obstetrical simulation models/task trainers/simulators gaumard advanced childbirth simulator cs “ob susie” $ https://www.gaumard.com/s simulaids obstetrical manikin $ https://www.simulaids.com/product/ - b scientific birthing simulator basic $ https://www.a bs.com/ b-birthing-simulator-basic- -p b- b- scientific,p_ _ .html b scientific birthing simulator pro $ https://www.a bs.com/ b-birthing-simulator-pro- -p p- b- scientific,p_ _ .html b scientific birthing simulator $ https://www.a bs.com/birthing-simulator- -vg - b- scientific,p_ _ .html kyoto kagaku vaginal delivery assistance simulator $ https://www.gtsimulators.com/kyoto-kagaku-vaginal-delivery-assistance- simulator-p/kk-mw .htm adam, rouilly desperate debra $ http://www.adam-rouilly.co.uk/productdetails.aspx?pid= &cid limbs & things prompt birthing simulator - standard $ https://www.limbsandthings.com/us/our-products/details/prompt-flex- standard limbs & things caesarean section module prompt flex(add-on) +$ https://www.limbsandthings.com/us/our-products/details/prompt-flex- cesarean-section-module operative experience c-celia - obstetric simulator for fetal extractions at cesarean deliveries $ , –$ , https://operativeexperience.com/fetal-extraction-simulator gaumard noelle s $ https://www.gaumard.com/s nasco life/form lucy maternal and neonatal birthing simulator - basic lucy $ https://www.enasco.com/p/lf u laerdal simmom $ , https://www.laerdal.com/us/products/simulation-training/obstetrics- pediatrics/simmom simulaids smart mom basic birthing simulator $ , https://www.a bs.com/smart-mom-basic-birthing-simulator gaumard victoria s $ , http://www.gaumard.com/s -victoria-childbirth-simulator lau et al. advances in simulation ( ) : page of https://www.gaumard.com/s https://www.simulaids.com/product/ - https://www.a bs.com/ b-birthing-simulator-basic- -p b- b-scientific,p_ _ .html https://www.a bs.com/ b-birthing-simulator-basic- -p b- b-scientific,p_ _ .html https://www.a bs.com/ b-birthing-simulator-pro- -p p- b-scientific,p_ _ .html https://www.a bs.com/ b-birthing-simulator-pro- -p p- b-scientific,p_ _ .html https://www.a bs.com/ b-birthing-simulator-pro- -p p- b-scientific,p_ _ .html https://www.a bs.com/birthing-simulator- -vg - b-scientific,p_ _ .html https://www.a bs.com/birthing-simulator- -vg - b-scientific,p_ _ .html https://www.gtsimulators.com/kyoto-kagaku-vaginal-delivery-assistance-simulator-p/kk-mw .htm https://www.gtsimulators.com/kyoto-kagaku-vaginal-delivery-assistance-simulator-p/kk-mw .htm http://www.adam-rouilly.co.uk/productdetails.aspx?pid= &cid https://www.limbsandthings.com/us/our-products/details/prompt-flex-standard https://www.limbsandthings.com/us/our-products/details/prompt-flex-standard https://www.limbsandthings.com/us/our-products/details/prompt-flex-cesarean-section-module https://www.limbsandthings.com/us/our-products/details/prompt-flex-cesarean-section-module https://operativeexperience.com/fetal-extraction-simulator https://www.gaumard.com/s https://www.enasco.com/p/lf u https://www.laerdal.com/us/products/simulation-training/obstetrics-pediatrics/simmom https://www.laerdal.com/us/products/simulation-training/obstetrics-pediatrics/simmom https://www.a bs.com/smart-mom-basic-birthing-simulator- -w -sb ,p_ _ .html?utm_source=google&utm_campaign=gmc_feed&utm_medium=shop&gclid=cj kcqjw yxxbrdxarisamzsquxvofx bnih rjzft jpjbtpscxdj wsyvqqzwwqktoxzgm jgnbzkaasgrealw_wcb http://www.gaumard.com/s -victoria-childbirth-simulator versus expensive hysterotomy task trainers (i.e., noelle) for procedural competency and knowledge retention of emergency hysterotomies. as the medical simulation in- dustry continues to advance, innovative medical moulage is expected to become more readily available and cost-effective, further increasing realism as well as alleviat- ing challenges that may emerge with using bio tissue. additional file additional file : appendix . detailed step-by-step construction guide to the biosimulation resuscitative hysterotomy model. appendix . post- biosimulation resuscitative hysterotomy survey. (docx kb) abbreviations ed : emergency department; em : emergency medicine; pgy : post graduate year; rcdp : rapid cycle deliberate practice acknowledgements we would like to acknowledge the department of emergency medicine and the rector clinical skills and simulation center (rcssc) at thomas jefferson university for their ongoing support with our academic endeavors. availability of data and materials the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. authors’ contributions ll and xcz were the primary facilitators for the study. ll reviewed the existing literature for resuscitative hysterotomy. es constructed the task trainer and contributed to the introduction section and appendix. et analyzed and interpreted the survey data. cw reviewed the existing literature for existing resuscitative hysterotomy models and was a major contributor to the discussion section. dp and xcz studied previous resuscitative hysterectomy task trainers and constructed the study methodology and were major contributors in writing the method and discussion sections as well as the reviewing process. all authors read and approved the final manuscript. author’s information dr. zhang is a triple graduate of tufts university, where he received a bachelor of science in mechanical engineering, masters in biomedical engineering, as well as a medical doctorate degree within years of rigorous and interdisciplinary training. despite this condensed training period, dr. zhang distinguished himself among his peers through his dedication towards medical education and technologic innovation, as evident from his involvement in medical education course developments, teaching opportunities, and innovative medical inventions. throughout his career, dr. zhang has been consistently and substantively involved with education, teaching, and simulation training. he has published numerous articles on simulation modules, debriefing techniques, augmented reality as an interactive learning platform, and the use of gamification frameworks in a simulated environment to tackle pedagogical and patient safety challenges. dr. zhang is currently the principal investigator of a study that aims to develop and implement simulation-based training to improve orthopedic distal radius fracture reductions in emergency department (ed) patients. dr. zhang is currently a clinical instructor and assistant clerkship director at thomas jefferson university, where he will be completing his education fellowship as well as the rigorous master of health profession education program at the university of illinois, chicago. dr. zhang recently received a certificate of completion for the prestigious american college of emergency physicians (acep) teaching fellowship and the pennsylvania medicine simulation facilitator’s course during his first year of fellowship. ethics approval and consent to participate the institutional review board (irb) has evaluated the involvement of human subjects in the proposed research study entitled: “a novel building a realistic high fidelity biosimulation task trainer for the deliberate practice of resuscitative hysterotomy” (departmental) cfr . ( -educational research, -survey; no ids) control # e. to be exempt from irb review on / / pursuant to title code of federal regulations part . (b) governing exempted protocol declarations. no further review and approval by the board will be required if the study is to be conducted as proposed. consent for publication not applicable competing interests the authors declare that they have no competing interests. publisher’s note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. author details department of emergency medicine, thomas jefferson university, sansom st., thompson bldg, suite , philadelphia, pa, usa. sidney kimmel medical school, thomas jefferson university, sansom st., thompson bldg, suite , philadelphia, pa, usa. university clinical skills and simulation center, thomas jefferson university, locust street, suite f, philadelphia, pa, usa. received: june accepted: september references . katz vl. perimortem cesarean delivery: its role in maternal mortality. semin perinatol. ; ( ): – . . lipman s, cohen s, einav s, et al. the society for obstetric anesthesia and perinatology consensus statement on the management of cardiac arrest in pregnancy. anesth analg. ; ( ): – . . einav s, kaufman n, sela hy. maternal cardiac arrest and perimortem caesarean delivery: evidence or expert-based? resuscitation. ; : – . . adams j, cepeda brito jr, baker l, et al. management of maternal cardiac arrest in the third trimester of pregnancy: a simulation-based pilot study. crit care resusc pract. ; : . . nadir n, leclair c, ahmed a, podolej g. the casserole perimortem caesarean section model. jetem. ; : – . . sampson c, renz n, wagner j. an inexpensive and novel model for perimortem cesarean section. simul healthcare. ; ( ): – . . taras j, everett t. rapid cycle deliberate practice in medical education – a systematic review. cureus. ; ( ):e . . hunt ea, duval-arnould jm, nelson-mcmillan kl, et al. pediatric resident resuscitation skills improve after “rapid cycle deliberate practice” training. resuscitation. jul; ( ): – . . eppich wj, hunt ea, duval-arnould jm, et al. structuring feedback and debriefing to achieve mastery learning goals. acad med. ; : – . . emergency medicine milestones. accreditation council for graduate medical education website. [accessed june , ]. available at: https:// www.acgme.org/portals/ /pdfs/milestones/emergencymedicinemilestones. pdf?ver= - - - - . lau et al. advances in simulation ( ) : page of https://doi.org/ . /s - - - https://www.acgme.org/portals/ /pdfs/milestones/emergencymedicinemilestones.pdf?ver= - - - - https://www.acgme.org/portals/ /pdfs/milestones/emergencymedicinemilestones.pdf?ver= - - - - https://www.acgme.org/portals/ /pdfs/milestones/emergencymedicinemilestones.pdf?ver= - - - - 	abstract 	introduction 	method 	results 	discussion 	limitations 	conclusion 	additional file 	abbreviations 	acknowledgements 	availability of data and materials 	authors’ contributions 	author’s information 	ethics approval and consent to participate 	consent for publication 	competing interests 	publisher’s note 	author details 	references establishment of a clinically relevant ex vivo mock cataract surgery model for investigating epithelial wound repair in a native microenvironment. | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . / corpus id: establishment of a clinically relevant ex vivo mock cataract surgery model for investigating epithelial wound repair in a native microenvironment. @article{walker establishmentoa, title={establishment of a clinically relevant ex vivo mock cataract surgery model for investigating epithelial wound repair in a native microenvironment.}, author={janice l. walker and b. bleaken and i. wolff and a. s. menko}, journal={journal of visualized experiments : jove}, year={ }, volume={ }, pages={ e } } 	janice l. walker, b. bleaken, + author a. s. menko 	published 	biology, medicine 	journal of visualized experiments : jove the major impediment to understanding how an epithelial tissue executes wound repair is the limited availability of models in which it is possible to follow and manipulate the wound response ex vivo in an environment that closely mimics that of epithelial tissue injury in vivo. this issue was addressed by creating a clinically relevant epithelial ex vivo injury-repair model based on cataract surgery. in this culture model, the response of the lens epithelium to wounding can be followed live in… expand view on pubmed europepmc.org save to library create alert cite launch research feed share this paper citationsbackground citations methods citations view all figures and topics from this paper 	 figure 	 figure 	cataract 	double-strand break repair via homologous recombination 	epithelium 	structure of lens capsule 	soft tissue injuries 	posterior capsule of the lens 	providing (action) 	leukemia, b-cell 	lens diseases citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency fibrosis: shared lessons from the lens and cornea 	a. s. menko, janice l. walker, m. a. stepp 	medicine 	anatomical record 	 	 	 	view excerpts, cites background save alert research feed in wound repair vimentin mediates the transition of mesenchymal leader cells to a myofibroblast phenotype 	j. walker, b. bleaken, a. romisher, a. a. alnwibit, a. s. menko 	biology, medicine 	molecular biology of the cell 	 	 	pdf 	view excerpts, cites methods save alert research feed resident immune cells of the avascular lens: mediators of the injury and fibrotic response of the lens 	a. sue menko, jodirae dedreu, caitlin m. logan, heather paulson, a. levin, janice l. walker 	medicine 	faseb journal : official publication of the federation of american societies for experimental biology 	 	 save alert research feed development of a novel ex vivo equine corneal model 	t. marlo, e. giuliano, a. sharma, r. mohan 	medicine 	veterinary ophthalmology 	 	 	 save alert research feed cells activated for wound repair have the potential to direct collective invasion of an epithelium 	b. bleaken, a. s. menko, janice l. walker 	biology, medicine 	molecular biology of the cell 	 	 	pdf 	view excerpts, cites methods and background save alert research feed references showing - of references sort byrelevance most influenced papers recency molecular mechanisms controlling the fibrotic repair phenotype in cornea: implications for surgical outcomes. 	b. m. stramer, j. zieske, jae-chang jung, j. austin, m. fini 	biology, medicine 	investigative ophthalmology & visual science 	 	 	pdf save alert research feed an in vivo model of wound healing in genetically modified skin-humanized mice. 	m. escámez, m. garcía, + authors m. del río 	medicine, biology 	the journal of investigative dermatology 	 	 	pdf save alert research feed disruption of the basement membrane after corneal débridement. 	d. d. sta iglesia, m. a. stepp 	biology, medicine 	investigative ophthalmology & visual science 	 	 	pdf save alert research feed removal of the basement membrane enhances corneal wound healing. 	s. pal‐ghosh, a. pajoohesh-ganji, gauri tadvalkar, m. a. stepp 	medicine 	experimental eye research 	 	 	 save alert research feed unique precursors for the mesenchymal cells involved in injury response and fibrosis 	janice l. walker, ni zhai, + authors a. s. menko 	biology, medicine 	proceedings of the national academy of sciences 	 	 	pdf save alert research feed wound healing in embryos: a review 	s. nodder, p. martin 	biology, medicine 	anatomy and embryology 	 	 save alert research feed a mouse model for the study of recurrent corneal epithelial erosions: α β integrin implicated in progression of the disease 	s. pal‐ghosh, a. pajoohesh-ganji, m. brown, m. a. stepp 	medicine 	 	 	pdf save alert research feed the epithelial reaction in the healing of excised cutaneous wounds in the dog. 	e. winstanley 	biology, medicine 	journal of comparative pathology 	 	 save alert research feed wound healing and inflammation: embryos reveal the way to perfect repair. 	michael j. redd, l. cooper, w. wood, b. stramer, p. martin 	biology, medicine 	philosophical transactions of the royal society of london. series b, biological sciences 	 	 	 save alert research feed scar-free healing: from embryonic mechanisms to adult therapeutic intervention. 	m. ferguson, s. o'kane 	medicine, biology 	philosophical transactions of the royal society of london. series b, biological sciences 	 	 	pdf save alert research feed ... ... related papers 	abstract 	figures and topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue erratum evaluation of a scaling approach for the bioequivalence of highly variable drugs sam h. haidar, , fairouz makhlouf, donald j. schuirmann, terry hyslop, barbara davit, dale conner, and lawrence x. yu published online september the affiliations listed in the pdf and online version of this article for donald j. schuirmann and terry hyslop were incorrect. the correct affiliations for these authors are: ( ) division of biostatistics, thomas jefferson university, chestnut st., suite m , philadelphia, pennsylvania, usa ( ) office of biostatistics, cder/fda, new hampshire ave, silver spring, maryland, usa - / / - / # american association of pharmaceutical scientists the aaps journal, vol. , no. , september (# ) doi: . /s - - -y the online version of the original article can be found at http://dx.doi. org/ . /s - - - . office of generic drugs, cder/fda, standish place, hfd- , rockville, md , usa. office of biostatistics, cder/fda, new hampshire ave, silver spring, md, usa. division of biostatistics, thomas jefferson university, chestnut st., suite m , philadelphia, pa, usa. to whom correspondence should be addressed. (e-mail: sam. haidar@fda.hhs.gov) http://dx.doi.org/ . /s - - - http://dx.doi.org/ . /s - - - 	evaluation of a scaling approach for the bioequivalence << /ascii encodepages false /allowtransparency false /autopositionepsfiles true /autorotatepages /none /binding /left /calgrayprofile (gray gamma . ) /calrgbprofile (srgb iec - . ) /calcmykprofile (iso coated v % \ eci\ ) /srgbprofile (srgb iec - . ) /cannotembedfontpolicy /error /compatibilitylevel . /compressobjects /off /compresspages true /convertimagestoindexed true /passthroughjpegimages true /createjdffile false /createjobticket false /defaultrenderingintent /perceptual /detectblends true /detectcurves . /colorconversionstrategy /srgb /dothumbnails true /embedallfonts true /embedopentype false /parseiccprofilesincomments true /embedjoboptions true /dscreportinglevel /emitdscwarnings false /endpage - /imagememory /lockdistillerparams true /maxsubsetpct /optimize true /opm /parsedsccomments true /parsedsccommentsfordocinfo true 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e f f f c a e e f d e f f e e f d e f f d e f f d e f f f d f f d f f f f e f f f e> /suo <feff b e e e e e b c b e c f f d f b d e a c a f b f b a f a e c f e e e e d e a c f d e e c f d f b d e f e f c c a f e a c c a d d c c e> /sve <feff e e e e e e c c e e e f d c c b f d f b d e f d f c c f c c e e f b e f b d e e b d f b d e b e f e f f f e f e e> /enu <feff a f f f e f f c c e e d f c f f e c e e d e d c d d d c f e e f e c f a f f f f e e e e f d d f e c f e c e f f c f f f f e c e f f c e f c f a f d f e e> >> >> setdistillerparams << /hwresolution [ ] /pagesize [ . . ] >> setpagedevice received / / review began / / review ended / / published / / © copyright mcdermott et al. this is an open access article distributed under the terms of the creative commons attribution license cc-by . ., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. shunting of oxygenated blood to the venous system in the avalon® cannula on venovenous extracorporeal membrane oxygenation with high-frequency oscillatory ventilation lydia mcdermott , nicholas c. cavarocchi , hitoshi hirose . surgery, thomas jefferson university, philadelphia, usa . cardiothoracic surgery, thomas jefferson university, philadelphia, usa  corresponding author: hitoshi hirose, genex@nifty.com disclosures can be found in additional information at the end of the article abstract high-frequency oscillatory ventilation (hfov) may assist in the prevention of volutrauma for high-risk patients with acute respiratory distress syndrome (ards) during venovenous extracorporeal membrane oxygenation (vv ecmo). in combined vv ecmo and hfov, we noted that increased intrathoracic pressure contributed to shunt formation in the dual-lumen avalon® cannula (maquet, rastatt, germany). a -year-old female with ards secondary to aspiration pneumonia was placed on vv ecmo using a single avalon cannula. by ecmo day , she became unable to ventilate due to elevated peak airway pressures, even with low tidal volume ventilation and an otherwise stable vv ecmo course. hfov was introduced to minimize ventilator-induced lung injury. shortly after hfov started, the patient desaturated, and consequently, the fraction of inspired oxygen (fio ) was increased to %. we noted that a flash of bright red, oxygenated blood was flowing retrograde in the avalon cannula at the same rate as the beat of the oscillator, while the patient's ecmo flow rate, arterial blood gas, and blood pressure all remained stable. the ecmo flow was increased above . l/min and the resolution of the retrograde shunt through the avalon cannula was immediately observed. concurrent use of hfov with vv ecmo using an avalon cannula may result in a shunt that becomes visible with arterial o saturations nearing %. due to pressure differences between the venous and arterial lumens of the avalon cannula, increasing the ecmo flow rate appeared to decrease this shunting effect caused by elevated intrathoracic pressure. categories: cardiac/thoracic/vascular surgery, cardiology, pulmonology keywords: high-frequency oscillatory ventilation (hfov), acute respiratory distress syndrome (ards), extracorporeal membrane oxygenation (ecmo), avalon cannula introduction in addition to removal of the initial insult, treatment of acute respiratory distress syndrome (ards) consists primarily of symptom management. conventionally, lung protective ventilation practices are used to decrease further volutrauma, while extracorporeal membrane open access case report doi: . /cureus. how to cite this article mcdermott l, cavarocchi n c, hirose h (november , ) shunting of oxygenated blood to the venous system in the avalon® cannula on venovenous extracorporeal membrane oxygenation with high-frequency oscillatory ventilation. cureus ( ): e . doi . /cureus. https://www.cureus.com/users/ -lydia-mcdermott https://www.cureus.com/users/ -nicholas-c-cavarocchi https://www.cureus.com/users/ -hitoshi-hirose oxygenation (ecmo) is introduced for added support in cases complicated by refractory hypoxia and/or hypercarbia. common additional adjuncts include prone therapy, deep sedation and paralysis, and nebulized vasodilators. for ards patients with high airway pressures intractable to maximum therapies, including lung protective ventilation and ecmo, high-frequency oscillatory ventilation (hfov) should be considered [ - ]. hfov provides a small tidal volume ( - ml/kg) in high-frequency ( - hz) to optimize alveolar gas exchange while eliminating peak pressure and full pulmonary expansion in the setting of restricted compliance. our current venovenous extracorporeal membrane oxygenation (vv ecmo) practice includes the use of a single, dual-lumen avalon® cannula (maquet, rastatt, germany) placed to the right internal jugular vein, although with this positioning, the applied intrathoracic pressure created by hfov may compete with the ecmo flow. herein, we report a case of blood shunting observed in an avalon cannula and treated with an increase of ecmo flow. case presentation a -year-old female (weight: . kg; height: cm) with ards secondary to aspiration pneumonia was placed on vv ecmo using a single fr avalon cannula to the right internal jugular vein. her peak airway pressure was cm h o, even with low tidal volume ( ml) ventilation, and eventually, she was unable to ventilate safely due to decompensated compliance. hfov with a frequency of bpm and hz was introduced on ecmo day # to decrease the risk of volutrauma while also preventing atelectasis from hypoventilation. her mean airway pressure (mpaw) became . cm h o with hfov, which comparatively had been cm h o on the conventional ventilator. at the time of transition to hfov, her settings were: ecmo flow . l/min, sweep l/min, fio %, with ventilator fio %. approximately two hours later, the patient desaturated requiring fio % on both the ecmo and hfov to maintain an o saturation (sao ) of %, although the ecmo flow was maintained at . l/min. these same settings were continued before a flash of bright red, oxygenated blood was noted flowing into the venous return lumen of the avalon cannula which synchronized with each beat of the oscillator (video ). video : avalon cannula flash of bright red, oxygenated blood is noted flowing into the outflow lumen in the patient from the avalon extracorporeal membrane oxygenation (ecmo) cannula (yellow arrow), suggesting recirculation of oxygenated and unoxygenated blood. view video here: https://youtu.be/ziueeo fhnc mcdermott et al. cureus ( ): e . doi . /cureus. of the correct placement of the avalon catheter and endotracheal tube were confirmed by chest x- ray, and an echocardiogram further confirmed the cannula position (the tip in the inferior vena cava and the access lumen facing the tricuspid valve), as well as ruled out a patent foramen ovale or an atrial septal defect. inter-atrial shunting within the avalon cannula was diagnosed, and the ecmo flow was increased above . l/min to overcome the additional resistance. this provided a resolution of the retrograde shunt. despite all efforts, this patient, unfortunately, expired due to multi-organ failure. her family elected to withdraw care after a total of days on ecmo and four days on hfov. discussion it was hypothesized that the pulses of applied intrathoracic pressure created by the hfov contrasted with the systemic low pressures of the venous system where the avalon cannula lies, causing the intra-atrial shunt. as described by sklar et al., elevation of the right atrial (ra) and pulmonary artery pressures (pap) were observed during hfov [ ]. in an ecmo circuit, negative pressure (approximately - mmhg assuming an ecmo flow of . l/min with an avalon cannula size fr) was maintained through the return lumen while positive pressure (approximately mmhg assuming an ecmo flow of . l/min with an avalon cannula size fr) is applied by the centrifugal pump into the access lumen. using the avalon cannula allows the circuit to suction de-oxygenated blood from the superior vena cava (svc) and inferior vena cava (ivc) and instill oxygenated blood toward the tricuspid valve simultaneously creating a vv ecmo system through only one insertion site. with augmented external pressure from hfov, the pap suddenly elevates and causes the avalon catheter’s oxygenated out-flows to face an increased resistance which can dilate the ra when sustained. thus, turbulent flow within the ra may cause shunting that can exacerbate hypoxia as oxygenated blood recirculates towards the venous return lumen of the avalon cannula. in our patient, we believe the intra-atrial recirculation became noticeable due to a deepened contrast between the venous and arterial blood as the fio from ecmo was raised to %. to decrease pap, deep sedation and paralysis may be necessary, though these were already being applied in this case. furthermore, inhaled vasodilators, such as nitric oxide or epoprostenol, are an additional adjunct; however, we have found this therapy to be impractical during hfov use. instead, we increased the vv ecmo flow above . l/min, which was able to unload the ra by overcoming the raised pap (access lumen approximately mmhg) and optimizing suction from the svc and ivc (return lumen approximately - mmhg), resolving the intra-atrial shunt. while maintaining a high ecmo flow is possible, this requires additional patient monitoring and care due to a concomitant heightened risk of mechanical hemolysis. for this reason, we determined that, while interesting to note, intra-atrial shunt presence is clinically relevant to the patient primarily when contributing to decompensated hypoxia refractory to typical management strategies (namely, increasing fio ). therefore, we elected to continue this patient’s ecmo management per usual protocols by setting the ecmo flow based on the body surface area (bsa) and symptom severity (with the goal to maintain the sao above % and a normal ph) rather than on the mere presence or visibility of a shunt. upon review of this case, we are reminded that the mpaw on hfov is higher than that of lung protective ventilation via a conventional ventilator. while this comparative increase is expected due to the need for accommodation of the loss of dynamic peep, perhaps the mpaw could have been decreased in a setting of resolved hypoxia. as suggested in sklar et al., elevated mpaw itself may contribute to volutrauma, potentially explaining the failure of hfov to be proven beneficial thus far [ ]. it should be considered that while lung protective ventilation has been shown to improve ards outcomes during conventional ventilation, standard practice settings are applied during hfov to maintain an adequate gas exchange. facilitation of lung protective ventilation while on hfov could be possible with the concurrent mcdermott et al. cureus ( ): e . doi . /cureus. of use of hfov and high-flow ecmo, however. while we were unable to attempt this method for our patient due to sustained hypoxia, it may simply be that stricter parameters and a decreased mpaw are required to create a mortality benefit, as well as limit intra-atrial shunting, as we described. further research is required to evaluate the outcomes of severe ards patients on minimized, lung protective hfov settings. it is known that hfov may promote hemodynamic instability and other sequelae, though once identified, mitigation of these problems may be possible. regardless, present information suggests that hfov worsens ards mortality for mild-moderate cases and remains unproven as a benefit for severe cases. its use continues to be up for debate; therefore, it is not recommended as an initial therapy. however, hfov can be a useful adjunct in patients who continue to fail after conventional ventilator management is maximized with concurrent use of ecmo, paralysis, prone therapy, and nebulized epoprostenol. the expansion of care modalities is critical to continue advancing the ability for high-risk patients to recover from severe episodes of ards. conclusions by maintaining safer pulmonary pressures with hfov, while improving the exchange of gasses via ecmo, lungs impaired by ards that have failed conventional ventilation may be further allowed to heal. in the event that a clinically relevant intra-atrial shunt occurs during the concurrent use of hfov with vv ecmo via an avalon cannula, it is likely that an increase in the ecmo flow rate will decrease the shunting effect. additional information disclosures human subjects: consent was obtained by all participants in this study. thomas jefferson university institutional review board issued approval d. . we are submitting a case report which is waived from consent form. all ecmo patient registry at thomas jefferson university was approved by thomas jefferson university irb file number # d. (outcome after ecmo (extracorporeal membranous oxygenation)). conf licts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. references . thompson bt, bernard gr: ards network (nhlbi) studies: successes and challenges in ards clinical research. crit care clin. , : - . . /j.ccc. . . . shaheen a, tanaka d, cavarocchi nc, hirose h: veno-venous extracorporeal membrane oxygenation (vv ecmo): indications, preprocedural considerations, and technique. j card surg. , : - . . /jocs. . azimzadeh n, baram m, cavarocchi nc, hirose h: prone position: does it help with acute respiratory distress syndrome (ards) requiring extracorporeal membrane oxygenation (ecmo)?. open j resp dis. , : . . /ojrd. . . skylar mc, fan e, goligher ec: high-frequency oscillatory ventilation in adults with ards: past, present, and future. chest. , : - . . /j.chest. . . mcdermott et al. cureus ( ): e . doi . /cureus. of https://dx.doi.org/ . /j.ccc. . . https://dx.doi.org/ . /j.ccc. . . https://dx.doi.org/ . /jocs. https://dx.doi.org/ . /jocs. https://dx.doi.org/ . /ojrd. . https://dx.doi.org/ . /ojrd. . https://dx.doi.org/ . /j.chest. . . https://dx.doi.org/ . /j.chest. . . 	shunting of oxygenated blood to the venous system in the avalon® cannula on venovenous extracorporeal membrane oxygenation with high-frequency oscillatory ventilation 	abstract 	introduction 	case presentation 	video : avalon cannula 	discussion 	conclusions 	additional information 	disclosures 	references doi: . /j.bpj. . . monday, february , a the c terminus of milton is an important regulator of the mitochondria associated motors and is involved in conferring the calcium sensitivity from miro to the motors. milton - is sufficient for the mitochondrial binding, whereas the - amino acids are critical for the control of calcium sensitivity of mi- tochondrial motility. -pos biophysical properties of mitochondria undergoing fusion xingguo liu , orian shirihai , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, boston university, boston, ma, usa. emerging evidence shows the importance of genes controlling mitochondrial fusion in physiology and their deregulation in neurodegenerative and metabolic disorders. however, apart from djm, the biophysical properties of the fusion- competent mitochondria remain elusive. to evaluate the conditions of contact formation and fusion, we used organelle-targeted fluorescent proteins, includ- ing photoactivatable gfp, which allow tracking of individual mitochondria. in h c cells, almost every mitochondrion is aligned with microtubules that pro- vide the primary tracks for mitochondrial movement. our results show that ~ % of fusion events involve moving mitochondria. however, fusion occurs irrespective of mitochondrial speed. furthermore, ~ % of fusion events in- volve the tip portion of the mitochondrion, whereas only ~ % of these events involve organelle side. nocodazol, a microtubule disrupting agent that inhibits mitochondrial movements decreases the fusion frequency and changes mito- chondrial fusion sites. strikingly, - % of the physical contacts between ad- jacent mitochondria did not result in fusion events. to evaluate whether the fu- sion efficacy depends on the spacing between the outer and inner mitochondrial membranes we used drugs that alter the matrix volume. valinomycin, a k þ ion- ophore that induces matrix swelling evoked a decrease in mitochondrial motil- ity leading to fewer contacts among mitochondria but the number of fusion events was maintained, indicating an increase in fusion efficacy. this change occurred at a low valinomycin concentration ( . nm) that did not affect djm or opa cleavage. nigericin ( . mm), a k þ /h þ ionophore that induces shrinkage of the matrix elicited fusion inhibition and mitochondrial aggrega- tion. importantly, no motility inhibition or opa cleavage occurred at the same time and the djm was increased. these results suggest that mitochon- drial fusion is facilitated by mitochondrial motility, the key determinant of the inter-mitochondrial encounter numbers and preferentially involves the front-tip of the moving organelle. in addition, fusion efficacy depends on the mitochondrial matrix volume. -pos mitochondrial fusion dynamics in human skeletal muscle-derived cells veronica eisner, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. mitochondria have a fundamental role in both muscle physiology and pathol- ogy. mitochondrial fusion and fission are important for energy metabolism, calcium homeostasis and cell death. however, the mechanisms underlying mitochondrial dynamics are poorly understood, especially in physiological models such as skeletal muscle. here we evaluated mitochondrial fusion dy- namics in human skeletal muscle cells (husmc). skeletal muscle satellite cells were isolated from human muscle biopsies and were maintained and dif- ferentiated in cell culture. mitochondrial fusion events were evaluated by con- focal imaging of cells expressing mitochondria matrix targeted dsred and matrix targeted or outer mitochondrial membrane (omm) targeted photoacti- vatable-gfp. when we tagged the mitochondria in ~ % of total cellular area with photoactivated-gfp, we found those mitochondria undergoing matrix fusion with a frequency of . . events/min/cell (n= ). among the fusion events, % led to complete fusion and only % was followed by separation at the apparent fusion site within to seconds. both complete and transient fusion events resulted mostly from longitudinal mergers, involving end to end interaction or from mergers of adjacent mitochondria in side to side orien- tation. furthermore, we found that omm and matrix fusion are sequential and separable steps, displaying . seconds gap (n= ). finally, we evaluated the mitochondrial fusion dynamics in husmc derived from both normal and malignant hyperthermia susceptible individuals. at resting state, no significant differences were found in the number of events or in their characteristics. thus, mitochondrial fusion commonly occurs in husmc, and enables mixing of both soluble and integral membrane factors. this process would help to maintain the stability of mitochondrial metabolism. the relatively low frequency of the tran- sient fusion is probably due to the parallel organization of the cytoskeletal tracks for mitochondria and to the limited mitochondrial motility. -pos imaging interorganelle contacts and local calcium dynamics at the er-mitochondrial interface györgy csordás , péter várnai , tünde golenár , swati roy , george purkins , tamás balla , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary, national institutes of child health and human development, bethesda, md, usa. the local coupling between er and mitochondria is essential for proper cell function. a main role of the er-mitochondrial junctions is to provide a local calcium signaling domain that is important both for keeping energy production in line with demand and for the control of apoptotic mechanisms. so far it has not been possible to visualize the tiny er-mitochondrial contact points in living cells or to monitor the localized [ca þ] changes in the narrow space between er and mitochondria ([ca þ]er-mt). here, we exploited rapamycin-mediated heterodimerization of fkbp and frb domains of fluorescent protein constructs respectively targeted to the outer mitochondrial membrane and the er as drug-inducible inter-organelle linkers to identify er-mitochondrial contacts and to measure the [ca þ ]er-mt. high- resolution fluorescence imaging and d reconstruction revealed rapamycin-in- duced clustering of the er-targeted fluorescent linker-half to the contact areas with the mitochondria without major changes in the spatial arrangement of the er. essentially all mitochondria displayed contacts with the er in both rbl- h and h c cells. plasma membrane-mitochondrial contacts were less frequent with er stacks being inserted between the two organelles. single mitochondria display discrete patches of er contacts as well as continuous as- sociations. cytoplasmic and mitochondrial matrix [ca þ] showed robust er-mitochondrial ca þ transfer with considerable heterogeneity even among adjacent mitochondria. pericam-containing linkers revealed ip -induced [ca þ ]er-mt signals that were resistant to buffering bulk cytosolic [ca þ ]c in- creases and exceeded um. the largest [ca þ ]er-mt signals did not occur at the tightest associations, indicating space requirements for the ca þ transfer machinery and functional diversity among er-mitochondrial junctions. these studies provide direct evidence for the existence of high ca þ microdo- mains between the er and mitochondria in living cells, and open new possibil- ities to probe the functional importance of this specialized compartment. -pos dependence of er-mitochondria calcium transfer on different ip receptor isoforms tunde golenar , szava bansaghi , gyorgy csordas , david i. yule , suresh k. joseph , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, university of rochester medical center, rochester, ny, usa. ip receptors (ip rs) release ca þ from the er, which is locally relayed to the mitochondria to control several aspects of mitochondrial function. recent stud- ies have suggested that type ip rs (ip r ) are particularly important for me- diating the ca þ transfer at the er-mitochondrial interface. we set out to sys- tematically evaluate the respective role of each ip r isoform in chicken dt cell lines that express only one ip r isoform (double-knockout, dko , dko and dko ) or provide a null-background (triple-knockout, tko) for analysis of mammalian ip rs and their mutants. simultaneous imaging of cytoplasmic and mitochondrial matrix [ca þ] ([ca þ]c and [ca þ]m) was performed in either permeabilized cells chal- lenged with ip or in muscarinic receptor overexpressing intact cells stimulated with carbachol (cch), an ip -linked agonist. saturating ip evoked complete discharge of er calcium and resulted in comparable [ca þ]m increases in each dko. furthermore, the cch-induced [ca þ]c spike was closely followed by a [ca þ]m rise in each dko. when tko cells were rescued with rat ip r or ip r , the latter mediated a larger [ca þ]c transient but the [ca þ]m increases were very similar for both isoforms. the relationship between the [ca þ]c peak and the corresponding [ca þ]m response was also very similar for ip r and ip r . to assess the impact of the release kinetic through ip r in the mitochondrial ca þ transfer we used two point mutants of the ip r , which display either enhanced inhibition by ca þ (d n) or are relatively insensitive to ca þ inhibition (d n). d n showed dampened [ca þ]m signal and [ca þ]m vs. [ca þ]c relationship, whereas d n displayed a steeper [ca þ]m vs. [ca þ]c relationship than the wild type ip r . thus, each ip r isoform can support local er-mitochondrial ca þ transfer and their competence to activate mitochondrial ca þ uptake depends on their deactiva- tion kinetic. 	biophysical properties of mitochondria undergoing fusion 	mitochondrial fusion dynamics in human skeletal muscle-derived cells 	imaging interorganelle contacts and local calcium dynamics at the er-mitochondrial interface 	dependence of er-mitochondria calcium transfer on different ip receptor isoforms biomed central page of (page number not for citation purposes) bmc psychiatry open accessoral presentation mental health courts – a human rights perspective grace kerr address: london school of economics and political science, houghton street, london, wc a ae, uk this presentation analyzes specialised mental health courts (mhcs), as one solution to the long-standing, growing challenge of dealing fairly and justly with persons with mental illness (pmis) coming before the criminal justice system, from a human rights (hr) perspective. mhcs have garnered professional and political support in north america. redefining their primary purpose from the determination of fault and the imposition of punish- ment to the provision of treatment and the enhancement of well-being, to date little consideration has been given to whether the costs of mhcs in terms of de-individual- ised justice are worth their benefits. as harris points out, 'sometimes wise policies and practices can have unin- tended side effects'. and as thomas jefferson reminds us, 'the price of liberty is eternal vigilance'. thus, addressing the hr implications of mhcs should rank highly on its advocates' agendas. potential hr concerns, arising from mhcs and relating to pmis essential dignity rights as well as their rights to non-degrading treatment, autonomy, pri- vacy, due process and non-discrimination, will be assessed. like other writers, the presenter urges that only through respecting pmis' rights to services and fulfilling society's duty to provide same, and not through mhcs, will pmis be afforded the full rights that democratic states ought to provide their citizens. the manner in which mdos are managed (or not) by the multiple services and systems they typically encounter creates a broad measure of dissatisfaction that goes beyond any single jurisdiction or country. moreover, the sufficient issue overlaps and fundamental commonalities in approaches to the prob- lems faced by mdos provide a general societal and judi- cial context for an analysis of mhcs and a related hr discussion, notwithstanding the presenter references the provisions of the european convention on human rights (echr) ( ) for her hr analysis. from wpa thematic conference. coercive treatment in psychiatry: a comprehensive review dresden, germany. – june published: december bmc psychiatry , (suppl ):s doi: . / - x- -s -s <supplement> <title> <p>world psychiatric association (wpa) thematic conference. coercive treatment in psychiatry: a comprehensive review</p> </title> <editor>thomas w kallert, john monahan, juan e mezzich</editor> <note>meeting abstracts – a single pdf containing all abstracts in this supplement is available <a href="http://www.biomedcentral.com/content/pdf/ - x- -s -full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/ - x- -s -info.pdf</url> </supplement> this abstract is available from: http://www.biomedcentral.com/ - x/ /s /s © kerr; licensee biomed central ltd. 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of living phytoplankton specimens, anoptral contrast illumination (magnification, × at mm). researchers say that phytoplankton will adapt to major sea temperature changes up to times more quickly than previously thought. 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(image © m. i. walker/science source.) download this issue 	 pdf . mb full text loading... /deliver/fulltext/microbe/ / /znw .html?itemid=/content/journal/microbe/ . /microbe. . . &mimetype=html&fmt=ahah related content /content/journal/microbe/ . /microbe. . . pub_author -contenttype:journal -contenttype:contributor -contenttype:concept -contenttype:institution related content from pubmed mike schmidt betsy kleba kathryn hanley 	 personal account sign-in / register access provided by: carnegie mellon university (# ) asm member status join asm 	 sign-in as administrator 	 username: password: sign in need login help? 	 sign out 	 share tools 	 export citations 	 bibtex 	 endnote 	 zotero 	 plain text 	 refworks 	 mendeley 	 recommend to library these fields are mandatory: * librarian details name: * email: * your details name: * email: * department: * why are you recommending this title? select reason: i need to refer to this publication frequently this publication is an essential resource for my studies/research i'll refer my students to this publication 	 i'm an author/editor/contributor to this publication 	 i'm a member of the publication's editorial board 	 other:   eventtype:personalisation;jsessionid:plhiklfazihq-jc_ rhiqvqj.asmlive- - - - ;itemid:http://asm.metastore.ingenta.com/content/journal/microbe/ . /microbe. . . ;timestamp: invalid site public key invalid site private key invalid request cookie incorrect. try again. unabled to verify parameters could not contact recaptcha for validation i am not a robot * recommend — recommend this title to your library thank you your recommendation has been sent to your librarian. 	 request permission/order reprints access key 	 free content 	 open access content 	 subscribed content back to top about us 	about asm 	contact us 	terms of use 	privacy policy 	copyright & licenses 	public access policy 	permission & reprints resources 	 for authors 	 for librarians 	 for advertisers 	 for instructors 	 for reviewers 	 for the press publications 	 individual member journal subscriptions 	 journal of microbiology & biology education® 	microbiology spectrum® 	ecosal plus® 	books 	colloquia reports 	faq series 	protocols 	curriculum archive american society for microbiology © this is a required field please enter a valid email address please check the format of the address you have entered. approval was a success invalid data an error occurred approval was partially successful, following selected items could not be processed due to error pii: - ( ) - historia mathematica ( ). - note thomas jefferson and douwes’ method for determining latitude james j. tattersall department of muthemutics. providence college. providence, rhode island ams subject classification: ola . - , - . key words: jefferson, douwes, douwes’ method, latitude determination. thomas jefferson’s utilitarian outlook toward mathematics, as well as his solid grounding and keen interest in the subject, is evident in his papers and correspon- dence. these aspects as well as his skill with the subject are clearly illustrated in a previously unpublished document entitled “trigonometry problems.” the work is in jefferson’s hand and details the mathematical computations involved when he made several latitude determinations from poplar forest, virginia, in the win- ter of . jefferson was a lawyer by training and a politician by profession; nevertheless he was well versed in science and mathematics and cognizant of their practical applications. furthermore, he was a member of the american philosophical soci- ety for years and served as its president for of those years. jefferson, like sir francis bacon, firmly believed that the chief function of science and mathematics was to benefit the common man, and that their wise use was the best way to advance social progress and human happiness [i]. his father, peter jefferson, and paternal great-grandfather, thomas jefferson, were surveyors, and undoubtedly jefferson acquired his interest in mathematics from his father, who willed his son all his books and scientific instruments. jeffer- son’s early education was quite standard for the gentry of his day. he spent years at the latin school of reverend william douglas in northam, virginia, and was tutored for years by the reverend james maury in fredricksville, virginia, near the present town of gordonsville. maury had a keen interest in natural science and mathematics and gave jefferson a good foundation in latin, greek, and the classics, and instructed him on the selection of books for his personal library. jefferson considered a good grounding in languages and mathematics indispensable for obtaining a quality education: the former exercises our memory while that and no other faculty is yet matured. and pre- vents our acquiring habits of idleness; the latter gives exercise to our reason. as soon as that had acquired a certain degree of strength, and stores the mind with truths which are useful in / $ . copyrtght by academic press. inc. all rights of reproductmn in any form reserved. note hm other branches of science. [jefferson to thomas mann randolph, jr., august ; boyd , jefferson entered the college of william and mary in . there as a student of william small, professor of natural philosophy and mathematics, jefferson was exposed to newton’s fluents and fluxions. he would later use that knowledge to solve the problem of finding the best form of a body to raise a sod and reverse it after the share has cut under it. in recognition of his achievements in designing a mouldboard of least resistance, he was elected an honorary member of the english board of agriculture in and awarded a gold medal by the agricultural society of paris in . with reference to small’s influence, jefferson wrote: it was my great good fortune, and what probably fixed the destinies of my life. that dr. william small of scotland, was then professor of mathematics, a man profound in most of the useful branches of science, with a happy talent of communication, correct and gentlemanly manners, and an enlarged and liberal mind. he, most happily for me, became soon attached to me, and made me his daily companion when not engaged in school; and from his conversa- tion got my first view of the expansion of science, and from the system of things in which we are placed. [autobiography; lipscomb & bergh , jefferson was only , and had not entered maury’s school yet, when his father died. after more than years had passed, jefferson reflected on his education and referred to small as being . . to me as a father. to his enlightened mind and affectionate guidance, i am indebted for everything. [jefferson to louis hue girardin, january ; lipscomb & bergh , jefferson’s breadth as well as depth in mathematics and astronomy can be estimated by noting the scientific books that he either owned or suggested to others. he assembled three libraries during his lifetime. the first consisted of about volumes, including inherited from his father, which were destroyed by fire a.t shadwell in . the second library consisted of approximately works, and was sold to congress in to replace the original library of con- gress, lost in the burning of the capitol by the british during the war of . the third library consisted of about works originally willed to the university of virginia, but eventually sold at auction by the executors of his estate in to meet outstanding debts. approximately of the books sold to congress dealt with either mathematics or astronomy, and from the many references to these works found in his correspondence, we can infer that he had more than just a cursory knowledge of their contents [ ]. jefferson’s avid interest and fondness for mathematics and astronomy pervaded his program of study for his grandson, thomas jefferson randolph. the program included instruction in surveying and celestial navigation. “trigonometry prob- lems” may relate to the part of this program carried out at poplar forest, the estate in bedford county, virginia, inherited by jefferson upon the death of his father-in-law, john wayles. jefferson approached the task zealously and wrote: hm note i have been for some time rubbing up my mathematics from the rust contracted by f i f t y years’ pursuits of a different kind. and thanks to the good foundation laid at college by my old master and friend small, i am doing it with a delight and success beyond my expectation. [jefferson to the reverend james madison, december : lipscomb & bergh , using letters that jefferson wrote from poplar forest to his daughter, martha jefferson randolph [ and february ; betts & bear , - , we can establish that he spent the month of february at that location. in , he referred to the latitude determinations at least twice in his correspondence. in the summer, he wrote: while here, and much confined to this house by my rheumatism, i have amused myself with calculating the hour lines of a horizontal dial for the latitude of this place which i find to be ” ’ ”. the calculations are for every five minutes of time, and are always exact to within less than half a second of a degree. [jefferson to the reverend charles clay, august : lipscomb & bergh , later that winter, he wrote: i had observed the eclipse of september th with a view to calculate from it myself, the longitude of monticello; but other occupations had prevented it before my journey. the elaborate paper of mr. lambert shows me it would have been a more difficult undertaking than i had foreseen, and that probably i should have foundered in it. i have no telescope equal to the observations of the eclipses of jupiter’s satellites, but as soon as i can fit up a room to fix up my instruments in, i propose to amuse myself with further essays of multiplied repeti- tions and less laborious calculations. i have a fine theodolite and equatorial both by ramsden, a hadley’s circle of borda, fine meridian and horizon as you know. once ascertaining the dip of my horizon, i can use the circle as at sea, without an artificial horizon. do you think of ever giving us a second edition of your map? i f you do i may be able to furnish you with some latitudes. i have a pocket sextant of miraculous accuracy, considering its microscopic graduation. with this i have ascertained the latitude of poplar forest, (say new london) by multiplied observations, and lately that of willis mountains by observations of my own, repeated by my grandson, whom i am carrying on in his different studies. [jefferson to the reverend james madison, december ; lipscomb & bergh , - the calculations in “trigonometry problems” correspond to those of douwes’ method of calculating latitude using double solar altitudes. the method was very popular among british navigators in the late th century because cornelius douwes ( - ), an examiner of sea officers and pilots for the college of admiralty at amsterdam, included tables containing logarithms for the sine, cose- cant, and versed sine of an angle in temporal measure of hours and minutes rather than in angular measure of degrees and minutes, reducing immensely the calcula- tions involved. by the time jefferson used the method, it had been further simpli- fied by nevil maskelyne ( - l), fifth astronomer royal at greenwich, in his requisite tables, where the logarithms of the appropriate functions significant for io-set intervals of time were included, thus avoiding some interpolation necessi- tated by douwes’ original tables. jefferson owned two copies of the edition of maskelyne’s tables requisite and was able to benefit from the modifications. note hm besides the simplicity of the mathematical computations involved, perhaps the overriding reason that jefferson used douwes’ method was that the interval of time between the two observations need only be measured with a common watch. “trigonometry problems” is two pages long and is horizontally partitioned into zones (fig. ). the first zone contains data relating to five solar altitude obser- vations taken on february , . the next zones contain the calculations for seven separate latitude determinations using a distinct pair of the solar altitudes in each zone. the th zone contains data on the solar altitude reading taken on february and six observations taken on february . data on solar altitude readings taken on february appear in the th zone. the latitude of poplar forest is ” ’ ” north of the equator and the deviations in the true latitude and the latitudes calculated by jefferson in the th and th zones are most likely the result of his relaxing the conditions which are necessary fig. . thomas jefferson, “trigonometry problems.” reprinted with permission from edgehill- randolph collection, thomas jefferson papers (fc- ). university of virginia library. hm note for the method to be at all accurate. for not only must a reasonably close estimate be given as a fu-st approximation to the true latitude (jefferson used ” ’), but the two solar altitude observations must be taken less than one hour apart, with one of the readings being an hour or less from noon. in addition, the actual method is a recursive one. hence, after a second approximation to the latitude has been calculated, the process should be repeated using the second approximation as the assumed latitude together with the original two solar altitude observations. thus, the process must be repeated several times if there is to be any consistent accu- racy in the determination of the latitude using douwes’ method. to those who are unfamiliar with douwes’ method and the mathematics in- volved, the following illustration is offered as a key to understanding the computa- tions that jefferson dealt with in calculating the latitude of poplar forest. the first four columns of data in the first zone contain, respectively, the time of the obser- vations, the observed altitude of the sun, the true altitude of the sun (the observed altitude corrected for dip or the height of the observer above sea level, the refrac- tion of the atmosphere, and the time of day), and finally the sine of the true altitude of the sun. for example, the data for the first observation of february was taken at h ” ”, the observed altitude of the sun at that time was ” ’ ”, the true altitude of the sun was ” ’ ”, and the sine of the true altitude was given by . . in the fifth column, we find the declination of the sun on february , ( ” ’ ”), the logarithm of the secant of the declination ( . ), the first approximation to the latitude ( ” ’), the logarithm of the secant of the assumed latitude ( . ), and the log ratio, or sum of the mantis- sas of the two preceding logarithms ( . ). then in the second zone, with reference to the first solar altitude reading taken on february , jefferson sub- tracted the sine of the lesser altitude ( . ) from the sine of the greater altitude ( . ) obtaining . , and in the last column recorded . (which should read . ), the common logarithm of . the figure . , appear- ing just below . in the last column, refers to the logarithm of the cosecant of half the elapsed time between the two observations ( m s), after the time has been converted into angular measurement, using the standard convention of ”/ hr. here jefferson made a minor error in interpolating, for the figure should actually be . . after adding these two logarithms to the log ratio to obtain . , and looking up its antilogarithm ( h m s), which is referred to as the middle time, jefferson subtracted the half time from the middle time to obtain h m s, which is the time from true noon when the greater solar altitude observa- tion was taken. the next figure ( . ), in the last column of the second zone, is the logarithm of lh ” ”, and is referred to as log rising or logarithm of the versed sine less half. subtracting the log ratio from the log rising, jefferson then obtained . , the antilogarithm of which divided by , is . . the addition of . to the sine of the greater altitude yields . . finally, by taking the arcsine of . we obtain the second approximation to the latitude of poplar forest, namely ” ’. a recursive algebraic formulation of douwes’ method is given by note hm sin(a) = sin(az) - sin(ar) cos(xjcos( )sill(t/ ) sin( + - hi+,) = sin(c) + cos(ai)cos(i )sit (b/ ), where aj is the true altitude of the sun at time tj, j = , , tr < tz? t = t - t, b = ia - (t/ )/ c = max(ar, ai) is the declination of the sun a; is the ith approximation to the latitude, i = , , . . . [cotter . in “trigonometry problems,” we are afforded a rare glimpse of thomas jeffer- son doing practical mathematics. not only are we able to follow his arithmetic manipulations, but we can also sense a feeling of accomplishment with the results, as jefferson himself must have done on those chilly winter days in . acknowledgment the author thanks the university of virginia library for permission to reproduce jefferson’s “trig- onometry problems.” notes . an informative account of jefferson’s utilitarian view of mathematics as well as some of his contributions to mathematics education can be found in [smith . an extensive list of bibliographic material relating to jefferson’s scientific contributions can be found in [arret & putney . . see [sowerby - for an annotated list of books that jefferson sold to congress, [tanner for a list of books willed to the university of virginia, and [poor for a list of books sold at auction. the books listed in peter jefferson’s will can be found in the virginia magazine of history and biography ( - ), . . in , as part of the governor’s summer program in science and mathematics for the state of rhode island, i had the opportunity to supervise a group of talented high school juniors and use douwes’ method to determine the latitude of providence. besides being a good exercise in practical mathematics the lesson opened up avenues of discussion regarding jefferson as an amateur mathemati- cian and scientist, the popularity of douwes’ method, and the mathematics and history of the period. the students found the assignment to be both mathematically and historically rewarding. it not only emphasized a branch of mathematics which has been sorely neglected in the high school curriculum, but also brought to light yet another hidden talent of mr. jefferson. references arret, l., & putney, r. t., jr. . thomas jefferson and science: a checklist. charlottesville: university of virginia library. betts. e., & bear, j. a., jr., eds. . thefamily letters of thomas jefferson. columbia: univ. of missouri press. boyd, j. p., ed. . the papers ofthomas.kfferson. vol. . princeton, nj: princeton univ. press. hm note cotter, c. h. . a hisrory ofnaurical astronomy. new york: amer. elsevier. jefferson, t. . “trigonometry problems.” edgehill-randolph collection of the papers of thomas jefferson, fc- , microfilm publication , reel . charlottesville: university of virginia li- brary. lipscomb, a. a., & bergh. a., eds. . the ~‘ritings of thomus jefferson. ~ s. washington, dc: thomas jefferson memorial association. poor, n. p. . caralogue: president jefferson’s library. washington, dc: gales & seaton. smith, d. e. . thomas jefferson and mathematics. scripta murhemarica , - . sowerby, e. m. - . caralogue of the library of thomas jefferson. ~ s. washington, dc: u.s. govt. printing office. tanner, d. . president jefferson’s catalogue of books for the university of virginia. . micro- film publication , reel . charlottesville: university of virginia library. delegate list f abbas aga khan university, karachi pakistan k akakura chiba university school of medicine japan m aragón-castro instituto nacional de cancerologia, mexico city mexico g aus ryhov hospital, jönköping sweden j baniel beilinson medical centre, tikva israel d bottke benjamin franklin medical school, berlin germany c cheng singapore general hospital singapore n clarke christie hospital, manchester uk r coffey university college dublin ireland s egawa kitasato university school of medicine, kanagawa japan n fleshner sunnybrook health sciences center, toronto canada f garcia-sanchez centro de transfusion de madrid spain c goessl benjamin franklin medical school, berlin germany m graefen university hospital, hamburg germany t habuchi akita university school of medicine, akita japan t hachiya ihon university school of medicine, tokyo japan n hegarty university college dublin ireland a kapoor mcmaster university, hamilton, ontario canada s langley royal surrey county hospital, guildford uk f liedberg lund university hospital, malmo sweden c llorente fundacion hospital, alcorcon spain v lokeshwar university of miami school of medicine usa w lynch st george’s hospital, sydney australia s machtens hannover university hospital, hannover germany b malavaud hôpital rangueil, toulouse france i mcintyre christie hospital, manchester uk j van moorselaar university medical centre, utrecht netherlands r morton baylor college of medicine, texas usa r miano tor vergata university, rome italy m müller benjamin franklin medical school, berlin germany c ohyama tohoku university school of medicine japan e plas lainz hospital, vienna austria h van der poel antonivan leeuwenhoek hospital, amsterdam netherlands f rabbani memorial sloan-kettering cancer center, new york usa r reiter jonsson comprehensive cancer center, los angeles usa g de rienzo university di bari, bari italy r scaletsky hospital das clinicas, federal university of rio grande do sul, porto alegre brazil a sciarra university la sapienza, rome italy prostate cancer and prostatic diseases ( ) , suppl , s –s � nature publishing group all rights reserved – / $ . www.nature.com/pcan s taneja new york university medical school usa b tombal university hospital ucl, brussels belgium r valicenti thomas jefferson university hospital, philadelphia usa c wood md anderson cancer center, houston usa a zlotta erasme hospital, university clinic of brussels belgium faculty m soloway (chairman) university of miami school of medicine usa r buttyan columbia university, new york usa f debruyne university medical center, nijmegen netherlands c evans university of california davis school of medicine, sacramento usa m gleave university of british columbia, vancouver hospital and health sciences centre canada p hammerer university hospital, hamburg germany w isaacs the johns hopkins university school of medicine usa h lilja lund university sweden j schalken university hospital, nijmegen netherlands delegate list s prostate cancer and prostatic diseases 	delegate list microsoft word - . antonucci_darkest italy revisited.docx darkest italy revisited: race, character and criminality in the history of italian immigration to the united states, - anthony antonucci california polytechnic university (pomona, ca) abstract from lucky luciano to tony soprano, the image and idea of italian criminality is a well- established component of american perceptions of italianità. where, when, and why did this stereotype originate? and what is the relationship between american prejudices about italian criminality and the history of italian immigration to u.s.? this paper answers these questions by documenting how american notions of italian criminality first emerged when american visited italy during the period of the early american republic ( - ). the paper shows how italian criminality was first developed and transmitted through the travel writings of american grand tourists, such as thomas jefferson’s secretary william short, the novelist washington irving, and the historian theodore dwight. this study shows how these notions of italian criminality, originating before the civil war ( - ), shaped the way italian immigrants were received upon arrival in the u.s. during the period of their mass migration, between the s and . in that year, the united states introduced a system of quotas based on national origin that “closed the door” to italians and other immigrants. tracing the genealogy of deep-rooted american stereotypes about italian criminality back to their th century origin, this paper shows the trans-national features upon which italians were categorized within the ethno-racial hierarchies that structured late th and early th century american society. keywords: transnationalism; grand tourism; immigration; criminality; ethno-racial formation. ost americans are proud of their country’s identity as a “nation of immigrants.” many would also like to believe that the united states has always been an “asylum of liberty,” offering refuge to the world’s “tired, poor huddled masses, yearning to breathe free.” yet, for most of its history, the united states has not been a particularly welcoming place for the foreign-born. according to the standards established by the naturalization expressed in many ways, by many speakers and authors over the years, the idea of the united states is a “nation of nations” was, perhaps most famously, expressed by poet walt whitman in the preface to his volume, leaves of grass. the publication of u.s. senator john f. kennedy’s book a nation of immigrants in ushered in an era in which the moniker has become a common reference. the idea of the united states as an “asylum of liberty” can be traced to thomas paine’s popular tract common sense ( ), written during the american war for independence ( - ). these lines are taken from emma lazarus, sonnet “the new colossus” ( ). in , lazarus’s iconic poem was inscribed on the inside of the pedestal of the statue of liberty. m | darkest italy revisited jam it! no. may | nationalism: hyper and post act of , the first law passed by congress under the constitution regulating the status of foreign-born people inside the u.s., only “free, white, male aliens of good character” who had resided in the u.s. for at least two years were eligible to become american citizens. persons who did not meet these criteria – for example, native americans, people of african descent, foreign-born women and all other “non-whites” – were classified either as property, dependents, or permanent aliens. reflecting this tacit cultural consensus, as early as benjamin franklin defended north americans’ application of the racial category of “whiteness” exclusively to persons of anglo-saxon descent in his treatise observations concerning the increase of mankind. in this tract, franklin advised his fellow englishmen to make every effort to exclude “all blacks and tawneys” from settling in north america. his list of undesirables also included “swarthy,” “non-white” european groups like “the spaniards, italians, french, russians and swedes,” and even most german populations as well. in his view, the only purely white populations were “the saxons, who with the english, make the principal body of white people on the face of the earth” (franklin , - ). the naturalization act of , reflecting the social and cultural hierarchies developed during the british colonial era, adopted the notions of “whiteness” and “good character” to identify qualities understood to be the unique provenance of people of protestant “anglo- saxon” (e.g. british/northern european) heritage. with only a few minor alterations, these criteria structured the relationship between race, character, immigration, and citizenship until the american civil war ( - ). until the eve of the american civil war, franklin’s ethno-centric sense of “true whiteness” as a quality exclusive to people of anglo- saxon heritage set the pace for the interpretive paradigms of race, national origin and character through which u.s. immigration and naturalization policy took shape. so long as the critical mass of “free, white” people seeking to naturalize as u.s. citizens hailed from the british isles, saxony and other parts of “pure white” northern europe, the formulation contained in the law helped maintain the cultural homogeneity of the predominantly protestant, anglo-american population. however, during the middle decades of the th century, the united states’ color-coded immigration system faced a crisis when a rising tide of immigration from the catholic and jewish parts of europe began to arrive en masse in anthony antonucci | the united states. the arrival of these new immigrant groups meant that the legal definition of what it meant to be “free and white” could no longer stand as easy proxy for people of protestant, anglo-saxon descent. the first waves of non-anglo-saxon newcomers of european descent arrived in the s and s and consisted of catholics from ireland and the french speaking parts of eastern canada seeking opportunity in the rapidly industrializing sectors of the u.s. economy. by the s, the largest immigrant groups to the u.s. included italians, greeks, lithuanians, poles, czechs, and russian jews, among others. to many native-born citizens, the mass arrival of “swarthy” catholic and jewish foreigners from southern and eastern europe threatened the stability and homogeneity of the anglo-american way of life. fearing that mass immigration would carry old world poverty, crime, and social divisions to american shores, anglo-saxon nativists mobilized a national movement for immigration restriction. by , the advocates for immigration restriction succeeded in redefining the criteria that determined naturalization. overturning the naturalization act, the national origins act of (also known as the johnson-reed act) restricted immigration visas to two percent of the total number of people of each nationality already in the united states as of . in effect, the reed- johnson act closed immigration for non-anglo-saxon european nationalities, as well as for all asians. consequently, from until the overhaul of reed-johnson with the hart- celler immigration act in , immigration and naturalization in the united states were regulated by national origin quotas, rather than by qualifications based explicitly on race and moral character. nevertheless, in the views of many u.s. citizens and government officials these categories and qualifications remained intimately intertwined. at the root of the divisive debates that have shaped u.s. immigration policy are fundamental nativism is an umbrella term encompassing the waves of social and political movements aimed at protecting the interests of native-born anglo-saxons above those of immigrants who did not hail from northern europe or the british isles. as the harvard-trained lawyer prescott hall, co-founder of the immigration restriction league, quipped in , “do we want this country to be peopled by british, german and scandinavian stock—historically free, energetic, progressive, or by slav, latin, and asiatic races—historically downtrodden, atavistic and stagnant?” (hall , ). see also higham, . specifically, the johnson-reed act granted people immigrating from countries of northern and western europe more than , visas each year; by contrast, southern and eastern european countries received just , visas and all the countries of asia and africa combined were given , . the law did not apply to persons emigrating from other nations in the western hemisphere, such as mexico and other parts of latin america and the caribbean. | darkest italy revisited jam it! no. may | nationalism: hyper and post questions about citizenship and national belonging: who and what is an american? who is qualified to become an american? to date, much of the scholarly literature examining this topic has focused on how variable constructions of race and ethnicity have been applied to successive waves of foreign groups, and how these various ethno-racial formations have shaped immigrants’ prospects for full participation in american life. inspired by critical perspectives developed by scholars such as david roediger and other contributors to the interdisciplinary field of “whiteness studies,” in the s and early s a new generation of immigration historians took up the task of uncovering what matthew frye jacobson describes in whiteness of a different color ( ) as the relationship between “european immigrants and the alchemy of race.” demonstrating the fluidity of late th and th century racial categories, jacobson’s influential study demonstrates that many of the people americans now widely regard as belonging to white ethnic groups were previously perceived as racial “others” understood to be “less than fully white.” as evidence, jacobson reported that, during the late th and th centuries, self- identified american anglo-saxons classified immigrants from the catholic and jewish parts of europe, such as irish and italians, as belonging to inferior “celtic,” “latin” or “mediterranean” races. jacobson convincingly argues that these inter-european racial differences reached their political apex with the immigration act and the u.s. decision to close the door to overseas immigration. he contends that during the inter-war years, europe’s racial others began the slow movement toward “becoming fully white” (and thus “fully american”) through a process of civic assimilation finally completed by the end of world war ii. thus, jacobson concludes, in the post-war period, europe’s “racial” others were transformed into members of a new, broad-based “caucasian” racial group able to enjoy the full privileges of american whiteness ( ). in conversation with jacobson’s thesis, other scholars have attempted to decode the racial construction of various european immigrant groups at the time of their enter upon american soil. beginning with noel ignatiev’s how the irish became white ( ) and karen brodkin’s how jews became white folks & what that says about race in america ( ), more recent contributions to this topic include: thomas a. guglielmo’s white on arrival: italians, race, color and power in anthony antonucci | chicago, - ( ), jennifer guglielmo and salvatore salerno’s edited volume are italians white? how race is made in america ( ), and david roediger’s working toward whiteness: how america’s immigrants became white: the strange journey from ellis island to the suburbs ( ). together, this body of work introduced the next generation of american studies scholars to the power and complexity of the contingent racial formations that structured the ruling hierarchies of american social and political life and shaped national debate on immigration through the national origins act and beyond. while these studies are extremely valuable, the patterns identified by jacobson and others overlook the extent to which, by the s, anglo-americans had already developed a distinctive corpus of ideas connecting the national origin, racial identity, and moral character of various southern and eastern european groups. in fact, as this paper demonstrates, the stereotypes american nativists applied to european immigrant “others” in the late gilded age and progressive era ( - ) were prefigured in american travel writings and works of fiction produced during the early national and antebellum periods ( - ). accordingly, i argue that anglo-american reactions to immigration at the turn of the th century cannot be properly understood without reference to american ideas about race, character, and national origin established during the earlier periods of trans- atlantic political and cultural history. most notable is the fact that until the s, prevailing american notions about the racial and moral character of various european populations were formed by u.s. travelers, journalists, businessmen and diplomats operating overseas. to illustrate how ideas about race and national character formed abroad before the civil war affected national discourse and policy decisions on immigration and citizenship after , this paper focuses on a specific group of immigrants to the united states between th and th century: italians. anglo-american ideas about italian “national character” originated prior to the great waves of migration that began after italian unification in and contributed to the classification of italians among southern and european immigrants. demonstrating how stereotypes about italians first emerged at the time of thomas jefferson’s office ( - ), this paper shows how opinions about the “italian character” preceding the civil war established a legacy behind the reception of | darkest italy revisited jam it! no. may | nationalism: hyper and post italians during the peak years of their migration to the united states ( - ). more specifically, i will show the genealogy of the longest american stereotype about the italian character: their alleged criminality. the story begins in naples. vedi napoli e poi muori despite the remarkable achievement of a victory over the greatest military force on the planet during their war of independence (thanks to french support), and an equally astounding record of economic growth and territorial expansion throughout the decades prior to the civil war, americans remained deeply insecure about their intellectual and cultural achievements as a nation. above all, late th and early th century americans feared the judgement of european aristocrats about their artistic and scientific achievements. compensating for their abiding sense of post-colonial inferiority, citizens in the early republic attempted to live up to european (in particular english) standards of taste and sensibility by adopting a range of imitative cultural practices. one of the principal rituals of refinement that american citizens appropriated from their former mother country was the british tradition of taking a grand tour of italy (baker , prezzolini ). the template that inspired americans to travel to the peninsula in the years prior to italian unification had its origins in the late th century, when fashionable young aristocrats from england concluded their classical educations by setting off in a private carriage accompanied by a tutor and perhaps by a few servants on an extended sojourn to learn about the politics, culture, art, and architecture of neighboring lands. the itinerary of what became known as the grand tour varied according to fashion but typically included destinations in france, germany, the netherlands, switzerland, and above all the italian peninsula and its islands. with roman ruins, ancient monuments, lavish palaces, rich collections of renaissance paintings, and picturesque natural beauty, italy was regarded as literally: “see naples and then die,” it means that one must see the beauty of naples before dying but it also offers warning about the dangers associated with visiting naples. the origins of this famous and repeatedly cited expression remain a topic of debate. appearing perhaps most notably in johann wolfgang von goethe’s italian journey: - ( ), the phrase is a nearly ubiquitous utterance in connection with travel writing about southern italy. for an overview of the origins, practices, and itinerary of the grand tour see black . anthony antonucci | the non plus ultra of an enlightened gentleman’s education. by , the year the united states declared their independence, italian travel had grown so fashionable among well- heeled britons that samuel johnson sardonically gibed: “a man who has not been in italy is always conscious of an inferiority, from his not having seen what it is expected a man should see. the grand object of travelling is to see the shores of the mediterranean” (boswell , ). the culmination of the italian grand tour was a visit to the southern italian kingdom of the two sicilies. comprising the vast domains of mainland italy south of rome as well as the island of sicily, the bourbon kingdom and its capital city naples captured the imagination of foreign visitors from throughout late th and early th century europe. this sentiment was epitomized by johann wolfgang von goethe’s admonishment that to live fully one must first go “see naples and then die” (boswell ). across the atlantic ocean, many citizens of the rising american republic, from thomas jefferson to herman melville, shared goethe’s interest in naples and southern italy (reinhold ). the exchange that developed between the u.s. and naples prior to the invasion of garibaldi’s mille is remarkable given the contrasts between the two countries. the united states was a republic, born in revolution, out of a british colonial past. the two sicilies was instead a catholic monarchy, with roots in antiquity, formed from the union of sicily and naples in the th century and ruled by a bourbon dynasty since . at a time when italians were governed by a half-dozen rival states, american tourists travelling abroad saw the southern kingdom as a critical symbol of italian otherness. some american travelers pictured naples as a benighted land defined by indolence, criminality and backwards superstitions; others saw it as a romantic refuge; a third contingent regarded southern italy as an emerging market inhabited by people with interests in increasing trade and national standing, but who remained mired in poverty as a result of a tyrannical government. in place of the theories of difference based on genetics that emerged by the early th century, late th and early th century grand tourists attributed the poverty and from through , the two constitutionally separate kingdoms of naples and sicily were ruled as a “personal union” under the control of the bourbon monarchy. during the two periods of french invasion in southern italy ( and - ), the bourbons maintained control of sicily but lost power in naples. after the restoration of the monarchy at the end of the napoleonic wars in , the two hitherto separate (yet united) crowns were merged as a united realm called the kingdom of the two sicilies which lasted until the unification of italy in . | darkest italy revisited jam it! no. may | nationalism: hyper and post underdevelopment they perceived in southern italy to a combination of geographical and climatic determinism, atavistic social practices, and the influence of the roman catholic faith. following the lead of protestant tourists from england, americans ascribed southern italy’s social conditions to the impact of the catholic church, an institution they derided as an engine of tyranny and ignorance (franchot ). when combined, these geographic and cultural factors crystallized into a distinctive set of american ideas about southern italian national character, a short-hand term for perceived cultural differences that chauvinistically celebrated american industry and pragmatism as compared to the stereotypical southern italians’ stereotypical preference for il dolce far niente (sweet doing nothing) and indulging their passions (brand ). in keeping with the conventions of british grand tourism, american travelers kept journals of their trips; if travel was a mode of cosmopolitan education, the travel journal was the school in which the lessons were preserved. the range and tenor of american ideas about southern italians that developed on the grand tour can be observed through a brief, comparative survey of writings by three representative anglo-americans: william short ( - ), who was thomas jefferson’s personal secretary; the novelist washington irving ( - ); and the historian theodore dwight ( - ). drawing upon first hand encounters with italians in all parts of the peninsula, each of these writers contributed to american interpretations of national character, morality and politics in the kingdom of the two sicilies. un paradiso abitato da diavoli? william short was the man whom jefferson would one day refer to as his adoptive son and who would later serve as the future president’s eyes and ears in the kingdom of naples. he was born to william short (the fifth) and elizabeth skipwith at spring garden in surry county, virginia, in (cullen , - ). short came of age closely connected to jefferson and his family. the mentor-mentee dynamic that would define their life-long bond began during short’s tenure as a law student under jefferson’s former tutor, george literally, “a paradise inhabited by devils.” delivered as a description of naples and southern italy, this phrase is attributed to the neapolitan philosopher benedetto croce. anthony antonucci | wyeth, at the college of william and mary (cullen - ). sufficiently impressed by short’s “peculiar talent for prying into facts,” jefferson hired the young man in the wake of his diplomatic appointment as u.s. minister to france (jefferson ). once abroad, jefferson encouraged his protégé to visit italy, which he did in the fall of . through short’s letters – the first extensive travel letters written by an american in southern italy – jefferson enjoyed a vicarious encounter with the conditions of life on the peninsula, all the way into the heart of bourbon naples. after passing through northern italy, short set forth from rome for the kingdom of naples on january , . like dozens of subsequent other american tourists, short’s tour of naples was modeled on the british travel plan and included stops at pompeii, herculaneum, campi flegrei, virgil’s tomb, the sibyl’s cave, and an ascent of mt. vesuvius (short ). in naples, social conditions captured short’s attention first. along the way from terracina to naples, short observed that despite the region’s natural marvels, everywhere there were “numberless objects of poverty and distress.” “there must be a cruel defect somewhere,” short concluded; “most certainly it is not either in the soil or climate” (short ). the fault, he implied, layd in the kingdom’s social institutions. arriving in the capital on january, short spent seventeen days exploring the sites around the bay of naples (short ). on february short wrote a second letter to jefferson detailing his journey: he began with a description of his entrance into naples. he was astonished by the size and poverty of “the immense crowds of people which are constantly in the streets:” the human spectacle of the lazzaroni had an unsettling effect on him. “many people are pleased with this circumstance and extol the vast population of naples,” he noted, but “i confess it produced a different effect on me. these crowds are composed only of people of the lowest and poorest order. they remain there because they have no other place to go to. they are ill clad dirty and have the marks of evident and pressing poverty upon them” (short ). naples, in his eyes, was a city of the homeless. for short, the misery of the urban poor was all the more striking in contrast with the wealth and finery of the upper classes: “the middle of these streets . . . are filled with the lazzaroni were a class of people often described as street people living under a chief and were frequently depicted as beggars despite the fact that many subsisted as day laborers. in contrast to the parisian sans-culottes, the neapolitan lazzaroni were conservative monarchists fiercely loyal to the bourbon government, especially to king ferdinand iv. | darkest italy revisited jam it! no. may | nationalism: hyper and post as much brilliancy and show as are the sides with wretchedness and poverty. the most superb carriages, and fine horses with elegant trappings, are in a kind of constant procession here” (short , - ).. by may william short was back at his post in paris (jefferson ). the observations he gathered on his tour of campania conveyed to jefferson an image of the bourbon capital and its famous bay as a region marked by venerable ruins, fertile soil, and an economy in need of the liberating force of free trade. in naples, short discerned the weight of feudal oppression and monarchical despotism. sixteen years later, a twenty-two-year-old writer from new york named washington irving followed in short’s footsteps and made his own pilgrimage to the italian mezzogiorno. like short, irving found that few aspects of southern italian society stood in greater contrast to life in the united states then the gap between the luxury of its upper classes and the deprivation of the poor. in addition to praising the scenery and lamenting the kingdom’s divisions of wealth, irving characterized naples as a land of banditi (criminals). when the young writer set out northward on the overland journey from syracuse to catania, he carried his fears of southern italian brigands with him at every turn in the road. as a precaution, irving travelled with a company of eleven mounted american marines, stationed in sicily as a part of the u.s. war against tripoli, then underway. at first, the presence of a military guard gave irving some comfort but travelling through the sicilian countryside aroused his dread: “the first day we passed through several solitary places where the mountains abounded in vast gloomy caverns that seemed the very haunts of robbery and assassination” (irving , ). by the end of march , irving was ready to leave the southern italian kingdom: he admired naples’s romantic scenery and artistic treasures, but he found the contrast between the opulent few and the impoverished many dispiriting and his fears of criminal attack exhausting. travelling north through the rural parts of campania on route to the papal states, he remained anxious about banditi. passing the night at an inn in terracina, he was awakened by a mysterious sound at the door; convinced that bandits were about to assault him, he cried out for help and rushed at the door armed with a pistol, discovering that it was only a dog begging for food (irving , ). in may irving arrived at the lateran gate unscathed. to his relief, the kingdom anthony antonucci | of naples proved to be a country of peaceful, if oppressed and impoverished, people. the ubiquitous lazzaroni were irksome, but unthreatening; and despite his fears he had avoided the unwanted encounters with brigands. the real scourge of the south, the new yorker concluded, was its tyrannical elites and corrupt government officials. this was a thesis he later developed in fiction (wright ). two decades after his visit to sicily and naples, irving indeed wrote “the italian banditti,” a series of southern italy-based short stories included in his popular tales of a traveller by geoffrey crayon, gent. ( ). surprisingly, rather than the marauding fiends who haunted irving’s travels in , the southern italian banditi he depicts in his fiction are hardworking peasants driven to brigandage by poverty and corrupt bourbon officials. in the cycle’s opening tale, “the inn at terracina,” irving’s narrator explains the bandit’s heroic place in southern italian society: [the banditti] secure . . . the good-will of the inhabitants of those wild regions, a poor and semi-barbarous race, whom they never disturb and often enrich. indeed, they are considered a sort of illegitimate heroes among the mountain villages, and in certain frontier towns where they dispose their plunder . . . it is true that they are now and then hunted and shot down like beast of prey by the gens- d’armes their heads put in iron cages and stuck upon posts by the road-side . . . but these ghastly spectacles only serve to make some dreary pass of the road still more dreary, and to dismay the traveler, without deterring the bandit. (wright , - ) the italian counterparts to robin hood, irving’s brigands are what the th century historian eric hobsbawm would dub “primitive rebels or social bandits, a peasant rebelling against landlords, usurpers and other representatives of . . . the conspiracy of the rich” (hobsbawm ). irving would have agreed. for all their fearsome reputations and occasional violence, his briganti are courageous, freedom-loving rebels aspiring to a better life. they are depicted as an organized militia at war against the bourbon authorities: donning “a kind of uniform, or rather costume that designates their profession . . . to give themselves a kind of military air in the eyes of the common people,” they attack symbols of bourbon power and avenge the abuses of the king’s police (irving , - - ). in this telling, the italian banditi were nascent republicans looking to the united states for their ideals and the promise of a better life. for example, at the end of “the story of the | darkest italy revisited jam it! no. may | nationalism: hyper and post young robber,” the final tale in irving’s cycle, a french painter temporarily held captive by a troop of sympathetic banditi recounts their captain’s desire for re-birth in the land of liberty: “he told me he was weary of his hazardous profession; that he had acquired sufficient property, and was anxious to return to the world and lead a peaceful life in the bosom of his family. he wished to know whether it was not in my power to procure him a passport for the united states of america.” confident that the young bandit would find a propitious future in the rising republic across the sea, irving’s narrator declares: “i applauded his good intentions, and promised to do everything in my power to promote its success” (irving , ). washington irving was not the only writer to suggest that discontented southern italians looked to the united states as the model for their political future. the trend gained momentum in the s in response to the early stirrings of the risorgimento in the mezzogiorno and elsewhere across the italian peninsula. four years before the publication of tales of a traveller ( ), tens of thousands of ordinary sicilians and neapolitans mobilized to demand that the bourbon government adopt a program of liberal reform. led by the carbonari (charcoal burners), the secret revolutionary societies founded in naples and other parts of italy in the early th century for the purpose of defining the rights of common people against absolutism, the revolutionary coalition cultivated widespread popular support throughout the kingdom’s provinces as well as in the capital city. under the command of the celebrated generals guglielmo pepe, pietro colletta, and luigi minichini, the revolutionary movement succeeded in forcing the bourbon government to agree to a constitution on july . the changes were bold: the government’s adoption of the radical spanish constitution of provided for democratic governments at all levels, with voting rights granted to all males over twenty-one regardless of literacy (davis , ). sadly, the neapolitan attempts to establish liberal, constitutional rule did not last: in may , backed by austrian support, king ferdinand reentered naples, revoked the constitution and immediately launched a policy of repression and retribution (davis , ). after the failure of the carbonari revolution, american tourists wondered whether or not the poor, huddled masses of the mezzogiorno were cut out for self-rule. on this topic, american opinion was divided. even anthony antonucci | washington irving seemed torn, as his fiction showed. the ennobling vision of poor, southern italians turning to crime and brigandage as a means of rebellion against bourbon misrule that irving represents in his “tales of the banditti” reflects the author’s nascent support for the early stirrings of the italian risorgimento. but his faith in southern italian capacity for american-style democracy was only partial. despite the optimism he expressed about the southern italian character in the “tales of the banditti,” irving harbored suspicions that the people of the mezzogiorno were ruled by violent passions and volcanic tempers that disqualified them from republican life. for instance, in other of his italian- based short stories, southerners are depicted as people with in-born violent tempers that drown out reason and the love of liberty. irving’s “story of the young italian,” also published in tales of a traveller by geoffrey crayon, gent. ( ), recounts the tale of ottavio, a young neapolitan painter driven to commit murder after a lifetime of victimization by corrupt laws and dishonest authorities. tragically, ottavio’s unwitting act of retributive violence turns him into a fugitive, exiling him from his true love, bianca, and destroying his future as an artist. mid-way through irving’s story ottavio warns his readers: “you who are born in a more temperate climate and under a cooler key, have little idea of the violence of passion in our southern bosoms” (irving , ). the fact that a crime of passion transforms irving’s protagonist from the would-be hero of a new social order into a criminal brigand offered irving’s readers a cautionary tale that later th century american nativists recycled in the name of restricting immigration from southern europe: if southern italians were to succeed as a self-governing people they must first overcome the irrationality of their inborn tempers and control their violent passions. unlike the ambivalence expressed by washington irving in his fiction, other american travel writers pondered the nature of southern italian national character and reached damning conclusions. in the eyes of historian theodore dwight, it was clear that sicilians and neapolitans did not possess the rational temperament that was a prerequisite for citizenship in a democratic republic. rather, in dwight’s prejudicial view, southern italians were inveterate criminals whose poverty and ignorance stemmed from laziness and inability to control their passions. arriving in naples in december , dwight ( - | darkest italy revisited jam it! no. may | nationalism: hyper and post ), a twenty-five-year-old yale graduate and scion of a prominent new england family, visited the two sicilies just six months after the carbonari led revolution in july and spent five weeks in naples during the kingdom’s nine-month experiment in constitutional government ( / ). in , the same year as irving’s tales of a traveller, the future american biographer of giuseppe garibaldi and author of a popular history of the roman republic of published his first book on an italian subject, a journal of a tour in italy in the year with a description of gibraltar ( ). compared to the ambiguous depiction of southern italians presented by irving, dwight’s journal depicts neapolitans as a servile and ignorant people, congenitally incapable of bringing about their own liberation from the twin manacles of the bourbon monarchy and the catholic church. though sympathetic to the cause of liberty, dwight could find in the southern italian character no seeds of independence and no hints of a successful revolution to come (dwight , ). throughout his journal, dwight’s pessimistic claims about southern italians are supported by the testimony of his principal native informant signore mattia, a neapolitan man he befriended on the voyage from gibraltar to naples. on route mattia warns the american that all neapolitans are “great thieves,” and he volunteers to escort dwight around the city, lest he “should be cheated, robbed and perhaps murdered” (dwight , ). it is not clear whether mattia was a real person or a literary device to reinforce national stereotypes. at times he comes across as a hustler exaggerating the dangers of naples for the sake of free dinners and a tip: “many of those extravagances which seemed to stamp him as a madman, are now converted into national peculiarities. he is not, as i can see, a whit more irascible than his countrymen. they all fly into fits of passion as hastily.” in the journal mattia plays a puckish virgil to dwight’s american dante as the two men tour naples infernal streets. heeding mattia’s warning to “take care of your pockets,” and “keep your mouth shut – or they will steal your teeth,” dwight declares: “i never would condemn a nation in the gross; but i think a traveller can hardly visit naples without being struck with the disposition to cheat him manifested by almost every person with whom he has any concern” (dwight , ). if conditions were miserable inside the capital city, the rural provinces were even worse. reporting on news of the kidnapping of two english gentlemen on the main carriage anthony antonucci | road north of rome, dwight emphasized the omnipresent danger of the kingdom’s banditi: “there is very little pleasure in travelling that road, i assure you. you hardly see a man in all that tract of country who does not look as if he were half an assassin” (dwight , ). in contrast to the bleak scenes he encountered in naples, northern italy – and turin in particular – presented an encouraging prospect. there he could confidently look for the spread of liberal institutions in the hands of rational men. writing from florence several weeks after he left the south, dwight drew a sharp line between northern and southern italy: “it is going back to past centuries to land at naples: and travelling north is to move along with time and the gradual progress of society.” in contrast to naples, where lazzaroni lived in the streets and bandits infested the countryside, the people in turin appeared ready for self-rule: “the houses are good and built with much regularity, and the principal streets are as straight and broad as those of philadelphia . . . these things argued at once a superior taste for what we consider many of the necessaries and comforts of life, and the dress and comportment of the citizens proved that they had advanced an important grade in civilization” (dwight , ). in the decades ahead, dwight’s opinion, that italy’s future as a modern constitutional state depended upon the rule of the purportedly more rational, orderly northern italians, led by the savoy monarchy, over the indolent, quick-tempered criminals who lived in the south, predicted u.s. policies. indeed, throughout the peak years of the italian risorgimento and into the period of mass migration of southern italians into the united states, dwight’s bi-furcated assessment of italy’s “two halves” and the perceived differences between their respective populations came to define prevailing american notions about italy and italians. back home, dwight played a central role in translating these ideas into political action. after his tour of naples and italy in , he returned to the united states and became a leading architect of what historian howard r. marraro would later call the american view of the risorgimento “as a religious problem” (marraro ). by dwight was publicly promoting the idea that italy’s future would be best developed under the piedmontese monarchy through the american philo-italian society, an organization based in new york. along with painter and inventor samuel f.b. morse ( - ), educator henry philip tappan ( - ), and others, dwight framed the | darkest italy revisited jam it! no. may | nationalism: hyper and post movement for italian unification as a struggle between protestant enlightenment and catholic darkness. his organization’s mission was “to unite protestant christendom in this holy war” (“the christian examiner and religious miscellany” , ). where could such “protestant” leadership be found? dwight looked to the italian provinces north of rome. after dwight was a vocal supporter of the movement led by the northern italian born giuseppe garibaldi, whom he called “the george washington of his people.” throughout the decade before the civil war, dwight promoted these views alongside other prominent american supporters of the risorgimento, most of whom were fellow alumni of the italian grand tour (d’agostino , ). darkest italy comes to the united states the negative stereotypes about southern italians generated by american travelers like william short, washington irving, and theodore dwight prior to took on a special resonance in the aftermath of italian unification when, between and , more than four million italians crossed the atlantic ocean to seek opportunities and build new lives in the united states (bodnar , handlin ). while some americans greeted italian immigrants as a welcome addition to the growing foreign-born industrial work force, many others did not. in fact, to large numbers of native-born anglo-saxon americans, italians appeared as unwanted aliens – a people at once exotic and strange, possessed of in-born traits and cultural habits that rendered them less than “fit” to become self-governing citizens of the american republic. the negative qualities that late th and early th century anglo-americans perceived in southern italians were composed of a litany of slurs and “one-size-fits-all” generalizations consistent with an earlier generation of stereotypes about people from the former domains of the kingdom of the two sicilies. inflected through the lens of “scientific racism” and the burgeoning field of eugenics, by the early th century southern italians were profiled as possessing a distinctive set of physical, moral, and cultural traits that were at odds with anglo-american values. echoing tropes for overviews of this history see: deconde ; gabaccia ; carnevale ; orsi . anthony antonucci | expressed in the writings of short, irving, and dwight decades earlier, the undesirable traits americans attached to southern italians included their roman catholic faith, peasant roots, inability to speak english, swarthy skin tones, and reputations for violent mediterranean tempers. above all, between and nativists charged that italians were predisposed to criminality and criminal behaviors, including a predisposition to commit crimes of passion and participate in organized criminal conspiracies. as a result of these widely circulating prejudices and stereotypes, italian immigrants to the united states faced frequent harassment, discrimination, and persecution by american citizens and u.s. officials alike (connell and gardaphé ). the prejudices that early th century anglo- americans held about italian racial and moral character are epitomized in the language and findings of the official reports prepared by the u.s. immigration commission (the so- called dillingham commission), a congressional body composed of u.s. senators, representatives, and social scientists appointed by president roosevelt in to investigate the effects of foreigners on american life. in the dillingham commission published a volumes report on all aspects of american immigration. drawing upon the corpus of preexisting ideas about the racial and moral character attributed to italians by earlier american writers, government officials recycled antebellum stereotypes that perpetuated the long-standing notion that people from southern italy constituted an inferior race predisposed to criminality. for example, the authors of commission report volume , investigating connections between immigration and crime, declared that “italian criminals are largest in numbers and create the most alarm by the violent character of their offenses in this country” (immigration commission vol. , ). expounding upon this claim, a report published in volume (the emigration of the criminal classes) announced: an alarming feature of the italian immigration movement to the united states is the fact that it admittedly includes many individuals belonging to the criminal classes, particularly named in honor of republican senator william p. dillingham (vt), the commission reports offered a range of perspectives identifying both the positive and negative impact of immigration on american life. proponents of immigration restriction mobilized those findings that supported the nativist agenda culminating in new restrictions on immigration in (instituting a literacy test) and (instituting quotas), on route to the landmark national origins act of . | darkest italy revisited jam it! no. may | nationalism: hyper and post of southern italy and sicily . . . (and by) the not unfounded belief that certain kinds of criminality are inherent in the italian race. in the popular mind, crimes of personal violence, robbery, blackmail and extortion are peculiar to the people of italy, and it cannot be denied that the number of such offenses committed among italians in this country warrants the prevalence of such a belief. (immigration commission vol. , ) consistent with antebellum theories of italian identity, the dillingham reports divided the italian race into two separate and unequal groups. in volume , u.s. officials declared: “ethnologically there are two distinct branches of the italian race – the north and the south italian . . . it may be briefly said, however, that the north italians have a large admixture of celtic and teutonic blood, while the south italians are largely a mixed type in which greek, spanish, saracen and other blood is more or less prominent” (immigration commission vol. , - ). the fact that american immigration officials classified italian nationals into two different racial groups was unique. specifically, southern italians (or south italians as they were also labeled) were believed to belong to the latin or mediterranean ethno-racial group, whereas northern italians were a branch of the allegedly superior alpine, nordic, or teutonic racial group also claimed by the predominantly protestant, anglo-saxon people. regarding phenotypic differences between northern and southern italians, u.s. officials explained: physically, the italians are anything but a homogeneous race . . . the apennine chain of mountains forms a geographical line which corresponds to the boundary between two distinct ethnic groups. the region north of this line . . . is inhabited by a very broad headed (alpine) and tallish race, the north italian . . . all italy south of the apennines and all of the adjacent islands are occupied by a long-headed, dark “mediterranean” race of short stature . . . the bureau of immigration places the north italian in the “keltic” division and the south italian in the “iberic.” (immigration commission vol. , ) elaborating on these distinctions, the commissioners observed that sicilians in particular were “vivid in imagination, affable, benevolent but excitable, superstitious and revengeful” (immigration commission vol. , ). to support these findings, u.s. officials drew upon a vast literature on the racial identities of italians and other europeans authored by european scientists. remarkably, works by leading italian scientists and government officials, including pasquale villari, giustino fortunato, sidney sonnino, anthony antonucci | leopoldo franchetti, and francesco saverio nitti, played a fundamental role in establishing the ethno-racial taxonomies used by u.s. officials to classify italians immigrants: this literature reflected political and sociological divisions taking place within italy after its unification, in (moe ). since at least , ethnographers employed by the victorious piedmontese army reinforced the long-standing notion that the newly unified italian nation was made up of two separate and unequal parts: an affluent, modern, industrial north and an impoverished, backward, agricultural south. in line with this formulation, the vexed relationship between italy’s “two halves” defined the central dilemma of the country’s political, social, and cultural history as a unified nation-state according to a debate as old as giuseppe garibaldi (petrusewicz ). in the wake of the risorgimento and the creation of the modern italian state, the first generation of meridionalisti (southern experts), sent into the former bourbon domains by the reigning authorities based in turin, blamed the questione meridionale (problem of the south) on the people of the mezzogiorno. in the racialist thinking of the day, the southerners were considered an inferior stock to the superior inhabitants of the northern italian provinces (lumley , moe , and dickie ). across the atlantic, american nativists picked up on these pseudo-scientific distinctions and applied them to their own preexisting prejudices when italian immigrants – the great majority of whom originated in the south – began to arrive massively on american shores in the s. in one striking example, the authors of the dillingham commission’s dictionary of races or peoples ( ) drew upon the typologies developed by the influential italian sociologist alfredo niceforo to organize the racial classifications used by u.s. immigration officials to identify the psychic character of northern versus southern italians. an italian sociologist, niceforo, has pointed out that these two ethnic groups differ as radically in psychic characters as they do in physical. he describes the south italian as excitable, impulsive, highly imaginative, impracticable; as an individualist having little adaptability to highly organized society. the north italian, on the other hand, is pictured as cool, deliberate, patient, practical and as capable of great progress in the political and social organization of modern civilization . . . niceforo shows from italian statistics that all crimes, especially violent crimes are more numerous among the south than the north italians. (immigration commission vol. , - ) | darkest italy revisited jam it! no. may | nationalism: hyper and post in addition to relying on this scientific evidence of congenital criminality amongst southern italian immigrants, the dillingham commission observed that southern italians were also prone to poverty and illiteracy. these qualities were especially alarming to u.s. immigration officials because, as the commission cautioned: to the student of italian immigration to the united states the south italian movement numerically and otherwise is of by far the greatest importance . . . the numerical preponderance of the former race adds vastly to its relative importance, but in popular opinion at least, it is the character rather than the number of south italians which constitutes the real problem. it is generally accepted that the north italians . . . are more easily assimilated than their southern countrymen, who, because of their ignorance, low standards of living and the supposedly great criminal tendencies among them are regarded by many as racially undesirable. (immigration commission vol. , - ) the racialized notions of southern italian criminality expressed in the dillingham commission reports are fundamental to understanding the history of italian immigration to the united states. among them is the fact that the commission reports resonated with perceptions and conceptions about italianità that had been a pervasive component of anglo-american culture since the days of thomas jefferson and washington irving. since the period of the early republic, southern italians had been depicted by american writers as stiletto-wielding “dagoes” prone to criminal violence and “vesuvian” fits of rage, or as banditi affiliated with organized criminal conspiracies such as the mafia, camorra, and the dreaded society of the black hand (mano nera). as this paper details, during the period of mass italian immigration to the united states that took place between and , these negative stereotypes had a determinative impact on how italians were treated on american soil. from the lynching of eleven sicilians in new orleans on suspicion of criminal conspiracy in to the execution of sacco and vanzetti for murder charges connected to their involvement with anarchist politics in , the notion that italians, especially southerners, constituted an inferior race with an in-born propensity for an alteration of diego, a common spanish name, “dago” was a derogatory term applied by anglo-americans to “latins” of italian, spanish, or portuguese descents during the th and early th centuries. anthony antonucci | violence and criminality was commonly accepted, and encouraged discrimination against italian immigrants and their descendants in myriad ways (botein ). while these extreme episodes of anti-italianism are well-known, what is less known is when and how the stereotypes of italian criminality first took root in american culture. equally opaque are the mechanisms through which these notions influenced national debate about u.s. immigration policy in the late th and early th centuries. this paper demonstrates that these historical developments are intimately linked. prior to , americans who travelled, did business, and practiced diplomacy overseas gathered ethnographic information about the character of particular foreign groups, including italians, and transmitted their observations to americans back home through a stream of published and unpublished travel writing, journalism, and fiction. through this process of trans-national cultural reportage, american merchants, diplomats, and travelers compiled and spread a catalogue of prejudices and stereotypes about various ethnic and racialized national groups in europe, which defined and influenced the perception of these same groups upon their arrivals to the united states during the period of mass immigration ( s- ). the specter of southern italian criminality originated out of this particular trans-national context of encounter. the biological-based constructions of race and racial difference that emerged during the late th century can be traced back to the period before the civil war: the stereotypes about southern italy and southern italians transmitted by the first american travelers turned into a corpus of prejudices that anglo-american nativists later applied to southern italians and italians in general upon their arrival. by explaining when, how, and why americans constructed and transmitted their negative ideas about the italian character from the th century onward, this paper marks an essential step toward the comprehension of how these deep-rooted stereotypes about race, character, and criminality have shaped the experiences of italians in the u.s. moreover, analyzing the historical relationships that developed between americans and italians prior to the era of mass migration through ellis island helps us to better understand the debates surrounding u.s. immigration policy that led up to , the year the united states introduced a system of national-origin-based quotas that effectively “closed the door” | darkest italy revisited jam it! 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no. may | nationalism: hyper and post question, orientalism in one country. edited by jane schneider. oxford: oxford university press. prezzolini, giuseppe. . come gli americani scoprirono l’italia, - . bologna: boni. reinhold, meyer. . “american visitors to pompeii, herculaneum, and paestum in the nineteenth century.” journal of aesthetic education : special issue: “paestum and classical culture: past and present” ( ): - . richards, david. . italian american: the racializing of an ethnic identity. new york, ny: new york university press. schneider, jane, ed. . italy’s “southern question”: orientalism in one country. oxford: berg. “secret societies of the south of italy: principles of the sect.” “the new-england galaxy and united states literary advertiser.” boston: ma, december, . stebbins, theodore e., ed. . the lure of italy: american artists and the italian experience, - . boston, ma: museum of fine arts. stowe, william. . going abroad: european travel in nineteenth-century american culture. princeton, nj: princeton university press. swinburne, henry. . travels in the two sicilies, - . volumes. london: p. elmsly. the reports of the united states immigration commission: with conclusions and recommendations, presented by mr. dillingham. . volumes. washington, d.c.: govt. print. off. the papers of thomas jefferson. - . volumes. princeton, nj: princeton university press. the papers of thomas jefferson. retirement series. volume , june to april . edited by j. jefferson looney. . princeton, nj: princeton university press. wright, nathalia. . american novelists in italy: the discoverers: allston to james. philadelphia, pa: university of pennsylvania press. anthony antonucci | anthony j. antonucci is a u.s. historian whose teaching and scholarship investigates the intersections of foreign relations, literary nationalism, ethno-racial formation and immigration policy in american politics and culture since . antonucci holds a ph.d. in u.s. history from the university of connecticut, storrs, an m.a. in american studies from the university of southern maine, portland, and a b.a. in political science from bard college, annandale, ny. antonucci’s scholarship has earned numerous awards, including a fulbright iie research fellowship based at the archivio di stato di napoli in naples, italy, as well as research fellowships at the massachusetts historical society in boston, massachusetts, the american antiquarian society in worcester, massachusetts and the university of connecticut humanities institute uchi, storrs, connecticut. antonucci’s writing on transnational u.s. history and culture is published widely in academic journals on both sides of the atlantic. his current research project offers a comparative cultural history of italian, mexican and chinese immigration to california and the united states, -present. when he is not busy in the archives at the huntington library in san marino, california, dr. antonucci teaches courses in u.s., world and california history, as well as african-american studies, chicano/latino studies and women’s studies at california polytechnic university, la verne university and citrus college in the san gabriel valley of los angeles, california. cd / t-cell responses to cmv reactivation and association with overall survival in t-cell replete haploidentical transplants: a retrospective analysis figure : comparison of th +th ctfh (left) and (th +th )/th ctfh ratio (right) in patients without cgvhd (n¼ ) and with cgvhd (n¼ ). figure . (left) recovery of ttfh and cd + t-cells/ml) after hsct. (right) frequencies of ctfh in the cd + t-cell gate beginning months after hsct. number of patients analyzed for each time point is indicated below the graph. dashed lines represent the median values from healthy donors ( % ci plotted in light red and light grey for the respective population). figure . assessment of b-tell helper function in ctfh subsets. ctfh (cd +cd ra-cxcr +) and non-ctfh (cd +cd ra-cxcr -) t cell subsets were purified by flow cytometric cell sorting. igg (left) and igm (right) production was measured in supernatants? after -day co-culture of purified t-cell subsets with naive b-cells stimulated with staphylococcal enterotoxin b. abstracts / biol blood marrow transplant ( ) s es s cgvhd patients, we observed a selective decrease of the th compartment in the ctfh subset ( . % and . % for no vs. cgvhd, p¼ . ), and relative increase of both th and th ctfh (th +th ¼ . and . % respectively, p¼ . ) leading to a greater (th +th )/th ratio (p¼ . ) (figure ). we did not find any differences in ctfh subsets when comparing mild vs. moderate and severe cgvhd. to further characterize ctfh, we analyzed bcl- and cd apoptosis pathways. th and th ctfh subsets appeared to express lower levels of cd and higher levels of bcl- compared to th ctfh. increased representation of th and th ctfh subsets that are relatively resistant to apoptosis may be a mechanism that promotes b-cell deregulation and pathologic antibody production in patients with cgvhd. targeting th /th ctfh or tfh-b cell interactions may provide novel therapies in patients with cgvhd. cd / t-cell responses to cmv reactivation and association with overall survival in t-cell replete haploidentical transplants: a retrospective analysis mahasweta gooptu , benjamin leiby , onder alpdogan , matthew carabasi , joanne filicko , margaret kasner , thomas klumpp , ubaldo martinez , barbara pro , figure . figure . abstracts / biol blood marrow transplant ( ) s es s manish sharma , john l. wagner , mark weiss , neal flomenberg , dolores grosso . medical oncology, thomas jefferson university hospital, philadelphia, pa; department of pharmacology and experimental therapeutics, thomas jefferson university, philadelphia, pa; medical oncology, thomas jefferson university, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; department of medical oncology, kimmel cancer center, thomas jefferson university, philadelphia, pa; medical oncology, thomas jefferson university, philadelphia, pa cmv reactivation has been associated with increased non- relapse mortality(nrm) and improved earlyrelapse incidence (ri) post hla matched allogeneic hematopoietic stem cell transplant (hsct), however, it’s effect has been less exten- sivelystudiedintcell repletehaploidentical(hi)hsct. inthe step approach to hi hsct developed at our institution, a large fixed dose of tcells ( x ) is administered after conditioning ( step ), followed days later bycyclophosphamide (cy) for t cell tolerization. in step , a cd -selected stem cell product is infused day after completing cy. a significant increase in t cell numbers, especially in cd / counts, was associated with cmv reactivation in many patients treated with this approach. we hypothesized that a cmv-associated increase in cd / counts would impact hsct outcomes. a retrospective outcomes analysis (os, nrm and ri) using multivariable proportional hazards regression was per- formed on all patients enrolled on a step clinical trial since , who were alive and disease free at d (n¼ ). high v low cd / count at d , a history of gvhd treated with steroids and cmv reactivation (defined by > copies/ml by pcr) both by d , were the factors of interest. known predictors of outcomes including disease at hsct and he- matopoietic comorbidity index (hct ci) were included in the analysis. the median cd / count for the group, cells/ul, was used to differentiate cd h v cd l levels. % patients reactivated cmv prior to d . the median cd / count for cmv-r (reactivators) v cmv-nr (non- reactivators) was . v . cells/ul (p< . ). for the whole group, cd h had a significant protective effect for os and nrm. cmv reactivation, disease at hsct and higher hct ci score had a significant negative impact. table . no var- iables were significantly associated with ri. in a subset analysis, patients with acute gvhd/cd h had superior os in both cmv-r and cmv-nr groups. cmv-nr patients with cd l/no acute gvhd had the poorest os. fig . cmv-r patients with cd l had equally poor os with or without acute gvhd. fig . higher cd / counts were significantly associated with improved os and lower nrm in all patients irrespective of cmv reactivation. higher cd / counts in cmv-r patients may mitigate the effects of cmv reactivation while preser- ving the beneficial effects of gvhd on os, a finding that re- quires further investigation. prospective analyses of cd / and cd / numbers and strategies to increase them such as early withdrawal of immunosuppression are warranted. table multivariable model for os variable comparison hazard ratio ( % ci) p-value cmv d r v nr . ( . , . ) . cd d cd l v cd h . ( . , . ) . gvhd/steroid d y v n . ( . , . ) . dz at hsct n v y . ( . , . ) . hctci unit increase . ( . , . ) . age year increase . ( . , . ) . conditioning myelo v ric . ( . , . ) . second allogeneic hematopoietic cell transplantation for graft failure: poorer outcomes for neutropenic graft failure troy christopher lund , jessica liegel , paul orchard , qing cao , jakub tolar , claudio brunstein , john e. wagner , michael r. verneris , daniel j. weisdorf . pediatric blood and marrow transplant, university of minnesota, minneapolis, mn; university of minnesota, minneapolis, mn; pediatrics blood and marrow transplantation, university of minnesota masonic cancer research building, minneapolis, mn; biostatistics and bioinformatics, university of minnesota, minneapolis, mn; university of minnesota medical center, minneapolis, mn; pediatric blood and marrow transplantation, university of minnesota, minneapolis, mn; pediatric hematology and oncology, university of minnesota medical center, fairview, minneapolis, mn graft failure (gf) after hematopoietic cell transplant (hct) occurs in - [dw ] % of patients. gf can be accompanied by neutropenia(ngf)orcan result withadequate neutrophils, but loss ofdonorchimerism (non-neutropenic graft failure, nngf). we analyzed the outcomes of patients (pediatric and adult) treated with a second hct for gf at the university of minne- sota; withngfand withnngf. the cumulative incidence of neutrophil engraftment at days after second hct was % for nngf, and % for ngf (p¼ . ). the incidence of grade iii- iv acute graft versus host disease (gvhd) was % ( % con- fidence interval (ci), e %) and % ( % ci, - %) for ngf and nngf, respectively (p ¼ . ). from the ndhct, -year 	cd / t-cell responses to cmv reactivation and association with overall survival in t-cell replete haploidentical transplan ... © macmillan magazines ltd the thomas jefferson paternity case the dna analysis of y-chromosome haplo- types used by foster et al. to evaluate thomas jefferson’s alleged paternity of eston hemings jefferson, the last child of his slave sally hemings, is impressive. how- ever, the authors did not consider all the data at hand in interpreting their results. no mention was made of thomas jeffer- son’s brother randolph ( – ), or of his five sons , . sons of sally hemings con- ceived by randolph (or by one of his sons) would produce a y-chromosome analysis identical to that described by foster et al. further collaborative data (for example, the whereabouts of any of those who might have been involved at conception) are needed to confirm that jefferson did indeed father his slave’s last child, as claimed in the title. we know thomas jefferson was there, but how about randolph jefferson and his sons? david m. abbey health science center, university of colorado, teakwood court, fort collins, colorado , usa e-mail: dabbey @aol.com if the data of foster et al. are accurate, then any male ancestor in thomas jefferson’s line, white or black, could have fathered eston hemings. plantations were inbred communities, and the mixing of racial types was probably common. as slave families were passed as property to the owner’s off- spring along with land and other property, it is possible that thomas jefferson’s father, grandfather or paternal uncles fathered a male slave whose line later impregnated another slave, in this case sally hemings. sally herself was a light mulatto, known even at that time to be thomas jefferson’s wife’s half sister , . gary davis evanston hospital, ridge avenue, evanston, illinois , usa foster et al. reply — it is true that men of randolph jefferson’s family could have fathered sally hemings’ later children. space constraints prevented us from expanding on alternative interpretations of our dna analysis, including the interesting one proposed by davis. the title assigned to our study was misleading in that it repre- sented only the simplest explanation of our molecular findings: namely, that thomas jefferson, rather than one of the carr broth- ers, was likely to have been the father of eston hemings jefferson. it had been suggested to us earlier (by herbert barger, who also helped to recruit the descendants of field jefferson who par- ticipated in our study) that isham jefferson, son of thomas jefferson’s brother ran- dolph, might have been the father of one or more of sally hemings’ children. barger’s proposal was based on a statement that isham was reared by thomas jefferson; he suggested that isham could have been at monticello or at snowden (snowden was across the james river from scottsville, which is about miles from monticello) when eston hemings was conceived. but it is not known for certain that isham was at monticello at that time, whereas it is docu- mented that thomas jefferson was. from the historical knowledge we have, we can- not conclude that isham, or any other member of the jefferson family, was as likely as thomas jefferson to have fathered eston hemings. we know from the historical and the dna data that thomas jefferson can neither be definitely excluded nor solely implicated in the paternity of illegitimate children with his slave sally hemings. when we embarked on this study, we knew that the results could not be conclusive, but we hoped to obtain some objective data that would tilt the weight of evidence in one direction or another. we think we have provided such data and that the modest, probabilistic interpretations we have made are tenable at present. e. a. foster*, m. a. jobling†, p. g. taylor†, p. donnelly‡, p. de knijff§, r. mieremet§, t. zerjal¶, c. tyler-smith¶ * gildersleeve wood, charlottesville, virginia , usa e-mail: eafoster@aol.com †department of genetics, university of leicester, adrian building, university road, leicester le rh, uk ‡department of statistics, university of oxford, south parks road, oxford ox tg, uk §mgc department of human genetics, leiden university, po box , ra leiden, the netherlands ¶department of biochemistry, university of oxford, south parks road, oxford ox qu, uk . foster, e. a. et al. nature , – ( ). . mayo, b. & bear, j. a. jr thomas jefferson and his unknown brother (univ. press of virginia, charlottesville, ). . brodie, f. m. thomas jefferson: an intimate history (norton, new york, ). . randall, w. s. thomas jefferson: a life (holt, new york, ). . history of todd county, kentucky ( ). scientific correspondence nature | vol | january | www.nature.com qualitative adjustment. rhea heart mass ( grams) conforms to that predicted for a mammal of the same body size and aero- bic power. volume densities of mitochon- dria in leg muscles are similar to those of mammals of the same size and aerobic capacity, whereas those in the relatively inactive flight muscles are only half as large and correspond to values reported for less aerobic mammals (table ). given that % of the rhea’s body mass consists of leg musculature, rates of oxygen uptake by mitochondria per millilitre dur- ing locomotion at the aerobic maximum appear to fall within the range reported for mammals. capillary densities in the rhea leg and flight muscles, like the mitochon- drial volume densities, also parallel values reported for the muscles of athletic and less mobile mammals. in contrast to the apparent conservation of structure–function relationships in most of the respiratory system, our results sug- gest that there are basic differences in the performance of the lungs of birds and mammals. we could not measure the lung volumes of the rheas directly, but in birds these are normally slightly more than half of those of mammals of the same mass , . the rheas therefore achieved maximum oxygen flux rates, equal to those of the most aerobic mammals of their size, using lungs that are probably only half as large. this supports the general belief that avian lungs provide relatively more function per unit volume than mammalian lungs , . although the aerobic limits of rheas and athletic mammals are similar, the metabolic power available in practice, and their func- tional needs, are not. unlike dogs, horses and other athletic mammals that sustain high metabolic rates for hours during pre- dation and migration, rheas do little or no sustained running and are poor at dissipat- ing metabolic heat loads . rheas have apparently not been under strong selective pressures like those that promoted the aero- bic power of extant running mammals. large flightless birds lead fairly inactive lives, and may have lost the ability to fly primarily because of a lack of predation. why rheas have an aerobic power that greatly exceeds their apparent functional needs remains a puzzle. matthew w. bundle*, hans hoppeler†, ruth vock†, june m. tester*, peter g. weyand* *museum of comparative zoology, harvard university, bedford, massachusetts , usa e-mail: pweyand@oeb.harvard.edu †department of anatomy, university of bern, buhlstrasse , ch bern , switzerland . seeherman, h. j., taylor, c. r., maloiy, g. m. o. & armstrong, r. b. respir. physiol. , – ( ). . lasiewski, r. c. & dawson, w. r. condor , – ( ). . ellington, c. p. j. exp. biol. , – ( ). . brackenbury, j. h. & el-sayed, m. s. j. exp. biol. , – ( ). . kooyman, g. l. & ponganis, p. j. j. exp. biol. , – ( ). . weibel, e. r., taylor, c. r. & hoppeler, h. proc. natl acad. sci. usa , – , ( ). . maina, j. n. & king, s. a. j. anat. , – ( ). . dubach, m. respir. physiol. , – ( ). . piiper, j. & scheid, p. in comparative physiology (eds bolis, l., schmidt-nielsen, k. & maddrell, s. h. p.) – (north- holland, ). . taylor, c. r., dmi’el, r., fedak, m. & schmidt-neilsen, k. am. j. physiol. , – ( ). acy .indd e-mail karger@karger.com review acta cytologica ; : – doi: . / review of cytology practice at thomas jefferson university hospital before and after high-risk human papillomavirus testing marluce bibbo a zi-xuan wang b krister jones a charalambos solomides a rossitza draganova-tacheva a robert stapp c a cytopathology laboratory, b molecular biology laboratory and c pathology informatics, department of pathology, anatomy and cell biology, thomas jefferson university, philadelphia, pa. , usa testing was due to the lengthening of the test interval when cotesting results were negative. practitioners adhering to guidelines accounts for increased molecular testing volume. a trend towards higher-grade cervical intraepithelial neo- plasia in the follow-up of detected hpv / was noted. so far there has been no demand for hpv as a stand-alone test. © s. karger ag, basel introduction over time, cervical cancer screening has evolved from a single glass slide smear to a test involving liquid-based processing and molecular hpv testing in the residual ma- terial. since the bethesda system for reporting cervical/ vaginal cytology introduced the atypical squamous cells of undetermined significance (ascus) category under epithelial squamous cell abnormality [ ] . it was noted, however, by the editors of the monograph [ ] that cervical/vaginal cytopathology includes an element of subjective interpretation and consequently the applica- tion of criteria should be viewed within this context. nu- key words thinprep test · papanicolaou test · human papillomavirus · reflex test · cotesting · cervical intraepithelial neoplasia abstract objective: we performed a retrospective review of papani- colaou (pap) testing to assess whether the cytology practice in our institution was affected by the introduction of high- risk (hr) human papillomavirus (hpv) assays over time. study design: cytology, hpv and histopathology records were retrieved from our laboratory information system from to . records for digene hybrid capture ® , hologic cervista ® and roche cobas ® hpv assays were ob- tained. a -month follow-up for hpv detected cases was performed, and results were correlated with cytology and biopsies. a -year follow-up of hpv / and other hr hpv detected cases was also performed. results: from to , a noticeable decrease in pap testing volume occurred, from , to , , while the percentage of hpv testing increased from to %. similar hpv detection rates and follow-up results for both reflex and cotesting were ob- served in the hpv assays. conclusions: the decrease in pap received: april , accepted after revision: april , published online: june , correspondence to: dr. marluce bibbo department of pathology, anatomy and cell biology thomas jefferson university hospital , main building, suite , south th street philadelphia, pa (usa) e-mail marluce.bibbo   @   jefferson.edu © s. karger ag, basel – / / – $ . / www.karger.com/acy http://dx.doi.org/ . % f cytology practice before and after hr hpv testing acta cytologica ; : – doi: . / merous clinicians were unhappy with the growing num- ber of ascus interpretations issued by cytology labora- tories. in the america society for colposcopy and cervical pathology (asccp) issued guidelines for human papillomavirus (hpv) testing [ ] , and reflex hpv testing was recommended for cases interpreted as ascus in pa- tients > years of age. when high-risk (hr) hpv was positive, the patient was referred to colposcopy and, when negative, returned to routine screening. the use of hpv cotesting was approved as a cervical cancer screening test in the usa in and endorsed by the american cancer society (acs) [ ] . it was approved in combination with papanicolaou (pap) testing, for women years or older every – years, but it was not approved as a stand-alone test. updated consensus guidelines from the acs, asccp and american society for clinical pathology were issued in [ ] . in roche cobas ® became the first hpv test approved by the fda to replace the pap test for pri- mary screening of cervical cancer [ ] . assays for hpv dna testing in our practice have in- cluded digene hybrid capture (hc ) ® approved by the fda in , hologic cervista ® approved in for detection of hr hpv, and roche cobas ® approved in for detection of hr hpv and genotyping hpv types and . the purpose of this retrospective review on pap testing was to assess whether the cytology practice in our institu- tion was affected by the introduction of hr hpv assays over time. materials and methods with institutional review board approval, we retrospectively reviewed cytology, hpv and histopathology records from our lab- oratory information system from to . these records were obtained in collaboration with the pathology informatics director (r.s.). no records for , , and hr hpv assays were found in our practice. records for hc ® hpv testing were ob- tained from to , for cervista ® from to and for the cobas ® from to . the hpv assays were performed in the residual material of thinprep specimens by the molecular pathology laboratory. a -month (january to march) follow-up of cases with detect- ed hr hpv was performed for hc ® , for cervista ® , and for cobas ® . the results of the hr hpv assays were correlated with pap cytology results. in addition, hr hpv positiv- ity of various cytologic interpretations in pap specimens and fol- low-up biopsies were obtained. a -year follow-up of ascus cases with hpv / and other hr hpv detected by roche cobas ® was also obtained for . results table  displays the volume of pap tests (conventional and thinprep) and hr hpv assays performed from to . no hpv tests are listed for , , and , and a small number of tests are listed for and . this table also shows the number and percent of reflex hpv and cotesting from to . from to , a noticeable decrease in pap testing occurred from , to , , while the percentage of hpv testing in- creased from to %. the percentage of reflex hpv tests remained stable from to and showed a decrease from to . the percentage of cotesting during the same time period remained relatively stable. testing volumes of all pap tests, thinprep, and hr hpv from to appear in figure a. a progressive decrease in pap test volume and an increase in hpv test- ing are seen over time. figure b shows the volume of hpv reflex and cotesting for the years – . a higher volume of cotesting compared to reflex testing is evident. table  shows a -month window of hr hpv testing at thomas jefferson university hospital by different as- says: hc ® in , cervista ® in and cobas ® in . the percentage of molecular tests increased from % in to % in and to % in . similar hpv detection rates in both reflex ( , , %) and co- testing ( , , %) in the hr hpv assays were ob- served. table . testing volume and percentage of hr hpv tests year pap, n thin- prep, n hpv reflex cotest n % n % n % , , – – – – , , – – – – , , – – – – , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , total pap tests, thinpreps and hr hpv testing including reflex and co- testing for the years – . http://dx.doi.org/ . % f bibbo/wang/jones/solomides/ draganova-tacheva/stapp acta cytologica ; : – doi: . / , , , , , , , , , pap totals thinprep totals hpv totals , te st in g v o lu m e (n ) year a te st in g v o lu m e (n ) yearb , , , , cotest hpv reflex hpv , , fig. . a testing volume of all pap tests, from thinprep and hr hpv testing for the years – ; see table  for details. b hpv reflex and cotesting for the years – . http://dx.doi.org/ . % f cytology practice before and after hr hpv testing acta cytologica ; : – doi: . / table  shows the follow-up of hr hpv detected cas- es in both reflex and cotesting categories for the same -month window of hr hpv testing using hc ® , cer- vista ® and cobas ® . for ascus cases where biopsy re- sults were available, cervical intraepithelial neoplasia (cin) was frequently diagnosed, followed by cin and negative for cin. forty-three percent of ascus hpv cases detected by hc ® ( / = %) and cobas ® ( / = %) showed cin or on a follow-up biopsy table . three-month analysis of hpv testing from assays used at thomas jefferson university hospital digene hc ® hologic cervista® roche cobas® date range january to march , january to march , january to march , thinprep tests, n total molecular tests / , ( %) / , ( %) / , ( %) reflex hpv / ( %) / ( %) / ( %) hpv detected / ( %) / ( %) / ( %) cotesting / ( %) / ( %) / ( %) hpv detected / ( %) / ( . %) / ( %) table . follow-up of hpv detected cases hpv digene hc ® hologic cervista® roche cobas® reflex from ascus reflex total cases hpv positive cases follow-up cin ( %) ( %) ( %) cin ( %) ( %) ( %) negative cin ( %) ( %) ( %) negative pap ( %) ( %) ( %) no follow-up ( %) ( %) ( %) cotest cotest total cases hpv positive cases initial diagnosis negative follow-up cin ( %) ( %) ( %) negative cin ( %) ( %) ( %) negative pap ( %) ( %) ( %) no follow-up ( %) ( %) ( %) lsil follow-up cin ( %) ( %) ( %) negative pap ( %) ( %) ( %) hsil follow-up cin ( %) cin ( %) ( %) cin / = cervical intraepithelial neoplasia; lsil = low-grade squamous intraepithelial lesion; hsil = high-grade squamous in- traepithelial lesion. table . ascus reflex hpv test by roche cobas®, -year follow-up cases, n percent ascus reflex hpv by roche cobas® total ascus cases total detected total not detected hr / positive hr other positive follow-up biopsy for positive hpv / total biopsies / cin cin cin negative cin follow-up biopsy for positive hr hpv total biopsies / cin cin cin negative cin lsil = low-grade squamous intraepithelial lesion; hsil = high-grade squamous intraepithelial lesion. http://dx.doi.org/ . % f bibbo/wang/jones/solomides/ draganova-tacheva/stapp acta cytologica ; : – doi: . / and % ( / = %) by cervista ® . some cases were followed by repeat pap tests, and some cases had no fol- low-up, as shown in table  . fewer cases of cin ( / = %, / = %, / = %) were found in the follow-up of negative cases with hpv detected by the cotesting as- says. most cases diagnosed as low- and high-grade squa- mous intraepithelial lesions were confirmed by cin and cin / , respectively, in the histologic follow-up. no cas- es of invasive carcinoma were found. table  demonstrates the total number of hpv reflex tests of ascus by roche cobas ® in . one hundred thirty-eight cases out of ( %) had hpv detected: hpv / and other hr hpv. the follow-up of these cases is also shown in table  . a higher percentage of cin and cin was found in the follow-up biopsies of hpv / detected cases. no statistical analysis was performed, as the total case number is small. to date, the molecular laboratory has no record of cobas ® hr hpv testing alone. discussion in the last decade it has become clear that infection with hr hpv is required for the development of most cervical cancers and high-grade precursor lesions. recent emphasis on molecular testing seeks to identify infection with hpv strains considered a high risk for carcinogen- esis. the clinical use of hpv testing started as additional screening for patients with ascus cervical cytology re- sults in order to determine the need for colposcopy [ ] . in our hospital practice, hr hpv reflex tests, automati- cally ordered by the cytology laboratory for ascus re- sults, were performed from (when covered by insur- ance) and continue through the present. in women years and older, the hr hpv assay can be used in combination with cervical cytology to adjunc- tively screen for the presence or absence of hr hpv types. this information, together with the physician’s as- sessment of the cytology history, other risk factors, and professional guidelines [ ] , may be used to guide patient management. table  shows that hpv cotesting at thom- as jefferson university hospital started in and pro- gressively increased from to % by . at the same time, the decrease in pap testing is striking from , in when the percentage of hpv testing was %, to , in with % utilizing hpv testing. it is known that a negative hr hpv test represents a low risk of de- veloping disease over years and safely allows lengthen- ing of the test interval. this rationale is reasonable to ex- plain our observed decrease in pap testing. also notice- able is the percentage decrease in hpv reflex testing and increase in hpv cotesting. most likely this was the result of increased adherence by practitioners to cotesting guidelines [ ] . of interest is the similar hr hpv detection rate in both reflex ( , , %) and cotests ( , , %) for the hpv assays, as shown in table  . the follow-up biopsies for ascus cases, when avail- able, revealed cin or in % of cases detected by hc ® and cobas ® and % by cervista ® . several biopsies showed absence of cin, and quite a few cases were fol- lowed only by negative pap tests. for cotesting, – % of negative pap tests showed cin in the follow-up bi- opsy. the majority of cases had only negative pap tests for follow-up. most low-grade squamous intraepithelial lesion cases were confirmed by cervical biopsy and all high-grade squamous intraepithelial lesion cases were confirmed by histology as shown in table  . it is not sur- prising that no cases of cervical carcinoma were found, since our female population is at low risk for cervical cancer. table  illustrates the number of hpv reflex tests with the cobas ® platform in , separating the hr hpv / ( = %) from other hr hpv types ( = %). follow-up shows % of the hpv / cases had subse- quent biopsies, in comparison to % for other hr hpv cases. a trend towards higher cin / for hpv / was noted. the lack of demand for hr hpv stand-alone testing in our institution is of interest. major changes to screen- ing guidelines in the last decade include initiation of screening at the age of years, conservative manage- ment of young women with abnormal cytology, ex- tended screening intervals for women aged ≥ years and cessation of screening in low-risk women over the age of years [ ] . hr hpv is a prerequisite for the development of almost all types of cervical cancer, therefore hr hpv has become an integral part of new screening strategies. with the fda approval of the first hpv test for primary cervical cancer screening of wom- en ≥ years [ ] , clinicians in the usa now have dif- ferent first-line screening options that they may offer to patients: the pap test, cotesting with pap and hpv, and hpv testing as a stand-alone test [ ] . the choice of the cervical screening method may vary for a variety of reasons including patient and provider preference along with geographic, socioeconomic, and practice settings. http://dx.doi.org/ . % f cytology practice before and after hr hpv testing acta cytologica ; : – doi: . / conclusions it is evident in our practice that thinprep pap testing decreased from , to , ( %) over years, while the percentage of hpv molecular testing (reflex plus co- testing) increased from to %. the decrease in pap testing is most likely due to an increased interval between tests when cotesting results were negative. the hpv de- tection rates assessed during a -month interval showed that the hr hpv assays used, namely hc ® , cervis- ta ® , and cobas ® , detected similar rates of hr hpv. a trend was noted towards higher-grade cin in the follow- up of hpv / detected cases. so far, the choices of the cervical screening method in our practice include the pap test, hr hpv reflex test and cotesting with no demand for the hpv stand-alone test. disclosure statement none of the authors have any relevant financial disclosures to report. references the bethesda system for reporting cer- vical/vaginal cytologic diagnoses. devel- oped and approved at the national cancer institute workshop, bethesda, maryland, usa, december – , . acta cytol ; : – . kurman rj, solomon d: the bethesda sys- tem for reporting cervical/vaginal cytologic diagnoses. berlin, springer, . wright tc, cox jt, massad ls, twiggs lb, wilkinson ej: asccp-sponsored consensus conference. consensus guidelines for the management of women with cytological abnormalities. jama ; : – . massad ls: guidelines for cervical cancer screening from the american cancer society. j low genit tract dis ; : – . saslow d, solomon d, lawson hw, et al: american cancer society, american society for colposcopy and cervical pathology and american society for clinical pathology screening guidelines for the prevention and early detection of cervical cancer. am j clin pathol ; : - . huh wk, ault ka, chelmow d, et al: use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. gynecol oncol ; : – . nayar r, goulart ra, tisconia-wasserman pg, davis d: primary hpv screening for cer- vical cancer in the united states – us food and drug administration approval, clinical trials and where we stand today. cancer cy- topathol ; : – . http://dx.doi.org/ . % f 	citref_ : 	citref_ : 	citref_ : 	citref_ : 	citref_ : 	citref_ : 	citref_ : wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ untitled troretinography and antiretinal antibody testing were not performed. previous cases of vitelliform retinopathy have had some clinical findings consistent with mar, , , , while others have not. , none of these reports had clinical evi- dence of choroidal involvement. the vitelliform lesions have been postulated to represent a new paraneoplastic clinical manifestation. the pathologic results in this case argue against a paraneoplastic entity but may suggest a local metastatic cause with subclinical choroidal involve- ment. another explanation is that choroidal involve- ment occurred after the vitelliform lesions with the dis- semination of the metastatic melanoma. further studies are needed to determine the etiology of these vitelliform lesions in metastatic melanoma. author affiliations: department of ophthalmology, uni- versity of california, san francisco (dr khurana), and northern california retina vitreous associates, moun- tain view (drs khurana, wieland, and boldrey); and de- partment of ophthalmology and visual sciences, uni- versity of wisconsin, madison (drs lewis and albert). correspondence: dr khurana, northern california retina vitreous associates, hospital dr, ste , moun- tain view, ca (rnkhurana@gmail.com). financial disclosure: none reported. . zacks dn, pinnolis mk, berson el, gragoudas es. melanoma-associated reti- nopathy and recurrent exudative retinal detachments in a patient with cho- roidal melanoma. am j ophthalmol. ; ( ): - . . palmowski am, haus ah, pföhler c, et al. bilateral multifocal chorioreti- nopathy in a woman with cutaneous malignant melanoma. arch ophthalmol. ; ( ): - . . jampol lm, kim hh, bryar pj, shankle jb, lee rt, johnston rl. multiple serous retinal detachments and subretinal deposits as the presenting signs of metastatic melanoma. retina. ; ( ): - . . sotodeh m, paridaens d, keunen j, van schooneveld m, adamus g, baarsma s. paraneoplastic vitelliform retinopathy associated with cutaneous or uveal melanoma and metastases. klin monbl augenheilkd. ; ( ): - . . nieuwendijk tj, hooymans jm. paraneoplastic vitelliform retinopathy asso- ciated with metastatic choroidal melanoma. eye (lond). ; ( ): - . . javaheri m, khurana rn, bhatti ra, lim ji. optical coherence tomography findings in paraneoplastic pseudovitelliform lesions in melanoma-associated retinopathy. clin ophthalmol. ; ( ): - . . eksandh l, adamus g, mosgrove l, andréasson s. autoantibodies against be- strophin in a patient with vitelliform paraneoplastic retinopathy and a meta- static choroidal malignant melanoma. arch ophthalmol. ; ( ): - . cutaneous halo nevi following plaque radiotherapy for uveal melanoma h alo nevi have been described in both dermatol-ogy and ophthalmology. , cutaneous halo neviare found more often in children than adults and are believed to result from an immune response. cho- roidal halo nevus represents % of all choroidal nevi and displays low risk for transformation to melanoma. the development of cutaneous halo nevi or vitiligo in adult- hood can occur following treatment of cutaneous mela- noma and correlates with decreased morbidity, presum- ably due to activation of a systemic immune response. there have been rare reports of vitiligo and/or cutane- ous halo nevi development following enucleation for uveal melanoma. , a comprehensive study on choroidal halo nevi found a statistical association with history of skin melanoma. herein, we describe a young woman with uveal melanoma who developed a halo ring around nu- merous pigmented cutaneous nevi following plaque ra- diotherapy for uveal melanoma. report of a case. a -year-old woman with photopsia in the left eye was diagnosed as having choroidal mela- a b figure . histopathologic findings. a, just posterior to the equator, a relatively flat, pigmented, cellular infiltrate is seen within the choroid. the tumor is mm thick and tapers at the ends (hematoxylin-eosin, original magnification � ). b, the infiltrate displays a dense population of spindle-shaped and epithelioid melanoma cells with pale cytoplasm that demonstrates marked cellular and nuclear pleomorphism. several small retinal pigment epithelial detachments are seen overlying the tumor (arrows). the retina is artifactually detached and not visible (hematoxylin-eosin, original magnification � ). rahul n. khurana, md mark r. wieland, md edwin e. boldrey, md david a. lewis, md daniel m. albert, md arch ophthalmol / vol (no. ), nov www.archophthalmol.com © american medical association. all rights reserved. downloaded from: https://jamanetwork.com/ by a carnegie mellon university user on / / noma. there was no history of cutaneous melanoma. vi- sual acuity was / od and / os. the melanoma measured mm in basal dimension and mm in thick- ness (figure, a). iodine plaque radiotherapy was performed. two months after therapy, the patient reported development of a noninflammatory, painless, circumscribed halo around numerous previously pigmented cutaneous nevi, and ne- vus lost nearly all pigmentation (figure, b-e). at months, the uveal melanoma regressed to . mm in thickness. meta- static evaluation findings were negative. comment. cutaneous melanoma can stimulate vitiligo or halo nevi through immune mechanisms. the pro- posed pathophysiology involves cytotoxic t-cell– mediated immune reaction targeted against antigens shared between normal melanocytes and melanoma cells such as mart- , tyrosinase, gp , tyrp , and tyrp . histopathologically, a lymphohistiocytic infiltrate pre- dominated by cd and cd t cells has been observed at the margin of such depigmented lesions. immuno- therapeutic strategies for cutaneous melanoma have been attempted based on this observation. in , nirankari et al described a -year-old man who underwent evisceration for panophthalmitis from undetected uveal melanoma. he developed vitiligo at years and orbital recurrence of uveal melanoma at years, for which orbital exenteration was performed. in , albert et al described patients with skin depigmenta- tion following enucleation for melanoma. case was a -year-old man who developed vitiligo years after enucleation, and case was a -year-old man who de- veloped cutaneous halo nevi year after enucleation. al- bert and colleagues speculated that this represented a heightened host response and more favorable progno- sis. in , duh et al described a -year-old woman with a . -mm-thick uveal melanoma who developed vitiligo years after enucleation. these reports suggest a possible role of the immune system following therapy of uveal melanoma, similar to cutaneous melanoma. we are not aware of other cases of cutaneous halo nevi de- veloping after plaque radiotherapy for uveal melanoma. the association of cutaneous halo nevus or vitiligo with treated uveal melanoma could be more frequent be- cause these dermal findings can be subtle, as in our case. author affiliations: department of ocular oncology, wills eye institute, thomas jefferson university, philadelphia, pennsylvania (drs sarici, shah, c. l. shields, and j. a. shields); and department of ophthalmology, walter reed army medical center, washington, dc (dr birdsong). correspondence: dr c. l. shields, department of ocu- lar oncology, wills eye institute, thomas jefferson uni- versity, walnut st, ste , philadelphia, pa (carol.shields@shieldsoncology.com). financial disclosure: none reported. funding/support: this study was supported by the eye tumor research foundation, philadelphia, pennsylvania. . speeckaert r, van geel n, vermaelen kv, et al. immune reactions in benign and malignant melanocytic lesions: lessons for immunotherapy. pigment cell melanoma res. ; ( ): - . . shields cl, maktabi am, jahnle e, mashayekhi a, lally se, shields ja. halo nevus of the choroid in patients: the henry van dyke lecture. arch ophthalmol. ; ( ): - . . rhodes a. neoplasms: benign neoplasias, hyperplasias, and dysplasias of melanocytes. in: fitzpatrick tb, eisen a, wolff k, freedberg i, austen kf, eds. dermatology in general medicine. new york, ny: mcgraw-hill; : - . . shields cl, furuta m, berman el, et al. choroidal nevus transformation into melanoma: analysis of consecutive cases. arch ophthalmol. ; ( ): - . . nordlund jj, kirkwood jm, forget bm, milton g, albert dm, lerner ab. vitiligo in patients with metastatic melanoma: a good prognostic sign. j am acad dermatol. ; ( ): - . . albert dm, todes-taylor n, wagoner m, nordlund jj, lerner ab. vitiligo or halo nevi occurring in two patients with choroidal melanoma. arch dermatol. ; ( ): - . . duh ej, schachat ap, albert dm, patel sm. long-term survival in a patient a b d e c figure. cutaneous halo nevi development following plaque radiotherapy for uveal melanoma. a, wide-angle fundus photograph of the left eye in a -year-old woman shows a ciliochoroidal melanoma. b-e, four months after treatment with iodine plaque radiotherapy, halo (arrows) around multiple cutaneous nevi involving the face, neck, upper chest, and back were documented, with almost complete depigmentation of of the nevi (arrowhead) (b). ahmet m. sarici, md sanket u. shah, md carol l. shields, md richard h. birdsong, md jerry a. shields, md arch ophthalmol / vol (no. ), nov www.archophthalmol.com © american medical association. all rights reserved. downloaded from: https://jamanetwork.com/ by a carnegie mellon university user on / / with uveal melanoma and liver metastasis. arch ophthalmol. ; ( ): - . . nirankari ms, khanna kk, mathur rp. uveal malignant melanoma with leucoderma. j all india ophthalmol soc. ; ( ): - . histopathologic, immunohistochemical, ultrastructural, and cytogenetic analysis of oncocytic uveal melanoma t he histological findings of malignant melanomamay be highly variable, and the tumor can mimicmany other neoplasms. oncocytic change is de- fined histologically by abundant, eosinophilic, finely granu- lar cytoplasm due to densely packed mitochondria. onco- cytic change has rarely been described in dermal nevi, meningeal melanocytoma, cutaneous melanoma, , or meta- static melanoma. to our knowledge, we give the first de- scription of exclusively oncocytic uveal melanoma. report of a case. a -year-old man visited the outpa- tient department of ophthalmology with signs of a para- central scotoma, decreased vision, and metamorphop- sia in his left eye for month. best-corrected visual acuity was / od and / os. on dilated funduscopic and ultrasonographic examination of the left eye, a mushroom- shaped hypopigmented subretinal mass was seen supe- rior and temporal to the fovea with a thickness of . mm, a diameter of . mm, and medium to low internal re- flectivity (figure, a). no atypical cutaneous pig- mented lesions were observed. systemic radiologic evalu- ation revealed no metastatic lesions. the patient opted for enucleation. after a follow-up of months, there were no signs of metastases. sections of the eye confirmed a mushroom-shaped tu- mor (figure, b) exclusively composed of a trabecular ar- rangement of epithelioid cells with abundant, finely granu- lar, eosinophilic cytoplasm (figure, c). mitotic figures were present at per high-power fields. intracytoplasmic brown pigment stained positive with masson-fontana stain. the cytoplasm stained positive with periodic acid–schiff stain with resistance to diastase treatment. vascular mim- icry with a closed loop pattern was present. the tumor did not show extrascleral extension. tumor cells stained posi- tive for melan-a, hmb- (figure, d), and tyrosinase, con- firming melanocytic lineage. they stained negative for kera- tin a /a , cd , chromogranin, and synaptophysin, excluding epithelial (neuroendocrine) metastasis. ultrastructural studies on formalin-fixed, paraffin- embedded tumor tissue that was deparaffinized, postfix- a b c d figure. ultrasonographic, whole-mount, histologic, and immunohistochemical appearance of the tumor. a b-scan of the tumor (a) and a whole-mount hematoxylin-eosin–stained section (b) of the left eye show a mushroom-shaped subretinal mass in the posterior pole. c, the tumor was exclusively composed of a nested and trabecular pattern of polygonal epithelioid cells with distinct borders and a granular eosinophilic cytoplasm that sometimes contained brown pigment. the nests and trabeculae were surrounded by a delicate capillary network. nuclei were enlarged with coarse open chromatin and prominent irregular nucleoli (hematoxylin-eosin, original magnification � ). d, the cells stained positive for the melanocytic marker hmb- (original magnification � ). arch ophthalmol / vol (no. ), nov www.archophthalmol.com © american medical association. all rights reserved. downloaded from: https://jamanetwork.com/ by a carnegie mellon university user on / / targets & mechanisms scibx: science–business exchange copyright © nature publishing group � grk : big-hearted target? by michael j. haas, senior writer a team of u.s. and u.k. researchers has uncovered a new role for g protein–coupled receptor kinase in pathological cardiac hyper- trophy, providing a first mechanistic target for this indication. it behaves more like an histone deacetylase kinase than a g pro- tein–coupled receptor kinase, activating histone deacetylase and triggering a signaling cascade that results in cardiac hypertrophy. the finding, reported in the proceedings of the national academy of sciences, may make it possible to treat hypertrophy with kinase inhibitors. in contrast to current therapeutic strategies that address more general conditions such as hypertension or ischemia, which can lead to cardiac hypertrophy, this research provides the potential to treat the condition directly at its mechanistic root. however, the effectiveness of such a therapeutic strategy will depend on whether the function of g protein–coupled receptor kinase (grk ) is unique in hypertrophy or is redundant with other histone deacetylase kinases (hdac kinases). the team of scientists from thomas jefferson university and university college london was led by walter koch, vp of research in medicine, professor of medicine and director of the center for translational medicine at thomas jefferson. “grk has been shown to be increased in heart failure,” koch told scibx. “consequently, it made sense to study it in hypertrophy. our work shows that myocytes with high grk levels are primed for hypertrophy.” failure of mighty-hearted mice left ventricular hypertrophy (lvh)—also known as pathological or maladaptive cardiac hypertrophy—is a condition in which the heart grows and accumulates scar tissue in response to stress, such as hypertension and injury. this enlargement compromises heart function over time and leads to heart failure. there are no approved therapeutics to treat hypertrophy. grk , a membrane-bound protein expressed in most tissue types, regulates signaling and function in myocytes. it is also known to be upregulated in pathological cardiac conditions such as heart failure, but how it contributed to those conditions was unknown. , “there are two grks in the heart—grk and grk ,” koch said. “previously we have focused on grk , which has a pathological role in heart failure, but we were also interested in hypertrophy.” last year, koch and colleagues at thomas jefferson university described how grk signaling accelerates heart failure in a heart whose function is already compromised. in an unpublished study conducted in by koch while at duke university medical center, mice that overexpressed grk were subjected to aortic banding, a surgical procedure that creates resistance to blood flow out of the heart, thus putting stress on the organ. koch’s group found that about % of these mice died of heart failure, compared with about % of mice having normal grk expression. ex vivo analysis revealed excessive hypertrophy in the grk - overexpressing mice, he said. koch said that prior to aortic banding “the hearts of the grk - overexpressing mice are slightly larger than normal but have no loss of function. the mice are healthy and normal until they are stressed.” in a team at university college london led by julie pitcher, senior lecturer of pharmacology and coauthor on the pnas paper, showed that grk contains a nuclear localization sequence that allows it to translocate from the membrane to the nucleus of myo- cytes in response to g protein–coupled receptor (gpcr) signaling. previous work by others had also shown increased nuclear localiza- tion of grk in a rat model of cardiac hypertrophy. together these results led pitcher to suggest that grk may have a role in modulating gene expression linked directly to hypertrophy. based on these two studies, koch’s team hypothesized that nuclear grk played a direct role in pathological hypertrophy via transcrip- tional regulation of genes responsible for this condition. to investigate their hypothesis, the team first repeated koch’s aor- tic banding experiment in grk -overexpressing mice and obtained similarly high rates of heart failure and mortality. ex vivo analysis showed both a significant increase in heart size and a greater accu- mulation of grk in the nucleus of myocytes relative to what was seen in mice with normal grk expression. by contrast, mice that overexpressed a mutant form of grk that lacked the ability to cross the myocyte nuclear membrane showed no increase in heart size or heart failure in response to aortic band- ing—suggesting that grk ’s nuclear function was indeed critical to hypertrophy. next, in vitro experiments demonstrated that stress-induced gpcr signaling in myocytes activated guanine nucleotide binding protein, q polypeptide (gq; gnaq), thereby triggering upregulation of grk , which then translocated to the myocyte nucleus. in the nucleus, grk activated histone deacetylase (hdac )—a class ii hdac—which then translocated to the cytosol, where it activated myocyte enhancing factor (mef ; d-mef ), a transcription factor known to upregulate expression of hypertrophic genes. the team said its results collectively demonstrate that grk is a class ii hdac kinase that plays a critical role in the development of cardiac hypertrophy in response to cardiac stress. koch acknowledged that the effects of grk ’s role in hypertrophy are probably exaggerated in his team’s mouse model because the mice http://www.scibx.com scibx: science–business exchange copyright © nature publishing group � targets & mechanisms overexpress grk . nonetheless, the findings should be relevant in animals with normal grk expression because hypertrophic stimuli result in the nuclear localization of grk in such animals as well, he said. best heart target researchers contacted by scibx agreed that koch’s team had identi- fied an important mechanism in the development of cardiac hyper- trophy, but they disagreed over whether the findings would easily translate into a therapeutic to treat the condition directly. suraj shetty, lab head and project team leader of cardiovascular and metabolism research at novartis ag’s novartis institute for bio- medical research, said that “hypertrophy is a harbinger of adverse cardiac events like heart failure. hence there has been a move to identify key targets involved in hypertrophy.” he added that nuclear factors involved in hypertrophy—such as the nuclear form of grk —are of particular interest because they could represent nodal points strategically located at the convergence of several different hypertrophic signaling pathways. “you want to be as downstream as possible to have the most impact,” he said. however, he noted that at least three other class ii hdac kinases are known: calcium/calmodulin-dependent protein kinase ii (camkii), protein kinase d (pkd) and microtubule affinity-regulating kinase (mark). “there might be some redundancies among these kinases,” shetty said. “so the question is whether grk is the key hdac kinase responsible for mediating pathological hyper- trophy” or whether the other kinases could compensate if grk is inhibited, he said. “we would need to ascertain the relationship and redundancy among these kinases” before determining that grk is a valid target, he said. “certainly there are redundancies,” koch agreed. “but these kinases act differently depending on the type of stress and which receptor system is activated.” he added that it isn’t yet known if grk is part of other receptor pathways, a question that is the focus of an ongoing study. junichi sadoshima, vice chair and professor of cell biology and molecular medicine and associate director of the cardiovascular research institute at the university of medicine and dentistry of new jersey, was more sanguine about grk ’s potential as a target. “this paper is very interesting because i believe the signaling mechanism regulating hdac translocations is really critical to pathological cardiac hypertrophy,” he said. “if this pathway is relevant for stimulus such as high blood pressure and ischemia, then grk could be a druggable target,” sadoshima said. sadoshima also wanted to know how grk is transported from the membrane to the nucleus. “if the molecule that associates with grk to move it to the nucleus could be identified, that could be a good target,” he said, and possibly preferable to grk because of the known difficulties in targeting kinases. novartis’s shetty said whether this unknown transporter would be a good target would depend on how specific or general its function is. “if the chaperone molecule is a general factor involved in nuclear shuttling, then targeting it could have severe side effects,” he said. in novartis began a phase iv trial comparing diovan valsartan plus the generic amlodipine to cozaar losartan plus the generic hydrochlorothiazide for the treatment of pathological hypertrophy. novartis markets diovan, an angiotensin ii receptor antagonist, to treat hypertension. merck & co. inc. markets cozaar, also an angiotensin ii receptor antagonist, for the same indication. direct benefit shetty said that treating pathological hypertrophy indirectly—by treating underlying conditions like hypertension—minimizes hypertrophy and protects against adverse cardiovascular events such as heart failure and arrhythmia. but he noted that growing evidence suggests that treating hypertrophy per se might confer similar protection. according to shetty, researchers had hypothesized that cardiac hypertrophy was a beneficial compensatory response to stress, and therefore inhibiting it directly would be detrimental. but that hypoth- esis has been challenged by short-term in vivo studies showing inhi- bition of pathological hypertrophy—induced in animals with otherwise normal blood pres- sure—is in fact beneficial. “this raises the possibility that inhibition of pathological cardiac hypertrophy per se could have salutary effects,” shetty said. “thus a concerted effort is underway to ascertain the long-term benefits of inhibition of hypertro- phy per se in the context of heart failure.” sadoshima believes direct treatment of hypertrophy might have several benefits. “regardless of the nature of the initial triggers—hypertension, ischemia, angiotensin and so on—many stimuli that induce patho- logical forms of hypertrophy utilize the hdac-mef pathway,” he said. “thus inhibitors of hdac kinases would be effective in many forms of pathological hypertrophy and have broad application against many forms of heart failure.” by contrast, sadoshima said blocking hypertrophic mechanisms upstream from grk and hdac—for instance, at the level of recep- tors or cytosolic kinases that have many cellular functions—could have undesirable side effects. “if you inhibit hypertrophy at final steps of signaling in cells, you can expect more targeted effects,” he said. sadoshima also speculated that specific inhibitors of hdac kinases might have fewer systemic side effects than inhibiting upstream targets, because class ii hdacs are mostly expressed in terminally differentiated cell types. besides investigating whether grk ’s action on hdac is redundant with other class ii hdac kinases, koch said the team is attempting to elucidate the specific mechanism of binding between grk and hdac . “this would give insight into how hdac is regulated by grk ,” he said. “if we know this, we could put small peptides into the nucleus to block that interaction.” “if this pathway is relevant for stimulus such as high blood pressure and ischemia, then grk could be a druggable target.” —junichi sadoshima, university of medicine and dentistry of new jersey scibx: science–business exchange copyright © nature publishing group � targets & mechanisms koch said another study by the team targets grk with a grk - specific viral microrna from adeno-associated virus (aav). koch said the findings reported in pnas are not patented, but added, “once we have more data on targeting grk specifically, maybe we will file a patent.” references . martini, j. et al. proc. natl. acad. sci. usa; published online aug. , ; doi: . /pnas. contact: walter j. koch, thomas jefferson university, philadelphia, pa. e-mail: walter.koch@jefferson.edu . premont, r. & gainetdinov, r. annu. rev. physiol. , – ( ) . dzimiri, n. et al. j. pharmacol. , – ( ) . rockman, h. et al. nature � , – ( ) . lymperopoulos, a. et al. nat. med. ��, – ( ) . johnson, l. et al. mol. cell biol. � , – ( ) companies and institutions mentioned duke university medical center, durham, n.c. merck & co. inc. (nyse:mrk), whitehouse station, n.j. novartis ag (nyse:nvs; swx:novn), basel, switzerland thomas jefferson university, philadelphia, pa. university college london, london, u.k. university of medicine and dentistry of new jersey, newark, n.j. mailto:walter.koch@jefferson.edu 	grk : big-hearted target? 	failure of mighty-hearted mice 	best heart target 	direct benefit 	companies and institutions mentioned 	references nat mx david adam, london final proof that scientists can work with the media, or an unfortunate clash of peer pres- sure and peer review? television viewers in britain can make up their own minds this week when a unique combination of science and reality tv gets its first screening. billed as both entertainment and serious research, the bbc programme the experi- ment attempts to recreate aspects of a psychology study by stanford university researcher philip zimbardo. in the original study, volunteers were asked to assume the role of either prisoner or prison guard, and were placed together in a simulated jail. those acting as guards were so brutal to the prisoners that a shocked zimbardo abandoned the experiment and said that it should never be repeated. it is now seen as an important demonstration of how social circumstances can make people conform to particular roles. but whereas the stanford guards bullied the prisoners and forced them to clean toilets with their bare hands, their british counter- parts tried to befriend the prisoners and even agreed to reorganize the prison as a com- mune. an edited version of the -day trial, held last december at a london television studio, will be shown in four one-hour programmes beginning this week. “this has been a ground-breaking collab- oration between academia and the media,” says alex haslam, a psychologist at exeter university who planned the experiment with steve reicher, a researcher at the university of st andrews and joint editor of the british journal of social psychology. “it is not a media creation on which psychologists were invited to comment. the guiding principle for us and the bbc was always the science.” others warn, however, that it is difficult to compare the two studies directly, as behav- ioural trials are hard to replicate. the tele- vision cameras will also have had “an immedi- ate constraint on what people do”, says donald laming, a psychologist at the univer- sity of cambridge. zimbardo, still at stanford university, could not be reached for comment. for the experiment, male volunteers were recruited through newspaper adverts, and divided into guards and prisoners. the prisoners shared cramped cells and carried out chores, whereas the guards enjoyed better food and separate rooms and were given lim- ited powers over their charges. as well as observing and recording the behaviour of the volunteers, haslam and reicher asked them to complete psychometric tests and analysed their saliva for the stress hormone cortisol. it soon became clear that the guards were news nature | vol | may | www.nature.com unable to organize themselves. “there was a lack of a common social identity, no leader- ship and they didn’t even develop a simple shift pattern,” says reicher. the guards showed more psychological stress than the prisoners. haslam says that he welcomed the chance to challenge the stanford results, and claims that the guards who behaved as tyrants in the original experiment did so only because they were encouraged to. n reality tv show recreates famed social study broadcasting behind bars: the experiment aims to explore how people conform to set roles. jefferson’s descendants continue to deny slave link erika check, washington thomas jefferson’s descendants have decided that the ancestors of one of his slaves cannot join their family club, despite dna evidence published in nature suggesting that he fathered at least one of her children. the monticello association, a group of nearly descendants of jefferson’s daughters, voted on may to keep sally hemings’s descendants out of their group. this means that hemings’s relatives cannot be buried in the graveyard at monticello, jefferson’s home in charlottesville, virginia. their vote is the latest twist in a racially charged controversy that has raged since jefferson’s own day, when it was noted that sally hemings’s children bore a likeness to the third president. that and other evidence fuelled speculation that the author of the declaration of independence fathered six children by hemings, who was a slave at monticello. she only became pregnant during times when jefferson stayed there. jefferson’s descendants have always disputed this speculation. jefferson’s grand- children claimed that one of his maternal nephews, samuel or peter carr, fathered hemings’s children. but genetic tests pub- lished in november (see nature , – ; ) eliminated that possibility. the tests compared the y chromosomes of men descended from sally hemings’s son eston with those from the jefferson and carr family lines. eston’s y chromosome was found to be virtually identical to jefferson’s and dissimilar to the carr chromosome. the study caused an outcry because it was published in the midst of then-president bill clinton’s impeachment process. clinton’s supporters seized on it as proof that previous presidents — even the most celebrated ones — had also engaged in sexual indiscretion. the findings prompted the thomas jefferson foundation, which owns and operates monticello, to investigate the hemings connection. in january , it concluded that the dna study, combined with other evidence, indicated a “high prob- ability that thomas jefferson fathered eston hemings, and that he most likely was the father of all six of sally hemings’s children”. but jefferson’s descendants remain unswayed, and now say that thomas’s brother randolph was probably eston’s father. “they have not provided conclusive evidence that thomas jefferson had a relationship with sally hemings,” says nathaniel abeles, the monticello association’s president. the association’s position cuts no ice with the academic community. “this decision is scientifically unsound, historically unsound and morally bankrupt,” says annette gordon-reed of the new york law school. “the issue is pretty much settled and the fact that the family association chooses to tell a story about itself doesn’t affect what scientists or historians think.” n b b c monticello, home of thomas jefferson, where his slave’s descendants have been denied burial. j. s o h m /c h r o m o so h m /c o r b is © macmillan magazines ltd 	jefferson’s descendants continue to deny slave link in situ detection of egf receptor mrna in human atheromatous lesions: implications for proliferation and migration of smooth muscle cells s. urn judith b. swain, and rkhara s. stack. has potential introduced into coronary ipheral arteries in vivo, with resultant expression of gene s. in addition, we show that a percutaneous catheter approach can be used for localized gene transfer into coronary arteries. this method offers an interventional approach to the treatment of cardiovascular disease through gene therapy. fibrinol’ tic agtiv t-y fouqwxmg vascuqr wall injury ui shi, andrew zalewski, donald nardone, paul walinsky, thorir d. bjornsson, thomas jefferson university, philadelphia, pa vessel wall injury in either acute coronary smdromes or during coronary angiaplasty is associated with increased procoagulant activity and frequent intracoronary thrombi. accordingly, the aim of this study was to assess plasma levels of tissue plasminogen activator activity (t-pa) and piasminogen activator inhibitor-l activity (pm-p) prior to and at i, , and hr after experimental vessel wall injury (ins). in atherosclerotic rabbits, in was produced by angioplasty of iliac arteries ipl , while rabbits with no n.l seared as controls (c). histology in rabbits from inj group revealed medial inj in all enimals. t-pa levels baseline hr hr hr c . k . . + . . + . . . inj . + . . . . . . + . t-pa levels were not different between c and inj groups. ai-l levels (au/ml, mean -+ sem) were as follows: baseline hr hr hr c .% + . . . . . . . inj . . . k . . & . + . k . thus. pai- activity increased significantly at hr followitlg inj (*qio.ol vs inj at baseline, , hr and vs all times in c group). in contrast, c group showed n, change throughout the study period. conclusions: ) fibrinolytic activity was transiently impaired following deep vascular wall injury as a result of an increase in pai- activity. ) in addition to other procoagulant mechanisms, pax- elevation in the presence of vessel wall injury may play a role in the pathogenesis of acute coronary syndromes. the effect of tpa gh restetil?sis foll’jwinc eallooe axioplasty: a study in the atherosclerotic rabbit. -lo<! gt!lm;ln, stephen l. slgai, @lrlgsheng chen, err?:& l. esqul~.vl, michael u. etekowltz, yale u, new haben, ct., alld the vamc, west haven, ct. to test the hypothesis that thrombosis and platelet dcri\,ed growth factors contribute to restenosls after angioplasty (a) and that their remo\.sl using a thrombclytlc agent will influence the restenosis rate, we performed a study in nzw rabbits with bilateral focal femoral atherosclerosis who were undergoing a. rabbits were randomized to either a hr infuslon of tissue plasminogen activator (tpa), mg/kg, or saline (s). balloon a ( . mm balloon; x osec, atm inflations ~~s apart) wjs performed . mln (mean l sd) after commencement of lnfuslon of tpa or . anglograms were obtained at basellne. min. and z days post-balloon a. rabbits were sac.riflced after the flnal anglogram. serum fibrinogen (me/dl! was measured at basellnt-: f fn tpa vs. l ?? ,‘n , ns, and after lnfuslon: - in tpa vs. % - in , pc . . there were no acute occlusions, perforations or hemorrhages: (hb; . . to . . , n’s, in tpa and . . to . . , ns ln , oxer t .e lnfuslar. prrlodi. the mlnlmum anglographlc lumen diameter measured days after a changed from . l . to . f. (pc. ) in the t-pa group and from . + . to . z . in the control (pc. ). thus cpa at a dose which decreased serum fibrinogen by about % resulted in a decrease in the restenosls rate. we postulate that this observation may be related to the removal of thrombus derived growth factors by the thrombolytlc agent. wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ medical school anatomy and pathology workshops for high school students enhance learning and provide inspiration for careers in medicine | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . / corpus id: medical school anatomy and pathology workshops for high school students enhance learning and provide inspiration for careers in medicine @article{zhang medicalsa, title={medical school anatomy and pathology workshops for high school students enhance learning and provide inspiration for careers in medicine}, author={g. zhang and b. fenderson and j. veloski and m. livesey and tracey wojdon-smith}, journal={academic pathology}, year={ }, volume={ } } 	g. zhang, b. fenderson, + authors tracey wojdon-smith 	published 	medicine 	academic pathology “anatomy and pathology workshop” is a cadaver-based outreach program that models medical education to large groups of high school students. this study was designed to evaluate the impact of this program on students’ knowledge of anatomy and interest in biomedical science. a total of high school students participated in the workshop in . preworkshop and postworkshop assessments were administered to assess students’ learning. a postworkshop survey was conducted to solicit students… expand view on sage ncbi.nlm.nih.gov save to library create alert cite launch research feed share this paper citations view all tables and topics from this paper 	 table 	 table 	 table 	 table 	 table view all figures & tables 	outreach 	anatomic structures 	science of anatomy 	health occupations 	learning disorders 	education, medical 	educational workshop 	evaluation procedure citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency an anatomy workshop for improving anatomy self-efficacy and competency when transitioning into a problem-based learning, doctor of physical therapy program. 	mona bains, d. kaliski 	psychology, medicine 	advances in physiology education 	 	 	 save alert research feed who is the teacher and who is the student? the dual service- and engaged-learning pedagogical model of anatomy academy 	molly m diaz, kenechukwu ojukwu, + authors j. wisco 	psychology, medicine 	journal of medical education and curricular development 	 	 	 save alert research feed introducing children to anatomy: “getting to know our bodies: the first step toward becoming a scientist” 	g. ortug, a. midi, sude elbizim, hasan karaot, elif yılık, işılsu ezgi uluışık 	medicine, psychology 	anatomical sciences education 	 save alert research feed a teaching program about zebrafish behavior experiment for undergraduate pharmacy teaching and popular science popularization 	zhongyi guo 	computer science 	 th international conference on educational and information technology (iceit) 	 save alert research feed apprentissage de l’anatomo-cyto-pathologie par les étudiants en médecine : comprendre le rôle de la motivation 	c. toquet, adeline normand, g. guihard 	psychology 	 save alert research feed improving physiology learning and understanding by adding outreach activities to the teaching: report of the iups and adinstruments teaching workshop . 	p. mello-carpes, f. carpes 	psychology, medicine 	advances in physiology education 	 	 	 save alert research feed references showing - of references sort byrelevance most influenced papers recency anatomy of a successful k– educational outreach program in the health sciences: eleven years experience at one medical sciences campus 	e. burns 	biology, medicine 	the anatomical record 	 	 	pdf 	view excerpt, references background save alert research feed a new way to teach an old topic: the cadaver-based anatomy short course for high school students. 	christopher j hubbard, j. miller, dan olson 	medicine 	anatomical record. part b, new anatomist 	 	 	view excerpt, references background save alert research feed enrichment programs to create a pipeline to biomedical science careers. 	cregler ll 	medicine 	 	 save alert research feed increasing the pool of qualified minority medical school applicants: premedical training at historically black colleges and universities. 	d. d. atkinson, e. spratley, c. e. simpson 	medicine 	public health reports 	 	 	view excerpt, references background save alert research feed minority enrichment programs at the new jersey medical school: years in review. 	m. soto-greene, l. wright, o. gona, l. feldman 	medicine 	academic medicine : journal of the association of american medical colleges 	 	 	 	view excerpt, references background save alert research feed the stanford medical youth science program: years of a biomedical program for low-income high school students 	m. winkleby 	medicine 	academic medicine : journal of the association of american medical colleges 	 	 	pdf 	view excerpt, references background save alert research feed healthy lungs: cancer education for middle school teachers using a “train and equip” method 	e. burns 	medicine 	journal of cancer education 	 	 	pdf save alert research feed outreach education: a possible preventer of teenage pregnancy. 	r. block, s. a. block 	medicine 	adolescence 	 	 	view excerpt, references background save alert research feed “cancer – educate to prevent” – high-school teachers, the new promoters of cancer prevention education campaigns 	a. barros, luís moreira, helena santos, n. ribeiro, l. carvalho, f. santos-silva 	medicine 	plos one 	 	 	pdf 	view excerpt, references background save alert research feed engineering design‐based science, science content performance, and science attitudes in elementary school 	kristen b. wendell, c. rogers 	engineering 	 	 	view excerpt, references background save alert research feed ... ... related papers 	abstract 	tables and topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our 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journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ sia (p= . ), mechanical ventilation (p= . ) or cate- cholamine treatment (p= . ) had no influence on the diurnal distribution of arrhy. during / ( %) episodes there was an elevated c-reactive protein (crp), in / ( . %) an elevated leukocyte count [l] and in / ( %) episodes were there elevated fibrinogen levels (fgen). these inflammation parameters on the day of arrhy did not differ significantly when compared to the respective values and h before arrhy onset (crp . ± , . ± , ± mg/dl, p= . ; l . ± , . ± , . ± . g/l, p= . ; fgen ± , ± , ± mg/dl, p= . ). conclusions: ) clinically significant, sustained arrhy occurred in ~ / of patients in this medical-cardiologic icu. ) vt and afib were the single most frequent arrhy. ) arrhy followed a circadian pattern irrespec- tive of the presence of sedoanalgesia, mechanical ventila- tion or catecholamine support. ) the vast majority of arrhy occurred while there were signs of inflammation without preponderance to the ascending or descending limb of inflammation. p transthoracic cardioversion with damped biphasic waveform shocks va vostrikov, kv razumov, pv kholin and al cyrkin department of cardiology, moscow medical academy, hospital n and hospital n , moscow, russia introduction: the biphasic waveform has been shown to have high efficacy for transthoracic ventricular defibrillation [ , ]. the objective of this prospective study was to evalu- ate the clinical efficacy of biphasic waveforms for car- dioversion of atrial fibrillation. methods: the pulse is an asymmetric quasi-sinusoidal biphasic waveform. the peak current of the second phase was approximately half that of the first phase. transtho- racic cardioversion ( emergent, urgent and elec- tive) were performed in patients who were receiving antiarrhythmic drugs (e.g., amiodarone). ischemic heart disease was the most common (about %) etiology. shocks were delivered through . cm paddles in the antero-apical position. the maximum delivered energy was j. results: see table. conclusions: our clinical results demonstrate that the biphasic waveform with a delivered energy of ≤ j was highly effective in cardioverting atrial fibrillation. references: . poole j et al.: resuscitation, , ( ):s ,(p– ). . vostrikov v et al.: resuscitation, , ( ):s ,(o– ). table delivered energy cumulative success % confidence interval ≤ j / ( %) %– % ≤ j / ( %) %– % ≤ j / ( %) %– % p evaluation of transesophageal atrial pacing in the prone and lateral position nm schwann, dp maguire, se mcnulty and jv roth departments of anesthesiology, thomas jefferson university hospital, jefferson medical college, and the albert einstein medical center, usa introduction: transesophageal atrial pacing (teap) is used for temporary treatment of hypotension and/or low cardiac output caused by sinus bradycardia or atrioven- tricular junctional rhythm. it can also be used for temporary overdrive pacing of reentrant tachycardias. a pacing esophageal stethoscope (pes) is easy to place in supine intubated patients. however, no guidelines exist for pes placement in the prone or laterally positioned intubated patient. methods: after irb approval and written informed consent, an fr pes with cm depth markings (model cardiocommand, inc) was inserted to a depth of insertion (doi) of cm from the edge of the maxillary alveolar ridge into the esophagus of adult intubated patients in the supine position. with the pacing rate set – beats per min faster than the patient’s intrinsic heart rate and the current output on the pulse generator (model a) set at its lowest current setting ( . ma), the current was gradually increased until atrial capture was achieved. the minimum current producing continuous atrial capture throughout the respiratory cycle was recorded as the pacing threshold. the pes was then with- drawn cm at a time and pacing thresholds were re- determined for each doi from to cm inclusive. after data collection in the supine position, each patient was then positioned into either the prone (p), right (rld) or left lateral decubitus (lld) position. data were collected in the same manner after the patients’ position was changed. the width of the “region of capture” (roc) represents http://ccforum.com/supplements/ /s http://ccforum.com/supplements/ /s early career award for excellence in teaching and innovation early career award early career award for excellence in teaching and innovation published online: december # international association of medical science educators this annual award honors an iamse member who has made significant innovations to the field in the short time they have focused their careers toward enhancing teaching, learning, and assessment. candidates for this award will be assistant professor or equivalent rank, or have demonstrated less than years of educational scholarship. an award recipient will have a record of excellence in teaching at his/her institution and possess a record of engagement within iamse. it is rec- ognized that, while the successful nominee will have a proven track record of innovating and helping advance the art of teaching, s/he may not yet have achieved significant accom- plishments in scholarship. the educational scholarship committee reviews all nominations and supporting documen- tation based on established criteria and selects finalists. final approval of each award recipient rests with the iamse board of directors. award winner—david harris, phd university of central florida, associate professor of physiology david received his phd in physiology from temple university’s school of medicine in . afterwards, he did a post doc at thomas jefferson university’s center for translational medicine in heart failure and hypertension re- search. in , he joined drexel university college of medicine as course director of medical physiology in the department of pharmacology and physiology. three years later, he moved away from his home area of philadelphia and accepted a founding faculty medical educator position at the university of central florida (ucf) college of medicine in . during his time at ucf, he has been able to develop his scholarly interests, which include active learning peda- gogies and the use of high fidelity patient simulation with pre-clerkship medical students. he has published articles in advances in physiology education (advances), medical science educator, and meded portal and has presented nu- merous educational posters, workshops, and focus sessions at iamse annual meetings. he has been active nationally by serving on american physiology society (aps) committees, serving as associate editor of advances, and serving on the leadership team of the aquifer sciences (formerly medu) to develop a national curriculum for preventing harm through basic science knowledge. he has also won numerous awards such as the aps new investigator award, the aps teaching career enhancement award, and the ucf pre-clinical innovative teaching award. he enjoys spending time with his wife renata and daughters isabella and alicia, who are his biggest accomplishment and volunteering to teach english as a second language. publisher’s note springer nature remains neutral with regard to jurisdic- tional claims in published maps and institutional affiliations. medical science educator ( ) (suppl ):s https://doi.org/ . /s - - - 	early career award for excellence in teaching and innovation 	 award winner—david harris, phd 	university of central florida, associate professor of physiology jefferson and the wolf: the sage of monticello confronts the law of slavery jefferson and the wolf: the sage of monticello confronts the law of slavery author(s): philip j. schwarz source: oah magazine of history, vol. , no. , life in revolutionary america (summer, ), pp. - published by: organization of american historians stable url: http://www.jstor.org/stable/ accessed: / / : your use of the jstor archive indicates your acceptance of jstor's terms and conditions of use, available at http://www.jstor.org/page/info/about/policies/terms.jsp. jstor's terms and conditions of use provides, in part, that unless you have obtained prior permission, you may not download an entire issue of a journal or multiple copies of articles, and you may use content in the jstor archive only for your personal, non-commercial use. please contact the publisher regarding any further use of this work. publisher contact information may be obtained at http://www.jstor.org/action/showpublisher?publishercode=oah. each copy of any part of a jstor transmission must contain the same copyright notice that appears on the screen or printed page of such transmission. jstor is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. we use information technology and tools to increase productivity and facilitate new forms of scholarship. for more information about jstor, please contact support@jstor.org. organization of american historians is collaborating with jstor to digitize, preserve and extend access to oah magazine of history. http://www.jstor.org http://www.jstor.org/stable/ ?origin=jstor-pdf http://www.jstor.org/page/info/about/policies/terms.jsp http://www.jstor.org/action/showpublisher?publishercode=oah jefferson and the wolf: the sage of monticello confronts the law of slavery philip j. schwarz the american revolutionaries so re vered the rule of law that they relied on the law to help rule their slaves. an apostle of republicanism in the united states, thomas jefferson is no exception to this generalization. he faced the same dilemma as did other slave-holding ameri can revolutionaries. how could the de fenders of liberty simultaneously deny liberty to the african ameri- . cans whom they held to slavery? how could they be slave holders without denying liberty itself? some revolutionaries answered these ques tions by freeing their slaves. jefferson chose not to ( ). thomas jefferson's legal transactions con cerning his bondspeople reveal that part of his answer to the problem of slavery in a revolutionary, republi can society was to make certain of the legality of his behavior as a - master. he believed that confor mity to the law of slavery constituted a civic duty, protected him from some of the dangers inherent in slavery, preserved his liberty to hold humans in bondage, and even secondarily gave some personal se curity to the enslaved. jefferson's legal oversight of african americans at monticello and elsewhere is revealed in his legal transactions concern ing his human property, which spanned more than half a century. these transac tions created a unique, rich, and nearly unrivalled record of the relationship be tween written laws and human behavior in a representative, developed slave society ( ). this essay focuses on the manner in which jefferson translated statutory law into practice or made practice into cus tomary, unwritten law, that is, his planta tion rules. thanks to jefferson's careful how could the defenders of liberty simultaneously deny liberty to the african americans whom they held to slavery? retention of his papers, we can reconstruct a better picture of his legal relationship to the bondspeople under his dominion than in almost any other case ( ). for example, among jefferson's pa pers are agreements, wills, and other docu ments by which slaves were transferred from one generation of the jefferson fam ily to another. to be sure, these transfers normally benefitted jefferson, but these and jefferson's other legal transactions concerning slaves show how the law of slavery also placed him and other slave owners within the confines of a prescribed system that was supposed to command their obedience just as it was meant to help them command their slaves. the day-to day transactions of slave holders, such as those by which jefferson family members inherited human property, are notable for their routine, prosaic quality. one , can find similar transactions con cerning bondspeople in the records of slave societies throughout the western hemisphere. these ar rangements provided some predict ability and security, two essential aspects of law. but the system of property laws, other civil laws, and criminal laws reflected in these docu ments also constrained slave own ers?whether they held two or two hundred people. control was the sine qua non of slave ownership. the law of slavery helped people like jefferson control the wills of their human chattel to some ex tent. uncontrolled, the wills of chattel could become the wills of human beings, threatening slavery and endangering prop erty or people. however, neither statutory nor customary laws concerning slave gov ernance were as effective in controlling bondspeople as were straightforward prop erty laws in safeguarding ownership of human property. treating people as prop erty to be bought and sold was one thing. oah magazine of history summer it was quite another thing to act as if those human commodities lacked wills. none did, so enslaved people always had the potential of contradicting the neat catego ries by which slave holders attempted to rule, even when those categories were incorporated into laws. consider the con stant worry of slave holders about fugi tives, as reflected in jefferson's often-quoted virginia gazette advertise ment of for a runaway slave ( ). old dominion law gave owners of "slaves who stole themselves" some help in find ing them, and it assured that once they did, there were legal means of establishing ownership. it is questionable, however, how much good the law did jefferson: while almost every man who ran away from him was initially captured and re turned, nearly every one of these run aways ultimately proved uncontrollable and often ran away again, sometimes per manently. still, noblesse oblige was within the reach of the slave master. the law of slavery allowed for acts that could reas sure slave holders of their legitimacy. the rationale for the customary laws of slavery by which jefferson was supposed to con trol his slaves was that bondspeople must be extensions of the will of their owner. this paradoxically allowed jefferson to delegate to african americans powers ordinarily reserved to whites. he could even base important decisions about his slaves on their preferences or behavior; he also sometimes paid them for unusual tasks. but jefferson was unquestionably capable of angrily asserting his rights when slaves claimed at least by their actions that they had customary rights that clashed with his. private and public accusations of criminal behavior against jefferson's slaves involved both customary law and statutes. "misbehavior"?violations of jefferson's mostly spoken plantation or customary law?occurred fairly regularly, bringing into play his conception of him self as lawgiver and law enforcer. jefferson could order whippings or even far more severe punishment when he thought it necessary. he also had fairly clear ideas concerning the differentiation between his enforcement of plantation law and gov ernmental enforcement of statutes. when a bedford county slave court gave three of his poplar forest slaves a light sentence after convicting them of attacking their overseer, jefferson promptly sold the three. it was part of the customary law of his plantations for jefferson to provide at least minimal protection of his slaves against various dangers, such as neglectful or bru tal hirers, as a corollary to his shielding of himself and his agents from certain slaves. jefferson paradoxically assumed, however, that the ultimate method of protecting his bondspeople was to keep them in bond age. hence there are few manumissions recorded in jefferson's papers, most of them in his will. but when jefferson chose to free any of his human property, he had to contend with statutes that both empow ered and limited him in more complex ways than did any laws concerning run mount vernon ladies' association archaeology department artifacts recovered from the excavation of a slave quarter cellar at mount vernon. oah magazine of history summer aways or alleged criminals. jefferson's attitude toward both bondspeople and the laws of virginia influenced his decision to free several members of the hemings fam ily. his testamentary petition for an ex ception to the old dominion law that required most emancipated people to leave the state reflects his assumptions that the state lawgivers would grant his wish and that only these enslaved men would be capable of living in freedom. still another way jefferson encoun tered the strictures of the slave code un derlines the reciprocal nature of his link to that body of laws. that was when other people entrusted him with the disposition or protection of their slave property as a trustee, agent, legal advisor, or lawyer. in these and other instances, thomas jefferson accepted the laws of virginia, thomas jefferson memorial foundation, inc. overhead view of the largest of the slave dwellings on mulberry row at monticello. the ethics of his one-time profession of lawyer, and the canons of his class. living in a world of shared obligations, preserv ing their reputation among slave-holding peers, and choosing to keep their slaves, jefferson and other slave owners had no choice but to acknowledge the force of slave law. yet is it not fair to expect more legal creativity from thomas jefferson than from other slave owners of his time? relatively vigorous in his public pronouncements on abolition in the s and s, he main tained silence thereafter. his greatest creativity concerning his bondspeople was limited to the de facto manumissions of beverley and harriet, children of sally hemings, and his unusually clear articula tion of his slaves' peculium, or right to the fruits of some of their labor. the problem was that the law of slavery virtually stifled any more creativity than this. the root of jefferson's subjection to the law of slavery was his decision to remain a slave holder. as long as he held human property, jefferson never could escape from slave law. while in public office, he was called upon to make legal decisions about slaves and slavery. dur ing the early years of his public service he made some antislavery pronouncements ( ). his governmental actions, which carried greater practical weight than did his pronouncements, were rarely antisla very. every time he took the side of progress and enlightenment, he encoun tered self-interest and the hard realities of economic and political life in the new nation ( ). sought after regularly for his opinion concerning slavery during his years of retirement, jefferson insisted upon pub lic silence. under the heavy pressure of events such as the missouri controversy, he privately pronounced with insight on the nation's problem of slavery without being able to offer a solution. his tortured formulation of the dilemma he thought lawmakers and enforcers like him faced? to his mind the impossible choice between giving up the benefits of the law of slavery and eliminating that law's self-evidently unjust consequences?reflects his pain and ambivalence: "but as it is, we have the wolf by the ear, and we can neither hold him, nor safely let him go. justice is in one scale and self-preservation in the other" ( ). this is not to say that jefferson was a mere product of his times who failed to solve a problem that very few people solved. in other respects, jefferson helped to "produce" his times. yet he refused to go as far as his neighbor edward coles, who emancipated his slaves; jefferson also failed to emancipate more than a handful of slaves in his will?in contrast to such contemporaries as george washington and john randolph of roanoke. "was tho mas jefferson an authentic enemy of sla very?" david b. davis asked in ( ). was thomas jefferson willing and able to act against his own interest in slave prop erty? the latter is a question that hits close to home because it touches on how jefferson lived, on what the laws of his slave society allowed, and on his concep tion of himself as an enlightened ruler. slave owners did enjoy a certain amount of independence from govern mental oversight of their "management" of slaves. in return for the protection provided by the laws and judiciary of any slave society, however, slave holders had to pay the price of abiding by the regula tions that laws and the judiciary applied to owners. jefferson and other holders were unwilling to take the risk of rejecting governmental regulation of them and their human chattel because of the very nature of their legal relationship with bondspeople. they regarded slaves as oah magazine of history summer _thomas jefferson memorial foundation, inc. archaeological excavations on mulberry row unearthed an assortment of objects used by the slaves after work and on sundays or holidays. shown here are a fragment of a writing slate (with inscribed words), pencils, a penknife, dominoes, marbles, a jews harp, and part of a fiddle bow. their property. had they rejected the governmental regulation of that "species of property," they would have jeopardized much of the law of property and the soci ety and economy in which they lived. the only way out of these difficulties was to free all of one's slaves. this thomas jefferson was unwilling to do. jefferson's legal transactions con cerning human chattel reveal that he had the wolf by just one ear, a particularly precarious circumstance. it was as if slavery were the wolf, and the law of slavery could not always protect slave owners from trouble that could ultimately be blamed on that wolf. "in a word," declared an anonymous letter writer in , "if we will keep a ferocious monster in our country, we must keep him in chains .... slavery is a monster?the most horrible of all monsters" ( ). the law of slavery only supported, and did not guarantee, the security of slave owners. that was to be expected: no law has ever been able to guarantee security. but the wolf (slavery) was especially dangerous. jefferson also could not es cape the contradiction between his role of master and the ideals of the american revolution. subjecting himself to the rule of law?required behavior for any repub lican leader?did not work. "the slave holder can never be a democrat," declared a "gentleman" in a newspaper letter in ( ). what then was a leader of a republican revolution and of the demo cratic-republican party to do if he also chose to keep his slaves? the best he could do was to act like an enlightened monarch whom laws limited and empow ered, and who reserved the right to make some laws of his own. it is this "bargain" between the osten sibly independent slave owner and the government that helps considerably to explain the sharp conflict between jefferson's pronouncements about slavery and his actual ownership of bondspeople. jefferson could not have it both ways: as a slave owner, he either had to obey the laws of slavery while he kept african ameri cans in bondage or else free all slaves and not have to abide by the slave code. any one who acted like an enlightened mon arch could not be a republican leader of human beings when they were in bondage. no matter how beneficent a master he may have been, he still was an owner of per sonal chattel. that committed him to support the law of slavery and to preserve the peculiar institution. unique and ex traordinary in some ways, and often the beneficiary of the laws, he was just as thomas jefferson memorial foundation, inc. _____________________________________f _i?f^? ;''t-_i___^_l__^_____-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_p^"' ^^^^i_________________________h ________________ri' ip __________________ ' ^_____ ______h ________________________________________%? : ' '^mm^^^^^^^^^^^m ,*'^^rr^l*,l^^^^^^^m some objects found during excavations of mulberry row show that african traditions were very much alive within the monticello slave community. pictured here are a cowrie shell, a carved horn ring, and two pierced eighteenth-century spanish coins. oah magazine of history summer subject to the law of slavery as any other slave owner. the approximately per cent of his enslaved laborers who remained in bondage as the property of at least twenty-one new owners after jefferson's death were living proof that the law of slavery was written on their skins immea surably more than on jefferson's, that they lived under the govern ment of men as well as of laws; yet his unwillingness or inability to free those people is partly attribut able to the way in which the law of slavery was also written on jefferson's skin ( ). endnotes . for conflicting viewpoints con cerning jefferson's choice, see paul finkelman, "jefferson and slavery: treason against the hopes of the world,'" in jeffersonian legacies, ed. pe ter s. onuf (charlottesville: the university press of vir ginia, ), - , and or lando patterson, "the unholy trinity: freedom, slavery, and the american constitution," social research (autumn ): - . . for a discussion of the law of slavery, see philip j. schwarz, twice condemned: slaves and the criminal laws of virginia, - (baton rouge: louisiana state university press, ), - , and the many articles in paul finkelman, ed., slavery, race and the american legal sys tem, - (new york: garland, ). . the major collections of jefferson manuscripts are at the huntington library, the library of congress, the massachusetts his torical society, and the alderman library, university of virginia. all these collections are available on mi crofilm. the most recently published edition of jefferson's writings covers only through the beginning of the s. julian p. boyd etal., eds., the papers of thomas jefferson (princeton, n.j.: princeton univer sity press, - ). the best recent survey of african-american monticello is lucia c. stanton, "those who labor for my happi tracy w. mcgregor library, university of virginia ^^^tjmjr-'p wax-'xx ' ! born a slave at monticello, isaac jefferson worked there for many years as a blacksmith, tinsmith, and nailmaker. at the time of this photograph, he was a free man practicing his ironworking trade in petersburg, virginia. ness': thomas jefferson and his slaves," in jeffersonian legacies, ed. peter s. onuf, - . . virginia gazette (purdie & dixon), september , reprinted in boyd et ah, eds., the papers of thomas jefferson, i, , or transcribed in lathan windley, ed., runaway slave advertisements: a documentary his tory from the s to (westport, conn.: greenwood press, ), v. . virginia and north carolina, . . the most famous pronouncements are in his notes on the state of virginia (new york: harper & row, ), - . . see, e.g., douglas r. egerton, gabriel's rebellion: the virginia slave conspiracies of and (chapel hill, n.c.: the university of north carolina press, ). . jefferson to john holmes, april , , jefferson papers, library of congress, microfilm reel ?a polygraph copy of the original. all published transcriptions of this letter erroneously misquote "ear" as "ears," a crucial difference for the person holding the wolf. . oxford, . much of this lecture is incorporated into davis's the problem of slavery in the age of revolution, - (ithaca, n.y.: cornell university press, ). . "extract of a letter from a gentleman ... to the editor," fredericksburg virginia herald, september , . . "extract of a letter from a gentleman ... to the editor," fredericksburg virginia herald, september , . . the number of owners who made purchases at the two sales of jefferson's bondspeople in and is an estimate based on sales slips and on "an acct. of sales of negroes of the est. of thomas jefferson st jan. ," photocopies of which are in the research department, thomas jefferson memorial foundation (monticello), charlottesville, virginia. philip j. schwarz is professor of history at virginia commonwealth university and author of twice condemned: slaves and the criminal laws of virginia, - ( ). oah magazine of history summer 	article contents 	p. 	p. 	p. 	p. 	p. 	issue table of contents 	oah magazine of history, vol. , no. , life in revolutionary america (summer, ) 	front matter 	from the editor: life in revolutionary america [pp. - ] 	revolutionary america: the historiography [pp. - ] 	political leadership: six lessons from the founding period [pp. - ] 	past presence: interpreting lifestyles through material culture [pp. - ] 	jefferson and the wolf: the sage of monticello confronts the law of slavery [pp. - ] 	women and the american revolution [pp. - ] 	material life in revolutionary america: artifacts and issues in the classroom [pp. - ] 	lesson plans 	william buckland: indentured servant at gunston hall [pp. - ] 	thomas jefferson and architecture [pp. - ] 	federalists and anti-federalists: is a bill of rights essential to a free society? [pp. - ] 	ladies' letters: rx for eighteenth-century health care [pp. - ] 	on teaching 	writing essays that make historical arguments [pp. - ] 	reviews 	review: untitled [pp. - ] 	review: untitled [pp. - ] 	history headlines [p. - ] 	back matter 'x . ' poster.qxd developing and sustaining a web-based library newsletter elizabeth g. mikita, mls, daniel g. kipnis, msi, anthony j. frisby, phd thomas jefferson university, philadelphia, pa abstract before the rising popularity of the internet in the mid 's, scott library, like most others, used printed newsletters to inform users about new resources and services. the jeffline forum, our attempt to resuscitate the library's newsletter by employing the technical advantages—and increasing presence—of the web, debuted in october of . the fifth anniversary of the forum seemed like a good time to look back at its evolution and to examine some of the challenges inherent in developing and sustaining a library newsletter. background and history in , scott library's director appointed a working group to develop an online newsletter with the following objectives: develop content to highlight and support: ■ library news and information (primary focus) ■ educational initiatives and activities involving the participation of library and aisr staff members (secondary focus) ■ faculty and student projects related to medical informatics and other healthcare literature. encourage and recruit university and hospital faculty and staff to contribute relevant articles (tertiary focus) implement these features for the site: ■ archive of previous issues ■ ability to search content (including current issue and all archived issues) ■ interactivity to allow readers to communicate with authors, and to discuss and rate topics. ■ email announcements of a new "newsletter" release to all patron's in the library's security system and to all others who "opt" in in addition, the name jeffline forum was chosen for the site to help associate scott library and its parent—academic information services and research (aisr)—with jeffline, the campus academic information system. the first issue of the jeffline forum, october . a contents page containing links to articles and at least one "image of the month" gave the forum its distinctive look. from the beginning the forum has highlighted the rich collection of objects and images in our university archives. these have been among the most frequently read articles according to our analysis of "hits." the same basic design is still used today, but the forum is now published times a year the current issue is available at: http://jeffline.jefferson.edu/education/forum/ regular features like question of the month (above) and infobits (below) have been added over time. the forum regularly offers searching tips focusing on a specific feature of a resource such as ovid, pubmed, or google. clicking view a demo launches a separate window containing an automated demonstration of the tip or technique discussed in the article. (flash movie) abstract challenges: ■ building and tracking readership ■ soliciting feedback ■ maintaining staff interest in participation ■ recruiting "outside" authors ■ incorporating technology ■ increasing efficiency successful strategies: ■ making contribution guidelines simple and easy to follow ■ establishing ties with library staff to contribute recurring series of articles (e.g., history corner, new books, powerpoint tips, search tips, infobits, photoshop phanatic) ■ recruiting non-library staff to contribute articles ■ using pagespinner as html editor ■ creating automated demos to accompany "how to" articles and "tips." ■ adding a printer-friendly link and email article features to each article experience and lessons learned: ■ it can be difficult to recruit new authors. tap campus connections and workshop attendees as potential contributors. ■ tracking reader's interests is tricky. we use imdpoll (freeware for online poll), but receive relatively few responses. ■ readers like the flash demos created using camtasia and robodemo which are incorporated into some articles. ■ we recognize that the forum is time consuming to edit and assemble—approximately hours per issue (not including writing time)—even with increased experience and efficiency. ■ as of february , over , jeffersonians and non-jeffersonians subscribe to the jeffline forum listserv. scott memorial library thomas jefferson university walnut street philadelphia, pa - -aisr / - - may is the activation gate closed in kv channel closed-state inactivation? sunday, february , a -pos board b access constraints and binding energetics of a potassium channel inactivation gate gaurav venkataraman, deepa srikumar, miguel holmgren. nih, bethesda, md, usa. voltage-activated potassium (kv) channels open an intracellular gate in re- sponse to changes in transmembrane voltage, allowing k þ to permeate at rates near diffusion. in some kv channels, permeation can be interrupted by the n-terminus of the protein acting as a blocking particle, binding at the intracel- lular cavity of the channel and physically obstructing the permeation pathway. despite being tetramers, kv channels require only one bound n-terminus to inactivate. in nature, inactivation is targeted by rna editing, which converts an isoleucine of the intracellular cavity into a valine. the functional conse- quence is a large increase in unbinding kinetics. how does each ‘‘wall’’ of the cavity contribute to the increase in unbinding kinetics of a single bound n-terminus? to address this question we made con- catenated shaker heterotetramers consisting of only one free n-terminus and a single isoleucine to valine mutation at position (i v), mimicking the rna editing site in humans and rodents. surprisingly, the rate of unbinding was the same for individual i v mutations in each wall; each corresponded to a decrease in binding energy of about . rt. in fact, the binding energy de- creased linearly as a function of the number of i v mutated subunits. these results suggest that despite being tethered to a particular subunit, the single in- activation particle has sufficient freedom to interact with position of each subunit with roughly equal probability. where does this freedom come from? it is expected that the inactivation gates enter the cavity through lateral ‘windows’, similarly to k þ . can our single tethered inactivation gate enter through each of the four windows of the protein? we will address this question by making individual cysteine mutations at each window and testing the inac- tivation gate’s binding kinetics after chemical modification. -pos board b gating interactions between the cytoplasmic t domain and pore of a kv channel brian urbani, manuel covarrubias. jefferson medical college of thomas jefferson university, philadelphia, pa, usa. whereas the gating roles of the voltage-sensing and pore domains of kv channels have been extensively investigated, much less is known about the mechanisms governing the regulation of gating by the cytoplasmic t domain. previous work from this lab strongly suggests that the kv . t domain un- dergoes conformational changes directly linked to gating (j. gen. physiol., : - , ); however, the structural basis of the communication between the activation gate and the t domain has remained elusive. to tackle this problem, we applied cysteine scanning mutagenesis, voltage- clamp electrophysiology, double mutant cycle analysis (dmca) and oxidizing reagents to probe specific interactions between the cytoplasmic t domain l helix, the s -s linker and s tail. the energetic impact of the mutations on activation gating is apparently small. by comparison, the energetic impact of the mutations on inactivation gating was significantly greater. dmca of k c(l )þa c(s ) revealed a significant interaction energy ( kcal/ mol), which suggests an interaction between k in the l helix and a in s . supporting this possibility, the currents induced by k c(l )þ a c(s ) are inhibited (~ % of control) by an oxidizing agent (tbuho ), whereas the single mutants are not; and the effect is reversed by the reducing agent dtt. these results indicate the formation of a disulfide bond between the interacting side chains, which is consistent with physical interaction between k (l ) and a (s ). overall, we conclude that regulation of inactivation gating by the t domain involves a physical interaction between the t l helix and the distal segment of s . supported by nih grant r ns (mc). -pos board b is the activation gate closed in kv channel closed-state inactivation? jeffrey d. fineberg, manuel covarrubias. thomas jefferson university, philadelphia, pa, usa. kv .x channel complexes including auxiliary subunits such as dpp -s and kchip undergo preferential closed-state inactivation (csi; baehring and covarrubias, , j physiol, . : - ; fineberg et al., , j gen physiol, in press). however, the molecular basis of csi in kv .x channels remains poorly understood. a key unanswered question of this problem is whether the channel’s activation is actually closed, as csi implies. we have previously proposed that csi results when the activated channel fails to open or simply prefers to close. this hypothesis specifically suggests that the intra- cellular activation gate may adopt a stable closed conformation, even under depolarized conditions that would initially favor the activated ‘‘up’’ state of the voltage sensors. to test this hypothesis, we are exploiting the trapping paradigm previously investigated by holmgren et al. to test the state of the intracellular activation gate ( , j gen physiol, : - ). essentially, if the activation gate closes behind a quaternary ammonium (qa) blocker inside the pore, the blocker cannot exit the pore; effectively, it is trapped. we are expressing the ternary kv . /i c channels (this mutation favors trap- ping) including dpp -s and kchip in xenopus oocytes. then, in the inside- out patch-clamp configuration, we are using a computer-controlled perfusion system to deliver the qa derivative decyltrimethylammonium bromide (c ) to the bath and probe the ability of the channel’s activation gate to trap c in the closed, open and inactivated states. preliminary results show that the trapping paradigm may yield an answer to the central question of this study. if the activation gate is indeed closed during csi, c trapping will only occur when the drug is applied to the conducting channel, but no trapping of c will be observed in the closed and inactivated states. supported by nih grant r ns (mc). -pos board b water at the potassium channel gate: quantum calculations show an oscillation in water structure alisher m. kariev, michael e. green. city college of the city university of ny, new york, ny, usa. quantum calculations on the open gate and the immediately surrounding re- gion of the kv . voltage gated potassium channel show that water adopts two conformations there, one when the ion is present, and another with no ion present. an energy minimum at the gate with no ion allows an ion to enter from the solution; from the gate it repels an ion in the channel pore cavity into the selectivity filter (essentially the ‘‘knock-on’’ mechanism). the pore cavity minimum can then be occupied by the ion moving from the gate minimum, leaving it available for anion from bulk, so the cycle continues. the arrange- ment of water, and the ion hydration, defines the gate energy minimum, and this in turn depends on the highly conserved prolines, especially p ( a pdb numbering), in the pvpv sequence in the gate. absent an energy minimum at the gate an ion entering from solution would be repelled back into solution by the ion in the cavity. furthermore, the ion remains hydrated by water molecules, at least more than in bulk, as it passes through the gate, based on optimizations with the ion at three different positions: ) at the gate position nearest p ) å above ) å below, this position. the open gate maintains very nearly the same protein atom positions throughout. additional calculations will be required to determine the exact interaction en- ergy with an ion in the cavity, and the amount of water that is present in the cavity. optimizations of the system configuration were done at hf/ - gsp level, with atoms ( with the ion). energy was determined using both b lyp/ - g* and bvp / - g*, but the system was too large for free en- ergy determination. -pos board b water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computational mutations, and the role of a histidine in gating alisher m. kariev, michael e. green. city college of the city university of ny, new york, ny, usa. conservation of the pvpv sequence at the potassium channel gate has not been well understood. quantum computations (optimization at hf/ - gsp level) of the gate of the kv . channel that are presented here show that the proline-proline distances (ring atoms) are preserved as the ion moves through the gate. this calculation is supplemented by mutating one of the prolines to valine (p v, a pdb numbering for all residues in this abstract) in the computation, producing a pvvv sequence. water structure changed dramati- cally, as the protein backbone moved inward nearly å, effectively closing the channel; the proline ring n-n distance between diagonally opposite pro- lines dropped from . å (distance from optimization: x-ray distance = . å) to . å, too small to allow passage of a hydrated k þ . this suggests that the prolines play a key structural role, modulating both protein and water structure. furthermore, protonation of h may close the channel. protonation of this histidine shows it moving toward the gate by about å, which should close the gate electrostatically, while deprotonation opens the gate. protonation was calculated with two added protons, the other being accepted by e of the t intracellular moiety. when deprotonated, the histidine does not move as much as å from the x-ray position in the optimization, and is linked to e ; this accounts for the known importance of the t segment in gating. e , also of t , could accept a third proton. there is a salt bridge structure including these residues similar to the one occupying a key position in the pro- ton pathway in the hv channel. 	access constraints and binding energetics of a potassium channel inactivation gate 	gating interactions between the cytoplasmic t domain and pore of a kv channel 	is the activation gate closed in kv channel closed-state inactivation? 	water at the potassium channel gate: quantum calculations show an oscillation in water structure 	water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computation ... t h e american journal of international law volume published by t h e american society of international l a w publication o f f i c e : editorial and executive o f f i c e : t h e r u m f o r d p r e s s jackson place concord, n . h. washington, d . c. copyright, , by the american society of international law board of e d i t o r s of t h e a m e r i c a n journal of i n t e r n a t i o n a l law chandler p . anderson, new york, n . y. e d w i n m . borchard, yale law school. p h i l i p marshall brown, princeton university. e d w i n d. dickinson, university of california school of jurisprudence. charles g. f e n w i c k , bryn mawr college. james w. garner, university of illinois. m a n l e y o. hudson, harvard law school. charles c h e n e y h y d e , columbia university law school. p h i l i p c. j e s s u p , columbia university law school. arthur k. k u h n , new york, n . y. j e s s e s. r e e v e s , university of michigan. e l l e r y c. stowell, american university. l e s t e r h . woolsey, washington, d . c. quincy w r i g h t , university of chicago. honorary editor-in-chief james brown scott, washington, d . c. editor-in-chief george grafton w i l s o n , harvard university managing editor george a. f i n c h , jackson place, n . w., washington, d. c. the object of the american society or international law is to foster the study of international law and promote the establishment of international relations on the basis of law and justice. for this purpose it will cooperate with other societies in this and other countries having the same object. t h e american journal of international law is supplied to all members of the society without extra charge, as the membership fee of five dollars per annum includes the right to all issues of the journal published during the year for which the dues are paid. (members residing in foreign countries outside the domestic postal zone pay one dollar extra per annum for foreign postage; canada fifty cents extra.) the annual subscription to non-members of the society is five dollars per annum (plus the above mentioned sums for foreign postage) and should be placed with the american society of international law, jackson place, n. w., washington, d. c. single copies of the journal will be supplied at $ . per copy. applications for membership in the society, correspondence with reference to the journal, and books for review should be sent to george a. finch, secretary and managing editor, jackson place, n. w., washington, d. c. contents of volume twenty-nine [no. , january, , p p . - ; n o . , april, , p p . - ; n o . , july, , p p . - ; n o . , october, , p p . - ] page t h e t h i r t e e n t h y e a r o f t h e p e r m a n e n t c o u r t o f i n t e r n a t i o n a l j u s t i c e . manley . hudson codification o f i n t e r n a t i o n a l l a w . philip marshall brown conditions o f w i t h d r a w a l from t h e l e a g u e o f n a t i o n s . josephine j. burns.. retroactive e f f e c t o f t h e r a t i f i c a t i o n o f t r e a t i e s . / . mervyn jones thomas j e f f e r s o n on t h e l a w o f n a t i o n s . charles m. wiltse belligerent a i r c r a f t , n e u t r a l t r a d e , and u n p r e p a r e d n e s s . charles warren. t h e p o s i t i o n o f a l i e n s i n n a t i o n a l socialist p e n a l l a w r e f o r m . lawrence preuss implied r e s o l u t i v e c o n d i t i o n s i n t r e a t i e s . charles fairman extraterritorial j u r i s d i c t i o n i n t h e a n c i e n t w o r l d . shalom kassan laws r e l a t i n g to n a t i o n a l i t y at b i r t h and to l o s s o f n a t i o n a l i t y . dur- ward v. sandifer t h e c o n c e p t o f a g g r e s s i o n i n i n t e r n a t i o n a l l a w . quincy wright c i t i z e n s h i p o f n a t i v e - b o r n a m e r i c a n w o m e n m a r r i e d to f o r e i g n e r s . edwin m. borchard armed n e u t r a l i t i e s to . carl j. kulsrud discovery and a n n e x a t i o n i n i n t e r n a t i o n a l l a w . f. a. f. von der heydte.... unilateral d e n u n c i a t i o n o f t r e a t i e s . j. w. garner and v. jobst, hi d e v e l o p m e n t o f i n t e r n a t i o n a l t a x l a w . mitchell b. carroll t h e b a l t i c s t a t e s and t h e s o v i e t u n i o n . gregory rutenberg c h i n e s e i n t e r s t a t e i n t e r c o u r s e b e f o r e b . c roswell s. britton t w o p r o b l e m s o f a p p r o a c h to p e r m a n e n t c o u r t o f i n t e r n a t i o n a l j u s t i c e . manley o. hudson n e u t r a l i t y o f t h e u n i t e d s t a t e s . james brown scott e d i t o r i a l c o m m e n t : philippine neutralization. george grafton wilson philippine independence. philip c. jessup t h e assassination of k i n g alexander. arthur k. kuhn b u d a p e s t resolutions on t h e briand-kellogg p a c t of paris. m. o. hudson leticia dispute between colombia a n d peru. lester h. woolsey u n i t e d s t a t e s - p a n a m a claims arbitration. edwin m. borchard generalization of t h e monroe doctrine. philip c. jessup afghanistan, ecuador a n d soviet union in league of nations. m. . hudson. secretary hull's t r a d e agreements. euery c. stowell i n t e r n a t i o n a l law a n d international t r a d e . charles g. fenwick iii i v contents page german rearmament and united states treaty rights. edwin m. borchard.... russian claims negotiations. chandler p. anderson the adjustment of the i'm alone case. charles cheney hyde the united states senate and the world court. manley . hudson treaties and changing conditions. george grafton wilson the doctrine of the thalweg as a rule of international law. james w. garner... the "gold clause" decision in relation to foreign bondholders. c. g. fenwick.. cramping our foreign service. ellery c. stowell treaties as domestic law. chandler p. anderson the constitution of the philippines. jesse s. reeves the world court interprets another international agreement. c. c. hyde acts and joint resolutions of congress as substitutes for treaties. j. w. garner. declaratory judgments in international law. edwin m. borchard the conflict of laws restatement. arthur k. kuhn the growth of the law. philip c. jessup the recent trade agreement with russia. chandler p. anderson concerning a russian pledge. charles cheney hyde respect for national flag. george grafton wilson neutrality and responsibility. charles g. fenwick the new neutrality legislation. philip c. jessup international revolution. philip marshall brown the deportation of aliens. ellery c. stowell denunciation of disarmament clauses of treaty of versailles. c. g. fenwick... cubhent notes: annual meeting of the society. george a. finch , the supplement. george a. finch a point of punctuation. hunter miller inter-american commercial arbitration commission. spruille braden the austrian constitution of . h. arthur steiner kidnaping of fugitives from justice on foreign territory. lawrence preuss a note on be piracy jure gentium. charles fairman chronicle of international events. m. alice matthews , , , judicial decisions involving questions of international law: judicial committee of the privy council: in re piracy jure gentium u. s. supreme court: pigeon river improvement, slide & boom co. v. cox, ltd new jersey v. delaware opinion, u. s. attorney-general: johnson act canada-u. s. reports of commissioners: british ship vm alone v. u. s arbitral award, oct. , : barcs-pakrac railway co. v. yugoslavia italo-ethiopian commission: award in walwal incident. sept. , royal hungarian supreme court: hungarian radio co. v. gramophone co book reviews and notes , , , books received , , , periodical literature of international law , , , index supplement section of official documents. (separately paged and indexed.) contents page t h e thirteenth year op the permanent court op international justice. manley . hudson t h e codification op international law. philip marshall brown conditions op withdrawal from the league op nations. josephine j. burns.. retroactive effect op the ratification op treaties. / . mervyn jones thomas jefferson on the law op nations. charles m. wiltse editorial comment: philippine neutralization. george grafton wilson philippine independence. philip c. jessup complaint of yugoslavia against hungary with reference to the assassination of king alexander. arthur k. kuhn budapest resolutions of on the briand-kellogg pact of paris. m. . hudson leticia dispute between colombia and peru. lester h. woolsey united states-panama claims arbitration. edwin m. borchard generalization of the monroe doctrine. philip c. jessup afghanistan, ecuador and the soviet union in the league of nations. m. . hudson current notes: annual meeting of the society the supplement a point of punctuation. hunter miller inter-american commercial arbitration commission. spruiue braden the austrian constitution of . h. arthur steiner chronicle of international events. m. alice matthews judicial decisions involving questions of international law: in re piracy jure gentium. judicial committee of the privy council pigeon river improvement, slide & boom co. v. cox, ltd. u. s. supreme court johnson act. opinion of u. s. attorney general book reviews and notes: bustamante, derecho internacional publico, ; cavaglieri, corso di diritto in- ternationale, ; commission of inquiry, international economic relations report, ; gettys, law of citizenship in the united states, ; goedhuis, la convention de varsovie, ; guggenheim, the united states and cuba, ; harley, documentary textbook on international relations, ; hudson, the permanent court of international justice, ; latand, history of american foreign policy, ; naurois, les traius tnternationaux devant us juridictions nationales, ; robinson, kommentar der konvention iiher das memelgebiet, ; salter, the united states of europe and other papers, ; savage, policy of the united states toward maritime commerce in war, ; scott, the catholic conception of international law, ; zancla, ii procedimento di mediazione e di concuiazione avanti al consiglio, . briefer notices: bourbousson, ; das, ; duden, ; hostie, ; ogg, ; owen, ; woodhead, ; coenen, ; munch, ; ferrero, ; war- ner, ; cooper, ; wheeler-bennett, ; ritsher, ; ermarth, ; riesch, ; von pfuel, ; von thadden, ; von weber, . books received periodical literature of international law board of e d i t o r s of t h e a m e r i c a n journal of i n t e r n a t i o n a l law chandler p . anderson, new york, n . y. edwin m . borchabd, yale law school. p h i l i p marshall brown, princeton university. edwin d . dickinson, university of california. charles g. fenwick, bryn mawr college. james w. garner, university of illinois. manley . hudson, harvard law school. charles c h e n e y hyde, columbia university. p h i l i p c. jesstjp, columbia university. arthur k. k u h n , new york, n . y. jesse s. reeves, university of michigan. ellery c. stowell, american university. lester h . woolsey, washington, d . c. quincy wright, university of chicago. honorary editor-in-chief james brown scott, washington, d . c. editor-in-chief george grafton wilson, harvard university. managing editor george a. f i n c h , jackson place, n . w., washington, d . c. the object of the american society of international law is to foster the study of international law and promote the establishment of international relations on the basis of law and justice. for this purpose it will cooperate with other societies in this and other countries having the same object. t h e american journal op international law is supplied to all members of the society without extra charge, as the membership fee of five dollars per annum includes the right to all issues of the journal published during the year for which the dues are paid. (members residing in foreign countries outside the domestic postal zone pay one dollar extra per annum for foreign postage; canada fifty cents extra.) the annual subscription to non-members of the society is five dollars per annum (plus the above mentioned sums for foreign postage) and should be placed with the american society of international law, jackson place, n. w., washington, d. c. single copies of the journal will be supplied at $ per copy. applications for membership in the society, correspondence with reference to the journal, and books for review should be sent to george a. f i n c h , secretary and manag- ing editor, jackson place, n. w , washington, d. c. nat mx david adam, london final proof that scientists can work with the media, or an unfortunate clash of peer pres- sure and peer review? television viewers in britain can make up their own minds this week when a unique combination of science and reality tv gets its first screening. billed as both entertainment and serious research, the bbc programme the experi- ment attempts to recreate aspects of a psychology study by stanford university researcher philip zimbardo. in the original study, volunteers were asked to assume the role of either prisoner or prison guard, and were placed together in a simulated jail. those acting as guards were so brutal to the prisoners that a shocked zimbardo abandoned the experiment and said that it should never be repeated. it is now seen as an important demonstration of how social circumstances can make people conform to particular roles. but whereas the stanford guards bullied the prisoners and forced them to clean toilets with their bare hands, their british counter- parts tried to befriend the prisoners and even agreed to reorganize the prison as a com- mune. an edited version of the -day trial, held last december at a london television studio, will be shown in four one-hour programmes beginning this week. “this has been a ground-breaking collab- oration between academia and the media,” says alex haslam, a psychologist at exeter university who planned the experiment with steve reicher, a researcher at the university of st andrews and joint editor of the british journal of social psychology. “it is not a media creation on which psychologists were invited to comment. the guiding principle for us and the bbc was always the science.” others warn, however, that it is difficult to compare the two studies directly, as behav- ioural trials are hard to replicate. the tele- vision cameras will also have had “an immedi- ate constraint on what people do”, says donald laming, a psychologist at the univer- sity of cambridge. zimbardo, still at stanford university, could not be reached for comment. for the experiment, male volunteers were recruited through newspaper adverts, and divided into guards and prisoners. the prisoners shared cramped cells and carried out chores, whereas the guards enjoyed better food and separate rooms and were given lim- ited powers over their charges. as well as observing and recording the behaviour of the volunteers, haslam and reicher asked them to complete psychometric tests and analysed their saliva for the stress hormone cortisol. it soon became clear that the guards were news nature | vol | may | www.nature.com unable to organize themselves. “there was a lack of a common social identity, no leader- ship and they didn’t even develop a simple shift pattern,” says reicher. the guards showed more psychological stress than the prisoners. haslam says that he welcomed the chance to challenge the stanford results, and claims that the guards who behaved as tyrants in the original experiment did so only because they were encouraged to. n reality tv show recreates famed social study broadcasting behind bars: the experiment aims to explore how people conform to set roles. jefferson’s descendants continue to deny slave link erika check, washington thomas jefferson’s descendants have decided that the ancestors of one of his slaves cannot join their family club, despite dna evidence published in nature suggesting that he fathered at least one of her children. the monticello association, a group of nearly descendants of jefferson’s daughters, voted on may to keep sally hemings’s descendants out of their group. this means that hemings’s relatives cannot be buried in the graveyard at monticello, jefferson’s home in charlottesville, virginia. their vote is the latest twist in a racially charged controversy that has raged since jefferson’s own day, when it was noted that sally hemings’s children bore a likeness to the third president. that and other evidence fuelled speculation that the author of the declaration of independence fathered six children by hemings, who was a slave at monticello. she only became pregnant during times when jefferson stayed there. jefferson’s descendants have always disputed this speculation. jefferson’s grand- children claimed that one of his maternal nephews, samuel or peter carr, fathered hemings’s children. but genetic tests pub- lished in november (see nature , – ; ) eliminated that possibility. the tests compared the y chromosomes of men descended from sally hemings’s son eston with those from the jefferson and carr family lines. eston’s y chromosome was found to be virtually identical to jefferson’s and dissimilar to the carr chromosome. the study caused an outcry because it was published in the midst of then-president bill clinton’s impeachment process. clinton’s supporters seized on it as proof that previous presidents — even the most celebrated ones — had also engaged in sexual indiscretion. the findings prompted the thomas jefferson foundation, which owns and operates monticello, to investigate the hemings connection. in january , it concluded that the dna study, combined with other evidence, indicated a “high prob- ability that thomas jefferson fathered eston hemings, and that he most likely was the father of all six of sally hemings’s children”. but jefferson’s descendants remain unswayed, and now say that thomas’s brother randolph was probably eston’s father. “they have not provided conclusive evidence that thomas jefferson had a relationship with sally hemings,” says nathaniel abeles, the monticello association’s president. the association’s position cuts no ice with the academic community. “this decision is scientifically unsound, historically unsound and morally bankrupt,” says annette gordon-reed of the new york law school. “the issue is pretty much settled and the fact that the family association chooses to tell a story about itself doesn’t affect what scientists or historians think.” n b b c monticello, home of thomas jefferson, where his slave’s descendants have been denied burial. j. s o h m /c h r o m o so h m /c o r b is © macmillan magazines ltd 	jefferson’s descendants continue to deny slave link technetium. m-polyphosphate is probably the current agent of choice for bone imaging, and satisfactory renal imaging can be obtained during whole.body bone scanning because the kidneys excrete s mtc.polypho ph@ge. in our ex perience, renal images noted during bone scan ning with somtc@polyphosphate are of diagnostic quality. technetium- m-polyphosphate has recently been introduced as a bone scanning agent ( — ), and it is probably the current agent of choice for bone imag ing. the localization of damtc@polyphosphate in the skeletal system is similar to other bone-seeking radio nuclides, and — % of the administered dose was localized in the skeleton of normal rabbits ( ). the mode of excretion is through the urinary tract, thus affording excellent images of the kidneys at the time of bone scanning. recently patients undergoing ddmtc@polyphosphate bone scanning at our institution were noted to have abnormal renal images. these abnormalities were confirmed, thus suggesting that renal lesions may be accurately imaged during bone scanning with this agent. methods technetium- m-polyphosphate is prepared from a sterile, pyrogen-free kit manufactured by diagnos tic isotopes inc. and new england nuclear co. the procedure involves adding °°@‘tc-pertechnetatesolu tion to a prernixed vial of polyphosphate and stan nous chloride and then mixing for — mm. scanning is started hr after the intravenous injection of mci of oomtc..polyphosphate on an ohio-nuclear model dual -in. scanner with s : minification using maximum speed of cm/mm. whole-trunk or total-body scanning including kidneys and bladder in both anterior and posterior projections is com pleted in approximately — mm. results nine out of patients who underwent odmtc@ polyphosphate bone scanning showed abnormal renal findings that were proven to be accurate on subse quent intravenous pyelograms. abnormal renal find received nov. , ; revision accepted feb. , . for reprints contact: chan h. park, div. of nuclear mcd icine, dept. of radiation therapy and nuclear medicine, thomas jefferson university hospital, lth and walnut sts., philadelphia, pa. . fig. . normalrenal image.posteriorscanshowsnormal kidneys in size, shape, position, and contour. arrow points to radioactivity in texas urosheath. r@ journal of nuclear medicine jnin/c ncibe communication reliability of renal imaging obtained incidentally in @lmtc@polyphosphatebone scanning chan h. park, leonard m. glassman,nobel . thompson,and julio s. mata thomas jefferson university hospital, philadelphia, pennsylvania ingsincludedisplacementof the kidney( ) , unilater ally poor functioning kidney ( ), nonfunctioning kidney ( ) , hydronephorosis, hydroureter ( ) , renal cyst ( ) , and hypernephroma ( ). the following cases are representative examples. normal renal image. figure is a posterior scan on an -year-old boy who was having pain in his back and urinary incontinence. bone scan is normal and both kidneys are normal in size, shape, and po sition. poor functioning kidney. jb is a -year-old man who had a bone scan because of pain in his back and right hip. in september , he had a cystectomy and bilateral ureteroileostomy for car cinoma of the urinary bladder. the scan showed a r p fig. . poorlyfunctioningkidney.anteriorscanrevealsradio. activity in ileal conduit in right pelvis and in collecting bag in region of right hip. posterior scan shows poor visualization of left kidney and intravenous pyelogram confirms poorly functioning left kidney. fig. . hydronephrosisand hydroureter.posteriorscanre veals no bone metastasis but hydronephrosis and hydroureter on left with poor renal function on right is apparent. subsequent in. travenous pyelogram documents hydronephrosis and hydroureter secondary to two stones obstructing ureterocele (arrow) and poor visualization of right kidney. volume , number i@@ :*:@!i @- : i f g. . surgicallyprovenbenignrenalcyst.posteriorscan shows discrete defect in upper pole of left kidney and increased uptake in region of left hip secondaryto arthritis. nephrotomogram of left kidney confirmscyst (arrows) in upper pole. poorly functioning left kidney and metastatic lesions in the pedicle of the l on the right side, right sacral wing, and the right proximal femur (fig. ). hydronephrosis and hydroureter. ok is a - year-old woman who had a past history of an en dometrial sarcoma and a bone scan was done because of pain in the upper thoracic region. she did not have any genitounnary complaints and the blood urea nitrogen was normal at the time of bone scanning. the scan failed to reveal bony metastasis but left hydronephrosis and hydroureter were found (fig. ) . a subsequent intravenous pyelogram the follow ing week showed the same finding secondary to two stones obstructing an ureterocele. space-taking lesions. ts is a -year-old woman who had a bone scan because of pain in the left hip and thigh. a mass lesion was noted in the upper pole of the left kidney (fig. ) and a renal cyst was found at surgery. increased uptake in the region of the left hip is due to arthritis. a similar mass lesion in the upper pole of the right kidney on a - year-old man was subsequently proven to be a hypernephroma at surgery. discussion renal excretion occurs probably as a simple phos phate and the cumulative renal excretion up to hr on rabbits ranged between — % ( ) . usually, renal radioactivity would not interfere with the skeletal imaging of the lumbar spine. however, it is very difficult to interpret the pelvic areas when the urinary bladder is filled with urine containing large amounts of radioactivity. to avoid this problem, the park, glassman, thompson, and mata patient voids just before the scan and the scanning is started from bottom to top. radiation dose to the kidneys is mrads per mci @'tc-polyphosphate assuming % of an injected dose in the kidneys and renal disappearance by physical decay alone ( ). to decrease radiation dose to the kidneys and bladder, hydration, and fre quent voiding are recommended to the patient. acknowledgments we thank joan franco for technical assistance, and mary ellen martin and jane russel for preparation of the manu script. references . subramanian g, mcafee jo: a new complex of mtcfor skeletal imaging. radiology : — , . subramanian , mcafee jo, bell eg, et al: mmtc labeled polyphosphate as a skeletal imaging agent. radi o/ogy : — , . blair rj, bell eg, subramanian , et al: evalua tion of @mtc-polyphosphateimaging for non-neoplastic skeletal disease. i nuc/ med : , . liebermane: personal communication, ‘ - october through november , holiday inn—rivermont memphis, tennessee the scientificprogramcommitteewelcomesthe submissionof original contributionsin nuclear medi cine from membersand non-membersof the society of nuclear medicine for considerationfor the scientific session. program: a. scientific session: selected papers of all aspects of nuclear medicine. b. continuingeducationseries: practical aspects of nuclear medicine instrumentation. guidelines: . absfractshouldcontaina statementofpurpose,methodsused,resultsandconclusions. . not to exceed words. . give title of paper and name of author(s) as you wish them to appear on the program. un derline the name of the author who will presentthe paper. . accepted abstracts will be published in the southern medical journal. . send abstract and four copies to: edwardv. staab,m.d. nuclear medicine division vanderbilt university hospital nashville, tennessee deadline: august , journal of nuclear medicine southeasternchapter the societyof nuclearmedicine fourteenthannual meeting announcementand call for extracts nd impact of topiramate for migraine prophylaxis on workplace productivity: results from two u.s. randomized, double-blind, placebo-controlled, multicenter trials a abstracts nd impact of topiramate for migraine prophylaxis on workplace productivity: results from two u.s. randomized, double-blind, placebo-controlled, multicenter trials gagne jj , lofland jh , rupnow m , smith kd , poston s , pizzi lt thomas jefferson university, philadelphia, pa, usa, ortho-mcneil janssen scientific affairs, llc, titusville, nj, usa objective: to compare the impact of topiramate mg/day versus placebo on workplace productivity among individuals with migraine, using data from two six-month randomized, double-blind trials. methods: a five-item survey for each migraine attack captured the participants’ number of hours absent from work (“absenteeism”, a), number of hours worked with migraine (wm), and degree of effectiveness (e) while working with migraine. presenteeism (p) was calculated as the product of wm and e. total lost productivity was the sum of a and p. the mean monthly ( -day) rate of lost productivity per person at baseline and double-blind periods was compared between the study arms using wilcoxon rank sum tests. results: a total of subjects were enrolled in the trials ( topiramate, placebo). of these, subjects reported any lost productivity at baseline ( topiramate, placebo). mean ± sd age was ± years, . % were female, and . % were caucasian. demographic characteristics were similar between groups. the most common adverse events for topiramate in the clinical trials included paresthesia, nausea, anorexia, and fatigue. at baseline, the mean rates of total lost productivity were . hours/ days for topiramate mg/d and . hours/ days for placebo (not significant). total lost productivity hours/ days for topiramate mg/d versus placebo were . versus . in month , and . versus . , . versus . , . versus . , . versus . , and . versus . over the next five months. improvements in productivity associated with topiramate mg/d in comparison with placebo were sta- tistically significant (p < . ) in months , , , , and . con- clusions: this is one of the first studies examining the impact of topiramate on workplace productivity, based on post-hoc analysis of randomized trials. our findings suggest that topira- mate mg/day may be associated with improvements in pro- ductivity among individuals with migraine. in memoriam: jim cathey full terms & conditions of access and use can be found at https://www.tandfonline.com/action/journalinformation?journalcode=uemp electric power components and systems issn: - (print) - (online) journal homepage: https://www.tandfonline.com/loi/uemp in memoriam: jim cathey ion g. boldea to cite this article: ion g. boldea ( ) in memoriam: jim cathey, electric power components and systems, : , - , doi: . / . . to link to this article: https://doi.org/ . / . . published online: may . submit your article to this journal article views: view related articles https://www.tandfonline.com/action/journalinformation?journalcode=uemp https://www.tandfonline.com/loi/uemp https://www.tandfonline.com/action/showcitformats?doi= . / . . https://doi.org/ . / . . https://www.tandfonline.com/action/authorsubmission?journalcode=uemp &show=instructions https://www.tandfonline.com/action/authorsubmission?journalcode=uemp &show=instructions https://www.tandfonline.com/doi/mlt/ . / . . https://www.tandfonline.com/doi/mlt/ . / . . electric power components and systems, : – , copyright © taylor & francis group, llc issn: - print/ - online doi: . / . . in memoriam: jim cathey with sadness, the electrical engineering community learned that professor jim cathey from university of kentucky, editor-in-chief for more than a decade of electric power components and systems, passed away in february. we join the family in grief for the irreparable loss. observing time and time again how short our lives are, we should ask ourselves every so often how we spent it. did we do enough good for the family and for the wider community to which we belong? in answering this question, we should adjust our trajectory in this world, for as long and as much as we can, based on virtue and talent, as thomas jefferson would say if he were still here with us. if aristotle was right in defining happiness as “when you can develop freely your predominant talent,” then jim cathey was happy. jim joined the faculty at university of kentucky decades ago, when i was there as a visiting scholar. coming from industry, jim had remarkable practical electrical engineering abilities, and all students who had electric machinery labs or design courses with him would testify to this. he was a devoted and passionate teacher. although he had many published papers, jim did not follow the crowd, and his published work was thorough and practical. his textbook on electric machinery is an excellent demonstra- tion of teaching talent: depth, balance, clarity, practicality, and impeccably worked-out numerical examples. more than a decade ago, jim took over this journal from its founding editor, professor syed a. nasar. since then, the review process has been streamlined and an on-line process implemented, with the number of papers published per year more than doubling. this all took time and effort, but jim was patient and hardworking, and he did it with diligence as a service to the worldwide electrical engineering community. for all of this and much else, the community is most grateful to jim. occasionally, during my many visits to university of kentucky, jim invited me to lunch and we discussed matters of education and life. jim was a religious man. miguel de unamuno, the great spanish writer and philosopher, asked himself in his “personal in memoriam: jim cathey journal” whether, in order to be religious, one had to be good first or if it was the other way around. well, jim was both. his ph.d. students, who are now well accomplished in life, will tell you about his goodness and dedication to them. jim enjoyed working afternoons and had a special sense of texan humor; his office door read “nothing makes sense before noon.” jim was a quiet and practical engineer, teacher, and researcher who combined hard work and modesty to serve our community in kentucky and around the globe through electric power components and systems. he did his share with dignity and honor, and we should always remember and praise his memory. professor ion g. boldea, ph.d., ieee life fellow founding member of the editorial board electric power components and systems [pdf] endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /jbc.ra . corpus id: endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature @article{neill endorepellinrt, title={endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature}, author={t. neill and e. andreuzzi and z. wang and s. peiper and maurizo mongiat and r. iozzo}, journal={the journal of biological chemistry}, year={ }, volume={ }, pages={ - } } 	t. neill, e. andreuzzi, + authors r. iozzo 	published 	chemistry, medicine 	the journal of biological chemistry regulation of autophagy by proteolytically cleaved fragments of heparan sulfate proteoglycans is a novel and current research focus in tumor biology. endorepellin is the c-terminal angiostatic fragment of the heparan sulfate proteoglycan perlecan and induces autophagy in endothelial cells. to further investigate this property, we used nanostring, a digital pcr platform for measuring pre-defined transcripts in biological samples to analyze a custom subset of autophagy-related genes in human… expand view on asbmb jbc.org save to library create alert cite launch research feed share this paper citationsbackground citations methods citations view all figures and topics from this paper 	 figure 	 figure 	 figure 	 figure 	 figure 	 figure view all figures & tables 	heparitin sulfate 	neoplasms 	endothelial cells 	autophagy 	proteoglycan 	transcript 	protein tyrosine kinase 	cleaved cell 	mitochondrial depolarization 	park gene 	mitofusin- 	endothelial growth factors 	kdr gene 	growth factor receptors 	transcriptome 	tchp gene 	tumor suppressor genes 	membrane potentials 	reverse transcriptase polymerase chain reaction 	umbilical vein 	subgroup citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency endorepellin evokes an angiostatic stress signaling cascade in endothelial cells 	aastha kapoor, c. g. chen, r. iozzo 	chemistry, medicine 	the journal of biological chemistry 	 	 	 	view excerpts, cites background and methods save alert research feed proteoglycan-driven autophagy: a nutrient-independent mechanism to control intracellular catabolism 	t. neill, simone buraschi, aastha kapoor, r. iozzo 	chemistry, medicine 	the journal of histochemistry and cytochemistry : official journal of the histochemistry society 	 	 	 save alert research feed autophagic degradation of has in endothelial cells: a novel mechanism to regulate angiogenesis. 	c. g. chen, maria a. gubbiotti, + authors r. iozzo 	chemistry, medicine 	matrix biology : journal of the international society for matrix biology 	 	 	pdf save alert research feed angiostatic cues from the matrix: endothelial cell autophagy meets hyaluronan biology 	c. g. chen, r. iozzo 	biology, medicine 	the journal of biological chemistry 	 	 save alert research feed proteoglycan signaling in tumor angiogenesis and endothelial cell autophagy. 	maria a. gubbiotti, simone buraschi, aastha kapoor, r. iozzo 	biology, medicine 	seminars in cancer biology 	 	 	 save alert research feed extracellular matrix: the gatekeeper of tumor angiogenesis. 	m. mongiat, simone buraschi, e. andreuzzi, t. neill, r. iozzo 	chemistry, medicine 	biochemical society transactions 	 	 save alert research feed tumor microenvironment: extracellular matrix alterations influence tumor progression 	s. brassart-pasco, s. brézillon, b. brassart, l. ramont, j. oudart, j. c. monboisse 	chemistry, medicine 	frontiers in oncology 	 	 	 	view excerpt, cites background save alert research feed role of extracellular matrix in gastrointestinal cancer-associated angiogenesis 	e. andreuzzi, a. capuano, + authors m. mongiat 	medicine 	international journal of molecular sciences 	 	 	pdf save alert research feed complexity of matrix phenotypes 	r. iozzo, a. theocharis, t. neill, n. karamanos 	medicine, computer science 	matrix biology plus 	 	 	 save alert research feed matrix modeling and remodeling: a biological interplay regulating tissue homeostasis and diseases. 	n. karamanos, a. theocharis, t. neill, r. iozzo 	biology, medicine 	matrix biology : journal of the international society for matrix biology 	 	 	 save alert research feed references showing - of references sort byrelevance most influenced papers recency endorepellin-evoked autophagy contributes to angiostasis * 	a. goyal, maria a. gubbiotti, daphney chery, l. han, r. iozzo 	biology, medicine 	the journal of biological chemistry 	 	 	pdf save alert research feed endorepellin evokes autophagy in endothelial cells* 	c. poluzzi, j. casulli, a. goyal, thomas j mercer, t. neill, r. iozzo 	biology, medicine 	the journal of biological chemistry 	 	 	pdf 	view excerpts, references background and results save alert research feed the role of perlecan and endorepellin in the control of tumor angiogenesis and endothelial cell autophagy 	stephen m. douglass, a. goyal, r. iozzo 	biology, medicine 	connective tissue research 	 	 	pdf 	view excerpts, references background save alert research feed endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through α β integrin 	g. bix, jian fu, + authors r. iozzo 	biology, medicine 	the journal of cell biology 	 	 	pdf 	view excerpts, references background save alert research feed endostatin and endorepellin: a common route of action for similar angiostatic cancer avengers. 	c. poluzzi, r. iozzo, l. schaefer 	biology, medicine 	advanced drug delivery reviews 	 	 	 save alert research feed role of tyrosine phosphatase shp- in the mechanism of endorepellin angiostatic activity. 	a. nyström, zabeena p. shaik, + authors r. iozzo 	biology, medicine 	blood 	 	 	 	view excerpt, references background save alert research feed endorepellin, the angiostatic module of perlecan, interacts with both the α β integrin and vascular endothelial growth factor receptor (vegfr ) 	a. goyal, nutan pal, + authors r. iozzo 	biology, medicine 	the journal of biological chemistry 	 	 	pdf 	view excerpts, references background save alert research feed endorepellin, a novel inhibitor of angiogenesis derived from the c terminus of perlecan* 	m. mongiat, s. sweeney, j. s. san antonio, jian fu, r. iozzo 	biology, medicine 	the journal of biological chemistry 	 	 	pdf 	view excerpts, references background save alert research feed bmp- /tolloid-like metalloproteases process endorepellin, the angiostatic c-terminal fragment of perlecan* 	e. gonzález, c. reed, + authors r. iozzo 	biology, medicine 	journal of biological chemistry 	 	 	pdf 	view excerpt, references background save alert research feed endorepellin affects angiogenesis by antagonizing diverse vascular endothelial growth factor receptor (vegfr )-evoked signaling pathways 	a. goyal, c. poluzzi, + authors r. iozzo 	biology, medicine 	the journal of biological chemistry 	 	 	pdf save alert research feed ... ... related papers 	abstract 	figures and topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue the distillery scibx: science–business exchange copyright © nature publishing group � this week in therapeutics indication target/marker/ pathway summary licensing status publication and contact information cardiovascular disease left ventricular hypertrophy (lvh) g protein–coupled receptor kinase (grk ); guanine nucleotide binding protein, q polypeptide (gnaq; gq); histone deacetylase (hdac ); myocyte enhancing factor (mef ; d-mef ) studies in mice and in cell culture suggest that targeting grk could help treat lvh associated with heart failure. in mouse models of pressure- overload cardiac stress, grk overexpression led to cardiac hypertrophy and increased the incidence of heart failure compared with what was seen in wild-type mice or mice that overexpressed a grk variant that did not enter the nucleus. in vitro, cardiac stress–induced g protein–coupled receptor signaling led to upregulation of grk and its subsequent translocation to the nucleus, where it induced hdac -mediated expression of hypertrophy genes. ongoing studies will assess the specificity of grk ’s activation of hdac and the effects of targeting grk with a grk -specific microrna. many companies market or are developing compounds to treat or prevent hypertrophy via treatment of hypertension and/or ischemia, two conditions that can lead to lvh and subsequent heart failure. not patented; licensing status undisclosed martini, j. et al. proc natl. acad. sci. usa; published online aug. , ; doi: . /pnas. contact: walter j. koch, thomas jefferson university, philadelphia, pa. e-mail: walter.koch@jefferson.edu http://www.scibx.com mailto:walter.koch@jefferson.edu 	g protein–coupled receptor kinase (grk ); guanine nucleotide binding protein, q polypeptide (gnaq; gq); histone deacetylase (hdac ); myocyte enhancing factor (mef ; d-mef ) 	summary 	licensing status 	references journal of clinical microbiology, nov. , p. – vol. , no. - / /$ . � doi: . /jcm. . . – . copyright © , american society for microbiology. all rights reserved. infections in international pregnancy study: performance of the optical immunoassay test for detection of group b streptococcus jadsada thinkhamrop, * sompop limpongsanurak, mario r. festin, sean daly, anne schuchat, pisake lumbiganon, elizabeth zell, tsungai chipato, aye aye win, mindy j. perilla, jorge e. tolosa, and cynthia g. whitney department of obstetrics and gynecology, faculty of medicine, khon kaen university, khon kaen, and department of obstetrics and gynecology, faculty of medicine, king chulalongkorn memorial hospital, bangkok, thailand; department of clinical epidemiology, university of the philippines, manila, the philippines ; coombe women’s hospital, dublin, ireland ; respiratory diseases branch and biostatistics and information management branch, division of bacterial and mycotic diseases, national centers for infectious diseases, centers for disease control and prevention, atlanta, georgia; department of obstetrics and gynaecology, university of zimbabwe school of medicine, harare, zimbabwe ; department of obstetrics and gynaecology, institute of medicine, yangon, myanmar ; and department of obstetrics and gynecology, divisions of research in reproductive health and maternal-fetal medicine, thomas jefferson university, philadelphia, pennsylvania received february /returned for modification april /accepted august we evaluated the strep b optical immunoassay (oia; thermobiostar, inc.) for detecting light and heavy group b streptococcus colonization in , pregnant women. the women were examined at to weeks gestation and were from six countries. compared to culture, the sensitivity and specificity of oia were . and . %, respectively, for light colonization and . and . %, respectively, for heavy colonization. heavy colonization with group b streptococcus (gbs) may place women at high risk of delivering preterm, low-birth- weight infants ( , , ). earlier recognition of such high-risk women would be useful for intervention strategies. detection of heavy colonization has traditionally relied on culture meth- ods, which may not be feasible in some health care settings and require to days before results are available. unfortunately, most rapid gbs tests have poor sensitivity ( , ). the strep b optical immunoassay (oia; thermobiostar, inc., louisville, colo.) is a rapid method which may have higher sensitivity for dense gbs colonization ( ). we evaluated the performance of this test in an international, multicenter study. we conducted the study at institutions participating in the global network for perinatal and reproductive health (http: //www.tju.edu/obgyn/rih/global.cfm). centers were located in khon kaen and bangkok, thailand; manila, the philippines; harare, zimbabwe; yangon, myanmar; dublin, ireland; and philadelphia, pennsylvania. participants were enrolled in the study between june and may . women attending prenatal care clinics and at to weeks gestation were eligible. exclusion criteria included vaginitis symptoms, fever, vaginal bleeding, multiple pregnancy, use of antibiotics in the past weeks, and active labor. informed consent was obtained. the study was approved by institutional review boards at all study centers and supporting institutions. at enrollment, study personnel conducted an interview and collected specimens. a sample for gbs rapid testing was col- lected from the cervix and lower vagina using a thermobiostar swab. oias were read by study site laboratory personnel and by the manufacturer’s laboratory personnel. oia kits and swabs were supplied by thermobiostar. methods for gbs culture and quantitation replicated those used in the vaginal infections and prematurity study ( ). after collection of the oia specimen, a dacron swab (copan swab) was used to collect a specimen from the cervix and lower vagina. samples were streaked onto blood agar plates using the four-quadrant method and then placed into lim broth (todd- hewitt broth containing selective antimicrobial agents). a clean catch urine specimen was collected for gbs culture on blood agar. suspect colonies showing �-hemolysis were iden- tified as gbs using latex agglutination. heavy colonization was defined as isolation of gbs from either urine or direct plating on blood agar. light colonization was defined as isolation of gbs from lim broth alone. dense gbs colonization was de- fined as growth in the third or fourth quadrant streaked on the blood agar plate ( ). data were entered by using epi-info version ( ) and trans- mitted to the centers for disease control and prevention monthly. we calculated the sensitivity, specificity, positive pre- dictive value, and negative predictive value of the oia using culture results as the “gold standard.” the chi-square test was used to compare the results of oia readings done by the manufacturer’s staff versus the readings done by study center personnel. we enrolled , women; their mean age was . years, and the mean gestational age was . weeks. gbs coloniza- tion was the highest in philadelphia, pa., ( . %) and lowest in yangon, myanmar ( . %). the rate of gbs isolation was higher from lim broth culture than from other methods (table ). compared to culture, the sensitivity of oia for detecting * corresponding author. mailing address: department of obstetrics and gynecology, faculty of medicine, khon kaen university, khon kaen , thailand. phone: - - . fax: - - . e- mail: jadsada@kku.ac.th. o n a p ril , a t c a r n e g ie m e l l o n u n iv l ib r h ttp ://jcm .a sm .o rg / d o w n lo a d e d fro m http://jcm.asm.org/ any gbs colonization was . % ( % confidence interval [ci], . to . %) and ranged from . % ( % ci, . to . %) in yangon, myanmar, to . % ( % ci, . to . %) in philadelphia, pa. oia sensitivity was . % for lightly colonized women, . % for heavily colonized women, and . % for densely colonized women (table ). oia sen- sitivity and specificity were . and . %, respectively, com- pared with culture on blood agar and . and . % com- pared with lim broth. the oia was positive in . % of women who were negative by all culture methods. oia test readings performed by the manufacturer and by study site personnel were similar (kappa of . ); the sensitivities from study site personnel and manufacturer readings was . % ( % ci, . to . %) and . % ( % ci, . to . %), respectively. our study demonstrated that the sensitivity of oia to detect gbs colonization compared with that of culture was low, al- though the sensitivity of oia in detecting heavy or dense colonization was higher than its sensitivity for detecting light colonization. our findings confirm earlier work that found reliance on blood agar alone was insensitive for detecting light colonization and that comparing rapid detection methods with blood agar alone falsely elevated the sensitivity of these tests. enrichment broth media, such as lim broth, enhance gbs growth while suppressing growth of other bacteria, thus im- proving identification in specimens with low bacterial inoculum ( , ). in previous studies, the performance of the oia has been compared with selective broth media. the specificity was uni- formly high, to %, similar to the . % in our study. conversely, previously reported test sensitivities varied widely but were generally higher ( to %) ( , , , – , – ) than the value we found ( . %). the most important reason for this variability may be the extent to which the subjects were colonized. the sensitivity of the oia has been higher ( to %) when compared with third- and fourth-quadrant posi- tive blood agar cultures ( , , , – ). our finding was within this range ( . %). our study had limitations, as it did not evaluate the perfor- mance of the oia to weeks before delivery or at delivery, when it would have the most clinical value ( ). however, the average gestational age for our participants was . weeks, a time when the fetus is considered viable in many centers, making our data potentially useful for evaluating the role of gbs in preterm birth. we did not collect specimens from the rectum; collecting both rectal and vaginal cultures increases the detection of gbs carriage in pregnant women ( ). if we had collected rectal specimens, we would have identified more gbs carriers, and the oia performance would have been worse. in conclusion, the low sensitivity of the strep b oia may limit its usefulness for detecting gbs in pregnant women, although the best performance of the test is in women who are heavily colonized and who therefore may be at highest risk for complications due to gbs infection. new tests, such as the newly licensed pcr test, may provide other options ( ). for now, culture of specimens from the rectum and lower vagina remain the gold standard for detecting gbs colonization in pregnant women ( ). this project was performed with the financial support of the rock- efeller foundation; the respiratory diseases branch, division of bac- terial and mycotic diseases, national center for infectious diseases; the prevention committee and the office of minority and women’s health, centers for disease control and prevention, atlanta, ga.; usaid; inclen; and thomas jefferson university. we thank the rockefeller foundation; the respiratory diseases branch, division of bacterial and mycotic diseases, national center for infectious diseases; the prevention committee and the office of minority and women’s health, centers for disease control and pre- vention, atlanta, ga.; usaid; inclen; and thomas jefferson uni- versity for technical support on this project. in addition, we thank thermobiostar, inc., for supplying the oia kits and for technical support for this study. j. thinkhamrop, s. limpongsanurak, m. festin, s. daly, a. schu- chat, p. lumbiganon, e. zell, t. chipato, a. a. win, m. j. perilla, j. e. tolosa, and c. g. whitney are members of the global network for perinatal and reproductive health (gnprh), department of obstet- rics and gynecology, thomas jefferson university, philadelphia, pa.. gnprh study centers and coinvestigators follow: khon kaen univer- sity (khon kaen, thailand), unchalee tatttawasart, kaewjai kham- suk, and ladda sriboonreung; chulalongkorn university (bangkok, table . prevalence of gbs according to various culture methods and oia by study center study site (no. of samples) prevalence (%) of gbs by method lim broth culture blood agar culture urine culture oia dublin, ireland ( ) . . . . yangon, myanmar ( ) . . . . manila, the philippines ( ) . . . . bangkok, thailand ( ) . . . . khon kaen, thailand ( ) . . . . philadelphia, pa. ( ) . . . . harare, zimbabwe ( ) . . . . all study sites ( , ) . . . . table . diagnostic performance of oia for detection of vaginal carriage of gbs compared to culture in women with light, heavy, and dense gbs colonization (n � , ) gbs colonization levela performance characteristicb sensitivity specificity positive predictive value negative predictive value light . ( . , . ) . ( . , . ) . ( . , . ) . ( . , . ) heavy . ( . , . ) . ( . , . ) . ( . , . ) . ( . , . ) dense . ( . , . ) . ( . , . ) . ( . , . ) . ( . , . ) a the gbs colonization levels were defined as follows: light, isolation of gbs from lim broth alone; heavy, isolation of gbs from either urine or direct plating on blood agar; dense, growth in the third or fourth quadrant streaked on the blood agar plate ( ). b the four performance characteristics, sensitivity, specificity, and positive and negative predictive values, are all given as percentages. the % cis are given in parentheses. vol. , notes o n a p ril , a t c a r n e g ie m e l l o n u n iv l ib r h ttp ://jcm .a sm .o rg / d o w n lo a d e d fro m http://jcm.asm.org/ thailand), sompop limpongsanurak, surasith chaithonhgwattana, pongpun nunthapisud, sumanee nin-gate, and wanwadee sripitak; coombe women’s hospital (dublin, ireland), amanda cotter, julie grantham, and james fagan; institute of medicine, women’s central hospital (yangon, myanmar), kyi kyi thinn, win win maw, cho cho oo, marlar win, thuzar han, mya mya aye, tin ohn myat, and katherine ba-thike; university of zimbabwe (harare, zimbabwe), alexio mashu, laina chidede, marshall munjoma, travor ny- amurera, and evelyn mudzviti; university of the philippines (manila, the philippines), guadalupe n. villanueva, maybelle cagayan, con- cepcion ang, francis sarmiento, daniel morales, and celeridad padri- nao; population council (bangkok, thailand), josephine sauvarin, christopher elias, and washiraporn suramaythangkoon; centers for disease control and prevention, falgunee parekh, carolyn wright, richard facklam, and john elliott; department of obstetrics and gynecology, university of alabama at birmingham, william andrews, martha lyon, sue cliver, and robert goldenberg; thomas jefferson university, catherine farrell, babu cheku, tracey james, letitia lee, michelle di vito, michelle pollino, donald jungkind, jim bondi, vincenzo berghella, jay goldberg, ratana komwilaisak, and jennifer culhane. references . badri, m. s., s. zawaneh, a. c. cruz, g. mantilla, h. baer, w. n. spellacy, and e. m. ayoub. . rectal colonization with group b streptococcus: relation to vaginal colonization of pregnant women. j. infect. dis. : – . . baker, c. j. . inadequacy of rapid immunoassays for intrapartum de- tection of group b streptococcal carriers. obstet. gynecol. : – . . baker, c. j., j. c. clark, and f. f. barrett. . selective broth medium for isolation of group b streptococci. appl. microbiol. : – . . bergeron, m. g., d. ke, c. ménard, f. j. françois, m. gagnon, m. bernier, m. ouellette, p. h. roy, s. marcoux, and w. d. fraser. . rapid detec- tion of group b streptococci in pregnant women at delivery. n. engl. j. med. : – . . boyer, k. m., c. a. gadzala, p. d. kelly, d. e. fisher, j. b. paton, and s. p. gotoff. . selective intrapartum chemoprophylaxis of neonatal group b streptococcal early-onset disease. i. epidemiologic rationale. j. infect. dis. : – . . boyer, k. m., c. a. gadzala, p. d. kelly, l. i. burd, and s. p. gotoff. . selective intrapartum chemoprophylaxis of neonatal group b streptococcal early-onset disease. ii. predictive value of prenatal cultures. j. infect. dis. : – . . carroll, k. c., d. ballou, m. varner, h. chun, r. traver, and j. salyer. . rapid detection of group b streptococcal colonization of the genital tract by a commercial optical immunoassay. eur. j. clin. microbiol. infect. dis. : – . . centers for disease control and prevention. . prevention of perinatal group b streptococcal disease—revised guidelines from cdc. morb. mortal. wkly. rep. (rr ): – . . dean, a. g., j. a. dean, d. coulombier, et al. . epi-info version : a word processing, database, and statistics program for epidemiology on mi- crocomputers. centers for disease control and prevention, atlanta, ga. . mckenzie, h., m. l. donnet, p. w. howie, n. b. patel, and d. t. benvie. . risk of preterm delivery in pregnant women with group b streptococ- cal urinary infections or urinary antibodies to group b streptococcal and e. coli antigens. br. j. obstet. gynecol. : – . . moller, m., a. c. thomsen, k. borch, k. dinesen, and m. zdravkovic. . rupture of fetal membranes and premature delivery associated with group b streptococci in urine of pregnant women. lancet : – . . nguyen, t. m., d. w. gauthier, t. d. mules, b. s. nuwayhid, m. a. viana, and p. c. schreckenberger. . detection of group b streptococcus: com- parison of an optical immunoassay with direct plating and broth-enhanced culture methods. j. matern. fetal med. : – . . ostroff, r. m., and j. w. steaffens. . effect of specimen storage, anti- biotics, and feminine hygiene products on the detection of group b strepto- coccus by culture and the strep b oia test. diagn. microbiol. infect. dis. : – . . park, c. h., d. ruprai, n. m. vandel, d. l. hixon, and f. e. mecklenburg. . rapid detection of group b streptococcal antigen from vaginal speci- mens using a new optical immunoassay technique. diagn. microbiol. infect. dis. : – . . regan, j. a., s. chao, and l. s. james. . premature rupture of mem- branes, preterm delivery, and group b streptococcal colonization of mothers. am. j. obstet. gynecol. : – . . regan, j. a., m. a. klebanoff, r. p. nugent, d. a. eschenbach, w. c. blackwelder, y. lou, r. s. gibbs, p. j. rettig, d. h. martin, and r. edelman. . colonization with group b streptococci in pregnancy and adverse outcome. am. j. obstet. gynecol. : – . . reisner, d. p., m. j. haas, r. w. zingheim, m. a. williams, and d. a. luthy. . performance of a group b streptococcal prophylaxis protocol combin- ing high-risk treatment and low-risk screening. am. j. obstet. gynecol. : – . . samadi, r., a. stek, and j. s. greenspoon. . evaluation of a rapid optical immunoassay-based test for group b streptococcus colonization in intrapartum patients. j. matern. fetal med. : – . . song, j. y., l. l. lin, s. shott, n. kimber, j. tangora, a. cohen, a. wells, m. maezes, a. aroutcheva, and s. faro. . evaluation of the strep b oia test compared to standard culture methods for detection of group b strep- tococci. infect. dis. obstet. gynecol. : – . notes j. clin. microbiol. o n a p ril , a t c a r n e g ie m e l l o n u n iv l ib r h ttp ://jcm .a sm .o rg / d o w n lo a d e d fro m http://jcm.asm.org/ untitled  | cancer discovery�january www.aacrjournals.org news in brief cdk inhibitor triples pfs in breast cancer women with estrogen receptor (er)– positive breast cancer who took an investigational drug targeting cyclin- dependent kinases and (cdk / ) in combination with the aromatase inhibitor letrozole experienced a “dra- matic and clinically meaningful effect,” researchers reported on december at the cancer therapy and research center (ctrc) and american associa- tion for cancer research (aacr) san antonio breast cancer symposium in texas. based on the positive results, these researchers expect to launch a phase iii trial of the agent in . in the current phase ii study, patients who took pfi zer’s cdk / inhibitor pd- with letrozole (femara; novartis) achieved a progression-free survival (pfs) period of . months compared with . months for patients who were treated with letrozole alone. “this was a welcome result,” commented norman sharpless, md, deputy director of the lineberger comprehensive cancer center at the university of north caro- lina (unc) at chapel hill, who was not associated with the study. “a tripling of pfs in this disease is a great fi nding.” cdks, which participate in cell prolif- eration, tend to be overactive in cancer. richard finn, md, associate professor of medicine at the jonsson comprehensive cancer center at the university of california, los angeles, and the study’s principal investigator, explained that the primary function of cdk / is to phosphorylate the retinoblastoma (rb) protein, which ordinarily blocks early events in the cell cycle. phosphorylation inactivates rb so that cells can continue to divide. in some cancers, however, cdk / hypherphosphorylates rb, which can lead to uncontrolled cell growth. by inhibiting cdk / , pfi zer’s experi- mental drug prevents rb hyperphos- phorylation. moreover, finn added, it has minimal side effects. according to finn, preclinical stud- ies indicate that only er-positive breast cancer cells had robust responses to pd- . “er positivity appears to be a marker for an intact rb pathway,” he said. that’s noteworthy, unc’s sharp- less added, given that rb loss occurs in roughly % of all cancers. “the drug won’t work in patients who lack the rb pathway,” he noted, “so that gives us a good negative biomarker for who won’t respond to treatment. what we need now is a better posi- tive biomarker to identify those who might respond best in breast cancer and other cancer types.” ■ surveillance network aids prostate research up to % of men diagnosed with prostate cancer have a form of the disease that grows so slowly that it’s unlikely to ever threaten their health if left untreated. unfortunately, physicians currently have no precise way to determine which patients can forego treatment. “we need to fi nd out whether a tumor is a wolf in sheep’s clothing or if it’s really a sheep,” says stuart holden, md, director of cedars-sinai’s louis warschaw prostate cancer center in los angeles, ca, and medical director for the prostate cancer foundation, a philanthropic organization that funds research on the disease. thanks to a $ -million grant from the foundation, researchers from johns hopkins medicine in baltimore, md, and colleagues at cedars-sinai have launched the national proactive surveil- lance network (npsn), a repository of patient information that will advance understanding of who needs treatment. patients at the institutions who are diagnosed with early-stage, low-volume prostate cancer will be invited to join the program; other institutions will be added to the network in mid- to late . patients pursuing proactive surveil- lance defer treatments such as surgery and radiation therapy. instead, they are closely monitored with physical exams and medical tests every months and a prostate biopsy every year. if cancer progresses, they may opt for treat- ment. this strategy is also called active surveillance, expectant management, or watchful waiting. participants regularly complete detailed lifestyle and nutrition ques- tionnaires, and their blood and urine samples and biopsy tissue are banked people glenn dranoff, md, a professor of medicine at dana- farber cancer institute and harvard medical school in boston, ma, has been named the founding editor-in-chief of cancer immunology research. published by the american association for cancer research, the journal will launch online at the organiza- tion’s annual meeting in april, followed by monthly print issues beginning in june. the leader of the dana-farber/ harvard cancer center program in cancer immunology, dranoff has devoted his research efforts to under- standing tumor immunity and to the development of cancer vaccines. karen e. knudsen, phd, began a -year term as editor-in-chief of molecular cancer research this month. she succeeds michael b. kastan, md, phd, executive director of the duke cancer institute in durham, nc. knudsen is a professor in the depart- ments of cancer biology, urology, and radiation oncology at philadelphia’s thomas jefferson university and deputy director for basic science at the affili- ated kimmel cancer center. in addition to authoring book chapters and dozens of peer-reviewed articles, she has held several leadership roles on scientific publications, including cancer research. richard nakamura, phd, has been chosen as the new director of the nih’s center for scientific review (csr). he will lead scientists and administrative staff, overseeing their efforts to manage , nih grant applications a year, the majority of which are reviewed by csr peer review groups. the csr holds , review meetings a year. prior to joining the csr in , nakamura spent years at the national institute of mental health, serving as both its scientific and deputy director. c e n te r fo r s c ie n ti fi c r e v ie w on april , . © american association for cancer research. cancerdiscovery.aacrjournals.org downloaded from published onlinefirst december , ; doi: . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/ ; : . published onlinefirst december , .cancer discovery cdk inhibitor triples pfs in breast cancer updated version . / - .cd-nb - doi: access the most recent version of this article at: e-mail alerts related to this article or journal.sign up to receive free email-alerts subscriptions reprints and .pubs@aacr.org to order reprints of this article or to subscribe to the journal, contact the aacr publications department at permissions rightslink site. click on "request permissions" which will take you to the copyright clearance center's (ccc) .http://cancerdiscovery.aacrjournals.org/content/ / / . to request permission to re-use all or part of this article, use this link on april , . © american association for cancer research. cancerdiscovery.aacrjournals.org downloaded from published onlinefirst december , ; doi: . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/lookup/doi/ . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/cgi/alerts mailto:pubs@aacr.org http://cancerdiscovery.aacrjournals.org/content/ / / . http://cancerdiscovery.aacrjournals.org/ lyman c. draper and early american archives by josephine l. harper state historical society of wisconsin wh e n applying for a position as paymaster — and inci-dentally historian and intelligence officer to the governor— to serve with the wisconsin volunteers after the out- break of the civil war, lyman c. draper, secretary of the state historical society of wisconsin, wrote to governor alexander w. randall: it is doubtless known to you that during our war of independence, gov- ernor jefferson & other governors, frequently dispatched to the main army, a special officer . . . to collect the most reliable intelligence of general army move- ments, and also to investigate and report the condition and wants of the troops of their respective states, & communicate fully & promptly to the executive. . . . i learned much of these things in my examinations of the public archives at richmond, at washington, and elsewhere. this was one of the few instances in which draper used the term "archives" in his writing. this rarity of usage should not imply that draper was unfamiliar with archival materials. it was prob- ably merely indicative of the undeveloped state of archival agencies, collections, and terminology in the united states during his life- time. in the federal government most of the departments still re- tained their own files, although during the mid-nineteenth century the library of congress began to collect records from other gov- ernment agencies. similarly some states had also begun to consider the preservation of their official documents and manuscript records, but in many cases the amount of care and organization of the papers depended upon the varying degrees of interest or apathy of state and county officeholders, for professional archivists were as yet unknown in north america. as early as the -year old draper had requested ex-presi- dent james madison to send him an autobiographical sketch, and letter dated april , , draper-wisconsin historical society correspondence. all letters cited hereafter are located in this manuscript collection in the library of the state historical society of wisconsin. this correspondence is not a part of the draper collection of manuscripts. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . n q g by c arnegie m ellon u niversity user on a pril the american archivist after the exchange of several letters the young man's persistence was rewarded with a brief account written by a member of madi- son's family. six years later the youthful historian had envisioned a plan for writing a series of biographical and historical studies about the heroic figures and events in the settlement of the early west beyond the allegheny mountains. he would portray accu- rately the exciting and adventurous lives of such frontier heroes as the famed kentucky hunter, daniel boone; border scouts and spies, simon kenton, samuel brady, and lewis wetzel; the conqueror of the old northwest, george rogers clark; the "gamecock of south carolina," thomas sumter; the courageous mohawk chief, joseph brant; the distinguished shawnee warrior and statesman, tecumseh; and their many associates, friends and foes. from this plan draper never departed. in accordance with his aim he gathered the thousands of papers that constitute the draper collection of manuscripts, bequeathed by him to the state historical society of wisconsin at his death. before he became in the first director of the society, a posi- tion to which he devoted most of his time and energy until his re- tirement years later, he had acquired the most significant por- tions of his collection, including nearly all of the original records that it contains. in he estimated that his collection comprised "some , foolscap pages of notes of the recollections of warri- or-pioneers, either written by themselves, or taken down from their own lips; and well nigh , pages more of original manuscript journals, memorandum books, and old letters written by nearly all the leading border heroes of the west." many of these papers he had acquired by extensive travels in the 's through many of the states in the eastern and southern sec- tions of the country. journeying sometimes by wagon, by stage, by boat, or by train, but frequently on foot, he eagerly interviewed pioneers and their descendants, unearthed long forgotten records, and copied the manuscripts, newspapers, and printed documents of which he could not obtain the originals. although not so pro- ductive of original manuscripts as were his earlier ventures, his several other excursions into the south after yielded addi- tional papers. after his days of research trips were over, he could claim that his collection was "the systematic result of over years labors & , miles of journeyings — ." whatever discomforts he endured in his travel were more than compensated for by his lyman c. draper, circular letter, may i, . draper to charles mcknight, february , . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . n q g by c arnegie m ellon u niversity user on a pril lyman c. draper and early archives elation at the discovery or acquisition of a valuable group of manu- scripts or notes. during one southern tour he particularly rejoiced at the finding of the papers of william fleming, commander of the botetourt regiment at the battle of point pleasant, which had lain untouched but well preserved for nearly years after flem- ing's death.* a few days later he examined " or bushels" of papers of william cocke, revolutionary militia captain near the present boundary of virginia and tennessee, but these had so de- teriorated that draper had difficulty in deciphering the parts he wished to copy. when traveling, he worked assiduously at collect- ing, arranging, and transcribing, "seldom going to bed before or at night, & up early & at it before breakfast — ." "it hasn't been a play-spell," he exclaimed after spending each day from o'clock in the morning until sundown copying documents in the new york state library for nearly weeks during november . on his research trips he utilized not only papers in private owner- ship but also those in existing federal and state archives in the united states and in canada. from the canadian archives he ac- quired copies of papers of daniel claus, sir william johnson, george clinton, and philippe de rocheblave. additional papers of johnson and clinton, as well as transcripts of documents in lon- don and paris, he copied at the new york state library at albany. at harrisburg he searched the pennsylvania archives for material on the revolution in the upper ohio river valley; at richmond he found material pertaining to virginia and neighboring regions. in washington he spent a total of many weeks transcribing excerpts from the records of the continental congress, from the correspond- ence of washington and jefferson in the state department, and from the military papers of william henry harrison in the war department. at the pension office he copied hundreds of state- ments of military service filed by aged revolutionary war veterans. he also visited courthouses in north carolina, virginia, kentucky, and tennessee to obtain copies of selected county records. moreover, in the period and area that draper had chosen to study, the trans-allegheny west from approximately to , the dividing line between government archives and private manu- scripts may sometimes seem almost indistinguishable. because few archival depositories were then organized in north america and draper to peter a. remsen, august , . b draper to remsen, august , . draper to remsen, august , . draper to remsen, november , . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . n q g by c arnegie m ellon u niversity user on a pril ao the american archivist because many of the western militia units in the revolutionary war and in indian border warfare were largely composed of citizen vol- unteers, the officers frequently retained their correspondence and military records among their personal papers. because draper him- self conceived the history of western expansion to be primarily in terms of military events and of the actions of heroic pioneers, many of whom were soldiers, he attempted to gather the surviving papers of as many of these men as possible. in the draper collection, there- fore, are manuscripts, usually military in nature, that might per- haps have been found in state and national archives if more such agencies had been organized in the eighteenth and nineteenth cen- turies. for the colonial period draper found but few original papers. these include, among the papers of william preston, the corre- spondence, muster rolls, receipts for pay and provisions, and court- martial records for the militia of augusta county, virginia, in the period from to . a few military records for other coun- ties of virginia and pennsylvania during the french and indian war may also be found in the papers of evan shelby and of james potter. scattered elsewhere in the collection are petitions to wil- liam tryon, royal governor of north carolina, and a few letters and land warrants written by lord dunmore, royal governor of virginia. most of the original manuscripts in the draper collection relate to the quarter-century from to , marked by the revolu- tionary war and by hostile disturbances with the indians on the frontiers of american settlement. draper gathered the extant pa- pers of many of the western military leaders for this period. the largest in number as well as perhaps the most notable are the pa- pers of george rogers clark. later bound together with draper's notes and correspondence about clark into large folio volumes, these include much of clark's official incoming correspondence from his officers and military associates, drafts of many of his own let- ters, records of his famous illinois regiment, and some captured british correspondence and documents of henry hamilton. draper acquired also the papers of several other leaders: william preston, organizer of the expedition under andrew lewis which repelled the indians at point pleasant in and participant in the negotia- tions with the cherokee indians in - ; david shepherd, coun- ty lieutenant of ohio, who supervised the defense of a large fron- tier area both during and after the revolution; william croghan, who raised a company for the eighth virginia regiment in d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . n q g by c arnegie m ellon u niversity user on a pril lyman c. draper and early archives and served throughout the revolution; and daniel brodhead, colo- nel of the eighth pennsylvania regiment and commandant at fort pitt during - . among smaller groups of manuscripts of border figures are those of evan and isaac shelby, arthur and wil- liam campbell, joseph martin, william harrod, james potter, thomas sumter, john sevier, samuel brady, and richard butler. most of these groups, large and small, consist mainly of military records for the units in which these men served; included are militia orders, muster rolls, pay rolls, and accounts for food, lodging, clothing, and horses, as well as a wealth of correspondence from many of the officers who served along the frontiers from pennsyl- vania to the carolinas and westward to the illinois country. much less numerous in the draper collection are records of the war of . they include a book of general orders kept by an- drew jackson's command from october to december and several small groups of papers of other participants: james win- chester, commander of the troops defeated at the river raisin in ; benjamin whiteman, a general of the ohio militia; nathan heald, commanding officer at fort dearborn until captured there in ; and martin d. hardin, major in the kentucky militia serving under william henry harrison. the papers of thomas forsyth, indian subagent for the sauk and fox indians near peoria, illinois, contain a number of official letters from william clark, governor of missouri territory and superintendent of indian af- fairs at st. louis, and from ninian edwards, territorial governor of illinois. in the draper collection records of officials of civil government may be found; but frequently, as in the case of the letters of gov- ernors edwards and clark, the papers pertain mainly to warfare, so closely were frontier military and civil affairs interwoven by troubles with the british and with the indians. besides clark and edwards, the executives of several other states and territories are represented by correspondence in the collection: george clinton of new york; patrick henry, thomas jefferson, edmund randolph, and henry lee of virginia; william blount, john sevier, and wil- lie blount of tennessee; isaac shelby of kentucky; and edward tiffin and thomas kirker of ohio. of these the papers of thomas jefferson are among the most numerous and most interesting, total- ing original letters and signed documents, in addition to con- temporary copies of several other letters. most of these are among the george rogers clark papers, although jefferson's correspond- ents included a number of other border leaders besides clark — d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . n q g by c arnegie m ellon u niversity user on a pril io the american archivist evan shelby, joseph martin, john todd, thomas walker, wil- liam preston, david shepherd, daniel smith, and joseph crockett. a dozen letters, dated from to , from henry knox, sec- retary of war, were addressed to david shepherd and are pre- served among his papers, as is also one letter from president wash- ington concerning a land claim. original records of county officers number only a very few pieces: an account of sheriff's fees kept for botetourt county, virginia, in ; several official papers, - , of john potter, sheriff of cumberland county, virginia; and a small group of documents kept by robert patterson as sheriff of fayette county, kentucky, in - , and as justice of the peace during - . aside from a few periodical articles and one large volume, king's mountain and its heroes, published in , draper's dream of writing a series of books on the history of the early west never materialized. his work as the successful organizer and promoter of the state historical society of wisconsin left him little time for personal research and writing. he was further hampered by an ex- aggerated fear that he would produce books which might contain errors in detail or prove incomplete in some small respect. "i w[oul]d sooner starve, or very nearly so, than suffer anything to go out in a shiftless and imperfect manner," he once declared after many years of study. draper urged the construction of a fireproof building for the library of the wisconsin historical society. he recognized that manuscripts are perishable, and that "important historical facts, narratives and documents are lost every year for want of proper foresight and care for their preservation." yet, in handling his own collection, draper did not share the insistence of the modern archivist or manuscript specialist upon orderly arrangement and special treatment for aged and fragile papers. the vast number of manuscripts he had acquired seemed to make their organization too overwhelming a task for his meager spare time after he came to wisconsin. nevertheless, he could not refrain from continuing to augment his collection by additional correspondence on minute de- tails. even the fleming papers, which he had gathered in , were unarranged more than years later. by that time ( ) he had had about volumes of manuscripts bound in accordance with draper to mcknight, february , . draper to george grimmer, september , . sixteenth annual report of the executive committee, , wisconsin historical collections, vi, p. . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . n q g by c arnegie m ellon u niversity user on a pril lyman c. draper and early archives the library practice of that time. he estimated that papers to fill another or volumes were nearly ready for the bindery, and the remaining material he believed would probably comprise be- tween and more volumes. when the state historical so- ciety received the collection years later, very few additional man- uscripts had been arranged or bound. draper kept his personal li- brary in a brick building to the rear of his madison residence. there the papers were somewhat safeguarded against the danger of fire. after the great collector's death in , however, it was discovered that the building was damp and infested with rodents, and that the unbound manuscripts were in a discouraging state of chaotic disorder. the collection was soon moved to the state historical society, where the loose papers were studied, sorted, and bound to conform as closely as possible to draper's intended scheme of arrangement whenever this could be discerned. as finally com- pleted, the draper collection numbers volumes divided among series or subcollections, most of which are grouped around an . individual, a subject, or a geographical area about which draper had planned to write. the manuscripts, both originals and copies, have proved to be a mine of valuable information for hundreds of authors and re- searchers since the draper collection was opened to public use nearly years ago. the importance of the records in transcript should not be underestimated, for in many cases the originals that draper copied have since been lost, dispersed, or destroyed by fire or war. even small excerpts from county archives have been grate- fully perused by later historians. in some instances, of course, the publications of state archives, such as those of virginia, pennsyl- vania, and other states, have superseded draper's copies. the pa- pers of josiah harmar, from which harmar's descendants per- mitted draper to make selected copies, have been fortunately ac- quired in the twentieth century by the william l. clements library. yet numerous articles, histories, and biographies of such figures as george rogers clark, william clark and meriwether lewis, daniel boone, james harrod, and william croghan, have been based in large measure upon the draper manuscripts. countless military records and pieces of correspondence have been printed, some as individual items, some in collections of documents, some in historical and genealogical periodicals. to cite only two rather draper to mcknight, february i , . wisconsin historical society, proceedings ( th annual meeting), , pp. - ; ( st annual meeting), , p. . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . n q g by c arnegie m ellon u niversity user on a pril i the american archivist recent examples, several of the letters of william blount, john sevier, and james robertson have been printed among the records of southwest territory in the fourth volume of the territorial papers of the united states, edited by clarence e. carter; the ma- jority of draper's letters of thomas jefferson have appeared in the papers of thomas jefferson currently being published under direction of julian p. boyd at princeton university. lyman c. draper probably never considered himself an archi- vist, but through his study of western history he had close associa- tions with the american archival depositories existing in the nine- teenth century. to succeeding generations of historians interested in the early westward movement draper rendered an incalculable service by searching for and preserving in his own library so many significant manuscripts, many of which may be considered closely related to or almost a part of the early military archives of the united states. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . n q g by c arnegie m ellon u niversity user on a pril pancan- - -ver -yeo_ p .. original article open access precious data: interim report from the jefferson pancreas tumor registry theresa p. yeo, , ,* harish lavu, avinoam nevler, , jennifer brumbaugh, dominique vicchairelli, jordan m. winter, jonathan r. brody, and charles j. yeo abstract purpose: the jefferson pancreas tumor registry ( jptr) is a voluntary hospital-based registry of persons with pancreas and related periampullary cancers, premalignant lesions, and nonaffected family members (nafms). the ultimate goals of the jptr are to provide a link between family history, gene mutations, and precision med- icine therapy, and to identify high-risk nafms for potential surveillance screening. methods: the jptr is an institutional review board approved longitudinal epidemiological study housed in the department of surgery at thomas jefferson university hospital. individuals who met the eligibility criteria and signed informed consent provide information on hereditary conditions, family history of cancers, environmental exposures, and occupational risk factors. data are collected using a self-administered questionnaire, the elec- tronic medical record, and the molecular analysis of tumor specimens. results: established in , > persons have enrolled in the jptr. the cohort is mostly composed of sporadic pancreas cancer, with % of enrollees having familial pancreas cancer and a control group comprising nonaf- fected persons. data from the registry have been utilized to inform clinical studies, molecular investigations, and to shed light on and gain insight into the lived experience of persons with these conditions. conclusion: the jptr contains precious qualitative data and is an invaluable repository of information about persons with pancreatic and related tumors. keywords: cancer registry; family history; pancreatic cancer; risk factors; quality of life introduction population-based cancer registries were first estab- lished in europe and north america in the s and s to generate statistics on the incidence of can- cer in a defined population. the essential variables to be recorded by cancer registries include personal iden- tification, gender, date of birth, address, ethnic group, incidence date, site of cancer, histology, tumor behav- ior (benign or malignant), and the source of informa- tion. recommended or desirable additional variables are date of last contact, survival status, stage at diagno- sis, and treatment. there are numerous types of can- cer registries including those that are nationally, state, and regionally mandated; cancer-type specific; those focused on end results; and voluntary hospital-based registries. since years lived after a cancer diagnosis is a crude measure of outcome, refined measures have evolved that include disease-free survival and evaluating the quality of life of participants. the jefferson pan- creas tumor registry ( jptr), a voluntary, hospital- department of surgery and the jefferson pancreas, biliary and related cancer center, thomas jefferson university, sidney kimmel medical college, philadelphia, pennsylvania. thomas jefferson university, jefferson college of nursing, philadelphia, pennsylvania. the dr. p. borenstein talpiot medical leadership program, chaim sheba medical center, israel. part of these data were presented as a poster at the pancreas club meeting, may – , , san diego, ca, and as an abstract in the oncology nursing form, may, . *address correspondence to: theresa p. yeo, phd, mph, acnp, department of surgery, thomas jefferson university hospital, walnut street, suite b, college building, philadelphia, pa , e-mail: theresa.yeo@jefferson.edu ª theresa p. yeo et al. ; published by mary ann liebert, inc. this open access article is distributed under the terms of the creative commons license (http://creativecommons.org/licenses/by/ . ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. journal of pancreatic cancer volume . , doi: . /pancan. . journal of pancreatic cancer based registry housed in the department of sur- gery (dos), is a longitudinal epidemiological study of individuals with pancreatic cancer (pc) and related periampullary malignancies, including ampullary can- cer, bile duct cancer, duodenal cancer, and entities such as intraductal papillary mucinous neoplasms (ipmns), and pancreatic neuroendocrine tumors (pnets). the jptr was established in at the thomas jef- ferson university hospital (tjuh) in philadelphia, pennsylvania (pa). it was modeled after the national familial pancreas tumor registry at the johns hop- kins hospital, in baltimore, maryland, with input from an advisory panel. the thomas jefferson univer- sity institutional review board (irb) has approved the jptr and it undergoes yearly continuing irb review. data from the registry have been utilized to inform clinical studies, treatment strategies, molecular investi- gations, and to cast light on the lived experience of per- sons with these conditions. provided herein is a short descriptive review of the cohort, the scholarly activities of the jptr to date, and the results from our – follow-up using the annual update and the sur- vivor survey. methods the aims of the jptr are threefold: ( ) to develop a data base of self-reported information on hereditary conditions, family history of cancers, environmental exposures, and occupational risk factors; ( ) to provide a link between gene mutations, family history, and precision medicine therapy (in conjunction with the ongoing jefferson tissue banking study); and ( ) to identify high-risk nonaffected family members (nafms) for potential surveillance screening. information on sociodemographic background, lifestyle factors, fam- ily history of any cancers, known inherited genetic syndromes, longest-held occupation, and known environmental risk factors, including tobacco exposure and industrial carcinogens, is collected through a self- administered questionnaire and entered into a password- protected access database maintained by the jptr co-director and the coordinator. the questionnaire may be accessed either directly from a co-investigator at our institution or through the dos website. data for analysis are collected through hard copies of jptr ques- tionnaires, electronic medical record, operative notes, molecular analysis, and pathology reports. family geno- grams are created using progeny � software. all persons with known or presumed pc and related cancers and premalignant lesions, who are years of age or older, are eligible to participate. nafms of the index case are encouraged to enroll as well and serve as a control group. both groups must provide written informed consent before completing the questionnaire. recruitment for the registry may occur at an initial out- patient consultation, after surgery, through the dos website, or at specialized patient symposiums at our institution. registrants are provided with printed in- formation on the registry and given the questionnaire, which can be returned through mail in a self-addressed stamped envelope. several jefferson-affiliated irb hos- pital sites in pa and new jersey also enroll a limited number of patients with pc at their facilities. these patients have typically received either chemotherapy or radiation therapy (rt) at that institution but have not had surgery there. jptr registrants are classified as either (a) familial pancreatic cancer (fpc) (defined as one or more first degree relative with pc in addi- tion to the index case), (b) sporadic pancreatic cancer (spc) (index case only has pc), which is consistent with other established cancer registries, or (c) control group, (defined as nafms). it should be noted that the control group is dynamic in that members may later be diagnosed with either fpc or spc and reclassified as necessary. annual follow-up of jptr registrants is conducted by three methods: ( ) an annual update is mailed di- rectly to all registrants or to a designated relative or next-of-kin. the update inquires about current health conditions, the recurrence of pc, or the development of other cancers or medical conditions in the index case, registrant, and in other family members, and ( ) a unique specialized survivor survey is mailed to those registrants presumed to be living. this survey includes probing questions on quality-of-life issues, ongoing disease, or postsurgery complications, and individual reflections on treatment decision-making, and ( ) the survivorship status of the cohort is documented through the use of internet searches for published obituaries, re- ports on the annual surveys, and by families notifying us directly by letter, e-mail, or phone call of a death. our newsletter, the jefferson pancreas tumor regis- try update, is published each year and is mailed to all registrants and to all listed contact persons. the news- letter is a benefit to those enrolled and features an uplifting survivor story and provides an update on the current status and results of ongoing pc research stud- ies at jefferson. in addition, the newsletter serves as a venue to report on the annual sidney kimmel cancer center jefferson pancreas cancer and related diseases yeo, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . symposium and to display the annual pc survivor group photo. the symposium, held every november (pancreas cancer awareness month), was initiated by the dos in as a community outreach effort for pc and related cancer survivors, their families, and interested community members. over the past years, it has grown in magnitude, focus, and influ- ence. it is a highly anticipated event with well > at- tendees. the complimentary program features a gastrointestinal-friendly breakfast followed by short re- ports on the current state-of-the-science in pancreas cancer research at jefferson and interesting clinical topics. the symposium is unique and likely the largest of its kind in the united states. these activities contrib- ute to an enhanced feeling of community for pc survi- vors and their loved ones. attendees receive a mailing from the thomas jefferson university office of institu- tional advancement and many make a contribution to support pancreas cancer research. results demographics since , * % of eligible patients at tjuh have been recruited to participate in the jptr. seven hun- dred eighty-four individuals have enrolled in the jptr, of which have mostly complete and useable information. the majority of registrants ( %) have spc, % are fpc cases, nafms (controls) constitute %, and the remaining % have other biliary condi- tions or nonpancreas cancers. (selected clinical charac- teristics of the cohort are shown in table ). ninety-two fpc cases were identified by defining fpc as the index case plus one first-degree family member with pc. using a more stringent definition of family history as the index case plus two first-degree family members and at least one second-degree relative with pc, ( %) cases were identified. thirty-six ( %) of the fpc cases also reported between three and seven other types of cancers in their first- or second-degree relatives. there was one fpc case who had a family history of hereditary pancreatitis, other- wise no high-risk familial syndromes were identified. genetic testing for specific gene mutations was not conducted. the characteristics of fpc cases and con- tributory risk factors for pc are shown in table . cig- arette smoking was reported by % of the fpc cases, attesting to the synergistic effect of smoking and a familial history of pc. as reported by schenk, a family history of pc or ever-smoking cigarettes doubles one’s risk of developing pc (relative risk . ), and for current smokers who were also related to someone with pc, the relative risk of pc jumped to . . the demographic background of the jptr is consis- tent with other published pc registry data, , although they differ somewhat from nationally published statis- tics in that the median age of those enrolled is years, the sample is % white, % african american, % asian or hispanic, and % of unknown race or eth- nicity. men ( %) and women ( %) have near equal representation. almost half of the cohort ( %) were either current or former cigarette smokers. twenty- eight percent of the registrants had diabetes at the time of enrollment. studies have shown that new onset of diabetes in persons years of age or older, coupled with weight loss and long-term smoking, should raise the index of suspicion by primary care clinicians about an underlying cancer and warrant screening by magnetic table . – jefferson pancreas tumor registry registrant characteristics (n = ), n (%) sporadic pc ( %) familial pc ( %) controls (nafms) ( %) related conditions ( %) high-risk nafms ( %) gender: women % median age: (range – years) race: white % african american % asian, hispanic % unknown % ashkenazi heritage: mother ( %) father ( %) both parents ( %) smoking (current or former) / ( %) diabetes / ( %) top exposures: asbestos / ( %) pesticides/herbicides / ( %) residential radon / ( %) heavy wood dust / ( %) related conditions: duodenal cancer, bile duct cancer, ipmns, pancreati- tis, cysts. denominators vary based on number that answered the question. pc, pancreatic cancer; ipmn, intrapapillary mucinous neoplasm; nafm, nonaffected family member. table . characteristics of familial pancreatic cases (n = ) n (%) index case and one first-degree relative with pc index case and two first-degree and at least one second-degree relatives with pc ( ) other contributory risk factors smoking ( ) second hand smoke exposure ( ) diabetes ( ) ashkenazi heritage ( ) yeo, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . resonance imaging/magnetic resonance cholangiopan- creatography (mri/mrcp). , among pc patients undergoing either pancreaticoduodenectomy or distal pancreatectomy, the prevalence of preoperative diabe- tes ranged from % to %. asbestos is the most commonly reported occupa- tional or environmental exposure reported followed by pesticides and herbicides, residential radon, and wood dust. this is consistent with previously reported findings on occupational and environmental risks for pc. however, it should be noted that most individu- als are not aware of potentially carcinogenic exposures throughout their lifetime and answer ‘‘don’t know’’ to the list of known exposures associated with pc. twelve percent of the registrants were either jewish or reported ashkenazi jewish heritage in one parent ( %) or both parents ( %). ashkenazi heritage has been reported to increase the risk of pc -fold when there is a germline brca , del t mutation. in addition, in unselected jewish populations, the preva- lence of the three founder mutations in brca ( de- lag, insc) or brca ( delt) was . %, higher than previously known. identifying brca / muta- tions has important therapeutic implications as poly (adp-ribose) polymerase inhibitors may have significant activity in brca-associated pc. although ascertain- ment bias is present in the jptr, we are nonetheless reaching an ashkenazi and jewish patient population that may benefit from participation in the jptr in terms of referral for surveillance screening and family consultation with a genetic counselor. eight years of jptr cohort follow-up has yielded at least one spc case in which a second family member developed pc during the follow-up period. this is con- sistent with the low incidence of fpc ( – %) in the general population. molecular risk factors the linkage of cancer registry data to a pre- or coexist- ing database is useful in the study of molecular risk fac- tors. in conjunction with our ongoing jefferson tissue banking study, jptr data have attempted to associ- ate single nucleotide polymorphisms (snps) with path- ological features or family history of cancers and/or germline mutations. (this requires that patients under- going surgery at tjuh have given consent for both studies.) a recent article by our laboratory described a correlation between a functional snp in an immune regulator gene encoding the enzyme indoleamine- , - dioxygenase- (known as ido ) and the risk of fpc. pcr amplification of dna extracted from resected spec- imens stored and annotated in our biobank was used to identify a wild-type, heterozygous, and a homozygous ido genotype, which has been previously shown to correlate with decreased enzymatic functionality. , in this preliminary, single-institution study, the homo- zygous genotype (ido ) was associated with an in- creased risk of fpc as compared with a control group. we also identified snps (insertions and deletions [indels]) embedded within the ¢utr of the mitotic kinase checkpoint inhibitor gene, wee .* this site is a previously published hur binding site. tumor samples from resected patients with pancreatic ductal adenocarci- noma in the fpc group from the jptr were analyzed using standard gene amplification techniques to identify wild-type, heterozygous, and homozygous wee allelic alterations. index pc cases with the t allele were sig- nificantly more likely to have first-degree relatives with lynch-type cancers (colorectal, endometrial, gastric, and ovarian) as compared with cases without a family history of these cancers.* both the ido and the wee snps may have significant implications for screen- ing high-risk individuals and may also have value as a predictive marker for therapy using novel immune checkpoint inhibitors or dna damaging therapies. decision counseling recruitment to cancer registries can be challenging in the era of internet access due to fears of confidentiality. thus in , the jptr served as the setting for a study designed to assess the impact of the decision counsel- ing program� (dcp), a shared decision-making soft- ware program, on recruitment to the jptr. the study was the first to evaluate the impact of a dcp specifi- cally on the registry enrollment of patients with pan- creas cancer. meyers et al. found that % of pc patients who received in-person decision counseling enrolled in the jptr as compared with only % of pc patients who had telephone counseling. altruism was the most frequently cited motivating factor for par- ticipating by both those who enrolled and those who did not enroll. this study added to the literature on cancer registries by identifying obstacles that led to the decision to decline enrollment in the jptr: that is, the complexity of the registration process, feeling overwhelmed by the process of recovering from surgery, and worry about the confidentiality of their information. *brown et al., ‘‘identifying a sequence alteration in the regulatory domain of cell cycle inhibitor, wee , could define a novel familial, lynch-like syndrome and have implications for the treatment of pancreatic cancer,’’ (unpublished data). yeo, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . based on these results, we have implemented a more per- sonalized enrollment procedure and highlight data secu- rity and the confidential nature of the jptr information. identification of high-risk nafms a cohort of high-risk nafms (n = ) have been iden- tified using the following criteria: first and second- degree relatives with confirmed pc, known high-risk familial syndromes (hereditary pancreatitis, hereditary nonpolyposis colorectal cancer [lynch syndrome], he- reditary breast and ovarian cancer, familial atypical multiple mole melanoma [fammm], peutz–jeghers [pj] syndrome), known brca or brca mutations, family or personal history of ovarian cancer, cigarette smoking, pack-years smoked, second-hand smoke ex- posure, and exposure to asbestos, pesticides, herbicides, or residential radon, wood dust, and other known carcinogens. canto et al. have shown some benefit in screening high-risk individuals through endoscopic ultrasound (eus) and computed tomography screen- ing. , the diagnostic yield for finding actionable pancreatic neoplasms was only . % ( / ) in a study of high-risk individuals with two or three family members with pc and one patient with pj syndrome. a prospective study of high-risk individuals and controls had a % diagnostic yield using eus at baseline and at months. thus, we encour- age high-risk nafms to seek consultation with a ge- netic counselor and a gastroenterology pancreas specialist (skilled in eus) to undergo assessment and a screening workup consistent with the interna- tional cancer of the pancreas screening (caps) con- sortium recommendations. annual tracking we have been conducting annual follow-up on the jptr cohort since . in , the response rate was a remarkable %. the most recent data from to are presented in table . the annual update was sent to persons: responses were received ( %), with persons ( %) either not responding or the letter was returned to sender. no new cases of pc were reported. concurrently, the annual survivor survey was mailed to registrants, presumed to be liv- ing. we received responses for a % return rate. of those persons responding, % had a cancer, ( % of which was pc, % periampullary, % bile duct, and % duodenal). twenty-nine percent had a benign condi- tion including ipmns, pancreas cysts, pancreatitis, and pnets. the majority of respondents had undergone surgery ( %) for either a malignant or benign neo- plasm. a subset received chemotherapy and/or rt after surgery, whereas four persons did not undergo sur- gery, but did undergo chemotherapy. ninety-six percent of the respondents were alive, with five spouses complet- ing the survey as a proxy for their deceased spouse. more women ( %) than men returned the survivor survey. quality of life as part of the survivor survey, patients were queried about their perceived quality of life and persistent symptoms (table ). on a scale of – , where repre- sents poor quality and represents excellent, quality of life was rated . / . the ability to perform activities of daily living on a scale of – was rated . / . seventy- six percent of respondents were walking regularly and % reported that they exercised regularly. the most common activities performed were in rank order: walk- ing, lifting weights, ‘‘going to the gym,’’ golfing, ellipti- cal use, biking, use of a treadmill, and going to physical therapy. eighty patients reported being involved in additional types of physical activity. persistent bothersome symptoms were reported by respondents as follows: fatigue ( %), diarrhea ( %), bloating ( %), weight loss ( %), and pain and poor appetite ( % each). these particular symptoms have table . – jefferson pancreas tumor registry annual update and survivor survey results surveys mailed n (%) ( ) annual update completed ( ) no response or rts ( ) survivor survey completed ( ) no response or rts survivor survey results (n = ) gender: women ( ) confirmed status: alive ( ) condition: cancer (n): ( ) pancreas periampullary bile duct duodenal not cancer (n): ( ) pancreas cyst pancreatitis ipmn pancreas endocrine tumor treatment: surgery only ( ) surgery + ct ( ) surgery + ct + rt ( ) ct only ( ) rts, returned to sender; ipmn, intrapapillary mucinous neoplasm; ct, chemotherapy; rt, radiation therapy. yeo, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . frequently been reported in the pc literature, with fatigue being the most persistent and bothersome adverse ef- fect. half of the respondents still required exogenous pancreatic enzymes on a daily basis. only % reported using medical marijuana to deal with pain issues. this year, we added a question on one’s ability to return to work. fifty respondents were retired at the time of diagnosis, were able to return to their preill- ness occupation, people reported inability to perform their previous job, and people reported that they were unable to get a position in their field because of per- ceived discrimination by employers regarding their cancer diagnosis. this perception merits further inves- tigation in future surveys. satisfaction with decision-making choices survivor survey respondents (n = ) were also asked a series of questions designed to determine their satis- faction with the decisions that they had made regard- ing their treatment options (table ). to clarify, of the respondents had either pancreatic, ampullary, bile duct, or duodenal cancers and had nonmalig- nant conditions at the time they entered the jptr. ninety-seven of these respondents underwent surgery, the pppd being the most common operation. the ma- jority of these patients also opted for adjuvant chemo- therapy and/or rt. four patients in the sample had cancer but did not undergo surgery; they received only chemotherapy. the stage of disease at the time of the survivor survey was not known. surgery was clearly felt to be the most valuable treat- ment choice with % responding ‘‘yes’’ they would have surgery again, % responding that they would have chemotherapy again, and only % felt that they would have rt again. cancer survivors were also asked a hypothetical question about treatment if their cancer returned. seventy-six respondents replied that they would have surgery again, two said ‘‘no,’’ and two replied ‘‘maybe,’’ indicating that they would have to con- sider ‘‘other factors.’’ more than respondents were aware of palliative care therapies and persons reported receiving palliative care at the time of the survey. table . – jefferson pancreas tumor registry quality-of-life findings rate your quality of life . / ( – , = poor, = excellent) ability to do activities of daily living . / ( – , = poor, = excellent) top three persistent symptoms (n = ) (%): fatigue ( ) diarrhea ( ) bloating ( ) walk regularly (n%): yes = ( ) no = exercise regularly (n%): yes = ( ) no = medical marijuana for symptoms (n%): yes = ( ) no = require pancreatic enzymes (n%): yes = ( ) no = return to work after treatment (n%): yes = ( ) no = n/a = most commonly reported physical activities in rank order (n = ): . walking . elliptical . lifting weights . biking . going to the gym . treadmill . golfing . physical therapy other activities reported by respondents (n = ): balance work core work occupational therapy water aerobics bow flex fishing pilates work on ranch cancer rehabilitation gardening skiing yoga cardiac rehabilitation hiking spinning zumba ‘‘cardio’’ housework swimming chopping wood hunting tennis n/a, not applicable, retired at time of diagnosis. denominators vary based on number that answered the question. table . satisfaction with decision-making (n = ) if you had to make the decision over, would you have surgery again? yes = % no = % would you have chemotherapy again? yes = % no = % would you have radiation therapy again? yes = % no = if your cancer came back would you have treatment again? yes = % no = % maybe = % have you received palliative care? yes = % no = % denominator = ; not all respondents answered every question, thus does not sum to %. yeo, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . strengths of the study this report provides a detailed report on our institu- tional experience and a paradigm for establishing a spe- cialized registry. the annual longitudinal follow-up on a cohort of pc and other survivors offers us the oppor- tunity to chart the natural history of the disease. the ability to correlate the tumor biology with family history is a window into actionable molecular targets and rec- ommendations for family member genetic testing. limitations of the study registry data are subject to inherent limitations that restrict its generalizability. quality control problems exist, such as incomplete and inaccurate data. most of the demographic information is self-reported and unverified, and measures of occupational and environ- mental exposures are not quantifiable. owing to the various methods by which one can join the jptr, we do not collect information on the stage of disease at the time of enrollment. issues that are more difficult are potential noncon- cordance between pathologists about the diagnosis of pancreas cancer, and the fact that persons can have more than one cancer and other comorbidities that in- fluence survival and quality of life. enrollment in a private disease-specific registry such as the jptr is voluntary and, therefore, does not represent the over- all u.s. epidemiology of pc, particularly with regard to race and ethnic demographics. in the case of the jptr, this is a geographic limitation and solely a func- tion of patients who chose to come to our center and not any intentional selection bias. all patients meeting the eligibility criteria are encouraged to participate. in addition, as is found across multiple institutions, biobanking and the integrity of the tissue preserved could be a limitation for specific molecular profiling studies performed in a retrospective manner, particularly with analytes susceptible to degradation, such as rna. discussion we report an above-average response rate (exceptional at % in ) to our two annual jptr follow-up sur- veys, which indicates a committed patient population and speaks to the quality and maintenance of the reg- istry database. jptr enrollees report a high degree of satisfaction with their decision-making choices despite some having conditions with a poor prognosis. this in- dicates the importance to patients of having input and a degree of control about their treatment options. more patients this year were aware of palliative care and a small number were receiving it. a high quality of life was reported by both patients with cancer and those treated for premalignant and benign disease. survivors remained physically active despite lingering adverse effects—fatigue and gastrointestinal problems being the most prevalent. overall this subset of jptr registrants is a high-functioning group. the availability and use of registry data such as the jptr enhance the ability to investigate potentially im- portant heritable gene mutations and snps that may be actionable. evaluating this type of data is impor- tant when advising patients on treatment options and when providing advice to individuals regarding screen- ing benefits and costs. in addition, the jptr offers a rare opportunity to glimpse into the lived experience of those who have pancreas, biliary, and other related cancers and condi- tions in a prospective longitudinal manner. as such, this is precious data. cancer registries have not rou- tinely tracked quality of life (such as long-term side effects of treatment and work disability) between diag- nosis and death because it requires complex data col- lection by direct patient contact. the jptr is unique in that through our annual update and survivor sur- vey, we have documented the lived experience of per- sons with pc. our future plans for the registry are to continue to evolve and query survivors about matters that are pertinent and relevant to their lives. scientifically, serial follow-up and linking individuals with pancreas and related cancers to genetic back- grounds (familial and ancestry) along with environ- mental landscapes will continue to allow us to gain insights into this disease. for example, the jptr may allow us to address the following: how can we better identify high-risk individuals? what life style changes may help curtail the development of this disease? which patients are best served by surgery and which pa- tients should receive other therapeutic interventions? conclusions this interim report of the jptr describes the utility of a specialized cancer registry for scientific discovery, monitoring disease status, determining survivorship, and identifying high-risk nafms for surveillance and screening. the jptr is an invaluable resource at our in- stitution for its ability to provide a link for families and their nonaffected relatives to monitor research progress related to their conditions. as researchers, it enables us to contact patients to determine comorbidities and survival status. as a community resource, it provides yeo, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . continuity between patients and their family members and the surgeons, nurses, oncologists, and scientists who are making unique discoveries about the biology of the diseases and innovative therapies. acknowledgments funding to support the ongoing activities of the jptr comes from the thomas jefferson university department of surgery, philadelphia, pa, and from gifts from many of our patients. a.n. was supported by the mary m. halinski pancreatic cancer fund as the mary m. halinski fellow. author disclosure statement: no competing financial interests exist. references . parkin dm. the evolution of the population-based cancer registry. nat rev cancer. ; : – . . progeny . progeny genetics. llc: delray beach, fl. . shi c, hruban rh, klein ap. familial pancreatic cancer. arch pathol lab med. ; : – . . the jefferson pancreas tumor registry update. sidney kimmel cancer center at jefferson. nci-designated. philadelphia, pa; – . . schenk m. familial risk of pancreatic cancer. j natl cancer inst. ; : – . . yeo tp, hruban r, brune k, et al. assessment of gene-environment in- teraction in cases of familial pancreatic cancer compared to cases of sporadic pancreatic cancer. j gastrointest surg. ; : – . . yeo tp, lavu h, brumbaugh j, et al. early lessons from the jefferson pancreas tumor registry ( jptr). oncol nurs forum. ; , ,e . (abstract). . yeo tp. demographics, epidemiology, and inheritance of pancreatic ductal adenocarcinoma. sem oncol. ; : – . . bruenderman e, robert cg, martin ii. a cost analysis of a pancreatic cancer screening protocol in high-risk populations. am j surg. ; : – . . burkhart ra, gerber sm, tholey rm, et al. incidence and severity of pancreatogenic diabetes after pancreatic resection. j gastrointest surg. ; : – . . ozçelik h, schmocker b, di nicola n, et al. germline brca delt mutations in ashkenazi jewish pancreatic cancer patients. nat genet. ; : – . . ferrone cr, levine da, tang lh, et al. brca germline mutations in jewish patients with pancreatic adenocarcinoma. j clin oncol. ; : – . . stadler zk, salo-mullen e, patil sm, et al. prevalence of brca and brca mutations in ashkenazi jewish families with breast and pancreatic can- cer. cancer. ; : – . . nevler a, muller a, cozzitorto ja, et al. a sub-type of familial pancreatic cancer: high prevalence of functional polymorphisms in the immune check point gene, ido , in patients with familial pancreatic cancer: evi- dence and implications. j am coll surg. ; : – . . lal s, burkhart ra, beeharry n, et al. hur post-transcriptionally regulates wee : implications for the dna damage response in pancreatic cancer cells. cancer res. ; : – . . meyers r, lavu h, keith sw, et al. decision counseling and participation in a pancreas cancer registry. j regist manag. ; : – . . canto mi, goggins m, yeo cj, et al. screening for pancreatic neoplasia in high-risk individuals: an eus-based approach. clin gastroenterol hepatol. ; : – . . canto mi, goggins m, hruban rh, et al. screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. clin gastroenterol hepatol. ; : – . . canto mi, harinck f, hruban hr, et al.; international cancer of the pan- creas screening (caps). international cancer of the pancreas screening (caps) consortium summit on the management of patients with in- creased risk for familial pancreatic cancer. gut. ; : – . . yeo tp, burrell s, sauter p, et al. a progressive post-resection exercise program significantly improves fatigue and health-related quality of life in pancreas and periampullary cancer patients. j am coll surg. ; : – . cite this article as: yeo tp, lavu h, nevler a, brumbaugh j, vicchairelli d, winter jm, brody jr, yeo cj ( ) precious data: interim report from the jefferson pancreas tumor registry, journal of pancreatic cancer : , – , doi: . /pancan. . . abbreviations used dos ¼ department of surgery eus ¼ endoscopic ultrasound fpc ¼ familial pancreatic cancer ipmns ¼ intraductal papillary mucinous neoplasms irb ¼ institutional review board jptr ¼ jefferson pancreas tumor registry nafms ¼ nonaffected family members pc ¼ pancreatic cancer pnets ¼ pancreatic neuroendocrine tumors rt ¼ radiation therapy snps ¼ single nucleotide polymorphisms spc ¼ sporadic pancreatic cancer tjuh ¼ thomas jefferson university hospital publish in journal of pancreatic cancer - immediate, unrestricted online access - rigorous peer review - compliance with open access mandates - authors retain copyright - highly indexed - targeted email marketing liebertpub.com/pancan yeo, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . http://www.liebertpub.com/crpc#utm_campaign=crpc&utm_medium=article&utm_source=advert analysis and lessons learned instituting an instant messaging reference service at an academic health sciences library rowan university from the selectedworks of daniel g. kipnis january , analysis and lessons learned instituting an instant messaging reference service at an academic health sciences library daniel kipnis, rowan university gary e. kaplan, mslis, thomas jefferson university available at: https://works.bepress.com/daniel-kipnis/ / http://www.rowan.edu https://works.bepress.com/daniel-kipnis/ https://works.bepress.com/daniel-kipnis/ / analysis and lessons learned instituting an instant messaging reference service at an academic health sciences library: the first year daniel g. kipnis gary e. kaplan abstract. in february , thomas jefferson university went live with a new instant messaging (im) service. this paper reviews the first transcripts to examine question types and usage patterns. in addition, the paper highlights lessons learned in instituting the service. im refer- ence represents a small proportion of reference questions, but based on user feedback and technological improvements, the library has decided to continue the service. doi: [article copies avail- able for a fee from the haworth document delivery service: - -haworth. e-mail address: <docdelivery@haworthpress.com> website: <http://www. haworthpress.com> © by the haworth press. all rights reserved.] keywords. instant messaging, virtual reference services, ask a librarian, chat, usage patterns, lessons learned, academic health sciences libraries, case study daniel g. kipnis, msi (dan.kipnis@jefferson.edu) is senior education services li- brarian, and gary e. kaplan, mslis (gary.kaplan@jefferson.edu) is information ser- vices librarian; both at thomas jefferson university, walnut street, mezzanine, philadelphia, pa . the authors would like to thank margy grasberger and the information services department, all the im staff, and ann koopman for web design. medical reference services quarterly, vol. ( ), spring available online at http://mrsq.haworthpress.com © by the haworth press. all rights reserved. doi: . / . / introduction in february , the scott memorial library at thomas jefferson university in philadelphia launched an instant messaging (im) refer- ence service. this paper examines the first archived messages to determine the nature of questions patrons asked reference librarians and provides statistical analysis on the frequency of im shorthand use, how often patrons and librarians introduced themselves, and when questions were typically asked. in addition, issues that went into setting up the im service and what the future holds will also be discussed. setting founded in , jefferson medical college is one of the largest pri- vate medical schools in the united states. the academic medical center includes the jefferson medical college, jefferson college of health professions, jefferson college of graduate studies, and thomas jefferson university hospital, a � bed teaching facility. scott memorial li- brary serves the three colleges in the university and the hospital. it is a member of the association of academic health sciences libraries (aahsl). the library’s collection includes nearly , print vol- umes, over , journals, and e-books. the library serves approxi- mately , students and over , full-time employees. instant messaging–global usage im claims to be the new e-mail. a pew internet and american life project study, “teenage life online: the rise of the instant-message generation and the internet’s impact on friendships and family rela- tionships,” conducted in , found that % of online teens use im, and % of these individuals use it regularly. a more recent pew study, “how americans use instant mes- saging,” posited that % of internet users ages to have used im. according to the pew study more than million americans use im, with % stating they use it more frequently than e-mail. the radicati group projects the number of ims sent daily will grow from . billion in to . billion in . another pew internet and american life project, “teens and tech- nology,” found that im is one of many new technologies preferred for talking to friends and that e-mail is used to communicate with “old peo- ple,” although other studies have refuted this claim. for example, the medical reference services quarterly ecar study of undergraduate students and information technology surveyed , students in and found they overwhelmingly pre- ferred e-mail to im. the henry j. kaiser family foundation’s study, “media multitasking among american youth: prevalence, predictors and pairings,” reports the total weekly hours (based on diary data) de- voted to im is one hour and four minutes, while the three most common multitasking activities paired with im include music, web surfing, and e-mail. im is popular, but still trails e-mail in popularity of use. fifty-three percent of adult internet users sent or read e-mail on a typ- ical day in december , which is an increase of just % since . as noted by the authors of “riding the waves of ‘web . ,’” the % of adult internet users who sent or read e-mail on a typical day is more than im, blogging, and online shopping combined. instant messaging–use in medical schools e-mail is still being used on college campuses, but with so many new forms of communication, the information services (reference) depart- ment decided to investigate them for opportunities to extend services. in august , the incoming medical school class of the jefferson medi- cal college ( students) answered a short survey. one question asked if the students im; % reported using im, with % not using any im program. the number of academic and research libraries using im or real-time digital reference services in various forms continues to grow and reflect its popularity among matriculating students. in the fall of , cleveland and philbrick conducted a study to de- termine current trends in virtual reference services in academic health sciences libraries. they examined the web sites of the academic health sciences libraries represented in the membership directory of the association of academic health sciences libraries (aahsl). the majority ( , or %) offered virtual reference services with only ( %) not offering virtual reference services. however, only ( %) offered chat reference services and ( %) offered im reference ser- vices. a similar study conducted several years earlier in found similar levels ( %) of virtual reference services. future studies could examine why more libraries have decided not to offer im or chat. jefferson librarians were aware that im had become a popular mode of communication. many businesses, including database vendors, had started offering im and chat functionality to their web sites. in an effort to offer these same services to patrons, jefferson librarians decided to add im to existing e-mail, phone, and in-person reference services. im daniel g. kipnis and gary e. kaplan would not replace these services but would be offered as a supplemen- tary communication method to reach and educate patrons, , in short, an extension of existing reference services. project set-up jefferson librarians considered commercial virtual reference soft- ware. however, evidence that these platforms had technical barriers to use, such as pop-up blockers and required forms, and that some librar- ies had discontinued their services for lack of added value led to the decision to begin with a low-cost im pilot. jefferson librarians selected the trillian software because it supported multiple im networks in one interface and the basic version was free. in the winter of , information services initiated the pilot im proj- ect. the reference service supported the aim, yahoo!, and msn net- works. screen names were added to the ask a librarian web page, which provides all of the methods for contacting the reference service: im, e-mail, chat, telephone, in-person, and a knowledge base of fre- quently asked questions. to better promote the service, a link was added to the library banner in the upper right-hand corner that appears on every library web page (see figure ). during the pilot, librarians practiced im within the department, test- ing the various networks on campus, testing the video and document transfer features, and trying to standardize a cohesive narrative includ- ing greetings and responses for frequently asked questions. software costs and staffing issues thomas jefferson paid $ to upgrade to trillianpro for its google talk and meebo support. despite the minimal software costs, the library staff did invest significant staff time to plan, design, and promote the service and continued to spend time evaluating and improving it. one librarian led the project, with eight librarians and two reference tech- nicians eventually trained, staffing the service and participating in its development. reference librarians were initially assigned im shifts from their of- fices in the afternoon. after a few weeks, im requests were few, so it was decided to expand the service to full reference hours, while still mon- itoring from librarian offices. because the scheduling was cumbersome medical reference services quarterly and traffic remained low, the service was consolidated with the librar- ian at the reference desk. this led to consistent scheduling and provi- sion of reference service. transcript analysis by february , im questions had been answered. coinciding with the first-year anniversary of the service, the transcripts were ana- lyzed. of the messages analyzed, september had the highest num- ber of im questions, with a total of . may had the lowest, with only one question. the numbers correlate with the start and end of the academic year. on average, the reference desk answered . questions per month (see figure ). most popular time of day for questions the most popular time of day for receiving im questions was between : p.m. and : p.m. (see figure ). the least popular time was during daniel g. kipnis and gary e. kaplan figure . ask a librarian link to chat, e-mail, im, and phone information the morning, from : a.m. to : a.m. the service was staffed from : a.m. to p.m., monday to thursday; : a.m. to : p.m. on friday; and : a.m. to : p.m. on saturday. there is no reference service on sunday. most popular day for questions the most popular day of the week to ask an im question was thurs- day ( questions) (see figure ). the least popular day was friday ( questions). average length of sessions in , the pew research center polled teenagers, finding that the average im session lasts more than a half hour. the average length librarians spent on im interactions was . minutes. a total of , minutes ( . hours) was spent answering im questions. the longest interactions lasted minutes, and two interactions lasted only one minute. medical reference services quarterly figure . session frequency per month types of questions asked via im to help examine the types of questions received via im, librarians created the following categories: • technology (login, access to database, wireless, course manage- ment systems, for example, “i’m having trouble logging into ovid. is it down?”) • document delivery (ill, catalog, requesting journal, book or ci- tation, license exceeded, for example, “the catalog says you don’t have the journal i need. how can i get an article from it?”) • reference question (statistics, phone numbers, database instruc- tion, for example, “i am trying to get a recent article on the follow- ing topic: retail health clinics such as take care systems [run by nurse practitioners] and quality of care delivered by them compared to primary care physicians.”) • library policy (hours, borrowing policies, etc., for example, “hi, when does the library close today?”) • curriculum/class assistance (help with specific class assignments, for example, questions from first-year medical students about their self-directed learning cases) • bibliographic management software question (refworks and how to cite resources, for example, “i’m off campus. how can i login to refworks?”) daniel g. kipnis and gary e. kaplan figure . most popular time of day to send im questions many jefferson librarians have noticed that the majority of questions asked at the reference desk are known item requests, which have been included in “document delivery,” and this is true of the im data as well (see figure ). a close second is the category of reference questions. navigating the library’s electronic collection continues to produce many questions from patrons. surprisingly more technology questions were not asked via im. this could be attributed to the learning resources center (computer lab) answering many of the technology questions on campus. bibliographic management continues to be a popular ques- tion type, for example, how to cite specific resources using apa, how to login to refworks from off-campus, and how to format a bibliography. policy and technology questions were almost all handled in min- utes or less. among the longer transactions taking over minutes were six questions ( %) concerning bibliographic management software. based on the time spent answering these, the library created, recorded, and printed tutorials to help address these questions. did the reference librarians introduce themselves? similar to the traditional face-to-face reference interview, an initial greeting is important and can establish approachability and credibility. medical reference services quarterly figure . day of the week im questions were asked according to research, patrons are more satisfied and have more positive reactions to their library interactions when employees use their names. some suggest that patrons feel more comfortable asking their questions anonymously without feeling embarrassed or frightened. , im tech- nology is ideal for this type of interaction. in “the generic librarian,” joan durrance reported that “citizen leaders” who knew a librarian by name were far more likely to think highly of the library as an important information source for their “real world” public policy activities than those who did not. for these reasons, reference librarians who answered im questions were instructed to introduce themselves by name and title. the analysis at jefferson looked at how many times the reference li- brarians introduced themselves by first name and how many times the pa- trons volunteered to share their names with the librarians. of the total interactions, librarians introduced themselves times ( %). patrons introduced themselves times ( %). user affiliations one hundred two questions were asked by unique users, of which asked more than one question. of the questions, self-re- ported their affiliation. more than three-fourths of these ( %) were daniel g. kipnis and gary e. kaplan figure . types of questions asked via im jeffersonians (students, staff, faculty, and alumni). other users included high school students, paralegals, and students from other universities. although the location of users was not solicited, the transcripts some- times made it apparent. of those, were off-campus and five were on campus. did patrons use im lingo that confused librarians? the chronicle of higher education and other media outlets have re- ported that college students have started to incorporate im acronyms in their essays and other class assignments. , the popularity of im acro- nyms posed a concern for librarians. during staff training a list of popu- lar acronyms was shared to familiarize librarians with lingo. however, very few chat sessions included any im lingo. of the sessions that did, were simply u for you and other variations (“r u there?”). only seven sessions used acronyms and only four unique terms were used (brb; lol; ic; afk). only once was a librarian uncertain of the meaning (afk, away from keyboard). while librarians who are new to chat may need to become accustomed to less formal language, im acronyms were not a barrier to use. survey results with each im interaction, librarians sent a short online survey to users to gather feedback on the new service. below are a few comments received from im patrons: great idea, thanks! i enjoyed it very much. a very valuable service. this was great. this is a wonderful service. my mother is a medical reference librarian and i told her how great and useful this is, especially for someone living off campus without easy access to the library and staff. medical reference services quarterly overall, the positive reactions echo those from other institutions who have published similar survey results. one patron did express technological frustrations: instant messaging–another technological bane of our existence. an- other interruption. another fixation on the “instant.” i don’t think it’s the right direction for us to be moving forward in our technologi- cal–or overly technological—society. we need to foster the personal, the long-range view, and depth. “instant messaging” fails on these counts. of the surveys received ( % response rate) from january , to february , , the majority of the users were very satisfied and would use the service in the future. the breakdown of respondents who answered the online survey included: students, staff members, one faculty member, and one alumnus. when asked if patrons would use the service in the future, responded “yes” and six indicated “no.” user satisfaction was high; patrons were very satisfied, four some- what satisfied, six neutral, and six had no response. perceptions from librarians who staff the im service by the end of the first year, all librarians who worked a shift at the reference desk were participating in the chat service. a survey of these staffers was distributed to determine if they valued the service and whether it should be continued. because the service is a project of cer- tain individuals on the staff, it was important for the chat operators to have a chance to express their opinions anonymously. a short question- naire with six questions was prepared, and the administrative assistant for the library’s parent organization administered it. all nine operators completed the survey. of those, ( %) said they would like to continue staffing the service over the coming year and that the library should continue the service. of the five non-exclusive options representing the value of the jefferson im reference service, its ability to improve relationships with users was the most frequently selected ( , %). broadening the reach of the library’s reference service to underserved populations and increas- ing users’ productivity were the next most commonly chosen ( , %). daniel g. kipnis and gary e. kaplan increasing speed ( , %) and accuracy ( , %) of the reference ser- vice were the least chosen benefits. three respondents added free-form comments. two qualified the values, and one requested improvements to procedures. • while use has been low, i think it is well appreciated by those who use it. • i don’t believe it improves accuracy–speed perhaps–but not accu- racy. • [reach] no evidence that the users were otherwise underserved. rather the opposite, because they found out about it as a result of either already using our online services or reading our promotional literature. • [accuracy] no reason an im answer should be any more or less ac- curate than any other medium. • [speed] maybe. it’s no faster than a phone call, but definitely faster than in-person visit or -hour email. it may actually be slower than a phone call. • [relationships] maybe. offers a different kind of relationship which seems to be welcome to some users. • we simply need to continue to offer reference service through all plausible means of communication. • the alert requiring folks to add a patron as a buddy before the chat box opens is frequently inadvertently ignored and the opportunity to chat w/a user is thwarted. is there a solution? • current stats for im are tedious! is this not something that can be compiled all at once and scored by person? lessons learned during the pilot, lessons learned included: • the university firewall prevented the use of trillian’s file transfer and video capabilities. e-mail continued to be the preferred method of sending files. • librarians needed practice to get in the habit of greeting patrons with an appropriate introduction. • a naming standard was important for saving transcripts to a reposi- tory. the information services staff devised the following standard: year, month, day, start time, im network, question (e.g., _ _aim_catalog.txt) medical reference services quarterly • determining who and how the librarians would answer ims changed during the pilot. initially librarians were assigned a shift in their office in addition to their traditional reference desk shift, but it worked more smoothly having reference librarians monitor im, answering questions directly from the reference desk when- ever it was open. • speakers with sound were installed at the reference desk to help li- brarians hear incoming messages. • until habits were formed, one librarian was assigned to monitor that all the reference librarians on duty be online and that all tran- scripts and statistics be recorded. • it should not be assumed that all reference staff have experience and are comfortable with im. all staff were encouraged to open their own accounts and practice with colleagues before answering questions from patrons. • the following techniques were stressed to all librarians who an- swered questions: introduce yourself by name, conduct a reference interview, make sure that the patron received what was needed, and send a link to the survey. • im offers reference departments an additional means of communi- cation for users to ask questions. some questions are straightfor- ward and resolved during the im transaction (see appendix a), while others are resolved with a follow-up phone call, e-mail, or in-person consultation (see appendix b). • several canned messages were drafted, but ultimately it was easier to respond to each message rather than to search for a canned mes- sage. moreover, canned messages seemed negative and impersonal, detracting from the goal of conveying that a librarian is answering their question and not just another automated answering service. • a disadvantage is the difficulty in conducting instruction via this platform. typing out directions is time consuming and this mode of communication makes it easy to just share a url or answer, rather than teaching users to become more information literate and self-sufficient. • an online survey was sent to im users who asked questions. after a question was answered the librarians would send the url to patrons to help gather their thoughts on the program and receive feedback to improve the service. • in an effort to promote the service, im information was added to multiple pages on the library web site, posters around campus, daniel g. kipnis and gary e. kaplan flyers at library service points, and included in all library orienta- tions to new students, staff, and faculty. • in december , trillian pro ($ ) was purchased for its sup- port of the jabber network used by google talk and meebo. it was installed on one reference desk computer. • a free meebo widget was added to the ask a librarian and im pages. this made it easy for patrons visiting the pages to submit questions without needing an im account. conclusion the trend towards communicating with students in new ways now includes cell phone text messages, ims, myspace, and facebook social- networking services. chat has evolved to include the next generation of features: location based chat, flexible identities, and contextual chat. qualitative studies confirm that im will continue to expand into the fu- ture. as noted in observations by students at the university of wisconsin- milwaukee, “i’m hopeful that the use of im will expand into the future, as the use of e-mail has. communication is an essential element of in- struction.” also, “as email is a step up from snail mail, im is a step up from e-mail and telephones in the educational and business setting. instant communication is essential in the fast-paced world of technology.” at thomas jefferson university the first step into these communica- tion channels was a pilot im reference service. analysis of the first year’s session transcripts demostrated that: • im acronyms are not as commonly used in academic chat as antici- pated. extensive staff training to learn im acronyms is not needed. • the most frequent im question type asked fell under the category of document delivery. • traditional reference statistics gathering does not offer the level of detail of an im transcript. • archived transcripts helped reference staff identify usage patterns. reference staff learned that afternoon and evening hours were pop- ular times to use im. • analyzing archived transcripts helped reference staff understand patrons’ needs. this helped library staff identify areas where more help documentation was needed. these findings highlight and confirm two assumptions. first, the ma- jority of questions asked via im continue to be document delivery, medical reference services quarterly demonstrating a need to improve how electronic resources are pre- sented to patrons. second, free im services are a viable means of offer- ing reference for a small-to-medium sized medical library. with the growth of online communication methods, such as im and chat, and the incorporation of these technologies in academic health sciences librar- ies, additional studies analyzing these services and their effects on tra- ditional reference models are needed. based on user survey results and transcript analysis, the im service at tju has proved to be sufficiently effective to offer it for a second year. staff will continue to improve it by monitoring the current service and investigating new developments in virtual reference software. received: may , revised: july , , august , accepted: august , references . thomas jefferson university. “facts: thomas jefferson university hospitals / .” available: <http://www.jeffersonhospital.org/rx_files/facts .pdf>. accessed: february , . . lenhart, a.; rainie, l.; and lewis, o. “teenage life online: the rise of the in- stant-message generation and the internet’s impact on friendships and family rela- tionships.” pew internet project. (june , ). available: <http://www.pewinternet. org/report_display.asp?r= >. accessed: october , . . farmer, r. “instant messaging: im online! ru?” educause review (november/december, ): - . available: <http://www.educause.edu/apps/er/ erm /erm .asp>. . carnevale, d. “e-mail is for old people.” the chronicle of higher education (october , ):a . available: <http://chronicle.com/free/v /i / a . htm>. accessed: october , . . salaway, g.; katz, r.n.; caruso, j.b.; kvavik, r.b.; and nelson, m.r. the ecar study of undergraduate students and information technology, . boulder, co: educause center for applied research, . (ecar research study ). avail- able: <http://www.educause.edu/ir/library/pdf/ers /ers w.pdf)>. accessed: january , . . foehr, u.g. “media multitasking among american youth: prevalence, predic- tors and pairings.” (december ). available: <http://www.kff.org/entmedia/ upload/ .pdf>. accessed: february , . . madden, m., and fox, s. “riding the waves of ‘web . .’” pew internet project (october , ). available: <http://www.pewinternet.org/pdfs/pip_web_ . .pdf>. accessed: october , . . cleveland, a., and philbrick, j. “virtual reference services for the academic health sciences librarian.” medical reference services quarterly (supplement , ): - . daniel g. kipnis and gary e. kaplan . association of american medical colleges. “member schools.” available: <http://services.aamc.org/memberlistings/index.cfm?fuseaction=home.search&search_ type=ms>. accessed: march , . . bobal, a.m.; schmidt, c.m.; and cox, r. “one library’s experience with live, virtual reference.” journal of the medical library association , no. (january ): - . . foley, m. “instant messaging reference in an academic library: a case study.” college and research libraries (january ): - . available: <http://www.ala.org/ala/acrl/acrlpubs/crljournal/backissues b/january /foley.pdf>. accessed: november , . . desai, c. “instant messaging reference: how does it compare?” the elec- tronic library , no. ( ): - . . connor, e. “real-time reference: the use of chat technology to improve point of need assistance.” medical reference services quarterly , no. (winter ): - . . ward, d. “instant messaging and chat reference.” internet reference services quarterly , no. ( ): - . . straw, j. “using canned messages in virtual reference communication.” internet reference services quarterly , no. ( ): - . . janes, j. “at arm’s length.” american libraries (august, ): . available: <http://www.ala.org/ala/alonline/inetlibrarian/ columns/internetaug .cfm>. ac- cessed: november , . . fagan, j.c., and ruppel, m. “instant messaging reference: users’ evaluation of library chat.” reference services review , no. ( ): - . . durrance, j.c. “the generic librarian: anonymity versus accountability.” ref- erence quarterly , no. ( ): - . . read, b. “the wired campus.” im-speak seeps into class work. the chronicle of higher education (february , ). available: <http://chronicle.com/wiredcampus/ article/ /im-speak-seeps-into-class-work>. accessed: march , . . aratani, l. “im shorthand slips off computer screens and into schoolwork.” washington post (december , ): a . available: <http://www.washingtonpost. com/wp-dyn/content/article/ / / /ar .html>. accessed: march , . . straw, j. “using canned messages in virtual reference communication.” internet reference services quarterly , no. ( ): - . . broughton, k. “our experiment in online, real-time reference.” computers in libraries (april ): - . . gonzalez, n. “the six biggest new ideas in chat.” techcrunch (november , ). available: <http://www.techcrunch.com/ / / /the-six-biggest-new- ideas-in-chat>. accessed: december , . . jeong, w. “instant messaging in on-site and online classes in higher educa- tion.” educause quarterly , no. ( ): - . available: <http://www.educause. edu/ir/library/pdf/eqm .pdf>. accessed: february , . medical reference services quarterly appendix a transcript of im session for journal look-up user ( : : pm): hi i have a question to ask about journals . . . if i know the author and title of the journal, how do i go about searching the internet on jeffline to seei f jefferson has them? smlreference ( : : pm): hi this is anna [pseudonym used]. we have an online catalog that you can search or i can check it for you user ( : : pm): hi this is carly [pseudonym used]. where would i go for the online catelog . . . “m new with this whole system so “m trying to learn smlreference ( : : pm): there is a tab titled scot t library, put you mouse on that tab and a drop down menu will appear, go to collections, and you will see another drop down menu, choose thomcat from that menu user ( : : pm): ok im in thomcat user ( : : pm): thank you smlreference ( : : pm): are you ok will finding the journal that you need from here user ( : : pm): yeah thanks smlreference ( : : pm): you are welcome. whould you mind taking a short survey at your convienence? user ( : : pm): sure smlreference ( : : pm): you can find it at http://jeffline.jefferson.edu/ sml/reference/aimsurvey.html smlreference ( : : pm): thanks, have a great day smlreference ( : : pm): bye user ( : : pm): thx you too user ( : : pm): bye daniel g. kipnis and gary e. kaplan appendix b transcript of im session about write-n-cite start of user buffer: tue jul : : [ : ] user: are you available to answer a write-n-cite question? [ : ] smlreference: in just a second. [ : ] smlreference: hi, thanks for waiting. this is jane [pseudonym used] [ : ] smlreference: how can i help you? [ : ] user: hello jane, i can’t seem to install write-n-cite on my mac [ : ] user: i’ve used the link provided on jeffline to the download page, but it never downloads a functioning program [ : ] smlreference: (just logging into refworks now so i can see what it looks like . . .) [ : ] smlreference: okay, you got to the refworks “download write-n- cite” page? [ : ] user: correct [ : ] user: i’ve clicked on the option for the mac version [ : ] smlreference: it should download a compressed file that you have to drag into your applications folder [ : ] user: when i double click to open the install program afterwards it says the file type is not supported [ : ] user: the file is called “archive.sitx” is that correct? [ : ] smlreference: hmmm. it should be a .dmg file [ : ] user: ok . . . well, i thought perhaps the safari browser wasn’t sup- ported, so i tried netscape next and got a completely different file that also does not seem to cooperate [ : ] smlreference: what kind of mac do you have (what operating system)? [ : ] user: os x [ : ] user: the macbook before the most recent version [ : ] smlreference: i wouldn’t think the browser would matter, just so long as you download the file. [ : ] smlreference: have you installed much other software on that machine? [ : ] user: nothing fancy, some palm software, the ms office suite, etc. [ : ] smlreference: is it os . ? or . ? [ : ] smlreference: is the file kb? [ : ] user: not sure, where do i find that? [ : ] user: no, kb [ : ] smlreference: under the apple menu “bout this mac,” maybe? medical reference services quarterly [ : ] user: actually, it says kb on the website, but the file i’m getting using netscape is only kb [ : ] user: . [ : ] smlreference: (i ask because my mac experience is with . ) [ : ] smlreference: what does the icon of the downloaded file look like? [ : ] user: a blank sheet [ : ] user: seems to be unrecognized [ : ] smlreference: i can try emailing you the file. [ : ] user: that would be great, [email address removed] [ : ] user: if that doesn’t work, perhaps i can stop in later in the week or try to put the file on my thumb drive using a mac in the lrc [ : ] smlreference: just sent it . . . [ : ] user: so then i drag it into the applications folder . . . [ : ] smlreference: right. . . . [ : ] user: and double click to install? [ : ] smlreference: oh . . . wait. try double-clicking the file i sent. hope- fully it will un-stuff. [ : ] smlreference: then the resulting folder should have a program to drag into applications [ : ] smlreference: or does the file i sent look like the same blank document? [ : ] user: still a blank document [ : ] user: no program recognized to open the file [ : ] smlreference: i'm looking around for anything about this as a known problem. . . . [ : ] user: ok, i appreciate your help . . . unfortunately, i have to leave the computer now, if you find anything out please send me an e-mail [ : ] user: if not, i’ll try to the macs in the lrc later on [ : ] user: thanks again [ : ] smlreference: will do . . . i’m reading about . discontinuting stuffit support . . . i’ll send you an email [ : ] smlreference: thanks for asking note: the problem was resolved during an email exchange. daniel g. kipnis and gary e. kaplan 	rowan university 	from the selectedworks of daniel g. kipnis 	january , 	analysis and lessons learned instituting an instant messaging reference service at an academic health sciences library 	analysis and lessons learned instituting an instant messaging reference service at an academic health sciences library: the first year wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ charged particles in radiotherapy: a -year update of a systematic review radiotherapy and oncology ( ) – contents lists available at sciverse sciencedirect radiotherapy and oncology j o u r n a l h o m e p a g e : w w w . t h e g r e e n j o u r n a l . c o m systematic review charged particles in radiotherapy: a -year update of a systematic review dirk de ruysscher a,⇑, m. mark lodge b, bleddyn jones c, michael brada d, alastair munro e, thomas jefferson f, madelon pijls-johannesma a a department of radiation oncology (maastro), maastricht university medical center, the netherlands; b international network for cancer treatment and research, oxford; c gray institute for radiation oncology and biology, university of oxford; d institute of cancer research, sutton; e department of radiotherapy, university of dundee, uk; f independent epidemiologist, rome, italy a r t i c l e i n f o a b s t r a c t radiotherapy and oncology ( ) – article history: received january accepted january available online february keywords: proton therapy charged particles radiotherapy - � elsevier ireland ltd. http://dx.doi.org/ . /j.radonc. . . ⇑ corresponding author. address: department of rad grow – school for oncology and developmental b medical center maastricht (mumc+), maastricht, the e-mail address: dirk.deruysscher@maastro.nl (d. d photons and x-rays are used in the text to descri opposed to protons, which we consider to be light particles. open access und although proton therapy has been used for many decades because of their superior dose distribution over photons and reduced integral dose, their clinical implementation is still controversial. we updated a sys- tematic review of charged particle therapy. although still no randomised trials were identified, the field is moving quickly and we therefore also formulated ways to move forward. in our view, the aim should be to build enough proton therapy facilities with interest in research to further improve the treatment and to run the needed clinical trials. � elsevier ireland ltd. open access under cc by-nc-nd license. charged particle radiotherapy (cpt) has been under the spot- light for many years. investigators are looking for an answer to the question: how does it influence the outcome of cancer patients [ – ]? based on the dose distributions, it has been concluded that the use of protons may lead to improved coverage of the planning target volume (ptv) and reduced doses to many organs at risk (oar) [ – ]. several systematic reviews performed during the last decade [ , – ] investigating the clinical efficacy of cpt show that, for most indications, no firm conclusions can be drawn. in part this is due to a lack of high quality data, making adequate comparisons impossible. in addition, cost-effectiveness analysis of this technol- ogy also could not clearly demonstrate that cpt was more cost- effective than the most advanced photon technology, such as stereotactic body radiotherapy (sbrt or stereotactic ablative radio- therapy, sabr) or intensity modulated radiotherapy (imrt) [ , , – ]. the published results generated a world-wide debate between proponents and sceptics [ ]. because so many patients have been treated with protons and c-ions world-wide, we performed a new systematic review of the literature, years after our previous publication [ ]. the full report is available on line as a supplementary file. our main goal was to explore to which extent previous recom- mendations were taken up by the radiation oncology community iation oncology (maastro), iology, maastricht university netherlands. e ruysscher). be the same beam quality as ions and c that are heavy er cc by-nc-nd license. and to determine if it is possible to draw firm conclusions about the clinical and cost-effectiveness of cpt as compared to best current practice. it was sobering to observe that no phase iii trials have been per- formed and from the many retrospective and the few prospective series, we still cannot conclude that protons or c-ions are truly superior to x-rays. moreover, many of the available clinical studies were performed at a time when the current proton techniques and the newest x-ray treatment, including imaging and adaptation, were not available. our former conclusion thus still stands: except for rare indications such as childhood cancer, the gain from intro- ducing proton therapies into clinical practice remains controver- sial. the contention that protons are more suitable when oar dose constraints limit the delivery of the most appropriate tumour x-ray radiotherapy doses is compelling, but remains unproven. nor do we know if cpt allows radiation dose escalation without increasing side effects – leading to improved local tumour control and survival. where dose escalation is achievable by the most recent x-ray based techniques, the gain from proton therapy is con- fined to a reduction in dose to organs away from the target region. these arguments depend on the accuracy of the predicted dose distribution and sound estimates of the relative biological effec- tiveness (rbe) values for the cancer and for each normal tissue [ ]. the debate between the advocates in favour of randomised studies for all circumstances, and those who consider this to be unethical when reduced radiation dose can be delivered to oar, continues [ – ]. x-ray (photon) treatment and imaging techniques have significantly improved over recent decades with increased implementation of imrt, arc and helical treatment and sabr in routine clinical practice [ – ]. together with imaging developments such as ct-, mri- and pet-based radiotherapy http://dx.doi.org/ . /j.radonc. . . mailto:dirk.deruysscher@maastro.nl http://dx.doi.org/ . /j.radonc. . . http://www.sciencedirect.com/science/journal/ http://www.thegreenjournal.com http://creativecommons.org/licenses/by-nc-nd/ . / http://creativecommons.org/licenses/by-nc-nd/ . / systematic review charged particles planning, d-ct and improved dose calculation and optimisation algorithms, x-ray therapy allows the delivery of radiotherapy to high doses. modern x-ray techniques in common malignancies such as non-small cell lung cancer are comparable to, or even supe- rior to, that of protons therapy delivered with passive scattering techniques [ ]. however x-ray techniques will always deliver a higher integral dose than protons and there is concern about low dose effects to a wider volume because of enhanced cancer induc- tion and circulatory system risks [ – ]. at the same time proton therapy has also significantly improved, allowing the delivery of intensity modulated proton therapy (impt) with commercial sys- tems [ ]. at present, many planning studies show that for the high dose regions, the best available x-ray and proton treatments result in similar dose distributions within and around the tumour. however the medium and low dose volumes are smaller and receive less radiation dose with impt than with any x-ray technique [ – ]. proponents of protons view the data as a proof that ultimately pro- ton therapy will supersede x-rays because it is generally agreed that the alara (as low as reasonably achievable) principle should be followed [ ]. arguments against this viewpoint are that a reduction of the medium and low dose volumes are not beneficial for the patient when only a shallow dose–response relationship be- tween an intermediate dose and side-effects exists or when the side effects are of no clinical relevance or occur in only a small pro- portion of patients. balanced arguments, considering many of the technical aspects have been published recently (e.g. [ , ]). when some oars can be spared more effectively with protons than x-rays, even for the medium or low dose levels, more effective dose-escalation may be possible, either for radiotherapy or for combined radiation and systemic treatment. because the absorption and range of protons is more dependent on electron density inhomogeneity than x-rays, small shifts of the tumour or of the oars in areas with high density gradients, e.g. in the lungs (where not only lung density but also tumour position varies with breathing), may directly result in large changes and er- rors in dose distribution. adaptive radiotherapy techniques thus become even more important for protons than for x-rays, and these are in development for each modality [ , ]. probability based treatment planning strategies taking into account volume changes and shifts of the tumour and the oars have been described allow- ing more robust dose distributions for scanned proton beams, although there is a longer history of using respiratory gating tech- niques in proton therapy than in the case of x-ray therapy [ ]. if proton therapy can fulfil its initial promise it may well turn out to be a cost-effective intervention [ ]. it is necessary to break the current vicious circle where the lack of robust clinical data leads to a lack of evidence to support funding and further develop- ment of proton beam therapy in state-of-the-art treatment centres with responsibilities to produce robust clinical data [ , ]. the root cause of the problem facing proton therapy is the historic fail- ure to leverage the collection and sharing of anonymised data in return for capital investment in what is, to all intents and purposes, still a developing and experimental technology. unless the present culture is radically changed this collaborative failure will continue to be proton therapy’s achilles heel. we believe that randomised phase iii trials will be needed for some, but not necessarily all, situations to investigate the role of protons and their cost-effectiveness. prospective phase ii studies using the best available techniques and reporting agreed endpoints of clinical relevance are the minimum requirement. as recom- mended previously, all studies should be fully integrated in large international networks and databases to make reliable and rapid progress: this needs urgent implementation. new particle beam centres should be funded with a provision for shared basic research, technical improvements and properly conducted trials. an enhanced level of global, or at least continen- tal or national, governance of particle therapy is of paramount importance. only then, will we be in a position to clarify the real gain of cpt and to bring an otherwise endless debate to an unequivocal conclusion. research support and disclaimer this article is based on the results of our update of ref. [ ], years after the original reviews. the work was supported by an unrestricted grant of the european investment bank. the european investment bank is not responsible for the contents or reliability of this review and does not necessarily endorse the views herein expressed. appendix a. supplementary data supplementary data associated with this article can be found, in the online version, at doi: . /j.radonc. . . . references [ ] suit h, delaney t, goldberg s, et al. proton vs carbon ion beams in the definitive radiation treatment of cancer patients. radiother oncol ; : – . [ ] van de water ta, bijl hp, schilstra c, et al. the potential benefit of radiotherapy with protons in head and neck cancer with respect to normal tissue sparing: a systematic review of literature. oncologist ; : – . 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[ ] peeters a, grutters jp, pijls-johannesma m, et al. how costly is particle therapy? cost analysis of external beam radiotherapy with carbon-ions, protons and photons. radiother oncol ; : – . 	charged particles in radiotherapy: a -year update of a systematic review 	research support and disclaimer 	appendix a supplementary data 	references cd binding induces an asymmetric transition of hiv- env from its native conformation into the prehairpin intermediate state a sunday, february , is currently unknown. in this work, we use density gradient centrifugation and liposome coflotation analysis to demonstrate that the anchoring energy of the dengue e protein in anionic membranes composed of popcþpopg is much greater than in membranes composed of popcþpope. -pos board b hiv fusion peptide perturbs membrane structure in a cholesterol dependent fashion alex liqi lai, jack h. freed. acert, cornell university, ithaca, ny, usa. the fusion between viral envelopes with host cell membranes is required for viral entry and infection, which is mediated by special glycoproteins anchored on the viral membrane. fusion peptide (fp) is the domain that initiates mem- brane fusion. however, the mechanism of membrane fusion is still unclear. we previously found that the influenza hemagglutinin fp increases the order of dmpc lipid bilayer. we hypothesize that inducing lipid ordering might be a critical step in fusion caused by a variety of fusion proteins. hiv gp fp plays a similar role as influenza ha fp. however, gp fp is polymorphic and changes from alpha helix to beta aggregation as cholesterol concentration in lipid increases. we used pc spin labels on the lipid head group and different positions on the acyl chain to detect the perturbation by gp fp to popc/ popg lipid bilayers with different cholesterol concentration ( % to %) by cw-esr. our data show that ) gp fp affects the lipid order in the same pat- tern as ha fp does, i.e., a cooperative effect vs. lipid/peptide ratio, thus sup- porting our hypothesis; ) gp fp induces membrane ordering in all tested lipid compositions, consistent with promoting membrane fusion in these com- positions; ) in the high cholesterol containing lipid bilayers, whereas gp fp is in the beta aggregation conformation, its effect on the lipid ordering reaches deeper into the bilayer, consistent with deeper membrane insertion for gp fp in this conformation. we are extending the esr studies to look for coexisting membrane microdomains induced by different conformations of fps and the fp partitioning between them and for precise separation of the effects of ordering and molecular motion. -pos board b cd binding induces an asymmetric transition of hiv- env from its native conformation into the prehairpin intermediate state mukta d. khasnis, konstantine halkidis, anshul bhardwaj, michael root. thomas jefferson university, philadelphia, pa, usa. hiv- membrane fusion is mediated by sequential binding of the viral homo- trimeric env (gp /gp ) to cellular cd and chemokine receptor (cxcr or ccr ). these binding events coordinate conformational transitions of the gp trimer from its native conformation into a prehairpin intermediate state (phi) and, subsequently, into its fusogenic trimer-of-hairpins structure (toh). in the phi, the gp trimer assumes an extended conformation that bridges the viral and cellular membranes, and exposes the n-hr and c-hr do- mains which are targeted by hiv- fusion inhibitors t and -helix, respec- tively. our previous work suggests that the phi-to-toh transition occurs in a concerted (symmetric) fashion. here, we investigate the transition from the native state to the phi using a functional complementation strategy that em- ployed heterotrimeric envs containing only one or two functional cd - and chemokine receptor-binding sites. additionally, by incorporating t - and -helix- resistance mutations into individual env protomers, we were able to interrogate exposure of discrete gp n-hr and c-hr domains. our data indicate that a single cd binding to an env trimer is sufficient to promote fusion. moreover, the first cd binding event appeared to expose only one of three possible binding sites for each fusion inhibitor, suggesting an asymmetric transition into the phi. this asymmetry was significantly more pronounced in the gp n-hr region compared to the gp c-hr region. these results can be used to explain the multiphasic titration of mutant env homotrimers that naturally form asymmetric n-hr domain structures. taken together, these data suggest that the native state-to-phi transition of env occurs in a multistep (asymmetric) fashion. -pos board b evolution of hiv- resistance to a cholesterol-linked d-peptide fusion inhibitor amanda e. siglin , nicholas francis , michael s. kay , micheal j. root . thomas jefferson university, philadelphia, pa, usa, university of utah, salt lake city, ut, usa. during hiv- entry, the n-hr and c-hr regions of the gp viral glycoprotein associate to form a trimer-of-hairpins critical for membrane fusion. the n-hr region contains a highly conserved hydrophobic pocket that is the target for a multivalent, d-peptide fusion inhibitor, pie -trimer. recently, a modified form of this inhibitor with a conjugated cholesterol (chol-pie -trimer) was shown to possess up to -fold increased potency, presumably due to mem- brane targeting. here, we determined the resistance profile of chol-pie - trimer starting from either inhibitor-naı̈ve or pie -trimer-resistant hiv- (nl - strain). viral propagation in increasing inhibitor concentrations pro- duced hiv- populations with - to -fold reduced sensitivity chol- pie -trimer. these viruses were also resistant to the parental, unconjugated inhibitor pie -trimer. using hiv- fusion inhibitors di-c and -helix, we were able to interrogate the effect of escape mutations on the exposure of the gp n-hr and c-hr regions, respectively. resistance to chol-pie - trimer resulted in a slight decrease in the temporal window of n-hr exposure, regardless of the starting viral population. exposure of the c-hr region was unchanged for resistant viruses generated from the inhibitor-naı̈ve viral pool. by contrast, the temporal window of c-hr exposure was significantly increased (> -fold) for resistant viruses that were generated from the pie -trimer-resistant viral pool. efforts to identify the mechanisms of chol- pie -trimer resistance and the decoupling of n-hr and c-hr exposure are underway. -pos board b fusogenic activity of the hiv- gp mper-tmd region: mechanism and targeting by immunogens and inhibitors jose l. nieva , beatriz apellaniz , carmen domene , nerea huarte , eneko largo . biophysics unit (csic-upv/ehu) and dept. of biochemistry, university of the basque country (upv/ehu), bilbao, spain, chemistry research laboratory, university of oxford, oxford, united kingdom. fusion of the viral envelope with the cell membrane marks the beginning of the hiv- replicative cycle. this event is targeted by inhibitors currently in clinical use and by preventive vaccines under development. antibodies e and e bind to the gp membrane proximal external region (mper)- transmembrane domain (tmd) junction and block fusion. these antibodies display the broadest viral neutralization known to date, which underscores the conservation and functionality of the mper-tmd region. in recent work, we have described that peptides representing this region have potent membrane-destabilizing effects. here, based on the outcome of vesicle assays, atomic force microscopy studies and molecular dynamics simulations, we propose a mechanism for the involvement of the mper-tmd region in hiv- fusion. in addition, we provide evidence that underpins the poten- tial use of its activity as a new target for inhibitor and immunogen development. -pos board b studies on the membrane-active behavior of outer membrane vesicles from a gram negative bacterium william bartos, rensa chen, donald y. kobayashi, paul r. meers. rutgers, the state university of new jersey, new brunswick, nj, usa. gram-negative bacteria are known to produce small ~ - nm vesicles by ‘‘blebbing’’ of their outer membranes. these outer membrane vesicles (omv) have been implicated in activities such as transmission of virulence fac- tors, horizontal gene transfer and development of biofilms. in this investigation, the interactions of omv from lysobacter enzymogenes (strain c ) with other membranes have been monitored using fluorescent assays for association and/or fusion. defined composition large unilamellar vesicles labeled with the fluorescence resonance energy transfer (fret) pair , -dipalmitoyl-sn- glycero- -phosphoethanolamine-n-( -nitro- - , -benzoxadiazol- -yl) (nbd- pe) and , -dipalmitoyl-sn-glycero- -phosphoethanolamine-n-(lissamine rho- damine b sulfonyl) (rh-pe) were incubated with isolated omv to observe the interaction via the fret ratio of donor/acceptor. omv substantially increased this ratio over the course of about an hour (t / ~ - min.) at �c, when added directly to vesicles comprising disordered or fluid lipids, such as -palmitoyl- -oleoyl-sn-glycero- -phospho-( ’-rac-glycerol) (popg), -pal- mitoyl- -oleoyl-sn-glycero- -phosphoethanolamine (pope) or -palmitoyl- - oleoyl-sn-glycero- -phosphocholine (popc). this apparent fusion was much more limited or absent with liquid ordered membranes of , -dipalmitoyl-sn- glycero- -phosphocholine/cholesterol (dppc/chol). in the case of popg/ pope / vesicles, apparent fusion was also confirmed by testing vesicles with exclusively inner monolayer fluorescent probes to diminish any fluores- cence changes from external interactions of outer monolayer fluorophores. when the omv were labeled with the fluorophore , -dioctadecyl- , , , - tetramethylindocarbocyanine, and incubated with a natural host, yeast cells (strain s ), association and/or fusion was observed by co-sedimentation of the omv label with yeast cells. these studies may help to elucidate the mech- anism of natural host-pathogen interactions and define the lipid specificity for 	hiv fusion peptide perturbs membrane structure in a cholesterol dependent fashion 	cd binding induces an asymmetric transition of hiv- env from its native conformation into the prehairpin intermediate state 	evolution of hiv- resistance to a cholesterol-linked d-peptide fusion inhibitor 	fusogenic activity of the hiv- gp mper-tmd region: mechanism and targeting by immunogens and inhibitors 	studies on the membrane-active behavior of outer membrane vesicles from a gram negative bacterium judicial foreign policy: lessons from the s judicial foreign policy: lessons from the s david sloss i. introduction in his dissenting opinion in hamdi v. rumsfeld, justice thomas cited justice jackson approvingly for the following proposition: “[t]he very nature of executive decisions as to foreign policy is political, not judicial. such decisions are wholly confided by our constitution to the political departments of the government . . . they are decisions of a kind . . . which has long been held to belong in the domain of political power not subject to judicial intrusion or inquiry.” under this view, which i will call the “exclusive political control” thesis, the judiciary is barred from participating in foreign affairs decision-making because the constitution grants the political branches exclusive control over foreign policy. several scholars have defended variants of the exclusive political control thesis. this article demonstrates that the exclusive political control thesis is incompatible with the original understanding of the founders. the article does not defend originalism as a method of constitutional interpretation; it merely shows that the exclusive political control thesis is inconsistent with an originalist approach. the article examines the implementation of u.s. neutrality policy in the period from to . other scholars have analyzed the initial formulation of u.s. neutrality policy in . scholars who focus narrowly on the year , when the u.s. first articulated its neutrality policy, have concluded that “the federal courts played a relatively minor role in resolving the nation’s foreign affairs problems.” however, if one expands the time frame of the analysis to include the years to , when the hamdi v. rumsfeld, us , ( ) (thomas, j., dissenting). id. at - (quoting chicago & southern air lines v. waterman s.s. corp., u.s. , ( )). see, e.g., john yoo, the powers of war and peace ( ) (claiming that the “founding generation” believed that “the bulk of the foreign affairs power was vested in the executive” and that “[c]ourts did not play a significant role”); jide nzelibe, the uniqueness of foreign affairs, iowa l. rev. , ( ) (“compared to the political branches, the courts suffer from peculiar institutional disadvantages that often warrant absolute deference to the decision of the political branches in most foreign affairs controversies”). for an insightful analysis of the application of originalist methodology to constitutional foreign affairs issues, see ingrid wuerth, an originalism for foreign affairs?, st. louis univ. l. j. xxx (fortcoming ). see charles marion thomas, american neutrality in : a study in cabinet government ( ); harry ammon, the genet mission ( ); william r. casto, foreign affairs and the constitution in the age of fighting sail ( ). casto, supra note , at . saint louis university law journal u.s. confronted a series of issues related to implementation of its neutrality policy, a different constitutional picture emerges. this article shows that the federal judiciary played a very significant role in implementing u.s. neutrality policy during this period. between february and february , the supreme court decided cases arising from french privateering activities, including fourteen published decisions and ten unpublished decisions. these cases accounted for roughly half of the supreme court caseload during this period. all of the cases raised issues that were directly related to the most important national security issue of the era: how best to maintain u.s. neutrality in the ongoing war that pitted france against england, spain, and other european powers. french diplomats repeatedly lobbied the executive branch to remove the privateering cases from the courts and resolve them through diplomatic means. from france’s perspective, the cases raised questions about sovereign prerogatives and the conduct of naval warfare, which were properly resolved through diplomatic negotiation, not private adjudication. initially, u.s. judges and executive officials were uncertain whether the cases should be resolved diplomatically, or by means of private adjudication in u.s. courts. however, a consensus soon emerged among cabinet officers and supreme court justices that the federal judiciary should decide the issues raised by the french privateering cases in the context of adjudication between the french captors and the original ship owners. subsequently, despite repeated french diplomatic protests, the executive branch steadfastly refused to intervene in ongoing judicial proceedings. the fourteen published decisions are: jennings v. brig perseverance, u.s. ( dall.) ( ); del col v. arnold, u.s. ( dall.) ( ); hills v. ross, u.s. ( dall.) ( ); moodie v. ship phoebe anne, u.s. ( dall.) ( ); moodie v. ship alfred, u.s. ( dall.) ( ); arcambel v. wiseman, u.s. ( dall.) ( ); cotton v. wallace, u.s. ( dall.) ( ); united states v. la vengeance, u.s. ( dall.) ( ); geyer v. michel, u.s. ( dall.) ( ); moodie v. ship betty cathcart, u.s. ( dall.) ( ); macdonough v. dannery, u.s. ( dall.) ( ); talbot v. jansen, u.s. ( dall.) ( ); united states v. peters, u.s. ( dall.) ( ); and glass v. sloop betsey, u.s. ( dall.) ( ). technically, u.s. v. peters and macdonough v. dannery are not “privateer” cases because they involved french naval vessels, not privateers. even so, they are included for the sake of completeness. the ten unpublished decisions are: wallace v. brig caesar, supreme court case no. ; moodie v. the ship mermaid, supreme court case no. ; moodie v. the brig eliza, supreme court case no. ; moodie v. the ship phyn, supreme court case no. ; moodie v. the brig tivoly, supreme court case no. ; moodie v. the brig favorite, supreme court case no. ; moodie v. the ship britannia, supreme court case no. ; moodie v. the snow potowmack, supreme court case no. ; moodie v. the brig eliza, supreme court case no. ; and don diego pintado v. ship san joseph, supreme court case no. . during this period, one other french privateering case was also entered onto the supreme court docket: morphy v. ship sacra familia. however, there was no supreme court decision because the french and spanish consuls agreed to discontinue the case. see vii documentary history of the supreme court of the united states, - (marcus, ed. ), pg. [hereinafter, dhsc]. during the s, the supreme court convened for two terms each year, in february and august. over the course of seven terms from february to february , the court decided approximately cases; this figure depends upon what, precisely, is counted. for present purposes, the main point is that the french privateering cases occupied a very substantial portion of the supreme court docket during this period. for detailed information about the supreme court docket, see i dhsc, supra note , at - , - (reproducing the supreme court minutes and docket for the period - ). traditional accounts of the neutrality crisis have emphasized the supreme court’s refusal to issue an advisory opinion to the executive branch. see thomas, supra note , at - ; casto, supra note , at judicial foreign policy: lessons from the s four features of the french privateering cases, viewed together, demonstrate conclusively that the exclusive political control thesis is contrary to the original understanding of the founders. first, the french privateering cases were directly related to the implementation of u.s. neutrality policy, which was the most important national security issue of the era. second, these cases accounted for a very substantial percentage of the supreme court docket in the initial decade after adoption of the constitution. third, executive and judicial officers reached a consensus that the cases should be resolved judicially, not diplomatically. fourth, the cabinet officers and supreme court justices who formed that consensus included many of the leading figures involved in drafting and ratifying the constitution. given their agreement that the federal judiciary should play a leading role in implementing u.s. neutrality policy, claims by contemporary jurists and scholars that the founders granted the political branches exclusive responsibility for foreign policy decision-making are simply untenable. it bears emphasis that all the french privateering cases involved disputes about the property rights of private parties, and that international law provided many of the key substantive rules for resolving those disputes. thus, the government’s choice to handle these cases through litigation in federal courts illustrates two points. first, the founders were very comfortable with the idea that federal courts would invoke international law to provide rules of decision in litigation. second, the founders recognized that - . in the summer of , the executive branch submitted a set of questions to the supreme court related to french privateering. see vi dhsc, supra note , at - . the court refused to provide an answer, stating that “[t]he lines of separation drawn by the constitution between the three departments of government . . . afford strong arguments against the propriety of our extrajudicially deciding the questions alluded to.” id. at . notwithstanding this incident, though, the supreme court and the lower federal courts decided dozens of french privateering cases in the period from to , and the executive branch consistently refused to intervene in judicial decision-making. see infra part iv. three men served as secretary of state during this period: thomas jefferson ( to dec. ), edmund randolph (jan. to aug. ) and timothy pickering (aug. to may ). jefferson’s credentials as one of the key constitutional founders are well known. randolph played a key role at both the constitutional convention and the virginia state ratifying convention. see julius goebel, jr., antecedents and beginnings to (vol. i of the history of the supreme court of the united states) ( ) pgs. - , - , - . pickering was not a representative to the constitutional convention, but he did participate in the pennsylvania ratifying convention. two men served as attorney general during this period: edmund randolph ( to jan. ) and william bradford (jan. to dec. ). before becoming attorney general, bradford was a justice on the pennsylvania supreme court ( - ) and attorney general of pennsylvania ( - ). alexander hamilton served as secretary of the treasury from to feb. . although he had no formal responsibility for u.s. foreign policy, he was a key presidential advisor on a wide range of issues. hamilton’s credentials as one of the key constitutional founders are well known. three men served as chief justice during this period: john jay ( to june ), john rutledge (aug. to dec. ), and oliver ellsworth (march to dec. ). john jay, as is well known, was one of three co-authors of the federalist papers. he played a central role during the new york ratifying convention. see goebel, supra, at - . rutledge and ellsworth both served on the committee of detail during the constitutional convention. see id. at - . they also played central roles in their state ratifying conventions. see id., at - (ellsworth and connecticut); - (rutledge and south carolina). in contrast to some modern litigation, the courts were not utilizing international law as a guide to constitutional interpretation. they were applying international law directly as a rule of decision. saint louis university law journal international law, or the “law of nations” as it was known at that time, did not merely regulate relations between nations: it also conferred rights on private parties. leading originalist accounts of the constitutional separation of powers in foreign affairs have tended to overlook, or give little weight, to the french privateering cases. this is understandable because the cases themselves say very little about the constitutional distribution of power in foreign affairs. ten of the cases did not yield published decisions; in most of those cases, the court did not produce any written rationale. in many of the published decisions, the court’s written rationale says nothing about the separation of powers issues that are the central focus of this article. to shed light on these issues, the author analyzed a wide variety of ancillary materials related to the french privateering cases, including the supreme court papers in the national archives, other sources that present arguments advanced by the parties in the privateering cases, the decisions of lower courts, executive branch documents and diplomatic correspondence with france and england. the analysis of these ancillary materials suggests that the founders did not envision the lines separating the three branches of the federal government as impenetrable, immovable walls. to the contrary, the key government decision-makers in the s believed that they were engaged in a cooperative effort in which all three branches of the federal government worked together to promote u.s. foreign policy objectives. responsibility for foreign policy decision-making was not divided into neat, see generally mark w. janis, the american tradition of international law, great expectations: - ( ). see, e.g., michael d. ramsey, the constitution’s text in foreign affairs ( ) (providing a very comprehensive account of the constitutional law of foreign affairs, as it was understood by the founding generation, but devoting very little attention to the french privateering cases). the author spent two days in the national archives conducting research for this paper. he reviewed the supreme court case files for of the cases referenced above, including two published cases, and eight unpublished cases. the two published cases are: moodie v. ship phoebe anne, u.s. ( ); and moodie v. ship alfred, u.s. ( ). the eight unpublished cases are: moodie v. the ship mermaid, supreme court case no. ; moodie v. the brig eliza, supreme court case no. ; moodie v. the ship phyn, supreme court case no. ; moodie v. the brig tivoly, supreme court case no. ; moodie v. the brig favorite, supreme court case no. ; moodie v. the ship britannia, supreme court case no. ; moodie v. the snow potowmack, supreme court case no. ; and moodie v. the brig eliza, supreme court case no. . many of the previously unpublished documents associated with the french privateering cases are collected in volumes and of dhsc, supra note . these materials, together with the materials in the national archives, are invaluable for understanding the arguments advanced by the parties in these cases. judge thomas bee, the federal district judge in south carolina, decided of the cases referenced above, as well as some other french privateering cases that never reached the supreme court. judge bee’s decisions in admiralty cases were published in in a separate volume entitled reports of cases adjudged in the district court of south carolina by the hon. thomas bee, judge of that court ( ) [hereinafter, bee’s admiralty reports]. many of these cases were also published later in the “federal cases” collection. numerous executive branch documents related to the privateering cases are reproduced in volumes and of dhsc, supra note , and in volumes and of the american state papers on foreign relations [hereinafter aspfr], available at http://memory.loc.gov/ammem/amlaw/lwsp.html. much of the extensive diplomatic correspondence related to the french privateering cases is preserved in volumes and of aspfr. http://memory.loc.gov/ammem/amlaw/lwsp.html judicial foreign policy: lessons from the s separate boxes labeled “legislative,” “executive,” and “judicial.” the foreign policy challenges facing the young nation were too important to allow artificial “walls” separating the branches of government to impede the active cooperation of all three branches in working together to solve vital national security problems. the remainder of this article is divided into four parts. part two provides background on french privateering in the s. parts three and four proceed chronologically. part three examines the period from february , when france declared war on great britain and holland, until june , when congress enacted legislation to address the problems posed by french privateering activities in the u.s. during this period, the u.s. government worked out the basic division of responsibility between the executive and judicial branches, and decided that the judiciary should handle many of the issues arising from french privateering activities. part four analyzes the period from june until february , when the supreme court decided jennings v. brig perseverance, the last of the french privateering cases. during this period, british consuls utilized the u.s. judicial system to harass french privateers and gain a tactical advantage in the ongoing naval war between france and britain. by instigating litigation in u.s. courts, the british consuls imposed substantial economic costs on french privateers. those costs, combined with other factors, ultimately induced the privateers to take their captured prizes elsewhere, rather than bringing the prizes to u.s. ports, where they would be subjected to protracted litigation. part five presents concluding observations about the contemporary relevance of the french privateering cases. ii. background: french privateering in the s in the late eighteenth century, “privateering” was a common means of warfare. if a nation with a relatively weak naval force became embroiled in warfare, it could augment its naval power by commissioning privateers to fight on its behalf. the term “privateer” refers both to privately owned ships that fought on behalf of a government and to people who operated those ships. if a man wanted to fight as a privateer on behalf of a government, he would have to bear the expense of purchasing an appropriate ship, fitting it for warfare, and hiring a crew. he would also have to obtain a commission, sometimes called a “letter of marque,” from a duly authorized government officer. armed with such a commission, the privateer was authorized to capture enemy merchant vessels. the privateer would bring captured vessels to a “prize court,” a judicial body authorized to declare whether the captured vessel was a lawful prize. if it was a lawful prize, the captors could sell the ship and its cargo and keep the money for themselves. an act in addition to the act for the punishment of certain crimes against the united states, june , , stat. - . u.s. ( dall.) ( ). the discussion of privateering in this paragraph is drawn primarily from william r. casto, foreign affairs crises and the constitution’s case or controversy limitation: notes from the founding era, am. j. legal hist. , - ( ). with respect to letters of marque, see ingrid brunk wuerth, international law and constitutional interpretation: the commander in chief clause reconsidered, mich. l. rev. , ( ). saint louis university law journal thus, the privateering system utilized the profit motive as a force multiplier to enhance the naval power of a nation at war. as of march , france was at war not only with england, but also with austria, prussia, spain, and the netherlands. france’s naval power was no match for the combined naval forces of its enemies. accordingly, france decided to make extensive use of privateers to supplement its naval forces. the chief mission of the privateers, from france’s perspective, was to disrupt the trade of its enemies. to perform this mission effectively, the privateers had to operate near the ports that were used to conduct the enemies’ trade. hence, france deployed some privateers in the european theater and others in the western hemisphere. deployment of privateers in the western hemisphere posed tactical problems for france. it made no sense for privateers operating in the western hemisphere to carry their prizes back to france to be condemned by prize courts in france. the trans-atlantic journey was time consuming and hazardous: too many prizes would be lost en route. france established some prize courts in french colonies in the caribbean, but the british effectively blockaded key french ports in the caribbean for at least some of the period under study, making it difficult for privateers to take their prizes to caribbean ports. accordingly, france instructed many of its privateers in the western hemisphere to take their prizes to u.s. ports. france’s attempt to utilize u.s. ports as a base of operations for french privateers posed a significant policy dilemma for the united states. on the one hand, the united states was eager to honor its treaty commitments to france. on the other hand, president washington declared in april that the united states would remain neutral in the war between france and its various enemies. the dilemma arose because the treaty with france seemingly obligated the u.s. to adopt a pro-french tilt in the war. specifically, article granted french privateers broad rights of access to u.s. ports, whereas article imposed severe restrictions on access to u.s. ports by “foreign privateers . . . who have commissions from any other prince or state in enmity with” france. see proclamation of neutrality, april , , i aspfr, at (noting that “a state of war exists between austria, prussia, sardinia, great britain, and the united netherlands, of the one part, and france on the other . . .”). see also edict of his majesty, king of spain, march , , i aspfr at - (noting that france declared war against spain on march ). see, e.g., united states v. peters, u.s. ( dall.) ( ) (french naval vessel captured merchant ship and took it to french port in caribbean, where it was condemned as prize by a french prize court). see melvin h. jackson, privateers in charleston, - , at - ( ). see id. at - . see proclamation of neutrality, april , , i aspfr, at . see treaty of amity and commerce, u.s.-fr., art. , feb. , , reprinted in treaties and other international acts of the united states of america , - (hunter miller ed., gov’t printing office ) [hereinafter treaty with france]. see id., art , pg. - . judicial foreign policy: lessons from the s as thomas jefferson stated, “it is an essential character of neutrality, to furnish no aids (not stipulated by treaty) to one party, which we are not equally ready to furnish to the other.” thus, to implement its neutrality policy and honor its treaty commitments to france, the united states had to decide what the treaties with france required. if the u.s. adopted an expansive view of its treaty obligations to france, the british (and others) would object that the u.s. was violating its duties as a neutral state; this course potentially risked war with great britain. if the u.s. adopted a narrow view of the scope of its treaty obligations, france would object that the u.s. was breaching its treaty commitments; this course potentially risked war with france. hence, the united states attempted to steer a middle course between the scylla of war with england and the charybdis of war with france. federal courts played a critical role in attempting to chart this middle course, in part because key officers in the executive and judicial branches agreed that the judiciary should assume primary responsibility for making some of the crucial decisions. iii. u.s. neutrality policy: from february to june part three analyzes developments from february , when france declared war against great britain and holland, until june , when congress enacted legislation to address french privateering activities. there were two main sets of foreign policy issues related to the conduct of french privateers during this period. the first set of foreign policy issues related to the substantive rules governing the conduct of french privateers. the political branches generally took the lead in framing substantive rules, and the judicial branch played a secondary role. the second set of foreign policy issues related to jurisdictional questions: when french privateers captured privately owned vessels, and the owners sought restitution of the captured property on the grounds that their property had been seized illegally, the question arose as to which branch of government should resolve these disputes. initially, there was some uncertainty as to whether the executive or the judicial branch should handle these questions. france urged resolution of these disputes through diplomatic means because france viewed the privateering cases as contests between nations about sovereign rights. however, a consensus soon emerged among u.s. government officials that the judicial branch should decide these issues, because the privateering cases also involved private disputes about individual property rights. ultimately, cabinet officials and supreme court justices agreed that the judiciary had the primary constitutional responsibility for deciding individual disputes over ownership of property, even though the law of nations provided most of the governing legal rules and the disputes were intimately linked to the wartime strategy of sovereign powers. part three is divided into three sections. the first section addresses the historical context. the second section analyzes the substantive rules governing the conduct of french privateers. the third section analyzes the interplay between the legislative, letter from thomas jefferson, secretary of state, to mr. pinckney, minister plenipotentiary from the united states with great britain, sept. , , i aspfr, at . saint louis university law journal executive and judicial branches in framing the jurisdictional rules that ultimately gave the judiciary primary responsibility for resolving disputes arising from french privateering activities. a. historical context in january , french revolutionaries executed louis xvi. shortly thereafter, on february , in the midst of revolutionary fervor at home, france declared war on great britain and holland. at that point, france was already at war with austria and prussia. in march , france also declared war on spain. although france declared war against britain on february , news of the war did not reach the united states until late march or early april. president washington was in mount vernon at the time, but he traveled to philadelphia as quickly as possible to convene a meeting of his cabinet. the cabinet officers at the time included thomas jefferson as secretary of state, alexander hamilton as secretary of the treasury, henry knox as secretary of war, and edmund randolph as attorney general. the president circulated a list of questions to the cabinet officers on april , and the group convened the next day to formulate u.s. policy. on april , the president publicly issued a formal proclamation of neutrality, declaring the u.s. policy to “pursue a conduct friendly and impartial toward the belligerent powers.” on april , , edmond genet arrived in charleston, south carolina to assume his position as the new french ambassador to the united states. beginning immediately after his arrival, genet undertook a series of actions that posed substantial challenges for u.s. foreign policy. first, genet began commissioning u.s. citizens to act as privateers in the service of the french government. second, genet provided financial assistance to u.s. and french citizens who accepted commissions to serve as privateers for france. with genet’s financial aid, the privateers purchased ships and utilized u.s. ports to arm their ships for naval warfare. additionally, genet instructed french consuls in major u.s. ports to establish prize courts. consequently, french privateers commissioned by genet and outfitted in the united states began bringing their prizes into u.s. ports so that french consuls operating prize courts on u.s. territory could adjudicate the lawfulness of their prizes. in part due to the policies he pursued, and in part due to his confrontational style, genet quickly made many enemies in the u.s. government. hence, in august , the thomas, supra note , at . see edict of his majesty, king of spain, march , , i aspfr at - . see thomas, supra note , at - . see id., at - . i aspfr, at . ammon, supra note , at vii. see the papers of thomas jefferson, at (john catanzariti, ed. ). id. see casto, supra note , at . judicial foreign policy: lessons from the s u.s. decided to request the recall of ambassador genet. the french government granted that request in october , and genet’s replacement, joseph fauchet, arrived in the u.s. in february . in the next months after president washington issued his neutrality proclamation, there were three key milestones in the development of the u.s. response to french privateering activities. first, on august , , the treasury secretary (alexander hamilton) promulgated regulations for the guidance of u.s. customs collectors. second, on february , , the supreme court issued its decision in glass v. sloop betsey. third, on june , , congress enacted legislation that was designed to regulate the activities of french privateers in u.s. ports. the treasury regulations and the subsequent legislation defined the key substantive rules governing the conduct of french privateers. in contrast, the supreme court decision in sloop betsey addressed important jurisdictional questions, and resolved key constitutional separation of powers issues that had been percolating in the executive branch and in the lower federal courts for the previous year. b. substantive rules governing privateers this section discusses the main substantive issues related to french privateering: ) whether french privateers could sell their prizes in u.s. ports; ) whether france could recruit u.s. citizens to serve as privateers on behalf of france; and ) whether french privateers could utilize u.s. ports to outfit civilian vessels for naval warfare, or to augment the military capabilities of vessels that were already equipped for naval warfare. . sale of prizes: in traditional european wars, a privateer who captured a prize would bring it to a prize court in his home country to obtain a judgment confirming that it was a lawful prize. then, when he sold the prize and its cargo, he could invoke the judgment of the prize court to prove that he had a legally valid title to the property he was selling. france attempted to export this model to the western hemisphere by establishing french prize courts on u.s. territory. the key strategic goal was to provide financial incentives for prospective privateers to operate in the american theater by establishing a juridical system that would ensure their ability to sell captured property for financial gain. without the economic inducement of a solid return on investment, france would be unable to enlist sufficient numbers of privateers, and its military strategy would fail. accordingly, genet instructed french consuls in the united states to establish prize courts on u.s. territory. genet believed that france had a right to do so under see the papers of thomas jefferson, supra note , at - . see ammon, supra note , at - . instructions to the collectors of the customs, aug. , , reprinted in i aspfr, at - . u.s. (dall.) ( ). the precise date is recorded in the minutes of the supreme court of the united states, feb. , , reprinted in i dhsc, at . an act in addition to the act for the punishment of certain crimes against the united states, june , , stat. - . see thomas, supra note , at - . saint louis university law journal article of the consular treaty between the u.s. and france. however, the washington administration did not agree that the treaty granted france any such right. moreover, the executive branch viewed genet’s effort to establish french prize courts on u.s. territory as a flagrant violation of u.s. sovereignty and neutrality. consequently, jefferson wrote directly to the french consuls and vice consuls in the u.s. (bypassing genet), warning them that they would be subject to prosecution and punishment if they “within the united states . . . assume to try the validity of prizes, and to give sentence thereon, as judges of admiralty.” importantly, although the executive branch determined that any judgment issued by a french prize court operating on u.s. territory was “a mere nullity,” the government did not attempt to block the sale of prizes in u.s. ports by french privateers. the decision not to interfere with the sale of captured prizes and their cargo was significant because it preserved a financial incentive for french privateers to bring their captured prizes to u.s. ports. if a privateer sold his prize without first obtaining a valid judgment from a prize court, the ship itself would sell at a discounted price because the buyer had to assume the risk that the original owner might file a legal action to claim title to the vessel. however, privateers could sell captured cargo at full value because the buyers did not face a significant risk of subsequent legal action by the original owners. overall, the financial incentives were sufficient to induce french privateers to bring captured prizes to u.s. ports and sell them for financial gain. convention defining and establishing the functions and privileges of consuls and vice consuls, nov. , , art. , u.s.-france, reprinted in treaties and other international acts of the united states of america , (hunter miller ed., ). article authorized french consuls, for example, to adjudicate disputes between a french captain and his crew while they were docked at u.s. ports. see id. it was quite a stretch, though, for genet to suggest that article authorized france to establish prize courts on u.s. territory. see, e.g., letter from thomas jefferson to george hammond, may , , papers of thomas jefferson, supra note , at - . letter from thomas jefferson to french consuls, sept. , , i aspfr, at . letter from thomas jefferson to george hammond, may , , papers of thomas jefferson, supra note , at . see message from president to congress, dec. , , reprinted in i aspfr at (“i have not thought myself at liberty to forbid the sale of the prizes, permitted by our treaty of commerce with france to be brought into our ports.”) see also letter from thomas jefferson to gouverneur morris, aug. , , papers of thomas jefferson, supra note , at , - (explaining and defending u.s. position on sale of prizes in u.s. ports). assume, for example, that a french privateer captured a british merchant vessel and sold the british vessel to an american merchant who wanted to use the vessel to conduct trans-atlantic trade. if the french privateer obtained a valid judgment from a prize court before selling the captured ship to the american buyer, then the buyer would obtain a secure title protected by that judgment. but if the american buyer purchased a ship that had not been condemned by a prize court as a valid prize, and the buyer then sailed the ship to a french port, the original british owner could initiate a legal action in a french prize court to challenge the legality of the initial capture. if the british owner prevailed, the american buyer would lose possession of the vessel and would have little recourse against the french privateer who sold him the vessel. see jackson, supra note , at - (providing detailed information about the sale of british, spanish and dutch prizes captured by french privateers and brought to the ports of charleston, sc and savannah, ga between april and april ). judicial foreign policy: lessons from the s in sum, the washington administration “split the baby” by prohibiting the establishment of french prize courts on u.s. territory, but permitting the sale of french prizes. this solomonic solution was generally consistent with france’s strategic interests. as long as french privateers could sell captured prizes and cargo in u.s. ports, there would be strong economic inducements for privateering, and france would be able to recruit a sufficient number of privateers to achieve its military objectives. . recruiting us citizens: as noted above, the success of france’s naval warfare strategy hinged on its ability to recruit a sufficient number of individuals to serve as privateers on behalf of france. article of the treaty with france prohibited u.s. citizens from taking “any commission or letters of marque for arming any ship or ships to act as privateers against” france. from france’s perspective, though, it was entirely permissible for u.s. citizens to accept commissions from france to act as privateers against france’s enemies. hence, immediately after genet arrived in the united states he began recruiting u.s. citizens to aid france’s war effort by serving as captains and/or crew on french privateers. the u.s. told france that it viewed genet’s recruitment of u.s. citizens as a contravention of u.s. neutrality policy and urged france to halt these activities. the august treasury regulations instructed u.s. customs collectors “to observe, and to notify . . . the case of any citizen of the united states who shall be found in the service of either of the parties at war.” in accordance with the president’s neutrality proclamation, federal prosecutors brought criminal charges against u.s. citizens who enlisted to serve on french privateers. some critics expressed doubts about the president’s constitutional authority to impose criminal penalties for violations of rules promulgated by the executive branch. in june , congress removed lingering doubts about the constitutionality of federal criminal prosecutions by enacting legislation that authorized criminal punishment. the legislation expressly authorized criminal penalties for u.s. citizens who “accept[ed] and exercise[d] a commission to serve a foreign prince or state in war,” and for those who treaty with france, supra note , art. , pg. . see casto, supra note , at - . see letter from thomas jefferson to jean baptiste ternant, may , , in papers of thomas jefferson, supra note , at - . instructions to the collectors of the customs, aug. , , i aspfr, at - . the proclamation expressly directed federal prosecutors to institute prosecutions “against all persons, who shall, within the cognizance of the courts of the united states, violate the law of nations, with respect to the powers at war, or any of them.” proclamation of neutrality, i aspfr, at . as a neutral nation, the united states believed it had a duty under the law of nations to ensure that its citizens did not take up arms against either side in the war. the instruction for federal prosecutors to prosecute individuals who “violate the law of nations” was intended to fulfill this perceived duty. whether the law of nations actually prohibited u.s. citizens from taking up arms on behalf of france is debatable. see casto, supra note , at - . see, e.g., henfield’s case, f.cas. (d. penn. ). an act in addition to the act for the punishment of certain crimes against the united states, june , , § , stat. - . saint louis university law journal “enlisted or entered in the service of any foreign prince or state . . . as a marine or seaman on board of any vessel of war . . . or privateer.” . outfitting ships in u.s. ports: to implement its naval warfare strategy, france needed ships equipped for naval warfare. article of the treaty with france prohibited privateers commissioned by france’s enemies from outfitting their ships in u.s. ports. france interpreted this provision to mean that privateers commissioned by france were permitted to outfit their ships in u.s. ports. hence, genet provided funding to french privateers to help them purchase civilian ships and convert them into military vessels by equipping the ships with guns and other armaments. the u.s. objected to france’s use of u.s. ports for this purpose, arguing that it would be contrary to the united states’ duties as a neutral nation to allow france to outfit privateers in u.s. ports without also granting equivalent privileges to france’s enemies. accordingly, the august treasury regulations declared: “the original arming and equipping of vessels in the ports of the united states, by any of the belligerent parties, for military service . . . is deemed unlawful.” the regulations instructed u.s. customs collectors to keep “a vigilant eye upon whatever may be passing within the ports,” and to notify the relevant governor and u.s. attorney if they observed activities inconsistent with u.s. neutrality. finally, the june legislation included three provisions to address the problem of illegal outfitting in u.s. ports. first, the statute made it a crime for any person within u.s. territory to “fit out and arm . . . any ship or vessel with intent that such ship or vessel shall be employed in the service of any foreign prince or state to cruise or commit hostilities upon the subjects, citizens or property of another foreign prince or state with whom the united states are at peace.” the statute imposed similar penalties for anyone who augmented or increased “the force of any ship of war, cruiser or other armed vessel” in the service of a foreign state that was at war with a state “with whom the united states are at peace, by adding to the number or size of the guns of such vessel . . . .” additionally, the statute authorized the president to detain any vessel that had been illegally outfitted, or whose force had been illegally augmented, in a u.s. port. in sum, during the period from february to june , the executive branch played the lead role in framing the substantive rules governing the conduct of french id., § , at . treaty with france, supra note , art. , pg. - . see thomas, supra note , at - . see letter from secretary of state to u.s. ambassador to great britain, sept. , , reprinted in i aspfr, at (“in the case where we found ourselves obliged, by treaty, to withhold from the enemies of france the right of arming in our ports, we thought ourselves in justice bound to withhold the same right from france also, and we did it.”) instructions to the collectors of the customs, aug. , , i aspfr, at - . see id. an act in addition to the act for the punishment of certain crimes against the united states, june , , § , stat. , . id., § , at . id., § , at . judicial foreign policy: lessons from the s privateers in the united states. congress later ratified key executive branch decisions by enacting legislation in june that gave the force of law to policies adopted by the executive branch the previous year. the supreme court did not make a significant contribution to the substantive rules governing the conduct of french privateers. however, in february , the supreme court reaffirmed the executive’s earlier decision concerning french prize courts by declaring “that the admiralty jurisdiction, which has been exercised in the united states by the consuls of france . . . is not of right.” c. jurisdictional issues involving french privateers there were several cases in which owners of vessels captured by french privateers alleged that the capture was unlawful because the privateer seized the alleged prize within u.s. territorial waters, or because the alleged prize was actually a neutral ship, not an enemy ship. france conceded that the law of nations prohibited captures of neutral vessels and captures in u.s. territorial waters. cases in which ship owners alleged violations of these agreed rules raised factual disputes about the ownership of ostensibly neutral vessels and the location where captures occurred. more fundamentally, though, these cases raised jurisdictional questions about who should decide the factual disputes. the ship owners who complained about unlawful captures of their vessels pursued two different avenues of relief. some took their claims to federal admiralty courts. others sought relief from the federal executive branch. from france’s perspective, the disputes between ship owners and french privateers were properly viewed as disputes between sovereign nations about the conduct of naval warfare. hence, france urged resolution through diplomatic channels. initially, the lower federal courts accepted france’s arguments and dismissed several cases for lack of jurisdiction. however, the supreme court ruled in glass v. sloop betsey that the federal courts had jurisdiction to adjudicate claims by ship owners who alleged that their vessels had been seized unlawfully by french privateers. the court’s decision reflected a very different conception of the privateering cases: the court viewed these cases as disputes between private parties about individual property rights. viewed from that perspective, it made sense for the judicial branch to resolve these disputes. after the court’s decision in sloop betsey, the executive branch consistently refused to intervene in judicial proceedings, maintaining that the judiciary should handle all disputes about seizures of particular vessels by particular french privateers. although france protested vehemently against the exercise of jurisdiction by u.s. courts, the executive branch rebuffed french protests and told french diplomats to direct their arguments to the judicial branch. glass v. sloop betsey, u.s. ( dall.) , ( ). by holding that french consuls lacked jurisdiction to operate prize courts on u.s. territory, the supreme court effectively denied res judicata effect to the prior judgments of french prize courts, thereby creating an opportunity for the owners of captured vessels to challenge the validity of (french) judgments condemning the vessels as prizes. see william r. casto, the supreme court in the early republic, at ( ). u.s. ( dall.) ( ). saint louis university law journal executive officers trusted the courts to resolve disputed cases in accordance with settled rules of international law, and assumed that the judicial application of international legal rules would help promote the u.s. goal of avoiding war with britain and france. this section examines the evolution of jurisdictional rules related to the french privateering cases in the period from april to june . the first sub-section discusses the role of the executive branch. the next sub-section examines decisions by lower federal courts before the supreme court decision in sloop betsey. the third sub- section reviews the supreme court decision in sloop betsey. the final sub-section briefly considers the role of congress. . the role of the executive branch: in late april, , the french naval vessel l’embuscade captured a british vessel, the grange, within the bay of delaware. under accepted principles of the law of nations, there was no question “that to attack an enemy in a neutral territory is absolutely unlawful.” hence, the capture of the grange raised two questions. as a factual matter, where did the capture occur? and as a legal matter, what were the boundaries of u.s. territorial waters? after investigating and analyzing these issues, attorney general randolph concluded that the capture occurred in u.s. territorial waters (i.e., neutral territory), and that “the duty arising from the illegal act, is restitution.” in deference to that judgment, genet agreed that the grange would be returned to its british owners. the grange was one of the few cases, though, where the executive branch performed the adjudicative function of deciding that the capture of a specific vessel was unlawful. after the u.s. resolved the case of the grange, it soon became apparent that there would be many such cases to resolve, and the executive grew uncomfortable with repeated demands from the french and british ambassadors, asking the executive to perform what it believed was an adjudicative function. within a period of a few days in june , secretary of state jefferson received formal protests from the british concerning the catharine and from the french concerning the william. these protests forced the cabinet to reconsider the respective roles of the executive and judicial branches in handling these disputes. first, on june , , george hammond, britain’s ambassador to the united states,” wrote to thomas jefferson to protest the seizure by french captors of the british brigantine catharine within the territorial waters of the united states. hammond requested “immediate restitution of this vessel” on the grounds that the seizure was “an aggression on the territory and jurisdiction of the united states.” the cabinet met the next day to formulate a u.s. response. they reached a unanimous agreement that the see opinion of edmund randolph (attorney general), may , , reprinted in papers of thomas jefferson, supra note , at - . id. at . id. at . see letter from citizen genet, minister plenipotentiary of the republic of france, to mr. jefferson, secretary of state of the united states, may , , i aspfr, at - . papers of thomas jefferson, supra note , at - . id. judicial foreign policy: lessons from the s matter should be resolved by judicial means. jefferson wrote to hammond to convey the u.s. views. jefferson asked hammond “to have the parties interested apprised without delay that they are to take measures as in ordinary civil cases for the support of their rights judicially.” the letter continued: should the decision be in favor of the jurisdiction of the court, it will follow that all future similar cases will devolve at once on the individuals interested to be taken care of by themselves, as in other questions of private property provided for by the laws. . . . this train of things is much more desireable for the executive, whose functions are not analogous to the questions of law and fact produced by these cases. two points are noteworthy. first, the executive branch preferred for the courts to resolve these cases because the cases involved private property rights and the application of law to fact. second, it was the judiciary’s responsibility to decide whether these were matters within the jurisdiction of federal admiralty courts. jefferson sent this letter to hammond on june . then, on june , ambassador genet wrote to jefferson to protest the seizure of the william by u.s. judicial officers: “you will see by the papers annexed hereto, that, in contempt of the treaties which unite the french and americans; that in contempt of the law of nations; civil and judiciary officers of the united states have permitted themselves” to seize prizes captured by french privateers. genet added: “i hope to obtain immediately . . . restitution, with damages and interest, of the french prizes arrested and seized at philadelphia, by an incompetent judge . . . .” genet also made clear that france believed these types of disputes should be resolved through diplomatic means, not through private adjudication. he wrote: “it is through the intervention of the public ministers, that affairs of the nature cabinet opinions on the republican and the catharine, june , , reprinted in papers of thomas jefferson, supra note , at - . letter from thomas jefferson to george hammond, june , , papers of thomas jefferson, supra note , at - . id. see letter from thomas jefferson to gouverneur morris, aug. , , papers of thomas jefferson, supra note , at , . letter from citizen genet, minister of the republic of france, to mr. jefferson, secretary of state, june , , i aspfr, at . id. the events preceding genet’s letter to jefferson merit brief comment. in the spring of , the french privateer citizen genet captured a british ship, the william, and brought it to philadelphia. the british owners filed an in rem action in federal court, alleging that the capture was illegal because the ship was seized in u.s. territorial waters. findlay v. the william, f.cas. (d. penn. ). meanwhile, on june , , an agent for the french captors proceeded to sell the cargo at a wharf in philadelphia. statement of francis dupont, french consul in philadelphia, june , , reprinted in i aspfr, at . in an effort to establish the court’s jurisdiction over the ship and its cargo, “a deputy marshal of the court of admiralty” attempted to halt the sale of the cargo. id. the agent for the french captors believed “that the admiralty could not . . . meddle in this business, agreeably to the th article of the treaty of commerce between france and the united states.” id. the agent proceeded to sell the cargo, but it allegedly sold below market value because the deputy marshal “discouraged the bidders, and even suspended their bidding.” id. saint louis university law journal which produce my present complaints and reclamations, ought to be treated.” this was consistent with france’s litigating position in these cases, which emphasized that disputes related to french privateers were, first and foremost, disputes involving sovereign rights. jefferson drafted a letter in response to genet’s protest, which included the following passage: the functions of the executive are not competent to the decision of questions of property between individuals. these are ascribed to the judiciary alone . . . you will therefore be sensible, sir, that though the president is not the organ for doing what is just in the present case, it will be effectually done by those to whom the constitution has ascribed that duty; and be assured that the interests, the rights and the dignity of the french nation will receive within the bosom of the united states all the support which a friendly nation could desire, and a neutral one yield. jefferson did not send the letter in this form, but his draft identifies an important element of the consensus position that later emerged. even though the french privateering cases implicated “the interests, the rights and the dignity of the french nation,” the judiciary had the constitutional responsibility for vindicating france’s interests, because the cases also involved “questions of property between individuals.” on june , one week after genet wrote to jefferson, judge richard peters, the federal district judge in philadelphia, ruled that the district court lacked jurisdiction in the case of the william. jefferson sent his reply to genet after the district court issued its ruling. in that letter, jefferson told genet: “the persons who reclaimed the ship william as taken within the limits of the protection of the united states, having thought proper to carry their claim first into the courts of admiralty, there was no power in this country which could take the vessel out of the custody of that court, till it should decide, itself, whether it had jurisdiction or not of the cause.” jefferson’s reply is noteworthy for two reasons. first, if an individual files an in rem action in an admiralty court, and the court seizes a vessel on that basis, the executive has no power to order the court to release the vessel, notwithstanding french protests that the seizure violates u.s. treaty obligations owed to france. second, questions about the jurisdiction of u.s. courts were matters to be decided by the judicial branch, without interference from the executive branch. letter from citizen genet, minister of the republic of france, to mr. jefferson, secretary of state, june , , i aspfr, at . see infra notes - and accompanying text. draft letter from thomas jefferson to edmond charles genet, june , , papers of thomas jefferson, supra note , at - . see papers of thomas jefferson, supra note , at . findlay v. the william, f.cas. (june , ). letter from jefferson to genet, june , , i aspfr, at . this, of course, assumes that congress has not exercised its legislative power to clarify the scope of federal court jurisdiction. judicial foreign policy: lessons from the s . early decisions by lower courts: before the supreme court’s decision in sloop betsey, the lower courts generally held that they lacked jurisdiction to entertain claims by ship owners who alleged that their vessels had been seized unlawfully by french privateers. in contrast, the supreme court held in sloop betsey that the lower courts did have jurisdiction to adjudicate such claims. however, the supreme court provided virtually no rationale for its decision. hence, to understand the supreme court decision in sloop betsey, it is helpful first to examine the prior lower court decisions. published documents contain fairly detailed information about four district court cases decided before the supreme court decision in sloop betsey. the federal district court in pennsylvania decided findlay v. the william and moxon v. the fanny, both of which are published in the “federal cases” collection. the district court in new york decided meade v. the catharine, which was published contemporaneously as a stand-alone volume. finally, the maryland district court’s opinion in sloop betsey is reproduced in the documentary history of the supreme court. this section analyzes these four district court opinions. all four cases originated when french privateers captured merchant vessels and brought them into u.s. ports. the william, the fanny, and the catharine were british vessels, and were thus enemy property. the libellants in those cases alleged, inter alia, that the captures were unlawful because the ships were seized in neutral territory, specifically, in u.s. territorial waters. the betsey was a swedish vessel. the libellants in that case alleged that the capture was unlawful because sweden was a neutral country. the substantive law governing these claims was undisputed: it was clearly illegal under the law of nations to capture a neutral vessel, or to capture an enemy vessel in neutral territory. the main dispute in all four cases revolved around the question whether u.s. admiralty courts had jurisdiction to entertain the claims. in all four cases, the district courts concluded that they lacked jurisdiction. the french captors raised four main objections to the exercise of jurisdiction by u.s. courts. first, they argued “[t]hat, by the laws of nations . . . a neutral nation has no right to be the judge, either of the lawfulness of the war between belligerent powers, or of their conduct towards each other in the prosecution of hostilities.” accordingly, under the law of nations, “the courts of the nation to which the captor belongs” have exclusive f.cas. (d. penn. ). f.cas. (d. penn. ). decree on the admiralty side of the district court of new york, in which the rights of sovereignty and neutrality concerning captures within neutral bounds; and the treaty of amity and commerce between france and the united states, and the jurisdiction of the neutral courts, as far as they are respectively connected with that subject are considered ( ) (available in microfilm) (copy on file with author) [hereinafter, the catharine]. all page references for the catharine refer to the author’s copy. see vi dhsc, supra note , at - . the french captors alleged that the betsey was british property, and hence subject to seizure as enemy property. see plea to the jurisdiction, reprinted in vi dhsc, supra note , at - . the french refused to participate in judicial proceedings in the catharine. hence, the summary of arguments adduced by french captors is based on the other three cases. findlay v. the william, f.cas. , (d. penn. ). saint louis university law journal jurisdiction to decide whether a captured vessel is a lawful prize. the district courts in the william, the fanny, and the betsey all accepted this argument, and agreed that the law of nations precluded the exercise of jurisdiction by u.s. courts. second, the french captors invoked article of the treaty between the u.s. and france as a bar to jurisdiction. the treaty stipulates: it shall be lawful for the ships of war of either party & privateers freely to carry whithersoever they please the ships and goods taken from their enemies . . . nor shall such prizes be arrested or seized, when they come to and enter the ports of either party; nor shall the . . . officers of those places . . . make examination concerning the lawfulness of such prizes . . . .” the treaty appears to bar in rem jurisdiction over the prizes (“nor shall such prizes be arrested or seized”), as well as subject matter jurisdiction over the dispute (precluding officers from making “examination concerning the lawfulness of such prizes”). hence, the french captors relied heavily on article to support their arguments against the jurisdiction of u.s. courts. however, of the four district court decisions under review here, the fanny was the only case in which the court gave much weight to the treaty argument to support its conclusion that it lacked jurisdiction. in contrast, the district court in the catharine expressly rejected the french interpretation of the treaty, concluding that the word “prizes” in article refers only “to captures on the high seas, according to the rights of war,” and not to captures in neutral territory. in addition to arguments based on the law of nations and the treaty with france, the french captors also argued, in effect, that the ship owners were not the proper plaintiffs to bring these claims. in their view, the allegation that a seizure occurred in neutral territory, if true, “did not give rights to [private] parties at war, but merely affected the neutral nation.” therefore, “the parties libellants . . . had no power to sue and recover on the point of violation of territory.” the district courts in the fanny and the catharine agreed with this argument: “i can find no sufficient reason for reducing the violation of a territory to the level of a private injury against an individual id. see the william, f.cas. at (“affairs of prizes are only cognizable in the courts of the power making the capture”); the fanny, f.cas. at (“neutral courts . . . are not clothed with authority to vindicate or carry on national contests”); the betsey, vi dhsc, supra note , at (“questions relative to such captures, as prize, can only be determined by the admiralty-courts belonging to that power, whose subjects make the capture.”). treaty with france, supra note , art. . see the william, f.cas. at ; the fanny, f.cas. at (contending “that the treaty forbids the courts from interfering”); the betsey, vi dhsc, supra note , at (quoting the treaty, and arguing “that the said prize ought not to be arrested or seized or the lawfulness of the said prize enquired into by the united states or any of its courts of justice”). see the fanny, f.cas. at (“the treaty with france . . . insisted on by the captors . . . has its due weight with me; but only in cases evidently comprehended in it. and it appears to me that this case is one of them.”). see the catharine, supra note , at - . the fanny, f.cas. at . judicial foreign policy: lessons from the s who has incidentally suffered a wrong. the offence consists in the affront to the state, by an attack upon its sovereignty.” finally, the french captors argued that separation of powers considerations precluded the exercise of jurisdiction by u.s. courts. for example, in the william, the french captors contended that any infringement of the territorial sovereignty of a neutral party “must be canvassed by the diplomatic body, and finally settled by the sovereigns,” but it could not be the subject of a “judiciary enquiry.” in the william, the fanny, the catharine and the betsey, the district judges all agreed that “complaints of this kind . . . must be preferred to the executive power of the united states, and not to the admiralty-courts.” however, in glass v. sloop betsey, the supreme court rejected this conclusion. . the supreme court: in glass v. sloop betsey, the french appellees raised many of the same objections to the jurisdiction of u.s. courts that had been raised in the district courts in the william, the fanny, the catharine and the betsey. they also raised one other objection: they argued that there was no federal statute that conferred jurisdiction on the federal district court. section of the judiciary act granted federal district courts “exclusive original cognizance of all civil causes of admiralty and maritime jurisdiction.” the appellees argued that a prize case is not a “civil cause” within the meaning of the statute because prize cases arise in wartime, not peace time. the appellants replied that the term “civil” in the statute “is used . . . in contra distinction to criminal,” and that maritime captures during wartime are “civil causes” within the meaning of the statute because they are not criminal cases. the supreme court agreed with the appellants on this point, holding expressly that “every district court in the united states, possesses all the powers of a court of admiralty, whether considered as an instance, or as a prize court.” like the french captors in the courts below, the french appellees in sloop betsey contended: ) that the libellants’ allegations should be addressed through diplomatic channels, not by adjudication in u.s. courts; ) “[t]hat by the law of nations, the courts of the captor can alone determine the question of prize, or no prize”; and ) that “the the catharine, supra note at . see also the fanny, f.cas. at . the william, f.cas. at . see also the fanny, f.cas. at (acknowledging “that a capture in a neutral territory was an offense to the neutral . . . [b]ut this is a matter of state policy, not of judicial proceeding.”). the betsey, vi dhsc, supra note , at . see also the catharine, supra note , at - ; the fanny, f.cas. at - ; the william, f.cas. at (“when two powers have any difference between them, the affair must be treated by negotiation, and not through the instrumentality of their courts of justice”). see sloop betsey, u.s., at - . an act to establish the judicial courts of the united states, sec. , stat. , - (sept. , ). u.s., at - . see id. at - . id. at . id. at - . id., at . saint louis university law journal interference of the american courts will be a manifest violation of the seventeenth article of the treaty with france.” the supreme court did not rule expressly on any of these arguments. even so, the court did hold expressly “that the district court of maryland . . . has jurisdiction competent to enquire, and to decide, whether, in the present case, restitution ought to be made to the claimants.” in so holding, the court implicitly rejected all three of the aforementioned arguments against jurisdiction. thus, to understand the reasoning behind the court’s decision, it is helpful to consider the appellants’ reply to each of these three points. first, the appellants noted that article of the treaty, by its terms applies only to “the ships and goods taken from their enemies.” therefore, they argued, “being in the affirmative, as to enemies, it affords a strong implication of a negative as to neutrals.” in other words, assuming that article limits the jurisdiction of u.s. courts, the limitation does not apply to cases, like sloop betsey, where the libellants claim that the captured vessel is neutral property. in such cases, the district court can exercise jurisdiction at least for the limited purpose of determining whether the captured vessel belongs to a neutral country, or a nation at war with france. by holding that the district court had jurisdiction in sloop betsey, the supreme court implicitly accepted this argument. strictly speaking, though, the court’s decision in sloop betsey did not address the treaty-based objection to jurisdiction in cases like the william, the fanny, and the catharine, where the libellants alleged that that the privateers seized enemy property in u.s. territorial waters. second, the appellants effectively conceded that, under the law of nations, the prize courts of the captor’s nation have exclusive jurisdiction to condemn a captured vessel as a lawful prize. nevertheless, the libellants had argued in the district court that although “the power to condemn belongs properly to the nation of the captor . . . the case before the court is not of a libel to condemn, but of a libel for acquittal and restitution; and . . . the courts of a neutral nation may sustain such a libel.” in other words, under the law of nations, the courts of a neutral nation cannot exercise jurisdiction over a prize case filed by a privateer who seeks a judgment that the captured vessel is a lawful prize, but they can exercise jurisdiction over a marine trespass case filed by the owner of a id., at . the french appellees added: “to decide in opposition to a compact, so unequivocal and unambiguous, would endanger the national tranquility, by giving a just and honorable cause of war to the french republic.” id., at - . this statement proved to be prophetic, because french allegations that the u.s. repeatedly violated article ultimately became a key factor that led to the so-called “quasi-war” between the u.s. and france. see infra note and accompanying text. id. at . treaty with france, supra note , art. . u.s. at . in a letter to gouverneur morris, then the u.s. ambassador to france, jefferson contended that article applied only to captures of enemy vessels on the high seas. see letter to gouverneur morris, aug. , , papers of thomas jefferson, supra note , at , - . if jefferson was right, then enemy vessels in u.s. territorial waters, like neutral vessels, would be outside the scope of article . vi dhsc, supra note , at . judicial foreign policy: lessons from the s captured vessel who seeks restitution of the captured property. by holding that the district court had jurisdiction in sloop betsey, the supreme court implicitly accepted this argument. in contrast to the treaty argument discussed above, this argument applies equally to cases in which a libellant alleges that a privateer captured enemy property in neutral territory. finally, the appellants devoted most of their argument to showing that, under the u.s. constitution, the judicial branch, not the executive branch, is responsible for adjudicating cases like sloop betsey. the appellees argued that the alleged injury “is an attack upon the sovereignty of sweden,” and that therefore the individual libellants must seek redress from the sovereign. the appellants replied as follows: [t]he legislative, judicial, and executive powers . . . in the contemplation of our constitution, are each a branch of the sovereignty. . . . the constitution designates the portion of sovereignty to be exercised by the judicial department; and . . . renders it sovereign, as to determinations upon property, whenever the property is within its reach . . . to the judicial, and not to the executive, department, the citizen, or subject, naturally looks for determinations upon his property.” by holding that the district court had jurisdiction in sloop betsey, the supreme court endorsed the view that the wartime capture of private property implicated not only sovereign rights, but also private rights, and that disputes about private rights were properly directed to the judiciary, not the executive branch. the presentation of appellants’ argument on this point by the supreme court reporter, alexander dallas, is not as lucid as it might have been, but dallas’ report of the case does show that they made this argument. see dall. at . the court’s opinion states “that every district court in the united states, possesses all the powers of a court of admiralty, whether considered as an instance, or as a prize court.” id. at . in adjudicating a marine trespass case, like sloop betsey, the district court was sitting as an instance court to decide, as the appellants stated, the question of “[r]estitution or no restitution.” id. at . however, the implication of the supreme court’s statement is that, once convened as an instance court, the district court also has the jurisdiction “to try every incidental question,” id. at , including the question whether the seizure of the vessel was legal under the law of nations (which would ordinarily be tried in a prize court). professor casto contends that the supreme court’s resolution of this issue was inconsistent with “settled legal doctrine.” see casto, supra note , at . granted, there was an established rule under the law of nations that the question of “prize or no prize” was to be decided by the courts of the captor’s nation. however, as jefferson noted six months before the court decided sloop betsey, the law of nations also obligated the united states to extend its protection to foreign vessels in u.s. waters. see letter to gouverneur morris, aug. , , papers of thomas jefferson, supra note , at , - . in effect, the court decided in sloop betsey that the u.s. obligation under the law of nations to protect neutral shipping took precedence over the rule that would otherwise have barred the exercise of u.s. jurisdiction. this decision was consistent with the position adopted by the u.s. executive branch. in this author’s view, the court’s decision was a reasonable way to reconcile two conflicting rules of international law, although it would have been preferable if the court had explained its rationale. u.s. at - . id. at . in several of the french privateer cases, the privateers detained the captain and crew of the captured vessels as prisoners. the appellants in sloop betsey argued that the necessity to decide on the detention of prisoners was another reason why the case should be resolved by the judiciary, not the saint louis university law journal the court’s decision in sloop betsey could be interpreted narrowly to mean only that federal district courts have jurisdiction to adjudicate cases in which libellants allege the capture of a neutral vessel. however, as discussed in part iv below, the courts subsequently interpreted sloop betsey to mean that federal district courts had jurisdiction to entertain all claims of illegal seizures by french privateers. hence, sloop betsey was significant because it enabled france’s enemies to utilize the u.s. judicial system to file in rem actions alleging unlawful captures by french privateers. when ship owners filed in rem actions, the courts would seize the captured vessels and force the privateers to defend their property claims in court, thereby disrupting the privateers’ naval warfare activities. in sum, when the french attempted to gain a tactical military advantage by extending the battlefield to u.s. ports, their enemies responded by forcing france to fight the war in u.s. courts. by holding that the judicial branch, not the executive branch, was the proper forum for the resolution of these disputes, the supreme court facilitated the implementation of this strategy by france’s enemies. . the role of congress: the court held explicitly in sloop betsey that federal district courts had jurisdiction over claims involving captures of neutral vessels. the decision also implied that courts had jurisdiction over claims involving captures in u.s. territorial waters. to remove any possible ambiguity on that point, congress enacted legislation in june stipulating “[t]hat the district courts shall take cognizance of complaints by whomsoever instituted, in cases of captures made within the waters of the united states, or within a marine league of the coasts or shores thereof.” with this legislation, congress endorsed the view, already adopted by the supreme court and the executive branch, that the federal courts were a proper forum for resolving claims by individual ship owners that their ships had been captured unlawfully by french privateers. iv eighteenth century lawfare: from june to feb. after congress enacted the june legislation, there was a distinct change in the nature of the claims raised by ship owners who challenged the legality of captures made by french privateers. before june , the ship owners generally alleged that the privateers had violated the law of nations by capturing a neutral vessel, or by making a capture in u.s. territorial waters. after june , the ship owners generally alleged that the privateers had violated federal statutes by outfitting their vessels in u.s. ports, and/or by recruiting u.s. citizens as crew members. although the june ’ legislation prohibited outfitting of privateers in u.s. ports and recruitment of u.s. citizens, it did not authorize private lawsuits to enforce those rules, nor did it explicitly authorize federal courts to exercise jurisdiction over such claims. moreover, it is debatable whether the executive branch. see id. at (“and shall even american citizens be detained as prisoners in our own harbours, depending for their liberty upon the will of a secretary of state?”). it is unclear whether, and to what extent, the supreme court may have been swayed by this argument. an act in addition to the act for the punishment of certain crimes against the united states, june , , section , stat. , . judicial foreign policy: lessons from the s french privateers were violating the law of nations by recruiting u.s. citizens or by outfitting their ships in u.s. ports. . part iv examines the u.s. response to this second wave of french privateering cases in the period from june to february , when the supreme court decided the last french privateering case. during this period, the supreme court decided cases related to french privateering activities in the u.s. to appreciate fully the significance of those cases, it is necessary to view them simultaneously from three different angles. first, the privateering cases involved disputes between private parties over ownership of private property. second, the cases involved an ongoing diplomatic dispute between the u.s. and france over the proper interpretation and application of article of the treaty with france. third, the cases involved a tactical ploy by britain and other enemies of france to utilize the u.s. judicial system to harass french privateers and to undermine france’s naval warfare strategy (which relied heavily on the use of privateers). the distribution of decision-making responsibility during this period can be summarized briefly as follows. the federal judiciary was the primary decision-maker with respect to the major issues raised by the french privateering cases. the executive branch performed two main functions during this period: it listened to french grievances when french diplomats complained that u.s. courts were violating article ; and it explained u.s. judicial decisions to french diplomats in an attempt to justify those decisions. meanwhile, congress did not enact any significant legislation related to french privateering between june ’ and feb. ’ . this division of decision-making responsibility stemmed, in part, from a failure to view the cases from all three angles mentioned above. the u.s. government viewed the cases primarily as disputes about private property; that is why the judiciary took the lead role in resolving the cases. the executive branch was well aware of french grievances about violations of article , but the executive trusted the judiciary to address those grievances in the ordinary course of litigation. the analysis suggests that judicial decision-making in the privateering cases was a key factor that contributed to the deterioration of u.s. diplomatic relations with france. france became increasingly agitated by judicial decisions that, in its view, not only violated article , but also interfered with france’s naval strategy by disrupting the activities of french privateers. moreover, france was exasperated by the executive’s refusal to intervene in ongoing judicial proceedings. by the end of , france had initiated a series of measures – intended partly to retaliate against the united states for alleged violations of article – that ultimately led to the outbreak of the so-called “quasi-war” between the u.s. and france. see infra notes __ and accompanying text. jennings v. brig perseverance, u.s. ( dall.) (feb. ). see infra part iv.b (presenting an overview of the cases). it is clear from the diplomatic correspondence of the era that france’s allegation that the u.s. repeatedly violated article was one of the key french grievances that led to the quasi-war. see, e.g., letter from mr. adet, minister plenipotentiary of the french republic, to mr. pickering, secretary of state of the united states, nov. , , reprinted in i aspfr, at - ; letter from ch. de la croix to the saint louis university law journal the analysis in part iv is divided into four sections. the first section explains how france’s enemies utilized the u.s. judicial system to thwart france’s naval warfare strategy. the second section provides an overview of the privateering cases decided by the supreme court during this period. the third section provides case studies of two cases to show how judicial decisions in the privateering cases became a primary focus of u.s. diplomacy with france. the final section contends that judicial decision-making by u.s. courts was one of three key factors that ultimately persuaded french privateers to stop bringing their prizes to u.s. ports. a. litigation as a means of warfare in march , the council on foreign relations defined “lawfare” as “a strategy of using or misusing law as a substitute for traditional military means to achieve military objectives.” the report described lawfare as a “new phenomenon” and warned of associated dangers. in fact, lawfare is not a new phenomenon. in the period from to , great britain (and to a lesser extent france’s other enemies) successfully utilized a lawfare strategy to counter the military maneuvers of french privateers who were using american ports as a base of operations for naval warfare. between june and february , the supreme court decided cases in which british consuls filed in rem suits seeking restitution of british merchant vessels captured by french privateers. the british consuls lost of those cases. even so, benjamin moodie, the british consul in south carolina who filed of the cases, was quite satisfied with the results. since these were in rem actions, the courts typically retained custody of the captured property (or the funds from sale of the property) for - months while judicial proceedings were pending. thus, by filing in rem actions in u.s. district courts, and then filing appeals in the circuit courts and the supreme court, the libellants successfully detained the privateers’ property for extended periods of time, and made it difficult for the privateers to initiate additional attacks on enemy merchant vessels. hence, in april , when most of these cases were pending before the minister plenipotentiary of the united states of america, dec. , , reprinted in i aspfr, at - . however, the leading history of the quasi-war, in providing a summary of french grievances, curiously omits any reference to the alleged u.s. treaty violations. see alexander deconde, the quasi-war: the politics and diplomacy of the undeclared war with france, - ( ), pgs. - . council on foreign relations, lawfare: the latest in asymmetries (march , ), available at http://www.cfr.org/publication.html?id= . these thirteen cases include four published decisions and ten unpublished decisions. the published decisions are: moodie v. ship phoebe anne, u.s. ( ); moodie v. ship alfred, u.s. ( ); cotton v. wallace, u.s. ( ); and moodie v. ship betty cathcart, u.s. ( ). the unpublished decisions are: moodie v. brig favorite, wallace v. brig caesar, moodie v. ship mermaid, moodie v. ship phyn, moodie v. ship britannia, moodie v. brig eliza( ), moodie v. brig tivoly, moodie v. brig eliza( ), and moodie v. snow potowmack. for further discussion, see infra notes __ and accompanying text. the one exception was cotton v. wallace, u.s. ( ). see infra notes __ and accompanying text. in johnson v. eisentrager, u.s. , ( ), justice jackson wrote: “it would be difficult to devise more effective fettering of a field commander than to allow the very enemies he is ordered to reduce to submission to call him to account in his own civil courts and divert his efforts and attention from the military offensive abroad to the legal defensive at home.” this is effectively what the british consuls http://www.cfr.org/publication.html?id= judicial foreign policy: lessons from the s supreme court, moodie wrote that he was “fully convinced that the detention of such considerable sums during the proceedings in the different courts has had as much if not greater effect in saving british property than even the success of his majesty’s cruizers.” french diplomats understood the british lawfare strategy and its consequences for french privateering. they protested vehemently that the u.s. was undermining france’s war effort by allowing u.s. courts to seize the assets of french privateers. thus, for example, the french ambassador, pierre adet, wrote a lengthy diatribe to the u.s. secretary of state, timothy pickering, which included the following statement: when the powers at war with the republic had the privilege . . . of causing to be arrested the privateers and their prizes, of detaining them in the ports of the united states, of ruining them by considerable costs, by the excessive expenses which they occasioned them, they drew from that privilege an immense advantage to the detriment of france. doubtless it was of little import to them that sometimes the privateers obtained justice, in the last resort, if they detained the privateer for a length of time, and if they, by that means, sheltered from their pursuit the commerce of the enemy of france. it is noteworthy that ambassador adet wrote this letter in november . during the february and august sessions in , the supreme court decided cases in which ship owners and/or their agents filed in rem suits seeking restitution of enemy merchant vessels captured by french privateers. the french privateers won of the cases on the grounds that article of the treaty with france barred the exercise of jurisdiction by u.s. courts. thus, adet’s protest came on the heels of what could be viewed as a remarkably pro-french set of decisions by the supreme court. even so, france alleged that u.s. courts were violating article by exercising jurisdiction, even temporarily, before they ultimately dismissed the libels for lack of jurisdiction. thus, for example, in the same november letter, adet wrote “[t]hat the th article of the treaty of , has been violated; that, in contempt of this article, the american tribunals have been permitted to take cognizance of the validity of prizes accomplished by forcing french privateers to defend admiralty actions in u.s. courts. the commanders of french privateering vessels were forced to remain on land to handle legal proceedings. moreover, since the courts typically detained the proceeds from the sale of prizes while the suits were pending, the commanders may not have had adequate funds to pay their crews until the courts agreed to release the funds. letter from benjamin moodie to phineas bond, april , , reprinted in vii dhsc, at - . letter from mr. adet, minister plenipotentiary of the french republic, to mr. pickering, secretary of state of the united states, nov. , , reprinted in i aspfr, at , . this figure of cases includes all cases listed in note supra, plus arcambal v. wiseman, u.s. ( ), geyer v. michel, u.s. ( ), and don diego pintado v. ship san joseph (unpublished decision). the one exception was cotton v. wallace, u.s. ( ). for a legal analysis of article , as applied to these cases, see infra notes - and accompanying text. saint louis university law journal made by french ships of war and privateers . . .” in sum, from france’s perspective, u.s. courts were violating treaty obligations owed to france and thwarting france’s military strategy by disrupting the naval warfare activities of french privateers. when french diplomats lodged their complaints with senior u.s. executive officials, seeking diplomatic solutions for foreign affairs controversies, u.s. executive officials told the french diplomats that the federal judiciary was the branch of government responsible for deciding these issues. for example, in june , french ambassador fauchet (adet’s predecessor) wrote to secretary of state randolph (pickering’s predecessor), presenting a litany of complaints related to french privateers. in particular, fauchet complained that u.s. courts detained valid french prizes based on the mere allegation that that they had been captured illegally. to address this problem, he suggested that, before judicial proceedings could commence, there should be prior “intervention of the executive upon the simple question—is there ground for prosecution or not?” secretary randolph replied as follows: the courts of justice exercise the sovereignty of this country in judiciary matters, are supreme in these, and liable neither to control nor opposition from any other branch of government. . . . the previous inquiry by the executive, which you have suggested, could only contribute to delay. for, if the president were even to decide that a prize ought not to be prosecuted in our courts, the decision would be treated as an intrusion by those courts, and the judicial proceedings would go on notwithstanding. so speak the constitution and the law. this exchange between fauchet and randolph was characteristic of the diplomatic dialogue between france and the united states in the period under study. from france’s perspective, issues related to french privateering were foreign policy issues to be resolved diplomatically between the executives of the two countries. the u.s. recognized the foreign affairs significance of the privateering cases, but it also recognized that the cases could legitimately be seen as disputes between private parties involving competing claims to ownership of property. viewed in this light, cabinet officers thought it proper to defer to the judiciary, and to allow u.s. courts to resolve the disputes without intervention by the executive branch. letter from mr. adet, minister plenipotentiary of the french republic, to mr. pickering, secretary of state of the united states, nov. , , reprinted in i aspfr, at , . see letter from joseph fauchet, minister plenipotentiary of the french republic, to mr. randolph, secretary of state of the united states, june , , reprinted in i aspfr, at - . id. at . letter from mr. randolph, secretary of state, to mr. fauchet, minister plenipotentiary of the french republic, june , , reprinted in i aspfr, at , . before this letter could be delivered to mr. fauchet, mr. adet replaced him as the french ambassador. hence, the letter was addressed to fauchet, but delivered to adet. see id. see, e.g., letter from u.s. attorney general william bradford, jr. to secretary of state edmund randolph, may , , reprinted in vii dhsc, supra note , at (“being therefore of the opinion that the proceedings in these causes have been regular, i presume they must wait the usual course of judicial decision; & that any previous interference on the part of the executive would be improper & unavailing.”). judicial foreign policy: lessons from the s b. an overview of supreme court cases between june and february , the supreme court decided a total of cases that are relevant to this study. the total of cases includes cases in which ship owners and/or their agents filed in rem suits seeking restitution of enemy merchant vessels captured by french privateers. the five cases that do not fit this description are: del col v. arnold, hills v. ross, united states v. la vengeance, macdonough v. dannery, and united states v. peters. peters is significant because it established an important limitation on the jurisdiction of u.s. courts: they could not exercise jurisdiction over private suits alleging unlawful captures unless the french captors brought their prizes into u.s. ports. the other four cases are noted for the sake of completeness, but they do not add anything significant to our story. the cases in which ship owners and/or their agents filed in rem suits seeking restitution of enemy merchant vessels captured by french privateers include eight published decisions and ten unpublished decisions. the eight published decisions are: jennings v. brig perseverance, moodie v. ship phoebe anne, moodie v. ship see infra notes __. the term “enemy merchant vessels” refers to vessels belonging to france’s enemies: britain, spain, and holland. u.s. ( dall.) (aug. ). del col involved the capture by a french privateer of an american ship, not an enemy ship. additionally, the suit was filed as an in personam action, not an in rem action, because the prize crew sank the captured vessel. see vii dhsc, supra note , at - . u.s. ( dall.) (aug. ); u.s. ( dall.) (feb. ). hills was an in personam action, not an in rem action, because the french captors sold the prize before the ship owners filed suit for damages. see vii dhsc, supra note , at - . u.s. ( dall.) (aug. ). la vengeance was an enforcement action against a french privateer filed by a u.s. attorney. the u.s. attorney sought forfeiture of the vessel, based on allegations that the privateer had been illegally outfitted in u.s. territorial waters, and had been used to export arms and ammunition in violation of a federal statute. see vii dhsc, supra note , at - . u.s. ( dall.) (feb. ). macdonogh involved a british merchant ship captured by a french naval vessel, not a french privateer. the litigation involved a three-way contest between the french captors, the original british owners, and the crew of an american vessel that saved the british ship, the mary ford, after she had been abandoned by her french captors. see vii dhsc, supra note , at - . u.s. ( dall.) (aug. ). in peters, the commander of a french warship filed a writ of prohibition in the supreme court to prevent richard peters, the district judge for the district of pennsylvania, from exercising jurisdiction over a libel filed in that court by james yard. see id. at - . yard was a u.s. citizen. in his libel in the district court, yard alleged that he was the owner of the schooner william lindsey, an american vessel, which had been captured illegally by a french warship, the cassius. id. at - . if the cassius had brought the william lindsey to philadelphia, the pennsylvania district court could have exercised jurisdiction under the principle announced in sloop betsey. however, the cassius took the william lindsey to port de paix, a french port in the caribbean. when the cassius subsequently returned to philadelphia without the william lindsey, yard filed a libel and moved to attach the cassius in an effort to secure compensation for the damages he sustained as a result of the allegedly illegal capture of his schooner. id. samuel davis, the commander of the cassius, responded by filing a writ of prohibition in the supreme court. the supreme court granted the writ, holding that the law of nations and the treaty with france precluded the district court from exercising jurisdiction in a case where a french warship had captured an american vessel and taken the captured vessel to a french port. id. at - . for more details on the case, see vi dhsc, supra note , at - . u.s. ( dall.) (feb. ). this was an in rem action against a british vessel, the perseverance, captured by the french privateer the sans pareil in july . the libellant, thomas saint louis university law journal alfred, arcambel v. wiseman, cotton v. wallace, geyer v. michel, moodie v. ship betty cathcart, and talbot v. jansen. the french privateers lost only two of these eight cases: talbot v. jansen and cotton v. wallace. jennings, was the british ship owner. he filed the libel in the u.s. district court in rhode island in september . the district court ruled in favor of the french captors in august . that decree was affirmed by the circuit court in june , and by the supreme court in february . for a detailed account of jennings, see vii dhsc, supra note , at - . see also infra notes __ and accompanying text. u.s. ( dall.) (aug. ). this was an in rem action against a british vessel, the phoebe anne, captured by the french privateer la mere michel in april . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action in the u.s. district court in south carolina in may on behalf of the british ship owners. the district court ruled in favor of the french captors in june . that decree was affirmed by the circuit court in november , and by the supreme court in august . information about phoebe anne is derived from vii dhsc, supra note , at - ; jackson, supra note , at - ; and from the author’s research in the supreme court archives. u.s. ( dall.) (aug. ). this was an in rem action against a british vessel, the alfred, captured by the french privateer le brutus in march . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action in the u.s. district court in south carolina in april on behalf of the british ship owners. the district court ruled in favor of the french captors in may . that decree was affirmed by the circuit court in october , and by the supreme court in august . information about the alfred is derived from jackson, supra note , at - ; and from the author’s research in the supreme court archives. u.s. ( dall.) (aug. ). arcambel v. wiseman was an in rem action against a spanish vessel, nuestra senora del carmen, captured by the french privateer le brutus in the summer of . the libellant, joseph wiseman, was the spanish vice-consul in rhode island. he filed the action, initially captioned wiseman v. nuestra senora del carmen, in the u.s. district court in rhode island in august on behalf of the spanish ship owners. two claimants contested the libel. jean gariscan, commander of le brutus, claimed ownership by capture. louis arcambal, the french vice-consul, sought recovery for france. the district court ruled against the spanish owners in may . since the vessel and cargo had been sold at auction, the court ordered the proceeds from the sale (held in the court’s custody) to be divided between gariscan and arcambal. wiseman appealed the dismissal of his libel, and arcambal appealed the order concerning distribution of funds to gariscan. the circuit court decided both appeals in june , and the supreme court reached its own decision in august . both courts affirmed the district court order dismissing the spanish libel, but they reached inconsistent rulings regarding the distribution of funds between gariscan and arcambal. for a detailed account of the case, see vii dhsc, supra note , at - . u.s. ( dall.) (aug. ). cotton v. wallace was an in rem action against a british vessel, the brig everton, captured by the french privateer the egalite in december . the libellant, john wallace, was the british consul in georgia. he filed the action, initially captioned wallace v. brig everton, in the u.s. district court in georgia in january on behalf of the british ship owners. the district court ruled in favor of the british owners in march on the grounds that the egalite had been illegally outfitted in the united states, in violation of u.s. neutrality. john cotton, one of the officers on the egalite, appealed that decision to the circuit court. the circuit court affirmed the district court decree in may , and the supreme court affirmed in march . however, the court postponed a decision on damages until the august term. for a detailed account of the case, see vii dhsc, supra note , at - . u.s. ( dall.) (feb. ). this was an in rem action against a dutch vessel, den onzekeren, captured by the french privateer le citoyen de marseille in november . the libellant, john geyer, was acting as an agent for the dutch ship owners. he filed the action, initially captioned geyer v. den onzekeren, in the u.s. district court in south carolina in february . the district court ruled in favor of the dutch owners in april on the grounds that the french privateer had illegally augmented its force in a u.s. port in violation of u.s. neutrality. after hearing additional evidence, the circuit court reversed that decree in november , ruling in favor of the french captors. the supreme judicial foreign policy: lessons from the s the ten unpublished decisions are: moodie v. brig favorite, wallace v. brig caesar, moodie v. ship mermaid, moodie v. ship phyn, moodie v. ship court affirmed the circuit court decree in march . for a detailed account of the case, see vii dhsc, supra note , at - . see also moodie v. the betty cathcart, f.cas. (d.s.c. ). u.s. ( dall.) (feb. ). this was an in rem action against a british vessel, the betty cathcart, captured by the french privateer le citoyen de marseille in november . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action on behalf of the british ship owners in the u.s. district court in south carolina in january . the district court ruled in favor of the british owners in april on the grounds that the french privateer had illegally augmented its force in a u.s. port in violation of u.s. neutrality. see moodie v. the betty cathcart, f.cas. (d.s.c. ). on appeal to the circuit court, the case was consolidated with geyer v. michel because both cases involved the same french privateer. see previous footnote. after hearing additional evidence, the circuit court reversed the district court decree, ruling in favor of the french captors. the supreme court affirmed the circuit court decree in march . for a detailed account of the case, see vii dhsc, supra note , at - . u.s. ( dall.) (aug. ). this was an in rem action against a dutch vessel, the vrow christina magdalena, captured in may . two privateers flying french flags were jointly responsible for the capture: the l’ami de la liberte, commanded by captain edward ballard, and the l’ami de la point-a-petre, commanded by captain william talbot. see jansen v. the vrow christina magdalena, f.cas. (d.s.c. ). when the captors brought the magdalena into charleston, joost jansen, the dutch master of the magdalena, filed a libel on behalf of the dutch ship owners seeking restitution of the captured vessel and its cargo. jansen alleged that the two ships claiming to be french privateers were owned by u.s. citizens, and that ballard and talbot were both u.s. citizens. see id. at - . talbot invoked the law of nations and article of the treaty with france as a bar to the jurisdiction of u.s. courts. the district court ruled in favor of the dutch owners in august . the circuit court affirmed that decree in november , and the supreme court affirmed in august . four supreme court justices wrote separate opinions in talbot: justice iredell’s opinion provides the clearest statement of the court’s rationale for rejecting talbot’s objection to the jurisdiction of u.s. courts. in his view, although article precludes u.s. courts from making “examination concerning the lawfulness of such prizes,” the courts must still examine the facts to ascertain whether a case fits within the scope of the exemption granted by the treaty. moreover, the treaty term “privateers” refers only to lawfully commissioned privateers. therefore, the district courts must first decide whether a privateer is lawfully commissioned before concluding that article precludes them from exercising jurisdiction. for a detailed account of the case, see vi dhsc, supra note , at - . see supreme court minutes, feb. , , reprinted in i dhsc, supra note , at . this was an in rem action against a british vessel, the favorite, captured by the french privateer la parisienne in march . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action in the u.s. district court in south carolina in march on behalf of the british ship owners. the district court ruled in favor of the french captors in april . that decree was affirmed by the circuit court in november , and by the supreme court in february . information about the favorite is derived from bee’s admiralty reports, supra note , at ; jackson, supra note , at - ; and from the author’s research in the supreme court archives. see supreme court minutes, feb. , , reprinted in i dhsc, supra note , at . this was an in rem action against a british vessel, the caesar, captured by the french privateer la parisienne in december . the libellant, john wallace, was the british consul in georgia. he filed the action in the u.s. district court in georgia in january on behalf of the british ship owners. the district court ruled in favor of the french captors in february . that decree was affirmed by the circuit court in may , and by the supreme court in february . information about the caesar is derived from vii dhsc, supra note , at - . see supreme court minutes, march , , reprinted in i dhsc, supra note , at - . this was an in rem action against a british vessel, the mermaid, captured by the french privateer general laveaux in january . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action in the u.s. district court in south carolina in february on behalf of the british ship saint louis university law journal britannia, moodie v. brig eliza( ), moodie v. brig tivoly, moodie v. brig eliza( ), moodie v. snow potowmack, and don diego pintado v. ship san joseph. in all ten cases, the french privateers scored consistent victories in the district court, the circuit court and the supreme court. owners. the district court ruled in favor of the french captors in april . that decree was affirmed by the circuit court in october , and by the supreme court in march . information about the mermaid is derived from vii dhsc, supra note , at - ; jackson, supra note , at - ; and from the author’s research in the supreme court archives. see also british consul v. the mermaid, f.cas. (d.s.c. ). see supreme court minutes, march , , reprinted in i dhsc, supra note , at . this was an in rem action against a british vessel, the phyn, captured by the french privateer general laveaux in january . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action in the u.s. district court in south carolina in february on behalf of the british ship owners. the district court ruled in favor of the french captors in april . that decree was affirmed by the circuit court in october , and by the supreme court in march . information about the phyn is derived from jackson, supra note , at - ; and from the author’s research in the supreme court archives. see supreme court minutes, aug. , , reprinted in i dhsc, supra note , at . this was an in rem action against a british vessel, the britannia, captured by the french privateer le vengeur in june . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action in the u.s. district court in south carolina in july on behalf of the british ship owners. the district court ruled in favor of the french captors in september . that decree was affirmed by the circuit court in november , and by the supreme court in august . information about the britannia is derived from the author’s research in the supreme court archives. see supreme court minutes, aug. , , reprinted in i dhsc, supra note , at . this was an in rem action against a british vessel, the eliza, captured by the french privateers general laveaux and la mere michel in january . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action in the u.s. district court in south carolina in february on behalf of the british ship owners. the district court ruled in favor of the french captors in april . that decree was affirmed by the circuit court in november , and by the supreme court in august . information about the eliza is derived from the author’s research in the supreme court archives. see supreme court minutes, aug. , , reprinted in i dhsc, supra note , at . this was an in rem action against a british vessel, the tivoly, captured by the french privateers general laveaux and la mere michel in january . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action in the u.s. district court in south carolina in april on behalf of the british ship owners. the district court ruled in favor of the french captors in april . that decree was affirmed by the circuit court in october , and by the supreme court in august . information about the tivoly is derived from the author’s research in the supreme court archives. see supreme court minutes, aug. , , reprinted in i dhsc, supra note , at . this was an in rem action against a british vessel, the eliza, captured by the french privateer le vengeur in september . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action in the u.s. district court in south carolina in september or october on behalf of the british ship owners. the district court ruled in favor of the french captors in october . that decree was affirmed by the circuit court in november , and by the supreme court in august . information about the eliza is derived from the author’s research in the supreme court archives. see supreme court minutes, aug. , , reprinted in i dhsc, supra note , at . this was an in rem action against a british vessel, the potowmack, captured by the french privateer le vengeur in june . the libellant, benjamin moodie, was the british consul in south carolina. he filed the action in the u.s. district court in south carolina in july on behalf of the british ship owners. the district court ruled in favor of the french captors in september . that decree was affirmed by the circuit court in november , and by the supreme court in august . information about the potowmack is derived from the author’s research in the supreme court archives. see supreme court minutes, aug. , , reprinted in i dhsc, supra note , at . this was an in rem action against a spanish vessel, the san joseph, captured by the french privateer la vengeance judicial foreign policy: lessons from the s overall, the french privateers prevailed in of the cases where ship owners and/or their agents filed in rem suits seeking restitution of enemy merchant vessels captured by french privateers. in of those cases, the courts at all three levels – district courts, circuit courts and supreme court – ruled in favor of the french privateers. this point is significant because it lends credence to the french allegation that these were frivolous lawsuits filed for the purpose of harassing the privateers and thwarting the accomplishment of their military objectives. british consuls were the named plaintiffs in of the cases, and a spanish vice-consul was the named plaintiff in one other case. as a formal matter, the consuls were merely representing the private interests of merchant ship owners. however, as a practical matter, the active participation of the british consuls also lends credence to the french allegation that the british government was pursuing a conscious “lawfare” strategy to disrupt the military activities of french privateers. it is also noteworthy that of the cases involved british merchant vessels, and the french privateers won of those cases. assuming that the british strategy was to deny the privateers any financial gain from their lawful prizes while the litigation was pending, that strategy was quite effective. the courts retained control of the captured property, or the money obtained from the sale of that property, until there was a final disposition of the cases by the supreme court. in descending order, the time lag between the initial libel and final disposition by the supreme court in the british cases where the privateers prevailed was as follows: perseverance ( months), eliza( ) ( months), tivoly ( months), alfred ( months), phoebe anne ( months), betty cathcart ( months), britannia ( months), potowmack ( months), phyn ( months), mermaid ( months), caesar ( months), eliza( ) ( months), and favorite ( months). in may . the libellant, don diego pintado, was the ship owner. he filed the action in the u.s. district court in new york in july . the district court ruled in favor of the french captors in december . that decree was affirmed by the circuit court in april , and by the supreme court in august . for a detailed account of the case, see vii dhsc, supra note , at - . see also united states v. la vengeance, u.s. ( dall.) ( ). the private action initiated by don diego pintado and the government enforcement action against la vengeance were litigated in tandem. see supra notes - . in both geyer v. michel and moodie v. ship betty cathcart, the district court ruled against the french privateers, but the circuit court reversed that ruling, and the supreme court affirmed a judgment in favor of the privateers. see supra notes - . see also u.s. ( dall.) ( ). these cases include the “moodie” cases cited in the preceding paragraphs, as well as wallace v. brig caesar and cotton v. wallace. arcambel v. wiseman, supra note . the british won cotton v. wallace. see supra note . in suits initiated by private parties, the courts seized captured prizes, but they never asserted control over the french privateering vessels. however, in enforcement actions initiated by the government, the courts would seize french privateering vessels. see, e.g., united states v. la vengeance, u.s. ( dall.) ( ). the dates of the libels and the supreme court decisions are included in notes - , supra. saint louis university law journal finally, the attentive reader may have noted that of the cases were filed in the u.s. district court in south carolina. in the s, the exclusive venue for an in rem admiralty action was the place where the ship was located. french privateers routinely brought their prizes to charleston, south carolina, in part because charleston “in the s was a bastion of francophilia.” once a privateer brought his prize to charleston, a ship owner who wanted to file an in rem action to obtain restitution of the captured prize had no choice but to file his claim in the south carolina district court. in those days, there was a single judge assigned to each federal district court. thomas bee was the federal district judge for the district of south carolina. as discussed more fully in the next section, judge bee’s decisions were very influential in shaping the law related to french privateers because he decided most of the french privateering cases at the district court level, and the supreme court affirmed most of those decisions without any written opinion. c. two case studies recall that the supreme court held in sloop betsey that federal district courts have jurisdiction over claims for restitution by ship owners who allege that a privateer captured a neutral ship. additionally, congress enacted legislation granting district courts jurisdiction over claims for restitution in cases where privateers captured enemy ships in u.s. territorial waters. however, the cases where ship owners and/or their agents filed in rem suits seeking restitution of enemy merchant vessels did not fit within either of these jurisdictional principles because all cases involved captures of enemy ships on the high seas. in these cases, the libellants generally raised two types of allegations. first, they alleged that the privateers had been illegally outfitted in u.s. ports, or had augmented their forces in u.s. ports. second, they alleged that the privateers were owned by americans, commanded by u.s. citizens, or manned by u.s. citizens. the legislation enacted by congress in june created criminal penalties for individuals who accepted a commission from a foreign state, enlisted to serve on a foreign privateer, outfitted a foreign privateer in a u.s. port, or augmented the force of a privateer in a u.s. port. however, congress did not explicitly authorize private claims for restitution to enforce these laws, nor did congress explicitly authorize federal courts to exercise jurisdiction over these types of claims. see supra notes - . vi dhsc, supra note , at . see also jackson, supra note , at - , - . judge bee’s decisions in admiralty cases are published in bee’s admiralty reports, supra note . many of these cases were also published later in the “federal cases” collection, first published in . that collection was intended to be “a comprehensive compilation of the decisions of the united states circuit and district courts” from to . see the preface to vol. i of the collection. see supra notes - and accompanying text. see supra notes and accompanying text. an act in addition to the act for the punishment of certain crimes against the united states, june , , stat. , § . id. at , § . id. at , § . id. at , § . claims alleging illegal recruitment of u.s. citizens and illegal outfitting in u.s. ports fell within the general grant of admiralty jurisdiction in section of the judiciary act. when congress enacted judicial foreign policy: lessons from the s when libellants filed claims seeking restitution of vessels captured by french privateers, the french captors routinely invoked article of the treaty with france as a bar to the jurisdiction of u.s. courts. in sloop betsey, the libellants persuaded the supreme court to sidestep article by noting that the article, by its terms, applies only to “ships and goods taken from their enemies.” therefore, they argued, the courts must undertake a factual inquiry to determine whether the vessel is an enemy vessel before they can conclude that article bars jurisdiction. in the cases referenced above, the federal district courts effectively extended this logic to all allegations of unlawful captures. although the district courts eventually dismissed most of the cases on the grounds that article barred jurisdiction, they first undertook a factual inquiry to determine whether the capture was lawful. france thought this approach violated article for two reasons. first, the district courts exercised in rem jurisdiction over french prizes while the claims were being adjudicated, thereby preventing french privateers from exercising their right under article “to carry whithersoever they please the ships and goods taken from their enemies.” second, even though article prohibited u.s. courts from making “examination concerning the lawfulness of such prizes,” the districts courts examined the merits of factual allegations supporting claims of unlawful captures before they dismissed the claims for lack of jurisdiction. this section presents two case studies to illustrate, first, judicial decision-making in the privateering cases, and second, u.s.- french diplomacy related to those cases. . the mermaid: a case study of judicial decision-making: on january , , the french privateer general laveaux captured a british merchant vessel, the mermaid, and brought her to charleston, south carolina. the british consul in south carolina, benjamin moodie, filed a libel seeking restitution of the mermaid to its british owners. the libel alleged three grounds for restitution: ) that the general laveaux was owned by u.s. citizens; ) that the general laveaux had been illegally outfitted in charleston; and ) that “the greatest part of the crew . . . consisted of citizens of the united states.” john gaillard, the captain of general laveaux, and nicholas gautier, the prize master of the mermaid, filed an answer to moodie’s libel. in their answer, they contested the factual allegations of the libel, and pled article of the treaty with france in bar to the libel. by invoking article as a “plea in bar” to the libel, the french new legislation in , it expressly authorized jurisdiction over claims involving captures in u.s. territorial waters, but said nothing about jurisdiction over claims alleging illegal recruitment or outfitting. thus, french litigants made an “expresio unius” argument that the legislation precluded jurisdiction over these types of claims. see supra notes - and accompanying text. treaty with france, supra note , art. . id. see vii dhsc, supra note , at - . british consul v. the mermaid, f.cas. (d.s.c. ). see vii dhsc, supra note , at . saint louis university law journal were making a procedural move analogous to what would now be called a motion to dismiss for lack of jurisdiction. judge thomas bee ruled “that the plea in bar of the seventeenth article of the treaty with france filed in this cause is relevant and that the libel be dismissed with costs.” in other words, judge bee dismissed the libel on the grounds that article barred the exercise of jurisdiction. however, judge bee reached this conclusion only after he addressed the merits of each of the three claims raised in the libel. after hearing evidence on those claims, judge bee concluded that the general laveaux was not an american vessel, that she was not illegally outfitted in the united states, and that there was no evidence to support the charge that her crew consisted mostly of american citizens. in short, judge bee first addressed the merits of the claims raised in the libel, and then dismissed the libel for lack of jurisdiction after concluding that those claims were without merit. the district court decided the mermaid fairly expeditiously. moodie filed his libel on february and judge bee issued his decree on april , . however, the circuit court did not affirm moodie’s decree until november , and the supreme court did not issue its final decision until march . since it was an in rem proceeding, the district court retained custody over the prize while the case was pending in the circuit court and the supreme court. france viewed this lengthy detention of the prize as a violation of art. , because judicial custody prevented the privateers from carrying their prize “whithersoever they please.” moreover, from france’s perspective, insofar as the appellate courts affirmed a lower court ruling that addressed the merits of the claim that the mermaid was captured illegally, the courts violated article by making “examination concerning the lawfulness of such prizes.” the supreme court never published an opinion in the mermaid. however, justice iredell produced a draft opinion that provides some support for french allegations that the courts were violating article . to understand justice iredell’s analysis, it is necessary to elaborate on the underlying facts. the general laveaux was originally an american vessel, the cygnet. the ship was docked in charleston, south carolina for some time during the year . while in charleston, work was done on the ship. according to the british libellants, this work constituted illegal outfitting. according to decree of federal district court, apr. , , supreme court archives, case no. . for reasons unknown to the author, the language quoted in the text is not reproduced in the district court opinion published in federal cases. however, judge bee used virtually identical language in dismissing all of the cases that the author reviewed in the supreme court archives. see british consul v. the mermaid, f.cas. (d.s.c. ). see vii dhsc, supra note , at . see id., at . see supreme court minutes, march , , reprinted in i dhsc, supra note , at - . treaty with france, supra note , art. . id. see james iredell’s notes for a supreme court opinion, march , , reprinted in vii dhsc, supra note , at - . this summary of the facts is drawn from three sources: vii dhsc, supra note , at - ; british consul v. the mermaid, f.cas. at - ; and jackson, supra note , at - . although the three sources differ in certain details, the account presented here is generally consistent with all three. judicial foreign policy: lessons from the s the french claimants, the ship underwent repairs, which were entirely legal. the ship sailed to saint-domingue, a french territory in the caribbean, where it was purchased by mathew moreau, a french citizen. (the british libellants alleged that the sale to moreau was fraudulent; hence, the ship was still american.) by the end of the year, the cygnet had been re-named the general laveaux. the general laveaux sailed as a privateer from saint-domingue in late with a french commission. it captured the mermaid in january . justice iredell’s analysis is divided into three parts. first, he considered the allegation that the privateer had been “fitted out & equipped in america.” justice iredell wrote: “admitting this fact, this only a local offence against the neutral nation . . . does not in itself divest the property. . . . if therefore truly & bona fide alienated, she became french property, & as such the owners under a real french commission had a right to cruise, & bringing her prizes into american ports entitled to the protection of the art.” the implication of this statement is clear. if a british libellant seeks restitution of a captured prize on the grounds that the french privateer was illegally outfitted in u.s. ports, the court should dismiss the claim without addressing the merits, because illegal outfitting, even if proven, would not invalidate the legality of a subsequent capture made by a french privateer with a valid commission. moreover, article precludes u.s. courts from inquiring into the lawfulness of the capture. if this analysis is correct, judge bee violated article by examining the merits of the illegal outfitting claim, even though he eventually relied on article as a basis for dismissing the libel. second, justice iredell considered the argument that the june legislation provided for forfeiture of a vessel that was illegally outfitted in u.s. ports. consistent with the preceding analysis, he wrote: “admitting a forfeiture had incurred by a special law of the u.s., this would not invalidate a prize taken by her after a bona fide alienation to a real french citizen in another country.” iredell agreed that the u.s. could institute a forfeiture action against the privateer, but forfeiture of the privateer “does not necessarily infer a forfeiture of all the prizes which such vessel might take.” moreover, “a fair capture under a real french commission by real french citizens would article of the treaty with france expressly grants french ships a right to carry out repairs in u.s. ports. see treaty with france, supra note , art. . see james iredell’s notes for a supreme court opinion, march , , reprinted in vii dhsc, supra note , at - . id. at . id. at . the quotes are taken from justice iredell’s notes, which did not contain complete sentences. the author has chosen to use the actual text of the original, rather than trying to correct the grammar. the same logic would apply to the allegation in the libel that most of the crew of the general laveaux were americans. dismissal of this claim was not appealed because the libellants failed to adduce any evidence in support of this claim in the district court. see id., at - . see also an act in addition to the act for the punishment of certain crimes against the united states, june , , § , stat. , . james iredell’s notes for a supreme court opinion, march , , reprinted in vii dhsc, supra note , at . id. at . saint louis university law journal be exempt from any enquiry of ours,” because such enquiry is prohibited by article and the law of nations. in short, the u.s. statute authorizing forfeiture of privateers that were illegally outfitted in u.s. ports did not authorize u.s. courts to adjudicate the merits of claims for restitution of vessels captured by those privateers. third, justice iredell addressed the allegation that the general laveaux was actually american property, not french property. “if this appeared clearly to the court,” he wrote, then the captured prize “ought to be restored.” although justice iredell did not fully articulate his rationale, he was probably drawing a distinction between actions that violated u.s. law, such as illegal outfitting, and actions that violated the law of nations. if an american-owned vessel purported to act as a french privateer, any capture made by that vessel would be invalid under the law of nations, and the illegality of the capture would require restitution of the captured prize. justice iredell emphasized the “importance of the article,” and warned that restitution based on alleged american ownership of the privateer should not be awarded “upon light or doubtful grounds.” if u.s. courts accepted allegations of american ownership too easily, then article would be “of no value,” and the owners of captured prizes would raise “a claim in every case.” by the time justice iredell wrote his draft opinion, in march , the french privateers had already abandoned american ports in favor of french ports in the caribbean. thus, even if iredell’s opinion had been published, it would not have had any effect on the decisions of lower courts, because those courts were adjudicating the french privateer cases in and , when the privateers were still bringing their prizes into u.s. ports. as illustrated by judge bee’s decision in the mermaid, the lower courts generally addressed the merits of illegal outfitting claims before they dismissed the claims for lack of jurisdiction (contrary to justice iredell’s preferred approach). by manifesting their willingness to adjudicate the merits of those claims, the courts, perhaps unwittingly, encouraged british, spanish and dutch libellants to file “a claim in every case,” as justice iredell warned. . the sans pareil: a case study of u.s.-french diplomacy: on july , , the french privateer sans pareil captured the british merchant vessel perseverance. the privateer put on board a prize crew led by jean bernard. bernard sailed perseverance to newport, rhode island, arriving there on august . the next day, thomas moore, the british vice-consul in rhode island, wrote to the governor alleging id. at . id. at . see talbot v. jansen, u.s. ( dall.) ( ) (affirming decree by judge thomas bee, which ordered restitution of a dutch vessel captured by individuals claiming to be french privateers, in part because one of the self-styled privateers was a u.s. citizen who had never received a valid commission from the french government). james iredell’s notes for a supreme court opinion, march , , reprinted in vii dhsc, supra note , at . id. see infra part iv.d. the summary of facts in this paragraph is taken from vii dhsc, supra note , at - . judicial foreign policy: lessons from the s that the perseverance had been captured illegally and seeking restoration of the captured vessel to its british owner. the governor, arthur fenner, seized the vessel pending resolution of the dispute. joseph fauchet, the french ambassador in philadelphia, soon learned about the case. on august , fauchet wrote to secretary of state randolph to protest. fauchet’s letter began by noting that he had received “a great number of complaints” regarding the “vexations which our privateers are made to experience at the instigation of english agents.” fauchet clearly believed that france’s enemies were initiating frivolous legal proceedings to harass french privateers. his letter referred to “those unjust and odious proceedings,” and to “those miserable chicaneries, shamefully employed to damp the courage of the mariners.” then, he specifically addressed the sans pareil: i pray you to cause orders to be given to the officers of the customs at newport, to restore to the agent of the republic, the prize made by the privateer sans pareil. . . . [t]his prize has been seized, and under the pretext that the privateer sans pareil had been armed in the ports of the united states. if this pretext had been really alleged, a more glaring injustice and more palpable falsehood could not have been disguised . . . but, perhaps, as has frequently happened, they have only wished to discourage and fatigue the captors, by injuring the prize, from the length of time required for obtaining the decision, which they will retard by a thousand unfair expedients. in this case, sir, it is at length time to take a determination which will secure the interests of the captors, who, without this precaution, will be always injured, whatever may be the determination of the courts; they will be affected, first by the loss of time; secondly, by the expenses in prosecuting this business; and, lastly, by waste in the merchandises and vessels which they shall have taken.” thus, from france’s perspective, even when french privateers ultimately prevailed in legal proceedings, they were still the losers, because the legal proceedings cost them valuable time and money. moreover, the loss of time and money adversely affected france’s strategic interests by providing economic disincentives to privateering, thereby making it harder to recruit additional privateers. on september , , secretary randolph wrote to fauchet to inform him that he had “urged the governor of rhode island to report, without delay, the case of the prize letter from mr. fauchet, minister plenipotentiary of the french republic, to mr. randolph, secretary of state, aug. , , i aspfr, at . id. id. it bears emphasis that the economic disincentive to privateering was not an ordinary incident of naval warfare during this era. in the “typical” naval conflict, a privateer could obtain a speedy judgment by bringing a captured vessel to a prize court in his home country; this process rarely led to protracted litigation. however, in the american theater of the war between france and britain, the british were able to exploit the geographic distance between the u.s. and the nearest french prize courts by subjecting french privateers to protracted litigation when they brought their captured prizes to u.s. ports. saint louis university law journal taken by the privateer sans pareil.” randolph added: “be assured, sir . . . that the government of the united states will not suffer the acquisitions of the french privateers to be wrested from them, without adequate cause; nor yet, that they should be wantonly vexed by unjust detentions.” two days later, on september , governor fenner ruled in favor of the french privateers and “ordered the perseverance delivered to” the french captors. on september , randolph wrote to fauchet to report the good news. however, the communication from governor fenner to secretary randolph to ambassador fauchet lagged far behind the pace of actual events. the french captors sold the perseverance and its cargo on september , . however, before they could escape with the funds, the british owner, thomas jennings, “secured a monition requiring the united states marshal to retain the funds” and filed a libel in the federal district court. in the libel, jennings alleged two violations of the june ’ legislation enacted by congress. he claimed “that the sans pareil had been augmented in force” in charleston, south carolina, in violation of section of the statute, and that the sans pareil was “to an extent manned with americans,” in violation of section . he also alleged that none of the frenchman on board the sans pareil had a valid commission. for all these reasons, he claimed that the capture of the perseverance was illegal, and he sought damages to compensate him for the loss of the ship and its cargo. when fauchet learned that the british owner initiated judicial proceedings, after the governor of rhode island had already ruled in favor of the french captors, he was furious. on october , , fauchet wrote to randolph as follows: you announce to me that la perseverance, prize to the sans pareil, had been delivered to the captors by order of the governor of rhode island; in contempt of that decision the english agents have just created new difficulties . . . it is impossible, sir, for this state of things to continue much longer. you are sensible how necessary it will be to retrench from our treaty the article letter from mr. randolph, secretary of state, to mr. fauchet, minister plenipotentiary of the french republic, sep. , , i aspfr, at . see also letter from mr. randolph, secretary of state, to the governor of rhode island, sep. , , i aspfr, at (discussing the sans pareil, and noting that the french ambassador is concerned that “the ardor of french privateers [may] be dampened by the vexations which a seizure of their prizes may produce”). letter from mr. randolph, secretary of state, to mr. fauchet, minister plenipotentiary of the french republic, sep. , , i aspfr, at . vii dhsc, supra note , at - . in august – after several district courts had dismissed french privateering cases for lack of jurisdiction, and before the supreme court issued its decision in glass v. sloop betsey – the secretary of war had written to state governors to encourage them to adjudicate these cases. see id., at . that is why the british sought relief from governor fenner and why he agreed to perform a judicial function in this case. letter from mr. randolph, secretary of state, to mr. fauchet, minister plenipotentiary of the french republic, sep. , , i aspfr, at . vii dhsc, supra note , at . id. id. id. judicial foreign policy: lessons from the s which reciprocally permits the ships of war of the two nations to conduct to, and sell their prizes in, their respective ports, should this right become illusory and void by the difficulty thrown in the way of its execution. i proposed a method as simple as it is just, for putting an end to this tyrannical chicanery: this method was, to require security from those who prosecuted prizes as illegal. were this measure adopted, it would render our enemies less ingenious in their proceedings, and prevent them from bringing so many actions . . . i expect, sir, that the federal government will put an end to these persecutions by the mode i have proposed, or by any other which its wisdom may suggest.” randolph was evidently sympathetic to fauchet’s plea. nevertheless, he told fauchet pointedly that the executive branch could not intervene in ongoing judicial proceedings, and that the judiciary was the proper branch of government to resolve disputes between french privateers and british ship owners: if, however, individuals conceive that they have a legal claim upon her, and draw her before a court of law, the executive of the united states cannot forbid them. the plea, under [article of] the treaty, that the court has no cognizance of french prizes, will be admitted if it applies, and the person by whom the process is instituted will be liable to a judgment for costs and damages, if he fails in his proof. the bond, which you propose as a security against vexation, we have no power to demand, because the executive do not mean to interfere, without presumptive proof of title; and this presumption, when established, would seem to be a sufficient protection against being harassed. the courts have their forms . . . i am not authorized to make the arrangement proposed.” thus, randolph tacitly acknowledged that article barred the exercise of jurisdiction by u.s. courts in certain cases. however, the courts had to exercise jurisdiction for the limited purpose of deciding whether article applied. moreover, in randolph’s view, if fauchet wanted to offer suggestions about procedural innovations to minimize vexatious lawsuits, he should direct those suggestions to the judiciary, because there was no basis for the executive to intervene in the affairs of an independent branch of government. despite ambassador fauchet’s best efforts to assist the privateers who had a legitimate claim to the funds from the sale of the perseverance, the judicial process consumed almost two-and-a-half years. the french captors could not obtain access to letter from mr. fauchet, minister plenipotentiary of the french republic, to mr. randolph, secretary of state, oct. , , i aspfr, at . see letter from mr. randolph, secretary of state, to mr. fauchet, minister plenipotentiary of the french republic, oct. , , i aspfr, at (expressing his wish “that we were always able to administer immediate relief”). id. saint louis university law journal the funds until february , when the supreme court issued its final decision in jennings v. brig perseverance. d. the end of french privateering in the u.s. “by early november ,” french privateering activities in u.s. ports “had all but ceased.” there were three key factors that contributed to the decline of french privateering in the united states: the jay treaty, lawfare in u.s. courts, and geo- political developments in the caribbean. in the spring of , “the british had a stranglehold on french possessions in the caribbean.” since the british denied french privateers access to french ports in the caribbean, and the privateers did not want to carry their prizes across the atlantic to sell them in france, the best economic choice was to sell their prizes in u.s. ports. however, the strategic situation in the caribbean changed dramatically between june and late . france launched a successful attack against the british in guadeloupe in june . having re-established a foothold in the caribbean, france bided its time over the next several months. then, between march and june of , france launched a major offensive that led to a string of french victories in the caribbean. in july , the treaty of basel terminated hostilities between france and spain. by the end of , france and spain had become allies in a war against great britain. as a result of these developments, french privateers were able to take their prizes to french prize courts in the caribbean. these “new privateering opportunities” in the caribbean operated as a “magnet that drew the french privateers away from” the united states. the economic magnet of privateering opportunities in the caribbean combined with the financial drain imposed by british lawfare in u.s. courts to lure french privateers away from u.s. ports toward french ports in the caribbean. the privateers did not need to be financial wizards to calculate the costs and benefits of the two options. since the french could not operate prize courts in the united states, prizes sold in the united states without prior condemnation by a prize court invariably sold at a reduced price. moreover, if a commander brought his captured prize to a u.s. port, he could expect the gains from his business venture to be tied up in u.s. courts for - months. unless he had a cushion of cash reserves on hand, he would be unable to pay his crew, making it difficult, if not impossible, to hire crew for the next voyage. in u.s. ( dall.) (feb. ). jackson, supra note , at . treaty of amity, commerce, and navigation, u.s.-gr. brit., nov. , , reprinted in treaties and other international acts of the united states of america (hunter miller ed., ) [hereinafter, jay treaty]. vi dhsc, supra note , at . jackson, supra note , at - . see id., at - . vii dhsc, supra note , at . jackson, supra note , at - . id. at , - . see supra note and accompanying text. see supra notes - and accompanying text. judicial foreign policy: lessons from the s contrast, if he took his prize to a french port in the caribbean, he could obtain a judgment from a french prize court, sell the prize quickly at full value, and use the profits to finance additional privateering ventures. the united states and great britain signed the jay treaty in november and the treaty entered into force in october . by october , many of the french privateers had already abandoned u.s. ports in favor of caribbean ports. for those who continued bringing prizes to u.s. ports, however, the jay treaty was the final nail in the coffin. article expressly prohibited privateers commissioned by france from selling their prizes in u.s. ports as long as france was at war with great britain. the french ambassador protested vehemently that “the stipulations of the treaty concluded with england . . . destroy the effect of [france’s] treaty with the united states.” article of the jay treaty preserved french rights under the treaty between the u.s. and france. however, secretary of state pickering maintained that article of the treaty never actually gave french privateers a right to sell their prizes in u.s. ports: the u.s. had simply permitted french privateers to sell their prizes in u.s. ports as a matter of policy. thus, although article of the jay treaty preserved france’s pre-existing legal rights under article of the treaty, article of the jay treaty provided the controlling rule because it expressly prohibited sales of french prizes in u.s. ports, and this prohibition was not contrary to any legal right granted under the treaty. in sum, the british lawfare strategy was undoubtedly a success, in the sense that it was one of three key factors that helped induce french privateers to abandon the use of u.s. ports as a base of operations. however, the broader military consequences of the strategy are difficult to assess. it is likely that britain gained some strategic advantage because british merchant vessels had easier access to u.s. ports after the french privateers moved south to the caribbean. on the other hand, the advantage to france of greater access to french ports in the caribbean may have offset the disadvantages for france associated with the exodus of french privateers from u.s. ports. v. conclusions the preceding analysis of the french privateering cases demonstrates that the exclusive political control thesis is inconsistent with the founders’ understanding of the jay treaty, supra note . id., art. , pg. . letter from ambassador adet to secretary of state randolph, june , , i aspfr, at . jay treaty, supra note , art. , pg. (“nothing in this treaty contained shall however be construed or operate contrary to former and existing public treaties with other sovereigns or states. but the two parties agree, that while they continue in amity neither of them will in future make any treaty that shall be inconsistent with this or the preceding article.”) secretary of state randolph explained to ambassador adet that, under article , “you shall continue to enjoy your rights under the seventeenth article of our treaty with france . . . the prohibition, on which you lay so much stress, is not against past but future treaties.” letter from randolph to adet, july , , i aspfr at - . letter from pickering to adet, july , , i aspfr, at - . see id. saint louis university law journal constitutional separation of powers in foreign affairs. this concluding section briefly highlights two important historical points and discusses the contemporary relevance of the privateering cases. the first key historical point relates to britain’s use of lawfare tactics. as noted above, the council on foreign relations wrote in that lawfare was a “new phenomenon.” part iv showed that lawfare is not a new phenomenon; britain used lawfare tactics successfully in the s to help induce french privateers to stop bringing their prizes into u.s. ports. second, although the privateering cases raised significant national security and foreign policy issues that were intimately connected to u.s. neutrality policy, the washington administration chose to defer to the judicial branch and allow judicial decision-making in the privateering cases to guide the implementation of u.s. neutrality policy. four factors help explain the government’s decision to handle these cases by means of private adjudication in the courts, rather than diplomatic negotiation conducted by the executive branch. first, many of the cases required someone to scrutinize large amounts of conflicting evidence, and the executive branch did not have the personnel to handle that task. second, the main goal of u.s. policy was to preserve u.s. neutrality; since the british and french were adversaries in most of the cases, it helped promote an appearance of neutrality to let the judiciary serve as a neutral decision-maker, rather than having the executive branch resolve legal disputes between the british and the french. third, given the natural law viewpoint that was prevalent among the founders, many of the founders probably believed that the ship owners had a natural right to present their claims in court to defend their property rights. finally, resolution of the privateering cases required a decision-maker to apply general legal rules in specific factual situations that involved disputes over the property rights of private parties. some members of the founding generation probably believed that the constitution granted the judicial branch primary (but not exclusive) responsibility for deciding cases involving the rights of private parties that required the application of law to fact. the french privateering cases are similar to modern war on terror cases in one key respect – in both sets of cases, questions of private rights are/were inextricably linked to questions of international law and u.s. foreign policy. of course, there are also key differences between the two sets of cases. the united states was a party in only two of the privateering cases that are the focus of this study. in contrast, the u.s. council on foreign relations, lawfare: the latest in asymmetries (march , ), available at http://www.cfr.org/publication.html?id= . during the period under study, there was no “department of justice,” and the attorney general did not have any staff to support him. the secretary of state had a total domestic staff (not counting overseas ambassadors and consuls) of about - clerks. see list of civil officers of the united states, except judges, with their emoluments, for the year ending oct. , , reprinted in american state papers, miscellaneous, vol. i, pg. - . see also roll of the officers, civil, military, and naval of the united states, reprinted in american state papers, miscellaneous, vol. i, pg. , , (cover. united states v. la vengeance, u.s. ( ); united states v. peters, u.s. ( ). http://www.cfr.org/publication.html?id= judicial foreign policy: lessons from the s government is a party to most of the modern war on terror cases. moreover, both the legislative and executive branches encouraged active judicial involvement in the privateering cases in the s. in contrast, the legislative and executive branches have worked together in the past few years to minimize judicial involvement in cases arising from the war on terror. despite these differences, the privateering cases do offer an important pragmatic lesson that is still relevant today. according to the new york times, “people in britain and france told pollsters last spring that they had even less confidence in [president bush] to do the right thing in world affairs than they had in president vladimir putin of russia.” u.s. foreign policy cannot succeed if our key allies do not trust us to comply with our international legal obligations. the founders understood this: they wanted to convey a message to the world that the u.s. was committed to the rule of law in international affairs. in the s, the executive branch reinforced this message by deferring to the judiciary and allowing federal courts to decide key issues related to french privateering activities. in the current geopolitical situation, if the government wants to persuade u.s. allies that the united states is committed to complying with its international legal obligations, it can promote that objective by inviting judicial scrutiny of u.s. policies in the war on terror, at least in cases where those policies are intimately bound up with questions of international law and individual rights. in contrast, continued resistance to judicial oversight reinforces the belief, which is widely shared among the citizens of some of our closest allies, that the united states views international law with a mixture of contempt and indifference. political realists might explain the differences between the s and today as a function of political power. weak states are receptive to international law because it has the potential to constrain their stronger adversaries. strong states are less receptive because international law tends to equalize power imbalances among states, thereby reducing the comparative advantage of stronger states. the united states embraced international law in the s because it was a weak state; the u.s. is suspicious of international law today because it is a strong state. this explanation is fairly persuasive, as far as it goes. but it does not answer the key normative question: is it generally in the national interest of the united states to comply with its international legal obligations, and to be perceived as complying with those obligations? there is ample room for disagreement on this question, but a president who wants to persuade the world that the u.s. takes its international legal obligations seriously could advance that goal by encouraging a more active role for the federal judiciary in the implementation of u.s. foreign policy. see, e.g., hamdan v. rumsfeld, u.s. ( ); hamdi v. rumsfeld, u.s. ( ); rasul v. bush, u.s. ( ). see military commission act of , pub. l. no. - , stat. (especially section (a)); detainee treatment act of , pub. l. no. - , stat. (especially section (e)). michael cooper, mccain offers soothing tones in trip abroad, new york times, sunday, march , , at a . the distillery scibx: science–business exchange copyright © nature publishing group � this week in therapeutics indication target/marker/ pathway summary licensing status publication and contact information cancer colon cancer guanylyl cyclase c (heat-stable enterotoxin receptor; gucy c) studies in mice suggest that immunization with gucy c could help treat or prevent metastatic colon cancer. in healthy mice, immunization with gucy c-expressing viral vectors before challenge with gucy c-expressing mouse colon cancer cells minimized metastasis to the liver and lungs compared with that seen in mock-treated control mice (p= . and p< . , respectively). in mice with established metastases, median survival was days for immunized mice compared with days for untreated mice (p= . ). the antitumor and prosurvival effects occurred without autoimmune reactions. completion of safety and efficacy studies in animals, as well as gmp studies, are necessary before the vaccine enters the clinic. castillo pharmaceuticals inc.’s sp- , a gucy c agonist, is in phase i testing to treat irritable bowel syndrome (ibs). ironwood pharmaceuticals and forest laboratories are developing md- , a gucy c agonist that is in phase ii testing to treat constipation and ibs. patent applications submitted; targeted diagnostics & therapeutics inc. has exclusive worldwide rights to the gucy c cancer technology and has sublicensed most of the cancer applications to millennium pharmaceuticals inc.; some of the vaccine applications available for sublicensing snook, a. et al. j. natl. cancer inst.; published online june , ; doi: . /jnci/djn contact: scott a. waldman, thomas jefferson university, philadelphia, pa. e-mail: scott.waldman@jefferson.edu http://www.scibx.com mailto:scott.waldman@jefferson.edu 	guanylyl cyclase c (heat-stable enterotoxin receptor; gucy c) 	summary 	licensing status 	references microsoft word - selfplagiarism.doc self-plagiarisim: dellavalle, banks, and ellis- editorial frequently asked questions regarding self-plagiarism: how to avoid recycling fraud robert p. dellavalle, md, phd, msph, , marcus a. banks, mlis jeffrey i. ellis, md author affiliations: department of veterans affairs medical center, denver, co department of dermatology, university of colorado at denver and health sciences center, denver, co new york university school of medicine, ehrman medical library, new york, ny department of dermatology, suny downstate medical center, brooklyn, ny corresponding author robert dellavalle, md, phd, msph department of dermatology university of colorado at denver and health sciences center p.o. box mail stop f aurora, co - tel - - x self-plagiarisim: dellavalle, banks, and ellis- fax - - e-mail: robert.dellavalle@uchsc.edu. [text word count = ; references= ] funding source: none disclosed interests: dr. ellis is president of the post publication peer review resource www.journalreview.org. dr. dellavalle and mr. banks are respectively chair and member of the advisory committee to www.journalreview.org. self-plagiarisim: dellavalle, banks, and ellis- . what is self-plagiarism? self-plagiarism, also known as recycling fraud, occurs when an author reuses text in subsequent writings without attributing the previous publication. - . is self-plagiarism ever acceptable? thomas jefferson repeated prose from previous writings in the declaration of independence and did not cite these works. few would argue this famous example of self-plagiarism as unacceptable. most also agree that experts providing opinions to popular newspapers or magazines need not cite specific previous writings. . what is copyright, and how does self-plagiarism involve copyright infringement? the us constitution grants congress the power to “promote the progress of science and useful arts, by securing for limited times to authors and inventors the exclusive right to their respective writings and discoveries.” copyright is this legal protection of a particular expression of an idea, but not of the facts or ideas themselves. in the us, copyright protection extends for the life of the author plus years. self-plagiarisim: dellavalle, banks, and ellis- authors of technical articles are often asked to assign copyright to a journal’s publisher as a condition for publication—such is the case for this journal (the jaad) and its publisher (elsevier). subsequent republication by the author of copyrighted text without citation is technically illegal. . have authors been legally sanctioned for violating copyright on their own words? few sanctions have been handed down as the courts have generally recognized that “authors have special rights to their words not withstanding copyright.” . if copyright law has not been enforced against authors repeating themselves, then why worry about self-plagiarism? self-plagiarism is not acceptable in academic writing because academic writing is grounded by its references, and authors are expected to cite their closely related previous writing. as post publication peer review and software developments make self- plagiarism ever easier to detect, the jaad urges all authors to promote transparency with full citation of text repeated from older publications. self-plagiarisim: dellavalle, banks, and ellis- references . hexham i. academic plagiarism defined. . available at: http://www.ucalgary.ca/~hexham/study/plag.html. accessed / / . . samuelson p. self-plagiarism or fair use? communications of the acm : ; . available at: http://portal.acm.org/citation.cfm?id= &coll=portal&dl=acm&cfid= &cftoken= . accessed / / . . scanlon pm. song from myself: an anatomy of self-plagiarism. plagiary: cross-disciplinary studies in plagiarism, fabrication, and falsification, : ; - . [temporary pagination for advance online copies of articles]. available at: http://www.plagiary.org/ /song-from-myself.pdf. accessed / / . . ellis jj. american sphinx: the character of thomas jefferson. ; . new york: vintage books. . copyright law of the united states of america and related laws contained in title of the united states code. available at: http://www.copyright.gov/title /circ .pdf. accessed / / . . hirtle pb. copyright term and the public domain in the united states. available at: http://www.copyright.cornell.edu/training/hirtle_public_domain.htm. accessed / / . . iparadigms llc. ithenticate-plagiarism detection. available at: http://www.ithenticate.com/static/products.html. accessed / / . self-plagiarisim: dellavalle, banks, and ellis- a profile of academic training program directors and chairs in radiation oncology international journal of radiation oncology biology physics www.redjournal.org clinical investigation: education a profile of academic training program directors and chairs in radiation oncology lynn d. wilson, md, mph,* bruce g. haffty, md,y and benjamin d. smith, mdz *department of therapeutic radiology, yale university school of medicine, smilow cancer hospital, new haven, connecticut, ydepartment of radiation oncology, the university of texas md anderson cancer center, houston, texas, and zdepartment of radiation oncology, umdnj-rwjms, cancer institute of new jersey, new brunswick, new jersey received sep , , and in revised form oct , . accepted for publication oct , summary the data provided offer basic information characterizing several factors that are asso- ciated with the program directors and chairs in addi- tion to information regarding training programs from which they received their training. the information may be of interest to indi- viduals considering leader- ship positions, and programs interested in establishing benchmarks for leadership positions. these findings facilitate evaluation of lead- ership trends over time and between specialties reprint requests to: lynn d. wilson, m therapeutic radiology, yale university scho , smilow ll , new haven, ct fax: ( ) - ; e-mail: lynn.wilson@y int j radiation oncol biol phys, vol. , no. - /$ - see front matter � elsevie doi:http://dx.doi.org/ . /j.ijrobp. . . purpose: to identify objective characteristics and benchmarks for program leadership in academic radiation oncology. methods and materials: a study of the accreditation council for graduate medical education radiation oncology training program directors (pd) and their chairs was per- formed. variables included age, gender, original training department, highest degree, rank, endowed chair assignment, national institutes of health (nih) funding, and hirsch index (h-index). data were gathered from online sources such as departmental websites, nih reporter, and scopus. results: there were a total of pd. the median age was , and ( %) were md/phd. a total of ( %) were female, and rank was relatively equally distributed above instructor. of the professors, at least ( %) were female. at least ( %) were working at the institution from which they had received their training. a total of individ- uals held endowed chairs. only pd had active nih funding in . the median h-index was (range, - ) but the index dropped to (range, - ) when those who served as both pd and chair were removed from the group. a total of chairs were identified at the time of the study. the median age was , and ( %) were md/phd. a total of ( %) of the chairs were female, and rank was professor for all with the exception of who was listed as “head” and was an associate professor. of the chairs, at least ( %) were working at the institution from which they received their training. there were a total of individuals with endowed chairs. a total of ( %) had nih funding in . the median h-index was (range, - ). conclusions: these data provide benchmarks for individuals and departments evaluating leadership positions in the field of academic radiation oncology. such data are useful for evaluating leadership trends over time and comparing academic radiation oncology with other specialties. � elsevier inc. d, mph, department of ol of medicine, po box . tel: ( ) - ; ale.edu conflict of interest: dr smith receives research funding from varian medical systems. dr wilson receives clinical research support from merck. dr haffty reports no conflict of interest. , pp. e , r inc. all rights reserved. delta: _given name delta: _given name delta: _given name delta: _surname delta: _given name delta: _given name delta: _given name delta: _surname delta: _given name mailto:lynn.wilson@yale.edu http://dx.doi.org/ . /j.ijrobp. . . http://www.redjournal.org table chair and program director characteristics characteristic program directors chairs total pd and chair female ( %) ( %) median age (y) md/phd ( %) ( %) working at institution of training ( %) ( %) endowed position ( %) ( %) nih funded ( %) ( %) median hirsch index abbreviations: nih z national institutes of health; pd z program director. volume � number � radiation oncology leadership introduction radiation oncology has experienced enhanced popularity over the past years, with expansion in the number and size of academic departments with training programs, but relatively little has been published regarding variables associated with departmental lead- ership ( ). understanding more about these details could poten- tially provide information for comparison between radiation oncology and other specialties, and could be of use to those aspiring to or considering such leadership positions. we sought to describe the basic characteristics and variables related to the training pd and chairs of academic departments with training programs, for descriptive informational purposes. methods and materials at the time of the study ( ), there were a total of residency training programs approved by the accreditation council for graduate medical education (acgme) “for current academic year and those newly accredited programs with future effective dates (year ending june , )” ( ). each program had a pd identified by the acgme. information regarding age, gender, original training department, highest degree, rank, and endowed chair assignment for pd and chairs was evaluated from online searches of departmental websites and other sites available to the public, and freely available. information regarding national institutes of health (nih) funding was obtained through the nih reporter system ( ), and hirsch index (h-index) ( ) was obtained though the author search feature on scopus ( ). h-index is the number of manuscripts that have been cited at least that many times and is considered an indication of academic productivity. for example, if manuscripts have each been cited at least times, the h-index would be . if manuscripts have each been cited at least times, the h-index is still only . if manuscripts have each been cited only times, the h-index is . the data and information were then tabulated, and descriptive statistics were evaluated for pd and chairs of the acgme training programs. if a program included multiple hospitals and potentially multiple chairs, only chair was selected to be associated with the training program for the purposes of this study. in this case, if the pd was also of the chairs, then this person was designated as the overall chair of the program. a request for exemption was granted by the institutional human investigation committee. results program directors there were a total of pd, and information regarding the vari- ables just described was available for at least %, depending on the variable under study. a total of of the pd also served as chair of the department. the median age was , all had an md degree or the equivalent, and ( %) were md/phd. a total of ( %) of the pd were female, and rank was distributed as follows: instructor, ; assistant professor, ; associate professor, ; and professor . of the professors, at least ( %) were female. of the pd, at least ( %) were working at the institution from which they had received their training, and at least ( %) had the additional roles of vice chair, associate chair, or medical director. a total of individuals held endowed chairs as identified by departmental websites. only pd had active nih funding in (table ). the median h-index was (range, - ) but dropped to (range, - ) when those who served as both pd and chair were removed from the group. regarding the institution where pd received their training, and using a minimum of pd from a given institution, the following training programs represented the institutions that trained % of the pd at the time of the study: harvard (massachusetts general hospital in combination with the former joint center program, now the combined harvard radiation oncology training program), ; university of chicago, ; university of california, san francisco, ; university of florida, ; cleveland clinic foundation, ; loyola university, ; university of pennsylvania, ; washington univer- sity, ; yale-new haven medical center, ; albert einstein college of medicine, ; william beaumont hospital, ; university of cincinnati, ; thomas jefferson university, ; mayo clinic college of medicine, ; medical college of wisconsin, ; university of virginia, ; and university of wisconsin, . chairs a total of chairs were identified. three departments were conducting active searches for chairs, and identification of the current chair was not publicly available for several departments. information regarding the variables just described was available for at least % of chairs, depending on the variable under study. the median age was , all had an md degree or the equivalent, and ( %) were md/phd. a total of ( %) of the chairs were female, and rank was that of professor for all with the exception of , who was listed as “head” and was an associate professor. of the chairs, at least ( %) were working at the institution from which they had received their training. a total of individuals held endowed chairs as identified by departmental websites. a total of ( %) had nih funding in . the median h index was (range, - ). regarding the institution where chairs had received their training, and using a minimum of chairs from a given institution, the following training programs represented the institutions that trained % of the chairs at the time of the study: harvard (massachusetts general hospital in combination with the former joint center program, now the combined harvard radiation wilson et al. international journal of radiation oncology � biology � physics oncology training program), ; national cancer institute, ; thomas jefferson university, ; university of chicago, ; university of california, san francisco, ; university of arizona, ; cleveland clinic foundation, ; duke university, ; mayo college of medicine, ; university of pennsylvania, ; stanford university, ; university of washington, ; washington univer- sity. ; and yale-new haven medical center, . chair and program director institution of training institutions that trained at least chairs and pd (note that chair and pd are the same individual in some cases) are as follows: harvard (massachusetts general hospital in combination with the former joint center program, now the combined harvard radia- tion oncology training program), chairs/ pd; university of chicago, / ; university of california, san francisco, / ; thomas jefferson university, / ; cleveland clinic foundation, / ; university of pennsylvania, / ; washington university, / ; yale-new haven medical center, / ; and mayo college of medicine, / (table ). discussion these data provide basic information regarding some of the characteristics of current pd and department chairs. the data serve only as a simple “snapshot” for those currently in leadership positions and by no means take into consideration other objective factors or more intangible attributes. programs grow, may change in quality, and have changes in leadership and philosophy. lead- ership is often a dynamic process, with departments taking different directions based on the perceived needs of the depart- ment and institution at a given time. the data provide several interesting findings. a total of individuals serve the dual role of pd and chair, and % of the pd versus % of the chairs were md/phd. women constituted a higher proportion of the pd, at %, compared with % for chairs. rank was relatively evenly distributed among the pd. age was lower for pd than for chairs, and this would likely be ex- pected, given the experience usually required of those considered for chair positions. the h-index is used by many in an effort to more objectively document the productivity of a faculty member. it is often considered in the promotions process or in the endeavor to make a direct comparison between faculty members’ productivity. table institutions that trained at least chairs and program directors institution chairs program directors harvard university of chicago university of california, san francisco thomas jefferson university cleveland clinic university of pennsylvania washington university yale school of medicine mayo college of medicine there are several issues with the h-index, though, that should be considered. the index does not take into account the subject matter at hand and the contribution of any particular author, and authorship position is not accounted for. despite these issues, it remains an objective benchmark for academic productivity within and across specialties. in a study published in by choi et al ( ), the h-index was evaluated for faculty at radiation oncology training programs in the united states. the th percentile h-index for all faculty was , the median for female chairs was , and the median for male chairs was . the authors also found that there was a “breakpoint” between senior and junior faculty, with the breakpoint being an h-index of . in our analysis, the median chair h-index seems significantly higher at . this is likely a function of the period of time under study. scopus analyzes h- index based on publications from onward, so additional years in total are captured in the current report, compared with the report by choi et al ( ) that reviewed the h-index with a sample through . a study more recently published by svider et al ( ) reveals interesting comparisons. the authors analyzed the h-index for otolaryngology, and the sample was inclusive of , which provides a similar time reference to our study. a random sample of residency programs was used, and the h-index calculated for otolaryngology faculty from these programs. the authors found the following h-index by rank: assistant professor, . ; associate professor, . ; professor, . ; and chairperson, . . the authors then selected chairpersons from the same “set” of institutions used in their otolaryngology analysis. the h-index was then determined for chairpersons from neurosurgery, otolar- yngology, orthopedic surgery, general surgery, internal medicine, anesthesiology, and radiology at institutions, which were selected randomly. the h-index for the chairpersons was as follows: general surgery, . ; internal medicine, . ; neuro- surgery, . ; orthopedic surgery, . ; otolaryngology, . ; radiology, . ; and anesthesia, . . our data, from a larger sample, and not randomly selected, reveal a median h-index of for radiation oncology chairs. the mean from our data for comparison purposes was . hence, the mean h-index for chairs of radiation oncology likely tracks very closely with those chairs from general surgery and slightly higher than chairs of internal medicine. gender inequality remains an important issue, and the gap in gender equity for the leadership positions in our study is substantial. this may change in the future because there is somewhat more gender equity among current trainees and recent graduates ( ). conclusions the information may be of interest both to individuals considering leadership positions and to programs interested in establishing benchmarks for leadership positions. these findings also facilitate the evaluation of leadership trends over time and between specialties. references . aneja s, wilson ld, haffty bg, et al. national residency matching program (nrmp) results for radiation oncology: update. int j radiat oncol biol phys ; : - . volume � number � radiation oncology leadership . http://www.acgme.org//adspublic/reports/program_specialty_list.asp. (september ). . http://projectreporter.nih.gov/reporter.cfm. (september ). . hirsch je. an index to quantify an individual’s scientific research output. pnas ; : - . . http://www.scopus.com (september ). . choi m, fuller cd, thomas cr. estimation of citation-based scholarly activity among radiation oncology faculty as domestic residency- training institutions: - . int j radiat oncol biol phys ; : - . . svider pf, choudhry za, choudhry oj, et al. the use of the h-index in academic otolaryngology. laryngoscope doi: . /lary. . . smith bd, haffty bg, wilson ld, et al. the future of radiation oncology in the united states from to : will supply keep pace with demand? j clin oncol ; : - . http://www.acgme.org//adspublic/reports/program_specialty_list.asp http://projectreporter.nih.gov/reporter.cfm http://www.scopus.com 	a profile of academic training program directors and chairs in radiation oncology 	introduction 	methods and materials 	results 	program directors 	chairs 	chair and program director institution of training 	discussion 	conclusions 	references pancreatic cancer in lynch syndrome: a case report | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /crpc. . corpus id: pancreatic cancer in lynch syndrome: a case report @article{gilani pancreaticci, title={pancreatic cancer in lynch syndrome: a case report}, author={m. gilani and c. intenzo and v. bar-ad and harish lavu and a. sama}, journal={case reports in pancreatic cancer}, year={ }, volume={ }, pages={ - } } 	m. gilani, c. intenzo, + authors a. sama 	published 	medicine 	case reports in pancreatic cancer abstract background: in the literature, pancreatic cancer is not frequently acknowledged among the tumors that are considered a part of lynch syndrome. case presentation: our case is one of a young man who was found, very early in life, to have pancreatic cancer. his tumor demonstrated germline microsatellite instability, and hence by definition the patient has lynch syndrome. he responded well to treatment, which included surgery and adjuvant chemotherapy. to date he remains in remission from… expand view on pubmed liebertpub.com save to library create alert cite launch research feed share this paper figures and topics from this paper 	 figure 	 figure 	pancreatic carcinoma 	neoplasms 	malignant neoplasm of pancreas 	hereditary nonpolyposis colorectal cancer 	chemotherapy, adjuvant 	sturge-weber syndrome references showing - of references pancreatic cancer 	h. kocher, w. alrawashdeh 	medicine 	methods in molecular biology 	 	 , 	pdf 	view excerpts, references background save alert research feed review of the lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications 	h. lynch, p. lynch, s. lanspa, c. snyder, j. lynch, c. boland 	medicine 	clinical genetics 	 	 	highly influential 	 	view excerpts, references background save alert research feed folfirinox versus gemcitabine for metastatic pancreatic cancer. 	t. conroy, f. desseigne, + authors m. ducreux 	medicine 	the new england journal of medicine 	 	 , 	pdf 	view excerpt, references background save alert research feed germ line deletions in epcam gene as a cause of lynch syndrome—literature review 	hered cancer clin pract. ; : 	 risk of pancreatic cancer in families with lynch syndrome 	j. stockman 	medicine 	 	 	highly influential 	view excerpts, references background save alert research feed related papers 	abstract 	figures and topics 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue in the blink of an eye … editorial in the blink of an eye . . . at first glance, five years seems like a long time. one can obtain an american m.d. in less time or complete a combined residency in anatomical pathology and labo- ratory medicine. under many circumstances, one can obtain a ph.d. in the biological sciences or finish a post- doctoral experience. on the other hand, it can seem like no time at all. the last five years reveal that america’s pop-culture idols carry on, american foreign policy is little altered, and nih funding remains depressingly flat. yet for us, five years marks the end of our stewardship of the american journal of pathology. as our terms at the ajp conclude, we are struck by how rewarding the past five years have been. the ac- complishments in this time are notable, from creating a scientific editor position to increasing reviews and other editorial content, arranging articles into subcategories, publishing the “power of ten”—the monthly report of the most-read ajp articles, and adopting a formal scientific integrity policy to disseminating ajp content through press releases, pubmed central, and publish-ahead-of- print. with these changes we believe that we have im- proved the value of the journal as well as enhanced the author experience. but beyond these efforts, we continue to believe that the greatest strength of the ajp is its commitment to unbiased peer review of the pathophysi- ologic mechanisms of disease. and just like the coca- cola company, we alter this time-tested formula at our own peril. the success of the journal’s initiatives manifests itself, in part, via the impact factor. although the ajp experienced a drop in impact factor, together with many other pathology journals, the ajp received a impact fac- tor of . , placing it again in the first position for gen- eral pathology journals. we believe this rebound is sus- tainable, as the ajp continues to be the most-frequently cited journal in the field, receiving over , citations in . of note, since the impact factor lags from date of publication to calculation, the prolonged effects of our changes in the last five years (good and bad) will extend into the next few years. however, the impact factor (largely unchanged since its inception half a century ago) faces strong competition from several emerging metrics that reflect modern journal usage, for example, revised pagerank score (red jasper) and eigenfactor (univer- sity of washington; http://www.eigenfactor.org/). interest- ingly, when using these new methodologies, ajp fares extremely well among pathology journals. while impact factor is important to the perceived suc- cess of the journal, our real success lies in publishing the strongest and most relevant science for our readers and the investigative pathology community as a whole. as a consequence of these lofty goals, we apologize to our colleagues who, perhaps more often than we would have wished, received rejection letters from us. as authors ourselves, we are not immune to the emotions such re- jection brings. with this as a guide, we rendered our decisions with utmost care and respect, without bias, and with only the scientific rigor of the journal in mind. it has only been with the assistance of our colleagues that we have maintained our high publication standards. we are grateful to all of the associate editors who have served with us during our tenure, drs. jeffrey cossman, patricia d’amore, lora ellenson, philip furmanski, mary hendrix, setsuo hirohashi, david hockenbery, dontscho kerjaschki, andrew lackner, kevin moore, brian nick- oloff, yasunori okada, charles parkos, sem phan, kevin roth, and jeffery saffitz. we extend a special thanks to dr. peter ward for taking the lead as special associate editor with responsibility for originating and implementing our high-profile review series biological perspectives. to- gether with our editors, the editorial board represents the breadth of expertise and experience in pathobiology, and we appreciate their hard work and dedication to the journal. we also reflect, with happiness, on the positive attributes the three managing editors have brought to the consistent quality of ajp over these five years as well as the editorial team in bethesda, md, and at the university of alabama at birmingham. we are aware that we may be the last of a certain kind of editor. the american society for investigative pathol- ogy, our publisher, has for decades selected its editors from the leadership of american academic departments of pathology. in a bold stroke, the asip selection com- mittee has chosen a new editor-in-chief who is outside that mold. dr. michael p. lisanti, who begins his term with the next issue, is professor of cancer biology at jefferson medical college of thomas jefferson university and jef- ferson’s kimmel cancer center in philadelphia, pa, and is among the top most-cited scientists in biology and biochemistry (thomson’s essential science indicators). he brings a depth of investigative experience and a breadth of research interests and knowledge in a variety of subject areas. given that greater than % of our the american journal of pathology, vol. , no. , june copyright © american society for investigative pathology doi: . /ajpath. . submissions are from corresponding authors who are not from pathology departments, dr. lisanti represents the diversity of our readers and authors. we wish him the very best of success as he steers this publication forward. as for our time at the helm, it has been a pleasure and an honor to serve the american journal of pathology. we thank our authors, reviewers, and readers for having allowed us to serve you over this last half decade, and we trust you will continue to support the journal by submit- ting your best scholarship for consideration, by agreeing to thoughtfully review submissions, and by continuing to read the ajp. finally, we remain grateful to the efforts of the editors, editorial board, and editorial office, as well as the support of asip leadership. the last five years have been, for us, quite a ride! reference . journal citation reports . science edition thomson isi philadelphia jay m. mcdonald, m.d. editor-in-chief gene p. siegal, m.d, ph.d. senior associate editor mcdonald and siegal ajp june , vol. , no. the isoform specific n terminus of vdac is dispensable for tbid induced cytochrome c release tuesday, february , a agent colchicine that is known to increase free tubulin, mitochondrial potential, as measured by tetramethylrhodamine methyester (tmrm) uptake, decreased. inhibition of pka activity with h increased mitochondrial potential and, fur- thermore, reversed mitochondrial depolarization induced by colchicine. to fur- ther explore a role vdac-tubulin interaction in cell proliferation and survival, we studied the effect of erastin, the selective anti-tumour agent involved in the ras-raf-mek signalling pathway, on vdac blockage by tubulin. we found that erastin reverses tubulin blockage of vdac isolated from hepg cells, pro- moting the unblocked state of the channel. our findings suggest a novel func- tional link between serine/threonine kinase signalling pathways, mitochondrial respiration, and highly dynamic microtubule network which is characteristic of carcinogenesis and cell proliferation. -plat the isoform specific n terminus of vdac is dispensable for tbid induced cytochrome c release shamim naghdi , peter varnai , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, department of pathology anatomy and cell biology, philadelphia, pa, usa, semmelweis university, faculty of medicine, department of physiology, budapest, hungary. vdac proteins represent a main component of the outer mitochondrial mem- brane (omm). the vdac family is composed of isoforms with more than percent similarity. although their primary role was known to be in ion and me- tabolite transport between mitochnodria and cytosol, it has been discovered that vdacs are involved in apoptotic pathways. we have recently found that spe- cifically the vdac isoform is needed for tbid-induced cytochrome c release, due to its role in supporting bak insertion to the omm (roy et al. . embo rep. : - ). sequence analysis of the mammalian vdac isoforms shows a unique n terminal end in vdac , which is likely to be exposed to the cyto- plasm. to test the functional significance of this n terminus, the first amino acids were removed from vdac or were added to vdac . vdac -/- mef cells that are resistant to tbid, were rescued with these constructs and cyto- chrome c release was monitored in permeabilized cells by single cell imaging and immunoblotting. these studies revealed that cytochrome c release upon tbid application is effectively supported by both full length vdac and the vdac n-terminal deletion mutant. furthermore, vdac extended by the n terminus of vdac failed to restore cytochrome c release in vdac -/- mefs. thus the n terminus of vdac seems to be dispensible for tbid- induced omm permeabilization. currently, we are designing different muta- tions which target some addititional unique sequences in vdac to find the specific domain that is essential for tbid induced cytochrome c release. -plat patch-clamp analysis of mitochondrial ca d uniporter in different tissues francesca fieni, yuriy kirichok. ucsf, san francisco, ca, usa. the mitochondrial ca þ uptake has been recognized as a central player in cel- lular pathophysiology for decades. pathways of ca þ transport across the inner mitochondrial membrane (imm) were investigated indirectly with biochemical techniques and most recently by applying the patch clamp technique to mito- plasts isolated from mammalian systems. patch-clamp recording of the imm have proved to provide an unambiguous picture of mitochondrial ca þ uptake under strictly controlled conditions. in this study, we evaluated and compared the biophysical properties of mito- chondrial ca þ uptake in different mouse tissues. freshly isolated mitoplasts from mouse heart, skeletal muscle, liver, kidney, spleen and brown adipose tis- sue were patch clamped in the whole-mitoplast configuration. voltage step and ramp protocols covering the whole range of physiological potentials were ap- plied to elicit the inwardly rectifying ca þcurrent sensitive to rur known as mcu. the distribution of mcu current densities between tissues was as fol- lows: spleen > brown adipose tissue z skeletal muscle > kidney > liver >> heart. interestingly, mcu current density in heart was about times smaller than in skeletal muscle. our results support the view of a differential tissue activity of mcu, which can be explained by either a different distribution of mcu channel and/or by a different expression of its regulatory subunits confer- ing various modes of physiological regulation. further on, in order to investigate the putative direct contribution of uncou- pling protein isoform and (ucp / ) to the uniporter, we investigated mcu properties in wild type (wt) mouse tissues where these two proteins have been found to have a major role and compared its properties in the corre- spondent tissues of ucp and ucp ko mice. we found no significant differ- ences in calcium currents of any of the wt tissues studied compared to their ucp / ko counterparts. -plat sr-mitochondrial ultrastructure in the heart of normal and ethanol-fed rats gyorgy csordas , david mankus , tanvir shaikh , xing meng , jan hoek , carmen mannella , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, wadsworth center, albany, ny, usa. chronic alcoholism causes various forms of stress in the heart, and this is often accompanied by mitochondrial dysfunction. a putative source of mitochondrial dysfunction is sr-mitochondrial stress and the ensuing mitochondrial ca þ overload. to test this possibility, first we isolated mitochondria from chronic ethanol-fed ( months) and paired control rats, and documented ethanol- dependent sensitization to ca þ and ros-induced permeabilization. to evalu- ate the ultrastructural basis of the mitochondrial impairments, we performed transmission electron microscopy (tem) and electron tomography studies of left ventricular muscle. the overall ultrastructure of the myocytes became less organized in the ethanol-fed condition. also, a considerable fraction of the mitochondria lost the highly ordered structure of the cristae and showed an increase in the cross-sectional area. however, the size of the sr- mitochondrial associations and the gap-width at the interface was unchanged. evaluation of the sr-mitochondrial tethers by electron tomography indicates that they occur in clusters and display heterogeneity in length, as previously re- ported for er-mitochondrial tethers in normal rat liver (csordas et al, , j cell biol, : ). overall tether length distribution appears to be unaltered by alcohol ingestion. analyses of effects of alcohol ingestion on tether membrane-surface density and structural classes (linear, v, y and more com- plex shapes) is in progress, as is d analysis of ser and mitochondrial inner- and outer-membrane topologies. (supported by nih grant rc aa .) -plat bcl-xl increases bax mitochondrial localization and activation in non- apoptotic cells laurent m. dejean , thibaud t. renault , oscar teijido , gisele velours , yogesh tengarai ganesan , nadine camougrand , bruno antonsson , stephen manon . california state university of fresno, fresno, ca, usa, cnrs, institut de biochimie et de génétique cellulaires, bordeaux, france, nih, nichd, bethesda, md, usa, memorial sloan kettering cancer center, new york, ny, usa, merck serrono s.a., geneva research center, geneva, switzerland. we report that, in non-apoptotic pro-lymphocyte cells, bcl-xl induced an in- crease of the mitochondrial localization of bax up to the level found in apopto- tic cells. furthermore bcl-xl stimulated both the active conformation of bax and increased the total amount of bax inserted in the outer mitochondrial mem- brane. in order to further investigate the molecular mechanisms involved in this effect, different bax and bcl-xl mutants were co-expressed in yeast. we found that wild-type bcl-xl increased the mitochondrial localization of both wild- type bax and of an active mutant bax-s d, while mutant bcl-xl-g a did not have this effect. further, wild-type bcl-xl protected bax-s d against proteolytic degradation. finally, we found that a c-terminally truncated mutant of bcl-xl, that lost its capacity to inhibit bax-induced release of cyto- chrome c, still increased the mitochondrial localization of wild-type bax, thus promoting the release of cytochrome c. these data suggest that bcl-xl, by act- ing as a modulator of mitochondrial bax localization, may play an active role along the pathway leading to bax activation. -plat the physiological response of intact ex vivo mitochondria upon apopto- tic stress: insight into the regulation of apoptosis at a mitochondrial level martin n. lidman , marcus wallgren , olivier keech , yong-zhi guo , tor ny , gerhard gröbner . chemistry department, umeå university, umeå, sweden, umeå plant science center, umeå, sweden, medical chemistry and biophysics, umeå university, umeå, sweden. apoptosis - programmed cell death - is vital for multicellular organisms to dis- pose of redundant, damaged or infected cells. this mechanism becomes dys- functional in cancer where tumor cells survive drug-induced death signals. reversely, upregulated apoptosis can induce premature neuronal cell death in amyloidogenic diseases such as alzheimer’s disease (ad) or amyotrophic lateral sclerosis (als). mitochondrion, the power plant of the cell, contains an arsenal of proteins which regulate programmed cell death. there, the pro- and anti-apoptotic bcl- proteins meet at the mitochondrial membrane to decide the fate of a cell. how the molecular activities of the anti-apoptotic 	the isoform specific n terminus of vdac is dispensable for tbid induced cytochrome c release 	patch-clamp analysis of mitochondrial ca + uniporter in different tissues 	sr-mitochondrial ultrastructure in the heart of normal and ethanol-fed rats 	bcl-xl increases bax mitochondrial localization and activation in non-apoptotic cells 	the physiological response of intact ex vivo mitochondria upon apoptotic stress: insight into the regulation of apoptosis a ... preface / préface copyright © canadian society for eighteenth-century studies / société canadienne d'étude du dix-huitième siècle, ce document est protégé par la loi sur le droit d’auteur. l’utilisation des services d’Érudit (y compris la reproduction) est assujettie à sa politique d’utilisation que vous pouvez consulter en ligne. https://apropos.erudit.org/fr/usagers/politique-dutilisation/ cet article est diffusé et préservé par Érudit. Érudit est un consortium interuniversitaire sans but lucratif composé de l’université de montréal, l’université laval et l’université du québec à montréal. il a pour mission la promotion et la valorisation de la recherche. https://www.erudit.org/fr/ document généré le avr. : lumen selected proceedings from the canadian society for eighteenth-century studies travaux choisis de la société canadienne d'étude du dix-huitième siècle preface préface don nichol volume , uri : https://id.erudit.org/iderudit/ ar doi : https://doi.org/ . / ar aller au sommaire du numéro Éditeur(s) canadian society for eighteenth-century studies / société canadienne d'étude du dix-huitième siècle issn - (imprimé) - (numérique) découvrir la revue citer ce document nichol, d. ( ). preface / préface. lumen, , v–vii. https://doi.org/ . / ar https://apropos.erudit.org/fr/usagers/politique-dutilisation/ https://www.erudit.org/fr/ https://www.erudit.org/fr/ https://www.erudit.org/fr/revues/lumen/ https://id.erudit.org/iderudit/ ar https://doi.org/ . / ar https://www.erudit.org/fr/revues/lumen/ -v -lumen / https://www.erudit.org/fr/revues/lumen/ lumen xxxi, • v-vii preface/ préface the th annual conference of the canadian society for eighteenth- century studies took place in st. john’s, nl, from to october . our theme was “charting the th century: encircling land & sea.” if anything, this conference was a testament to longevity: two plenary speakers from our last csecs conference held here in returned eighteen years later as hale and as intellectually hardy as ever. the eighteenth century constantly surprises us. in her lifelong mapping out of lady mary wortley montagu’s mental terrain, isobel grundy has uncovered philocles, “a vision of male charms… a femi- nised man of sensibility, the only character in the story who is capable of reciprocating her deep and passionate love. he turns out, however, not to be human, but a visitor from space, heir apparent to the ruler of the planet venus.” so gender-sensitive, extra-terrestrial soul-mates were not an invention of steven spielberg after all. jean-françois palomino applies his expertise in cartography to the mapping of new france. pat rogers illuminates an occupation not often thought of beyond the realm of property acquisition, essential in determining boundaries: that of surveyor who followed the trailblazer (thomas jefferson, we are reminded, came from a long line of surveyors). other papers from new and established scholars alike cover poetry, prose, drama, art, history, biography, philosophy, and religion. i would like to thank gary kachanoski, the president of memorial university of newfoundland, and his predecessor, chris loomis, for supporting this endeavour. i am also grateful to my head of depart- ment, donna walsh, for providing me with two graduate assistants, amber parker and rebeccah hearn, for help with the editing of these papers. lumen .final.indd - - : pm vi don nichol another delegate, jay macpherson, returned to us in . as a schoolgirl, jay crossed the atlantic from england in the dark days of wwii. she attended bishop spencer college in st. john’s before mov- ing on to victoria college in toronto where she taught for nearly forty years. she recalled the last time she stayed at our conference venue, seventy years earlier. it was hallowe’en , and she wandered the halls of the old hotel draped in a bed-sheet for her ghostly disguise. an influential poet and swift scholar, she was a longstanding member of csecs. jay passed away at the age of eighty on march . this volume is dedicated to her. * * * c’est à st. john’s, terre-neuve, que s’est déroulé du au octobre le trente-sixième congrès de la société canadienne d’étude du dix-huitième siècle. le thème retenu était « cartographier le dix- huitième siècle : mesurer la terre & la mer ». ce congrès fut notam- ment l’occasion d’une belle démonstration de longévité : deux conférenciers invités au dernier congrès de la scedhs à terre-neuve, en , étaient de retour dix-huit ans plus tard, plus inspirés et inspi- rants que jamais. le dix-huitième siècle peut encore nous surprendre. au détour de ses recherches consacrées à la cartographie de l’univers intellectuel de lady mary wortley montagu, isobel grundy est tombée sur le person- nage de philocles : « a vision of male charms […] a feminised man of sensibility, the only character in the story who is capable of reciprocating her deep and passionate love. he turns out, however, not to be human, but a visitor from space, heir apparent to the ruler of the planet venus. » il semblerait que steven spielberg n’ait pas été le premier à imaginer la rencontre entre des âmes sœurs venues de l’espace et sensibles aux rapports entre les sexes. jean-françois palomino, dans le cadre d’une enquête sur le rôle des savoirs géographiques en milieu colonial, se livre à l’examen des pratiques cartographiques en nouvelle-france. pat rogers, quant à lui, s’intéresse à une profession mal connue (sauf peut- être par ceux qui s’apprêtent à devenir propriétaire), mais qui joua un rôle pourtant essentiel dans la détermination des frontières par les pionniers : arpenteur (thomas jefferson, dit-on, était issu d’une longue lignée d’arpenteurs). les autres articles, fruits du travail de jeunes lumen .final.indd - - : pm preface/préface vii chercheurs et de chercheurs confirmés, portent sur des domaines variés tels que la poésie, la prose, le théâtre, l’art, l’histoire, la biographie, la philosophie et la religion. je voudrais remercier gary kachanoski, recteur de l’université memorial de terre-neuve, ainsi que son prédécesseur, chris loomis, pour avoir rendu possible la réalisation de cette aventure. je suis également reconnaissant envers la directrice de mon département, donna walsh, qui a permis l’embauche de deux assistantes, amber parker et rebeccah hearn, pour m’appuyer dans le travail d’édition de ces articles. déjà présente au congrès de , jay macpherson nous a fait l’honneur de revenir pour celui de . alors qu’elle était encore étudiante, jay a traversé l’atlantique et quitté l’angleterre qui subissait alors les affres de la deuxième guerre mondiale. après des études à bishop spencer college à st. john’s, elle a pris la direction de victoria college, à toronto, où elle a enseigné pendant près de quarante ans. elle avait toujours en mémoire son précédent séjour sur le lieu de notre congrès, il y a soixante-dix ans. À l’occasion de la fête d’halloween de , il lui avait pris l’idée de se dissimuler sous un drap et de parcou- rir les couloirs du vieil hôtel en se faisant passer pour un fantôme. poète renommée et spécialiste de swift, elle figurait parmi les mem- bres de longue date de la scedhs. jay est décédée le mars à l’âge de quatre-vingt ans. ce volume lui est dédié. don nichol department of english memorial university of newfoundland / université memorial de terre-neuve lumen .final.indd - - : pm wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, 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has become a vital part of assessing lower limb ischemia and peripheral vascular disease in international studies. the -item vascuqol was developed in uk english and investigates domains: symptoms, pain, activities, social life and emotional state. prior to use in an international trial the measure underwent linguistic validation in lan- guages. methods: a qol specialist coordinated the translation process in each target country using the fol- lowing methodology: ) two forward translations by pro- fessional, native speaking translators of the target lan- guage fluent in english; ) comparison and reconciliation of the translations by a qol specialist and translators; ) backward translation by a native english speaker; ) comparison of the source and backward versions; ) re- view of the translation by a clinician in each country; ) comprehension test in a sample target population; ) in- ternational harmonization. results: linguistic and conceptual issues emerged when translating idiomatic phrases and response scales. linguistic equivalents had to be found for expressions such as “being (or becoming) housebound” and “social activities”. the notions of “discomfort”/“distress” did not have direct equivalents in some languages where a single notion had to be used. in most languages the frequency scale expressed in amounts of time had to be simplified to establish equidis- tant responses. conclusions: a rigorous translation methodology was performed to ensure conceptual equiv- alence and acceptability of translations. international feedback obtained through the translation process re- vealed issues regarding the original instrument, indicating that future amendments to the original may be necessary. future psychometric testing will be conducted to ensure reliability and validity of each translation, appropriate- ness of the questionnaire in each country and compara- bility of data across countries. pmt assessing physician practice profitability using an activity based costing model stephens jm, bell cf, klingman d parexel international, outcomes research group, alexandria, va, usa physicians are increasingly challenged to maintain prac- tice profits in the face of tightening reimbursements from payers. while office visits generate a revenue stream for physicians, it is not clear whether frequent lower com- plexity visits (e.g., nurse visits to administer injections) are actually profitable for physician practices. objec- tive: to develop an adaptable model and methodology to evaluate profitability and financial incentives for vari- ous in-office services provided by physicians and their staff. methods: a literature and expert opinion based model was developed from the physician practice per- spective and was designed to be flexible for a variety of office-based services. the practice cost component of the model was developed using activity-based costing princi- ples and included direct (drug acquisition, supplies, clini- cal labor time, office visits) and indirect (malpractice in- surance, office rent) expenses. the practice revenue component of the model consisted of the reimbursement amount from payers, including: drug reimbursement; of- fice visits for physician evaluation, injections, end of treatment follow-up and adverse events; and laboratory tests. results: practice profitability is inversely pro- portional to the number of low complexity office visits per year. payer mix is also an important determinant of profitability for in-office services, with medicare reim- bursements generally resulting in a net loss for practices (� loss per office visit for the lowest complexity ser- vices) and typical managed care reimbursements provid- ing only small profits (approximately per low complex- ity visit). conclusions: frequent low-complexity office visits for administration of drug therapies do not appear profitable for physician practices under medicare reimbursement. alternative modes of drug delivery such as implantable drug delivery devices or patient self-ad- ministration may be more profitable for physician prac- tices by allowing substitution of more highly reimbursed office services. pmt valuing non-workplace productivity lost in migraineurs: human capital approach and replacement cost method kim ss, lofland jh office of health policy and clinical outcomes at thomas jefferson university hospital, philadelphia, pa, usa objective: to determine the non-workplace produc- tivity costs (nwpc) for migraineurs using the human capital approach (hca) and replacement cost method (rcm). method: this was a supplemental analysis to a prospective, observational migraine outcomes study conducted at a managed care organization. migraineurs self-reported their work status, occupational category, number of days missed from normal ‘activities’ outside of paid job(s) due to migraine symptoms, number of days performing normal ‘activities’ with migraine symptoms, and percent effectiveness while performing normal ‘activ- ities’ with migraine symptoms, at baseline, months, and months after the initiation of sumatriptan. daily occu- pational wages were obtained from the bureau of labor statistics. nwpc were calculated using the hca and php a systematic review of the european pharmaceutical market and the impact of european union regulation and jurisdiction a abstracts php a comparative analysis of the financing, pricing and reimbursement systems for prescription drugs in the nordic countries kristensen fko, sverre jm, holm lb pharmecon as, asker, norway objectives: to elicit similarities and differences in the poli- cies and practices for financing, pricing and reimbursing pre- scription drugs in the often perceived similar nordic countries of denmark (d), finland (f), norway (n) and sweden (s). methods: a review of the four countries’ authorities’ stated policies and practices on the matter were performed through a search of the literature and of the respective authorities’ home- pages. the information was validated through interviews with key personnel of the reimbursement agencies in each country, and the final study reports for the respective countries were reviewed by the same persons. results: all countries have a national health care system financed by taxation. there are dif- ferences in the reliance upon patient co-payment (n %, others – %) and whether financing is a county (s) or national (others) responsibility. all have regulated prices for reimbursed drugs; based either upon international comparisons (n, d) or country-specific decisions (s, f). the criteria used for deciding to reimburse a drug vary between the countries, and reimbursement is practiced differently in several other dimensions: mandatory requirement for pharmacoeconomic analysis (f, n, s), the existence of patient-specific reimbursement systems (d, f, n), product- (s) or indication-based (others) reimbursement, use of graded (f), conditional (n, s) or temporary (s) reimbursement, use of reimbursement contracts (n), and different processes for handling disagreement about decisions. conclusion: the nordic countries all have a national health care system financed by taxation and encompassing prescription drugs, but differ in a number of other dimensions with respect to financing, pricing and reimbursing such drugs. php a systematic review of the european pharmaceutical market and the impact of european union regulation and jurisdiction van ginneken ej, schreyögg j, gericke ca, busse r berlin university of technology, berlin, germany objectives: to examine the impact of the increasing role of the european union (eu) on the european pharmaceutical market, focusing on industry and national policies. to give a sys- tematic overview of the current state of the european pharma- ceutical market as a whole. methods: systematic literature review for the years – , including “grey” sources of information, online databases, european commission docu- ments and european court of justice rulings, relevant journals and systematically tracing back relevant references. results: the eu attempts to liberalise the pharmaceutical market and the realisation of a single european market (sem) came to a stand- still, after some considerable achievements (e.g. marketing authorisation). instead, the eu seems to concentrate on coor- dination of results through the adoption of the so-called g recommendations. eu member states successfully—and inten- tionally—kept control on the issues of pricing, reimbursement, pharmacies and prescribing. over the last years they adapted increasingly convergent measures to cope with rising pharma- ceutical expenditures, without long-lasting cost containment effects. however, recent european case law might prove to have far reaching consequences on the provision of medicines. the european pharmaceutical industry—although profitable—is underperforming compared to the usa, which is blamed on restrictive regulatory frameworks in the member states. con- clusions: the future of the actors in the european pharma- ceutical market is not clear. will it bring more european influence or a strengthening of national influence? in the short term, major change towards a sem seems unlikely, but in the longer term european history showed that major change is pos- sible. it seems clear that much depends on the attitude of member states towards the new approach and the interpretation and influence of european case law. for the european industry, adoption and implementation of g recommendations is of great importance for future competition with us-based companies. php using an italian population database to profile prevalence and costs of chronic conditions yuen ej, maio v, louis dz, rabinowitz c, robeson m, smith kd jefferson medical college, thomas jefferson university, philadelphia, pa, usa objective: individuals with chronic medical illness may have multiple health problems, and are often costly and difficult to manage. this study identifies those with highly prevalent chronic conditions and assesses related health service use and costs in the population of emilia romagna (rer), a large northern italian region. methods: pharmaceutical, hospital, and demographic data from and have been assembled for the entire population of rer ( million). pharmaceutical and hospital tariffs were a proxy for costs. pharmacy and hospital records were used to identify individual morbidity. data included demo- graphic and geographic information, encounter dates, diagno- sis/procedure codes, pharmaceutical information, and health care costs. individuals were classified as having a chronic condi- tion in , and we examined pharmacy and hospital use/costs in . descriptive analyses compared mean and total costs, as well as proportions within the population. results: we iden- tified five highly prevalent chronic conditions: cardiovascular dis- eases (n = , , . % of the population); rheumatologic conditions (n = , , . %); gastric acid disorders (n = , , . %); chronic respiratory illnesses (n = , , . %); and psychiatric disorders ( , , . %). . % of the population had one or more of these five chronic conditions, and these individuals accounted for . % of the pharmacy costs and . % of the hospital costs in the following year. for persons with these five conditions, we also described use and costs by age and gender, residence, and income. conclusions: interest- ingly, one-fourth of the population with selected chronic condi- tions accounted for large proportions of cost and use of health services. the ability to identify those with chronic conditions would help planners and governmental agencies to address health care needs, increase quality of care, avoid unnecessary hospitalizations, and save costs. these types of data can be used to estimate health care financing and risk adjustment models, and profile specific clinical, demographic or geographic sub-groups. php adherence index of performance—a new method and tool for ongoing evaluation of medication adherence improvement initiatives day d pfizer, new york, ny, usa objectives: to develop a standardized means for measuring the impact of medication adherence improvement initiatives in disparate pharmacy claims databases over sequentially overlap- ping periods of time. methods: the adherence index of s y m p o s i u m : p a p e r s p r e s e n t e d a t t h e a n n u a l m e e t i n g s o f t h e k n e e s o c i e t y papers presented at the annual meetings of the knee society editorial comment mark w. pagnano md published online: november � the association of bone and joint surgeons the papers presented at the annual meetings of the knee society symposium includes selected manuscripts read at the members meeting of the knee society held in boston in october and the open scientific meeting of the knee society held in new orleans in march . the knee society education committee and program chair, richard iorio, md, assembled a broad array of scientific work for presentation at the meetings and this symposium issue includes the best of those presented. each paper has gone through a rigorous peer review and revision process for the authors but has resulted in a group of manuscripts that are of substantial value for readers. my sincere thanks go to the staff at corr for their timely and valuable hard work in assisting authors through the publication process. the insall award paper was authored by dr. douglas dennis and colleagues from denver who have delineated several risk factors for the development of symptomatic patellar crepitus after total knee arthroplasty. contemporary posterior-stabilized knee designs have lar- gely eliminated the problem of patellar clunk in which a fibrous nodule forms proximal to the patella and catches palpably and often audibly in the intercondylar box as the knee extends from a flexed position. however, patellar crepitus remains a clinical issue in a subset of patients and essentially represents a milder form of the same basic phenomena. after reviewing patients with patellar crepitus and matching them to patients without crepitus, the authors suggest several simple surgical strategies, including using larger patellar components whenever possible, maintaining patellar composite height after patellar replacement, and avoiding increases in posterior condylar offset. the ranawat award paper was authored by dr. thomas fehring and gathered data from colleagues around the united states regarding the fate of patients who fail an initial attempt at irrigation, débridement, and com- ponent retention for deep prosthetic infection around a total knee arthroplasty. much prior work has focused on the relative risks and on the rates of success/failure after irri- gation, débridement, and component retention. most contemporary authors would suggest that management strategy offers a % chance of success in controlling infection. little attention has been given to the subsequent efforts to control infection in those patients who fail an attempt at débridement and component retention. fehring and colleagues note that subgroup of patients is at much higher risk of treatment failure after two-stage fig. mark w. pagnano, md, is shown. m. w. pagnano (&) department of orthopedic surgery, mayo clinic, first street sw, rochester, mn , usa e-mail: pagnano.mark@mayo.edu clin orthop relat res ( ) : – doi . /s - - - reimplantation total knee arthroplasty than is the typical patient who undergoes the two-stage reimplantation as the first intervention for deep prosthetic infection. before abandoning débridement and component retention for at least a subgroup of patients, however, many surgeons will want to see further work to determine the effect of selection bias on the reported high reinfection rates for those for whom débridement has failed. the coventry award paper was authored by dr. hany bedair and colleagues and included collaboration between rush university and thomas jefferson university investigators. the authors introduce useful guidelines for the analysis of synovial fluid in ruling out infection in the early postoperative period (within weeks). prior work by numerous investigators provided data regarding synovial fluid analysis of late deep prosthetic infection and sug- gested synovial white blood cell counts of cells/ll or more indicated infection particularly when accompanied by a predominance of polymorphonuclear cells. in the early postoperative period, however, the present data show the cutoff value climbs substantially to , cells/ll. at that level the synovial fluid white blood cell count was % sensitive and % specific in detecting deep prosthetic infection. the remaining papers in this symposium cover a range of topics regarding the management of the arthritic knee, including unicompartmental knee arthroplasty, techniques in primary total knee arthroplasty, results of primary total knee arthroplasty, complications, and topics in revision tka. the high quality of these papers reaffirms the com- mitment of the knee society to advancing the international orthopaedic community’s collective understanding of sur- gery for the arthritic knee. we hope in this issue the typical reader finds useful information that can be incorporated into daily practice as well as some intellectual puzzles that spur further inquiry. pagnano clinical orthopaedics and related research 	papers presented at the annual meetings of the knee society: editorial comment << /ascii encodepages false /allowtransparency false /autopositionepsfiles true /autorotatepages /none /binding /left /calgrayprofile (gray gamma . ) /calrgbprofile (srgb iec - . ) /calcmykprofile (iso coated v % \ eci\ ) /srgbprofile (srgb iec - . ) /cannotembedfontpolicy /error /compatibilitylevel . /compressobjects /off /compresspages true /convertimagestoindexed true /passthroughjpegimages true /createjobticket false /defaultrenderingintent /perceptual /detectblends true 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/addcropmarks false /addpageinfo false /addregmarks false /convertcolors /converttocmyk /destinationprofilename () /destinationprofileselector /documentcmyk /downsample bitimages true /flattenerpreset << /presetselector /mediumresolution >> /formelements false /generatestructure false /includebookmarks false /includehyperlinks false /includeinteractive false /includelayers false /includeprofiles false /multimediahandling /useobjectsettings /namespace [ (adobe) (creativesuite) ( . ) ] /pdfxoutputintentprofileselector /documentcmyk /preserveediting true /untaggedcmykhandling /leaveuntagged /untaggedrgbhandling /usedocumentprofile /usedocumentbleed false >> ] >> setdistillerparams << /hwresolution [ ] /pagesize [ . . ] >> setpagedevice john r. fowler jr., nandkumar m. rawool: ultrasound of the hand and upper extremity. a step-by-step guide vol.:( ) surgical and radiologic anatomy ( ) : https://doi.org/ . /s - - - review john r. fowler jr., nandkumar m. rawool: ultrasound of the hand and upper extremity. a step-by-step guide thieme, new york stuttgart delhi rio de janeiro, , p., format  ×  .  cm, isbn - - - - , eisbn - - - - bruno grignon received: december / accepted: december / published online: december © springer-verlag france sas, part of springer nature since its recent technical advances, mobile ultrasonography has become an extremely practical tool, allowing both diag- nosis and treatment of various musculoskeletal disorders. according to the authors, this book aims at being a “cookbook” for busy clinicians, including hand surgeons, orthopaedic surgeons, radiologists, and sports medicine spe- cialists. it is divided into five sections, subsequently entitled: introduction (dealing with basic ultrasound principles), fin- gers and wrist, forearm and elbow, shoulder, and masses. designed to allow clinicians to find information quickly and apply it to the intended clinical situation, the content includes bullet-point text, informative figures, and detailed clinical examples. each chapter is presented as follows: appropriate setup, anatomic landmarks, probe and patient positioning, normal anatomy, and relevant pathologic anat- omy. available injection techniques for anatomic areas and conditions are illustrated by pictures showing how to hold the probe and where to place the needle. in addition, selected chapters have video to demonstrate the techniques. the editors are: john r fowler jr, assistant professor, department of orthopaedic surgery, university of pittsburg medical center, pittsburg, pennsylvania, usa, and nandku- mar m rawool, associate professor, department of radio- logic sciences, thomas jefferson university, philadelphia, pennsylvania, usa. eleven american contributors have col- laborated in writing this work. richly illustrated and nicely written, this guidebook is also pleasantly and clearly presented. all the figures (pho- tographs, anatomical drawings, and ultrasound images) are demonstrative and of high quality. the bullet-points text makes it really easy to use. however, it must be kept in mind that it was the choice of the authors to deliver a “high-yield” format rather than dense paragraphs of information. as a result, the book may be of lesser interest for experienced clinicians. to sum up, this practical step-by-step guide may be greatly helpful for all physicians, seniors and residents, aim- ing to integrate musculoskeletal ultrasound in their clinical practice. * bruno grignon b.grignon@chu-nancy.fr university of lorraine, chu nancy, nancy, france http://crossmark.crossref.org/dialog/?doi= . /s - - - &domain=pdf 	john r. fowler jr., nandkumar m. rawool: ultrasound of the hand and upper extremity. a step-by-step guide new retina md . /issue young investigators by s. k. steven houston iii, md; nadim rayess, md; carl d. regillo, md; and allen c. ho, md a sticky situation: the effect of the vitreomacular interface on neovascular amd treatment n eovascular age-related macular degeneration (amd) is the leading cause of vision loss and blindness in patients older than years in the united states. before the advent of anti-vegf agents, the natural history of neovascular amd was a rapid decline in vision with a resultant disciform scar and poor central vision. the phase marina and anchor trials showed not only that intravitreal administration of ranibizumab (lucentis, genentech) could maintain visual acuity in patients with wet amd, but also that treatment often led to improve- ment in vision, with a mean increase of to letters. , subsequently, the view and studies established the noninferiority of intravitreal aflibercept (eylea, regeneron) to ranibizumab in the treatment of neovascular amd. finally, the catt and ivan studies , established that bevacizumab (avastin, genentech) and ranibizumab had similar levels of efficacy when used as monthly intravitreal injections. protocols for neovascular amd treatment include monthly, as-needed (prn), and treat-and-extend (tae) reg- imens. tae is now the most commonly utilized treatment protocol for wet amd, with more than three-quarters of responders to the preferences and trends survey of the american society of retina specialists using this regi- men. several retrospective studies have demonstrated the efficacy of a tae protocol, and the prospective lucas trial has shown similar data at year. despite the excellent efficacy of anti-vegf agents in many patients with neovascular amd, some patients do not respond completely or continue to progress and lose vision over time despite maximal anti-vegf therapy. there is an ongoing effort to identify personal characteristics that may elucidate, influence, or predict one’s response to anti-vegf therapy. role of vma in an attempt to better understand these differences in response to anti-vegf therapy, the focus of current study has turned to an evaluation of the vitreomacular interface. higher rates of vitreomacular adhesion (vma) and lower rates of posterior vitreous detachment (pvd) are found in eyes with neovascular amd compared with either healthy eyes or those with dry amd. - what is not known is whether vma influences the development of wet amd or whether wet amd promotes vma. the excite trial included a subgroup analysis of patients in which the influence of the vitreomacular interface on wet amd treatment was investigated. based on findings from time-domain optical coherence tomog- raphy (td-oct), patients were divided into three groups: those with pvd, those with release of vitreomacular con- tact, and those with vma. the study found that in patients with a pvd, there was no significant difference in visual acuity in patients treated monthly or quarterly. conversely, in patients with release of vitreomacular contact or with vma, quarterly treatment resulted in significantly inferior visual acuity gains compared with monthly treatment. the study concluded that patients with vma might need more intensive treatment to achieve similar visual acuity results. we performed a study to determine the influence of /issue . new retina md young investigators the vitreomacular interface on treatment outcomes in patients with neovascular amd treated with anti-vegf agents using a tae protocol. this was a retrospective, consecutive case series of eyes of patients with new-onset neovascular amd. patients were divided into two groups based on spectral-domain optical coherence tomography findings: those with no vma (non-vma) and those with vma. mean age in the non-vma group was . and in the vma group . . in the non-vma group, mean pre-treatment visual acuity was / and mean central retinal thickness (crt) was . µm; in the vma group, the numbers were / and . µm, respectively. use of bevacizumab, ranibizumab, and aflibercept was similar between the groups. visual acuity in both groups improved significantly from baseline at years and . the non-vma group improved to / at year and / at year , while the vma group improved to / at year and stabilized at / at year . in each group, approximately % of patients gained or more lines of vision at years and . additionally, more than % of patients in each group avoided loss of or more lines of vision. crt decreased in conjunction with improving visual acuity. in the non-vma group, crt decreased to µm at year and µm at year . in the vma group, crt decreased to µm at year and µm at year . the vma group showed an increased percentage of persis- tent choroidal neovascular activity in comparison with figure . a -year-old man with neovascular amd in the left eye was treated with ten intravitreal bevacizumab injections followed by five intravitreal aflibercept injections using a tae protocol. sd-oct shows broad vma with persistent subretinal fluid. the treatment interval could not be extended past to weeks. figure . a -year-old man with neovascular amd in the left eye was treated with one intravitreal bevacizumab injection followed by eight intravitreal ranibizumab injections using a tae protocol. sd-oct shows broad vma with mild persistent subretinal fluid. the treatment interval could not be extended past to weeks. new retina md . /issue young investigators the non-vma group ( % at year compared with %, respectively). finally, mean numbers of injections at years and were significantly different. patients in the non-vma group needed . injections in year on average, while patients in the vma group required . injections. at year , patients in the non-vma group required a mean . injec- tions compared with . injections in the vma group. the mean longest interval extension was also significantly longer for the non-vma group ( . weeks at year and . weeks at years) compared with the vma group ( . and . , respectively). clinical utility the clinic utility of treating vma associated with neovas- cular amd was recently explored by novack and cowork- ers as they investigated the use of intravitreal ocriplasmin (jetrea, thrombogenics) in combination with anti-vegf agents. their randomized, prospective phase trial enrolled patients with vma and wet amd to compare combi- nation therapy (ocriplasmin plus anti-vegf) versus sham (anti-vegf alone). at year, safety profiles were similar to those of previous ocriplasmin trials, and the group treated with ocriplasmin had higher rates of vma release ( . % versus %) and total pvd ( % versus %) compared with the sham-treated group. of note, the combination group required % fewer injections ( . versus . ) com- pared with the sham group. with improved imaging technology, we are learning more about the vitreoretinal interface and its effect on numerous retinal diseases. there is much debate regarding whether vma is pathologic in nature or whether it repre- sents only a stage in the development of a pvd. additionally, there is the question whether vma is caus- ative or a bystander in the process. does vma with associ- ated tractional forces contribute to the development and pathophysiology of neovascular amd, or does the choroidal neovascularization result in a focal inflammation leading to abnormal adhesion of the posterior vitreous cortex to the internal limiting membrane and retina? there is evidence that traction from the vitreous may be proinflammatory and may even cause mechanical stress on retinal pigment epithelial cells and result in elevated vegf expression. the vitreous and vitreomacular interface may also act as a diffusion barrier. vitrectomy and pvd result in a more liquefied vitreous with decreased viscosity, leading to increased diffusion of oxygen, cytokines, growth factors, and medications. the vitreomacular interface, notably vma or vitreomacular traction, may act as a barrier to the diffusion of small anti-vegf molecules across the densely arranged collagen matrix of the posterior hyaloid and cortical vitreous into the retina. vma may also confine proangiogenic molecules in the retina by preventing their diffusion into the vitreous cavity. our current study suggests that anatomic factors may contribute to individual treatment responses and should be considered in treatment decisions for neovascular amd. although eyes with neovascular amd had similar visual acuity outcomes regardless of the configuration of the vitreomacular interface, eyes with vma may require more frequent and intensive anti-vegf treatment and have a decreased ability to extend the interval between injections (figures and ). n allen c. ho, md, is the director of retina research at wills eye hospital and a professor of ophthalmology at thomas jefferson university in philadelphia, pennsylvania. dr. ho may be reached at acho@att.net. s. k. steven houston iii, md, is a second-year vitreoretinal fellow at wills eye hospital in philadelphia, pennsylvania. dr. houston may be reached at shouston @gmail.com. nadim rayess, md, is a retina research fellow at wills eye hospital in philadelphia, pennsylvania. dr. rayess may be reached at nmrayess@gmail.com. carl d. regillo, md, is the director of the retina service of wills eye hospital and a professor of ophthalmology at thomas jefferson university in philadelphia, pennsylvania. dr. regillo may be reached at cregillo@aol.com. . rosenfeld pj, brown dm, heier js, et al; marina study group. ranibizumab for neovascular age-related macular degeneration. n eng j med. ; ( ): - . . brown dm, kaiser pk, michels m, et al; anchor study group. ranibizumab versus verteporfin for neovascular age-related macular degeneration. n eng j med. ; ( ): - . . heier js, brown dm, chong v, et al; view and view study groups. intravitreal aflibercept (vegf trap-eye) in wet age-related macular degeneration. ophthalmology. ; ( ): - . . martin df, maguire mg, ying gs, et al; catt research group. ranibizumab and bevacizumab for neovascular age-related macular degeneration. n eng j med. ; ( ): - . . chakravarthy u, harding sp, rogers ca, et al; ivan study investigators. ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the ivan randomized trial. ophthal- mology. ; ( ): - . . berg k, pedersen tr, sandvik l, bragadottir r. comparison of ranibizumab and bevacizumab for neovas- cular age-related macular degeneration according to lucas treat-and-extend protocol. ophthalmology. ; ( ): - . . krebs i, brannath w, glittenberg c, et al. posterior vitreomacular adhesion: a potential risk factor for exudative age-related macular degeneration? ophthalmology. ; ( ): - . . robison cd, krebs i, binder s, et al. vitreomacular adhesion in active and end-stage age-related macular degeneration. am j ophthalmol. ; ( ): - . ) mojano f, cheng l, bartsch du, et al. the role of abnormal vitreomacular adhesion in age-related macular degeneration: spectral optical coherence tomography and surgical results. am j ophthalmol. ; ( ): - . . mayr-sponer u, waldstein sm, kundi m, et al. influence of the vitreomacular interface on outcomes of ranibi- zumab therapy in neovascular age-related macular degeneration. ophthalmology. ; ( ): - . . houston sk iii. influence of vitreomacular interface on anti-vegf therapy using treat and extend treatment protocol for age-related macular degeneration (vintrex). paper presented at: american society of retina special- ists annual meeting; august - , ; san diego, ca. . novack rl, staurenghi g, girach a, narendran n, tolentino m. safety of intravitreal ocriplasmin for focal vitreomacular adhesion in patients with exudative age-related macular degeneration [published online ahead of print november , ]. ophthalmology. doi: . /j.ophtha. . . . . donoso la, kim d, frost a, callahan a, hageman g. the role of inflammation in the pathogenesis of age- related macular degeneration. surv ophthalmol. ; ( ): - . . seko y, seko y, fujikura h, pang j, tokoro t, shimokawa h. induction of vascular endothelial growth factor after application of mechanical stress to retinal pigment epithelium of the rat in vitro. invest ophthalmol vis sci. ; ( ): - . wp-p m- .ebi.ac.uk params 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or article title). http://europepmc.org/abstract/med/ [pdf] social determinants of methadone in pregnancy: violence, social capital, and mental health | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . / . . corpus id: social determinants of methadone in pregnancy: violence, social capital, and mental health @article{alexander socialdo, title={social determinants of methadone in pregnancy: violence, social capital, and mental health}, author={k. alexander}, journal={issues in mental health nursing}, year={ }, volume={ }, pages={ - } } 	k. alexander 	published 	medicine 	issues in mental health nursing mothering and methadone can occur together with the right resources and support. methadone mothers need to be seen in the context of their social risks and environment. societal attitudes, social capital, and other contextual variables can be changed through policy. the purpose of this article is to describe the contextual risks experienced by drug abusing mothers in order to direct further research and policy changes that protect their children. research has focused on biological or genetic… expand view on taylor & francis duq.edu save to library create alert cite launch research feed share this paper citationshighly influential citations background citations view all topics from this paper 	methadone 	mental disorders 	substance-related disorders 	mental health 	morbidity - disease rate 	battered women citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency contributions of psychology to research, treatment, and care of pregnant women with opioid use disorder. 	h. preis, elizabeth m inman, m. lobel 	psychology, medicine 	the american psychologist 	 	 save alert research feed a call for compassionate care 	k. alexander 	medicine 	journal of addictions nursing 	 	 	view excerpt, cites background save alert research feed engaging mothers to implement nonpharmacological care for infants with neonatal abstinence syndrome 	clayton j shuman, a. weber, katherine vanantwerp, r. wilson 	medicine 	advances in neonatal care : official journal of the national association of neonatal nurses 	 save alert research feed implementation of a mindfulness intervention for women in treatment for opioid use disorder and its effects on depression symptoms 	karen alexander, rebecca a kronk, kathleen sekula, vanessa l. short, d. abatemarco 	medicine 	issues in mental health nursing 	 	 	view excerpt, cites background save alert research feed dietary intake among opioid- and alcohol-using pregnant women 	shikhar shrestha, e. jimenez, + authors l. bakhireva 	medicine 	substance use & misuse 	 	 	 	view excerpts, cites background save alert research feed dementia caregiver burden association with community participation aspect of social capital. 	e. papastavrou, p. andreou, n. middleton, h. tsangari, s. papacostas 	psychology, medicine 	journal of advanced nursing 	 	 save alert research feed improving assessment, treatment, and understanding of pregnant women with opioid use disorder: the importance of life context 	h. preis, d. garry, kimberly herrera, diana garretto, m. lobel 	medicine 	 	 save alert research feed the effect of a mindfulness intervention on the depression symptoms of mothers in treatment for an opioid use disorder 	karen alexander 	medicine 	 	highly influenced 	view excerpts, cites background save alert research feed analyzing and conceptualizing the theoretical foundations of nursing 	j. m. m. p. faan 	sociology 	 	 	pdf 	view excerpt, cites background save alert research feed a call for compassionate care aq 	pdf save alert research feed references showing - of references sort byrelevance most influenced papers recency substance use before and during pregnancy: links to intimate partner violence 	s. martin, j. beaumont, l. kupper 	psychology, medicine 	the american journal of drug and alcohol abuse 	 	 	highly influential 	view excerpts, references background save alert research feed the social ecology of addiction: race, risk, and resilience. 	j. wallace 	medicine 	pediatrics 	 	 	view excerpts, references background save alert research feed contextual determinants of drug use risk behavior: a theoretic framework 	s. galea, j. ahern, d. vlahov 	psychology, medicine 	journal of urban health 	 	 	highly influential 	 	view excerpts, references background save alert research feed drug addiction and pregnancy: policy crossroads. 	w. chavkin 	medicine 	american journal of public health 	 	 	 save alert research feed low-income women's use of substance abuse and mental health services 	daniel rosen, daniel richard m lynn a tolman, d. warner 	medicine 	journal of health care for the poor and underserved 	 	 	highly influential 	view excerpts, references background save alert research feed race/ethnicity and nativity differences in alcohol and tobacco use during pregnancy. 	k. perreira, kalena e. cortes 	medicine 	american journal of public health 	 	 	highly influential 	pdf 	view excerpts, references background save alert research feed management of the pregnant substance abusing woman 	m. sheehan, mary g sheehan 	medicine 	clinical obstetrics and gynecology 	 	 	view excerpt, references background save alert research feed suicidality, aggression, and other treatment considerations among pregnant, substance-dependent women with posttraumatic stress disorder. 	a. m. eggleston, p. calhoun, d. svikis, m. tuten, m. chisolm, h. jones 	psychology, medicine 	comprehensive psychiatry 	 	 	highly influential 	 	view excerpts, references methods and background save alert research feed methadone in pregnancy: treatment retention and neonatal outcomes. 	l. burns, r. mattick, kim lim, c. wallace 	medicine 	addiction 	 	 	highly influential 	view excerpts, references background save alert research feed the teds report, data spotlight: trends in substances of abuse among pregnant women and women of childbearing age in treatment 	d. dawes, jennifer schoden, j. greene 	medicine 	 	 	pdf save alert research feed ... ... related papers 	abstract 	topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue pms the effect of lifestyle choices on the risk of impairment in rheumatoid arthritis patients: an analysis of aerobic exercise and cigarette smoking abstracts a symptom). the health assessment questionnaire (haq) was used to measure func- tional status (scores – ). qol was measured by the mental (mcs) and physical (pcs) component summary scores of the short form- (sf- ). work/productivity loss was measured by the work productivity and activity impairment (wpai) instrument. comparisons were made between patients who currently use sc biologics versus those who discontinued treatment. results: of the , survey respondents ( % female; average age . years), ( . %) used sc biologics. the average dura- tion of ra was . years, with % reporting severe disease. the patient-reported mean scores were: morning stiffness . , fatigue . , pain . , haq . , mcs . and pcs . . patients reported . % work impairment and . % impairments in daily activity. patients who had discontinued sc biologic therapy (n , . %) reported signifi cantly worse scores in morning stiffness, fatigue, pain, and pcs (all p . ) versus patients currently treated with sc biologics (n , . %). patients who discontinued therapy had more work/activity loss; only activity impair- ment was statistically signifi cant (p . ). there was no signifi cant difference in haq scores between groups. conclusions: ra patients using current sc biolog- ics still suffer from serious impairments in symptoms, functional status, qol, and work/productivity. however, patients who discontinued sc biologic therapy have sig- nifi cantly worse symptom scores, physical functioning, and activity impairment com- pared with those currently being treated. both fi ndings indicate there is still an unmet medical need in ra patients. pms utility and quality of life of patients with osteoarthritis treated with the cyclooxygenase inhibiting nitric oxide donator (cinod) naproxcinod jonsson b , pfi ster p , holmstrom s , kobelt g uppsala university, uppsala, sweden, nicox, sophia antipolis cedex, france, nicox, sophia antipolis, france, european health economics, speracedes, france objectives: to estimate changes in quality of life (sf ) and utility (sf ) in patients treated with naproxcinod, naproxen or placebo for weeks, and to explore the effect of different disease measures on utility. methods: sf was available from international ph clinical trials in patients with knee or hip osteoarthritis comparing doses of naproxcinod ( and mg bid) to naproxen ( mg bid) and placebo. effi cacy was based on the pain, function and composite scales of the womac™ osteoarthritis index. co-morbidity measures included hypertension (ht) which increases with nsaid therapy, body mass index (bmi) and diabetes. changes in sf and individual sf domains were compared between the groups using anova and dunett’s -sided test. the effect of the womac™ indices, bp, bmi and diabetes on utility scores was explored using multiple regression analysis. results: all sf subscales except mental health as well as utility changed signifi cantly from baseline for all groups, and were correlated with changes in the womac™ indices (p . ). the change in the active groups was signifi cantly better than placebo for pain and physical function ( . ), but not signifi cantly different between treatments. however, absolute changes in utility, pain, physical function and general health were generally larger for naproxcinod mg than naproxen mg by around %. utility scores correlated signifi cantly with womac™, and patients with high bmi and bp or diabetes had lower utility scores and worse womac™ indices. increase in utilities were larger for patients with mg naproxcinod than for the other groups. conclusions: the slightly larger utility and quality of life changes with naprox- cinod mg despite a similar effect as naproxen on womac™ may be explained by a different side-effect profi le and a neutral blood pressure effect. pms an assessment of self reported outcomes in a nationally representative sample of elderly person diagnosed with rheumatoid arthritis rajpura jrjp j st. john’s university, fresh meadows, ny, usa objectives: to utilize webtv technology as a tool to measure hrqol in elderly persons having rheumatoid arthritis (ra) in a nationally representative sample and to describe their socio-demographic characteristics, medication use and other treat- ment choices. methods: a cross- sectional online survey research design. random digit dialing (rdd) survey procedures were used to draw a sample of elderly arthritic individuals from us households across states. a subsample of individu- als previously diagnosed with ra completed sf- v survey, as part of a larger study. eight sf- domain scores and physical and mental component summary (pcs and mcs) scores were computed and compared with cross-sectional norms for general us population. results: compared to the general population, our study sample per- formed poorly with respect to all the sf- domains except mental health (mh) and social functioning (sf) domains. ra is more prevalent in whites ( %) and males reported higher scores for all the eight sf- domains than females. about % of the sample reported the use of at least one available otc arthritic medication; % of the sample was taking prescription drugs, while about % reported having used natural/herbal remedies for arthritis. a signifi cant difference (p . ) was found between males and females with respect to only pcs scores. age was found to correlate negatively (p . ) with pcs and mcs summary measures, particularly for indi- viduals years and older. conclusions: webtv is an effective survey administra- tion tool for measuring hrqol. as expected, elderly perform poorly on three of the sf- domains (pf, rp, bp) having the most physical factor content. prescription drug use is fairly prevalent and use of otc medications and other forms of treatment is popular in the population under study. pms the effect of lifestyle choices on the risk of impairment in rheumatoid arthritis patients: an analysis of aerobic exercise and cigarette smoking shah a , plumb j , brawer r , tang b thomas jefferson university, philadelphia, pa, usa, centocor ortho biotech, inc, horsham, pa, usa objectives: through data analysis we will examine and identify the lifestyle factors that impact clinical outcomes of rheumatoid arthritis (ra) patients. methods: patients’ self-reported data was collected from the ra patient survey, an internet survey of ra patients. we studied the effects of aerobic exercise ( minutes a day per month), and cigarette smoking on ra patients. sign and symptom scores for morning stiffness, fatigue, and pain are defi ned from (no symptom) to (severe symptom) within the survey. the health assessment questionnaire (haq) was used to measure functional status scores ( – ). quality of life was measured by the mental component score (mcs) and physical component score (pcs) of the short-form (sf- ). productivity was measured by the work productivity and activity impairment (wpai) scale. there were no non-ra controls included in the study. results: a total of respondents were included in the analysis patients exercised and patients smoked cigarettes. the average age was . years and average ra duration was . years. patients’ mean mcs and pcs scores in the exercise ( . , . ) and non-smoking groups ( . , . ) were signifi cantly higher, than in the non- exercise ( . , . ) and smoking groups ( . , . ). overall work and productivity impairment was . % (exercise) versus . % (non-exercise), and . % (smoking) versus . % (non-smoking). signs, symptoms, and haq scores were signifi cantly better in the exercise and non-smoking groups (all p . ). conclusions: ra patients who exercise regularly have higher quality of life scores and clinical outcomes. those that smoke cigarettes have lower quality of life scores and higher symptom/ haq scores suggesting that this habit may be detrimental to their clinical outcomes. these results suggest that these lifestyle choices infl uence the overall risk of impairment in ra patients. pms is the health utilities index valid and responsive in assessing patients with ankylosing spondylitis? gooch k , feeny dh , wong r , pangan a , revicki d , van der heijde d abbott laboratories, abbott park, il, usa, kaiser permanente center for health research, portland, or, usa, abbott laboratories, parsippany, nj, usa, united biosource corporation, bethesda, md, usa, leiden university medical center, leiden, netherlands objectives: qalys are an important outcome used in cost-effectiveness analysis. the health utilities index mark (hui- ) is a self-reported measure covering attri- butes of health status. our objective was to assess construct validity and responsiveness of hui- in ankylosing spondylitis (as). methods: data were derived from the adalimumab trial evaluating long-term effi cacy and safety in as (atlas). we speci- fi ed a priori hypotheses regarding the direction and magnitude of associations expected between overall and single-attribute hui- scores and other health status and quality of life measures—sf- , asqol, bath as functional index (basfi), bath as disease activity index (basdai), and patient’s global assessment (pga). using baseline data, we calculated correlation coeffi cients and interpreted them via guidelines suggested by guyatt for negligible, weak, moderate, and strong associations. responsiveness was assessed by calculating standardized response means (srms) of hui- scores from baseline to week for patients meeting the minimum clinically important differences (mcid) for the asqol ( . ). responsiveness analysis was limited to patients with -week hui- scores. results: a total of of the patients enrolled in atlas were included in the analysis. mean age was years, . % were male, and mean duration of as was years. correlation coeffi cients between hui- scores and other instruments confi rmed . % of the a priori hypothesis, with an additional . % being under- or over-estimated by only one category. results of responsiveness analysis demonstrated that there were signifi cant differences in overall hui- (srm . ) and most single-attribute change scores for patients whose changes were greater than the asqol mcid vs. those whose changes were mcid. conclusions: these results suggest that hui- constructs are related to similar constructs in other measures, as expected. this study provides evidence of cross-sectional and longitudinal construct validity of the hui- for deriving utility scores for as patients. pms validation of the multi-attribute health utility (mahu) derived from a computer adaptive instrument, cat- d-qol, in osteoarthritis kang wg , sayre ec , steininger g , doerfl ing p , ratzlaff c , esdaile j , kopec j university of british columbia, vancouver, bc, canada, arthritis research centre of canada and simon fraser university, vancouver, bc, canada, arthritis research centre of canada, vancouver, bc, canada objectives: we aimed to validate the multi-attribute health utility (mahu) derived from the cat- d-qol, a computer-adaptive instrument composed of domains (walking, handling objects, daily activities, pain/discomfort, and feelings) in people with self-reported osteoarthritis (oa), and to compare it with womac_hui , the utility derived from the standard disease-specifi c measure in oa. methods: data were collected from participants (age ) who completed questionnaires cat- d- qol in two waves and womac in one wave of a canada-wide online survey. to assess construct validity, we used multivariable regression to examine the associations slide . % . % . % . % received book (n = ) recommended book (n = ) n u m b e r o f p a rt ic ip a n ts book status vs. amount of book read read at least some of book did not read book prospective randomized control trial using best-selling smoking cessation book james foshee; anita oh, md; adam luginbuhl, md; joseph curry, md; william keane, md; david cognetti, md thomas jefferson university hospital, department of otolaryngology – head and neck surgery patients recruited between april and august • patients with long-term follow-up scheduled before sept. eligible for follow-up • patients voluntarily unenrolled • patients could not be reached for follow-up • patients had disconnected or non- working phone numbers • patient died during the course of the study • patients voluntarily unenrolled • patients could not be reached for follow-up • patients had disconnected or non-working phone numbers abstract: this study aimed to evaluate the efficacy of the educational, self-help book the easy way to stop smoking by allen carr in achieving smoking cessation in patients being screened or currently being treated for cancers of the head and neck. a prospective, randomized control trial was conducted involving patients being screened or undergoing treatment for head and neck cancer at the thomas jefferson university hospital department of otolaryngology. participants completed surveys assessing readiness to quit smoking, amount of tobacco usage, and amount of time actively smoking. the easy way to stop smoking was provided to half of the participants, while the other half received a recommendation to purchase the book. all patients received physician directed smoking cessation counseling. phone surveys were conducted at short and long-term follow-up intervals to determine if the patients had purchased and/or read the book and whether they were still smoking. of the patients recruited, were eligible for follow-up, and only completed the long-term follow-up survey. the remaining participants were lost to follow-up for various reasons. those who received the book for free were more likely to read at least some of the book, p = . , although reading the book did not appear to correlate with successful smoking cessation, p = . . only % of patients who received the book (n = ) quit, while % of patients (n = ) who were recommended the book quit smoking, although this difference was not significant, p = . . patients who indicated “readiness” or “actively trying” to quit (n = ) appeared more likely to be successful than those who would only “consider” quitting (n = ), but the differences were not significant, p = . . smoking cessation rates did not appear to be impacted by reading allen carr’s the easy way to stop smoking. cessation rates between groups who read and did not read the book were similar, and the small differences were not statistically significant. despite a majority of the cohort indicating at least a readiness to quit smoking, only a small portion of patients managed to achieve successful smoking cessation. this study seems to support the notion that there is no single method to promote cessation, and that patient motivation remains an important factor in achieving long-term smoking abstinence. introduction: smoking is the most common preventable risk factor in the development of head and neck cancers[ ]. patients who smoke can be up to times more likely to develop cancers of the head and neck than non-smokers[ ]. oral cancer patients who continue to smoke are also at increased risk for developing additional primary malignancies[ ]. smoking cessation can reduce the risk of oral cancer by % within the first five years. after ten years, the risk of developing oral cancer approaches the risk of non-smokers[ ]. as such, it is extremely important to promote smoking cessation counseling in all patients who smoke, particularly those who have already been diagnosed with a head and neck malignancy. even after diagnosis, successful smoking cessation can improve survival rates. there are a variety of programs and interventions aimed at smoking cessation, although maintaining smoking abstinence is always a challenge. printed education materials have been found to improve physician practices, but their efficacy is as of yet inconclusive for patient outcomes[ ]. in the thomas jefferson university hospital department of otolaryngology, we believe one method that may be effective in convincing patients to quit smoking is the best-selling self-help book the easy way to stop smoking, by allen carr. this book explores the reasons people smoke, aiming to change smoker’s feelings about their addictions and challenge misconceptions in order to promote cessation. this study aimed to evaluate the efficacy of the educational, self-help book the easy way to stop smoking by allen carr in achieving smoking cessation in patients being screened or currently being treated for cancers of the head and neck. additionally, this study aimed to determine if providing the book for free improved the likelihood patients would read the book over recommending the purchase of the book. methods: study participants over the age of were recruited during office visits to the thomas jefferson university hospital – department of otolaryngology. current smokers who either underwent screening or were actively being treated for cancers of the head and neck were eligible for recruitment in this study. consenting participants were randomized into two treatment groups: intervention group: received physician counseling on smoking cessation with a recommendation to purchase the book the easy way to stop smoking by allen carr. control group: received physician smoking cessation counseling in addition to a free copy of the book the easy way to stop smoking books were provided by research nurses to allow for adequate blinding of the study physicians. recruited patients completed an “intake questionnaire” to determine, among other things, amount of cigarettes smoked per day, obstacles to quitting, family support, and readiness to quit smoking (evaluated on the following likert scale): = “not planning to quit” = “would consider [quitting] if a reasonable solution was provided” = “ready to take action” = “actively trying to quit” after the initial intake survey, patients were followed-up via phone at short (two weeks to six months) and long term intervals (six months to one year). timing of follow-ups depended on ability to reach the patients via phone. discussion: the easy way to quit smoking does not appear to be an effective intervention to promote smoking cessation by itself. reading the book did not appear to be associated with an increased likelihood to quit smoking. interestingly, those patients who did not read the book at all had the highest percentage of smoking cessation ( . %), as well as the highest mean cigarette reduction ( . %), although neither of these values were statistically significant, p = . and p = . , respectively. additionally, those patients who read the entire book (compared to those who read some or none of the book) showed the lowest average cigarette reduction ( . %), p = . . a cancerous diagnosis correlated with a minor increase in the likelihood that patients would quit smoking, although it was not a significant difference, p = . . these findings are inconsistent with the literature, as cancer has been shown to be an effective motivator for smoking cessation[ , ]. anecdotally, several patients surveyed admitted their cancer diagnosis was the major reason for their smoking cessation, and not the easy way to stop smoking. providing the intervention (i.e. allen carr’s book) free-of-charge ensured patients were more likely to utilize the intervention. those who received the book free of charge from the tjuh department of otolaryngology were more likely to read the book ( . %) than those who were only recommended to purchase the book ( %), p = . . when suggesting other smoking cessation interventions, cost to the patient may be a factor affecting compliance. identifying patients who are ready or motivated to quit smoking may be useful in targeting smoking cessation interventions, as these patients may be more likely to successfully quit smoking. finding the motivation to quit seems to be a major obstacle in smoking cessation, and is supported in the literature[ ]; those who are motivated to quit smoking are more likely to be successful. many of the study participants enjoyed reading the book, although few managed to successfully quit smoking during the study. patients who initially reported readiness to quit or were actively trying to quit smoking were successful in higher percentages ( . % and . %, respectively) than those who would only consider quitting ( %), p = . . despite a lack of statistical significance, these trends are certainly interesting. a similar study illustrated that patients with low motivation or low readiness to quit were unlikely to benefit from self-help materials, such as a smoking cessation book[ ]. the small sample size and large participant attrition are limitations of this study. while some attrition was expected, we did not anticipate losing the number of patients we did ( %). conducting the follow-up surveys via phone also presented challenges, as many of the study participants were either undergoing or recovering from treatment for head and neck cancers. likely, the stress and hardships associated with a cancer diagnosis contributed to some of the participant loss. another limitation was the study’s reliance on self-reported data collected in surveys. patients have been known to underestimate their cigarette intake[ ], and it’s entirely possible some patients may have overestimated the amount of the book they read. conclusion: nearly every patient surveyed that read the book enjoyed the the easy way to stop smoking, finding it both helpful and informative, although only a small percentage of patients managed to translate the book’s message into practice and achieve smoking cessation. due to the small sample size, it is difficult to make any concrete conclusions about the efficacy of allen carr’s the easy way to stop smoking, although the small percentage of patients who did quit smoking suggests there is no single “magic-bullet” approach that can tackle the intense nature of nicotine addiction. identifying a patient’s motivation to quit may be a useful tool in tailoring future cessation strategies and treatment, but achieving long-term smoking cessation still remains a major challenge to both patients and otolaryngologists. any attempts at promoting smoking abstinence should likely involve a multi- faceted approach. f( , ) = . , p = . acknowledgements: tara difabio, amy wotlinksi, and kristin loeb for their help in recruiting study participants. elizabeth duddy for coordinating the study, as well as recruiting and following-up with study participants. results: # c ( , n = ) = . , p = . . % . % . % . % received book (n = ) recommended book (n = ) n u m b e r o f p a rt ic ip a n ts book status vs. smoking status quit smoking did not quit smoking % . % . % % % % % % % would consider quitting (n = ) ready to quit (n = ) actively trying to quit (n = ) p a rt ic ip a n ts w h o q u it s m o k in g ( % ) readiness to quit vs. smoking status . % . % . % . % . % . % . % . % . % . % read entire book (n = ) read some of book (n = ) did not read book (n = ) m e a n c ig a re tt e r e d u c ti o n ( % ) mean cigarette reduction vs. amount of book read c ( , n = ) = . , p = . % % % % % % % % self-reported obstacles to quitting anxiety or stress exposure to smokers at work/home craving for nicotine or habit of smoking fears of weight gain, depression, or boredom feels unable to quit or lacks willpower enjoy smoking or does not want to quit no obstacle reported multiple obstacles reported references: . marur, shanthi, and arlene a forastiere. “head and neck cancer: changing epidemiology, diagnosis, and treatment.” mayo clinic proceedings. mayo clinic , no. (april ): – . doi: . / . . . . day, terry a, angela chi, brad neville, and james r hebert. “prevention of head and neck cancer.” current oncology reports , no. (march ): – . . marron m., boffetta p., zhang z-f., et al. “cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk.” int j epidemiol , ( ): – . . giguère, anik, france légaré, jeremy grimshaw, stéphane turcotte, michelle fiander, agnes grudniewicz, sun makosso-kallyth, fredric m wolf, anna p farmer, and marie-pierre gagnon. “printed educational materials: effects on professional practice and healthcare outcomes.” the cochrane database of systematic reviews ( ). . pinto, bernardine m., elizabeth eakin, and nancy c. maruyama. “health behavior changes after a cancer diagnosis: what do we know and where do we go from here?” annals of behavioral medicine , no. (march , ): - . . blanchard, chris m., maxine m. denniston, frank baker, stuart r. ainsworth, kerry s. courneya, danette m. hann, dean h. gesme, douglas reding, thomas flynn, and john s. kennedy. “do adults change their lifestyle behaviors after a cancer diagnosis?” american journal of health behavior , no. (may , ): – . . hymowitz, n, k m cummings, a hyland, w r lynn, t f pechacek, and t d hartwell. “predictors of smoking cessation in a cohort of adult smokers followed for five years.” tobacco control suppl ( ): s – . . dijkstra, a, h de vries, and j roijackers. “targeting smokers with low readiness to change with tailored and nontailored self-help materials.” preventive medicine , no. (february ): – . . morales, nelson a, michelle a romano, k michael cummings, james r marshall, andrew j hyland, alan hutson, and graham w warren. “accuracy of self-reported tobacco use in newly diagnosed cancer patients.” cancer causes & control: ccc , no. (june ): – . % . % . % . % cancerous diagnosis (n = ) non-cancerous diagnosis (n = ) n u m b e r o f p a rt ic ip a n ts diagnosis vs. smoking status quit smoking did not quit smoking c ( , n = ) = . , p = . c ( , n = ) = . , p = . n = c ( , n = ) = . , p = . . % . % . % % % % % % read entire book (n = ) read some of book (n = ) did not read book (n = ) p a rt ic ip a n ts w h o q u it s m o k in g ( % ) amount of book read vs. smoking status mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide a wednesday, february , co-expression and co-evolution with mcu. micu has been demonstrated to be a ca þ -sensing protein, which both sets a threshold for low ca þ concentration while it assures cooperative activation during high ca þ rises. mitochondrial ca þ uptake shows tissue specific differences and interestingly, mrna level for micus and mcus also displays tissue specificity. we set out to investigate if the stoichiometry between micu and mcu could account for the previously described differences between heart and liver in mitochondrial ca þ uptake. immunoblotting showed higher expression for all micu , micu and mcu in mouse liver versus heart mitochondria, and a . fold higher micu to mcu ratio in liver. in fluorometric measurements of mitochondrial ca þ uptake, heart mitochondria displayed a decreased threshold and lesser cooperativity compared to liver mitochondria. additionally, nad(p)h elevation was detect- able after exposure to moderate [ca þ ] elevations only in heart mitochondria. overexpression of micu in the heart using aav -micu tail-vein injection significantly increased the micu protein level without any changes of micu or mcu. this increased the micu to mcu ratio in the heart and led to increased thresholding and cooperativity, reproducing the liver-like mito- chondrialca þ uptakephenotype.viceversamicu downregulationintheliver has been shown to lower the threshold and cooperativity of mitochondrial ca þ uptake in hepatocytes. thus, heart and liver mitochondria show different levels of ca þ threshold and cooperative activation of ca þ uptake, which seem to result from differential quantitative relationship between micu and mcu. -pos board b er calcium release is tuned by mitochondrial redox nanodomains david m. booth , balázs enyedi , miklós geiszt , péter várnai , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, department of physiology, semmelweis university, budapest, hungary. spatially and temporally controlled increases of h o emerge as an intracellular signal. we hypothesized that ros and ca þ interact locally, in the restricted vol- ume of the er-mitochondrial interface. these physically tethered structures host enrichments of ion transport proteins such as the ip receptor, which support elevated nanodomains of ca þ during signalling events and are sensitive to h o . we used the genetically encoded h o sensor hyper incorporated into an inducible linker system to probe the redox environment at the er- mitochondrial interface in hepg cells. we found a moderately elevated h o nanodomain which developes into a h o transient following ip receptor- mediated er ca þ release and mitochondrial ca þ uptake. pharmacological in- hibition showed that the transient was dependent upon er ca þ, mitochondrial membrane potential and functional electron transport chain. hyper measure- ments of the mitochondrial intermembrane space revealed significantly elevated h o within this volume. using electron microscopy we found that hepg mito- chondria possess a cohort of dilated cristae, which disappeared following ip - linked ca þ release. paxilline that inhibits mitochondrial bkca channels blocked the cristae reshaping and also abolished the h o transient at the inter- face. furthermore, paxilline caused suppression of the ip -linked calcium signal, whereas interface targeted killer red, a photoactivated h o source, induced sensitization to the ip -linked agonist. we conclude that the intermembrane/ cristae volume of mitochondria represents an oxidized pool fed by the electron transport chain. ca þ -uptake stimulates expansion of the mitochondrial matrix via kþ and concomitant water uptake, squeezing the oxidized volume of the cristae to the interface. here, a transient h o nanodomain sensitizes ip recep- tors to further stimulation. we demonstrate a physiological setting where ca þ release may autoregulate using mitochondrial h o released from the cristae. -pos board b reactive oxygen species (ros) suppress mitochondrial motility valentina debattisti, masao saotome, sudipto das, gyorgy hajnoczky. mitocare center, thomas jefferson university, philadelphia, pa, usa. mitochondrial distribution and transport play pivotal roles for many cellular functions, including cell differentiation, cell division to ensure proper inheri- tance, apoptosis, atp supply at the local sites of demand, ca þ buffering for intracellular ca þ homeostasis. we previously showed that mitochondrial motility (mito-motility) is regulated by the cytosolic ca þ concentration ([ca þ]c), providing the basis for a homeostatic circuit in which the organelles decrease their movements along microtubules to locally buffer high [ca þ ]c and contribute to atp supply. mito- chondria are also a major site for production and scavenging of ros that serve as both a messenger and regulator of calcium signaling and are particularly rele- vant for the control of mitochondrial function. here we tested the hypothesis that ros target mito-motility to control mitochondrial function. h c myoblast cells were transfected with a mitochondrial matrix targeted yfp and then loaded with fura , to monitor the mito-motility simultaneously with [ca þ ]c. h o ( mm) caused a decrease in mito-motility ( %) and an elevation in [ca þ ]c (from to nm) at the same time. when the cells were incu- bated in a ca þ -free medium and were pretreated with thapsigargin to prevent ca þ entry and intracellular ca þ mobilization, respectively, h o continued to inhibit the mito-motility dose-dependently without any changes in [ca þ]c. these results indicate that h o can cause suppression of mito-motility through a ca þ independent mechanism we are currently analyzing. -pos board b miro is dispensable for calcium-mediated inhibition of mitochondrial movement david b. weaver , agnieszka lewandowska , tammy t. nguyen , valentina debattisti , janet m. shaw , gyorgy hajnoczky . mitocare center, dept of pathology, anatomy and cell biology, thomas jefferson university, philadelphia, pa, usa, biochemistry, university of utah school of medicine, salt lake city, ut, usa. miro and are (rhot and ) are two highly similar gtpases that are bound to the surface of mitochondria and possess ef-hand calcium binding motifs. several groups have reported that miro is involved in mitochondrial motility and inheritance, and particularly its calcium regulation, but the roles of the two isoforms have not been established. genetic deletion of miro in mouse is lethal at birth (nguyen et al., ) and fibroblasts (mefs) derived from miro ko em- bryos show abnormal mitochondrial distribution, but the calcium-dependent in- hibition of motility is unaffected and the respiratory and calcium buffering capacities are normal. neuron-specific knockout of miro leads to progressive deficits of upper motor neuron function, however mitochondria in processes of cortical neurons from miro ko and wild-type embryos showed comparable calcium-sensitive motility inhibition. while no significant increase in miro pro- tein was observed in miro ko mefs, these data raise two possibilities: miro and are interchangeable with regard to calcium regulation of mitochondrial motility or miro is the key player in this regard. to finally resolve this question, we are in the process of generating miro ko and miro / ko cell lines. -pos board b mitochondrial fusion dynamics in the heart veronica eisner , ryan cupo , erhe gao , györgy csordás , lan cheng , jessica ibetti , j. kurt chuprun , walter j. koch , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, center for translational medicine, temple university school of medicine, philadelphia, pa, usa, center for translational medicine, thomas jefferson university, philadelphia, pa, usa. heart physiology depends on oxidative metabolism that likely requires dy- namic and permanent reorganization of mitochondria by fusion and fission. to directly evaluate mitochondrial fusion dynamics in cardiomyocytes (cm), mitochondrial matrix-targeted photoactivatable gfp and dsred were intro- duced either in vitro or in vivo by adenovirus and were followed by confocal microscopy. four conditions were analyzed: to h cultured neonatal and in vitro transduced adult cm, and cm from in vivo infected rat hearts. in the latter case, cm were isolated - days after infection and were imaged promptly or - h post harvesting. neonatal cm mitochondria form a highly connected network, whereas both in vitro and in vivo transformed cultured cm displayed only some connectivity. impressively, in vivo transduced adult cm that were imaged promptly after harvesting, unveiled a significantly higher con- nectivity among mitochondria than the - h cultured adult cm. furthermore, fusion events (f.e./ square micrometers/min) were almost absent in cultured in vitro transduced cm, meanwhile in vivo transduced and cultured cm showed . . f.e./min, whereas isolated, freshly-imaged cm displayed . . f.e./min. imaging in perfused whole heart ex vivo, showed consider- able mitochondrial continuity and fusion activity in ventricular cm. to study more directly the role of cm’s contractile activity in mitochondrial fusion, cm were incubated with verapamil ( mm), that blocked spontaneous contrac- tion and partially suppressed the fusion activity of mitochondria. also, mito- chondrial fusion activity appeared to be higher after spontaneous contraction or short term field stimulation in isolated freshly-imaged cm. thus, mitochon- dria are dynamic in both neonatal and adult cm, but under culture conditions, adult cm lose mitochondrial fusion activity. this might be at least in part, because cardiomyocyte contractile activity is altered in culture and contractions likely provide some factors to support mitochondrial fusion activity. -pos board b mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide venkat r. pannala, ranjan k. dash. bioengineering and biotechnology, department of physiology, medical college of wisconsin, wauwatosa, wi, usa. the thioredoxin system plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (h o ). specifically, wednesday, february , a thioredoxin (trx) donates electrons to peroxiredoxin (prx) to remove h o and then thioredoxin reductase (trxr) maintains the reduced trx concentration with nadph as the cofactor. despite a great deal of kinetic information gath- ered on the removal of h o by the trx system from various sources/species, a mechanistic understanding of the associated enzymes is still not available. we address this issue by developing a thermodynamically-consistent mathematical model of the trx system which entails mechanistic details and provides quan- titative insights into the kinetics of the trxr and prx enzymes. consistent with experimental studies, the model analyses of the available data show that both enzymes operate by a ping-pong mechanism. the proposed mechanism for trxr, which incorporates substrate inhibition by nadph and intermediate protonation states, well describes the available data and accurately predicts the bell-shaped behavior of the effect of ph on the trxr activity. most impor- tantly, the model also predicts the inhibitory effects of the reaction products (nadpþ and trx(sh) ) on the trxr activity for which suitable experimental data are not available. the model analyses of the available data on the kinetics of prx from mammalian sources reveal that prx operates at very low h o con- centrations compared to their human parasite counterparts. furthermore, the model is able to predict the dynamic overoxidation of prx at high h o con- centrations, consistent with the available data. the integrated prx-trxr model simulations show that the coupling of trxr- and prx-dependent reduction of h o allowed ultrasensitive changes in the trx concentration in response to changes in the trxr concentration at high prx concentrations. -pos board b higher mitochondrial membrane potential induces ros production in the familiar form of frontotemporal dementia with mapt mutations noemi esteras gallego, selina wray, elisavet preza, andrey y. abramov. molecular neuroscience, institute of neurology, university college london, london, united kingdom. frontotemporal dementia and parkinsonism linked to chromosome (ftdp- ) is a neurodegenerative disorder caused by mutations in the mapt gene en- coding tau protein. mitochondrial alterations have been associated with neuronal death in several diseases. the objective of our study was to analyse the mitochondrial function in human ips cells from a patient of ftdp- car- rying the þ mapt mutation. in addition, we have selected three different time points of the differentiation from pluripotent stem cells to cortical neurons to study how mitochondrial alterations develop. we have used fluorescence imaging techniques to examine the mitochondrial function: tmrm to measure the mitochondrial membrane potential (dcm) and dyhidroethidium (dhe) to measure the rate of reactive oxygen species (ros) production. dcm was higher in ips-derived neurons from the patient bearing the mapt mu- tation ( . . % of control). higher dcm was also found in non- differentiated pluripotent stem cells ( . . %) and in the neural rosettes, which represent an earlier stage of the differentiation ( . . %). in contrast, mitochondrial mass was lower in mutant ips-derived neurons ( . . %), although it was similar in non-differentiated cells. we have also found that the rate of ros production, measured using dhe, was also higher in ips-derived neurons from the patient ( . % of control). the increased rate of ros production in these cells may be the consequence of the enhanced membrane potential. consistently, the rate of ros production in non-differentiated cells and in neural rosettes was also significantly higher ( . % and . %, respectively). our study indicates that this mapt mutation leads to a higher mitochondrial membrane potential, which induces a higher ros production that may be a trigger for neurodegeneration. -pos board b the overexpression of superoxide dismutase restores growth defect in a porin -less yeast strain and improves mitochondrial metabolism andrea magrı̀ , simona reina , flora m. tomasello , maria c. di rosa , angela messina , vito de pinto . biological, geological and environmental sciences - section of biochemistry and molecular biology, university of catania, catania, italy, cnr – institute of biostructure and bioimaging, section of catania, catania, italy. metabolic exchanges between cytosol and mitochondria are made possible by the presence of the pore-forming protein vdac on the outer mitochondrial membrane [ - ]. vdac is directly involved in atp/adp, glucose and ions transportation, calcium homeostasis and apoptosis regulation. moreover, it shows high level of sequence conservation in all eukaryotes: the homologous por in yeast s. cerevisiae shows % of identity and similar functional prop- erties [ ]. recent studies have highlighted the existence of a link between vdac and sod enzyme, the most important cytosolic defense against superoxide anion. in yeast, sod is required to protect vdac from oxidation but also from carbonylation induced by ros [ ]; in addition, yeast strains devoid of endogenous sod show down-regulated vdac and tom levels, and vdac shows a significantly less pronounced voltage dependence and conductance [ ]. to unravel sod metabolic role in relation to vdac -mediated metabolism, we expressed human sod in yeast devoid of endogenous vdac (dpor ). while dpor strain cannot grow in the presence of a not-fermentable carbon source, possibly due to altered mitochondria, our results indicates that the overexpression of hsod in dpor strain relieves the growth defect, suggesting that sod participates in the mitochondrial metabolic intersection with the cytosol. acknowledgments: prin csjx f (vdp) and arisla (am). [ ] messina et al, , bba , - [ ] de pinto et al, , bba , - [ ] tomasello et al, plosone, , , e [ ] o’brien et al, , jbc , - [ ] karakitos et al, , febs lett , - -pos board b the role of complex i in mitochondrial reactive oxygen species formation in cochlear sensory and supporting cells during ototoxic aminoglycoside exposure danielle desa , michael g. nichols , heather jensen smith . physics, creighton univeristy, omaha, ne, usa, biomedical sciences, creighton univeristy, omaha, ne, usa. aminoglycosides (ags) are the most widely used class of antibiotics in the world despite causing permanent hearing loss by damaging inner ear sensory cells. although the mechanisms of cochlear sensory cell damage are not fully known, reactive oxygen species (ros) are clearly involved. during normal mitochondrial metabolism low levels of ros, primarily superoxide, are pro- duced at complexes i and iii in the electron transport chain. these levels can increase when mitochondrial dysfunction occurs. complex i-specific ros for- mation was evaluated in acutely-cultured murine cochlear explants exposed to gentamicin (gm, mg/ml), a representative ototoxic ag antibiotic. mito- chondrial membrane potential and pro-apoptotic signaling were measured using tetramethylrhodamine and apoptosis-inducing factor (aif) labeling, respec- tively. fluorescence intensity-based measurements of nicotinamide adenine dinucleotide (nadh) were used to detect changes mitochondrial metabolism. relative amounts of superoxide and hydrogen peroxide produced during acute gm exposure were measured using mitosox red and dihydrorhodamine , respectively. gm increased nadh fluorescence intensity in low- and high-frequency sensory cells. the complex i inhibitor rotenone ( nm) significantly increased superoxide, not hydrogen peroxide, in low- and high- frequency sensory cells (p < . ). gm significantly increased superoxide and hydrogen peroxide formation in low- and high-frequency sensory cells (p < . ). rotenone increased gm-induced superoxide formation but decreased gm-induced hydrogen peroxide formation. this effect was greatest in high- frequency cells indicating fundamental differences in ros formation in high- and low-frequency sensory cells exposed to ototoxic antibiotics. this project provides a base for understanding the underlying mechanisms of mitochondrial ros production in cochlear cells during exposures to ototoxic antibiotics. supported by the national institute on deafness and other communication disorders (nidcd,ro dc ), and cobre ( p gm - ) to hjs and a ferlic undergraduate research scholarship to dd. -pos board b mitochondrial iron and sphingosine synergize initiation of hepatocyte death by augmenting oxidative stress sergei a. novgorodov , tatyana i. gudz , andaleb kholmukhamedov , raymond deepe , john j. lemasters , . neurosciences, medical university of south carolina, charleston, sc, usa, drug discovery & biomedical sciences, medical university of south carolina, charleston, sc, usa, biochemistry & molecular biology, medical university of south carolina, charleston, sc, usa, institute of theoretical & experimentla biophysics, pushchino, russian federation. hepatocytes exposed to ischemia/reperfusion (i/r) succumb to cell death after reperfusion. sphingosine and ceramide profiles revealed substantial accumula- tion of sphingosine after h of ischemia to rat hepatocytes, whereas other sphin- goid bases did not change. a lysosomotropic inhibitor of acid ceramidase suppressed i/r-induced death, indicating a lysosomal origin of sphingosine. addition of exogenous sphingosine to hepatocytes increased cell death, which was insensitive to the ceramide synthase inhibitor, fumonisin b . this finding indicates that accumulation of sphingosine, not ceramide formed from sphingo- sine, promoted cell death. exogenous sphingosine also inhibited complex iv (cytochrome oxidase), the terminal component of the respiratory chain, in 	er calcium release is tuned by mitochondrial redox nanodomains 	reactive oxygen species (ros) suppress mitochondrial motility 	miro is dispensable for calcium-mediated inhibition of mitochondrial movement 	mitochondrial fusion dynamics in the heart 	mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide 	higher mitochondrial membrane potential induces ros production in the familiar form of frontotemporal dementia with mapt mu ... 	the overexpression of superoxide dismutase restores growth defect in a porin -less yeast strain and improves mitochondria ... 	the role of complex i in mitochondrial reactive oxygen species formation in cochlear sensory and supporting cells during ot ... 	mitochondrial iron and sphingosine synergize initiation of hepatocyte death by augmenting oxidative stress [cancer research , – , february , ] advances in brief exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer annegret müller, tina bocker edmonston, diana a. corao, deborah g. rose, juan p. palazzo, heinz becker, robert d. fry, josef rueschoff, and richard fishel genetics and molecular biology program, department of microbiology and immunology, kimmel cancer center [a. m., t. b. e., r. f.], and departments of pathology [t. b. e., d. a. c., j. p. p.] and surgery [d. g. r., r. d. f.], thomas jefferson university, philadelphia, pennsylvania - ; department of general surgery, university of göttingen, göttingen, germany [a. m., h. b.]; and department of pathology, klinikum kassel, kassel, germany [j. r.] abstract hereditary nonpolyposis colorectal cancer (hnpcc) is an autosomal dominant genetic predisposition syndrome that accounts for – % of all colorectal cancers. diagnosis of hnpcc is based on family history (de- fined by amsterdam or bethesda criteria), which often includes a history of multiple synchronous or metachronous cancers. the majority of hnpcc results from germ-line mutations in the dna mismatch repair (mmr) genes hmsh and hmlh with rare alterations in hmsh and hpms in atypical families. both hnpcc and sporadic mmr-deficient tumors invariably display high microsatellite instability (msi-h). two types of hnpcc families can be distinguished: type i (lynch i) with tumors exclusively located in the colon; and type ii (lynch ii) with tumors found in the endometrium, stomach, ovary, and upper urinary tract in addition to the colon. a proposed association of breast cancer with type ii hnpcc is controversial. to address this important clinical question, we examined msi in a series of female patients who presented with synchronous or metachronous breast plus colorectal cancer. although msi-h was found in of ( . %) of the colon cancers, in all cases the matched breast cancer was microsatellite stable. we also examined the breast tumors from three women who were carriers of mmr gene mu- tations from hnpcc families. none of these three breast tumors dis- played msi nor was the expression of mmr proteins altered in these tumors. we conclude that breast cancer largely arises sporadically in hnpcc patients and is rarely associated with the hnpcc syndrome. introduction hnpcc is the most common human cancer predisposition syn- drome, accounting for approximately – % of the total colorectal cancer burden ( – ). hnpcc is clinically characterized by colorectal cancers, a proclivity to the proximal colon, and high frequency of metachronous and synchronous cancers ( ). the inclusion of extra- colonic cancers (endometrial, gastric, ovarian, and upper urinary tract) in addition to colorectal cancer, as well as a less stringent family history, distinguishes amsterdam criteria families from bethesda criteria families ( – ). the addition of breast cancer in bethesda criteria and/or type ii (lynch ii) hnpcc is controversial ( – ). alterations of the human mmr genes hmsh and hmlh account for the vast majority of hnpccs ( – ). mutations of other mmr genes are either absent (hmsh , hpms , and hmlh ) or rare and largely associated with atypical families (hmsh and hpms ; refs. and ). the detailed mechanism of tumorigenesis in hnpcc remains enigmatic ( , ), although it clearly begins with a “second hit” on the remaining mmr allele ( ). loss of mmr function results in elevated spontaneous mutation rates (mutator phenotype) that ac- celerate the adenoma-carcinoma transition associated with hnpcc tumors ( , ). the mutator phenotype associated with mmr defects is an example of induced genomic instability that leads to tumorigen- esis ( , , ). malignant transformation ensues when genes rele- vant for growth control and differentiation are affected as secondary mutation events. simple repeat sequences (microsatellites) are particularly prone to replication errors associated with the type of genomic instability that results from the loss of mmr function ( – ). tumor dna con- taining such replication errors can be distinguished by msi-h (when � % of the microsatellite markers are altered) or msi-l (when � % of the microsatellite markers are altered; ref. ). tumor tissues from � % of patients with an hnpcc syndrome (amster- dam or bethesda criteria) and % of patients with verified germ- line alterations of the hmsh or hmlh gene display msi-h ( , , ). mononucleotide repeat sequences appear to be the most unstable in bona fide hnpcc tumors ( ). these observations have led to the widespread use of microsatellite analysis as a diagnostic screening test for hnpccs ( ). in addition to hnpcc, msi-h is also found in – % of sporadic colorectal carcinomas ( , ). breast cancer affects one in nine women in the united states population ( , ). such a high incidence makes it is difficult to determine whether breast cancer is coincidental in hnpcc families or caused by the germ-line mutation in one of the mmr genes linked to hnpcc. the inclusion of breast cancer as an integral tumor in the hnpcc (lynch ii) spectrum rests largely on an analysis of breast and colon cancer tissues from a single female from a large hnpcc kindred ( ). the breast tumor from this individual displayed msi-h ( of or % of microsatellites analyzed) and a distinct pattern of msi-h in the colon tumor. moreover, loss of the wild-type mmr allele, in this case hmlh , was observed in the breast tumor tissue. supporting evidence for the inclusion of breast cancer in the type ii (lynch ii) syndrome comes from msi analysis of single breast tumors from five additional hnpcc kindreds. using the nci and the icg- hnpcc criteria ( , ), three of these breast tumors displayed msi-h. only one of these three breast tumors displayed instability at mono- nucleotide repeats. although these studies were performed prior to a clear definition of diagnostic msi ( , ), it appeared to provide compelling evidence for a correlation between breast cancer, hnpcc, and the litmus of mmr defects, msi-h. the frequency of msi in sporadic breast tumors is also controversial, with some reports sug- gesting the occurrence of msi in breast tumors ( , – ) and others suggesting a lack of msi in breast tumors ( , , ). recent interest in the relationship of breast cancer to the hnpcc received / / ; accepted / / . the costs of publication of this article were defrayed in part by the payment of page charges. this article must therefore be hereby marked advertisement in accordance with u.s.c. section solely to indicate this fact. the study was initiated by margeaux (to r. d. f.) and supported by nih grant ca (to r. f.). to whom requests for reprints should be addressed, at kimmel cancer center, blsb , south th street, philadelphia, pa . phone: ( ) - ; e-mail: rfishel@hendrix.jci.tju.edu. the abbreviations used are: hnpcc, hereditary nonpolyposis colorectal cancer; mmr, mismatch repair; msi-h, microsatellite instability-high; msi-l, msi-low; nci, national cancer institute; icg, international collaborative group; mss, microsatellite stable; mgmt, methylguanine methyltransferase. on april , . © american association for cancer research. cancerres.aacrjournals.org downloaded from http://cancerres.aacrjournals.org/ type ii (lynch ii) spectrum has been intensified by the observations of scott et al. ( ). a survey of hnpcc families suggested a significant elevation in breast cancer susceptibility when hmsh - carrier families are compared with hmlh -carrier families. these observations would appear to have important implications for patient management and cancer surveillance, just as the exclusion of endo- metrial carcinoma as an integral hnpcc tumor resulted in a signif- icant delay in the diagnosis of hnpcc ( ). in a response to these studies, vasen et al. ( ) reported that a similar analysis of a hnpcc family cohort found that only of hmsh or hmlh mutation carriers had developed breast cancer. there was no differ- ence in the breast cancer risk for hmsh or hmlh carriers. both the scott et al. ( ) and vasen et al. ( ) studies cited the need for an analysis of colon and breast tumors from hnpcc individuals for clear signatures of mmr defects ( , ). synchronous or metachronous cancers are frequently associated with hnpcc and are among the criteria for identifying hnpcc patients and families ( ). here we have examined msi in patients identified with synchronous or metachronous breast plus colon cancer. we found that of ( %) of the colon tumors displayed msi-h. none of the corresponding breast tumors showed msi. in addition, independent breast cancer tissues from female members of three mmr mutation-positive hnpcc families were analyzed. although all of the colon tumors of those families displayed msi-h, all of the breast tumors were mss. taken together, these results suggest that breast cancer caused by mutation of the mmr genes is rare and should not be included in the hnpcc type ii (lynch ii) spectrum. materials and methods patients. this retrospective study is based on women with breast plus colon cancer who were treated at thomas jefferson university in philadelphia between and . a total of , female patients with colorectal cancer were seen as well as , with breast cancer. a total of women had both breast and colon cancer. paraffin blocks of both breast and colon tumors were acquired for of these patients. three additional women with breast cancer from confirmed mutation-positive hnpcc families where recruited from the german hnpcc registry. tumor blocks and blood were studied after obtain- ing informed consent. data on msi status of synchronous or metachronous extracolonic cancers (e.g., endometrial, stomach, ovarian, and upper urinary tract) were obtained from the thomas jefferson university familial cancer registry. of the patients analyzed with breast plus colon tumors, only was a member of the thomas jefferson university familial cancer registry. dna extraction. paraffin-embedded tumor and corresponding normal tis- sue sections were mounted on glass slides and stained with h&e. microdis- section was performed on paraffin sections stained briefly with methylene blue. areas of interest were selected by a surgical pathologist (t. b. e. and j. p. p.), scraped off the slide, and subjected to proteinase k digestion at a final concentration of mg/ml (qiagen, valencia, ca). dna was extracted with the qiaamp dna mini kit (qiagen), according to the manufacturer’s recommendations. for sequence analysis, dna from blood was extracted with qiaamp dna maxi blood kit (qiagen) following the manufacturer’s recommendations. microsatellite analysis. in accordance with the recommendations by the nci and the icg-hnpcc ( , ), six microsatellite loci were used to detect msi-h. three loci with mononucleotide runs (bat , bat , and bat ) and three loci with dinucleotide repeats (d s , d s , and d s ). these microsatellite loci had been recommended by dietmaier et al. ( ) as having the highest diagnostic sensitivity and specificity. primers were �-end labeled with hex, tam, or tet (perkin-elmer, foster city, ca). dna was ampli- fied in a standard reaction mix using amplitaq gold (perkin-elmer). the pcr products were run on an abi automated sequencer using fragment analysis software (genescan; perkin-elmer). additional peaks in tumor tissue dna, when compared with normal tissue dna, indicated msi. instability in � % of the markers was reported as msi-h, � % was classified as msi-l, and no instability was reported as mss. losses of heterozygosity were excluded as msi. immunostaining for hmsh and hmlh . to determine the presence or absence of mmr proteins, the breast tumors of the three members of the hnpcc families were subjected to immunohistochemical analysis. briefly, slides were deparaffinized and hydrated through graded alcohols. antigen retrieval was achieved by microwave treatment ( w for min) and incubation with % h o . nonspecific binding was blocked by incubation with goat serum for min. the slides were incubated with primary antibody against hmsh ( . �g/ml; oncogene sciences, cambridge, ma) or against hmlh ( �g/ml, clon g - ; pharmingen, san diego, ca) overnight at °c. the sections were then washed with pbs and incubated with the secondary biotinylated antibody. after rinsing with pbs, the sections were incubated with streptavidin-conjugated horseradish peroxidase (vector laboratories, burlingame, ca). for detection, the chromogen -amino- - ethylcarbazole (sigma chemical co., st. louis, mo) was used according to the manufacturer’s recommendations, and counterstaining was done with hematoxylin. mutation analysis. germ-line mutation analysis in the three hnpcc families was done by automated dna sequencing using big dye terminator chemistry (perkin-elmer) for sequence analysis on the applied biosystems model dna sequencing systems (pe applied biosystems, foster city, ca). pcr was performed on ng of genomic dna for each exon. the pcr products were purified using the qiaquick pcr purification kit (qiagen) and submitted for sequence analysis. the sequence was analyzed with the dnas- tar sequencher (gene codes cooperation, ann arbor, mi). results synchronous and metachronous cancers have been established by the icg-hnpcc as one of the criteria (bethesda criteria) for identi- fying hnpcc individuals and families ( ). for hnpcc type ii (lynch ii), synchronous and metachronous cancers include both colon as well as well-defined extracolonic tumors such as endometrial, ovarian, stomach, and upper urinary tract cancer ( ). to examine the role of breast cancer in type ii (lynch ii) hnpcc, we identified patients that presented with synchronous or meta- chronous colon plus breast tumors at thomas jefferson hospital. the tumor blocks for both the colon and breast tumor were acquired for of these patients, and microsatellite analysis of six different nci/icg- hnpcc recommended markers was performed on dna isolated from microdissected normal and tumor tissue regions (fig. ). the pathol- ogy and msi status of the breast and colon tumors from these patients are shown in table . msi-h was observed in colon tumors ( %; table ). none of the breast tumors examined displayed msi-h, which includes the corresponding breast tumors associated with the msi-h colon tumors (table ). consistent with previous observations, % of the msi-h colon tumors displayed instability in at least one of the mononucleotide microsatellites (bat , bat , or bat ). immunohistochemical analysis of a subset of the tumor tissue pairs confirmed the loss of expression of mmr proteins in the colon tumor tissue but not the breast tumor tissue (fig. ). we have previously characterized low microsatellite instability (msi-l; defined as instability in � % of examined microsatellite sequences). the genetic causes of the msi-l phenotype are unknown, although rare alterations of the hmsh mmr gene have been found within this cohort (data not shown; ref. ). approximately two- thirds of msi-l tumors display methylation inactivation of the mgmt promoter ( ). loss of mgmt exacerbates mutation rates by leaving unrepaired methylguanine damage in dna ( ). the majority of msi in mgmt-deficient tumors appears to be confined to dinu- cleotide repeats. these data suggest that the msi-l phenotype is unlikely to be significantly associated with mmr defects ( ). we found that of colon tumors ( %) and of breast tumors ( %) displayed msi-l (table and table ). in % of the msi-l tumors, instability was confined to the dinucleotide microsatellite markers. msi-l was found in two pairs of the synchronous and/or exclusion of breast cancer as tumor of hnpcc on april , . © american association for cancer research. cancerres.aacrjournals.org downloaded from http://cancerres.aacrjournals.org/ metachronous breast plus colon tumors. these data appear similar to sporadic colorectal tumors, which appear unrelated to hnpcc ( ). to further investigate the role of breast cancer in hnpcc, we identified three kindreds fulfilling the amsterdam criteria in which at least one female family member was diagnosed with breast cancer. molecular diagnostics of a proband in two families revealed deletion mutations within the hmsh gene (del c at codon ; del tc at codon ; fig. , a and b). a proband in the third family was found to contain an insertion in the hmlh gene (ins c at codon ; fig. c). all three of these mutations cosegregate with hnpcc and are pathogenic as a result of a premature truncation of the protein. moreover, the colon tumor tissues from affected family members of each of these kindreds display msi-h (data not shown). immunohis- tochemical analysis of the respective colon cancers suggested the loss of expression of hmsh in tumor tissues from family members that carried the hmsh deletion mutations and loss of expression of hmlh in the colon cancer from family members that carried the hmlh insertion mutation (see fig. for illustrative example; data not shown). a single female family member from each of these kindreds was confirmed to be a mutation carrier (data not shown), as well as presenting with breast cancer. we determined that all of the micro- satellite sequences analyzed using the dna isolated from breast tumors of these female family members were stable (mss). immu- nohistochemical staining revealed no loss of protein expression of either hmsh or hmlh in any of the breast cancers (see fig. for illustrative example; data not shown). in contrast, analysis of multiple colorectal or endometrial tumors from affected family members of all three families invariably displayed msi-h (data not shown). these data strongly suggest that the breast tumors of the mmr mutation- positive female family members arose independently of the hnpcc predisposition syndrome. discussion the lifetime risk of developing breast cancer in united states women is approximately % (one of nine). the lifetime risk of developing colon cancer in the general population is � % ( of ). the risk of colon cancer increases – -fold in persons who have a first-degree relative with colon cancer ( ). in the case of the devel- opment of two different cancer types, synchronous or metachronous, a hereditary predisposition must be suspected ( ). the recognition of hnpcc-associated cancers led to the bethesda criteria or the type ii (lynch ii) cancer predisposition syndrome. in , aarnio et al. ( ) performed a detailed pedigree analysis of hnpcc families to evaluate the cumulative risk of cancers other than colon cancer. at that time, endometrial cancer generated a cumulative risk high enough to suggest a specific surveillance program. these results underline the importance of identifying the correct hnpcc- associated tumors toward the recognition of affected families as well as appropriate clinical surveillance. endometrial, gastric, ovarian, and upper urinary tract tumors are generally accepted as integral tumors of the type ii (lynch ii) hnpcc syndrome. the inclusion of breast cancer in type ii (lynch ii) hnpcc is controversial ( , , – ). the use of well-defined microsatellite markers has established diagnostic msi as a valuable tool in the diagnosis of hnpcc ( , ). tumors from hnpcc patients that have been identified as carriers of pathogenic mmr mutations invariably display msi-h ( , , ). moreover, msi-h has been observed in % of the early adenomas from hnpcc mmr mutation carriers ( ). these studies have con- firmed the importance of msi-h as a fundamental indicator of mmr defects. table pathology and msi status of breast and colon tumors case no. breast cancer pathology msi status (breast) colon cancer pathology msi status (colon) inv. duct. caa mss muc adeno mss lcis msi-l carcinoid mss inv. duct. ca mss adenoca msi-l inv. duct. ca msi-l adenoca msi-l dcis msi-l muc adeno msi-l inv. duct. ca mss adenoca mss inv. duct. ca mss adenoca msi-l inv. lob. ca mss adenoca mss inv. duct. ca mss adenoca msi-h inv. duct. ca mss adenoca mss inv. duct. ca mss adenoca msi-h inv. duct. ca mss adenoca mss dcis mss adenoca msi-l inv. duct. ca mss adenoca mss dcis mss adenoca msi-h ln-metb msi-l adenoca mss inv. duct. ca mss adenoca mss inv. duct. ca mss adenoca mss inv. duct. ca mss adenoca mss inv. duct. ca mss adenoca mss lcis mss adenoca msi-h inv. duct. ca mss adenoca msi-l inv. duct. ca mss adenoca mss dcis mss adenoca mss inv. duct. ca mss adenoca mss inv. duct. ca mss muc adeno msi-h inv. duct. ca mss adenoca msi-l a inv. duct. ca, invasive ductal carcinoma; lcis, lobular carcinoma in situ; dcis, ductal carcinoma in situ; inv. lob. ca, invasive lobular carcinoma; muc. adeno, mucinous adenocarcinoma; adenoca, adenocarcinoma. b metastasis in axillary lymph node consistent with breast primary; primary tumor not found in mastectomy specimen. fig. . microsatellite instability. microsatellite analysis of dna isolated from micro- dissected normal tissue (n) adjacent to colon tumor tissue (c), and breast tumor (b) tissue. shown are the abi genescan chromatograms for the mononucleotide repeats bat , bat , and bat . a chromatogram pattern showing additional peaks that are clearly different from the normal control is defined as msi. exclusion of breast cancer as tumor of hnpcc on april , . © american association for cancer research. cancerres.aacrjournals.org downloaded from http://cancerres.aacrjournals.org/ to clarify the involvement of breast cancer in hnpcc, we exam- ined the tumors from patients with synchronous and metachronous breast plus colon cancer as well as the breast or colon tumors from affected members of hnpcc families for msi-h. in our experience, � % of patients with metachronous or synchronous hnpcc-related cancers display msi-h. of these, % were found to harbor a mutation in either hmsh or hmlh . we found that none of the synchronous or metachronous breast tumors examined in the present study displayed msi-h. moreover, in this cohort the frequency of msi-h in the colon tumors ( %) was similar to that found in sporadic colon tumors ( ). these data suggest that, unlike bona fide hnpcc-associated tumors, identifying synchronous or metachronous breast plus colon tumors does not enrich for mmr-defective type ii (lynch ii) hnpcc tumors. none of the breast tumors from confirmed mutation-positive hnpcc family members displayed msi. combined with the obser- vation of a normal mmr protein expression pattern in the breast tumor tissue, these data suggest that the breast tumors from these mmr mutation carriers developed independently of hnpcc and their mmr mutation-carrier status. previous reports have described the identification of mmr muta- tions in two unrelated families fulfilling the amsterdam criteria, where both male and female gene carriers were affected with breast cancer ( , ). in one family, the affected female patient diagnosed at the age of with breast cancer revealed a mutation in both hmlh and brca ( ). the second family was also diagnosed with an hmlh mutation ( ). patients from this family presented with both colon and endometrial cancer. a male member was affected with colorectal cancer in addition to breast cancer. importantly, microsat- ellite analysis of dna isolated from the breast cancers from these two families revealed an msi-l status. several studies have concluded that a defective mmr system is uncommon in human breast cancer and that breast cancer should not unpublished data from the thomas jefferson university familial cancer registry. table msi analysis of synchronous or metachronous breast plus colon tumors tumor msi status colon msi-h (% mn msi)a msi-l (% mn msi)a mss (% mn msi)a breast msi-h msi-l ( %) ( %) mss ( %) ( %) a the percentage of tumors with instability in at least one mononucleotide repeat microsatellite sequence. fig. . immunohistochemical analysis of a matched pair of breast and colon tumors. matched pair breast and colon tumor samples from the msi-h patient shown in fig. . a–c, breast tumor. a, h&e stain, � . b, anti-hmsh stain, � . c, anti- hmlh stain, � . note the nuclear staining of the malignant cells in both b and c indicating the presence of intact hmsh and hmlh protein. d–f, colon tumor. d, h&e stain, � . e, anti-hmsh stain, � . f, anti-hmlh stain, � . note the nuclear staining of the malignant cells in e indicating the presence of intact hmsh protein. in contrast, the absence of nuclear stain- ing of malignant cells in f indicates loss of intact hmlh protein. nuclear staining of endothelial cells provides a positive control for the anti-hmlh antibody. exclusion of breast cancer as tumor of hnpcc on april , . © american association for cancer research. cancerres.aacrjournals.org downloaded from http://cancerres.aacrjournals.org/ be included as an integral part of the hnpcc tumor spectrum ( , ). in one study, unselected breast cancer dnas, representing all major histological types, were subjected to a microsatellite analysis with microsatellite markers, including five of the six markers used in our study ( ). additional bands were observed in of , ( . %) of the microsatellite amplification reactions when dna iso- lated from the tumor site was compared with normal dna. these authors concluded that replication errors were not involved in the pathogenesis of the majority of breast cancers ( ). a second study performed microsatellite analysis on primary breast tumors using different chromosomal loci, including one from the nci/icg- hnpcc recommended panel (d s ; ref. ). although of ( %) of the breast tumors could be classified as msi-l ( ), msi-h was not observed in any of the cases, and no differences were identified between patients with sporadic and hereditary breast cancer ( ). we remain perplexed by the original report of a molecular associ- ation between breast cancer and hnpcc ( ). it is important to note that the apparently confirmatory study by scott et al. ( ) contains no individual tumor molecular diagnostics and could therefore be easily attributed to chance association between familial susceptibility and sporadic tumors. although we were unable to identify any association between breast cancer, msi, and hnpcc, the results of risinger et al. ( ) would appear to suggest at least the rare occurrence of breast tumors associated with mmr defects. however, based on our studies, we propose that breast cancers should not be considered as an asso- ciated cancer when assessing hnpcc families. acknowledgments we gratefully acknowledge speculative discussions with henry lynch as well as comments and criticism by jeremy jass and kristine yoder. references . lynch, h. t., and lynch, j. genetic counseling for hereditary cancer. oncology, : – , . . lynch, h. t., smyrk, t., and lynch, j. f. overview of natural history, pathology, molecular genetics and management of hnpcc (lynch syndrome). int. j. cancer, : – , . . lynch, h. t., lemon, s. j., karr, b., franklin, b., lynch, j. f., watson, p., tinley, s., lerman, c., and carter, c. etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (lynch syndromes): genetic counseling implications. cancer epidemiol. biomark. prev., : – , . . lynch, h. 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research. cancerres.aacrjournals.org downloaded from http://cancerres.aacrjournals.org/content/ / / http://cancerres.aacrjournals.org/content/ / / .full#ref-list- http://cancerres.aacrjournals.org/content/ / / .full#related-urls http://cancerres.aacrjournals.org/cgi/alerts mailto:pubs@aacr.org http://cancerres.aacrjournals.org/content/ / / http://cancerres.aacrjournals.org/ computational study of the prokaryotic sodium channel a sunday, february , stabilized by surrounding hydrophobic residues. we propose that mutations of the asparagines affect activation-inactivation of the channels and drug action through destabilizing the open state. diversity of h-bonding partners explains different effects of mutations of individual asparagines on the channel activa- tion, inactivation, and drug sensitivity. supported by nserc grant to bsz, the ras program ‘‘molecular and cell biology’’ to dbt, and cihr award to ib. -pos board b binding of isoflurane to a bacterial voltage-gated sodium channel: structure and accessibility of distinct interaction sites srinivasa g. raju , vincenzo carnevale , david n. lebard , annika f. barber , michael l. klein . temple university, philadelphia, pa, usa, yeshiva university, new york, ny, usa, thomas jefferson university, philadelphia, pa, usa. the most likely targets for volatile anesthetics (va) are ion channels. the mechanism of volatile anesthetic action is not completely understood. identify- ing the molecular pathway for drug binding is crucial to understand the effect of va on voltage gated sodium channels. we use molecular dynamics simula- tions to identify the binding sites for a hydrophobic general anesthetic isoflur- ane, on voltage gated bacterial sodium channel nachbac. apart from the voltage sensing domain (s -s ), linker and the pore domain (s -s ), bacterial sodium channels also have fenestrations, which provide a hydrophobic tunnel through the lipid-embedded portion of the channel to the central cavity, where the known local anesthetic site is located. unbiased ‘‘flooding’’ simulations were performed on the activated open confirmation of nachbac. we per- formed a cluster analysis to identify all the possible binding sites of isoflurane. the three most important ones among them are: a region near the selectivity filter, called the extracellular site, a region near the s -s linker, called the linker site, and a region within the cavity, called the cavity site. the most important observation is that isoflurane enters the central cavity through the fenestrations. free energy perturbation method was employed to calculate the binding affinities of isoflurane for each of these sites. we also studied the interactions between isoflurane and the amino acids in these three binding sites. -pos board b a key gating charge interaction required for slow inactivation of the navab bacterial sodium channel tamer m. gamal el-din, todd scheuer, william a. catterall. university of washington, seattle, wa, usa. bacterial voltage-gated sodium (nav) channels are considered an ideal model for structure-function studies. the elucidation of the crystal structure of the bacterial channel navab (payandeh et al., nature , - , ) opened an avenue to understand electrical signaling in excitable cells at the structural level. navab expressed in hi insect cells as for structural studies has unusually negative voltage-dependent activation (va ~ mv). navab also has three phases of inactivation, a biphasic early inactivation process (t ~ ms, t ~ . s, at � mv) followed by an unusually strong and use-dependent slow-inactivation process. to search for the molecular basis for negative activation and slow inactivation of navab, we mutated the outer- most gating charge partner in the s segment, asn , to lys. this mutation shifted the activation curve ~ mv toward more positive potentials. surpris- ingly, it also completely abolished use-dependent slow inactivation. we showed previously that the equivalent residue in nachbac (asp ) interacts with the r gating charge in the s segment during activation using the disul- fide locking method (decaen et al, pnas ( ) - ). to test whether this interaction between r and n was critical for slow inactivation, we mutated navab r to cys. the resulting mutant navab_r c also had positively shifted channel activation (þ mv) and no use-dependent slow inactivation. the fact that these reciprocal mutations have the same functional effects suggests that interaction between r in the s segment and n in the s segment is an important link that stabilizes the activated state of the voltage sensor and triggers the slow inactivation process. -pos board b computational study of the prokaryotic sodium channel karen m. callahan, benoit roux. university of chicago, chicago, il, usa. ion-selective voltage-gated ion channels allow ions of a specific element or set of elements to pass, but exclude other ions. recently, the crystal structure of navab was published (payandeh et al ( ) nature , ), giving an un- ambiguous picture of the structure of the sodium channel selectivity filter (sf) of the prokaryote arcobacter butzleri. the filter is much wider than that of the narrow, carbonyl-lined potassium channels, allowing ions to penetrate with minimal dehydration, multiple pathways, and even to pass each other. previous computational studies have attempted to explain sodium selectivity, and claimed consensus (corry and thomas ( ) jacs , , furini and domene ( ) plos , e ). experimental ion selectivity determina- tion from pore-only constructs of a sodium channel with the same sf sequence shows stronger ion selectivity from reversal potential than from the ratio of the fluxes of sodium and potassium (shaya et al ( ) pnas , ), but selectivity, na þ/kþ, was still less than five. simulations based upon the closed-pore crystal structure could not determine selectivity directly from con- duction. to investigate this issue, we first calculated multi-ion potentials of mean force in the selectivity filter of pore-domain-only navab with an ex- tended equilibration period, and a replica-exchange molecular dynamics scheme, which allows for improved sampling. we then explored the non- equilibrium conduction of sodium and potassium in the presence of an applied electric field through a model navab pore truncated to mimic the conformation of the open pore. we also present multi-ion pmf calculations to illustrate similarities and differences between this model and the intact pore. when taken together, these two methods provide complementary views of ion selectivity and conduction based upon the conformation of the navab crystal structure of payandeh et al ( ). -pos board b volatile general anesthetic interactions with a bacterial sodium channel annika f. barber , srinivas g. raju , david lebard , vincenzo carnevale , michael l. klein , manuel covarrubias . thomas jefferson university, philadelphia, pa, usa, temple university, philadelphia, pa, usa. general anesthesia results from complex interactions involving ion channels in the brain. voltage-gated ion channels are modulated by halogenated inhaled general anesthetics, however the drug-channel interactions are generally believed to be non-specific making it difficult to investigate the molecular mechanisms of anesthetic action. we find, however, that the bacterial sodium channel nachbac exhibits differential regulation by different general anes- thetics, suggesting that there may be specific interactions. molecular dynamics (md) simulations have identified several possible binding sites for isoflurane in the nachbac channel structure. here, we have characterized the affinity, occu- pancy and hydrogen bonding for these sites and identified key interactions. in addition, experimental evidence suggests that both isoflurane and sevoflurane have dual actions on nachbac, possibly involving action at two different sites. consistent with pore block, sevoflurane accelerates the decay of the current ( % faster at . mm sevoflurane) but, at the same time, increases the peak current ( % increase with . mm sevoflurane), which argues against the blocking mechanism. we hypothesize that an additional mechanism involving a distinct site is necessary to explain the latter effect. we are currently employ- ing md simulation and structural modeling combined with mutagenesis and electrophysiology to test this two-site hypothesis and investigate the molecular mechanisms of these opposing effects. supported by ninds f ns (afb) and nigms p gm (mlk). -pos board b polymodal, high affinity actions of m-conotoxins on a bacterial voltage- gated sodium channel rocio k. finol-urdaneta , robert glavica , jeff r. mcarthur , robert j. french . university of calgary, calgary, ab, canada, rmit, melbourne, australia. m-conotoxins (mctxs) are potent blockers of eukaryotic sodium channels, and individual members of the mctx family are highly specific for particular nav isoforms. we have begun to explore mctx interactions with nachbac, a pro- karyotic nav channel closely related to navab, whose crystal structure was re- cently determined (payandeh et al, , nature : ). our data reveal actions on both ion conduction and gating, consistent with polymodal actions on the pore domain. under voltage clamp, whole-cell currents from nachbac expressed in tsa- cells were reduced, up to nearly complete block, by concentrations in the pm to mm range, for wildtype toxins and derivatives of mctx piiia and kiiia. for wildtype piiia, dose-response data ( . - , nm) yielded the following: ic = . nm; maximal fraction of current blocked = . ; hill coefficient = . . chen & chung ( , biophys. j. : ) predicted an ic of . nm for piiia when the navab channel is occupied by sodium ions. even at very low [piiia] ( pm), the unblocked currents showed increasing rates of inactivation as the peptides were washed in, suggesting a gating mod- ulation, that was not tightly associated with pore block. for mctx piiia ( . nm), or kiiia ( nm), inactivation accelerated by ~ -fold. substitution of key basic residues (piiia-r a and kiiia-k a) reduced blocking potency and decreased the speeding of inactivation to less than -fold. given the remarkably high selectivity and affinity that mctxs show for certain eukaryotic nav channels with highly asymmetric pores, it may seem surprising that they bind to symmetric bacterial nav channels with such high affinity. 	binding of isoflurane to a bacterial voltage-gated sodium channel: structure and accessibility of distinct interaction sites 	a key gating charge interaction required for slow inactivation of the navab bacterial sodium channel 	computational study of the prokaryotic sodium channel 	volatile general anesthetic interactions with a bacterial sodium channel 	polymodal, high affinity actions of μ-conotoxins on a bacterial voltage-gated sodium channel microsoft powerpoint - postermmcglotticwebsfinal revised.ppt poster design & printing by genigraphics® - . . objectives: to review the efficacy of mitomycin c in the treatment of preexisting anterior glottic webs in patients undergoing microdirect laryngeal surgery over a six year period. methods: from through following treatment for recurrent respiratory papillomatosis or a persistent anterior glottic by either laser excision or microdebridement, twenty-five patients underwent topical application of mg/ml mitomycin – c to the anterior commisure. we retrospectively evaluated the efficacy of topical mitomycin – c in preventing web formation at the anterior glottis. results: nineteen manifested anterior webs during treatment, whereas six were successfully treated with mitomycin c without developing a web. % demonstrated resolution of the agw. conversely three patients developed new web formation following application of mitomycin c, all of which were subsequently cleared. only one patient was recalcitrant to therapy and required surgical lysis with keel placement. no patients developed laryngeal cancer during our study period. conclusion: topical application of mitomycin appears to effectively limit the recurrence or progression of anterior glottic webs in a significant portion of patients. topical mitomycin-c use in surgery of the anterior commisure ryan c murray, md; jeanine speilberger, md; maurits boon, md; joseph r spiegel, md thomas jefferson university hospital, philadelphia, pa a total of twenty five patients were identified including eighteen male and nine female patients. six patients were successfully treated with mitomycin following instrumentation at the anterior commisure and never manifested anterior webbing. the remaining nineteen patients were observed to have an anterior glottic web at some point during therapy (table ). of these patients were initially taken to the or for surgical treatment of an agw. mmc resulted in resolution of agw scarring in of those patients, of which after only a single administration. patients were subjectively evaluated for the extent of web involvement over the course of treatment. the majority of patients experienced resolution of the agw following mmc application (fig ). an anterior web in one patient increased in size despite therapy with mitomycin and required subsequent open surgery with endolaryngeal keel placement. three patients developed new webs during treatment all of which resolved with subsequent therapy. only two patients had evidence of agw at the time of last clinical evaluation, whereas twenty three patients did not demonstrate webbing at their last evaluation. one patient had juvenile rrp but was an adult at the time of agw formation. one patient who had previously undergone a renal transplant and was on well controlled long term immunosuppression was included in the study. two patients had previously been treated for t laryngeal squamous cell carcinoma by primary radiation therapy. one patient with congenital glottic webbing treated with mmc was excluded from analysis, however did experience resolution of disease following a single treatment. no patients developed significant dysplasia or laryngeal cancer during the study period. following initial enthusiasm for the use of mmc in the anterior glottis has had limited but encouraging results (roh, ; spector, ). animal models appear to indicate mmc is a useful tool to prevent scarring when operating at this area. however traditional surgical lysis of anterior glottic lesions persist. previous studies using surgical lysis followed by keel insertion report recurrence of agw between and % (edwards, ; lichtenberger, ) in our cohort more than % of the patients treated with mmc demonstrated objective and sustained resolution of the agw. six patients underwent surgery at the anterior commisure without subsequent development of agw, whereas three developed new webbing after mmc application. all of these patients were able to be treated more aggressively than if mmc was not used. mmc primarily acts to inhibit dna translation thus exerting an effect to decrease proliferation of fibroblasts. additionally it has been shown to induce fibroblast apoptosis and limit angiogenesis. topical application appears to be safe for use in the head and neck with little or no systemic side effects (veen, ). in our cohort there were no incidences of malignant degeneration, or worsening dysplasia. previous reports examining mmc in patients developing webs following scca confirms our results (knott, ). we recognize inherent limitations to this study. firstly the retrospective nature of the review limited more sensitive assessment of web size. many of the patients also received concurrent or metachronous cidofovir injections, the impact of which is unclear. this study was approved by the thomas jefferson university hospital irb study number d. . a retrospective chart review was conducted to evaluate all patients over the age of undergoing endoscopic surgery at the anterior commisure between january , and december , . all procedures were performed at the lead investigators institution. all patients subjected to instrumentation at the anterior commisure with subsequent application of mitomycin c were included in the study. instrumentation was most frequently cold steel, but could include microdebridement or laser excision. patients with a history of adult or juvenile onset recurrent respiratory papillomatosis as well as those with previously known anterior glottic webs were included. patients previously or concurrently undergoing treatment with cidofovir were also included. all patients with a known history of connective tissue disease, wegner’s disease and sarcoidosis were excluded. application of mitomycin c was performed subsequent to all other endoscopic instrumentation and immediately preceding the end of surgery (fig ). from until late patients were treated with a topical preparation of mg mitomycin/ml. this was applied to the anterior commisure for minutes then removed for minute and reapplied for an additional minutes. from late until the conclusion of the study period mitomycin at a concentration of mg/ml was applied topically for a continuous minute period. charts were reviewed for presence of and size of anterior glottic webbing and mmc application to the anterior commisure. patients were noted to have resolved, improved, stable, worsened or new web formation, based on clinical or operative exam. - mmc is effective in treating anterior glottic webs in more than % of patients - more than half of patients that demonstrated a resolution of agw following mmc did so after a single treatment - mmc allows for more aggressive surgery at the anterior commisure - mmc results in less morbidity and faster recovery than traditional keel prostheses endolaryngeal surgery for benign lesions at the anterior commisure is performed cautiously due to the risk of acquired glottic webs (agw). agw presents a difficult management dilemma due to the risks of airway compromise and impacts on voice (mcguirt, ). conventional therapies of agw have included intralesional kenalog injection, keel insertion, division followed by repeated dilation and mucosal grafting (hsiao ty, ). in recent years a shift in management toward endoscopic laser lysis of laryngeal stenosis has resulted in significant improvements in voice outcomes (knott, ), but has relied on the use of keel or sialastic stent placement to prevent the risk of glottic webbing (monnier, ). while these adjuvant therapies have demonstrated acceptable outcomes they typically require tracheotomy placement and carry a risk of granulation formation requiring additional surgery (edwards, ). mitomycin c (mmc) is now routinely employed for prevention of scar formation in tracheal stenosis as well as subglottic and posterior laryngeal stenosis (perepelitsyn, ). limited animal models as well as in vivo human studies addressing its use for anterior glottic stenosis indicate it may prove to be a useful adjunct in the treatment of agw. introduction methods and materials . edwards, j., tanna, n., bielamowicz, s.a. endoscopic lysis of anterior glottic webs and silicone keel placement. annals of otology, rhinology and laryngology ( ), pp. - . hsiao, t.-y. combined endolaryngeal and external approaches for iatrogenic glottic web. laryngoscope ( ), pp. - . knott, p.d., milstein, c.f., hicks, d.m., abelson, t.i., byrd, m.c., strome, m. vocal outcomes after laser resection of early-stage glottic cancer with adjuvant cryotherapy. archives of otolaryngology - head and neck surgery ( ), pp. - . lichtenberger g., toohill r.j. new keel fixing technique for endoscopic repair of anterior commissure webs ( ) laryngoscope, ( i), pp. - . . mcguirt w.f., salmon j., blalock d. normal speech for patients with laryngeal webs: an achievable goal. ( ) laryngoscope, ( ), pp. - . . monnier, p., george, m., monod, m.-l., lang, f. the role of the co laser in the management of laryngotracheal stenosis: a survey of cases. european archives of oto-rhino-laryngology ( ), pp. - . perepelitsyn, i., shapshay, s.m. endoscopic treatment of laryngeal and tracheal stenosis - has mitomycin c improved the outcome? otolaryngology - head and neck surgery ( ), pp. - . roh, j.-l., yoon, y.-h. prevention of anterior glottic stenosis after bilateral vocal fold stripping with mitomycin c. archives of otolaryngology - head and neck surgery ( ), pp. - . spector, j.e., huang, s., werkhaven, j.a., sanders, d., spector, n.c., reinisch, l. prevention of anterior glottic restenosis in a canine model with topical mitomycin-c. annals of otology, rhinology and laryngology ( ), pp. - . . veen, e.j.d., dikkers, f.g.topical use of mmc in the upper aerodigestive tract: a review on the side effects. european archives of oto-rhino-laryngology ( ), pp. - . conclusions discussionresults references figure . clinical response to mmc therapy in patients that developed agw. all patients who developed new webbing during therapy subsequently cleared the agw and were web free at the last clinic visit. figure . a) preoperative glottic web secondary to previous papilloma excision. b) endoscopic laser excision of agw. c) application of mitomycin c. d)post treatment appearance of anterior commisure. abstract a b c d table . demographic and clinical data on patients who manifested agw during treatment with mmc. srn-alsirworkshop submitted.doc [title] workshop on applications of coherent infrared synchrotron radiation [text] a workshop focused on scientific applications of and plans for a coherent far-infrared (fir) synchrotron source at the als was convened on october , as part of the annual advanced light source users’ meeting. it was organized by michael c. martin (als), wayne mckinney (als), dmitri basov (university of california, san diego), and joseph orenstein (university of california, berkeley, and berkeley lab). coherent synchrotron radiation (csr) presents an opportunity to create a source with intensities about six orders of magnitude higher than conventional fir sources. this workshop was held to further explore different types of science that could be enabled by such a novel source in this traditionally difficult spectral region. following a welcome by martin, the first speaker was tatiana globus (university of virginia). she described her group’s recent measurements and theoretical modeling of the transmission spectroscopy of biological macromolecules at submillimeter wavelengths. high resolution and very good signal-to-noise ratios are required for these measurements, and a higher intensity source extending to wavelengths longer than a millimeter would be very useful for these studies. next, erik helgren (university of california, los angeles) discussed his recent investigations of a coulomb glass system with microwave and millimeter-wave spectroscopy. the workshop then turned towards recent csr source developments starting with a talk by martin, standing in for george neil (thomas jefferson national accelerator facility), describing the very high-power thz csr observed using a energy-recovery linac. these exciting results were recently published [nature , , ( )]and verify that a gain of , in intensity over conventional far-ir sources is truly achieved. john byrd (als) then presented recent work showing that the onset of broadband self-amplified spontaneous coherent terahertz synchrotron radiation in a storage ring is now understood and can be avoided in the design of a dedicated csr source. the workshop attendees then heard from ulrich shade (bessy) about the recent achievement of powerful, steady-state coherent thz synchrotron radiation at bessy ii. this accomplishment, made possible by lowering the momentum compaction in the storage ring, provides the first demonstration of stable csr from a storage ring. this talk was followed by a presentation by jason singley (als) who described the general need for a new far-ir source for the study of strongly correlated materials and a proposal for a specific experiment to try and measure the josephson plasma resonance in the high- temperature superconductor bi sr cacu o with the csr source at bessy ii. the workshop concluded with a presentation by martin on the current state of plans for a dedicated coherent fir storage ring at the als. this source would be built on top of the als booster ring, and would be designed specifically for creating and using csr in the thz region. several unique features of the ring design were pointed out, and the planned next steps towards a full proposal for this source were presented. [author and institution] michael c. martin advanced light source, berkeley lab [figure caption—irring.tif] drawing showing the main als storage ring and a proposed dedicated coherent far- infrared (fir) ring (in color) located on top of the shielding for the als booster ring. the red and purple show the shielding for the new ir ring, and the green tables schematically show where fir beamlines can be located. crt- gender difference on procedural and -day outcomes in patients treated with orbital atherectomy for de-novo, severely calcified coronary lesions: results from the orbit ii trial s j a c c : c a r d i o v a s c u l a r i n t e r v e n t i o n s , v o l . , n o . s , s u p p l s , c o r o n a r y conclusion: despite a greater risk of target vessel revascularization in patients switched from clopidogrel to a gen apt, there was not an increased risk of stent thrombosis. this data suggests that gen apt may be employed in higher risk patients but do not increase the risk of stent thrombosis, implying adequate compli- ance in these high-risk patients. atherectomy devices crt- comparing the procedural and -day outcomes in patients with or without a history of coronary artery bypass graft when treating de novo, severely calcified coronary lesions with orbital atherectomy: results from orbit ii jeffrey w. chambers, michael s. lee, arthur c. lee metropolitan heart and vascular institute, coon rapids, mn; ucla medical center, los angeles, ca; the cardiac and vascular institute, gainesville, fl background: in prior studies, patients with previous coronary artery bypass grafting (cabg) experienced significantly greater incidence of adverse clinical events upon subsequent repeat cabg, percutaneous coronary intervention, or medical treatment, compared to patients with no prior cabg. in this analysis, we evaluate the procedural and -day outcomes in patients with and without a history of previous cabg in the orbit ii trial. methods: the orbit ii trial, a prospective, multicenter, non-blinded clinical trial that enrolled consecutive patients, was designed to evaluate the safety and efficacy of the coronary orbital atherectomy system to prepare de novo, severely calcified coronary lesions for stent placement. procedural and -day outcomes in patients with history of previous cabg (n¼ ) and no history of cabg (n¼ ) were evaluated in this analysis. results: compared to patients without history of previous cabg, patients with history of cabg were more likely to be male (p¼ . ) and have a higher prevalence of diabetes mellitus (p¼ . ), history of dyslipidemia (p¼ . ), hypertension (p¼ . ), and myocardial infarction (mi) (p< . ). the rate of procedural success (stent delivery with residual stenosis < % without the occurrence of an in-hospital major adverse cardiac event (mace)) was similar . % (previous cabg) and . % (without previous cabg) (p¼ . ). statistically similar low rates of severe dissection ( . % vs. . %: p¼ . ), perforation ( % vs. . %: p¼ . ), persistent slow flow ( % vs. . %: p¼ . ), and abrupt closure ( . % vs. . %: p¼ . ) were observed in the history of cabg and no history of cabg groups, respectively. as estimated by kaplan meier at -days, patients had similar low rates of mace (previous cabg: . % vs. without previous cabg: . %, p¼ . ). conclusion: preparation of severely calcified coronary lesions with the coronary orbital atherectomy system facilitated stent delivery in patients with a history of previous cabg, resulting in low rates of -day mace. crt- outcomes in chronic kidney disease patients treated for coronary arterial disease utilizing the orbital atherectomy system: an orbit ii sub-analysis arthur c. lee, stevan i. himmelstein, jeffrey w. chambers the cardiac and vascular institute, gainesville, fl; the stern cardiovascular center, memphis, tn; metropolitan heart and vascular institute, mercy hospital, coon rapids, mn background: cardiovascular disease is common in patients with chronic kidney disease (ckd) and often results in severely calcified lesions that are difficult to cross and treat. as a result, this population may have worse clinical outcomes following percutaneous coronary intervention compared to patients without ckd. clinical trials typically exclude this patient population. methods: orbit ii patients with severely calcified coronary lesions treated with the coronary orbital atherectomy system (oas) were divided into three groups based on the estimated glomerular filtration rate (egfr, ml/min/ . m ) at baseline: i (ckd stages - ), egfr< (n¼ ); ii (ckd stages - ), egfr to < (n¼ ); and iii (normal), egfr� (n¼ ). results: patients in groups i and ii were older (p< . ), and there were more females in these two groups than in group iii (p¼ . ). history of previous stroke (p¼ . ) was more prevalent in groups i and ii. in addition, the total length of calcium was significantly longer in group ii (p¼ . ). similar successful stent de- livery occurred in . %, . % and . % (p¼ . ) of cases with < % residual stenosis in . %, . % and . % (p¼ . ) of subjects in groups i, ii and iii, respectively. statistically similar low rates of severe dissection ( . %, . %, . %: p¼ . ), perforation ( . %, . %, . %: p¼ . ), persistent slow flow ( . %, . %, . %: p¼ . ), and abrupt closure ( . %, . %, . %: p¼ . ) were observed in groups i, ii, and iii, respectively. the day freedom from mace rates in groups i ( . %), ii ( . %), and iii ( . %) were similar (p¼ . ). conclusion: severely calcified coronary lesion pre-treatment with the coronary oas resulted in similar day freedom from mace rates and low rates of procedural complications in ckd patients compared with the non-ckd patients despite the older demographic and longer length of calcium in the ckd patients. crt- gender difference on procedural and -day outcomes in patients treated with orbital atherectomy for de-novo, severely calcified coronary lesions: results from the orbit ii trial christopher kim, jeffrey w. chambers utah cardiology, pc, layton, ut; metropolitan heart and vascular institute, mercy hospital, coon rapids, mn background: previous studies have shown a negative correlation between female gender and adverse events after percutaneous coronary intervention (pci). in this analysis, we evaluate the procedural and -day outcomes of male and female patients in the orbit ii trial. methods: the orbit ii trial, a prospective, multicenter, non-blinded clinical trial that enrolled consecutive patients, was designed to evaluate the safety and efficacy of the coronary orbital atherectomy system to prepare de novo, severely calcified coronary lesions for stent placement. procedural and -day outcomes in male patients (n¼ ) were compared to female patients (n¼ ). the primary safety endpoint was freedom from major adverse cardiac events (mace) at days post-procedure. the primary efficacy endpoint was procedural success defined as stent delivery with a residual stenosis of < % without the occurrence of an in- hospital mace. results: compared to males, females were older (p¼ . ) and had lower egfr at baseline (p¼ . ). however males had a higher rate of previous coronary artery bypass graft (p¼ . ). both males and females met the primary safety endpoint goal of % ( . % [ % ci: . %- . %] vs. . % [ % ci: . %- . %]) and primary efficacy endpoint of % ( . % [ % ci: . %- . %] vs. . % [ % ci: . %- . %]). as estimated by kaplan meier at -days, males and females had similar low rates of mace ( . % vs. . %, p¼ . ), myocardial infarction (mi) ( . % vs. . %, p¼ . ), target vessel revascularization/target lesion j a c c : c a r d i o v a s c u l a r i n t e r v e n t i o n s , v o l . , n o . s , s u p p l s , s revascularization (tvr/tlr) ( . % vs. . %, p¼ . ) and cardiac death ( % vs. . %, p¼ . ). conclusion: this sub-analysis of the orbit ii study demonstrates that males and females treated with orbital atherectomy for severely calcified coronary arteries (generally regarded as high-risk revascularization) demonstrate similar -day out- comes. in the context of the larger study, one can presume that the novel coronary orbital atherectomy system is a safe and effective adjunctive therapy for severely calcified coronary lesions in both men and women. c o r o n a r y bifurcation crt- feasibility of the use of the tryton™ dedicated bifurcation stent via the transradial route - a single centre experience ashish shah, muezz uddin, shantu bundhoo, richard anderson, tim kinnaird university hospital of wales, cardiff, cardiff, united kingdom background: the use of the transradial access (tr) for the treatment of coronary bifurcation lesions (cbl) with percutaneous coronary intervention (pci) can be limited where a two stent strategy is required as larger sheath and guide catheters are required to facilitate stent delivery. with the development of newer dedicated bifur- cation stents, there is an increasing trend of these stents to be adopted in pci centres to treat cbl’s. we report our experience of the use of the tryton� dedicated side branch bifurcation stent at our default tr centre where % of all pci are carried out via the tr. methods: this was a prospective study of all patients who were found suitable to undergo pci to cbl’s using the tryton stent between september and june . data on patient demographics and procedure characteristics was collected from the local hospital database. results: patients (male . %, age . years) underwent pci using the mm long tryton� bifurcation stent. most of the cbl’s treated were located in the lad/branch ( . %), followed by the circumflex/branch ( . %), left main stem/branch ( . %), rca/branch ( . %) and lima graft ( . %). tryton� stents dimensions (side branch/main branch diameters) deployed were ( . / . mm - . %; . / . mm - %; . / . mm - . %; . / . mm - . % and . / . mm - . %). . % of cases were carried out via f guide catheters with the remaining cases carried out via the f. mean contrast volume, radiation dose and fluoroscopy times were mls, . gy/cm and . minutes respectively. . % of all cases were successfully carried out via the tr route with remaining cases switching to the transfemoral route to successfully complete the procedure. conclusions: when treating cbl’s, a wide range of tryton� dedicated side branch stents can be safely and effectively deployed via the tr route using f/ f guide catheter systems. this can avoid the use of the transfemoral route and its associated potential vascular complications. cabg crt- under-utilization of statins and aspirin following coronary artery bypass graft surgery kevin curl, bryan lebude, nicholas ruggiero, david fischman, andrew rose, sulay patel, david ogilby, paul walinsky, babu jasti, michael savage thomas jefferson university hospital, philadelphia, pa background: coronary artery bypass graft (cabg) surgery is commonly performed to treat ischemic heart disease, but long term benefits are limited by patency of saphenous vein grafts. both statin medications and aspirin hold class i indications for all post-cabg patients and should be continued indefinitely unless contraindication exists. unfortunately, there is limited data regarding long-term usage of these medi- cations. we assessed utilization rates among post-cabg patients without docu- mented contraindication. methods: a retrospective analysis of post-cabg patients presenting to the thomas jefferson university cardiac catheterization laboratory for a catheterization procedure at least years after surgery was performed. inpatient and outpatient records were reviewed to assess prescribing patterns of these medications, as well as other pertinent clinical and laboratory data. results: the study population consisted of consecutive patients who presented on average � years from the time of cabg. mean age of our study population was � years with % male. the most common indications for catheterization were unstable angina ( %), non-stemi ( %), and an abnormal stress test ( %). only % of patients were being prescribed a statin, while % were prescribed aspirin. only % were prescribed both at the time of catheterization. three percent had a documented intolerance to statin therapy. patients prescribed a statin had a significantly lower mean ldl ( vs. [p< . ]) and total cholesterol values ( vs. [p< . ]). thirty five percent of patients had ldl � . only % of saphenous vein grafts among the patients not on statin medications remained patent an average of years post-cabg surgery. conclusions: long-term statin and aspirin use following cabg surgery remains suboptimal despite clear guideline recommendations and clinical trial evidence of their effectiveness. coordinated efforts are needed to improve long-term medication usage in this subset of high risk patients. cardiovascular pharmacology crt- omeprazole use is associated with increased cardiovascular complications in asian patients on aspirin and clopidogrel after percutaneous coronary intervention min sen yew, poh shuan daniel yeo, jau lueng paul ong, lijuan mira shen, hee hwa ho, fahim haider jafary, yau wei ooi, kwok kong jason loh, ko beng julian tan, chee guan david foo tan tock seng hospital, singapore, singapore background: dual anti-platelet therapy (dapt) with aspirin and a thienopyridine- derivative p y inhibitor (commonly clopidogrel) is mandatory after percutaneous coronary intervention (pci). h receptor antagonists (h ra) or proton pump inhibitors (ppi) are prescribed to reduce gastrointestinal bleeding risk. 	outline placeholder 	conclusion 	comparing the procedural and -day outcomes in patients with or without a history of coronary artery bypass graft when tre ... 	background 	methods 	results 	conclusion 	outcomes in chronic kidney disease patients treated for coronary arterial disease utilizing the orbital atherectomy system: ... 	background 	methods 	results 	conclusion 	gender difference on procedural and -day outcomes in patients treated with orbital atherectomy for de-novo, severely calc ... 	background 	methods 	results 	conclusion 	feasibility of the use of the tryton™ dedicated bifurcation stent via the transradial route - a single centre experience 	background 	methods 	results 	conclusions 	under-utilization of statins and aspirin following coronary artery bypass graft surgery 	background 	methods 	results 	conclusions 	omeprazole use is associated with increased cardiovascular complications in asian patients on aspirin and clopidogrel after ... 	background new editorial board members new editorial board members t imothy r. billiar,md, is a summacum laude grad- uate of doane college, c r e t e , n e b . d r b i l l i a r received his md degree from the university of chicago pritzker school of medicine, chicago, ill. from to , dr billiar was a resident at the university of minne- sota and a research fellow at the university of min- nesota and the university of pittsburgh, pittsburgh, pa; he completed his residency at the university of pitts- burgh. he is the watson professor of surgery at the university of pittsburgh. e ddie l. hoover,md, received anab degree from the university of north caro- lina, chapel hill, in and an md degree from duke university, durham, nc, in . he began his s u r g i c a l p o s t g r a d u a t e t r a i n i n g i n s u r g e r y a t duke university and com- pleted his training at cor- nell university medical center; he also completed a thoracic surgery residency at cornell university medi- cal center. dr hoover is certified by the american board of surgery and the american board of thoracic surgery. he is professor and chair of the department of surgery, state university of new york, buffalo. j ohn p. roberts, md, received a bs degree (biol-ogy) from stanford university, stanford, calif, in and an md degree from the university of cali- fornia, sandiego, school of medicine in . his postdoctoral training took place at the univer- sity of washington, se- attle, during which time he was a research fellow at cornell university. from to , he was a transplant fellow at the university of minnesota. dr roberts is a professor of surgery at the university of california, san francisco. j oel j. roslyn, md,received a bs de-gree in from u n i o n c o l l e g e , schenectady, ny, and an md degree in from albany medical college, albany, ny. he is a mem- ber of phi beta kappa and the alpha omega alpha honor medical society. dr roslyn’s postgraduate train- ing at the university of california, los angeles, was combined with research and clinical fellowships in gastroenterology at the same university. he is professor and chair of the department of surgery, allegheny university of the health sciences, philadelphia, pa. g race s. rozycki,md, received bsd e g r e e s ( c u m laude, biology and chemis- try) from the college miseri- cordia, dallas, pa, an ms de- gree (biochemistry) from the university of scranton, scranton, pa, and an md de- gree from jefferson medical college of thomas jefferson university, philadelphia, pa. her postgraduate training in surgery ( - ) took timothy r. billiar, md eddie l. hoover, md john p. roberts, md joel j. roslyn, md grace s. rozycki, md new board member announcements arch surg/ vol , mar © american medical association. all rights reserved. downloaded from: https://jamanetwork.com/ by a carnegie mellon university user on / / place at virginia commonwealth university medical col- lege of virginia school of medicine, richmond, and at the university of tennessee, knoxville ( - ), fol- lowed by a fellowship at the washington hospital cen- ter, washington, dc, from to . dr rozycki is an associate professor of surgery at emory university school of medicine, atlanta, ga. g. thomas shiresiii, md, re-ceived his md degree from duke univer- sity in and was certi- fied by the american board of surgery in . from to , his postdoc- toral training at emory uni- versity, atlanta, ga, in- cluded a harvey cushing fellowship in surgical re- search at cornell univer- sity ( - ). he is an associate professor of surgery at the university of texas southwestern medical center and chairman of the surgical services at the presbyterian health care system, dallas. new international advisory board members l eigh w. delbridger e c e i v e d a b s c(med) degree (hons i) from the university of sydney, sydney, australia, in , an mbbs degree (hons i) from the univer- sity of sydney in , and an md degree from the uni- versity of sydney in . his surgical training at the royal north shore hospi- tal, sydney, included a re- search fellowship at the middlesex hospital, london, england. he is chairman and clinical unit head at the royal north shore hospital. s. t. fan, mb, bs(hong kong),m s ( h o n g k o n g ) , f r c s ( g l a s g ) , facs, fcshk, hfkam (surgery), frcs(edin), ad hominem, received his mb and bs degrees in hong kong, the people’s repub- lic of china, in . his surgical training took place at queen mary hospital, hong kong, and the mid- dlesex hospital, london, england. dr fan is a pro- fessor in the department of surgery, university of hong kong, and an international authority in biliary, pancreatic, and liver surgery. g. thomas shires iii, md leigh w. delbridge, md s. t. fan, mb, bs (hong kong), ms (hong kong), frcs(glasg), facs, fcshk, hfkam (surgery), frcs(edin) arch surg/ vol , mar © american medical association. all rights reserved. downloaded from: https://jamanetwork.com/ by a carnegie mellon university user on / / n-terminal regulation of herg k+ channel deactivation sunday, february , a receptor x were transfected into cho cells. the cho transfectants were char- acterized by facs and then scaled up for kinexa binding studies. kinexa has been used to measure binding affinity of adnectin-a to the cell surface ex- pressed receptor x to measure the effect of avidity of the multivalent adnectin binding to receptor clusters. as controls for the functional activity of the adnectin-a and the affinity of the monovalent interaction, the same kinexa assay was used, substituting the soluble receptor x extracellular domain for the transfected cho cells. the binding avidity measured by kinexa for cho expressed receptor is pm for both species of receptor x. however, the affinity of adnectin-a for monovalent soluble receptor x was quite different between the species suggesting that avidity due to receptor clustering equilizes the functional avidity at the cell surface. platform: voltage-gated k channels: activation/ inactivation mechanisms -plat a-type kv channel closed-state inactivation is modulated by the tetramerization domain interacting with auxilary kchip a yi-quan tang , fan yang , jingheng zhou , jie zheng , kewei wang . peking university, beijing, china, university of california at davis, davis, ca, usa. a-type kv potassium channels undergo a conformational change towards a non-conductive state at negative membrane potentials, a dynamic process known as closed-state inactivation (csi). csi causes inhibition of channel ac- tivity without prerequisite of channel opening, thus providing a dynamic regu- lation of neuronal excitability, dendritic signal integration and synaptic plasticity. however, the structural determinants underlying kv csi remain largely unknown. we have recently demonstrated that auxiliary kchip a sub- unit contains an n-terminal kv inhibitory domain (kid) that directly interacts with kv . channels to enhance csi. in this study, we utilized the fret two- hybrid mapping and bifc-based screening combined with electrophysiology, and identified the intracellular tetramerization (t ) domain that functions to suppress csi and serves as a receptor for the binding of kid. disrupting kv . t -t interaction by mutating c a within the c h motif of t domain facilitated csi, and ablated the kid-mediated enhancement of csi. furthermore, replacing the characteristic c h motif of kv . t domain with the t domain from kv . without the c h motif or kv . with the c h motif resulted in channels functioning with enhanced or suppressed csi, respectively. taken together, our findings reveal a novel role of the t domain in suppressing kv csi with the c h motif functioning to stabilize the channel activation gate; and kchip a kid directly interacts with the t domain to relieve the stabilization, leading to facilitation of csi and inhibition of channel function. -plat two-in-one: activation and inactivation at the intracellular gate of a kv channel manuel covarrubias , jeffrey d. fineberg . neuroscience, jefferson medical college of thomas jefferson university, philadelphia, pa, usa, physiology and molecular biophysics, jefferson medical college of thomas jefferson university, philadelphia, pa, usa. n-type and p/c-type inactivation are firmly established mechanisms of inac- tivation in voltage-gated kþ (kv channels). however, kv .x channel com- plexes, which undergo fast preferential closed-state inactivation (csi; fineberg et al., , jgp . : - ), appear to use a distinct but un- known inactivation mechanism. previously, we hypothesized that a weak interaction between the voltage sensing domain and the intracellular activa- tion gate underlies csi (bähring & covarrubias, , j physiol : - ). thus, csi is essentially governed by the intracellular activation gate, which fails to open and adopts an inactivated conformation. to directly test this hypothesis, we investigated the heterologously expressed kv . ternary channel complex including accessory subunits kchip and dpp , and ex- ploited the ‘‘trap-door’’ paradigm of the activation gate. the results show that kv . inactivation traps intracellularly applied quaternary ammonium blockers (btbua and tbua) inside the channel’s pore. the trapped blockers can only escape if the channels are opened again by subsequent depolariza- tions. by contrast, inactivation cannot trap tea, whose binding kinetics is faster than that of channel gating. moreover, under identical conditions, a shaker kv channel (shb-t k) known to exhibit fast p/c-type inactivation cannot trap btbua. these findings conclusively suggest that the intracellular activation gate of the kv . ternary channel complex plays a novel dual role, controlling both activation and inactivation. supported in part by nih grant r ns (mc). -plat development and validation studies of universal pharmacophore models for herg channel openers serdar durdagi , , matthew patterson , sergei y. noskov . department of biophysics, bahcesehir university, faculty of medicine, istanbul, turkey, biological sciences, institute for biocomplexity and informatics, university of calgary, calgary, ab, canada. the intra-cavitary drug blockade of herg channel, a common off-target for many drugs, have been extensively studied both experimentally and theoreti- cally. structurally diverse ligands inadvertent blockade of rapid component of delayed rectifying kþ currents are potentially pro-arrhythmic and may lead to drug-induced long qt syndrome-lqts. there are a number of natural strategies for rational drug design; one dubbed the ‘‘passive’’ approach avoids block of herg whereas the ‘‘proactive’’ strategy designs treatments to acti- vate the channel. while ‘‘passive’’ approach has been developed for decades, studies of structural mechanisms of herg channel activation by small mole- cules are truly novel. accordingly, design of the herg openers or current ac- tivators may offer a momentum for modern anti-arrhythmia drug development. significant number of small molecules with capacity for herg activation was identified in mandatory herg screens. to establish possible correlation be- tween activators structure and reactivity, we attempted to construct a universal pharmacophore model for herg channel openers using phase protocol. the biochemical data on kþ channel activators are used in training and test sets. these compounds span a wide range of structurally different chemotypes with ~ ^ -fold variances in binding affinity, which is sufficient for statistically sound model. a developed five sites aahhr (a, hydrogen-bond accepting, h, hydrophobic, r, aromatic) pharmacophore model has showed reasonable high statistical results compared to other constructed models and was selected for steric and electrostatic contour maps analysis. the predictive power of the model was also tested with external test-set (as true unknowns) compounds. pharmacophore model is also combined with previously developed receptor- based homology model of herg k channel and novel activators are generated and screened. the developed ligand-based models may serve as a basis for the synthesis of novel potential therapeutic herg activators. -plat n-terminal regulation of herg kd channel deactivation steven j. thomson, angela hansen, michael c. sanguinetti. nora eccles harrison cardiovascular research and training institute, university of utah, salt lake city, ut, usa. slow deactivation of herg (kv . ) potassium channels maintains ikr dur- ing final repolarization of the cardiac action potential and opposes asynchro- nous early depolarization. inherited point mutations in herg that accelerate deactivation of ikr cause long qt syndrome (lqts), a disorder of ventricular repolarization that increases the risk of lethal cardiac arrhythmia. the intracellular n-terminal domain of herg is known to be essential for slow deactivation. deletion of the entire (~ residues) or just the initial residues of the n-terminus accelerates deactivation -fold. the same effect is achieved by neutralization of the charged residues, arg or arg . how many of the n-termini are required to slow channel deactivation is unknown. herg , like other kv channels, is a homotetramer. by repeatedly linking the c-terminal of one subunit to the n-terminal of the next subunit we constructed concatenated herg tetramers. a variety of homomeric and heteromeric concatenated tetramers were characterized (i.e., wtn/r a:r a( -n); where n = to ). the concatenated channel containing a single r a/r a subunit and wild-type subunits deactivated as fast as the concatenated channel con- taining only r a/r a subunits. the lqts-associated mutation r q, located in the n-terminal of herg was also studied. again, a concatenated tetramer containing a single mutant subunit deactivated as fast as channels with r q mutations in all four subunits. our results show that all n-termini are required to mediate slow deactivation in wild-type herg channels. -plat lipid affinity to the voltage-gated potassium channel kvap elise faure , christine thompson , rikard blunck , . physiology, université de montréal, géprom, montréal, qc, canada, physique, université de montréal, géprom, montréal, qc, canada. voltage-gated potassium channels (kv) are formed by a central conducting pore surrounded by four voltage sensor domains. functional studies have re- vealed that biophysical properties of lipid molecules in the channels environ- ment can have strong effects on the activity of kv channels. here, we investigated the influence of different lipids as well as their affinity to kvap channels. we carried out electrophysiology measurements by fusing vesicles containing purified channels into planar lipid bilayers with varied lipid compo- sitions. we found that kvap properties are mainly determined by the lipid 	a-type kv channel closed-state inactivation is modulated by the tetramerization domain interacting with auxilary kchip a 	two-in-one: activation and inactivation at the intracellular gate of a kv channel 	development and validation studies of universal pharmacophore models for herg channel openers 	n-terminal regulation of herg k+ channel deactivation 	lipid affinity to the voltage-gated potassium channel kvap case reports thrombolytic therapy in a patient with suspected pulmonary embolism despite a negative computed tomography pulmonary angiogram urvashi vaid md, michael baram md, and paul e marik md we report a case of a -year-old male who presented to our intensive care unit with hypoxemia hours after retinal surgery. he had a negative computed tomography (ct) pulmonary angiogram, but an emergency echocardiogram revealed the mcconnell sign. he was thrombolysed and had rapid improvement in oxygenation and hemodynamics. thrombolysis in hemodynamically unstable pulmonary embolism is not controversial, but most algorithms require confirmation of the diag- nosis. our patient had a negative ct pulmonary angiogram but was thrombolysed based on the clinical picture. autopsy confirmed the diagnosis of multiple pulmonary emboli and unexpectedly discovered a patent foramen ovale that explained paradoxical embolism to the brain. key words: pulmonary embolism; computed tomography; paradoxical embolism; thrombolytic therapy. [respir care ; ( ): – . © daedalus enterprises] introduction massive pulmonary embolism is associated with a mor- tality of up to % acutely. we present a patient who had a negative multidetector computed tomography (ct) an- giogram but was nevertheless thrombolysed for acute pul- monary embolism. case report a -year-old white male with a history of hyperten- sion, hyperlipidemia, and retinal detachment underwent an elective vitrectomy for tractional retinal detachment. pre- operatively his mobility was limited by poor vision, but he was ambulatory. his preoperative oxygen saturation was % on room air. the procedure was uneventful and he was ambulatory postoperatively. six hours post-procedure he developed acute dyspnea with hypoxemia. he was trans- ferred to the medical intensive care unit with an oxygen saturation of % while on % oxygen via non-rebreather mask, and was intubated and mechanically ventilated. he had no known drug allergies. his medications in- cluded spironolactone mg and atorvastatin mg daily. he had retinal surgery months prior. he had no history of tobacco, ethanol, or illicit drug use. on arrival in the intensive care unit, his temperature was . °c, heart rate beats/min, respiratory rate breaths/min, and blood pressure / mm of hg. he had an eye patch over the right eye. auscultation found occasional crackles. cardiac examination found tachycardia, normal heart sounds, and no murmurs. he had no abdominal distention or organo- megaly. before intubation he was neurologically intact. there was no lower-extremity edema. electrocardiogram revealed sinus tachycardia but no right-ventricular (rv) strain. at that point we considered differential diagnoses of acute pulmonary edema, massive pulmonary embolism (thrombotic or non-thrombotic), cardiogenic shock from acute myocardial infarction, and acute respiratory distress syndrome. a ct pulmonary angiogram showed no central urvashi vaid md and michael baram md are affiliated with the divi- sion of pulmonary and critical care medicine, thomas jefferson uni- versity, philadelphia, pennsylvania. at the time of this study, paul e marik md was associated with the division of pulmonary and critical care medicine, thomas jefferson university, philadelphia, pennsylva- nia, but is now affiliated with the division of pulmonary and critical care medicine, department of internal medicine, eastern virginia med- ical school, norfolk, virginia. the authors have disclosed no conflicts of interest. correspondence: urvashi vaid md, division of pulmonary and critical care medicine, thomas jefferson university, walnut street, suite , philadelphia pa . e-mail: urvashi.vaid@ jeffersonhospital.org. doi: . /respcare. respiratory care • march vol no intravascular filling defect, infiltrate, or pneumothorax, but the ct was limited by respiratory motion artifact. initial blood tests were unremarkable, with a normal methemo- globin concentration. two hours after admission to the intensive care unit his oxygenation worsened and he de- veloped hypotension requiring vasopressors. an arterial blood sample revealed a ph . , paco mm hg, and pao mm hg while on pressure-control ventilation, fio . , and peep of cm h o. he became increasingly hypoxic on those settings, and paralytics were initiated. an emergency echocardiogram showed that the left ven- tricle was hyperdynamic, there was severe right-atrial and rv enlargement and decreased rv function, but with spar- ing of the apex (the mcconnell sign) (fig. ). based on the high clinical probability of acute pulmonary embolism, he was given intravenous recombinant tissue plasminogen ac- tivator, despite the normal ct pulmonary angiogram. later, upper and lower extremity venous doppler ultra- sound were negative for femoropopliteal thrombosis. the pelvic veins were not imaged by a venogram, and could well have been the source of pulmonary embolism. he was started on intravenous heparin, and contrast echocardio- gram was repeated in hours. the right atrium and right ventricle normalized, with no evidence of a shunt on a bubble study. over the next days he continued to im- prove hemodynamically. by day he was off vasopressors and on fio . and peep cm h o. once the sedation was discontinued, he was found to be unarousable, and he developed diabetes insipidus. an emergency brain ct re- vealed recent left middle and posterior cerebral artery in- farctions, with a -mm midline shift (fig. ), confirmed by a subsequent magnetic resonance image (fig. ). his family decided to withdraw care. autopsy revealed mul- tiple sub-segmental pulmonary emboli and a patent fora- men ovale. discussion little controversy exists in the administration of throm- bolytic therapy for massive pulmonary embolism in he- fig. . representative transthoracic echocardiogram showing a hypokinetic right ventricle with preservation of the apex (the mc- connell sign). fig. . noncontrast computed tomogram of the brain shows hy- podensities compatible with infarction in the left middle and pos- terior cerebral artery and right middle cerebral artery territories, with midline shift. fig. . magnetic resonance t axial flair image shows abnormal signaling in the left middle cerebral and posterior cerebral artery and right middle cerebral artery territories, with a midline shift. thrombolytic therapy in a patient with suspected pulmonary embolism respiratory care • march vol no modynamically unstable patients. , thrombolytic therapy decreases vascular obstruction by % at hours, com- pared to heparin. it is established that rv dysfunction in pulmonary embolism is central to the patient’s outcome acutely. pressure overload from pulmonary embolism, re- sultant myocardial ischemia, poor left-ventricular filling and diminished cardiac output ultimately lead to cardio- genic shock, which, if not reversed promptly, results in death. making a decision to aggressively treat acute pul- monary embolism becomes simpler if there is radiologic evidence of pulmonary embolism. the prospective investigation of pulmonary embolism diagnosis (pioped ii) study, completed in , reported that multidetector ct pulmonary angiogram had % sen- sitivity and % specificity in detecting pulmonary embo- lism. notably, % of patients with a high clinical prob- ability of pulmonary embolism had a negative ct pulmonary angiogram. pioped ii and our case exem- plify the bayesian theorem of conditional probability, which states that the probability of disease depends on its pre-test probability and the sensitivity and specificity of the test. our patient had a high clinical likelihood of massive pulmonary embolism, an echocardiogram highly sugges- tive of pulmonary embolism (the mcconnell sign), but a negative ct pulmonary angiogram. in that life-threatening scenario, recent ophthalmic surgery became a relative (not an absolute) contraindication to thrombolysis. the mcconnell sign (regional variations of rv systolic wall motion abnormalities, with sparing of the apex), when prospectively tested in patients, had a sensitivity of % and a specificity of % for the diagnosis of acute pulmonary embolism. more recently, lodato et al reported the right- and left-ventricular end-diastolic dimension as the most accurate echocardiographic predictor of pulmo- nary embolism in patients referred for helical ct, but found the mcconnell sign to be most specific ( %). this finding resolved in our patient after thrombolytic therapy. unfortunately, our patient developed an unexpected com- plication of his initial diagnosis. autopsy confirmed pul- monary embolism with paradoxical embolism to the brain via a patent foramen ovale. we postulate that the initial acute pulmonary embolism resulted in high right-side pressure, leading to paradoxical embolism and subsequent cerebral infarctions. this case emphasizes the importance of understanding the specificity and sensitivity of a test and applying it appropriately to a clinical scenario. references . konstantinides sv. massive pulmonary embolism: what level of aggression? semin respir crit care med ; ( ): - . . kearon c, kahn sr, agnelli g, goldhaber s, raskob ge, comerota aj; american college of chest physicians. antithrombotic therapy for venous thromboembolic disease: american college of chest phy- sicians evidence-based clinical practice guidelines ( th edition). chest ; (suppl ): s- s. erratum in: chest ; ( ): . . jerjes-sanchez c, ramirez-rivera a, de lourdes garcia m, arriaga- nava r, valencia s, rosado-buzzo a, et al. streptokinase and hep- arin versus heparin alone in massive pulmonary embolism: a ran- domized controlled trial. j thromb thrombolysis ; ( ): - . . dalla-volta s, palla a, santolicandro a, giuntini c, pengo v, vi- sioli o, et al. paims : alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism: plasminogen activator italian multicenter study . j am coll cardiol ; ( ): - . . lualdi jc, goldhaber sz. right ventricular dysfunction after acute pulmonary embolism: pathophysiologic factors, detection, and ther- apeutic implications. am heart j ; ( ): - . . stein pd, fowler se, goodman lr, gottschalk a, hales ca, hull rd, et al. multidetector computed tomography for acute pulmonary embolism. n engl j med ; ( ): - . . mcconnell mv, solomon sd, rayan me, come pc, goldhaber sz, lee rt. regional right ventricular dysfunction detected by echocar- diography in acute pulmonary embolism. am j cardiol ; ( ): - . . lodato ja, ward rp, lang rm. echocardiographic predictors of pulmonary embolism in patients referred for helical ct. echocardi- ography ; ( ): - . erratum in: echocardiography ; ( ):ii. thrombolytic therapy in a patient with suspected pulmonary embolism respiratory care • march vol no direct anterior approach: risk factor for early femoral failure of cementless total hip arthroplasty a multicenter study | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /jbjs. . corpus id: direct anterior approach: risk factor for early femoral failure of cementless total hip arthroplasty a multicenter study @article{meneghini directaa, title={direct anterior approach: risk factor for early femoral failure of cementless total hip arthroplasty a multicenter study}, author={r. meneghini and addison s. elston and a. chen and m. kheir and t. fehring and b. springer}, journal={the journal of bone and joint surgery}, year={ }, volume={ }, pages={ – } } 	r. meneghini, addison s. elston, + authors b. springer 	published 	medicine 	the journal of bone and joint surgery background: the direct anterior approach for total hip arthroplasty (tha) is marketed with claims of superiority over other approaches. femoral exposure can be technically challenging and potentially lead to early failure. we examined whether surgical approach is associated with early tha failure. methods: a retrospective review of consecutive early revision thas performed within years after the primary thas at academic centers from through was carried out. exclusion criteria… expand view on wolters kluwer ncbi.nlm.nih.gov save to library create alert cite launch research feed share this paper citationshighly influential citations background citations methods citations results citations view all tables and topics from this paper 	 table i 	 table ii 	 table iii 	total hip replacement (procedure) 	thas gene 	hip arthroplasty 	liver failure, acute 	hip dislocation, congenital 	revision procedure 	body mass index 	handedness 	somatotype citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency early failure of primary total hip arthroplasty: is surgical approach a risk factor? 	marc r. angerame, t. fehring, j. masonis, j. b. mason, s. odum, b. springer 	medicine 	the journal of arthroplasty 	 	 save alert research feed impact of femoral stem design on failure after anterior approach total hip arthroplasty. 	krishna r. cidambi, s. barnett, paige r mallette, j. patel, nader a. nassif, r. gorab 	medicine 	the journal of arthroplasty 	 	 	view excerpts, cites results save alert research feed mechanical complications following total hip arthroplasty based on surgical approach: a large, single-institution cohort study. 	a. fleischman, m. tarabichi, zachary magner, j. parvizi, r. rothman 	medicine 	the journal of arthroplasty 	 	 save alert research feed a comparison of risk of dislocation and cause-specific revision between direct anterior and posterior approach following elective cementless total hip arthroplasty. 	m. charney, e. paxton, + authors h. a. prentice 	medicine 	the journal of arthroplasty 	 	 save alert research feed surgical approach to total hip arthroplasty affects the organism profile of early periprosthetic joint infections 	daniel b. buchalter, g. teo, david j. kirby, v. aggarwal, w. long 	medicine 	jb & js open access 	 	pdf save alert research feed the effect of surgical approach on early complications of total hip arthoplasty 	kenny tay, andrew tang, camdon fary, s. patten, r. steele, r. de steiger 	medicine 	arthroplasty 	 	 	highly influenced 	 	view excerpts, cites background save alert research feed direct anterior versus mini-anterolateral approach for primary total hip arthroplasty: early postoperative outcomes and complications 	carl l. herndon, nathan drummond, n. sarpong, h. cooper, r. shah, j. geller 	medicine 	arthroplasty today 	 	 	 	view excerpts, cites background save alert research feed the effect of size for a hydroxyapatite-coated cementless implant on component revision in total hip arthroplasty: an analysis of , stems. 	w. hoskins, r. bingham, m. lorimer, r. de steiger 	medicine 	the journal of arthroplasty 	 	 save alert research feed perioperative fracture risk and two-year survivorship of a short tapered femoral stem following direct anterior approach cementless total hip arthroplasty with a fracture table 	samantha n. andrews, gregory j. harbison, ian g hasegawa, emily unebasami, c. nakasone 	medicine 	 save alert research feed the bikini incision anterior cemented total hip arthroplasty: assessment of radiological and clinical outcomes 	ikram nizam, avinash alva, s. gogos 	medicine 	sicot-j 	 	pdf 	view excerpt, cites background save alert research feed ... ... references showing - of references sort byrelevance most influenced papers recency early failures in total hip arthroplasty -- a changing paradigm. 	j. s. melvin, t. karthikeyan, r. cope, t. fehring 	medicine 	the journal of arthroplasty 	 	 	pdf 	view excerpt, references background save alert research feed direct anterior total hip arthroplasty: complications and early outcome in a series of cases. 	thomas de geest, p. vansintjan, g. de loore 	medicine 	acta orthopaedica belgica 	 	 	pdf save alert research feed new approach and stem increased femoral revision rate in total hip arthroplasty. 	p. panichkul, n. l. parks, h. ho, r. hopper, w. hamilton 	medicine 	orthopedics 	 	 	pdf save alert research feed outcome after proximal femoral fractures during primary total hip replacement by the direct anterior approach 	h. rüdiger, m. betz, p. zingg, j. mcmanus, c. dora 	medicine 	archives of orthopaedic and trauma surgery 	 	 	pdf save alert research feed surgeons changing the approach for total hip arthroplasty from posterior to direct anterior with fluoroscopy should consider potential excessive cup anteversion and flexion implantation of the stem in their early experience 	h. kobayashi, y. homma, + authors k. kaneko 	medicine 	international orthopaedics 	 	 save alert research feed minimal incision surgery as a risk factor for early failure of total hip arthroplasty 	bradley p. graw, s. woolson, h. huddleston, s. goodman, j. huddleston 	medicine 	clinical orthopaedics and related research 	 	 	 save alert research feed no difference in dislocation seen in anterior vs posterior approach total hip arthroplasty. 	j. maratt, j. gagnier, paul d. butler, b. hallstrom, a. urquhart, k. roberts 	medicine 	the journal of arthroplasty 	 	 save alert research feed early outcome comparison between the direct anterior approach and the mini-incision posterior approach for primary total hip arthroplasty: consecutive cases. 	m. zawadsky, m. paulus, p. j. murray, matthew a johansen 	medicine 	the journal of arthroplasty 	 	 save alert research feed long-term results using the anatomic medullary locking hip prosthesis 	c. engh, a. claus, r. hopper, c. engh 	medicine 	hip international : the journal of clinical and experimental research on hip pathology and therapy 	 	 save alert research feed acetabular abduction and dislocations in direct anterior vs posterior total hip arthroplasty: a retrospective, matched cohort study. 	krishna r. tripuraneni, natalie r. munson, m. archibeck, j. carothers 	medicine 	the journal of arthroplasty 	 	 save alert research feed ... ... related papers 	abstract 	tables and topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue science american association for the advancement of science science serves its readers as a forum for the presentation and discussion of important issues related to 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( - - ); beverly hills, ca : winn nance, n. la cien- ega blvd. ( - - ); san jose, ca : bob brind- ley, s. st. ( - - ); dorset, vt : fred w. dieffenbach, kent hill rd. ( - - ). instructions for contributors appears on page xi of the march issue. editorial correspondence, including re- quests for permission to reprint and reprint orders, should be sent to h street, nw, washington, dc . tele- phone: - - . advertising correspondence should be sent to tenth floor, broadway, ny . telephone - - . june i volume number the biotechnology issue p resident kennedy once invited a large group of distinguished scientists to the white house for dinner and there remarked, "i think this is the most extraordinary collection of talent, ofhuman knowledge, that has ever been gathered together at the white house, with the possible exception of when thomas jefferson dined alone." adapting this observation to the new biotechnology industry, we might say that we are today mobilizing the most amazing collection of brains for a new technology since louis pasteur worked alone. the biotechnology industry has been around for a long time, starting with the herb doctors and wine-makers ofancient civilizations. for deliberate application of the problems of science to the needs of health and the economy, however, louis pasteur is unique. he represents in one person the combination of pure research and practical application that is the hallmark of the current biotechnology industry. in pasteur's early studies he pursued the academic problem of optical antipodes, performing his classic work on the separation of dextro and levo tartaric acids. he also performed his seminal studies on the spontaneous generation of life, demonstrating that fermentation was the product ofliving cells and that life was necessary to create new life. his understanding of microbes and their behavior was the handle in his generation that recombinant dna is in ours. pasteur's genius and the smaller size of his scientific world produced a different relationship, however. pasteur personally was involved in one major industrial application after another. he discovered the cause ofthe souring ofwine and beer, thereby providing enormous economic savings for his own country as well as england and germany. he corrected the devastation of the silk industry by identifying the parasite preying on the silkworm. he developed the technique for attenuating viruses and protected chickens from cholera. he then studied the disease of anthrax and demonstrated the protection of sheep in one of the great experiments illustrating the scientific method. in the culminating act ofhis incredible career, pasteur saved the life ofa young boy who had rabies by giving him ground-up tissues from organs of infected animals. the modem technology industry parallels in uncanny ways the approach of louis pasteur. its hallmark is the continuously changing line between basic academic research and practical industrial applications. basic research in academia leads to applications in industry. questions posed by industrial problems generate new academic initiatives. to the credit of many modem biotechnology companies, they have become more permissive in allowing their scientists to publish and less secretive in regard to their procedures than the pharma- ceutical industries in the past. it is a farsighted approach, since secrets are difficult to secure and the industry itself thrives on the constant interaction with academia. this issue ofscience deals with new advances from which new medicines and industrial products may be produced. even those who do not like broccoli will have to concede that a member of the broccoli family that goes through its life cyde in weeks can provide a powerfuil research tool for plants (williams and hill). vietmeyer describes some "poor people's plants" that may provide more new bases for industrial crops than the species on which most modem agriculture now focuses. parkman discusses those diseases for which bone marrow transplantation is most appropriate, a technology whose importance is accentuated vividly by the chemobyl disaster. arathoon and his colleagues describe the improving expertise in growing large amounts of mammalian cells, a critical requirement for such products as vaccines, interferons, and monoclonal antibodies. blumenthal provides insight into the opportunities and hazards of university-industry relations, and dibner discusses the growth of biotechnology in europe. weetall and pitcher describe factors involved in scaling up an immobilized enzyme system. it is worth noting that pasteur operated with an incredible freedom not given to modem researchers. his treatment of the boy bitten by a rabid dog was done without extensive field trials, which would have delayed its application for years. his studies on soured wines and diseased silkworms were not greeted with cries that he was introducing organisms into the environment. allowing one genius unparalleled freedom is easier than attempting to control a boisterous and explosively growing technology. pasteur's willing- ness to take risks for good cause and to tackle academic and practical problems with equal enthusiasm are standards of conduct that have aged as well as the wines he preserved. -daniel e. koshland, jr. june i editorial o n a p ril , h ttp ://scie n ce .scie n ce m a g .o rg / d o w n lo a d e d fro m http://science.sciencemag.org/ the biotechnology issue de koshland jr doi: . /science. ( ), . science article tools http://science.sciencemag.org/content/ / / .citation permissions http://www.sciencemag.org/help/reprints-and-permissions terms of serviceuse of this article is subject to the is a registered trademark of aaas.sciencescience, new york avenue nw, washington, dc . the title (print issn - ; online issn - ) is published by the american association for the advancement ofscience no claim to original u.s. government works. copyright © the authors, some rights reserved; exclusive licensee american association for the advancement of science. o n a p ril , h ttp ://scie n ce .scie n ce m a g .o rg / d o w n lo a d e d fro m http://science.sciencemag.org/content/ / / .citation http://www.sciencemag.org/help/reprints-and-permissions http://www.sciencemag.org/about/terms-service http://science.sciencemag.org/ dimer at : delaware’s best value for medical education sherman l. townsend and omar khan, md . chair, delaware institute of medical education and research board . president & ceo, delaware health sciences alliance; faculty, thomas jefferson university; faculty, philadelphia college of osteopathic medicine; faculty, university of delaware; attending physician, family medicine, christianacare background the delaware institute for medical education and research (dimer) was founded in , with its first class entering medical school in ( years ago). at the time, as now, it was an alternative to an in-state medical school, addressing the concern of access to high-quality medical education for delaware residents in the absence of such a school. dimer initially formalized a relationship with thomas jefferson university for twenty admission slots for delawareans at jefferson medical college (now sidney kimmel medical college (skmc)). in , dimer expanded its education relationships to also include the philadelphia college of osteopathic medicine (pcom), further increasing access to medical education for delawareans. upon creation, pcom held five admission slots for qualified delaware applicants. in , that number was increased to ten. in the last years, dimer and the delaware health sciences alliance (dhsa) have worked closely together to gather data; enhance outreach to students; conduct evaluations; and bring the entire delaware healthcare together to focus on medical education and provider workforce. the dhsa was founded by core members: christianacare, nemours, thomas jefferson university and university of delaware. recently, membership has expanded to include bayhealth, pcom, and the delaware academy of medicine/delaware public health association. the dimer advantage there are five us states without an in-state allopathic medical school: alaska, delaware, idaho, montana, and wyoming. one of those, idaho, has an osteopathic school of medicine. excepting delaware, the other four are part of the wwami consortium by which the university of washington serves as their medical school. the dimer program predates wwami by two years, as the latter was started in . there are important differences between the two programs, notably, that wwami provides for the states of medical student origin to also house them for the basic sciences part of their medical education (e.g., a student from wyoming would complete a foundations phase at the university of wyoming before proceeding to the university of washington for their clinical training, and then return back to their home states in many cases for clinical experiences). as a state with no in-state medical school, this potentially presents a barrier to medical education for delaware residents. however, through its relationships with skmc and pcom, delaware has secured a minimum number of slots for qualified delaware applicants. on annual average, skmc and pcom each receive an estimated , applications for approximately slots per respective institution. as dimer applicants, delaware applications are pulled from the overall , applications received and evaluated against other delaware applicants. this significantly improves the odds of being in the applicant pool, and being offered one of or more medical school slots reserved for delaware students. dimer provides one of the best medical education admission advantages in the country for qualified applicants from the first state. delaware branch campus and residency while dimer’s charge is to ensure access to quality medical education for delaware residents, dimer’s mission and values extend beyond access. dimer and its partners are committed to providing a network of support for its students and engage students throughout the academic year in a variety of ways. ensuring delaware students understand the opportunities that are available to them through dimer’s partnerships will help to increase the qualified delaware applicant pool and ensure delaware is well-represented from all three counties. the dimer-dhsa partnership has resulted in providing personal letters to each student at the beginning of each academic year; co- hosting receptions with pcom and skmc for dimer students to network with both dimer and institutional leadership; and conducting participatory panels in every county with prospective students and families to discuss the many benefits of dimer. outreach events provide an opportunity for students to hear from a panel of experts including dimer leadership, current dimer medical students, dimer alumni, dhsa leadership, and practicing physicians as well as representatives from all our medical education partners and admissions offices. we are optimistic that through continued partnership, outreach and engagement, more delawareans will seek high quality medical education opportunities from our exceptional partner institutions. dimer is not only focused on providing medical education opportunities for delawareans but also in the retention of delaware physicians to serve our communities. dimer medical students at skmc and pcom have an opportunity to conduct their third- and fourth-year rotations at the delaware branch campus. the delaware branch campus provides medical students clinical training at christianacare, nemours / a.i. dupont hospital for children, and the wilmington va medical center, and dimer-dhsa has co-hosted graduation receptions for graduating branch campus students. in addition, pcom clinical rotations have grown to now also include bayhealth’s kent and sussex campuses. it is clear that many physicians stay to practice where they trained for residency; dimer’s relationships thus extend beyond its education partners and into delaware’s health systems. delaware residency match opportunities are not limited to delaware branch campus partners, as st. francis also has a family medicine residency program, and bayhealth is in the process of launching its own family medicine residency. this range of options will provide increased opportunity for delawareans to complete their medical training and serve their community in their home state. dimer results since , dimer has matriculated , delaware students ( students to skmc and students to pcom). of these, are male and are females. by county, originated from new castle county, while kent and sussex counties were represented by a combined total of students. dimer graduates from skmc and pcom went into primary care (n= ) and specialty care (n= ). as of , dimer students have returned to practice in delaware. twenty percent have stayed in delaware, while . % have ever practiced in delaware (i.e. . % ultimately practiced elsewhere). the full dimer anniversary report details data on the significant impact that dimer and partners are making in the first state. next steps dimer has been a successful model of delaware’s medical education program, focusing on access for delaware students. we increasingly recognize the importance of financial and debt burden, and several measures are underway this legislative session to provide greater incentives to return to the state for practice. through partnership with dhsa, dimer will continue to play an active role in the arc of education through workforce: • educating entering college students about their career choices, • assisting pre-medical students in applying to partner schools, • maintaining close touch with learners through medical school and residency, and • linking graduates to employment opportunities throughout the state upon completion of their graduate medical education. conclusion the dimer program at is revitalized and strong through its partnerships. it continues to represent high value for delawareans’ medical education. we refer readers to the full dimer anniversary report which provides more in-depth information on demographics and data on dimer graduates, as well as personal stories from state and institution leadership and dimer alumni. dimer’s partnering with the dhsa has resulted in a robust array of services intended to facilitate delawareans’ pathway to medical school and improved chances of returning to delaware to practice needed specialties in their home communities. there remain important areas of needed investment, such as more robust student financial support. we are confident that with the support of the state and our many partners, we can improve healthcare access for our communities with the best-trained medical workforce anywhere. in this way we hope to address any foreseeable barriers to a high-quality education for qualified delawareans, and to supporting a healthier delaware. references . university of washington medicine. (n.d.). wwami. retrieved from: https://www.uwmedicine.org/school-of-medicine/md-program/wwami . delaware institute for medical education and research. ( ). dimer anniversary report. retrieved from: https://dhss.delaware.gov/dhcc/files/dimer annrpt_ .pdf 	dimer at : 	delaware’s best value for medical education 	background 	the dimer advantage 	delaware branch campus and residency 	dimer results 	next steps 	conclusion 	references student perspectives with a high-utilizing patient | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . / corpus id: student perspectives with a high-utilizing patient @article{shoemake studentpw, title={student perspectives with a high-utilizing patient}, author={jennifer dell shoemake}, journal={journal of patient experience}, year={ }, volume={ }, pages={ - } } 	jennifer dell shoemake 	published 	psychology, medicine 	journal of patient experience it could have been any time, on any day, in any doctor’s waiting room, but today was different. today, i was sitting with mrs murphy and she was scared. she insisted we call her paula. she stopped smoking a month ago, but she was nervous and the undeniable smell of parliaments wafted from her clothes while we waited. the analog clock on the wall ticked to : pm. we were waiting for a : pm appointment to see dr green. he was the first doctor that paula told us about when we met. it was a… expand view on sage ncbi.nlm.nih.gov save to library create alert cite launch research feed share this paper topics from this paper 	incest (event) 	arecaceae 	wounds and injuries 	melkersson-rosenthal syndrome 	occupational medicine field 	drug abuse 	general equivalency diploma completion 	love 	auditory perception 	analog 	telephone number 	ability to sit question related papers 	abstract 	topics 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue the papers of thomas jefferson n june , , thomas jefferson noted in his "epistolary ledger" the receipt of a letter from v. w. southall. on june he closed the record of almost half a century's correspondence with a memorandum of letters written to george stevenson and ber- nard peyton. the letters received, endorsed with the writer's name and the date and place written, he filed with copies of their answers. on june , he made a last entry in his pocket account books, "pd. isaacs for cheese ..s .." and on july , , he died, leaving behind in good condition the well ordered accumulation of correspondence and papers that has been called "the richest treasure house of in- formation ever left by a single man." in bequeathing a watch to his favorite grandson, thomas jefferson randolph, jefferson further provided, ". . . my papers of business going of course to him as my executor, all others of a literary or other character i give to him as of his own property." from this bequest, the large jefferson collections at the library of congress (about , pieces), at the massachusetts historical society (about pieces), and at the missouri historical society ( pieces) were acquired. fragments from the same bequest are scattered in smaller collections, public and private, from california to western europe. three other jefferson collections, at the virginia state library (number of pieces undetermined), in the national archives (number of pieces undetermined), and at the university of virginia ( pieces) are derived wholly or in part from sources independent of the bequest and consist of jefferson's papers as legislator and governor, as secretary of state, and as the "father" and first rector of the uni- versity of virginia. the rare book and manuscript division of the university of vir- ginia library has attempted to trace all surviving letters to and from jefferson in public repositories, in private custody, and in printed form, a project which has been in progress for upwards of ten years. at the present time this list is in the form of a chronological check two index volumes in the jefferson papers, library of congress. photostat, univer- sity of virginia. account book, - . see note . gilbert chinard, thomas jefferson, the afostle of americanism (boston, ), xvi. original holograph will, clerk's office, albemarle county, va. photostat, university of virginia. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril thomas jefferson papers list written on thousands of temporary slips. it embraces most of the large collections just mentioned, many scattered holdings, fiye of the collected editions of jefferson's writings, and printed items in his- torical journals and other publications. like many other educated virginia planters of his day, jefferson wrote his own letters, saved copies of them, and preserved his entire correspondence. in this, and in the keeping of orderly daily accounts of cash receipts and expenditures jefferson merely followed a fairly usual custom; but his natural aptitude for organization and system and his insatiable intellectual curiosity led him to improve upon the customary form and to keep, in addition, many other valuable rec- ords. he kept, for example, a garden book, a farm book, and three separate records of meteorological observations. but it was in the amassing of a vast correspondence with writers in every walk of life throughout the united states, england, and the continent, covering every type of subject from mammoth skeletons to the napoleonic wars, that jefferson left his most valuable bequest to posterity. in fact, when his friend robert walsh of philadelphia asked him in to furnish materials for writing his biography, he declined graciously, on the plea that "the letters of a person, especially one " the dispersal of jefferson's papers is well illustrated by the following table showing the present location of the account books. photostatic sets of the entire group are now at the university of virginia and at the library of congress. — lc—kean mhs mhs lc mhs huntington - mhs — lc - -index uva - ° mhs - nyp .- nyhs - nyhs - nyhs mhs ( miscellaneous pages, various dates between and , with an index.) 'garden book [ - ]. original, massachusetts historical society. photostat, university of virginia. ' f a r m book [ - ]. original, massachusetts historical society. photostat, uni- versity of virginia. "weather observations. mss vols. - , - , - . originals, massachusetts historical society. photostats, university of virginia. see also the article by fred. l. francis and fred. j. randolph in monthly weather review (u.s. dept. of ag., ), pp. - . u.s. weather bureau bulletin, no. . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril the american archivist whose business has been chiefly transacted by letters, form the only full and genuine journal of his life, and few can let them go out of their hands while they live. a life written after these hoards become opened to investigation must supercede any previous one. . . ." this vast hoard was first opened by his grandson, thomas jefferson randolph, who published a memoir, correspondence, and miscel- lanies, from the papers of thomas jefferson ( vols., charlottesville, ). until this time, the papers had remained more or less undis- turbed as jefferson had left them; but in , george tucker undertook to write a life of jefferson, chiefly to answer henry lee's observations on the writings of thomas jefferson (new york, ). h e made use of an unpublished selection of the letters made by nicholas p. trist, who had married virginia jefferson randolph, daughter of martha jefferson and thomas mann randolph. this suggests a first possible division of the correspondence. before this, in ,when the library of congress purchased jefferson's library, and again at their purchases from the auction of his second library in , they had acquired some manuscripts. in addition to the un- published selection, tucker was able to recover from john page, jr., a series of letters to jefferson's lifelong friend, john page of rose- well, written before . in february, , when the family plan- tation shadwell burned, jefferson had written page that he had lost every paper he had in the world, and almost every book. the page letters, therefore, are among the few early letters that have survived. any other letters antedating may be expected to have survived among the papers of their recipients. the collection of public papers was offered to congress in , and on august of that year, an act was passed authorizing their purchase for $ , from thomas jefferson randolph and their deposit in the state department for a separation of public and private papers. then began a leisurely process of selection in the state de- partment as the private papers were culled, probably by henry a. washington, the librarian of the state department, who in - edited the somewhat inadequate congressional edition of the writings. " t h o m a s jefferson, monticello, april , , to robert walsh, philadelphia. origi- nal, university of virginia. i george tucker, the life of thomas jefferson ( vols., london, ) , i, xv. i i andrew a. lipscomb and albert ellery bergh, eds., the writings of thomas jef- ferson ( vols., washington, ) , iv, . hereafter cited as lipscomb and bergh. henry a. washington, ed., the writings of thomas jefferson . . . ( vols., new york and washington, ) . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril thomas jefferson papers early in , henry s. randall began work on his life of jeffer- son, visiting the descendants of edgehill and interviewing old neigh- bors for personal recollections of the sage of monticello. at the randolph home, edgehill, was found a large collection of papers and accounts of peter jefferson, jefferson's father, dealing chiefly with the administration of the estate. these are now in the henry e. huntington library in california. by about , the randolph collection of papers had finally been scrutinized by a joint committee of the library of congress and the department of state, and the private papers not purchased were re- turned to the family. the subsequent career of the residuum can be traced only in part. the selection of public papers had been neither thorough nor consistent: papers of public interest had been returned and some private ones retained. part of the collection retained by congress was then "arranged and bound in a manner defying every rule governing due historical treatment." moreover, after this had been done, and twenty-six years after the private papers had been returned to thomas jefferson randolph, a. r. spofford, then li- brarian of congress, found a large parcel, evidently selected as public papers by the committee, which had been overlooked. these were bound in nineteen additional volumes. nor was the entire collection yet together, for the department of state turned over to the library of congress additional letters in , and in or a box containing more than additional pieces was found in mr. spof- ford's office. the transfer of this box finally brought the govern- ment's holdings from the randolph heirs together under one roof and one direction. in the meantime, the private papers were being subjected to that scattering of manuscripts among a "multitude of inheritors," as randall feared in . they were used, while still together, by sarah nicholas randolph, daughter of thomas jefferson randolph, henry s. randall, the life of thomas jefferson ( vols., new york, ), i, i n. calendar of the corresfondence of thomas jefferson. part i, letters from jefferson. part ii, letters to jefferson. part iii, supplementary. bulletin of the bureau of rolls and library of department of state, nosj , , . (washington, dept. of state, - ). hereafter cited as bur. of rolls. worthington c. ford in "the jefferson papers," preface to fiske kimball, thomas jefferson, architect (boston, privately printed, ), . for ford's later comments, see his introductory note to the bixby collection: thomas jefferson corresfondence . . , (boston, ). bur. of rolls, no. ( ), iii. " ford, of. cit., . randall, of. cit., i, viii. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril the american archivist to write her charming domestic life of thomas jefferson (new york, ). in , she offered the papers to the united states, and a bill, h.r. , was referred to the committee on the library. sarah randolph died in , leaving the papers to her sisters, caro- lina ramsay randolph and cary ann nicholas randolph. in , the committee reported on the bill, describing a portion of the col- lection in detail, as containing pieces bound in portfolios, none of them duplicated in the department of state collections. the committee urged the purchase of the collection for its historical as well as its biographical value, but the bill failed to pass, and the chance to reassemble jefferson's correspondence in one place was lost." thomas jefferson coolidge of boston, a great-grandson of jeffer- son, purchased a collection of about pieces from these private papers in , which he presented to the massachusetts historical society in june of that year. a selection of these was printed in in the society's proceedings. from mrs. wilson cary nicholas randolph in , the library of congress received drafts of jefferson's letters on the uni- versity of virginia, and some years earlier wilson cary nicholas randolph had presented to the university of virginia of jeffer- son's sketches and plans of its original buildings. in , william k. bixby acquired a collection of about pieces from mr. george p. coleman of williamsburg and richmond. mr. coleman's ancestor, st. george tucker, "the american black- stone," was a close friend of jefferson. mr. coleman's mother had married henry a. washington, and after his death, dr. charles washington coleman. it seems probable that part of the coleman collection had been in st. george tucker's papers, and another por- tion in mr. washington's, in connection with his work on the con- gressional edition of the writings. there is still a collection of about pieces, chiefly letter-press copies and incoming letters owned by mr. coleman and deposited in the department of research and records of colonial williamsburg, inc., which he had generously permitted the university of virginia to microfilm for reference pur- poses. mr. bixby distributed upwards of pieces of his collection "house miscellaneous reports. th congress, nd session. nos. - . report to accompany h.r. , jan. , . "report of the librarian of congress, , . memorandum by wilson cary nicholas randolph, april , . university of virginia. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril thomas jefferson papers among individuals and institutions which he thought should own them, and he presented to the missouri historical society. a selection of these was printed in boston in with notes by worth- ington c. ford, thomas jefferson correspondence, printed from the originals in the collection of william k. bixby; and the missouri historical society has since printed another selection, but the greater part of the bixby group is still unpublished. collections of the private papers have continued to come into pub- lic repositories. thomas jefferson coolidge, jr., in visited monticello and was inspired by the idea of reproducing in manches- ter, mass., his ancestor's famous dwelling. h e found jefferson's architectural drawings for monticello owned by mrs. william mann randolph (nee mary walker randolph, daughter of thomas jeffer- son randolph, jr.) and miss cornelia j. taylor (daughter of thomas jefferson randolph taylor, who had married martha jef- ferson randolph, daughter of thomas jefferson randolph). these he acquired and presented to the massachusetts historical society. he also sponsored their publication in fiske kimball's definitive work on thomas jefferson, architect? the library of congress added "inedited letters" to its collec- tion at a sale in philadelphia, and has since acquired other jefferson items as part of other collections, or as separate purchases or gifts. these, with scattered holdings among the "multitude of inheritors," complete the record of the collection which jefferson bequeathed to thomas jefferson randolph in . it is interesting to note that in connection with the records of the commonwealth of virginia, jefferson evinced that interest in the preservation of historical documents that characterized his entire adult life. while he was still a law student at the college of william and mary in , and the records of the colony were kept in the public record office in the capital at williamsburg, he took a keen interest in the frail and crumbling records of the colony's earliest laws and made extensive transcriptions from them. beyond this, he collected as many of the printed and manuscript laws of the colony "correspondence of thomas jefferson, - ," missouri historical society, glimfses of the past, iii, nos. - (april-june, ), - . also separately reprinted. of. cit. "refort of the librarian of congress, , . see also the later reports. "thomas jefferson, philadelphia, may , , to hon. st. george tucker, wil- liamsburg. jefferson papers, lib. of cong. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril the american archivist as possible, and of these he wrote judge george wythe from monti- cello on jan. , : . . . these i preserve by wrapping and sewing them up in oiled cloth, so that neither air nor moisture can have access to them. very early in the course of my researches into the laws of virginia, i observed that many of them were already lost, and many more on the point of being lost, as existing in only single copies in the hands of careful or curious individuals, on whose deaths they would probably be used for waste paper. i set myself therefore to work, to collect all which were then existing, in order that when the day would come in which the public should avert to the magni- tude of their loss in these precious monuments of our property, and our history, a part of their regret might be spared by information that a portion had been saved from the wreck, which is worthy of their atten- tion and preservation. in searching after these remains, i spared neither time nor expense; and am of the opinion that scarcely any law escaped me, which was in being as late as the year in the middle or southern parts of the state. in the northern parts, perhaps something might still be found. in the clerk's offices in the ancient counties, some of these manuscript copies of the laws may possibly still exist, which used to be furnished at the public expense to every county, before the use of the press was introduced. . . . this collecting saved for virginia its earliest laws, because after the removal of the capital to richmond in december, , the state's records were also transported, and there many were destroyed or seized by the british in . jefferson placed his collection at the disposal of william waller hening, who was compiling the statutes at large, and in doing so realized an ambition to insure its preserva- tion "from the worm, from the natural decay of the paper, from the accidents of fire, or those of removal when it is necessary for any pub- lic purposes . . . [from] ravages of fire and ferocious enemies." in his advice to hening on the publication he advocated another sound principal of preservation, " i shall have no doubt of the exact- ness of your part of the work, but hope you will take measures to have the typography and paper worthy of the work"—advice which hening was unfortunately not able to follow. nor did his efforts to recover the state's official archives end there. on may , , he wrote the president of the united states that thomas jefferson, monticello, jan. , , to judge george wythe, in lipscomb and bergh, ix, - . [incorrectly dated by hening as jan. , .] the letter was first printed in broadside form in . see evans, . thomas jefferson, washington, jan. ., , to william waller hening, in the statutes at large-, being a collection of all the laws of virginia . . . , edited by william waller hening (richmond, - ), vii-viii. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril thomas jefferson papers he was attempting to restore the records destroyed by the british, particularly the transactions of the revolution between june , , and june , . he asked to be allowed to borrow official letters he had addressed to washington of those dates. two years later he was still engaged in this task, and wrote to major general horatio gates from philadelphia on march , , "i am endeavoring to recover copies of my letters from the hands to whom they were ad- dressed, and have been happy to find this more practicable than i had apprehended. . . . the whole shall be sacredly returned." the first two pages of jefferson's epistolary ledger are quite ap- parently a record of official letters during his governorship which he recovered in this manner. with the records which survived the brit- ish raid, and a copy of the executive letter book from july - september , (captured by the british and later deposited in the british museum), the virginia state library in was able to bring out a fairly complete record of the official letters, under the editorship of h. r. mcllwaine. jefferson's drafts of bills and reso- lutions presented to the virginia house of delegates while he was a member of that body, have been rediscovered recently in the capitol and deposited in the archives of the new virginia state library build- ing, where they are being catalogued under the direction of dr. wil- liam j. van schreeven, the archivist. the university of virginia is the fortunate possessor of a collection of more than items, some of which accumulated as official uni- versity archives. others were acquired by gift and purchase. the col- lection includes a large photostatic and microfilm collection acquired for research, such as the complete file of jefferson's account books from to copied from many different sources, copies of un- published letters in the massachusetts historical society collections, and copies of scattered single letters still in private hands. a catalogued and indexed calendar of this collection has been prepared by the writer for publication in the near future. the thomas jefferson memorial foundation, which owns monti- cello, and is engaged in its restoration and maintenance as a national shrine, has received many gifts of jefferson manuscripts, and has thomas jefferson, philadelphia, may , , to george washington, in lipscomb and bergh, viii, . thomas jefferson, philadelphia, mar. , , to major general horatio gates, in ibid., ix, - . official letters of the governors of the state of virginia. vol. ii. the letters of thomas jefferson. edited by henry r. mcllwaine (richmond, ) . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril the american archivist purchased others. all of these have been microfilmed for the library's collection, and are thus available for research. this collection in- cludes, in addition to a few legal papers, a magnificent collection of music owned by jefferson and his daughters and grandchildren at monticello, presented by miss fanny maury burke, a descendant. there are some manuscript music books in the lot, which may or may not be original compositions by jefferson, still others are copies by him, his daughters, and grandchildren of well chosen selections by leading eighteenth and nineteenth century composers. one music book contains jefferson's directions for tuning the harpsichord. in the university of virginia's group of papers which could be classed as official are the original architectural drawings of the uni- versity already mentioned; a pocket memorandum book containing specifications; a few drawings and calculations used by jefferson in directing the building operations; minutes of the board of visitors of central college (may , -feb. , ) and of the uni- versity of virginia (to april , ) kept by thomas jefferson as rector; papers from the proctor's office dealing with financial affairs of the university and written or endorsed by jefferson. an extensive correspondence with jefferson's good friend and fellow sponsor of the university, joseph cabell, much of which pertains to the founding of the university, was presented by mr. robert c. taylor. eighteen letters written by jefferson to john hartwell cocke, a fellow member of the board of visitors, were presented by william andrews clark, jr., an alumnus who collected and pre- sented a number of other jefferson manuscripts. a collection of manuscripts and printed items in the mc- gregor library consists of legal papers, surveyor's drawings, and correspondence relating chiefly to jefferson's lands in albemarle, bedford, and campbell counties, and a lawsuit over land at milton, virginia. a group of items are of jefferson's dealings, during his term as president, with george barnes, a georgetown merchant. some important single items, particuuarly manuscript volumes or printed volumes with jefferson's notations have also been acquired by the mcgregor library. among materials of this type at the uni- versity library are the following: many of these were printed with tactful omissions in nathaniel francis cabell, early history of the university of virginia as contained in letters of thomas jefferson and josefh c. cabell . . . (richmond, ). d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril t h o m a s j e f f e r s o n papers collection of ordinances and bills prepared by the committee of the convention for the revision of the laws of virginia. - . pp., and index pp. by thomas jefferson, with notes on the bills. copy of jefferson's notes on the state of virginia, with his manu- script revisions, additions, maps and plates, which was used by j. w . randolph to bring out a revised edition in . the copies of the new testament from which jefferson clipped, in the preparation of the philosofhy of jesus of nazareth . . . inscribed copy of the notes which jefferson had presented to la- fayette. an essay or introductory lecture towards facilitating instruction in the anglo-saxon and modern dialects of the english language. for the use of the university. ad pp., and rough draft, ad pp. president jefferson's catalogue of books for the university of vir- ginia library. . in the writing of jefferson's granddaughter, vir- ginia randolph. signed by jefferson as rector of the university. scrap book of political songs and poems compiled by jefferson, chiefly of the period of his presidency and clipped from newspapers and periodi- cals. thomas jefferson's designs for the president's house and capitol in washington. . four sheets with rough pencil drawings and two finished floor plans of the designs submitted anonymously by jefferson in the competition announced by the commissioners of the federal build- ings (of which he was one). letters continue to accumulate at the university, both from the descendants who still retain fragments of the great mass of "private papers," and from descendants of those to whom the original letters were addressed. just this year the mcgregor library obtained a col- lection of items, chiefly intimate letters between members of the carr, cary, randolph, nicholas, and jefferson families. in this group were letters to and from thomas jefferson, including a series from peter carr concerning his education at william and mary and his beginning law practice; jefferson's correspondence with his brother randolph of snowden over family finances, agriculture, spinning jennies, and the latter's domestic difficulties (now ready for publication by the mcgregor library under the editorship of pro- fessor bernard mayo); and letters of wilson miles cary asking for advice in educating his grandchildren. it is hoped that in the coming year the check list can be brought nearer to completion by the addition of records of letters to or from jefferson in repositories having only small holdings. the epistolary ledger will then be transferred to this check list, and many letters now d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril the american archivist undated, or to or from unknown correspondents can be assigned their proper designation. this list will be mimeographed or printed and circulated widely in the hope of locating as far as possible all jeffer- son correspondence, whether original, polygraph or letter press copy, or printed. in this connection, the missouri historical society has arranged through miss brenda richard, its assistant archivist, to contribute a list in card form of its holdings; dr. earl g. swem of the college of william and mary has sent a list of his library's jef- ferson collection to be recorded in the check list; the maryland historical society has permitted photostating of its collection; and dr. william smith mason has contributed photostats of the jefferson material in the franklin papers at yale university library. this co-operative work of institutions and individuals is bringing order back to the confusion resulting from the wide scattering of the rich treasure house that was once a single collection. in anticipation of the jefferson bi-centennial celebration in , the university of vir- ginia hopes to contribute as an aid to jefferson scholarship a printed calendar of its holdings, and an extensive checklist locating all pos- sible jefferson papers, and will welcome any lists which can be con- tributed. one is reminded, in this task of jefferson's own tireless labors on behalf of the preservation of the records of the state of virginia and of the united states; and of his labor in amassing and organizing a vast correspondence, only to have it scattered by various mischances. the man who made use of copying presses and polygraph to preserve his correspondence, and who urged printing as another means of multiplying copies, would have welcomed microfilming. that he anticipated some of the soundest principles of modern archival prac- tice is evidenced in his letter to ebenezer hazard, which is dated philadelphia, feb. , : sir i return you the two volumes of records, with thanks for the oppor- tunity of looking into them. they are curious monuments of the infancy of our country. i learn with great satisfaction that you are about com- mitting to the press the valuable historical and state papers you have been so long collecting. time & accident are committing daily havoc on the originals deposited in our public offices. the late war has done the work of centuries in this business. the lost cannot be recovered; but let us "thomas jefferson, philadelphia, feb. , , to ebenezer hazard. original, his- torical society of pennsylvania. facsimile copy, university of virginia. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril thomas jefferson papers save what remains; not by vaults and locks which fence them from the public eye and use in consigning them to the waste of time, but by such multiplication of copies as shall place them beyond the reach of acci- dent. this being the tendency of your undertaking be assured there is no one who wishes it more complete success than sir your most obedient & most humble sert t h : jefferson mr. hazard. h e l e n d u p r e y b u l l o c k university of virginia d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . r by c arnegie m ellon u niversity user on a pril springer a++ viewer publisherinfo publishername : biomed central publisherlocation : london publisherimprintname : biomed central antisense oligonucleotide treatment for human astrocytoma articleinfo articleid : articledoi : . /gb-spotlight- - articlecitationid : spotlight- - articlesequencenumber : articlecategory : research news articlefirstpage : articlelastpage : articlehistory : registrationdate : – – onlinedate : – – articlecopyright : biomed central ltd articlegrants : articlecontext : tudor toma email: ttoma@mail.dntis.ro active antisense oligonucleotides directed against the insulin-like growth factor type i receptor (igf- ir/as odn) have shown potential as an antitumour agent in animal studies. in the april issue of journal of clinical oncology david andrews and colleagues from thomas jefferson university hospital, philadelphia, describe their novel implantation of igf-ir/as odn-treated cells in patients with astrocytoma. andrews et al. studied patients treated by surgery for malignant astrocytoma. glioma cells collected at surgery were treated ex vivo with an igf-ir/as odn and reimplanted in the rectus sheath within hours of craniotomy. examination of the igf-ir/as odn-treated cells after a -hour in situ incubation showed that only % were intact, and none of the intact cells was viable in culture thereafter. igf-ir was down regulated to % after ex vivo antisense treatment (j clin oncol , : - ). in addition, clinical and radiographic improvements were observed in eight of patients. this suggests that ex vivo igf-ir/as odn treatment of autologous glioma cells can induce apoptosis and an in vivo host response without side effects. references . andrews dw, resnicoff m, flanders ae, kenyon l, curtis m, merli g, baserga r, iliakis g, aiken rd: results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type i receptor in malignant astrocytomas. j clin oncol , : - ., [http://www.jco.org/cgi/content/abstract/ / / ] . thomas jefferson university hospital, [http://www.jeffersonhospital.org/show.asp?durki= ] this pdf file was created after publication. http://www.jco.org/cgi/content/abstract/ / / http://www.jeffersonhospital.org/show.asp?durki= 	antisense oligonucleotide treatment for human astrocytoma 	references wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); 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// // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ a picture (and biography) is worth words ronald g. driggers downloaded from: https://www.spiedigitallibrary.org/journals/optical-engineering on apr terms of use: https://www.spiedigitallibrary.org/terms-of-use a picture (and biography) is worth words according to wikipedia (so it must be true), the phrase “a pic- ture is worth a thousand words” is attributed to an article by fred r. barnard in the trade journal printers’ ink in . he went on to say later that he attributed it to a chinese proverb so people would take it seriously. i’ve always liked the pictures and biographies of authors in optical engineering because it lets me get to know the more personal side of my colleagues, see what they look like, and review their background and major accomplishments. we’ve even had authors send in pictures of themselves in the infra- red so that you could see their bright faces in heat rather than in reflectivity. we’ve had authors send in pictures of them- selves on motorcycles, in airplanes, in front of sports cars, and as author groups. some of the biographies are pretty funny and interesting too. i remember one (and i can’t find it) that went something like: “john doe has just completed his doctoral degree at the university of somewhereville and is so burnt out that he has no further research interests. he plans to spend the rest of his life riding and working on his motorcycle.” a close friend of mine wrote one for an optical engineering paper in : “jeffrey s. sanders received his bsee in from memphis state university. during and he worked as an electro-optics engineer for martin marietta electronic systems division on the lantirn program. in he returned to memphis state to pursue a phd in engineering. in between donning armor and hitting his friends with sticks (society for creative anachronism), and a few cases of tequila, he somehow managed to complete an ms in . his current research interests include visual perception of infrared imagery and multispectral imaging with frequency modulated reticles.” most of the pictures and biographies are more conservative, but they are still interesting to read and help us know our colleagues better. the pictures and biographies have been a nice personal touch to the journal, but beginning in , spie will be standardizing all of the journals to be more uniform. the increasing preference for digital formats, reduction in print quantities (and increase in costs), increased number of papers published per issue, and lengthy article page counts are all influencing factors in the decision to dis- continue inclusion of author photographs in spie journals. going forward, biographies will be limited to words, so you will have to do like thomas jefferson and spend the time to make your words count. this will all lead to an increased efficiency and a shorter publication turnaround time. so, why am i writing about this in an editorial? first, i wanted to inform you of the change. but, more importantly, i would like all of you to spend a little time with your online spie profile. do you know that you likely already have one? spie profiles rank high in search engine results, often above facebook and linkedin. profiles automatically link to spie conference participation and publications, and you can add a biography statement, upload a photograph, and list any other publications and professional interests. all papers published on the spie digital library include links on the authors’ names that take you to their online profiles. please spend some time creating or improving your spie profile footprint by going to http://spie.org/app/profiles/ default.aspx. you can use your profile to tell others more about you. i am still interested in learning about all of you, and i think most people are curious about others working in their field. like most print and computer technology progress, we are moving more to digital media, and photos/biographies are no exception. so, how about a new comparison? an interesting spie profile is worth a handshake! ronald g. driggers editor optical engineering - october /vol. ( ) editorial downloaded from: https://www.spiedigitallibrary.org/journals/optical-engineering on apr terms of use: https://www.spiedigitallibrary.org/terms-of-use http://spie.org/app/profiles/default.aspx http://spie.org/app/profiles/default.aspx http://spie.org/app/profiles/default.aspx http://spie.org/app/profiles/default.aspx preparing a manuscripts guide for a learned society by murphy d. smith* american philosophical society during september whitfield j. bell, jr., associatelibrarian of the american philosophical society library,and i embarked on the project of preparing a guide for the manuscripts collections of the library. we looked forward to gar- nering the rich harvest of manuscripts assembled over two centu- ries by this, the oldest continuous learned society in the united states. much of our time since then has been spent assembling the history of the collections, and it is of this history that i write. the american philosophical society, held in philadelphia, for promoting useful knowledge, "proposed & set on foot [in ] by b[enjamin] f[ranklin]—dormant some years: resumed in " began its collection of manuscripts with the minutes of the society. it made no attempt at first to acquire manuscripts per se; rather, if anything was acquired "for the advancement of useful knowledge," the society printed it. such was the case of the first recorded manuscript sent to the society, when david rittenhouse, on march , , "communicated by the hands of dr. smith a description of his new invented orrery," and it was referred to the committee on astronomy. on april the committee reported: they think m r rittenhouse deserves great applause for having projected so useful and curious a machine, and that if it shall answer his intention, which they have the greatest reason to expect from his known abilities, they are of opinion that it will do honor to himself & to this province, the place of his nativity; and the commitee beg leave to recommend it to the society to order his description to be published; not doubting but it will give pleasure to persons of a curious and philosophical turn. • t h e author is manuscripts librarian of the library of the american philosoph- ical society, south fifth street, philadelphia , pa. his paper was read before the conference on science manuscripts in washington, d. c, on dec. , . this is a manuscript note in franklin's hand on the title page of a copy of volume of the transactions of the american philosophical society, held in phila- delphia, for promoting useful knowledge (philadelphia, william and thomas brad- ford, ). american philosophical society, minutes, mar. , . minutes, apr. , . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u by c arnegie m ellon u niversity user on a pril the american archivist the manuscript was published as the first article of the first vol- ume of the society's first publication: the transactions. subse- quent communications were read and many were praised and printed, but as time passed committees grew more blase and con- sequently less effusive in their praise. manuscript items, acquired occasionally through the years, were preserved and became the basis of the archives of the society. it appears that the society originally planned no library whatsoever. as items began to accumulate, however, something had to be done to preserve them. and so, before the american revolution, a library was organized and the first librarian, david rittenhouse, was appointed. the society rarely purchased items; it received them from eminent men or as exchange. with the first volume of the transactions in the society began to exchange publica- tions with other learned organizations, and this exchange has con- tinued with some of these to the present. the american philo- sophical society library, as william e. lingelbach, librarian emeritus, has aptly said, "is the product. . . not of a great collector or maecenas, but of the interest and devotion of the officers and members—scientists and scholars—of a great society, united, says the charter, 'for promoting useful knowledge.' " by scientists and scholars were interested enough in the library so that a special committee was formed "to collect infor- mation respecting the past and present state of this country," for "the american philosophical society have always considered the antiquity, changes, and present state of their own country as pri- mary objects of their research." membership of this committee was of extremely high caliber: thomas jefferson, gen. james wilkinson, caspar wistar, charles willson peale, and jonathan williams, jr. appended to jefferson's name on the list of com- mittee members is: "president of the american philosophical society, at monticello in virginia." had jefferson lived nearer philadelphia, better results might have been obtained. as it was, the committee seems to have done little more than to circularize its intention of collecting information for the society and to reprint this circular in the transactions, volume . basically, the collection of manuscripts began in , when the historical and literary committee was formed. that remark- william e. lingelbach, "the american philosophical society library from to , with a survey of its historical background," in american philosophical society, proceedings, : - (philadelphia, ). d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u by c arnegie m ellon u niversity user on a pril m si / • : . • . - • & / y • £—- # . f gift of the franklin papers —courtesy of the american philosophical society d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u by c arnegie m ellon u niversity user on a pril jmt&tx-tfj d&jo. */ atm»t* jitter cw*wt***</ **tj^j&//iaf y^* tv*xm**t*& <*«*!) j {?<tf fa* c'at/j/sciittuyj ait /t>>/' f/tt tt&t <* *ant*/i *>f//n ja/ti* '/jrtwfta <****//*./*' fjjttertff** aj*tj at till : vafutittt', ji>/,,ofim<s&/ , jmatu/tutn . tfc'lmf/jottm (",i c/,</j} - • t,taf>.>t, , f laj/& t/.,tt,/,,,,u/, , fti < - - cat,:,*,<//:'•>» ou»r f>u s/limtjsyr'i , utl& ffu. •utt<£utif,i /actf/iiai ssmt &„<*<,<* / y u*- sitaijtoujtj t tefft# t£ j£«*fi£>*t& {t.*r- o >< n ' . / i / ^ f f fj <f if <f tu/*.'*,;ti tftf/f i'j/*•**/• prw jf/att * %ejjbe*(/f i'j 'fififtt** stt&vt tfoec* au*it -£**> ( ar c(u{~z?i€ ft&tumi eaifittct cotia cmj%o£sfu •ji/^m'tmtji^anj j &c if a/ of . du ponceau's questions to heckewelder —courtesy of the american philosophical society d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u by c arnegie m ellon u niversity user on a pril manuscripts guide able franco-american, peter stephen du ponceau, was made cor- responding secretary, and in many ways he became the committee. on august , , the committee adopted the following reso- lution : that the chairman & secretaries be authorized to solicit thro' the channel of the newspapers or other periodical publications or otherwise in such man- ner & form as they shall think most expedient the aid of those citizens & others who may be possessed of public or private documents, or be otherwise acquainted with interesting facts sufficiently authenticated & coming within the range of the objects of this committee. du ponceau personally wrote such men as thomas jefferson, elias boudinot, isaiah thomas, and david hosack, informing them of the committee's aim and asking their assistance. and the news- paper aurora, on september , , published an open letter asking the donation to the society of "the historical memoirs of individuals, public documents, scarce pamphlets, manuscript notes, public and private letters from eminent men, and from men of knowledge and observation: in short, every thing which may be considered as interesting to this country in an historical, statistical, geographical or topographical point of view." a note at the end of this "literary notice" read: "the editors of newspapers and other periodical publications, friendly to the literature of their country, are invited to give publicity to the above." although our records show that the committee was really active for only three years, the response to this appeal was little short of astounding. people in the united states were beginning to be concerned over the lack of repositories for precious manuscripts; massachusetts and new york had already organized historical societies to collect and preserve such records. that remarkable past president of the united states (and of the american philosophical society), thomas jefferson, presented such items, among others, as his collection of american indian language manuscripts; a copy of benjamin hawkins' "sketch of the creek country in the years - ," written in hawkins' hand; and memoire sur la possibilite, les avantages, et le moyens d'ouvrir un canal dans vamerique septentrionale, pour communi- quer de la mer atlantique . . . a la mer pacifique. jefferson en- dorsed the last item: "this memoire was procured for me by the chevalier bourgoyne [chevalier jean frangois bourgoing], au- historical and literary committee of the american philosophical society, min- utes, aug. , . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u by c arnegie m ellon u niversity user on a pril t h e american archivist thor of the travels into spain." jefferson also urged others to leave manuscripts to the society, and such treasures as the lewis and clark journals and the william byrd journals for the history, and the secret history, of the running of the virginia—north caro- lina boundary line were acquired. m r . du ponceau, interested in the study of linguistics, solicited and received much information pertaining to the american indian from the moravian missionary johann gottlieb ernest hecke- welder and from others. the committee accepted copies of manuscripts with the same enthusiasm as it accepted originals. copies of many early laws and records of the commonwealth of pennsylvania were pre- sented by redmond conyngham. m r s . deborah norris logan and her husband, dr. george logan, presented copies of corre- spondence of their ancestor james logan, secretary to william penn. with such gifts, the manuscript collection of the library began to develop. subsequently, however, little active collecting was done. items were presented to the society, and some of these gifts were of great value and of major import. joel poinsett, for example, gave the society many valuable papers, books, and latin american items; among this group was an aztec item, the montezuma trib- ute roll, since returned to mexico. mrs. dolly payne madison presented her husband's "meteorological journal" for — , in two volumes. the primary gift of manuscripts to the library was made by charles and m a r y fox—the benjamin franklin papers. this vast mass of papers, bequeathed by benjamin franklin to his grandson, william temple franklin, was left in america with george fox, the friend of temple franklin; and after temple's death it found its home in the library. n o other gift to the soci- ety has ever matched this one; with this gift the american philo- sophical society library became a primary repository for ameri- can history. meanwhile other institutions grew and interest in the society waned. major changes in attitudes toward societies are noticeable in the emergence of state and local historical societies and the development of a great national scientific organization, the smithsonian institution. the library did not undergo major change for almost a century; it merely continued to grow. shortly after receiving the munificent bequest of richard alexander fullerton penrose and thus acquir- ing financial freedom, the society appointed a special committee on the library. its report, made in , stated that "since this d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u by c arnegie m ellon u niversity user on a pril manuscripts guide special committee was established, not a few members of the society have spoken of the fine reputation the library bears in their communities. upon investigation, this high repute proved almost invariably to be based upon the use of manuscripts, chiefly in the franklin collection, but also of journals of travel and of rare printed material also on similar lines." the special committee stressed that the members of the society should not think of the library contents as simply valuable and unused material relating to the history of science, but should realize that the library possesses "in the society's archives and collections an extraordinary record of intellectual interests and activities in this country." in conclu- sion, the committee's report "reiterates that an obligation rests upon the society to make known the contents of its library, for the benefit of students, in other ways than by forcing them to come to the building and consult the card catalogue." the library began in to publish a serial, the library bul- letin, also published as part of the proceedings ( — ). this publication has guided many scholars to the library. further pub- licity for the library has come from the erection of a handsome new building, across the street from philosophical hall, the home of the society, on independence square. although such publicity was good, it was judged insufficient and plans were formulated for compiling published guides to the manuscript collections. one of the major fields of the library, stemming from the inter- est of such men as thomas jefferson and peter stephen du pon- ceau, is its collection of manuscripts relating to the american indian. in addition to its indian collections built up for more than years, the library acquired in the huge franz boas col- lection of american indian linguistics. at present, these american indian manuscripts occupy roughly percent of the shelving for manuscripts. the late clyde kluckhohn, anthropologist, recom- mended that a guide to these collections be prepared, to provide eventually a complete listing of the data at hand on each language and tribe together with a brief evaluation of the reliability and significance of such data. the listing will encompass linguistic, ethnological and historical sources whether published or unpublished. the "guide" will of course indi- cate the relevant dates of the information and what topics (such as vocabu- lary, grammar, material culture, social organization, etc.) are covered . . . the "report of the special committee on the future policy of the library," in amer- ican philosophical society, year book, , p. - (philadelphia, ). the american philosophical society library bulletin was published for years, beginning in and ceasing with the issue of . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u by c arnegie m ellon u niversity user on a pril t h e a m e r i c a n a r c h i v i s t availability of this "guide" will make much more economical the work of scholars and should greatly increase the utilization of the society's holdings. this guide is being prepared by john finley freeman. his report on it appears in ethnohistory (vol. , no. ; spring ). dr. freeman's guide will be a separate finding aid, complementary to but not incorporated into ours. the holdings of the library, as the special committee reported, contain "an extraordinary record of intellectual interests and activ- ities in this country." it is hoped that our projected guide will make the contents of the collections—and the collections them- selves—more widely known. for example, an outstanding collec- tion, especially in the field of american science, is the vast mass of the society's own archives. many major scientists were society members, and active members, and many of their communications and letters are available. the archives are individually cataloged through the year and are arranged chronologically for easy use. also in the library are the peale-sellers papers, a very large group of papers of such outstanding men as charles willson peale, rembrandt peale, nathan sellers, coleman sellers, and george escol sellers. these papers afford a marvelous study of a large family and its artistic, social, intellectual, scientific, and technolog- ical interests over years. charles willson peale, the famous painter, was also an outstanding naturalist and inventor. his mu- seum in philadelphia and the museums he aided his sons to set up in baltimore and new york city spread interest in natural history and natural philosophy. he invented and manufactured the poly- graph, which made copies of letters without carbon paper or let- ter-press methods; and he worked on such projects as perfecting the making of false teeth and developing the velocipede. rem- brandt peale was, of course, a famous painter and naturalist of his day. nathan sellers was a paper maker and, with his brother david, a maker of machinery. coleman sellers, a professor at the university of pennsylvania, is well represented in his correspond- ence, ca. — , with his architect son, horace wells sellers, concerning the harnessing of niagara falls to manufacture elec- tricity. george escol sellers promoted railroads in the united states and actively worked for the building of a rail line across the isthmus of panama. clyde kluckhohn, "the library's new program in american indian linguistics and ethnohistory," in american philosophical society, proceedings, : - (philadelphia, ). d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u by c arnegie m ellon u niversity user on a pril manuscripts guide many people still do not know that there is in the library a major collection of the papers of charles darwin and papers about the spread of his theory of evolution. this collection is supple- mented with microfilm from the darwin papers at down house, kent, england. social history is well illustrated by the extensive papers of john frederick lewis, an outstanding philadelphia lawyer and philan- thropist. his papers were acquired, chiefly, to keep them from being scrapped. and what a rich treasure for the social and intel- lectual historian this collection turned out to be! it contains rec- ords about the building of mr. lewis' great collections of medieval manuscripts and cuneiform inscriptions, now in the free library of philadelphia. activity in the intellectual life of the city, espe- cially the artistic and musical life, is well documented. there is also material on the furnishing of his great city house, his car- riages and automobiles, country estate management, and his legal activity. other manuscripts of note acquired over the years are meteoro- logical observations kept at spring mill, pa., - , by peter legaux; chief justice john marshall's opinions; the correspond- ence of general nathanael greene, of richard henry lee and arthur lee, and of general weedon; and miscellaneous volumes of notes and records kept by gotthilf heinrich ernst miihlenberg. these are a fair but very spotty sample of the holdings in the library. on such disparate groups, accumulated over so many years, whitfield j. bell and i are working. we feel that the only sen- sible approach is strictly historical. we are using the guide to the manuscript collections of the historical society of pennsyl- vania as our exemplar. our entries will be alphabetical, under author, collector, or primary person represented in the collection and will contain the same material, greatly augmented, that was furnished the library of congress for the national union cata- log of manuscript collections. where possible, we give the name of the major figure of the collection, his life span, a brief identifi- cation of him, a note on his membership in the american philo- sophical society (if he was a member), and reference to biograph- ical information about him in a standard reference work. the name of the collection or item follows, with dates and physical description, including the language, if other than english. a brief description, including major figures in the collection, is then given, d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u by c arnegie m ellon u niversity user on a pril the american archivist unless the entire collection has been published or there is a pub- lished guide for it. a sample entry is the following: lewis, meriwether, - . explorer, governor. aps [american philo- sophical society] . dab [dictionary of american biography]. journal of the river trip from pittsburgh to winter camp; aug. -dec. , . a.d. [autograph document] leaves of which leaves are by lewis and leaves are notes by nicholas biddle, containing questions and answers with clark when he visited clark in . printed: the journals of captain meriwether lewis and sergeant john ordway, kept on the expedition of western exploration, — ; ed. with introduction and notes by milo m. quaife. madison, the state his- torical society of wisconsin, collections, vol. xxii. . deposited, , by edward and charles biddle. presented by charles j. biddle, june . we believe that such information will be sufficient, and we hope that the guide will be widely disseminated and thus will attract more scholars to study the treasures in the library. the more we work on the varied collections, the more we agree with the special committee: "in the society's archives and collections [is] an extraordinary record of intellectual interests and activities in this country." whatever is presented will be carefully preserved i have commenced a collection for the state library of letters and of the manuscript matter relating to the history of the state and the lives of its early and leading citizens. i wish it also to contain autograph letters by the dis- tinguished men of the state, their manuscript speeches reports and other writings, anything in short which will throw light on their character, intellec- tual peculiarities, habits of labor, &c &c. i would be glad to have any manu- scripts of yours, speeches, or whatever you may have preserved, also letters of eminent statesmen with whom you may have corresponded. whatever is presented will be carefully preserved in the fire proof state library. — rutherford b. hayes, governor of ohio, to ex-u. s. senator william allen, later governor of ohio, oct. , (allen papers, library of congress). [ruth l. douthit, reference librarian, ohio state library, informs us that the papers of arthur st. clair, r. g. meigs, thomas worthington, and e. a. brown were received by the library during hayes' administration as governor. a packet of miscellaneous papers, including a letter from allen, may have been received in response to hayes' letter to allen. —ed.] d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j u by c arnegie m ellon u niversity user on a pril doi: . /j.jvs. . . a new anatomic variant of the aorta: a case report eric hager, md,a gerald isenberg, md,a carin gonsalves, md,b neil moudgill, md,a steve dong, md,a and paul dimuzio, md,a philadelphia, pa anatomic anomalies of the infrarenal aorta and iliac arteries are rare. we report a -year-old man who presented with an ileo-cecal fistula secondary to crohn disease. a computed tomography scan and subsequent arteriography noted his aorta bifurcated immediately inferior to the main renal arteries, at the level of the second lumbar vertebrae. associated vascular anomalies included a common superior mesenteric artery/celiac axis plus multiple renal arteries. to our knowledge, this is the first report of this aortic anomaly in the literature. ( j vasc surg ; : - .) anomalies of the aortoiliac arteries are exceedingly rare, with few case reports in the literature. - most vascular variations are asymptomatic and noted incidentally upon imaging for other medical concerns; when detected, how- ever, further arterial imaging may be important for patient care. the current imaging modalities of choice include conventional arteriography and computed tomography an- giography (cta) with three-dimensional reconstruction. we present a congenital vascular anomaly wherein the aortic bifurcation arises just inferior to normally located main renal arteries, with a dominant left common iliac artery giving rise to the inferior mesenteric artery as well as the paired lumbar arteries. to our knowledge, this anomaly has not been previously reported. case report a -year-old man presented with right flank pain, nausea, and emesis for weeks. he had no significant past medical or surgical history, and his family history was unremarkable. a non- pulsatile, tender mass was noted on examination of his right lower quadrant. he had normal upper and lower extremity pulses with- out evidence of a peripheral aneurysm. a ct scan revealed an inflammatory mass at the terminal ileum with creeping fat consistent with crohn disease. coinciden- tally, his aortic bifurcation occurred immediately distal to the main renal arteries, at the level of the second lumbar vertebra (fig , a). the right common iliac artery traveled in a circuitous route through the right retroperitoneum (fig , c) and ultimately bifur- cated at the level of the superior acetabular rim (fig , f ). the left common iliac artery coursed straight into the pelvis, bifurcating high at the fifth lumbar vertebra (fig , e). associated findings on this scan included the inflammatory mass (fig , d) and a malro- tated left kidney (fig , b). he received outpatient treatment for the crohn disease; how- ever, the symptoms returned weeks later. a ct scan revealed an abscess with a fistula at the terminal ileum, indicating the need for right hemicolectomy. because the right common iliac artery coursed within the planned operative field, an arteriogram was from the departments of surgerya and radiology,b thomas jefferson university. competition of interest: none. reprint requests: eric hager, md, thomas jefferson university hospital, s th st, philadelphia, pa (e-mail: erichager @yahoo.com). - /$ . copyright © by the society for vascular surgery. doi: . /j.jvs. . . performed to characterize further the aberrancy (fig ). in addi- tion to the nonbranching right iliac artery (fig , a) and high bifurcation of the aorta, additional views noted: . a common celiac axis-superior mesenteric artery trunk (fig , b); . paired lumbar arteries off the dominant left iliac artery (fig , b) and a replaced right hepatic artery; . four left renal arteries and three right renal arteries; . the medial sacral artery branching off the left proximal common iliac cm proximal to the left renal artery; and . the low right iliac bifurcation at the acetabular rim and the high left iliac bifurcation at the level of the fifth lumbar vertebra (fig , c ). an uncomplicated right hemicolectomy was performed to remove the nonperforated inflammatory mass. the right common iliac artery coursed within the right retroperitoneum but was not involved in the inflammatory process and did not require mobili- zation. the patient recovered from surgery without vascular com- plications. discussion the patient described exhibits numerous variants of arterial anatomy. most unusual is the iliac bifurcation lo- cated at the second lumbar vertebrae with a circuitous retroperitoneal course of the right common iliac artery. in conjunction with a common celiac-superior mesenteric ar- terial trunk, supernumerary renal arteries, and dominance of the left common iliac artery, the patient demonstrates truly unique anatomy. understanding of the normal embryologic develop- ment of the abdominal aorta lends light in understanding this anomaly. in the embryo, development of the aorta begins in the third gestational week with the dorsal migra- tion of two lines of cells from the endocardial mesenchyme. these cells grow along the neural groove, eventually fusing into a single aorta. numerous segmental arteries form and regress, with the th, th, and nd persisting to form the celiac, superior mesenteric, and inferior mesenteric arteries, respectively. the common iliac arteries form by way of anastomoses between the allantoic and fifth lumbar dorsal intersegmental arteries. the umbilical artery gives rise to the internal iliac artery, and the external iliac artery forms from a bud from the common iliac artery. in this patient, we hypothesize that a partial interrup- tion of the normal fusion between the dorsal aorta gave rise mailto:erichager @yahoo.com colon; (e) left iliac artery bifurcation at l ; (f) right iliac artery bifurcation of the aorta and sweeping right common iliac artery. journal of vascular surgery july hager et al to a dominant left common iliac artery and with it, the origin of the inferior mesenteric and paired lumbar arteries. the natural history of this variation is unknown; however, correlation between this and a replaced right subclavian artery suggests that aneurysm formation might be ob- served. as such, follow-up imaging may be important for early detection of potential aneurysmal disease. although this variant is unique, the literature describes known variations of iliac anatomy, with a reported inci- dence of in patients. tamisier et al classified these variants into three major categories: group are anomalies of origin or course, group are hypoplasia or atresia with a persistent sciatic artery, and group are isolated hypoplasia or atresia. group variants are usually asymptomatic and coincidentally found. group have a high incidence of aneurysm formation, typically presenting with acute occlu- sion or embolism. most published case reports involve this classification. - group often presents with claudication, typically in the second through fifth decades of life, and may necessitate surgical intervention. , humans may exhibit other abdominal aortic branch anomalies, with most aberrancy involving the celiac axis and mesenteric arteries. a study by koops et al examined patients who underwent celiac and superior mesenteric angiography and found aberrancy in % of patients. the most common variant cited was a replaced right hepatic artery arising from the superior mesenteric artery in % rather than the celiac axis, followed by a replaced left hepatic artery emanating from the left gastric artery in %. celiac axis anatomy variants existed in % of patients, along with a combination of these variants in %. these anoma- lies, however, are exceedingly rare in conjunction with iliac trast demonstrate various anomalies: (a) high bifurcation of artery bifurcation at l ; (d) inflammatory mass of the right bifurcation at the level of the sacrum. fig . serial computed tomography scans with intravenous con the aorta at l ; (b) malrotated left kidney; (c) right common iliac fig . arteriogram with pelvic runoff demonstrates the high anatomic variation and were not noted in any of the journal of vascular surgery volume , number hager et al patients. this case demonstrates a common origin of these arteries. herein we have described a unique variant of aortic anat- omy, one that has not been described to our knowledge in the literature. associated vascular findings included multiple bilateral renal arteries and a common celiac-mesenteric trunk. although it was discovered upon investigation of right retroperitoneal pathology, we do not believe the inflammatory process had any bearing on the patient’s noted vascular anatomy. long-term follow-up is suggested given the possibility of aneurysmal degeneration. references . oduro gd, cope lh, rogers im. case report: lower limb arterial blood supply arising from the renal artery with congenital absence of the ipsilateral iliac arteries. clin radiol ; : - . . koyama t, kawada t, kitanaka y, katagiri k, ohno m, ikeshita m, et al. congenital anomaly of the external iliac artery: a case report. j vasc surg ; : - . fig . selective arteriograms show (a) circuitous ro (b) common superior mesenteric/celiac trunk and paired iliac arteries as well as the femoral bifurcations. . greeb j. congenital anomalies of the iliofemoral artery. j cardiovasc surg ; : - . . tamisier d, melki jp, cormier jm. congenital anomalies of the exter- nal iliac artery: case report and review of the literature. ann vasc surg ; : - . . lin p, chaikof e. embryology, anatomy and surgical exposure of the great abdominal vessels. surg clin north am ; : - , xiv. . austin eh, wolfe wg. aneurysm of aberrant subclavian artery with a review of the literature [review]. j vasc surg ; : - . . williams lr, flanigan dp, o’connor rj, schuler jj. persistent sciatic artery: clinical aspects and operative management. am j surg ; : - . . martin kw, hyde gl, mccready ra, hull da. sciatic artery aneu- rysms: report of three cases and review of literature. j vasc surg ; : - . . mclellan gl, morettin lb. persistent sciatic artery: clinical, surgical and angiographic aspects. arch surg ; : - . . howard jm, goudelock wj, couves cm. congenital atresia of the external iliac artery. arch surg ; : - . . koops a, wojciechowski b, broering d, adams g, krupski-berdein g. anatomic variations of the hepatic arteries in selective celiac and superior mesenteric angiographies. surg and radiol anat ; : - . of the right common iliac artery with no branches, ar arteries, and (c) bifurcation points of the left and right ute lumb submitted dec , ; accepted feb , . 	a new anatomic variant of the aorta: a case report 	case report 	discussion 	references hla disparity and rapid immune reconstitution do not overcome propensity to relapse in patients undergoing haploidentical hematopoietic stem cell transplant (hsct) with persistent disease at the time of transplant poster session i s conclusion: our results indicate an increased risk of acute gvhd in association with dpb mismatch regardless of the tce classifica- tion. tce classification did not correlate with any transplant out- come considered in our cohort. this analysis does not support the clinical relevance of ranking dpb mismatches based on the tce algorithm. a scoring system predicting outcome after unrelated donor stem cell transplantation in primary refractory acute mye- loid leukemia craddock, c.f. , labopin, m. , schmid, c. , mohty, m. , rocha, v. queen elizabeth hospital, birmingham, united kingdom; faculte de medecine st-antoine, paris, france; klinikum augsburg, germany; nantes hospital, nantes, france; hopital st louis, paris, france treatment options for adults with primary refractory aml (pref aml) are extremely limited. whilst sibling allogeneic stem cell transplantation can result in long term survival most pa- tients lack a matched family donor and are destined to die of refrac- tory disease. greater availability of unrelated donors and improvements in supportive care have increased the proportion of patients with pref aml in whom allografting is technically fea- sible but the outcome of unrelated donor transplantation in this population has not been extensively studied. we therefore analysed overall survival in patients with pref aml who underwent unrelated donor transplantation between and with a me- dian follow-up of months ( - ). patients received three or more courses of induction chemotherapy. the median percentage of bone marrow (bm) blasts at transplant was %. the -year overall survival for the whole group was %. in multivariate anal- ysis, fewer than three courses of induction chemotherapy, a lower percentage of bm blasts at transplant and patient cmv seropositiv- ity were associated with improved survival. we used the prognostic factors identified in multivariate analysis to develop a scoring sys- tem. this allowed the delineation of four prognostic groups with survival rates ranging between % and %. this study dem- onstrates an important role for unrelated donor transplantation in the management of selected patients with pref aml and confirms the importance of initiating an urgent unrelated donor search in pa- tients with no matched sibling donor who fail to respond to induc- tion chemotherapy. pre-transplant factors allow the identification of patients with pref aml who are likely to benefit from unre- lated donor transplantation. hla disparity and rapid immune reconstitution do not over- come propensity to relapse in patients undergoing haploi- dentical hematopoietic stem cell transplant (hsct) with persistent disease at the time of transplant grosso, d. , alpdogan, o. , carabasi, m. , colombe, b. , cornett farley, p. , filicko-o’hara, j. , flomenberg, p. , gitelson, e. , kasner, m. , martinez-outschoorn, u. , o’hara, w. , wagner, j.l. , weiss, m. , werner-wasik, m. , flomenberg, n. thomas jefferson university kimmel cancer center, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa while increasing hla disparity is known to be associated with increased risk of significant graft versus host disease (gvhd), there is less data as to whether increasing hla disparity is corre- lated with stronger, clinically significant graft versus leukemia ef- fects. we examined a group of patients with acute leukemia undergoing haploidentical hsct to assess whether ) there was a marked difference in relapse rates based on the degree of hla mismatch and ) if early recovery of donor lymphoid subpopula- tions was associated with less relapse after hla mismatched hsct. thirty-four adult patients with aml ( ) and all ( ) underwent haploidentical hsct between and using a step process which separates the infusion of the lymphoid and myeloid portions of the graft while attempting to render the lymphocytes tolerant utilizing cyclophosphamide. the patients re- ceived x e /kg donor cd cells (dli) after conditioning with either tbi gy (n ) or fludarabine mg/m � , thiotepa mg/m � , and tbi gy (n ). two days after the dli, all patients received cyclophosphamide (cy) mg/kg � followed by a cd selected donor product. the tbi based regimen was given to % of patients with all and % with aml. we exam- ined relapse rates based on the number of antigen mismatches at a, b, cw, and drb in the gvh direction. there were no discern- able differences based on degree of hla disparity with even the most haplodisparate group exhibiting high rates of relapse when disease was present at hsct. in contrast, the presence of active leukemia at the time of hsct had far more impact on subsequent relapse rates (see table). table . outcomes based on degree of hla disparity antigen antigen antigen antigen mismatch mismatch mismatch mismatch number of patients relapsed/ total relapsed/ total relapsed/ total relapsed/ total active disease at hsct ( %) / ( %) / ( %) / ( %) n/a cr at hsct ( %) / ( %) / ( %) n/a / ( %) total / ( %) / ( %) / ( %) / ( %) we also examined the impact of immune recovery on relapse. ab- solute numbers of nk, and cd and cd t cells were examined in the first months post hsct. t cell, mnc, and total chimerism was greater than % donor-derived at the time of the assessment. for patients who did or did not relapse post hsct the median numbers of lymphoid subsets (cells/ul) were: nk ( - ) vs ( - ), cd ( - ) vs ( - ), and cd ( - ) vs ( - ) respectively. in this small series of patients treated with the step transplant method, relapse was associated more with the presence of disease at hsct than with any discern- able trend in degree of hla disparity or early immunologic recov- ery. other approaches to treat resistant leukemia are required to substantially improve disease free survival in these high risk patients. anti-hla antibodies predict graft failure, time to engraft- ment and umbilical cord unit dominance in double umbilical cord blood transplantation cutler, c. , kim, h.t. , sun, l. , sese, d. , kao, g. , vasquez, m. , armand, p. , koreth, j. , ho, v.t. , alyea, e. , soiffer, r.j. , ballen, k. , ritz, j. , milford, e. , antin, j.h. dana-farber cancer institute, boston, ma; dana-farber cancer institute, boston, ma; brigham and women’s hospital, boston, ma anti-hla antibodies (hla-ab) predict graft failure in unrelated donor and single umbilical cord blood (ucb) transplantation. we measured hla-ab in double ucb transplantation (ducbt) with the hypothesis that hla-ab would predict time to engraftment, graft failure and ucb unit dominance. methods: patients with banked pre-transplant sera who under- went ducbt using / or better allelic hla-matched ucb units ( - ) were studied. labscreen (one lambda inc.) was used to capture class i/ii hla-ab and the luminex is system was used to detect fluorescent tagged binding of human igg. visual software was used to normalize results and to deter- mine the presence of mixed class i/ii hla-ab. positive samples were tested using single antigen-coated microbeads. beads with a mean fluorescent intensity above baseline were considered positive. chimerism was measured using str typing of informa- tive alleles. graft failure was defined as the absence of neutrophil engraftment days from ducbt or loss of ucb chimerism by day without malignant relapse. ucb dominance was defined as . % contribution to hematopoiesis by a single ucb unit at day . 	a scoring system predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leu ... 	hla disparity and rapid immune reconstitution do not overcome propensity to relapse in patients undergoing haploidentical h ... 	anti-hla antibodies predict graft failure, time to engraftment and umbilical cord unit dominance in double umbilical cord b ... target value-tailored apheresis can improve prediction of product hematopoietic progenitor cells prior to autologous transplantation abstracts / biol blood marrow transplant ( ) s es s quintile was associated with a % decrease in the risk of engraftment failure (or . , % ci . - . ). even when adjusted for cell dose infused, a higher # of collected cd + cells was associated with decreased time to platelet engraftment (hr . , ci . - . , p¼. ), but not anc engraftment (hr . , p¼. ). positive blood cultures within days of asct were associated with engraftment failure (p¼. ), while race, sex, # of collections for the trans- planted dose and mobilization regimen did not appear to affect engraftment. we also observed that prior imid use demonstrated a trend toward less engraftment failure (or . , %ci . - . ; p¼. ). although a moderate correlation was observed between the variables cd cells collected and cd cells infused, a sensitivity analysis by omitting either variable did not iden- tify a significantly different estimates. a plerixafor-based strategy allows adequate hematopoietic stem cell collection in poor mobilizers: results from the canadian special access program dawn sheppard , christopher n. bredeson , lothar huebsch , david s. allan , jason tay . the ottawa hospital, ottawa, on, canada; the ottawa hospital blood & marrow transplant program, ottawa, on, canada; hematology, ottawa hospital, ottawa, on, canada; the ottawa hosp/hem, ottawa, on, canada; the university of ottawa, ottawa, on, canada background: the collection of a minimum number of he- matopoietic stem cells (hsc), generally defined as x cd + cells/kg, is a prerequisite for proceeding to hsct. primary mobilization failure occurs in e % of patients. - when used to unselected patients undergoing a first mobi- lization attempt, plerixafor plus gcsf allows more cd + cells to be mobilization with fewer aphereses than gcsf alone. , there are no publications describing the patterns of plerixafor use at canadian transplant centres, nor is there data to guide determinations of cost-effectiveness of mobi- lization using plerixafor from the canadian perspective. methods: the objectives of this study were to: ) summa- rize the published studies of plerixafor-based mobilization during compassionate access programs, and ) describe the canadian experience with plerixafor during its availability though health canada’s special access program (sap). a literature search was performed and studies were grouped into three strategies: upfront, preemptive and salvage. in canada, plerixafor was available through the sap, and fun- ded by genzyme/sanofi from september to december . results: thirteen articles were identified. in all but one study, plerixafor was used as part of a preemptive and/or salvage strategy. the proportion lf patients in whom a min- imum of x cd + cells/kg was collected ranged from e %. at the time of publication, e % of patients had proceeded to transplantation. thirteen canadian centres provided data on a total of patients, the majority of whom had multiple myeloma or lymphoma, and had undergone a median of prior mobili- zation attempt (range e ). plerixafor was used preemp- tively in ( %) patients and as salvage in ( %) patients. in ( %) patients, there was successful collection. of the patients in whom plerixafor was used preemp- tively, ( %) had successful collections. of the patients in whom the drug was used as part of a salvage strategy, ( %) had successful collections. of the entire cohort, ( %) of patients went on to receive an autologous transplant. discussion: our study summarizes the published experience with plerixafor-based mobilization during compassionate drug access programs and describes the canadian experience when plerixafor was freely available through health cana- da’s sap. canadian practice was similar to published inter- national experience. plerixafor use decreased significantly when it was no longer freely available. this may be a reflection of limited resources, a lack of belief in the preemptive use of plerixafor or knowledge of the most cost-effective way to use it. the pharmacoeconomics of mobilization likely vary from centre to centre and are affected by multiple factors such as the patient population, infrastructure, available resources, and who is paying for plerixafor. target value-tailored apheresis can improve prediction of product hematopoietic progenitor cells prior to autologous transplantation dawn sheppard , jason tay , lothar huebsch , sheryl ann mcdiarmid , lisa gilliard martin , doug palmer , paul birch , anargyros xenocostas , linda hamelin , christopher n. bredeson . the ottawa hospital, ottawa, on, canada; the university of ottawa, ottawa, on, canada; hematology, ottawa hospital, ottawa, on, canada; bmt program, ottawa general hospital, ottawa, ontario, canada; canadian blood services, ottawa, on, canada; division of hematology, london health sciences centre/ u western ontario, london, on, canada; bmt, the ottawa hospital, ottawa, on, canada; the ottawa hospital blood & marrow transplant program, ottawa, on, canada background: collection of a minimum number of hemato- poietic progenitor cells (hpc), usually defined as x cd + cells/kg, is required to ensure timely neutrophil and platelet recovery. - the majority of centres use peripheral blood-mobilized hpcs as the source of progenitor cells for autologous transplantation, but the method used to predict the final apheresis product cd + cell content, and thus the whole blood volume to process during apheresis collection, has not been standardized. in the mid- s, mitterer et al. demonstrated on a -patient cohort that the correlation between the pre-apheresis peripheral blood cd + cell count and the number of cd + cells/kg collected could be used to determine the blood volume to process during apheresis to harvest the desired number of cd + cells/kg (target-value tailored, tvt, collection). using this concept and local data, the ottawa canadian blood services stem cell laboratory created a similar regression model to help determine the blood volume to process during apheresis collection. methods: we conducted a retrospective study of all pe- ripheral blood hpc apheresis collections performed at the ottawa hospital from january , to december , . our objective was to validate the tvt approach, as modified by our institution. results: from to , there were peripheral blood hpc collections by apheresis. the majority, ( . %), were autologous collections and ( . %) were allogeneic do- nors. the most common diagnoses were multiple myeloma and aggressive non-hodgkin lymphoma (nhl). the median age of the cohort was . (range . e . ) years. the median number of prior chemotherapy regimens was (range e ). the majority of collections, ( . %), were first attempts. the median pre-collection peripheral blood cd + cell count was . (interquartile range, iqr . e )/ml. the table . collection of autologous stem cells chemo- mobilization cytokine mobilization p-value median cd cells/kg collected (in millions/kg) . . . median number of apheresis days (mean) ( . ) ( . ) . target dose achieved: yes no ( . %) ( . %) ( . %) ( %) . abstracts / biol blood marrow transplant ( ) s es s median number of apheresis days was (range e ). in ( . %) collections one day of apheresis was required to achieve the minimum number of hpcs. the median apher- esis volume for day collections was (range . e ) l. the correlation coefficient between the pre-collection pe- ripheral blood cd + cell count and the final product cd + cell content is . (p<. ; figure ). the tvt estimate was highly predictive of the final product cd + count (r¼ . , p<. ; figure ). a minimum of x cd + cells/kg was collected in . % of collections. discussion: using the correlation between the pre-collec- tion peripheral blood cd + count and the final product hpc content, the tvt formula can accurately determine the blood volume to process during apheresis collection. this has resulted in reduced apheresis time, fewer apheresis days, and less nursing time. ultimately, the tvt formula has allowed our program to improve our resource utilization by accu- rately predicating the required apheresis volume. autologous stem cell mobilization with pegfilgrastim and planned plerixafor is equally effective and safer as compared with cyclophosphamide, pegfilgrastim and plerixafor sherilyn tuazon , manish sharma , tingting zhan , margaret kasner , onder alpdogan , ubaldo martinez , dolores grosso , joanne filicko , barbara pro , john l. wagner , matthew carabasi , neal flomenberg , mark weiss . medical oncology, thomas jefferson university, philadelphia, pa; department of pharmacology and experimental therapeutics, thomas jefferson university, philadelphia, pa; medical oncology, thomas jefferson university hospital, philadelphia, pa; department of medical oncology, kimmel cancer center, thomas jefferson university, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa background: autologous stem cell mobilization can be achieved using chemo-mobilization (chm) or growth factors alone (cytokine-mobilization, ctm). mobilization with peg- filgrastim and “just-in-time” plerixafor has been shown to be a successful strategy. experience with pegfilgrastim and planned plerixafor is limited. we here describe our experi- ence using two mobilization strategies with pegfilgrastim plus plerixafor (ctm) or cyclophosphamide, pegfilgrastim plus plerixafor (chm). methods: we retrospectively identified patients who received an auto-sct for a diagnosis of myeloma at tju be- tween july and june . these patients who had stem cell mobilization using either chm ( patients) with cyclophosphamide ( grams/m ), pegfilgrastim ( mg) and plerixafor ( . mg/kg once daily until target dose collected or maximum of days of apheresis), or ctm with pegfil- grastim plus plerixafor ( patients). plerixafor was only administered as an outpatient. we hypothesized that more patients in the chm group reached the prescribed total cd -positive stem cell collection as compared to the ctm group. to test this hypothesis we used the two-sample test on proportions. for the comparison of the median total cd cells/kg dose collection and the median number of apheresis days we used the wilcoxon rank sum test and the t-test, respectively. results: there was no difference in patient age at transplant, sex, and myeloma subtype. the median number of prior in- duction therapies was similar; there was no significant dif- ference in the prior exposure to lenalidomide, however as expected, bone marrow plasmacytosis was higher in the chm group ( % vs. %). in the chm group, % were hospi- talized due to complication (typically neutropenic fevers) and thus only patients ( %) received the planned dose of plerixafor as compared to % in the ctm group. there were no hospitalizations in the ctm group due to toxicity. chm was associated with a significantly higher median total cd + cell collection ( . x /kg vs. . x /kg, p¼ . ) (table ). ctm is associated with fewer collection days (median day vs. days, p¼. ) and more patients achieving the target cd + cell dose of . x /kg ( . % vs. . %, p¼. ). conclusion: the preferred method to mobilize autologous stem cells should be with pegfilgrastim and planned plerix- afor since it is able to achieve the prescribed cell dose, is associated with less toxicity and risk of hospitalization. this analysis suggests that per patients collected a total of days of plasmaphresis could be avoided if all patients were mobilized with growth factors alone. twenty years of autologous stem cell transplantation in diffuse large b-cell lymphoma e a single center experience margarida dantas brito , fernando manuel de castro campilho , rosa branca ferreira , carlos pinho vaz , susana roncon , antonio campos . serviço de hemato-oncologia, instituto português de oncologia do porto, porto, portugal; bone marrow transplant unit, instituto português de oncologia porto, porto, portugal; bone marow transplantation unit, instituto português de oncologia do porto, porto, portugal; bone marrow transplantation unit, instituto português de oncologia porto, porto, portugal; serviço de terapia celular, instituto português de oncologia do porto, porto, portugal; bone marrow transplantation unit, instituto portugues de oncologia centro do porto, porto, portugal background: patients (pt) with advanced stage and high international prognostic index (ipi) or relapsed/primary re- fractory diffuse large b-cell lymphoma (dlbcl) have an adverse prognosis and are frequently consolidated with autologous stem cell transplantation (sct). aim: evaluation of a single center experience with sct in dlbcl. methods: retrospective analysis of outcome of adult pt submitted to sct in dlbcl, between october and december . data were collected from the database and the medical records. results: sct were performed in various histological subtypes of dlbcl, during this time period. statistical anal- ysis was performed in pt with "classical" dlbcl and histological variants were excluded. median age at sct was years ( - ), males/ females. at diagnosis the majority of pt were in advanced stage ( %) and had an ipi or ( %, % respectively). 	a plerixafor-based strategy allows adequate hematopoietic stem cell collection in poor mobilizers: results from the canadia ... 	background 	methods 	results 	discussion 	target value-tailored apheresis can improve prediction of product hematopoietic progenitor cells prior to autologous transp ... 	background 	methods 	results 	discussion 	autologous stem cell mobilization with pegfilgrastim and planned plerixafor is equally effective and safer as compared with ... 	background 	methods 	results 	conclusion 	twenty years of autologous stem cell transplantation in diffuse large b-cell lymphoma – a single center experience 	background 	aim 	methods 	results engraftment and immune recovery (ir) in good risk patients undergoing hematopoietic stem cell transplantation (hsct): comparison of two different approaches using cyclophosphamide (cy) for t-cell tolerization abstracts / biol blood marrow transplant ( ) s es s seasonal influenza (sflu) in hm patients versus hsct re- cipients are lacking. methods: we evaluated characteristics, diagnostic results, management and outcomes of all influenza a infections (pandemic h n versus sflu) and determined the risk fac- tors associated with pneumonia and all-cause mortality in hm patient and hsct recipients at md anderson cancer center (mdacc) from april to july . results: a total of patients were identified, including ( %) hm patients and ( %) hsct recipients. majority of patients ( , %) were adults, males ( , %) with un- derlying diseases in remission ( , %). about half of pa- tients required hospitalization for outcomes including pneumonia % ( pts) and death % ( pts). majority of patients ( , %) received antiviral therapy within a me- dian of days (range, d e d) after onset of first symptom. compared to hct recipients, a significantly higher percent- age of hm pts were in active stages of cancer with severe neutropenia ( , %) and severe lymphopenia ( , %) and required hospitalization ( , %). multivariable logistic regression analysis identified hematologic malignancy (aor: . ( % ci: . , . ), decreased albumin (aor: . ( % ci: . , . ), and delay in initiation of antiviral therapy (aor: . ( % ci: . , . ) as significant risk factors for devel- opment of pneumonia (p ¼ . ), after adjusting for the virus strain. interestingly, h n infections were more prevalent in hispanic population ( , %) and required more mechanical ventilation ( , %) compared to sflu, but no significant dif- ferences were observed with respect to pneumonia or mor- tality between these two viruses. conclusions: influenza remains a significant cause of morbidity and mortality in hm patients and hsct recipients. compared to hct recipients, hm patients were more likely to progress to pneumonia, probably owing to active cancer stage and pancytopenia. h n patients did not have higher mortality rate compared to sflu in either of the groups. early antiviral therapy remains crucial in preventing morbidity in this population. favorable outcomes from allogeneic hematopoietic cell transplantation in thailand for thalassemias and hemoglobinopathies preeda vanichsetakul. blood and marrow stem cell transplant, bangkok hospital medical center, bangkok hospital group, bangkok, thailand background: thalassemia syndromes are very prevalent in many parts of the world including asia. allogeneic hemato- poietic cell transplantation (hct) is the only curative therapy accepted worldwide. objectives: to assess outcomes of hct for thalassemias and hemoglobinopathies in single medical center in thailand. methods: case series study for thalassemia and hemoglo- binopathy patients undergoing hct at bangkok hospital medical center from february thru october . results: there were totally patients. cases were thais, was french-thai, was bangladeshi, was lao, and was omani who had sickle cell disease (scd). cases were diagnosed as beta-thalassemia/hemoglobin e diseases, as transfusion-dependent alpha-thalassemia, and as scd. among hcts, patients underwent bone marrow trans- plant (bmt), patients underwent umbilical cord blood transplant (cbt), and patient underwent combined cord blood and marrow transplantation. all related donors were fully-hla-matched, had normal typing, had thal- assemia trait, and had sickle cell trait. male to female pa- tients ratio were : . patients’ ages at transplant varied from years to years months with median of years months. patient’s body weight varied from . to kilo- gram (median . kilogram). according to pesaro classifi- cation, among thalassemia patients there were class i, and class ii patients. busulfan, fludarabine, and rabbit atg were mainly used as myeloablative conditioning regimen. cyclosporine and short-course methotrexate were mainly used as graft-versus-host disease (gvhd) prophylaxis in bmt group, while cyclosporine alone was used in cbt group. cd + cell doses per kilogram body weight recipients were ranged from . to . x (median . x ) in bmt group (n¼ ), and from . to x (median . x ) in cbt group (n¼ ). complete donor engraftments were achieved in patients. mixed-chimerism states with donor predominance were present in patients from bmt and patient from cbt group. no patients experienced graft failure. neutrophil re- coveries were evident on days + to + (median day + ), and platelet recoveries were observed on days + to + (median day + ). patients had mild veno-occlusive dis- eases and were later completely reversible. no patients developed acute or chronic gvhd. there were no mortalities. patient had treatable pneumocystis pneumonia at months post cbt. median follow-up time for all patients was years ( month to years months). overall (os) and disease-free survival (dfs) were % and % for all pa- tients (n¼ ). based on risk class, the os and dfs for class i thalassemia patients (n¼ ) were % and %, and class ii patients (n¼ ) were % and %, respectively. conclusions: our experiences in hct for thalassemias and hemoglobinopathies were very favorable. regular follow-up visits are encouraged to determine long term outcomes. engraftment and immune recovery (ir) in good risk patients undergoing hematopoietic stem cell transplantation (hsct): comparison of two different approaches using cyclophosphamide (cy) for t-cell tolerization john l. wagner , dolores grosso , onder alpdogan , matthew carabasi , joanne filicko , margaret kasner , ubaldo martinez , mark weiss , neal flomenberg . department of medical oncology, kimmel cancer center, thomas jefferson university, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; medical oncology, thomas jefferson university, philadelphia, pa we developed a step haploidentical hsct where pa- tients received myeloablative or reduced intensity regimens followed by a dli containing a fixed dose of . x /kg t cells (hsct step ). after days, mg/kg/d x of cy was infused, followed a day later by a cd selected pbsc product [hsct step median dose x /kg (range . - )]. we concurrently used a step hsct approach in a group of patients, with unrelated donors (urd) and patients ( with haploidentical, with matched related donors) with comorbidities precluding eligibility for the step protocol. the step patients were given the same conditioning, but afterwards received unmanipulated pbsc’s [median cd dose . x /kg, (range . - ); median t cell dose . x /kg, (range . - . )]. cy mg/kg/d x was infused abstracts / biol blood marrow transplant ( ) s es s hours later. because avoidance of stem cell exposure to cy occurs only in the step approach, we compared engraft- ment rates and ir between the groups. all patients had good risk disease. in the step vs the step study, median time to anc > /ul was (range - days) vs [range - days (p¼ . -mann-whitney)], and for platelets > , /ul, (range - days) vs (range - days) respectively (ns). the significant difference in time to anc recovery in the step group was possibly from the exposure of the donor pbsc’s to cy. when we accounted for the later occurrence of day in the step group, the median time to anc recovery was still days longer in the step group even though this group received a higher median cd dose. possibly due to the earlier count recovery in the -step group, the median cd / count at day was (range - /ul) in the step group vs (range - /ul) in the step group. by day , differences between the groups resolved, with a median cd / count of (range - /ul) vs (range - /ul) in the and step groups respectively. median cd / count at day was (range - /ul) vs (range - /ul) and at day was (range - /ul) vs (range - /ul) in the and step groups respectively. the percentages of patients on steroids for gvhd at day ( % in the step group vs %) and ( % vs %) was not significantly different between the two groups (p¼ . and . respectively, pearson chi square). the median length of stay (los) was (range - days) vs (range - days) in the and step groups respectively. the step approach to hsct allows for the administration of a fixed dose of t cells from which to optimize outcomes and cir- cumvents exposure of donor cells to the effects of cy. our experience with a step approach suggests later anc re- covery and possibly initial t cell recovery versus the step approach. there may be a slightly longer los in the step group possibly from longer time to count recovery. formal analyses of the differences between the two approaches will be performed when more patients are treated at our insti- tution with the step approach. table patient characteristics comparing cases and controls cases (n¼ ) controls (n¼ ) p value age (median with range) ( - ) ( - ) . male gender ( %) ( . %) . type of transplant allogeneic e related, unmatched ( %) ( %) . allogeneic e unrelated, matched ( %) ( . %) . allogeneic e unrelated, unmatched ( %) ( . %) . autologous ( %) ( %) . immunosuppressive therapy on day + tacrolimus ( %) ( . %) . corticosteroids ( %) ( . %) . mycophenolate ( %) ( . %) . gvhd ( %) ( . %) . wbc . ( . - ) . ( . - . ) . anc . ( . - . ) . ( . - . ) . hemoglobin . ( . - ) . ( . - ) . platelets ( - ) ( - ) . cr . ( . - . ) . ( . - . ) . alk phos ( - ) ( - ) . total bilirubin . ( . - ) . ( . - . . alt ( - ) ( - ) . albumin . ( . - . ) . ( . - . ) < . end organ disease in the context of human herpes virus viremia in pediatric allogeneic hematopoietic stem cell transplant patients: a case series lena winestone , rajni agarwal , jose montoya , kenneth i. weinberg , matthew h. porteus , benjamin pinsky , elizabeth soda , jesse waggoner , john tamaresis , sandhya kharbanda . pediatrics, stanford university, palo alto, ca; pediatric stem cell transplantation, stanford university, palo alto, ca; stanford university, palo alto, ca introduction: hhv (human herpes virus ) reactivation occurs in approximately one-half of patients following allo- geneic hematopoietic stem cell transplant (hsct). the target tissues of hhv and the extent to which hhv causes dis- ease in those with viremia is not resolved. methods: biopsies or body fluid sampling are routinely performed at our center to determine the cause of otherwise unexplained end-organ disease. we describe pediatric hsct patients who were found with hhv pcr end-organ tissue positivity on these studies. of these patients, had received myeloablative conditioning, had received an unrelated donor graft, had underlying malignant disease, patients had acute gvhd, and were diagnosed with chronic gvhd. results: robust statistical partitioning identified two distinct subgroups within this population based on the highest hhv viral load in blood. in of the patients, a peak blood viral load (> , copies/ml) occurred developed while the other patients had peak blood viral loads < copies/ml. all patients received antiviral treatment to treat their viremia. at the time of biopsy and/or fluid sampling, only patient out of had a blood viral load > , copies/ml and the remainder had very low (< copies/ml) or un- detectable hhv virus in the blood despite having detectable virus in their tissues. in total, / patients biopsied patients who had tissue/body fluid viral positivity did not have con- current detectable virus in blood, in / , the blood viral load was < copies/ml, while only in one patient who had encephalitis there was a high copy number of , copies/ml detected in blood at the time of detection of the virus in the cerebrospinal fluid (csf). hhv was found in csf ( patients), bal fluid ( patients), gi tract ( patients), bone marrow ( patients), pericardial fluid ( patients), liver ( patient), and gallbladder ( pa- tients). statistical analysis showed no difference between the two subgroups with respect to age, gender, stem cell graft, stem cell donor, hla compatibility between the donor and the recipient, acute/chronic graft-versus-host disease, or survival. of note, out of patients had co-existent cmv viremia. there was a decreasing linear trend (cochran- armitage p¼ . ) in the association (fisher’s exact p¼ . ) between cmv viremia and hhv viral load group: patients with cmv viremia were in the low hhv viral load group versus patient in the high group. five of the fourteen patients died (one of whom relapsed), suggesting a high non-relapse mortality rate ( %) in this population. conclusion: end-organ disease/dysfunction with hhv positivity can persist despite a decrease in peripheral viral load after antiviral treatment. further studies will elucidate whether prolonged or intensive antiviral treatment is war- ranted in such cases. impact of adenovirus viremia in bone marrow transplant patients, - steven wu , nicole theodoropoulos , stanley i. martin , leslie a. andritsos , steven m. devine . the ohio state university college of medicine, columbus, oh; division of 	outline placeholder 	methods 	results 	conclusions 	favorable outcomes from allogeneic hematopoietic cell transplantation in thailand for thalassemias and hemoglobinopathies 	background 	objectives 	methods 	results 	conclusions 	engraftment and immune recovery (ir) in good risk patients undergoing hematopoietic stem cell transplantation (hsct): compa ... 	end organ disease in the context of human herpes virus viremia in pediatric allogeneic hematopoietic stem cell transplant ... 	introduction 	methods 	results 	conclusion 	impact of adenovirus viremia in bone marrow transplant patients, - received / / review began / / published / / © copyright ludwig et al. this is an open access article distributed under the terms of the creative commons attribution license cc-by . ., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. from the patient’s point of view: patient- centered outcomes in spine surgery cassie a. ludwig , anand veeravagu , michael zhang , mitchell gil. maltenfort , phillip dowzicky , john k. ratliff . stanford university school of medicine, stanford university school of medicine . department of neurosurgery, stanford university school of medicine . department of neurosurgery, stanford university school of medicine . rothman institute, philadelphia, pa . university of pennsylvania school of medicine, philadelphia, pa . department of neurosurgery, stanford university medical center  corresponding author: cassie a. ludwig, caludwig@stanford.edu disclosures can be found in additional information at the end of the article abstract introduction: a patient-centered approach to outcomes assessment necessitates knowledge of the outcomes that patients deem most important for their quality of life and overall health. to assess patient expectations with regard to seeking spine care, we conducted a prospective study of what outcome metrics were deemed most valuable to patients seeking evaluation at a tertiary spine surgery center. materials & methods: patients seeking evaluation at an academic spine surgery practice at thomas jefferson university in philadelphia were offered a survey at intake. the two-question survey explored the issues most important for consulting a neurosurgeon. survey data was acquired over three months in early . of the surveys distributed, responded, with patients completing the full survey and responding to the first question alone. results: pain was the primary impetus for patients seeking evaluation: . % of the total surveyed group reported that pain in the back or neck was one of the major concerns for their visit. similarly, % of responders indicated that pain in the back or neck was the single most important issue they wanted addressed. frequency of responses dropped significantly for the next responses, including weakness/numbness in the leg ( . %), problems walking ( . %), pain shooting down the leg ( . %), and problems sleeping ( . %). conclusions: it is possible that current outcomes measures for spine surgery, including the vas, odi, sf- , and eq- d, are either excessive or insufficient and should be adjusted to reflect patient concerns. changing these measures, enforcing conformance with patient-centered choices of which outcome measures are most valuable, would be one approach to producing patient-specific outcomes measures in spine surgery. alternatively, present measures may be more comprehensive, and by reducing measures to what patients care about, the quality of data captured may be limited. to determine future directions for patient-centered care, similar surveys should be rigorously conducted, reviewed, and compared to validated outcomes. categories: miscellaneous, neurosurgery keywords: outcomes, practice science, quality, registry, value introduction efficient and affordable access to medical knowledge is now a reality for physicians and patients alike [ ]. the emergence of electronic medical records (emr) and the ubiquity and power of computing have increased the prospects for mass collection and analysis of healthcare data. open access original article doi: . /cureus. how to cite this article ludwig c a, veeravagu a, zhang m, et al. ( - - : : utc) from the patient’s point of view: patient-centered outcomes in spine surgery. cureus ( ): e . doi . /cureus. http://cureus.com/users/ -cassie-a-ludwig http://cureus.com/users/ -anand-veeravagu http://cureus.com/users/ -michael-zhang http://cureus.com/users/ -mitchell-gil-maltenfort http://cureus.com/users/ -phillip-dowzicky http://cureus.com/users/ -john-k-ratliff computer database systems have been established within institutions for the efficient accumulation and translation of patient data into meaningful statistics that impact the process of patient care and clinical decision-making [ ]. the world wide web increasingly provides patients with affordable access to medical knowledge, though often of variable quality and navigability. with a myriad of healthcare data readily available for both patients and physicians, physicians remain responsible for the meaningful synthesis and interpretation of patient data. recent interest in patient centered outcomes and a patient-centric approach to outcomes assessment suggests that the flow of data compilation and interpretation may be reversed. rather than attempting to derive meaning from broadly collected outcomes data and wide-range outcome metrics, physicians may begin an approach to outcomes assessment by determining what outcomes are most important to their individual patients. data can then be centralized according to the outcomes that patients deem most important for their quality of life and overall health. while numerous outcome measures have been reported in the literature, minimal effort has been directed at determining whether or not these measures actually capture the specific outcome metrics most valuable to patients. to begin assessing patient expectations with regard to seeking spine care, we conducted a prospective study of what outcome metrics were deemed most valuable to patients seeking evaluation at a tertiary spine surgery center. abbreviations aaos = american academy of orthopaedic surgeons aca = patient protection and affordable care act aco = accountable care organizations cdosd = chronic disabling occupational spinal disorders emr = electronic medical records eq- d = euroqol- d iccer = institute for comparative clinical effectiveness research odi = oswestry disability index pcori = patient-centered research outcomes institute sf- = short form health survey vas = visual analogue scale of spinal pain vsc = vanderbilt spine center materials and methods population this study accrued patients from an academic spine surgery practice at thomas jefferson university in philadelphia. the survey was offered to all patients in intake, irrespective of previous diagnoses, therapy, or stage. there were no negative sequelae for not filling out the survey and no incentives for filling out the survey. survey data was acquired over three months ludwig et al. cureus ( ): e . doi . /cureus. of in early . of the surveys distributed, responded, with patients completing the full survey and responding to the first question alone. the institutional review board of thomas jefferson university reviewed the experimental protocol and provided appropriate sanction for performing the study. informed consent was waived. the investigators complied with ethical guidelines for research involving human subjects. measures the researchers developed a list of separate elements from outcome metrics widely used in spine surgery. these elements comprise the foundation measures used in compiling the visual analogue scale of spinal pain (vas), oswestry disability index (odi), short form health survey (sf- ), and euroqol five dimension questionnaire (eq- d). these common measures are widely reported in the literature for the evaluation of spine patients and have been validated in a variety of spine surgery conditions. the two-question survey explored the issues most important for consulting a neurosurgeon (table ). the first question prompted respondents to “circle the top five concerns and/or complaints that you would like addressed through your visit to our clinic.” the second question asked patients to “pick the single most important issue you would like addressed and underline it.” ) please circle the top concerns and/or complaints that you would like addressed through your visit to our clinic ) from these, pick the single most important issue you would like addressed and underline it pain in my back/neck limitations with traveling pain shooting down my leg problems participating in sports weakness/numbness in my leg problems climbing stairs amount of pain medications i am taking problems bending over overall general health problems doing normal housework problems with personal grooming/hygiene (making bed, washing dishes, vacuuming) problems with dressing myself problems doing my job due to pain putting on shoes and socks relationships with problems lifting light objects co-workers/supervisor/family/friends problems lifting heavy objects due to my pain problems walking (distance, speed) depression or anxiety problems sitting irritability or becoming easily angered problems standing feeling exhausted or tired problems sleeping problems with normal social activities problems with sex life problems with bladder control table : questions asked and possible responses in survey offered to patients in intake. statistical analysis categorical data were summarized with frequency/percentage and compared. results ludwig et al. cureus ( ): e . doi . /cureus. of initial survey of a patient’s motivations for consulting a neurosurgeon elicits a distribution of concerns with moderate consensus (figure ). pain was the primary impetus for seeking evaluation: . % of the total surveyed group reported that pain in the back or neck was one of the major concerns for their visit (table ). similarly, this was the primary concern affecting the majority of patients. frequency of responses dropped significantly for the next responses, including weakness/numbness in the leg ( . %), problems walking ( . %), pain shooting down the leg ( . %), and problems sleeping ( . %). for the remaining options, about a quarter or less of patients indicated that one was among his or her major concerns. sexual and social issues and return to work were of very low frequency, with such activities selected by less than % of patients. figure : top concerns and/or complaints patients wanted addressed during visit outcome responses (n= ) frequency (%) pain in back/neck . weakness/numbness in leg . problems walking . pain shooting down leg . problems sleeping . problems standing . problems lifting heavy objects . problems sitting . feeling exhausted or tired . problems bending over . table : most common responses selected by patients when asked to indicate top five concerns and/or complaints to be addressed. ludwig et al. cureus ( ): e . doi . /cureus. of http://assets.cureus.com/uploads/figure/file/ /lightbox_ - fig .png when considering which issue was the primary concern for a patient, the highest cited responses were similar (figure ). as before, pain in the back or neck was a dominating issue as indicated by % of responders (table ). weakness/numbness in the leg ( . %), pain shooting down the leg ( . %), and problems with walking ( . %) contributed to the top four issues. these last three lower limb concerns compose approximately one-quarter ( . %) of the available responses. none of the remaining individual options assumed more than % of the total responding sample. figure : single most important issue outcome responses (n= ) frequency (%) pain in back/neck weakness/numbness in leg . pain shooting down leg . problems walking . overall general health . problems standing . problems participating in sports . problems doing job due to pain . amount of pain medications taking . problems with sex life . table : most common responses selected by patients when asked to indicate single most important issues for consulting neurosurgeon. pain was consistently the most common complaint voiced by patients. axial neck or back pain was the most common complaint offered for both the top five issue and single issue questions. ludwig et al. cureus ( ): e . doi . /cureus. of http://assets.cureus.com/uploads/figure/file/ /lightbox_ - fig .png radicular pain was the third most common single complaint and fourth most common complaint from the multiple issue question. job problems were not a common complaint for this cohort of patients. only . % of patients noted that problems doing their job due to pain were among the top five issues prompting evaluation at a spine center. only . % noted this was the most important issue for which they sought evaluation. notably, only . % of the total patient sample ultimately provided a submission for the survey’s second question. the implications of this partial response rate are uncertain and varied, as this could reflect a patient’s unwillingness or inability to provide a single answer, or could represent a deficiency in survey design or execution. while the number of responses tallied for the single most important issues are deflated, the true percentage distribution cannot be determined. discussion patient-centered outcomes the results of this study indicate that pain in the back or neck is the single most important issue that prompts a patient to consult a spine surgeon. this may suggest higher utility for pain- centered validated outcomes measures, such as the vas. pain is included in the sf- , eq- d and odi as well, though it is only one of eight dimensions that contribute to the total score for the sf- , only one of five for the eq- d, and distributed throughout the sections of the odi. in the results of both survey questions, the three concerns that followed pain in the back or neck in importance to patients involved both pain and the functional consequences of their pathology: weakness/numbness in the leg, pain shooting down the leg, and problems with walking. only walking is addressed in the sf- and eq- d, while all these specific measurements are incorporated within the odi. it is possible that other outcomes measured by spine surgeons (ex: self-care, daily activities, and anxiety/depression) are not patient-centered as the majority of patients did not indicate that these issues were of primary concern. therefore, this survey raises the question of whether neurosurgical outcomes assessments should be moved closer to assessments of the issues identified as most important to patients. this may enable physicians to quantify patient expectations without relying on previously validated outcomes measurements that over- or underemphasize concerns. the patient protection and affordable care act the patient protection and affordable care act (aca) was signed into law march , and will be fully implemented on january , [ ]. since the creation of the aca, the emphasis of health care reform has shifted considerably from quantity to quality [ - ]. present efforts seek to link physician reimbursement to “value measures” which take into account both quality and cost variation [ ]. aca legislation will invest nearly $ . trillion between and in an attempt to make coverage affordable—an investment hoped to be offset in part by a reduction in medicare and medicaid spending through an emphasis on high quality and low cost care [ ]. therefore, data on effectiveness of care in everyday practice will be imperative to ensure that patients receive the highest quality rather than simply the lowest-cost care in the future. the aca introduces several changes pertinent to the present shift in focus on quality of care, three of which include the creation of accountable care organizations (acos), a national quality strategy, and the institute for comparative clinical effectiveness research. the first, acos, include a group of physicians and hospitals that will take responsibility for an expressed population of patients [ ]. acos will provide physicians and hospitals with incentive to improve integration and increase quality measurement and reporting, ultimately leading to improved outcomes and a reduction in healthcare cost. a central measurement of performance in acos is ludwig et al. cureus ( ): e . doi . /cureus. of the patient-reported outcome, which further incentivizes physicians to focus patient care and quality measures on patient-specific concerns. the second, the development of a multi-payer national quality strategy, aims to generate multi- payer quality and efficiency measures to promote value purchasing, improve safety, and provide increased health information to private and public insurers [ ]. in addition to the drive for increased comparative effectiveness research, the national quality strategy encourages increased performance reporting to increase patient’s access to information about their care and about the quality of their care. lastly, the institute for comparative clinical effectiveness research (iccer) was established by the aca “to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that improve health care at both the individual and population levels” [ , ]. this builds on the american recovery and reinvestment act of that allocated . billion dollars for new comparative effectiveness research in the u.s [ ]. patient-centered outcomes research institute the patient-centered research outcomes institute (pcori) was created as part of the aca effort to foster research on informed decision-making, patient care, and re-directing research efforts to be patient-centered. the pcori has led to an increased focus on patient-centered outcome measures and on framing research in a fashion immediately applicable to patients. the foundation of the pcori approach may ultimately move outcomes assessment away from previously validated outcome measures. while many outcomes projects have been completed in spine surgery, limited research has been directed at understanding patient expectations and ensuring that outcome metrics appropriately capture the goals of patients in seeking care. outcome metrics in spine surgery spine surgery serves as an appropriate model for patient centered outcomes in neurosurgery as it is an elective procedure performed for a degenerative process. patient outcomes are therefore of utmost importance in a patient’s decision to proceed with surgery. current validated measures for patient outcomes in spine surgery include the vas [ ], odi [ - ], sf- [ ], and eq- d [ - ] (table ). the vas is a self-reported, one-dimensional pain rating scale. in contrast to the vas, the odi is a self-reported questionnaire with seven (aaos version . ) sections. the odi measures condition-specific disability and focuses on pain and can be used for both assessment and outcomes data collection. a more general measure of quality of life, the sf- , is a multipurpose, short-form health survey with items that yields an eight- scale profile of scores as well as overall physical and mental health summary measures [ ]. similarly, the eq- d is a two-part self-reported multi-dimensional questionnaire that generates possible health states based on three possible answers for five dimensions [ ]. the eq- d also measures general quality of life and yields a single utility score of - : representing death and one representing full health. vas odi sf- eq- d pain pain * bodily pain pain/discomfort functionality walking, sitting, standing, sleeping,lifting, traveling, personal care physical functioning, role-physical, general health, social functioning, mobility, daily activities, self- care mental health role-emotional, mental health, vitality anxiety/depression table : validated measures for patient outcomes in spine surgery ludwig et al. cureus ( ): e . doi . /cureus. of * incorporated throughout the measure these measures are frequently used in conjunction to report patient outcomes pre- and post- surgery. however, they may not all represent the outcomes most important to patients themselves. study limitations the external validity of the study is limited by the fact that it is a single-institution study with a small cohort. limiting the study to a single institution yields optimal data for the institution itself. however, to obtain more generalizable data, future multi-institutional studies should be performed. additionally, the generalizability of this study is limited by the high prevalence of psychiatric disorders amongst spine patients. dersh et al. have reported that a majority ( %) of patients with chronic disabling occupational spinal disorders (cdosd) were diagnosed with at least one current disorder (not including pain disorder), compared with only % of the general population [ ]. while the patient population in this study is composed of all patients at an academic spine surgery practice with no inclusion criteria based on diagnosis, the potential increase in psychiatric disorders amongst this population must be considered as a variable affecting patient centered outcomes. furthermore, lack of an overall calculated response-rate yields high response bias and a lower response-rate for question two [ / ( . %)] limits the internal validity of this study. a more rigorous approach to survey administration and collection should be applied in future studies to maximize internal and external validity and minimize response bias. collecting both admission and follow-up data may yield more information as to the benefits/constraints of patient-centered outcomes in the future. to obtain this data, the stringent methodology utilized by berkowitz et al. in developing a gamma knife radiosurgery registry could be applied [ ]. berkowitz et al. ensure % patient inclusion in studies by monitoring their , member patient registry through the use of clerical staff checks, server data back up, and quality assessment in six-month intervals via built-in software. similarly, the vanderbilt spine center (vsc) includes all patients undergoing spine surgery in a prospective longitudinal spine registry, regardless of diagnosis or surgical treatment through the use of registry associates, web-based research electronic data capture, and emr [ ]. the vsc employs validated outcomes measures to capture baseline, three month and month outcomes data. such strict forms of data-collection will be critical in developing accurate data to provide true patient-centered outcomes on an institution basis in the future. cost and infrastructure development remain the largest drawbacks to this methodology. results of this study knowing the issues of greatest concern to patients seeking evaluation for spinal disease will provide clinicians with the opportunity to reassess measurements of surgery outcomes. assessment of patient expectations in seeking spine care may offer a valuable means to ensure that patients have appropriate expectations in seeking surgical treatment. in this survey, the majority of patients seeking evaluation at a spine surgery center did so for complaints of pain. some concerns that are focused upon by outcome metrics used in spine surgery were not listed as primary concerns by patients. functional deficits, as outlined by the sf- measure, were not commonly noted to be primary issues for which individual patients sought treatment. similarly, return to work is often reported as a proxy for recovery after spine surgery procedures. however, this patient cohort did not note that workplace concerns were significant to their seeking evaluation. this may, in part, explain the results of a study by hodges et al. that found no correlation between osw, vas and sf- and return-to-work rates in workers’ compensation patients who underwent lumbar spine surgery [ ]. ludwig et al. cureus ( ): e . doi . /cureus. of present approaches to outcome measures in spine surgery may not be entirely representative of patient expectations. reviewing the commonly used outcome measures and comparing them to patient choices for most important issues for consulting a spine surgeon, the vas is the single most valuable outcome metric. the odi, similarly through relating pain to functional level, captures many issues deemed important by patients. conclusions it is possible that measures used today are insufficient and should be adjusted to reflect patient concerns. some present, widely-used outcomes measures report elements that patients may not find valuable. changing these measures, enforcing conformance with patient-centered choices of which outcome measures are most valuable, would be one approach to producing patient- specific outcomes measures in spine surgery. alternatively, present measures may be more comprehensive, and by reducing measures to what patients care about, the quality of data captured may be limited. routinely used and validated outcome measures may be providing a broader measure of patient outcomes. by focusing solely on what patients are interested in, physicians may be limiting their opportunity to improve patient health across multiple measures. both possibilities have implications for the future of patient-centered care in neurosurgery. as healthcare transforms under reform efforts, it is important for physicians and patients alike to recognize that what makes patients happier does not necessarily make them healthier. the goals of health care need to be defined on a national, institutional and individual basis. to determine future directions for patient-centered care, similar surveys should be rigorously conducted, reviewed, and compared to validated outcomes. a survey of both patients and surgeons should be performed to determine whether patients and health professionals differ in their perspectives with respect to quality in spine surgery. additional information disclosures human subjects: the institutional review boards of thomas jefferson university issued approval n/a. animal subjects: this study did not involve animal subjects or tissue. acknowledgements this article has not been submitted for publication elsewhere, nor has it been published elsewhere in whole or in part. we authors report no conflicts of interest, and have received no funding for this project. this study was performed with the approval of the institutional review board of thomas jefferson university. informed consent was waived. the investigators complied with ethical guidelines for research involving human subjects. all authors listed on the title page have read and substantially contributed to the writing of the manuscript. no other persons have contributed significantly to the manuscript’s preparation. this information was added on / / . references . asher al, mccormick pc, kondziolka d: introduction: the science of practice: addressing the challenges of modern health care. neurosurgical focus. , :introduction. . berkowitz o, kondziolka d, bissonette d, niranjan a, kano h, lunsford ld: the evolution of a clinical registry during 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iom (institute of medicine) http://scholar.google.com/scholar?q=intitle:american recovery and reinvestment act of , law p no. - , h.r. stat. http://scholar.google.com/scholar?q=intitle:prospective validation of clinically important changes in pain severity measured on a visual analog scale http://scholar.google.com/scholar?q=intitle:the oswestry low back pain disability questionnaire. http://scholar.google.com/scholar?q=intitle:the oswestry disability index http://scholar.google.com/scholar?q=intitle:the roland-morris disability questionnaire and the oswestry disability questionnaire http://scholar.google.com/scholar?q=intitle:sf- health survey update http://scholar.google.com/scholar?q=intitle:long-term outcomes of revision fusion for lumbar pseudarthrosis: clinical article http://scholar.google.com/scholar?q=intitle:health-related quality of life (eq- d) before and one year after surgery for lumbar spinal stenosis http://scholar.google.com/scholar?q=intitle:utility of minimum clinically important difference in assessing pain, disability, and health state after transforaminal lumbar interbody fusion for degenerative lumbar spondylolisthesis http://scholar.google.com/scholar?q=intitle: prevalence of psychiatric disorders in patients with chronic disabling occupational spinal disorders http://scholar.google.com/scholar?q=intitle:outcome science in practice: an overview and initial experience at the vanderbilt spine center http://scholar.google.com/scholar?q=intitle:predicting factors of successful recovery from lumbar spine surgery among workers' compensation patients 	from the patient’s point of view: patient-centered outcomes in spine surgery 	abstract 	introduction 	abbreviations 	materials and methods 	population 	measures 	table : questions asked and possible responses in survey offered to patients in intake. 	statistical analysis 	results 	figure : top concerns and/or complaints patients wanted addressed during visit 	table : most common responses selected by patients when asked to indicate top five concerns and/or complaints to be addressed. 	figure : single most important issue 	table : most common responses selected by patients when asked to indicate single most important issues for consulting neurosurgeon. 	discussion 	patient-centered outcomes 	the patient protection and affordable care act 	patient-centered outcomes research institute 	outcome metrics in spine surgery 	table : validated measures for patient outcomes in spine surgery 	study limitations 	results of this study 	conclusions 	additional information 	disclosures 	acknowledgements 	references the eighteenth century cherokee archives t t is common knowledge that various indian tribes residing east •*• of the mississippi attempted to preserve their several histories in the eighteenth century. the method usually employed was to entrust various designated persons with the task of memorizing im- portant transactions. these men were expected to produce the mat- ters placed in their care whenever desired. when wampum strings and belts came into general use as mnemonic aids in the delivery of oral messages between these indians, the establishment of archives became inevitable, since tribal historians could stimulate their memo- ries by means of the wampum. the need for saving the strings and belts of the white and purple beads for ready reference was recog- nized by many nations, notably by the iroquois; and a hut or struc- ture of some sort was chosen as an archival deposit. however, it is not generally known that the cherokee actually preserved docu- ments in their national archives before the american revolution. the cherokee were less barbarous than their indian neighbors in the eighteenth century. their achives, located at chote, the "mother town" and council place of the nation, on the little tennessee river a short distance from the site of old fort loudoun, were established before , perhaps much earlier. by the cherokee realized the wisdom of safekeeping the letters and other documents sent or given to them by the british, for they had lost more than one dispute to the british because the whites were able to produce writ- ings to support their contentions. ouconnostotah, otherwise known as the great warrior, their most powerful chief during the period on the use of wampum see frederick webb hodge, ed., handbook of american indians north of mexico, smithsonian institute, bureau of american ethnology, bulletin , pt. ii (washington, ), - . the famous james adair relates that the cherokee also preserved records of events by carving and painting "hieroglyphics" upon the stems of their pipes. samuel c. williams, ed., adair's history of* the southern indians (johnson city, tenn., ), . adair also noted (p. - ) that atta- kullakulla, the little carpenter, preserved letters from the south carolina government in a bundle, often showing them to traders to demonstrate the perfidy of that govern- ment and commenting that they ought to have been burned in the old year's fire—giving an interesting turn to an archival principle now widely discussed. northern tribes put records in the shape of red and black "hieroglyphics" on trees in the forests. plowden c. j. weston, ed., documents connected with the history of south carolina (london, ), . see e. b. o'callaghan, ed., documents relative to the colonial history of the state of new york. . . . (albany, - ), viii, - . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j thw by c arnegie m ellon u niversity user on a pril the cherokee archives - / was perhaps the first of the cherokee to place great value upon the talking papers, for he was all too well acquainted with the perfidy of the palefaces. h e could never have forgotten that he traveled to charleston in in an effort to maintain peace with the british and that his reward was seizure and imprisonment as a hostage. certainly the cherokee archives were in his care during the american revolution. preserved in the cherokee archives were wampum strings and belts, bronze medals given to prominent chiefs by "king george," and papers on cherokee history dated as early as and as late as . included in the papers were messages (or "talks") to the cherokee by indian superintendent john stuart, lord dunmore, patrick henry, and other british and american officials} a copy of one important treaty and an abstract of another; and a map of the proposed colony of vandalia sent to ouconnostotah by stuart. one curious item was a formal certificate attesting the election of oucon- nostotah to membership in the st. andrews club of charleston on november , . the most extraordinary document was a letter from stuart to the great warrior of june, , in which the super- intendent suggested that the chief persuade a british trader to read the letter to him. no description of the depository has been found, but it was probably ouconnostotah's own hut or the council chamber of the nation. in any case, arrangements to protect the records were not completely inadequate, since part of them are still in existence and in good condition. alas, oucconostotah and his followers, though able to defend their archives from the weather, were unable to ward off seizure by the palefaces. when the revolution broke out, the cherokee there is a brief sketch of this remarkable indian, correct except for one or two details, in the dictionary of american biografhy. his name is given therein as ocono- stota, but the form used above was most commonly used by his english contemporaries. medals were widely used by the british, french, and spanish as tokens of authority among- tribal leaders. small medals were sometimes distributed to all the tribe's warriors as decorative symbols of loyalty. in addition, the southern english colonies gave parch- ment commissions comparable to letters patent which were recognition of the rank of tribal leaders. the indians preserved these well and when going to war included them among the objects carried in the war chest. at the time ouconnostotah was stuart's guest at charleston. stuart was president of the club, and arranged for the election. no cherokee at that time could read english. communication between british of- ficials and the southern indians was commonly carried on by writing. traders and officers in the wilderness translated messages to the indians and also served as scribes for them. chiefs and warriors affixed their signatures when necessary by making their marks. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j thw by c arnegie m ellon u niversity user on a pril the american archivist espoused the cause of "king george," and they were a serious menace on the frontiers of the southern states as late as . toward the close of that year, however, colonel arthur campbell and lieu- tenant colonel john sevier invaded the cherokee country at the head of seven hundred militiamen from the backwoods of virginia and north carolina. in a preliminary skirmish with the cherokee on the broad river of north carolina on december , a detachment led by sevier defeated seventy cherokee, and captured "all their baggage &c; in which were some of clinton's proclamations and other documents expressive of their hostile designs against us." but these papers, which apparently have disappeared, were not included in the national archives. on december the whole american force advanced into the very heart of the cherokee country, sweeping aside the feeble opposition of the indians. on december , they captured and burnt chote itself. ouconnostotah managed to elude the american riflemen, but abandoned the records of his nation in the hurry of his flight. wrote campbell to thomas jefferson, then governor of virginia, on january , , "we found in okanas- toters baggage, which he left behind in his fright, various manu- scripts, copies of treaties, commissions, letters and other archives of the nation. . . ."t fortunately for the historian, a considerable part of these records ultimately found their way into the division of manuscripts of the library of congress. jefferson forwarded a copy of campbell's letter to john hanson, president of the continental congress. in the hope that the papers seized by the militiamen would contain useful infor- mation, hanson requested that they be sent on to philadelphia. jefferson relayed this request to campbell on may . campbell was unable immediately to forward all the papers, for part of them had passed into the possession of the north carolina officers. after taking copies of certain documents which aroused his interest, camp- bell sent the originals in his possession to jefferson on june . h e also promised to try to obtain the remainder from the north caro- linians for hanson, but evidence that he was successful is lacking. ' w . p. palmer, s. mcrae, and w . h . fleurnoy, eds., calendar of virginia state papers, - (richmond, ) , '> - - h . r. mcllwaine, ed., official letters of the governors of the state of virginia (richmond, ), ii, . "campbell to jefferson, june , , papers of thomas jefferson, vii, library of congress. campbell to jefferson, june , , papers of the continental congress, no. , vol. , lib. cong. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j thw by c arnegie m ellon u niversity user on a pril the cherokee archives but those which he sent to jefferson were forwarded by the governor to hanson on december , and became part of the papers of the continental congress. they cover pp. - of no. , vol. , in that series. appropriately enough, they have received the title, "archives of the cherokees." a list of these documents follows. . , jan. , alex [ande] r cameron to the great warrior attakullakulla willinanan and the other head chiefs of the chero- kee nation. a.d.s. pp. f°. (pp. - .) . , mar. , talk, lord dunmore to the little carpenter and the chiefs of the cherokee nation of indians. d.s. pp. f°. (pp. - .) . , july , "his majesty's instructions to all the govern- ours of his provinces in america." printed broadside, sealed, and signed by john stuart, ip. f°. (p. .) . , july , alex [ ande ] r cameron to "friends and brothers" [of the cherokee nation]. a.d.s. pp. f°. (pp. - .) - , june , talk to the cherokees. d. pp. f°. (pp. - i -) - , june , "abstract of the treaty of cession to his maj- esty of certain lands for the payment of the debts due by the creek & cherokee indians to their traders at a congress of the chiefs of both nations . . ." d.s. (by john stuart, etc.) ip. f°. (p. .) . , mar. , alex[ande]r cameron to ouconnastotah and the ruling chiefs of the over hill cherokees. a.d.s. pp. f°. (pp. - .) . , mar. , alex[ande]r cameron to all whom it may concern. (passport of the "great warrior of chote.") a.d.s. ip. p. (p. .) . , feb. , alex[ande]r cameron to "friends and brothers" [of the cherokee nation]. a.d.s. pp. p. (pp. - .) . , jan. , john stuart to "the head beloved man and principal warriors of the cherokee nation at chote." a.d.s. pp. . (pp. i -i -) . , july , edw[ard] wilkinson to the great warrior occonnistota at chote. a.d.s. pp. . (pp. - .) jefferson to hanson, dec. , , papers of the continental congress, no. , vol. ii, lib. cong. am indebted for this list and for generous assistance in pursuing the history of these papers to dr. thomas p. martin of the division of manuscripts, library of congress. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j thw by c arnegie m ellon u niversity user on a pril the american archivist . , apr. , w[illia]m preston to ocanastota the little carpenter, judge friend, and the other chiefs of the warlike nation of the cherokees. d.s. pp. f°. (pp. - .) * - , jan. , david taitt to aconostota at chote, a.d.s. pp. f°. (pp. - .) . [june, ], john stuart to oukonnestotah great war chief of the cherokee nation. a.d.s. pp. f°. (pp. - .) . [june, , john stuart], map of "new province." ip. p. (pp. - .) . , feb. , john stuart to the warrior of chote oucconnas- tote. a.d.s. pp. f°. (pp. - .) x - i > nov. , certificate of oucconnastotah's membership in st. andrew's club (of charles-town, south carolina). printed form, filled in. ip. . signed by john stuart and james brisbane, (p. .) . , mar. , p[atrick] henry to ouconostotah and the other chiefs of the cherokee nation. copy of d. pp. f°. (pp. - .) . , nov. , pfatrick] henry to brother ouconostotah. d.s. p. f°. (p. .) . undated, p[atrick] henry to brother ouconostotah. d.s. pp. . (pp. - .) . , june , john stuart to the principal warriors and the governing beloved headmen of the cherokee nation. d.s. pp. f°. (pp. - .) . , july , articles of a treaty of peace between the commissioners of virginia and the chiefs of that part of the chero- kee nation called the overhill indians. d.s. ip. large f°. (p. .) john richard alden michigan state normal college d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j thw by c arnegie m ellon u niversity user on a pril [pdf] yellow nail syndrome chylous pleural effusions: defective lymph valves involved? | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /chest. - corpus id: yellow nail syndrome chylous pleural effusions: defective lymph valves involved? @article{maldonado yellowns, title={yellow nail syndrome chylous pleural effusions: defective lymph valves involved?}, author={f. maldonado and j. ryu}, journal={chest}, year={ }, volume={ }, pages={ - } } 	f. maldonado, j. ryu 	published 	medicine 	chest we believe that dynamic parameters such as stroke volume variation are currently the best markers of volume responsiveness. while the models of guyton and starling are magnificent in their simplicity, therapeutic interventions based on these principles may lead to therapeutic errors in complex critically ill patients. this is demonstrated by the fact that no clinical study (of which we are aware) has shown central venous pressure to be a reliable tool in the fluid management of critically ill… expand view on pubmed journal.publications.chestnet.org save to library create alert cite launch research feed share this paper citations view all topics from this paper 	pleural effusion disorder 	critical illness 	venous blood pressure 	sepsis 	central venous pressure 	cd protein, human 	cerebrovascular accident 	stroke volume one citation citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency yellow nails, lymphedema and chronic cough: yellow nail syndrome in an eight-year-old girl. 	i. siddiq, d. m. hughes 	medicine 	canadian respiratory journal 	 	 	pdf save alert research feed references showing - of references mutations in foxc are strongly associated with primary valve failure in veins of the lower limb 	r. mellor, g. brice, + authors p. mortimer 	medicine 	circulation 	 	 	 save alert research feed surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 	r. dellinger, m. levy, + authors j. vincent 	medicine 	critical care medicine 	 	 , 	pdf save alert research feed yellow nail syndrome or diffuse lymphatic network disease. 	k. christu, c. pastaka, d. papadopoulos, e. klimi, k. gourgoulianis 	medicine 	acta medica 	 	 	pdf save alert research feed endothelial/pericyte interactions 	a. armulik, a. abramsson, c. betsholtz 	biology, medicine 	circulation research 	 	 , 	 save alert research feed noninvasive hemodynamic monitoring in the intensive care unit. 	p. marik, michael s. baram 	medicine 	critical care clinics 	 	 	pdf save alert research feed yellow nail syndrome: analysis of consecutive patients 	b. thiers 	medicine 	 	 save alert research feed new therapy for sepsis infection raises hope but many questions 	wall street journal 	 early goal-directed therapy in the treatment of severe sepsis and septic shock 	s. dzik 	medicine 	 	 , save alert research feed the major route for absorption of fluid from the pleural space. 	k. gourgoulianis, c. hatzoglou, p. a. molyvdas 	medicine 	lymphology 	 	 save alert research feed goal directed therapy for sepsis [ letter ] related papers 	abstract 	topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue springer a++ viewer publisherinfo publishername : biomed central publisherlocation : london publisherimprintname : biomed central tumor suppression by fez articleinfo articleid : articledoi : . /gb-spotlight- - articlecitationid : spotlight- - articlesequencenumber : articlecategory : research news articlefirstpage : articlelastpage : articlehistory : registrationdate : – – onlinedate : – – articlecopyright : biomed central ltd articlegrants : articlecontext : jonathan b weitzman email: jonathanweitzman@hotmail.com the fez /lzts gene maps to chromosome p , a region lost in many tumors. in the early edition of the proceedings of the national academy of sciences, hideshi ishii and colleagues, from thomas jefferson university, philadelphia, describe a mechanism for fez -mediated growth suppression. they created an inducible gene-expression system in mcf breast cancer cells, in which fez expression was controlled by tetracycline. fez expression inhibited cell growth in vitro (at the s-phase to g /m transition in the cell cycle) and tumor formation in vivo. ishii et al.demonstrated that the fez protein is phosphorylated by camp-dependent protein kinase (pka) during the cell cycle. two-hybrid protein- protein interaction analysis in yeast showed that fez interacts with elongation factor ef γ. also, fez is associated with microtubule components and with the p cdc mitotic kinase. fez appears to suppress tumor growth by regulating microtubule dynamics and progression through mitosis. references . the fez gene at chromosome p encodes a leucine-zipper protein, and its expression is altered in multiple human tumors. . proceedings of the national academy of sciences , [http://www.pnas.org] . thomas jefferson university , [http://www.tju.edu] . fez /lzts gene at p suppresses cancer cell growth and regulates mitosis., [http://www.pnas.org/cgi/content/abstract/ v ] this pdf file was created after publication. http://www.pnas.org http://www.tju.edu http://www.pnas.org/cgi/content/abstract/ v 	tumor suppression by fez 	references wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - 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: : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ databases: cinahl cochrane ovid pubmed search terms: population: stroke, "poststroke", "post-stroke", “hemiparesis”, “cva", "cerebral vascular accident", "cerebrovascular accident", "upper extremity", "upper limb", hand intervention: "motor imagery", "mental practice", imagery, visualization outcome: “activities of daily living", function, motor n recovery, "self care", grasp acute verses chronic stroke: strong evidence supports the use of motor imagery for individuals with acute and chronic stroke to improve upper extremity function. o total time post-stroke: days - . years o average time post-stroke: acute = . weeks/ chronic = . years o statistically significant results for use of motor imagery for patients  articles with chronic stroke ( level i, level ii, level iii)  articles with acute stroke ( level i, level ii, level iii) protocol: perspective: strong evidence supports a first-person perspective to improve upper extremity function; there is preliminary evidence for a third-person perspective and a combined perspective. o first-person perspective: articles ( level i, level ii, level iii) o first compared to third-person perspective: article (level i) (not statistically significant) o combined first and third-person perspectives: article (level ii) protocol: motor imagery with relaxation: strong evidence supports the use of relaxation as the first step within a motor imagery protocol to improve upper extremity function. o articles using this approach ( level i, level ii, level iii) o relaxation, ranging from - minutes, was used as the first step of motor imagery protocol: motor imagery with graded performance: strong evidence supports the use of motor imagery with graded performance. o this involves using motor imagery with gradually more complex tasks or environments (timmermans et al., ) o articles ( level i, level ii, level iii) using this approach had statistically significant results delivery method: intervention: strong evidence supports the use of audio delivered motor imagery to improve upper extremity function; moderate evidence supports the use of therapist delivered motor imagery; preliminary evidence supports the use of video & therapist delivered, video delivered & audio, video, therapist scripted delivery. further research is needed to identify the most effective delivery method. o video recording: article (level i) o audio recording: articles ( level i, level ii) o therapist delivered: articles ( level ii, level iii, level iii) o video, audio, & therapist scripted: article (level i) (not statistically significant) o video & therapist delivered: article (level i) (not statistically significant) delivery method: duration, frequency, intensity: preliminary evidence supports varied duration, frequency, and intensity of motor imagery intervention. o statistically significant outcomes were seen as early as weeks with sessions/week lasting minutes each, and as late as weeks with sessions/week lasting minutes each. o studies most frequently used minute sessions (ranged from - minutes) o studies used an average of . treatment sessions most frequently used outcome assessments: o fugl-meyer test of sensorimotor impairment: articles ( level i, level ii, level iii) o action research arm test: articles ( level i, level ii) o barthel index of activities of daily living: articles ( level i)(not statistically significant) presented in partial fulfillment of the master of science in occupational therapy degree at thomas jefferson university clinical effectiveness of motor imagery post stroke: an evidence based review azzey narimanian, amanda reese, karina ryabo, rachel shepp, and annalisa synnestvedt faculty mentor: teal benevides objectives:  understand the current evidence for motor imagery, as presented in an evidence-based review of articles.  identify three clinical implications of this evidence in treatment for individuals post-stroke.  distinguish the unique role of occupational therapy using motor imagery to enhance occupational participation.  analyze supports and barriers to implementing the evidence for motor imagery to current practice settings through group discussion. two authors critiqued each article utilizing the pedro scale to minimize bias what is the effectiveness of motor imagery to increase upper extremity function for daily activities for individuals post-stroke? themes preliminary moderate strong acute ✓ chronic ✓ st perspective ✓ rd perspective ✓ combined perspective ✓ relaxation ✓ graded performance ✓ video delivery ✓ audio delivery ✓ therapist delivered ✓ audio,video, & therapist scripted ✓ video & therapist delivered ✓ duration, frequency, & intensity ✓ author contact information: azzey narimanian amanda reese karina ryabo rachel shepp annalisa synnestvedt azzeyn@gmail.com amanda.n.reese@gmail.com karinarachel @gmail.com res @gmail.com alsynnestvedt@gmail.com references american occupational therapy association. ( ). occupational therapy practice framework: domain and process ( nd ed.). american journal of occupational therapy, , – . barclay-goddard, r. e., stevenson, t. j., poluha, w., & thalman, l. ( ). mental practice for treating upper extremity deficits in individuals with hemiparesis after stroke. stroke, ( ), e -e . doi: . / .cd .pub *bovend'eerdt, t. j., dawes, h., sackley, c., izadi, h., & wade, d. t. ( ). an integrated motor imagery program to improve functional task performance in neurorehabilitation: a single-blind randomized controlled trial. archives of physical medicine and rehabilitation, ( ), - . center for disease control. ( ). stroke facts. retrieved from http://www.cdc.gov/stroke/facts.htm centre for evidence-based physiotherapy. ( ). pedro scale. retrieved july , , from http://www.pedro.org.au/ university of illinois at chicago, library of the health sciences. ( ). levels of evidence pyramid [image], retrieved august , from http://gollum.lib.uic.edu/nursing/node/ *craje, c., van der graaf, c., lem, f. c., geurts, a. c., & steenbergen, b. ( ). determining specificity of motor imagery training for upper limb improvement in chronic stroke patients: a training protocol and pilot results. international journal of rehabilitation research, ( ), - . de vries, s., tepper, m., otten, b., & mulder, t. ( ). recovery of motor imagery ability in stroke patients. rehabilitation research & practice print, , - . dickstein, r., & deutsch, j. e. ( ). motor imagery in physical therapy practice. journal of the american physical therapy association, ( ), - . doi: . / ptj. *guttman, a., burstin, a., brown, r., bril, s., & dickstein, r. ( ). motor imagery practice for improving sit to stand and reaching to grasp in individuals with poststroke hemiparesis. topics in stroke rehabilitation, ( ), - . *ietswaart, m., johnston, m., dijkerman, h. c., joice, s., scott, c. l., macwalter, r. s., & hamilton, s. j. ( ). mental practice with motor imagery in stroke recovery: randomized controlled trial of efficacy. brain, ( ), - . kwakkel, g., et al. ( ). effects of augmented exercise therapy time after stroke a meta-analysis. stroke, ( ), - . *liu, k. p. ( ). use of mental imagery to improve task generalisation after a stroke. hong kong medical journal, ( suppl ), - . *liu, k. p., chan, c. c., wong, r. s., kwan, i. w., yau, c. s., li, l. s., & lee, t. m. ( ). a randomized controlled trial of mental imagery augment generalization of learning in acute poststroke patients. stroke, ( ), - . maher, c. g., sherrington, c., herbert, r. d., moseley, a. m., & elkins, m. ( ). reliability of the pedro scale for rating quality of randomized controlled trials. physical therapy, ( ), - . *muller, k., butefisch, c. m., seitz, r. j., & homberg, v. ( ). mental practice improves hand function after hemiparetic stroke. restorative neurology & neuroscience, ( - ), - . *nilsen, d. m., gillen, g., dirusso, t., & gordon, a. m. ( ). effect of imagery perspective on occupational performance after stroke: a randomized controlled trial. american journal of occupational therapy, ( ), - . *page, s. j., levine, p., & leonard, a. ( ). mental practice in chronic stroke: results of a randomized, placebo-controlled trial. stroke, ( ), - . *page, s. j., levine, p., & leonard, a. c. ( ). effects of mental practice on affected limb use and function in chronic stroke. archives of physical medicine & rehabilitation, ( ), - . priganc, v. w., & stralka, s. w. ( ). graded motor imagery. journal of hand therapy, ( ), - . *page, s. j., murray, c., hermann, v., & levine, p. ( ). retention of motor changes in chronic stroke survivors who were administered mental practice. archives of physical medicine & rehabilitation, ( ), - . *riccio, i., iolascon, g., barillari, m. r., gimigliano, r., & gimigliano, f. ( ). mental practice is effective in upper limb recovery after stroke: a randomized single- blind cross-over study. european journal of physical & rehabilitation medicine, ( ), - . shenn, j., & leishear, k. ( ). novel techniques for upper extremity training for hemiparesis after stroke. retrieved from http://pmr.medicine.pitt.edu/content/pdfs/rgr_ .pdf *simmons, l., sharma, n., baron, j. c., & pomeroy, v. m. ( ). motor imagery to enhance recovery after subcortical stroke: who might benefit, daily dose, and potential effects. neurorehabilitation & neural repair, ( ), - . *sun, l., yin, d., zhu, y., fan, m., zang, l., wu, y., jia, j., bai, y., zhu, b. & hu, y. ( ). cortical reorganization after motor imagery training in chronic stroke patients with severe motor impairment: a longitudinal fmri study. neuroradiology, ( ), - . *timmermans, a. a., verbunt, j. a., van woerden, r., moennekens, m., pernot, d. h., & seelen, h. a. ( ). effect of mental practice on the improvement of function and daily activity performance of the upper extremity in patients with subacute stroke: a randomized clinical trial. journal of the american medical directors association, ( ), - . * references marked with an asterisk indicate studies included in the evidence-based review mailto:azzeyn@gmail.com mailto:amanda.n.reese@gmail.com mailto:karinarachel @gmail.com mailto:res @gmail.com mailto:alsynnestvedt@gmail.com wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} 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to conclude that state governments have a long-standing commitment to protecting fetal life. and yet, over the last several decades, state governments and local law enforcement are increasingly taking steps that actively undermine fetal health. through the passage of state fetal endangerment laws and the prosecution of pregnant women under stretched interpretations of existing criminal laws, states are actively creating conditions that result in poorer fetal health outcomes—including an increase in fetal and infant death. 							 						 												 							 								read more in vol . 								 									 								 							 						 											 				 			 						 				 										 						 														 														creating space for community representation in police reform litigation														 													 						 							 								ayesha bell hardaway input from affected communities is an essential component of the reform process aimed at remedying unconstitutional police practices. yet, no court has ever granted a community organization’s motion to intervene as a matter of right in police reform, consent decree cases initiated by the department of justice. judicial opinions in those cases have truncated the federal civil rule analysis when evaluating the interests of impacted communities. thus, the most success achieved by a few community organizations has been permissive intervention or amici status. the models used by the department of justice to elicit the community perspective have been frustrating and have failed to incorporate community voice with equal weight and authority in the process. 							 						 												 							 								read more in vol . 								 									 								 							 						 											 				 			 						 				 										 						 														 														“when you’re a star”: the unnamed wrong of sexual degradation														 													 						 							 								daniel maggen the #metoo movement is often criticized for its conflation of sexual assault, sexual harassment, and offensive but not legally actionable behavior. this objection is often accompanied by criticism of #metoo’s failure to adhere to the legal paradigms that inform sexual assault and harassment, presumably setting back the efforts to advance them. finally, the #metoo movement is often faulted for its failure to accord those it accuses with the procedural safeguards of due process. 							 						 												 							 								read more in vol . 								 									 								 							 						 											 				 			 						 				 										 						 														 														presidential review: the president’s statutory authority over independent agencies														 													 						 							 								cass r. sunstein & adrian vermeule many presidents have been interested in asserting authority over in-dependent regulatory agencies such as the federal trade commission, the federal communications commission, the nuclear regulatory commission, the securities and exchange commission, and the federal reserve board. the underlying debates raise large constitutional questions, above all about the meaning and justification of the idea of a “unitary executive.” 							 						 												 							 								read more in vol . 								 									 								 							 						 											 				 			 						 				 										 						 														 														is this really the best we can do? american courts’ irrational efforts clause jurisprudence and how we can start to fix it														 													 						 							 								charles thau this note presents an original argument regarding a significant and recurring issue within commercial contract law: efforts clauses. many practitioners perceive efforts clauses as operating on a sliding scale, with “best efforts” imposing more burdensome obligations than “reasonable efforts,” for example. the majority of american courts, however, reject this hierarchical notion. reasoning on both a linguistic and prudential basis, this note argues that efforts clauses should be interpreted hierarchically. 							 						 												 							 								read more in vol . 								 									 								 							 						 											 				 			 					 	 	 		featured news 	 		 				the new top editor of georgetown’s flagship law journal is ‘undocumented and unafraid’ 		march , 				"with every accomplishment she achieves, she turns around and thinks of how to smooth the road for those behind her.” the georgetown law journal editor in chief agnes lee's activism for undocumented immigrants has continued throughout her time at georgetown university. as an undergraduate, lee stood out as a leader among students who opposed then-homeland security secretary jeh johnson's invitation to be a graduation speaker and also delivered a tedx talk which revealed her own undocumented status. lee is believed to be the first openly undocumented student elected to lead a flagship journal at a top u.s. law school. at the journal's helm, lee is working to broaden and diversify the ranks of authors and student leaders. 	 		 				for the first time, flagship law journals at top u.s. law schools are all led by women, by ann e. marimow, the washington post 		february , 				volume editor-in-chief grace paras and volume editor-in-chief toni deane are featured in the washington post. for the first time ever, all editors-in-chief for the top sixteen law schools in the country are women. toni deane is our first black editor-in-chief. 	 	 			 		 		 	 		 	 		 			connect with us 		 		 				 					 						 							 								 									 								 							 							twitter 						 					 				 	 					 						 							 								 									 								 							 							facebook 						 					 				 		 	 	 	 			 			 			 				 					 						 							 								 																		 										 											visit our campus											 												 													 												 											 										 									 																		 										 											about											 												 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issue (february )									 										 											 										 									 								 							 	 								 									volume , issue (december )									 										 											 										 									 								 							 	 								 									volume , issue (october )									 										 											 										 									 								 							 	 								 									women & law									 										 											 										 									 								 							 	 								 									 th amendment edition									 										 											 										 									 								 							 											 	 						symposia 											 	 						online 											 	 						arcp 											 	 						glj confronts racism 												 							expand navigation 							 								 									 								 							 						 					 								 									the breonna taylor prize									 										 											 										 									 								 							 	 								 									a deep dive into qualified immunity									 										 											 										 									 								 							 											 			 			 					 				 	 				 		masthead						 											 	 				 	 				 		prospective members						 											 			 			 					 	 			visit our campus 					 	 	 			about 					 	 	 			make a gift 					 	 	 			accessibility 					 	 	 			aba required disclosure 					 			 		 		 		 		 	 pin impact of complicated skin and soft tissue infections on inpatient costs for an academic medical center abstracts from eight managed care organizations. index claims were out- patient or emergency department visits in – by indi- viduals aged – with a primary diagnosis of pneumonia, antibiotic prescription within three-days, chest x-ray on index date, continuous enrollment for -months prior, -days after index visit. exclusion criteria: antibiotic prescription, pneumo- nia diagnosis, or hospitalization in prior -days; initial therapy with multiple antibiotics; in prior -months residence in a long-term care facility or diagnosis of lung cancer, secondary malignancy, hiv/aids, cystic fibrosis, immunodeficiency. we considered the following comorbid illnesses: chronic liver, renal or lung disease; cerebrovascular disease; cardiac disease; diabetes mellitus; malignancy. follow-up claims were considered cap-related if the primary diagnosis, using the clinical classifications software, was pneumonia; septicemia; pleurisy, pneumothorax or pulmonary collapse; respiratory failure, insuf- ficiency or arrest; other lower respiratory infection. results: in total, cases met criteria; . % had no comorbidities, . % had one comorbidity, and . % had two or more comor- bidities. mean total charges were $ . : . % inpatient, . % outpatient, . % outpatient testing and diagnostics, . % antibiotic prescriptions, . % emergency department, . % presenting to the emergency department had initial mean charges of $ . compared with mean initial charges for out- patients of $ . . in total, . % utilized follow-up services with . % requiring hospitalization. mean total charges for those eventually hospitalized were $ , . compared with $ . for the . % of patients who failed initial treatment but were not hospitalized, and $ . for the . % of patients requiring no additional antibiotics. number of comorbidities was strongly associated (p < . ) with charges: $ . for those without comorbidities vs. $ . for those with multi- ple comorbidities. conclusion: cost of outpatient cap for non-elderly adults is large even for those without comorbid illness. pin impact of complicated skin and soft tissue infections on inpatient costs for an academic medical center patel n , goldfarb n , hartmann cw , maio v , horn dl , pizzi l jefferson medical college, philadelphia, pa, usa; thomas jefferson university, philadelphia, pa, usa objectives: to determine the additional costs and lengths of stay (los) attributable to complicated skin and soft tissue infec- tions (cssi) for patients admitted to thomas jefferson university hospital, an urban academic tertiary care hospital. methods: all patients admitted between january , and december , were identified using the hospital billing system. patients with a potential cssi were identified using the specific icd- diagnosis codes. costs of care and lengths of stay, based on the hospital’s true cost accounting system, were compared by diagnosis related group (drg) between the cssi population and the non-cssi population. results: of the , patient discharges in , , ( . %) included one of the cssi diag- nosis codes; these encompassed drgs. the mean cost for cssi cases was $ , higher than for non-cssi cases, and mean los was ten days higher for cssi cases. for surgical and medical drgs, mean cost of cssi added $ , onto the cost for cases in surgical drgs compared to an average increase of $ , added to cost of medical drgs. differences in costs and los were observed in analyses by major disease categories (mdcs) and individual drgs as well. for mdcs, myeloproliferative dis- orders, multiple trauma, and diseases of the nervous system, costs were $ , , $ , , and $ , , higher for the cssi cases, respectively. this difference was also reflected in additional days of stay of , , and days, respectively. for patients with cssi, the three specific drgs responsible for the maximum total health care dollars expended were bone marrow trans- plants, rehabilitation, and small and large bowel procedures. conclusions: cssis significantly increase hospital resource consumption and costs. the difference in costs is especially pro- nounced for patients undergoing surgical procedures. results suggest that measures taken to avoid or more effectively treat cssis could yield significant savings to hospitals. pin cost-utility of chronic hepatitis “c” treatment with thymosin alpha in mexico nevárez-sida a, garcía-contreras f, constantino-casas p, castro-rios a, mould j, garduño-espinosa j mexican institute of social security, mexico city, mexico objective: to estimate cost-utility of the following alterna- tives in the treatment of chronic hepatitis c (chc) in the mexican institute of social security (imss): peginterferon, peginterferon plus ribavirin, peginterferon plus ribavirin plus thymosin alpha- and finally, not using any drug. methods: in mexico, more that one million persons are infected with chc virus and % of them develop chronic infection that might lead to hepatic cirrhosis and other complications that affect quality of life and costs of health care institutions. cost-utility analysis was carried out using institutional perspective and time horizon of years, discount rate of % for both, costs and effective- ness. the base case was a -year-old man with chc without hepatic cirrhosis or cancer and cost and effectiveness data were taken from literature, a mexican expert panel and an on-going clinical trial, not yet reported. effectiveness data are reported in qalys and costs in usd. a decision tree using a bayesian approach and a markov model were developed. sensitivity analysis was univariate, bivariate, threshold and probabilistic. acceptability curves and health net benefits were estimated. results: triple therapy (peginterferon plus ribavirin plus thy- mosin alpha- ) was dominant over the rest of alternatives costing $ per qaly, while peginterferon plus ribavirin $ per qaly and peginterferon only $ per qaly. not using any drug was the most costly alternative with $ per qaly. sen- sitivity analysis confirmed the strength of the base study. triple therapy was not dominated in any comparative case. con- clusions: triple therapy had the best cost-utility ratio and not using any drug was the opposite, most expensive and with less utility than all the compared alternatives. although triple therapy is initially very expensive, it provides the highest gains in the long run, both in the improvement of quality of life and in saving costs. pin a comparison of methods to assess quality of life in economic analyses of hepatitis c treatments yeh ws, skrepnek gh, armstrong ep, malone dc university of arizona college of pharmacy, tucson, az, usa objectives: this study investigated the effect of using differ- ent utilities for a cost-utility analysis comparing peginterferon alpha- b plus ribavirin, interferon alpha- b plus ribavirin, and no treatment for chronic hepatitis c from a u.s. payer’s per- spective. methods: a markov model was developed to sim- ulate the lifetime disease progression of hepatitis c virus (hcv) for a -year-old male. the analysis was conducted by stratify- ing hcv genotypes. health-state utilities were obtained from previously published literature. standard gamble patient-elicited utilities were used as the base case. five other expert-estimated wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( 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ЕКОНОМІКАІСТОРІЯ УДК ( ) / ФЕРМЕРСЬКА РЕСПУБЛІКА - ПОЛІТИЧНИЙ ІДЕАЛ ТОМАСА ДЖЕФФЕРСОНА В РОЗВИТКУ СПОЛУЧЕНИХ ШТАТІВ АМЕРИКИ ТЕТЯНА СТАЦЕНКО, аспірант Донецького національного університету У статті виконано огляд та аналіз ідеї американського просвітника, демократа і прези- дента США Томаса Джефферсона ( - ) щодо розвитку Сполучених Штатів Америки аграрним шляхом. Визначено пріоритети спілки окремих дрібних фермерів, які протистав- лялися промисловості. Показано вплив політичних та економічних чинників на ідею фер- мерського розвитку держави. Охарактеризована суть драми Т. Джефферсона, що полягала у відмові від аграрного розвитку держави. Визначена його роль у розвитку Сполучених Штатів Америки демократичним шляхом. Ключові слова: фермерська республіка, аграрний шлях розвитку, американська демократія, Томас Джефферсон, рання історія Сполучених Штатів Америки. Постановка проблеми. Для українського сьо- годення приклад установлення та розвитку амери- канської демократії є повчальним, особливо цікаві основи демократії, що базувалися на просвітниць- ких ідеях Томаса Джефферсона. У своїй історії су- часна Україна не мала тривалого досвіду держав- ного будівництва. Після розпаду Радянського Со- юзу для нашої країни актуальною є проблема пере- ходу від тоталітарного до демократичного устрою державотворення, тому становлення американської державної системи становить практичний інтерес. Дослідження ідеї аграрного розвитку країни, чин- ників, котрі вплинули на становлення демократич- ної теорії Томаса Джефферсона, а також історична практика формування держави в Сполучених Шта- тах Америки має велике теоретичне та практичне значення. Аналіз досліджень та публікацій. Історіогра- фія дослідження історичної постаті Томаса Джеффер- сона представлена роботами вітчизняних та закор- донних (в основному американських та російських) істориків. Потрібно зауважити, що майже всі вони присвячені аналізу політичної діяльності лідера Аме- риканської революції і Війни за незалежність та тре- тього президента Сполучених Штатів Америки. Українська історіографія - це дослідження В. М. Ка- лашнікова [ ], В. П. Газіна [ ], котрі узагальнили погляди на діяльність Томаса Джефферсона в кон- тексті ранньої історії Сполучених Штатів Америки. Серед американських дослідників Дж. Морзе, Т. Таккер, Г. Рендол, Р. Хілдрет [ ] переважають дві тенденції трактування діяльності Т. Джефферсона - більш позитивна і більш критична: роботи характе- ризуються відсутністю єдиної думки щодо ролі аг- рарної політики Томаса Джефферсона в амери- канській історії. Російські вчені-американісти, а саме: Н. Н Бол- ховітінов [ ], В. В. Согрін [ ], Г. М. Севостьянов [ ], А. І. Уткін [ ] у своїх дослідженнях позитивно оціню- вали діяльність Джефферсона, щодо втілення де- мократичних норм у життя держави. Слід зазначити, що в наукових працях мало ува- ги присвячено вивченню та аналізу демократичної теорії Томаса Джефферсона, його ідеї фермерсько- го розвитку республіки. Метою статті є дослідження та аналіз ідеї фер- мерського шляху розвитку США в контексті демок- ратичної теорії Томаса Джефферсона. Виклад основного матеріалу. Для американсь- кої історії ХvІІІ століття є переломним: колонії здобу- ли незалежність у боротьбі проти Англійської метро- полії. Лідери, які очолили Американську революцію та Війну за незалежність, були представниками аме- риканського Просвітництва. Наприкінці ХvІІІ століття в економіці Сполучених Штатів Америки основною галуззю було сільське господарство. Серед факторів, що визначали його розвиток, були такі: використання праці рабів, спе- ціалізація районів: - у колоніях Нью-Гемпшир, Массачусетс, Коннек- тикут, Вермонт, Род-Айленд займались обробкою лісу, заліза, суднобудуванням; - у колоніях Нью-Йорк, Нью-Джерсі, Пенсильва- нія на плантаціях вирощували пшеницю, льон та займались розведенням худоби, а саме: овець, сви- ней та коней; - у Джорджії, Віргінії, Меріленді, Північній та Пів- денній Кароліні вирощували тютюн, бавовну, рис, індиго (рослину, що після переробки давала стійкий синій колір). Розвиток демократичних традицій нерозривно пов'язаний з ім'ям Томаса Джефферсона, просвітни- ка, демократа, політичного та громадського діяча. Він був носієм передових ідей часів Американської революції, які втілив у свою демократичну теорію. Демократизація країни, на думку Т. Джефферсо- на, характеризувалася такими аспектами: поєднан- ням прав окремих штатів та місцевого самовряду- pdf создан испытательной версией pdffactory pro www.pdffactory.com http://www.pdffactory.com № ( ) січень-лютий р. ЕКОНОМІКА вання, суворим дотриманням Конституції, заохочен- ням сільського господарства на противагу торгівлі й промисловості і, насамперед, вірою в розумові здібності простих людей, які обирають владу. Підсумком революції ХvІІІ століття та Війни за незалежність стало завоювання незалежності аме- риканськими колоніями. Перед політичними лідера- ми Т. Джефферсоном, Б. Франкліном, Дж. Адамсом, К. Колденом, Т. Пейном постає питання становлен- ня та розвитку держави. Організацію законодавчої бази Томас Джефферсон уважав своєю головною роботою в цей час. Він розробив основоположні законодавчі документи Сполучених Штатів Амери- ки, серед яких Декларація незалежності, Білль про права, Статут про релігійну свободу у Віргінії. В ос- нові цих документів закладені його просвітницькі ідеї щодо демократичного розвитку країни. Він був при- бічником рівності людей, критикував економічну нерівність народу, англіканську церкву, політичну неправоспрожність деяких прошарків населення. У роботі простежено формування ідеї Томаса Джефферсона, що стосувалася аграрного розвит- ку. Вона базувалася на ідеях англійських філософів Дж. Локка та Монтеск'є. Т. Джефферсону імпонува- ли принципи представницького поділу влади, їх взає- мообмеження, збалансованість і рівновага. Американський демократ стверджував, що саме аграрний розвиток найбільше відповідає амери- канській дійсності. Головною фігурою американсь- кого суспільства повинен стати не промисловець, плантатор чи купець, а дрібний незалежний фермер, який користується всіма політичними правами. Демократичним ідеалом розвитку держави він вважав фермерство як єдину міцну основу респуб- ліканської форми правління. Томас Джефферсон різко критикував суспільний лад, заснований на при- ватному володінні. Уважав, що тільки на американсь- ких землях можливе встановлення "природної спра- ведливості", що означало рівне право кожної люди- ни на володіння землею. У році в проекті Конституції Віргінії Т. Джеф- ферсон запропонував програму повернення до сус- пільних надбань усіх незайнятих земель, які потрібно поділити між небагатими американськими громадя- нами. Передбачалось безкоштовне надання ділян- ки розміром акрів. Це був один із перших доку- ментів революційної пори, де вирішувалось питан- ня політичного устрою тринадцяти незалежних шта- тів. Т. Джефферсоном була висунута концепція, згід- но з якою рівний розподіл земельної власності се- ред працездатного населення держави повинен складати фундамент демократичного устрою. Т. Джефферсон наголошував, що нерівномірне розділення власності й демократія є несумісними поняттями. У листі до Дж. Медісона, професора ко- леджу Уїльяма та Мері, він закликав зробити все можливе для того, щоб обмежити економічну та по- літичну владу плантаторів та магнатів. "Земля на- дається людині як загальний набуток, щоб вона обробляла її та жила на ній" [ ]. Жодна людина не має права на жодний акр землі, самочинне присвоєн- ня землі, що має місце в суспільстві. Надання землі - це міра для заохочення старанності людей, які її обробляють. Зрозуміло, що в демократичній фермерській рес- публіці не має бути ганебного інституту рабства. Американський філософ протягом свого життя та діяльності засуджував використання рабів, перед- бачав, що в майбутньому це може призвести до конфлікту. Ним було розроблено програму поступо- вого відходу від рабства та ліквідації його. Перед- бачала вона таке: - для запобігання розповсюдженню рабства на нових територіях передбачалося заборонити ввезен- ня нових рабів до Сполучених Штатів Америки; - на території держави вже проживала досить ве- лика кількість темношкірих людей, потрібно було ви- рішити їх долю. Томас Джефферсон рішення цієї про- блеми бачив у забезпеченні дітей рабів обов'язковою безкоштовною освітою для того, щоб у дорослому віці вони могли працювати, отримувати гроші та вес- ти життя не гірше, ніж представники білої раси. Американське середовище, умови, в яких виріс Т. Джефферсон (до вісімнадцяти років він не бачив поселення більше, ніж у двадцять будинків), а та- кож спостереження над життям дрібних фермерів із нехитрим самоврядуванням зробили його аграрним демократом. Він уважав, що фермерський шлях розвитку виключає можливість масової убогості; аграрні країни, на відміну від промислових, застра- ховані від виникнення й розвитку політичної корупції, що перетворилася на велику проблему для торго- вельно-промислової Англії. Ним були визначені мо- ральні переваги фермерства: невибагливість, неви- гадливість і простота вдачі. Ідея аграрного розвитку фермерським шляхом при співвіднесенні з американською реальністю мала ряд слабких місць. Панівне становище в сільсько- му господарстві США посідали аж ніяк не фермери, а плантатори-рабовласники. У рамках "джефферсо- нівського аграрного шляху" неминуче мав виникну- ти суперечливий, приречений на розпад альянс плантаторів і фермерів, тому плантаторам відводи- лася керівна роль у створеній під керівництвом Т. Джефферсона республіканській партії. Найпростіше було б назвати аграрну теорію уто- пічною та історично обмеженою частиною філософії Томаса Джефферсона. Один із найбільш видатних теоретиків та практиків демократії небезпідставно пов'язував реалізацію демократичного ідеалу із сільською цивілізацією. Аграрна програма Т. Джеф- ферсона в кінцевому варіанті включала в себе не тільки ідею уведення мінімуму земельного володін- ня та безкоштовного надання землі для всіх грома- дян. Передбачалось обмеження власності латифун- дистів та знищення залишків феодальної системи - прав майорату та першонаслідування. Фермерська програма розвитку країни не була втілена в життя в період американської революції. У - роках фракція великих плантаторів у Вірджинській асамблеї на чолі з Е. Пендлтоном от- римала перемогу, вони домоглися прийняття рішен- ня про розпродаж західного земельного фонду. Уво- дились розміри ділянки, яку можна придбати за низь- кою ціною. Розміри були великими - акрів, що робило неможливим розвиток дрібного фермерства. Менші за розміром ділянки можна було отримати на Заході, де фермери селилися в порядку скватер- ства або за посередництва земельних спекулянтів, на правах орендаторів. У - роках Томас Джефферсон обіймав посаду президента Сполучених Штатів Америки. Він упроваджує необхідні для фермерського шляху розвитку закони щодо надання ділянки землі за зни- женими цінами (з до , доларів) та розмірами (розміри ділянок зменшувались у два етапи - у році з до , потім у році з до акрів). Були ліквідовані деякі сільськогосподарські ІСТОРІЯ pdf создан испытательной версией pdffactory pro www.pdffactory.com http://www.pdffactory.com № ( ) січень-лютий р. ЕКОНОМІКАІСТОРІЯ податки, а саме акцизні збори та прямий податок. Президент пропонував продаж ще менших ділянок, але ця ідея була відкинута членами Конгресу, се- ред яких були представники плантаторів та купців на чолі з Д. Каролліном та Діксоном. Ці реформи були проведені в період першого терміну президен- тства Т. Джефферсона. У період другого терміну його президентства в Сполучених Штатах Америки розвивається промис- ловість, скорочуються господарства дрібних фер- мерів. Президент визнає, що для розвитку держави необхідні і фермери, і підприємці. Вони будуть оп- лотом незалежності держави. Основна його діяль- ність цього періоду була зорієнтована на ліквідацію зовнішнього боргу США перед Англією, скорочення чисельності армії. Томас Джефферсон у році купує землі Луї- зіани у Франції, чим суттєво збільшує територію тодішніх Сполучених Штатів Америки. Великі роз- міри цих земель, за його задумом, дозволяли роз- селитися афро-американцям, європейцям, що пе- реїжджали до Америки, та індіанцям. Нові землі мали врятувати націю від расового конфлікту. Томас Джефферсон виступав проти тиранії та олігархії. Радикальною є його ідея про народну ре- волюцію, що визначається природним правом на- роду зняти озброєним шляхом уряд, який не вико- нує своїх обов'язків, або тирана, котрий знаходить- ся при владі. На початку ХІХ століття фермерська республіка фактично поступилася в позиціях Америці промис- ловців та фінансистів. Фермерам не судилося стати панівним прошарком Сполучених Штатів Америки. Їх чисельність стрімко зменшувалась. Усупереч своїм філософським, демократичним та політичним ідеалам Томас Джефферсон змушений був визнати необ- хідність промислового розвитку для майбутнього існу- вання держави, хоча до року застерігав Амери- ку від згубного, на його погляд, впливу промисло- вості, яка сприяла розвитку корупції та олігархії. Ідеї Т. Джефферсона щодо переваг розвитку США аграрним шляхом та ліквідації рабства були здійснені після завершення громадянської війни - рр. вже президентом Авраамом Лінкольном. Заслуга американського просвітника Томаса Джефферсона в тому, що, починаючи від року, його думки накреслили майже на сто років уперед стратегію прогресивного розвитку американського капіталізму в сільському господарстві, що втілила- ся в році з прийняттям гомстедакту. Висновки . Томас Джефферсон - американський про- світник, філософ, основоположник американської демократії. Його філософія базувалася на ідеях представників англійського та французького Про- світництва. Ним було окреслено демократичний шлях розвитку Сполучених Штатів Америки, за яким визначалася свобода людини та держави, відокрем- лення церкви від держави, усебічне розповсюджен- ня знань, розділення влади на судову, виконавчу, законодавчу та двопартійна система. . В основі демократичної теорії Т. Джефферсо- на знаходились дрібні фермерські господарства. Американський демократ уважав, що фермерів тре- ба наділити всіма політичними правами. На прак- тиці ця ідея виявилася суперечливою, вела до кон- флікту між аграріями та промисловцями. Щоб запо- бігти цьому, Т. Джефферсон відмовляється від неї в період другого терміну президентства. . Головне, чим був відзначений фермерський шлях розвитку держави, це демократизація, котра полягала в позбавленні від феодальних пережитків у вигляді законів першонаслідування, майорату та обмеження земельного володіння. . Для політичної філософії Томаса Джефферсо- на були характерними риси класичного республіка- нізму. Він підкреслював важливе значення грома- дян, які беруть активну участь у політичному житті. Вони є економічно незалежні та освічені. . Заслуга Томаса Джефферсона в історії Сполу- чених Штатів Америки полягає в утіленні демокра- тичних основ у життя американського суспільства законодавчим шляхом. Насамперед, це концепція "життя, свободи та прагнення до щастя" кожної лю- дини, не залежно від соціального стану, віку, статі та кольору шкіри. Вона викладена в Декларації не- залежності. Концепцію "освіти та духовного зростан- ня" викладено Томасом Джефферсоном у Біллі про всебічне розповсюдження знань у штаті Віргінія. Американський просвітник був противником релігій- ного фанатизму й прихильником віротерпимості, сво- боди віросповідання. Статут США р. про релі- гійну свободу містить заклик до свободи віроспові- дання, відокремлення церкви від держави. Демок- ратизація передбачала також усебічну безкоштов- ну освіту громадян. Цю ідею викладено в Біллі про загальну освіту. Ці закони становлять базу амери- канського законодавства до сьогодні. ЛІТЕРАТУРА: . Калашніков В. М. Еволюція інститутів держави і права у північноамериканських колоніях європейських країн (ХvІІ - ХvІІІ ст.) / В. М. Калашніков. - Донецьк : Наука і освіта, . - с. . Газін В. П. Актуальні проблеми сучасності: історія, світо- ва політика / В. П. Газін. - К. : Слово, . - с. . morse j. t. thomas jefferson / j. t. morse. - boston, ; tucker g. the life of thomas jefferson. - vol. -ii / g. tucker. - london, ; randall h. s. the life of thomas jefferson. - vol. -iii / h. s. randall. - new york, ; hildreth r. the history of the united states of america. - vol. i-vi / r. hildreth. - new york, . . Болховитинов Н. Н. США: проблемы истории и совре- менная историография / Н. Н. Болховитинов. - М. : Наука, . - с. . Согрин В. В. Джефферсон: человек, мыслитель, поли- тик / В. В. Согрин. - М. : Наука, . - с. . Севостьянов Г. Н. Томас Джефферсон / Г. Н. Севость- янов, А. И. Уткин. - М. : Мысль, . - с. . Біографії президентів США. Томас Джефферсон [Елект- ронний ресурс] "biography of thomas jefferson // w hite house". - Режим доступу : www. peoples. ru / state / king /usa / jefferson / index. . silvio a. bedini. thomas jefferson: statesman of scilnce / silvio a. bedini. - new york : macmillan ; london : collier macmillan, con. . - xviii, р. references: . kalashnіkov v. m. ( ), evoluciia instytutiv derzhavy i prava u pivnichnoamerykanskykh koloniiakh (ХvІІ – ХvІІІ ст.) [the evolution of institutions of law in the northern american colonies of european countries (xvii – xviii century)], nauka ta osvita, donetsk, p. . hazіn v. p. ( ), aktualni problemy suchasnosti: istoriia, svitova polityka [actual problems of modernity: history, global politics], slovo, kyiv, p. . morse j. t. ( ), thomas jefferson, boston; tucker g. ( ), the life of thomas jefferson, vol. -ii, london; ran- dall h. s. ( ), the life of thomas jefferson, vol. -iii, new pdf создан испытательной версией pdffactory pro www.pdffactory.com http://www.pdffactory.com № ( ) січень-лютий р. ЕКОНОМІКА york; hildreth r. ( ), the history of the united states of america, vol. i-vi, new york. . bolkhovitinov n. n. ( ), ssha: problemy istorii i sovre- mennaya istoriografiya [united states of america: challenges history and modern historiography], nauka, moskow, p. . sogrin v. v. ( ), jefferson: chelovek, myslitel, politik [jef- ferson: the man, the thinker, politician], nauka, moskow, p. . sevostianov g. n. & utkin a. i. ( ), thomas jefferson, mysl, moskow, p. . biography of thomas jefferson, w hite house, available at: www. peoples. ru / state / king /usa / jefferson / index. . silvio a. bedini ( ), thomas jefferson: statesman of scilnce, macmillan, new york, london, xviii, р. tеtіana statsenko farm republic is thomas jefferson's political ideal in the further development of the united states of america american bourgeois revolution of the eighteenth century led to the formation of the independent united states of america. among the leaders who led the fight the special place is occupied by the apostle, the founder of american democracy - thomas jefferson. he sharply criticized the social system that existed in the time of monarchy and was based on private ownership. based on the natural and socio-economic conditions, he proposed the farm development as the best political path of the united states of america. it provided that every person had the equal titles to land. so the democratic theory of thomas jefferson began to form. first of all, it provided the union of small independent farmers in the future. comparing agricultural and industrial countries the social activist jefferson emphasized the benefits of farming which primarily consisted in the absence of corruption at the state level. he saw in farmers the moral contrast to urban residents, especially european residents. the idea of agricultural development concerning the american reality found an obvious sensitiveness. it became evident that the dominant position was not occupied by farmers, but by growers and slaveholders between which the coflict was inevitable in the future. being the president of the united states of america thomas jefferson had gradually to refuse the development of the state according to the farming way for the benefit of industrial economy of the country. the drama of american democrat jefferson was that the agrarian theory in practice was utopian. the democratic and political ideal of jefferson was not to come true because of the relation of class forces of contemporary u.s.a. keywords: farm republic, agrarian way of development, american democracy, thomas jefferson, the history of the united states. © Т. Стаценко Надійшла до редакції . . ІСТОРІЯ УДК ( ): - . " " ПОЛІТИЧНІ ЗАСОБИ РЕГУЛЮВАННЯ СОЦІАЛЬНОГО СКЛАДУ СТУДЕНТСТВА УСРР У -ті роки ХРИСТИНА ХОРУЖЕНКО, кандидат історичних наук, доцент Красноармійського індустріального інституту У статті визначаються та аналізуються основні засоби політичного регулювання соціаль- ного складу студентства УСРР упродовж -х років. Акцентується увага на тому, що запро- вадження політичних репресивних форм та методів регулювання складу студентського за- галу стало наслідком неспроможності вирішення цих питань за допомогою так званої систе- ми "відряджень" та "куріального представництва". Ключові слова: організації студентів, соціально-класові перевірки, пролетаризація ВНЗ, со- ціальний склад. Постановка проблеми. Процеси, що відбува- лися у вищій школі впродовж -х рр., відобра- жали як старі (дореволюційні) прагнення й традиції, так і нові (комуністичні) прояви й тенденції, які див- ним чином певний час існували поряд. Проте по- ступово, крок за кроком дореволюційний уклад життя вищої школи неминуче змінювався під тиском новітніх тенденцій, втрачаючи елементи демокра- тичних здобутків і завоювань. Цей процес знахо- дився в прямій залежності від соціального складу студентства, який на початку -х рр. залишав- ся різночинським і складався з усіх верств соці- pdf создан испытательной версией pdffactory pro www.pdffactory.com http://www.pdffactory.com water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computational mutations, and the role of a histidine in gating sunday, february , a -pos board b access constraints and binding energetics of a potassium channel inactivation gate gaurav venkataraman, deepa srikumar, miguel holmgren. nih, bethesda, md, usa. voltage-activated potassium (kv) channels open an intracellular gate in re- sponse to changes in transmembrane voltage, allowing k þ to permeate at rates near diffusion. in some kv channels, permeation can be interrupted by the n-terminus of the protein acting as a blocking particle, binding at the intracel- lular cavity of the channel and physically obstructing the permeation pathway. despite being tetramers, kv channels require only one bound n-terminus to inactivate. in nature, inactivation is targeted by rna editing, which converts an isoleucine of the intracellular cavity into a valine. the functional conse- quence is a large increase in unbinding kinetics. how does each ‘‘wall’’ of the cavity contribute to the increase in unbinding kinetics of a single bound n-terminus? to address this question we made con- catenated shaker heterotetramers consisting of only one free n-terminus and a single isoleucine to valine mutation at position (i v), mimicking the rna editing site in humans and rodents. surprisingly, the rate of unbinding was the same for individual i v mutations in each wall; each corresponded to a decrease in binding energy of about . rt. in fact, the binding energy de- creased linearly as a function of the number of i v mutated subunits. these results suggest that despite being tethered to a particular subunit, the single in- activation particle has sufficient freedom to interact with position of each subunit with roughly equal probability. where does this freedom come from? it is expected that the inactivation gates enter the cavity through lateral ‘windows’, similarly to k þ . can our single tethered inactivation gate enter through each of the four windows of the protein? we will address this question by making individual cysteine mutations at each window and testing the inac- tivation gate’s binding kinetics after chemical modification. -pos board b gating interactions between the cytoplasmic t domain and pore of a kv channel brian urbani, manuel covarrubias. jefferson medical college of thomas jefferson university, philadelphia, pa, usa. whereas the gating roles of the voltage-sensing and pore domains of kv channels have been extensively investigated, much less is known about the mechanisms governing the regulation of gating by the cytoplasmic t domain. previous work from this lab strongly suggests that the kv . t domain un- dergoes conformational changes directly linked to gating (j. gen. physiol., : - , ); however, the structural basis of the communication between the activation gate and the t domain has remained elusive. to tackle this problem, we applied cysteine scanning mutagenesis, voltage- clamp electrophysiology, double mutant cycle analysis (dmca) and oxidizing reagents to probe specific interactions between the cytoplasmic t domain l helix, the s -s linker and s tail. the energetic impact of the mutations on activation gating is apparently small. by comparison, the energetic impact of the mutations on inactivation gating was significantly greater. dmca of k c(l )þa c(s ) revealed a significant interaction energy ( kcal/ mol), which suggests an interaction between k in the l helix and a in s . supporting this possibility, the currents induced by k c(l )þ a c(s ) are inhibited (~ % of control) by an oxidizing agent (tbuho ), whereas the single mutants are not; and the effect is reversed by the reducing agent dtt. these results indicate the formation of a disulfide bond between the interacting side chains, which is consistent with physical interaction between k (l ) and a (s ). overall, we conclude that regulation of inactivation gating by the t domain involves a physical interaction between the t l helix and the distal segment of s . supported by nih grant r ns (mc). -pos board b is the activation gate closed in kv channel closed-state inactivation? jeffrey d. fineberg, manuel covarrubias. thomas jefferson university, philadelphia, pa, usa. kv .x channel complexes including auxiliary subunits such as dpp -s and kchip undergo preferential closed-state inactivation (csi; baehring and covarrubias, , j physiol, . : - ; fineberg et al., , j gen physiol, in press). however, the molecular basis of csi in kv .x channels remains poorly understood. a key unanswered question of this problem is whether the channel’s activation is actually closed, as csi implies. we have previously proposed that csi results when the activated channel fails to open or simply prefers to close. this hypothesis specifically suggests that the intra- cellular activation gate may adopt a stable closed conformation, even under depolarized conditions that would initially favor the activated ‘‘up’’ state of the voltage sensors. to test this hypothesis, we are exploiting the trapping paradigm previously investigated by holmgren et al. to test the state of the intracellular activation gate ( , j gen physiol, : - ). essentially, if the activation gate closes behind a quaternary ammonium (qa) blocker inside the pore, the blocker cannot exit the pore; effectively, it is trapped. we are expressing the ternary kv . /i c channels (this mutation favors trap- ping) including dpp -s and kchip in xenopus oocytes. then, in the inside- out patch-clamp configuration, we are using a computer-controlled perfusion system to deliver the qa derivative decyltrimethylammonium bromide (c ) to the bath and probe the ability of the channel’s activation gate to trap c in the closed, open and inactivated states. preliminary results show that the trapping paradigm may yield an answer to the central question of this study. if the activation gate is indeed closed during csi, c trapping will only occur when the drug is applied to the conducting channel, but no trapping of c will be observed in the closed and inactivated states. supported by nih grant r ns (mc). -pos board b water at the potassium channel gate: quantum calculations show an oscillation in water structure alisher m. kariev, michael e. green. city college of the city university of ny, new york, ny, usa. quantum calculations on the open gate and the immediately surrounding re- gion of the kv . voltage gated potassium channel show that water adopts two conformations there, one when the ion is present, and another with no ion present. an energy minimum at the gate with no ion allows an ion to enter from the solution; from the gate it repels an ion in the channel pore cavity into the selectivity filter (essentially the ‘‘knock-on’’ mechanism). the pore cavity minimum can then be occupied by the ion moving from the gate minimum, leaving it available for anion from bulk, so the cycle continues. the arrange- ment of water, and the ion hydration, defines the gate energy minimum, and this in turn depends on the highly conserved prolines, especially p ( a pdb numbering), in the pvpv sequence in the gate. absent an energy minimum at the gate an ion entering from solution would be repelled back into solution by the ion in the cavity. furthermore, the ion remains hydrated by water molecules, at least more than in bulk, as it passes through the gate, based on optimizations with the ion at three different positions: ) at the gate position nearest p ) å above ) å below, this position. the open gate maintains very nearly the same protein atom positions throughout. additional calculations will be required to determine the exact interaction en- ergy with an ion in the cavity, and the amount of water that is present in the cavity. optimizations of the system configuration were done at hf/ - gsp level, with atoms ( with the ion). energy was determined using both b lyp/ - g* and bvp / - g*, but the system was too large for free en- ergy determination. -pos board b water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computational mutations, and the role of a histidine in gating alisher m. kariev, michael e. green. city college of the city university of ny, new york, ny, usa. conservation of the pvpv sequence at the potassium channel gate has not been well understood. quantum computations (optimization at hf/ - gsp level) of the gate of the kv . channel that are presented here show that the proline-proline distances (ring atoms) are preserved as the ion moves through the gate. this calculation is supplemented by mutating one of the prolines to valine (p v, a pdb numbering for all residues in this abstract) in the computation, producing a pvvv sequence. water structure changed dramati- cally, as the protein backbone moved inward nearly å, effectively closing the channel; the proline ring n-n distance between diagonally opposite pro- lines dropped from . å (distance from optimization: x-ray distance = . å) to . å, too small to allow passage of a hydrated k þ . this suggests that the prolines play a key structural role, modulating both protein and water structure. furthermore, protonation of h may close the channel. protonation of this histidine shows it moving toward the gate by about å, which should close the gate electrostatically, while deprotonation opens the gate. protonation was calculated with two added protons, the other being accepted by e of the t intracellular moiety. when deprotonated, the histidine does not move as much as å from the x-ray position in the optimization, and is linked to e ; this accounts for the known importance of the t segment in gating. e , also of t , could accept a third proton. there is a salt bridge structure including these residues similar to the one occupying a key position in the pro- ton pathway in the hv channel. 	access constraints and binding energetics of a potassium channel inactivation gate 	gating interactions between the cytoplasmic t domain and pore of a kv channel 	is the activation gate closed in kv channel closed-state inactivation? 	water at the potassium channel gate: quantum calculations show an oscillation in water structure 	water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computation ... examining possible influences of the classics on early american leaders examining possible influences of the classics on early american leaders ronald l. hatzenbuehler reviews in american history, volume , number , march , pp. - (review) published by johns hopkins university press doi: for additional information about this article [ access provided at apr : gmt from carnegie mellon university ] https://doi.org/ . /rah. . https://muse.jhu.edu/article/ https://doi.org/ . /rah. . https://muse.jhu.edu/article/ examining possible influences of the classics on early american leaders ronald l. hatzenbuehler peter s. onuf and nicholas p. cole, eds. thomas jefferson, the classical world, and early america. charlottesville: university of virginia press, . xii + pp. illustrations and index. $ . . on october and , , a renowned group of scholars representing the academic disciplines of art, art history, classics, history, and political science convened at the american academy in rome in order to discuss the influence of the classical world—especially greek and roman texts and artistic forms—on early american leaders. taken together, the authors of this resulting collection seem to agree to disagree on the extent to which individuals like thomas jef- ferson drew lessons from the classics, ranging from “prescriptive” to “merely illustrative” (p. ix) or—as with many of them—a complex mixture of both. three of the essays focus specifically on jefferson: peter onuf’s “ancients, moderns, and the progress of mankind: thomas jefferson’s classical world”; caroline winterer’s “classical taste at monticello: the case of thomas jef- ferson’s daughter and granddaughters”; and richard guy wilson’s “thomas jefferson’s classical architecture: an american agenda.” two prominently feature him in relation to others: maurie d. mcinnis’ “george washington: cincinnatus or marcus aurelius?” and eran shalev’s “thomas jefferson’s classical silence, – : historical consciousness and roman history in the revolutionary south.” onuf and shalev share the perspective that jef- ferson loved the classics—especially in their original languages—but did not draw practical applications from what he read. in onuf’s words, “jefferson’s deepest satisfaction came from the ancients’ languages, not the wisdom of the philosophers” (p. ). in shalev’s, jefferson “saw the classics as a comforting luxury, a source of cerebral pleasure, and a symbol of social and intellectual status” (p. ). when it came to politics, especially, the authors concur that jefferson saw little to be gained from reading the classics because americans were grounding their new country’s government on people’s ability to break from the past and chart new pathways to the future. key to this transformation would be devising how to create a republican form of government based on federalism and progressivism. according to shalev, “classical antiquity was reviews in american history ( ) – © by the johns hopkins university press reviews in american history / march irrelevant to what jefferson considered the american—exceptional—situa- tion” (p. ). perhaps because their essays are more specific in their treatments of jeffer- son’s use of the classics, winterer and wilson find evidence that he borrowed directly from them as he fashioned an educational model for his daughters and granddaughters and when he designed buildings. winterer emphasizes that jefferson relied on the classics as a way of cultivating the development of “women of taste and learning” (p. ). from his travels in europe, jeffer- son saw a world “that was palpably physical and enhanced by the delights of polite society” (p. ), and the objects that he shipped back to monticello formed the nucleus of the world he envisioned for the females in his family. in winterer’s view, ellen randolph coolidge and her sisters were eventually able to break the bands of tradition and leverage their classical upbringings to achieve parity—in at least this one area—with the schooling that men of the time received. for his part, wilson emphasizes that jefferson employed mathematical proportions and hierarchies that he learned from the classics in his architec- tural styles: “jefferson looked very closely at classical precedent and usually followed the rules” (p. ). not only did jefferson rarely deviate from the geometry, composition, and proportion of classical models, but also he wanted his creations to inspire and instruct, as with his design of ten different facades for the professors’ pavilions adjacent to the lawn at the university of virginia. indeed, he helped produce “a cadre of trained architects and workers who could design and build” in the style of classical architectural forms as resur- rected by the treatises of giacomo leoni and charles errand and roland freart de chambray (p. ). two additional essays address the influence of the classics on jefferson less directly. michael p. zuckert’s essay mentions jefferson in the title, but it is less about jefferson and the classics than an argument that he followed lockean natural rights philosophy more than the views of scottish philosopher francis hutcheson (“thomas jefferson and natural morality: classical moral theory, moral sense, and rights”). that said, zuckert argues that, aside from garry wills’ thesis in inventing america, on balance there are few differences between john locke’s emphasis on natural rights and hutcheson’s moral sensitivities. in fact, zuckert concludes that, in hutcheson’s writings, “any notion that the moral sense points to a politics drastically different from that associated with lockean rights theory disappears” and that, by jefferson’s time, locke’s and hutcheson’s views had become compatible due to the writings of david hume, henry home kames, and others (p. ). “george washington: cincinnatus or marcus aurelius” by maurie d. mcin- nis focuses, in the first portion of the essay, on jefferson’s probable influences on jean-antoine houdon’s marble sculpture of washington that stands in the hatzenbuehler / influences of the classics virginia state capitol. according to mcinnis, jefferson in all likelihood met with the famous french sculptor in his paris studio and helped barter the effective combination of “the antique model with washington’s contemporary dress” that makes the sculpture so distinctive (p. ). enhancing support for this in- terpretation is mcinnis’ sensitive handling of the complex and vitally important diplomatic relations between france and the united states during washington’s first administration and jefferson’s willingness to compromise his antipathy for the society of the cincinnati with the need to placate french sensitivities. according to mcinnis, jefferson did this by commissioning a marble bust of the marquis de lafayette wearing the symbol of the society of cincinnati for the city of paris (presented in ) but requested that emblem be removed from houdon’s presentation of washington. the effect, according to mcinnis, is striking because washington appears “as cincinnatus, not washington as a member of the society of cincinnati,” since houdon’s statue presents him as a man relinquishing power (p. ). (in the second part of the essay, mcinnis shows how virginians in the s found the need to recast washington’s image as a military leader and commissioned a sculpture presenting him in the image of roman emperor marcus aurelius to accomplish that purpose.) the other essays in this volume touch indirectly on jefferson but are more expansive in their coverage, including focusing on founders such as john adams, alexander hamilton, and george mason, who embraced classical influences, or thomas paine and benjamin rush, who did not. nicholas p. cole acknowledges that the problem of pinning down the precise influence of the classics on the other founders proves to be as problematic for them as it is for jefferson (“america and ancient and modern europe”). cole finds what he terms “classical motifs” (p. ) to be prevalent in the writings of adams, hamilton, and others, but he expresses doubt that one can automatically as- sume that their readings of the classics or histories of greece and rome carried over directly to their political ideas. according to cole, the classics primarily provided an important backdrop for the founders’ criticisms of the british constitution in the period leading to the american revolution and provided inspiration for their commitment to republicanism. for his part, peter thompson (“aristotle and king alfred in america”) shifts attention from the founders’ attachment to the classics to their interest in “the ancients” more generally, especially “anglo-saxon precedent imagery [that] addressed american population growth and the corruption of government more neatly than greek or roman writing on government” (p. ). especially for jefferson, anglo-saxon precedents more than those of the classics provided “core values . . . that should be transmitted across generations,” including attachment to “the federative principle” (p. ). paul a. rahe (“cicero and the classical republican legacy in america”) and jennifer t. roberts (“pericles in america: the founding era and beyond”) reviews in american history / march concur. in rahe’s telling, patriots like paine and rush had no place for the classics because these stories idealized war, royalty, and titles. this antipathy for ancient stories was especially strong for adams, rahe argues, because rome meant empire and luxury as well as corruption, vice, and venality—callings that eventually brought the romans down: “pride drove the romans to at- tempt the conquest of an empire, and strength and courage enabled them to succeed” (p. ). just because the founders did not read the classics for precedents, how- ever, does not indicate that they did not owe them a debt. rahe emphasizes that the writings of aristotle, cicero, and others “kep[t] alive the memory of self-government through a long epoch in which despotism was the norm . . . . what made the american revolution truly revolutionary was the americans’ commitment to an understanding of man’s inalienable rights that not only distinguished them from the slave-holding, empire-building republicans of the past but also set them in opposition to the ancient example” (pp. – ). as for roberts, pericles and other greek authors played less of a role in revolutionary america than in later generations because they were too demo- cratic for the founders. regarding pericles specifically, roberts argues that he “served as an emblem of the danger of too much power in the hands of one man” during the revolutionary period (p. ); but by the nineteenth and twentieth centuries, orators (especially edward everett) invoked his name as representative “of the newly popular democratic ethos” (p. ). then, in the twentieth century, orators portrayed the athenian statesman as “the champion of an ominous militarism,” which convinces roberts that, both for the found- ers and american leaders in later periods, “modern history impress[es] itself on ancient more often than the other way around” (p. ). in the foreword to the book, andrew jackson o’shaughnessy (saunders di- rector, robert h. smith international center for jefferson studies at monticello) reveals that the authors of these essays circulated their efforts in advance in order to stimulate a discussion of their views. it would have been wonderful to hear these discussions, given the various—and often conflicting—views of the contributors and to have heard whether the give-and-take addressed important topics outside those the authors chose to address. consider, for example, the fact that only a handful of the authors touched on the topic of slavery (thompson, rahe, and mcinnis) and that none addressed the fact that, in notes on the state of virginia, jefferson compared virginian slavery directly to roman slavery. in notes, jefferson concluded, on the one hand, that roman slaves (especially in the augustan age) were much more severely treated than slaves in america; on the other, he conceded that some roman slaves became artists and scientists and were frequently tutors for roman children. “but they were of the race of whites,” jefferson concluded. “it is not their condi- tion then, but nature, which has produced the distinction.” he then observed hatzenbuehler / influences of the classics that it was the color of africans that most differentiated them from roman slaves. consequently, “among the romans emancipation required but one ef- fort. the slave, when made free, might mix with, without staining the blood of his master. but with us a second is necessary, unknown to history. when freed, he is to be removed beyond the reach of mixture” (notes, query xiv). similarly, shalev in his essay calculates that, in the run-up to the revolu- tion, jefferson was “silent” regarding classical references. especially notable for shalev is the fact that in his most important writing during the period to , a summary view of the rights of british america, jefferson “referred to and elaborated an idealized version of anglo-saxon history, and had no reference whatsoever to classical history” (p. ). shalev may be technically correct in this assertion, but it is difficult to believe that when jefferson wrote some passages he was confining his views to the saxons exclusively, as for example: “single acts of tyranny may be ascribed to the accidental opinion of a day; but a series of oppressions, begun at a distinguished period . . . too plainly prove a deliberate, systematical plan of reducing us to slavery.” in short, one wonders if slavery—whether classical or modern—surfaced as a topic for discussion among the conference attendees. finally, a quote from john adams that cole used in his essay from “dis- sertation on the canon and feudal law” ( ), reveals just how difficult it is to try to parse classical references from the texts of the founders. according to adams, american settlers were determined to break from european cor- ruptions that linked church and state: they knew that government was a plain, simple, intelligible thing, founded in nature and reason, and quite comprehensible by common sense. they detested all base services and servile dependencies on the feudal system. they knew that no such unworthy dependencies took place in the ancient seats of liberty, the republics of greece and rome; and they thought all such slavish subordinations were equally inconsistent with the constitution of human nature and that religious liberty with which jesus had made them free. [p. ] except for the religious reference at the end of the quotation, no one in early america would have agreed with adams’ statement more than thomas jeffer- son, which suggests that—perhaps not unlike the authors of these essays—the classics offered lessons for early american leaders that were complex and even, perhaps, contradictory. ronald l. hatzenbuehler is professor of history in idaho state university. he is the author of “i tremble for my country”: thomas jefferson and the virginia gentry ( ). initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart development wednesday, february , a like ursodeoxycholic acid (udca) and tauroursodeoxycholic acid (tudca), are cytoprotective and inhibit cell death. the mechanisms associated with these distinct effects are not entirely clear. however, the effect of hydrophilic bile acids seems to be related with the blockage of a series of processes that converge on mitochondrial damage. bax is a pro-apoptotic protein that belongs to the superfamily of the bcl- proteins and is involved in mitochondrial pore formation. submicellar concentrations of cytoprotective bile acids have been shown to modulate bax concentration in mitochondria, suggesting that these molecules may interact directly with the protein. in this study, our objective was to evaluate the affinity of bile acids to recombinant bax protein, making use of fluorescence spectroscopy (fret and fluorescence anisotropy), as well as fluorescence correlation spectroscopy (fcs). our results show that the cytoprotective bile acids udca and tudca associate with recombinant bax protein with high affinity, while the cytotoxic bile acid dca only seems to be able to adsorb to the protein with much lower affinity. notably, the bind- ing site for udca seems to be located in a hydrophobic pocket of the protein. this interaction could be responsible for the disruption of bax translocation to the mitochondrial outer membrane in the presence of udca and/or tudca. supported from fct/portugal (projects ptdc/qui-biq/ / and reci/ctm-pol/ / ). t.s. and f.f. acknowledges fct grants sfrh/bd/ / and sfrh/ bpd/ / -pos board b mac inhibitors neutralize the pro-apoptotic effects of tbid pablo m. peixoto , oscar h. teijido , laurent m. dejean , evgeny pavlov , bruno antonsson , kathleen w. kinnally . natural sciences, baruch college - cuny, new york, ny, usa, national institute of child health and human development, baltimore, md, usa, chemistry, california state university of fresno, fresno, ca, usa, new york university college of dentistry, new york, ny, usa, merck serono, geneva research center, geneva, switzerland. since our initial characterization of the imacs, different di-bromocarbazole derivatives with anti-apoptotic function have been developed and tested in several mouse models of brain injury and neurodegeneration [ - ]. owing to the increased therapeutic potential of anti-apoptotic di-bromocarbazole de- rivatives, we sought to expand our knowledge of the mechanism of action of these small molecule inhibitors. we investigated the kinetics of mac inhibi- tion in mitochondria from wild type, bak, and bax knockout cell lines using patch clamp electrophysiology, fluorescence microscopy, elisa, and quantita- tive western blot analyses. our results show that imacs work through at least two mechanisms: ) by blocking relocation of the cytoplasmic bax protein to mitochondria and ) by disassembling bax oligomers in the outer membrane. a comparison of the inhibitory effects over channel conductance and cyto- chrome c release suggests that the imacs interacted with both bax and bak with similar kinetics. interestingly, wild type mitochondria were more suscep- tible to inhibition than the bak or bax knockouts. a quantitative western blot analysis showed that wild type mitochondria had lower steady state levels of bak, which suggests an uneven stoichiometry of the mac components. -pos board b tyrosine phosphorylation of mitochondrial ca d uniporter regulates mitochondrial ca d uptake jin o-uchi, stephen hurst, jyotsna mishra, xiaole xu, bong sook jhun, shey-shing sheu. depariment of medicine, center for translational medicine, jefferson medical college, thomas jefferson university, philadelphia, pa, usa. mitochondrial ca þ has a critical role for balancing cell survival and death. ca þ influx into mitochondrial matrix is mediated primarily by the mitochondrial cal- cium uniporter (mcu). however, the signaling pathways that regulate mcu channel functions via post-translational modifications of mcu are completely unknown. here we show that adrenergic signaling induces mcu tyrosine phos- phorylation and accelerates mitochondrial ca þ uptake in cardiac cells. adren- ergic signaling induces activation of proline-rich tyrosine kinase (pyk ) and translocation into the mitochondrial matrix; enhancing the interaction between pyk and mcu, which subsequently accelerates mitochondrial ca þ uptake via pyk -dependent mcu tyrosine phosphorylation. mcu contains tyrosine res- idues ( in the n-terminus, in the pore-forming region, in transmembrane do- mains and in the c-terminus), which are conserved across all eukaryotic species. among them, only of these tyrosine residues (y at n-terminus, y , and y at c-terminus in mouse mcu) remained as potential phosphor- ylation candidate sites for protein tyrosine kinases using phosphorylation predic- tion programs. we mutated these tyrosine residues to phenylalanine and generated non-phosphorylation mimetic mcu mutants (mcu-yfs). we confirmed that only two tyrosine sites were phosphorylated in response to adren- ergic stimulation in situ using cell lines stably expressing mcu-yfs. in addi- tion, overexpression of these mcu-yfs failed to increase mitochondrial ca þ uptake in response to cytosolic ca þ elevation by thapsigargin, whereas wild- type mcu transfection dramatically accelerates mitochondrial ca þ uptake compared to non-transfected cells. in summary, mcu contains pyk -specific phosphorylation site(s) and pyk -dependent tyrosine phosphorylation of mcu can modulate its channel functions and regulate mitochondrial ca þ uptake. -pos board b cardioprotective roles of neuronal ca d sensor- during stress tomoe y. nakamura-nishitani , shu nakao , shigeo wakabayashi . molecular physiology, natl.cer.cardiovasc.ctr., suita, japan, cardiac physiology, natl.cer.cardiovasc.ctrwakabayshi, suita, japan. dysregulation of ca þ homeostasis in cardiomyocytes often results in heart fail- ure. identifying molecular targets that regulate cardiomyocyte survival is of ther- apeutic importance. neuronal ca þ -sensor- (ncs- ) is an ef-hand ca þ - binding protein, which is important for excitable cell functions. we previously found that ncs- -deficient (ncs �/�) mice had excess neonatal mortality (circ. res. ).the aim ofthe present study isto examinewhether ncs- plays beneficial roles in cardiac survival during stress and the possible mechanisms un- derlying these effects. neonatal mouse ventricular myocytes orwhole hearts from wild-type (wt) and ncs �/� mice were subjected to stressors, and the resistance to stress was evaluated. ncs �/� mouse hearts were more susceptible to stress induced by oxidative impairment and ischemia-reperfusion injury. stress- inducedactivationofphosphatidylinositol -kinase (pi k)/akt signaling, a major survival pathway, was substantially reduced in the ncs �/�group, and overex- pressionofncs- ortheconstitutiveactive formofakt increased the survivalrate of ncs �/� myocytes. cellular atp levels, as well as mitochondrial respiration rates (both basal and maximal o consumption) were significantly depressed in ncs �/� myocytes; especially with oxidative stress. furthermore, intracellular ca þ handling was more easily dysregulated in stressed ncs �/� myocytes than wt myocytes. since ncs- levels were increased by stress, the data suggest that ncs- is a survival-promoting factor, which is upregulated by stress stimuli. interestingly, however,supra-physiological ncs- expression was toxic to cells. taken together, our data suggest that moderate ncs- expression during stress promotes cardiomyocyte survival by maintaining proper ca þ handling, which is required for activation of akt survival pathways and mitochondrial function. -pos board b initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart development gisela beutner, george a. porter, jr. pediatrics, university of rochester medical center, rochester, ny, usa. mitochondria in early embryonic hearts are not thought to produce atp, yet they do produce reactive oxygen species (ros) that regulate myocyte differen- tiation. to assess changes in atp and ros generation in the developing heart, we measured mitochondrial oxygen consumption, the activity of the complexes (cx) and of the electron transport chain (etc), etc supercomplex assem- bly, and ros in embryonic mouse hearts. at embryonic day (e) . , mitochon- drial etc activity and oxidative phosphorylation (oxphos) are not coupled, even though the etc complexes are present. we show that cx- is able to accept electrons from the krebs cycle, but enzyme assays that specifically mea- sure electron flow to ubiquinone or cx- show no activity at this early embry- onic stage. at e . , mitochondria appear functionally more mature; etc activity and oxphos are coupled and respond to etc inhibitors. in addition, the assembly of highly efficient respiratory supercomplexes containing cx � , � , and � , ubiquinone, and cytochrome c begins at e . , the exact time when cx- becomes functional activated. at e . , etc activity and oxphos of embryonic heart mitochondria are indistinguishable from adult mitochon- dria. in contrast, generation of reactive oxygen species (ros), as measured with amplex red, is high at e . and drops significantly by e . , coinciding with activation of the etc. in summary, our data suggest that between e . and e . dramatic changes occur in the mitochondria of the embryonic heart, which result in a decrease of ros generation and an increase in oxphos due to the activation of cx- and the formation of supercomplexes. -pos board b the stoichiometry between micu and mcu determines the different mitochondrial ca d uptake phenotypes in heart and liver melanie paillard, györgy csordás, tünde golenár, cynthia moffat, erin seifert, györgy hajnóczky. mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa. mitochondrial ca þ uptake is central to oxidative metabolism and cell death signaling. the first clues to its molecular mechanism have emerged from the recent identification of the mitochondrial ca þ uniporter’s pore forming protein (mcu) as well as its regulators. among the regulators, micu shows striking 	mac inhibitors neutralize the pro-apoptotic effects of tbid 	tyrosine phosphorylation of mitochondrial ca + uniporter regulates mitochondrial ca + uptake 	cardioprotective roles of neuronal ca + sensor- during stress 	initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart de ... 	the stoichiometry between micu and mcu determines the different mitochondrial ca + uptake phenotypes in heart and liver pancan- - -ver -nagle_ p .. case report open access central pancreatectomy with pancreaticojejunostomy for an insulinoma: a case report with literature review ramzy t. nagle,* valerie e. takyi, and charles j. yeo abstract background: insulinomas are a rare entity commonly treated by resection. central pancreatectomy represents an uncommon type of resection for pancreatic lesions. case presentation: a -year-old female underwent a central pancreatectomy with roux-en-y pancreaticoje- junostomy and pancreatic stump oversew after presenting with symptoms of hypoglycemia concerning for an insulinoma. her hospital course was uncomplicated and her symptoms resolved after resection. conclusion: resection of insulinomas is the preferred approach of treatment, and resection by central pancre- atectomy is a safe option for benign lesions in the neck of the pancreas. keywords: central pancreatectomy; ct scan; insulinoma; intraoperative ultrasound; pancreatic neuroendocrine tumor; symptomatic hypoglycemia introduction pancreatic neuroendocrine tumors (pnets) are rare en- tities of the endocrine pancreas with poorly understood progression. pnets represent % of pancreatic neo- plasms and insulinomas account for % of all pnets. insulinomas are commonly sporadic but sometimes arise within the setting of multiple endocrine neoplasia- type . symptoms that accompany insulinomas are re- lated to hypoglycemia and include confusion, dizziness, behavioral changes, seizures, visual disturbances, weight gain, and, in severe cases, coma. resection of pancreatic tumors is determined by lo- cation of the lesion within the pancreatic gland. enu- cleation is the preferred approach to excising pnets; however, tumors that arise in the head of the pancreas are often resected by pancreaticoduodenectomy and lesions arising in the body or tail of the pancreas are typically resected by distal pancreatectomy. central pancreatectomy for lesions in the neck and proximal body of the pancreas is performed much less fre- quently, but has been shown to be a safe operation that preserves maximal pancreatic endocrine and exo- crine function while avoiding the morbidity and mor- tality associated with pancreaticoduodenectomy. in this study, we present a case of an insulinoma resected through central pancreatectomy with pancrea- ticojejunostomy. presentation of case the patient is a -year-old female who presented with symptomatic hypoglycemia in september . she had a - to -year history of syncopal and near- syncopal events. three years prior, she had a neurolog- ical work-up for an episode of seizures, was diagnosed with a seizure disorder, and was started on lamictal. during a recent trip to the emergency department month before presentation, her blood glucose was found to be mg/dl and a computed tomography (ct) scan of the abdomen and pelvis was obtained. although the ct was initially read as normal, there was a hypervascular mass evident in the neck of the pancreas. she underwent a follow-up octreoscan, which was negative. she subsequently had a set of syn- chronous laboratories that were significant for a serum department of surgery, thomas jefferson university, philadelphia, pennsylvania. *address correspondence to: ramzy t. nagle, bs, department of surgery, thomas jefferson university, walnut street, curtis building, suite , philadelphia, pa , e-mail: rtb @jefferson.edu ª ramzy t. nagle et al. ; published by mary ann liebert, inc. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. journal of pancreatic cancer volume . , doi: . /pancan. . journal of pancreatic cancer glucose of mg/dl, a c-peptide level of . ng/ml, and an insulin level of . mcu/l. her carcinoem- bryonic antigen, ca - , and bilirubin levels were nor- mal. she underwent an endoscopic ultrasonography that showed an mm mass thought to be in the head of the pancreas. her ct scan was reviewed at her initial outpatient consultation visit, and she was noted to have a hypervascular mass in the central pancreas with no evidence of dissemination (fig. ). the clinical impres- sion was that she had an insulinoma located in the cen- tral pancreas that was causing her hypoglycemic episodes and symptoms, which were previously attrib- uted to a seizure disorder. the patient underwent central pancreatectomy with roux-en-y pancreaticojejunostomy and right-sided pancreatic stump oversew in september . intrao- perative ultrasonography identified a -mm hypervascu- lar lesion in the neck of the gland (fig. ). enucleation of the lesion was initially attempted; however, it appeared to traverse the entirety of the gland from the anterior to posterior pancreas, taking up most of the neck of the pancreas and dilating the pancreatic duct. given the potential risk of damaging the pancreatic duct in the process, enucleation was abandoned. distal pancreatectomy and an extended whipple procedure were also considered, but the patient would lose a large amount of normal functioning gland with both op- tions. therefore, central pancreatectomy was ultimately chosen as it allowed for the most amount of normal pan- creatic parenchyma to be preserved. the lesion proved to be a well-differentiated low- grade neuroendocrine tumor that stained positive for insulin expression on immunohistochemistry, with negative margins. her postoperative hospital course was uncomplicated and she was discharged on postop- erative day . she remained euglycemic throughout her postoperative course and her seizure medication was discontinued, under the presumption that her seizures were likely because of the insulinoma. during her follow-up visit in the office, she revealed that she was fig. . computed tomography scan at the initial presentation. fig. . intraoperative ultrasonography identified a mm hypoechoic hypervascular mass in the neck of the pancreas. no additional lesions were present. nagle, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . no longer having syncopal events or seizures despite being off her seizure medication, and had begun to lose weight since her operation. discussion the diagnosis of a pancreatic insulinoma can be chal- lenging. nikfarjam et al. found that the most common presenting symptoms of an insulinoma were nonspe- cific and included confusion, visual disturbances, dia- phoresis, fatigue, and weight gain. these symptoms were often present for months before diagnosis. syncope and seizures, which were the presenting symp- toms for our patient, were found to be present in only % and % of patients, respectively. the diagnostic criteria of an insulinoma include low blood glucose, elevated serum insulin, and elevated c-peptide levels. ct imaging has been found to be the most successful technique for preoperative localization of an insulinoma, with a sensitivity of %. intraoperative ultrasonogra- phy was able to detect the lesion in – % of cases. , insulinomas have been found to be relatively evenly dis- tributed throughout the head, body, and tail of the pan- creas. insulinomas in the neck of the pancreas, as in our case, represent only % of all insulinomas. prognosis after resection of an insulinoma is gener- ally very good. bilimoria et al. determined that patients with functional tumors, tumors < cm, node-negative tumors, absence of metastasis, and well-differentiated histology had better -year survival. nikfarjam et al. found that patients with resected insulinomas had a -year disease-specific survival of %. medical management of insulinomas is almost never chosen as the first-line of treatment because of the potential for malignant transformation of an insulinoma, which has been shown to occur in up to % of patients. , the most common procedure to remove a pancre- atic insulinoma is enucleation. , central pancreatec- tomy is rarely performed. for our patient whose tumor was localized to the neck of the gland, we per- formed central pancreatectomy with roux-en-y pan- creaticojejunostomy to preserve maximal pancreatic endocrine and exocrine function. in a study on central pancreatectomy with pancreaticogastrostomy, the most common complication was pancreatic fistula, which was found to occur in up to % of patients; however, these fistulas were able to be managed conservatively with drains. postoperatively, patients were found to be without evidence of pancreatic insufficiency, leading to the conclusion that central pancreatectomy is a safe procedure for benign lesions in the central pancreas. as exemplified in this case report, insulinomas may present with nonspecific symptoms for a long duration of time. localization is best achieved by ct scan and intraoperative ultrasonography. central pancreatec- tomy with pancreaticojejunostomy is a safe option for patients with insulinomas located in the neck of the pancreas. author disclosure statement no competing financial interests exist. references . bilimoria ky, talamonti ms, tomlinson js, et al. prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of patients. ann surg. ; : – . . nikfarjam m, warshaw al, axelrod l, et al. improved contemporary sur- gical management of insulinomas: a -year experience at the massa- chusetts general hospital. ann surg. ; : – . . efron dt, lillemoe kd, cameron jl, et al. central pancreatectomy with pancreaticogastrostomy for benign pancreatic pathology. j gastrointest surg. ; : – . . vaidakis d, karoubalis j, pappa t, et al. pancreatic insulinoma: current issues and trends. hepatobiliary pancreas dis int. ; : – . cite this article as: nagle rt, takyi ve, yeo cj ( ) central pan- createctomy with pancreaticojejunostomy for an insulinoma: a case report with literature review, journal of pancreatic cancer : , – , doi: . /pancan. . . abbreviations used pnets ¼ pancreatic neuroendocrine tumors ct ¼ computed tomography publish in journal of pancreatic cancer - immediate, unrestricted online access - rigorous peer review - compliance with open access mandates - authors retain copyright - highly indexed - targeted email marketing liebertpub.com/pancan nagle, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . http://www.liebertpub.com/pancan#utm_campaign=pancan&utm_medium=article&utm_source=advert www.ecmjournal.org j melrose et al. murine spine models abstract disc degeneration and associated back and neck pain elicits a substantial burden on healthcare systems and the individuals affected, necessitating the development of novel therapeutic strategies. this goal can only be achieved by a better understanding of intervertebral disc development, homeostasis and pathogenesis. a number of genetic and in-bred murine models are reviewed to underscore the importance of the mouse as an animal model of choice for the assessment of intervertebral disc pathobiology. appraisals of the differences between mouse and human musculoskeletal systems and proteoglycan structures are also included. a number of important target pathways and molecules have been identified, many of which are worthy of further examination, requiring that the activity of these be confirmed in large animal models and assessed in the context of therapeutic intervention. keywords: murine model, intervertebral disc, nucleus pulposus, annulus fibrosus, spine. *address for correspondence: makarand v. risbud, phd, department of orthopaedic surgery, thomas jefferson university, walnut street, suite college bldg., philadelphia, pa , usa. fax number: + email: makarand.risbud@jefferson.edu copyright policy: this article is distributed in accordance with creative commons attribution licence (http://creativecommons.org/licenses/by-sa/ . /). european cells and materials vol. (pages - ) doi: . /ecm.v a issn - g e n e t i c m u r i n e m o d e l s o f s p i n a l d e v e l o p m e n t a n d d e g e n e r at i o n p r o v i d e va l u a b l e i n s i g h t s i n t o i n t e rv e r t e b r a l d i s c pat h o b i o l o g y j. melrose , , ,§,*, s. tessier , ,§ and m.v. risbud , ,* research associate, kolling institute of medical research and the institute of bone and joint research, north sydney area health authority, university of sydney at the royal north shore hospital, st. leonards, new south wales , australia department of surgery, northern clinical school, university of sydney, australia professor graduate school of biomedical engineering, the university of new south wales, australia lewis katz school of medicine, temple university, philadelphia, pa, usa department of orthopaedic surgery, sidney kimmel medical college, thomas jefferson university, philadelphia, pa, usa graduate program in cell biology and regenerative medicine, jefferson college of life sciences, thomas jefferson university, philadelphia, pa, usa § these authors contributed equally to this work list of abbreviations adamts a disintegrin and metalloproteinase with thrombospondin motifs af annulus fibrosus akr b aldo-keto reductase family member b alpl alkaline phosphatase ank ankyrin ap- activator protein aqp aquaporin- arp / actin-related proteins / atm ataxia-telangiectasia mutated kinase b gat beta- , -glucuronyltransferase bach- btb and cnc homology- bgn biglycan bmp bone morphogenic protein bnip blc interacting protein ca carbonic anhydrase can aggrecan ccl monocyte chemoattractant protein- , aka mcp- cd cluster of differentiation cdk cyclin-dependent kinase cep cartilaginous endplates chm chondromodulin i col a collagen type i alpha chain col a collagen type ii alpha chain cox- cyclooxygenase- cs chondroitin sulphate j melrose et al. murine spine models www.ecmjournal.org ctgf connective tissue growth factor e f elongation factor enpp ectonucleotide pyrophosphatase/ phosphodiesterase ent equilibrative nucleoside transporter ercc excision repair endonuclease non-catalytic subunit erk extracellular signal-regulated kinase fasl fas ligand fgf fibroblast growth factor fgfrs fibroblast growth factor receptors flnb filamin b fmod fibromodulin foxa / forkhead box a /a foxo / / forkhead box o /o /o gag glycosaminoglycan gal d-galactose galnac n-acetylgalactosamine gdf growth differentiation factor glca glucuronic acid glcnac β - d-n-acetylglucosamine glcua glucuronic acid ha hyaluronic acid has hyaluronan synthase hif- / α hypoxia-inducible factor alpha/ alpha ho- haem oxygenase- hox homeobox hs heparan sulphate hspg perlecan igd interglobular domain igf- insulin-like growth factor igfr insulin-like growth factor receptor il- rn interleukin receptor antagonist il- α/β interleukin alpha/beta il- interleukin- ivd intervertebral disc jnk / jun n-terminal kinase / ks keratan sulphate lamshf lamb-shaffer syndrome ldl low density lipoprotein ldlr low density lipoprotein receptor lp link protein lrp low-density lipoprotein receptor- related protein mapk mitogen-activated protein kinase mcp- monocyte chemoattractant protein- mct monocarboxylate transporter mkx mohawk mmp matrix metalloproteinase mt -mmp membrane type -matrix metalloproteinase, aka mmp mtor mechanistic target of rapamycin nf- neurofibromatosis type nfat nuclear factor of activated t-cells nf-κb nuclear factor kappa-light-chain- enhancer of activated b cells noto homeobox protein notochord np nucleus pulposus orebp osmotic response element binding protein p cyclin-dependent kinase inhibitor a pax / paired box / phlpp ph domain leucine-rich repeat protein phosphatase prg lubricin pt pintail ptch patched qtl quantitative trait locus ras rat sarcoma rb retinoblastoma transcriptional corepressor rhamm receptor for ha-mediated motility scx scleraxis sd danforths short tail shh sonic hedgehog skt sickle tail slc a sodium- and chloride-dependent taurine transporter slrp small leucine-rich proteoglycan smad mothers against decapentaplegic homologue smo smoothened sox / / sry-related hmg box / / sparc secreted protein acidic and rich in cysteine t brachyury tc truncate tgfb tgf-β type ii receptor tgf-β transforming growth factor beta tnf-α tumour necrosis factor alpha tnmd tenomodulin tonebp tonicity enhancer binding protein tsc tuberous sclerosis complex vegf vascular endothelial growth factor wnt wingless/integrated introduction insight into disc pathobiology through the murine model the murine model is an invaluable experimental tool for the investigation of several degenerative human conditions. studies of a number of genetically modified mice have contributed immensely to our understanding of spinal development and homeostasis (table - ). indeed, manipulations of the mouse genome through mis-expression, knocking- out, knocking-in, or the introduction of mutations into genes, as well as inbred mouse models, have transformed our understanding of spinal development and the complex functional properties of the ivd. in many cases, such mutants are also genetic models of relevant human degenerative disorders characterised by, for example, reduced bone mass (osteopenia, osteoporosis) or abnormalities in endochondral bone formation affecting development www.ecmjournal.org j melrose et al. murine spine models and growth of the skeleton (chondrodysplasias). the value of the murine model is further underscored by the high conservation of skeletal development between mice and humans, despite differences in skeletal size and time required for reaching skeletal maturity. from a regenerative perspective, understanding the regulatory molecules that are operative during such developmental processes provides information applicable to therapeutic tissue repair strategies (tessier and risbud, ). moreover, the development of quantitative histopathological scoring schemes for murine ivds have further increased the utility of the murine model for pathobiological evaluations. it is within this context that we have summarised numerous studies, whose insightful conclusions relied heavily upon the use of the mouse as an experimental model. intervertebral disc structure and comparative anatomy the spinal column was evolutionarily preceded by the notochord, a rod-like structure that provided protection to the underlying neural tube and mechanical support to the chordate organism. in higher vertebrates, which possess the advantage of distinct spinal joints (syndesmosis/symphysis) consisting of mineralised vertebral bodies joined by ivds, the notochord exits as merely a transient embryonic structure. while transient, it is crucial for mechanical support and morphogenic signalling during development. its fate is to give rise to the np, a tissue found at the centre of the ivd, distinguished for its gel-like appearance on gross examination, high proteoglycan content, and load-bearing properties. the uniqueness of the np is further exemplified by its microenvironmental conditions (i.e. hyperosmolarity, hypoxia and loading), which have guided the focus of research efforts in the quest of delineating the molecular mechanisms that underly np cell survival. such salient discoveries, facilitated by the mouse model, will be discussed in this review. the circumferential disc tissue that surrounds the np is called the af. under the microscope, the collagenous lamellae so characteristic of the af are conspicuously prominent and show a graded transition between the inner-most and outer-most regions. af cells, or annulocytes, also differ morphologically by regional location along the af (bruehlmann et al., ). together, the np and af make up the bulk of disc tissue. also important to disc anatomy are the thin layers of hyaline cartilage that form the superior and inferior boundaries, called the ceps. it is their presence that prevents the disc from applying its biomechanical forces directly against the vertebral bone. the ceps, due to their porous nature, permit diffusion and exchange of nutrients and metabolites between the vascular beds in subchondral vertebral bone and avascular compartments of the disc. this is a process facilitated by the diurnal loading and unloading of the spinal motion segments. the disc, along with the adjoining vertebrae, forms a complex polyaxial, diarthrodial joint that allows for wide ranges of -dimensional movement (shapiro et al., ). the murine ivd shares the structural characteristics described above with that of humans. an important difference to highlight, nonetheless, is that notochord- like np cells persist longer in the murine model than in humans. the murine and human ivd are embryonically derived from the aggregation of the notochord and perinotochordal mesenchyme during vertebral column development. notochordal cells produce a matrix rich in proteoglycan, important for generating central swelling pressure in the developing ivd and essential for normal np formation (adams et al., ). in humans, within to years of age after birth, the notochordal cells of the disc disappear or undergo significant morphological changes, whereas they persist throughout adulthood in the healthy murine system (trout et al., ). human np cells acquire a round, chondrocytic appearance as they age, becoming increasingly dispersed throughout the matrix. by contrast, the adult vacuolated np cells of the healthy mouse disc assemble into a central band. for reference to the histomorphology of human disc tissue, please consult the studies cited here (boos et al., ; rutges et al., ). notochordal np cells are large and vacuolated, often forming groups and clusters and described as a physaliforous cell type (pandiar and thammaiah, ). they are relatively quiescent with regards to proteoglycan metabolism, but have a marked influence on the metabolism of proteoglycans within the np (aguiar et al., ). a series of mouse mutants with defective notochordal development such as the brachyury curtailed (stott et al., ), truncate (tc) (theiler, ), pintail (pt) (hollander and strong, ), and sickle tail (skt) (semba et al., ) allow for testing of the relationship between disc health and notochordal cell defects. these mutants show acceleration in age onset-ivd degeneration correlated with the loss of notochordal cells from the np. in severe cases, the np actually does not develop (table ). accordingly, vacuolated notochord-like np cells are typically associated with a healthy ivd. there are other differences between humans and the murine system that should be taken into account. unlike humans, for one, the quadrupedal mouse does not ambulate vertically. quadrupedalism subjects the horizontally oriented spine to greater amounts of axial compression stress, which results in higher trabecular bone density when compared to humans. nevertheless, both murine and human spines are primarily loaded along the cephalic-caudal axis, and the lumbar discs of both species are loaded by ground-reactionary and endogenous forces (smit, ). the lumbar vertebrae and discs, too, are the largest in both species. when geometry is normalised, the average compressive and torsional stiffness of the murine disc is quite similar to that measured in humans (elliott and sarver, ). another obvious difference is that the mouse has an additional j melrose et al. murine spine models www.ecmjournal.org table . mouse spinal models assessing the effects of mutations in genes to morphogens, regulatory signalling molecules, and transcription factors. acancreert sox fl/fl severe degeneration of all disc compartments. matrix remodelling, cell death, and compartment-specific transcriptomic changes. henry et al., tsingas et al., pax- / double knockout vertebral column and disc defects; sclerotomes fail to undergo chondrogenesis. peters et al., mkx knockout af degeneration. nakamichi et al., bach- knockout protective effects on annular puncture. ohta et al., col a cre;foxo fl/fl; foxo fl/f; foxo fl/fl progressive increase in np cellularity. marked degeneration by months. kyphosis. alvarez-garcia et al., acancreert ;foxo fl/fl; foxo fl/f; foxo fl/fl marked disc degeneration by months of age. alvarez-garcia et al., hoxd- knockout & hoxb- knockout transformation of atlas and axis of the craniocervical joint, deletion of dens and superior facet joints, axis shows atlas like characteristics. condie and capecchi, ) ramfrez-solis et al., hox- knockout & hox- knockout lumbar vertebrae do not develop in hox- knockouts, sacral vertebrae do not develop in hox- knockouts; associated downline abnormalities in ivd development. wellik and capecchi, shhgfpcre;smofl/fl defective notochord sheath formation, axial patterning, and ivds. choi and harfe, wnt/β-catenin knockout reporter (topgal) deterioration of the gp and af when β-catenin is overexpressed in both col a and col a -expressing cells; accelerated subchondral bone formation when β-catenin is deleted in col a -expressing cells. dahia et al., kondo et al., notocre;ccn fl/fl age-associated degeneration of ivds, decreased levels of aggrecan and type ii collagen, and increased levels of type i collagen within the np. bedore et al., col acre;tgfbr fl/fl mutant embryos with irregularities in the size and shape of vertebrae. the intervertebral discs were either completely lost or reduced in size due to af defects. baffi et al., , acancreert ;tgfbr fl/fl progressive degenerative phenotype with calcifications in the disc space by months of age. alkhatib et al., smad- knockout spinal malformations and kyphosis, changes in cep structure, and decreased ivd proteoglycan and collagen content. li et al., igf r haploinsufficiency accelerated disc degeneration. li et al., gdf- knockout reduced proteoglycan content. li et al., model phenotype/insight references pintail (pt) and truncate (tc) mouse models premature truncation of notochord /development of the vertebral column, loss of notochordal cells. accelerated age onset disc degeneration. total absence of np at all levels in the sd knockout mouse. hollander and strong, theiler, skt sickle tail mouse skt is a gene linked to the danforth sd short tail locus, required for correct ivd development. size of np in wt mouse is normal until birth, after birth the skt np does not expand and is dislocated to the periphery, resulting in a kinky tail phenotype in the adult. semba et al., foxa knockout defective node and notochord formation; secondary impairment of dorsal-ventral neural tube patterning. ang and rossant, foxa -/-;foxa c/c; shhcreert double mutant defective notochord sheath, deformed np, cell death, and reduced shh signalling; secondary impairment of dorsal- ventral neural tube patterning. maier et al., t deficiency homozygous null: lack notochord, abnormal somites, allantois defect, lethal. haploinsufficiency: short-tailed phenotype. stott et al., noto deficiency disruption of the caudal notochord. the autosomal recessive mutation in the mouse is known as truncate (tc). ben abdelkhalek et al., tonebp deficiency homozygous null: delayed spinal development and expression of notochord markers. haploinsufficiency: accelerated age-dependent degeneration, matrix fibrosis, alterations to the actin cytoskeleton, and decreased expression of proinflammatory genes. tessier et al., , b mitoqc reporter np cells possess numerous tubular and hypoxia-responsive mitochondrial networks that undergo increased mitophagy with ageing. madhu et al., mct knockout disc degeneration with increased aggrecan degradation, mmp , and type x collagen levels. silagi et al., foxa cre; hif- αfl/fl shhcre; hif- αfl/fl notochordal cell loss and severely prominent fibrosis of the disc by month of age. wu et al., merceron et al., tnmd-/- tnmd-/-;chm -/- increased angiogenesis and macrophage invasion of the outer af; accelerated disc degeneration including hypertrophic cells residing in the np compartment. lin et al., sox / double knockout defective notochord sheath formation, apoptosis of notochord cells, and spine lacking np. smits and lefebvre, sox knockout notochord disintegration and disc degeneration. barrionuevo et al., col a cre; nf fl/fl progressive scoliosis and kyphosis with ivd defects. wang et al., tsc knockout congenital spinal defects. yang et al., col a cre; jnk fl/fl/jnk -/- severe, early onset scoliosis with disc fusions. ulici et al., phlpp knockout preserves cellularity and matrix homeostasis in an injury model. zhang et al., ercc deficiency advanced age-related degenerative changes in the vertebral bodies and intervertebral discs, including reduced proteoglycan content, increased apoptosis, and increased p . vo et al., tnfα overexpression (tg and htnfαtg) compromised vertebral bone parameters, greater propensity for herniations at the ep/af junction, evidence of af defects, expanded np cell band. gorth et al., , il- α/β double knockout evidence of af degeneration. gorth et al., acancreert ; p ink a decreased senescence markers with age-dependent degenerative changes. novais et al., il- rn knockout spinal abnormalities. phillips et al., vertebra at the thoracic and lumbar spinal levels, one vertebra less at the sacral level, and up to coccygeal/tail vertebrae. the tail vertebrae and discs have morphological features that differ from the lumbar segments likely due to differences in weight- bearing loads (elliott and sarver, ). in addition, there are important species-dependent differences in the structure of disc proteoglycans, which will be addressed in the following section. consideration of differences between murine and human proteoglycans high proteoglycan content, most notably aggrecan, is a hallmark feature of the healthy ivd, as it provides the tissue with robust load-bearing properties. structurally, the aggrecan core protein comprises globular domains: g and g , positioned at the n-terminal end, and g , positioned at the c-terminal end. the g and g domains are separated by an www.ecmjournal.org j melrose et al. murine spine models fig. . schematic depictions of the structural organisation of aggrecan, perlecan, and their ks-ii and cs chains. these schematics should be viewed as generic depictions based on reported structural data. the depictions shown are for human (a) aggrecan and (b) perlecan; murine aggrecan has a truncated ks rich region and domain iv of murine perlecan also has a kda truncation (farach-carson et al., ). (b) n- and o-sulphation positions of an hs disaccharide of perlecan in a highly modified region of the hs chain are also shown. note: while perlecan is referred to as an hs-proteoglycan, intervertebral disc cells synthesise a hybrid form where at least one of the hs chains is replaced by a cs chain. (c) typical regions of mono-, di- and non-sulphated regions of ks-ii are shown along with possible fucosylation and neuraminic acid regions (caterson and melrose, ). (d) the cs disaccharides of aggrecan are heterogenous with regard to their sulphate distributions. j melrose et al. murine spine models www.ecmjournal.org igd and the g and g domains are separated by an extended region. the extended region contains a ks attachment domain and cs attachment domains (cs- , cs- ). during its synthesis, several o-linked oligosaccharides on the aggrecan core protein are extended to form ks chains, while cs is attached by a tetrasaccharide linkage region of glca-gal-gal- xyl. several aggrecan molecules attach to ha by their g domains and lp, forming a supramolecule that holds a huge density of electro-negative charges (fig. a,c,d). these charges attract water and ions into the disc compartment through the gibbs-donnan effect, creating a hyperosmotic niche within which the resident cells must survive (silagi et al., b). unlike human aggrecan, the murine aggrecan core protein is truncated and largely devoid of a ks-rich region. complete sequencing of the murine core protein (walcz et al., ; watanabe et al., ) shows that it does not contain the consensus sequences for attachment of ks as found in human aggrecan core protein (e-(e,k)-p-f-p-s or e-e-p-(s,f)- p-s) (antonsson et al., ; doege et al., ). core protein sequencing data thus explains the reduced ks content of rodent aggrecan compared to other species (stevens et al., ; venn and mason, ). while the ks-attachment region is shorter in murine aggrecan, some ks in the igd of mouse aggrecan is thought to be present (fosang et al., ). it should be noted that species-specific differences have been demonstrated in the amino acid sequences of the aggrecan igd (flannery et al., ). these differences can have consequences on the susceptibility of this region to proteolysis by adamts- / and mmps (lark et al., ; little et al., ). yet still, the mouse aggrecan core protein ( - kda) shares . % homology with human aggrecan, and the g , g , and g domains are homologous (walcz et al., ; watanabe et al., ). in addition, the spatio-temporal distribution of aggrecan in murine disc and cartilages is similar to that observed in humans, suggesting that murine aggrecan has similar weight-bearing roles in joint tissues despite the aforementioned subtle differences in structural organisation. some differences are also evident in the gag substitution pattern of human and murine perlecan, the hs proteoglycan found in disc and cartilage (knox et al., ; melrose et al., ; melrose et al., ). perlecan has domains, labelled i-v, where domains i and v may be substituted with hs or cs (fig. b). domain i, a domain unique to perlecan, is the main region of gag substitution and contains a cluster of potential attachment sites, while domain v has additional gag attachment sites (costell et al., ; tapanadechopone et al., ). furthermore, domain iv of mouse perlecan contains less igg repeats than human perlecan. consequently, its core protein is ~ kda smaller than the human counterpart (kallunki and tryggvason, ; noonan et al., ). mouse perlecan also contains an rgd cell attachment sequence in domain iii, which is absent in human perlecan (chakravarti et al., ), although a cell adhesion site in domain iv has been identified in human perlecan (farach-carson et al., ) indicating that the overall functionality of the molecule is preserved between the species. while results obtained from murine ivds should be interpreted with these points in mind and with regard to genetic background, the ease with which the mouse can be genetically manipulated and the abundance of knowledge the murine model has offered strongly outweighs the differences described above. murine model systems transcription factors the formation of the notochord during embryonic development requires the coordinated action of many transcription factors (tessier and risbud, ). among these, foxa (ang and rossant, ), t (stott et al., ), and noto (ben abdelkhalek et al., ) are instrumental as their absence results in failure of notochord formation and np development. the loss of a notochord in foxa null mice is lethal, precluding the study of foxa and foxa and their roles in ivd formation. nevertheless, by using a conditional foxa allele in conjunction with a tamoxifen inducible cre allele (shhcreert ), foxa was removed from the notochord of e . mice, which were also null for foxa . these double mutant animals had defects in the notochord sheath, severely deformed np, increased cell death in the tail, decreased shh signalling, and resultant disruption of dorsal-ventral patterning of the neural tube. notably, embryos that were foxa null or that had foxa conditional deletion alone did not show abnormalities in the ivds, demonstrating functional redundancy (maier et al., ). once the embryonic spine has successfully developed, the maturing notochordal-np cells produce a proteoglycan-rich matrix that creates a hyperosmotic niche for resident cells. seminal studies conducted by tsai et al. revealed that the osmoadaptive transcription factor, tonicity enhancer binding protein (tonebp aka nfat or orebp), is required for survival of np cells under these hyperosmotic conditions (tsai et al., ). tonebp modulates intracellular concentrations of organic osmolytes and the hyperosmotic environment by controlling the transcription of osmosensitive and matrix-related genes such as slc a , akr b , aqp , acan, b gat , and col a (gajghate et al., ; johnson et al., ). tonebp has also been shown to regulate pro-inflammatory genes including cox- (choi et al., a), il- , and ccl (johnson et al., ). the understanding of tonebp in disc homeostasis has been elaborated upon by recent studies of tonebp- deficient mice. while complete ablation of tonebp is perinatally lethal with most embryos dying around e . , embryonic investigations have revealed that tonebp loss causes developmental delay of the spinal column and aberrant levels of the notochord markers shh, t, ca , and vimentin. interestingly, this study www.ecmjournal.org j melrose et al. murine spine models raised an interesting possibility that shh receptor ptch is a transcriptional target of tonebp (tessier et al., ). subsequent studies of adult tonebp haploinsufficient mice showed accelerated age-related disc degeneration and matrix fibrosis, with greater propensity for annular and endplate herniations. moreover, tonebp haploinsufficient mice displayed disc compartment-specific effects evidenced by increased expression of actin cytoskeleton-related genes in af cells and reduced expression of immune and pro-inflammatory genes in np cells (tessier et al., b). an important determinant of the np niche is its avascular and hypoxic nature. this notion of limited oxygen availability has led to the general belief that np cells primarily produce energy via glycolysis with little dependence on mitochondrial metabolism. remarkably, however, recent investigations of mitoqc reporter mice have conclusively shown that np cells possess mitochondrial networks consisting of numerous tubular mitochondria which undergo increased mitophagy with aging, emphasising the importance of the mouse model as a key investigational tool. furthermore, mitochondrial fragmentation, morphology, and mitophagic flux was shown to be mediated by hif- α and mitochondrial receptor bnip (madhu et al., ). among its numerous functions, hif- α regulates np cell metabolism under hypoxic conditions by coordinating interactions between glycolysis and the tca cycle (madhu et al., ). hif- α also contributes to the transmembrane balance of high intracellular h+ and lactate concentrations by mediating expression of mct (silagi et al., ) and the bicarbonate recycling enzymes carbonic anhydrase and (silagi et al., a). mct null mice show classical signs of disc degeneration with increased aggrecan degradation, elevated mmp , and collagen x levels (silagi et al., ). as one would thus expect, analyses of the ivds of hif- α conditional knockout mice in either shh or foxa expressing cells has demonstrated early-onset postnatal degenerative features with notochordal cell loss and severely prominent fibrosis (merceron et al., ; wu et al., ). hif- α also regulates galectin- , a highly expressed lectin in the ivd. while its in vivo role in this tissue is poorly understood, in vitro studies suggest that galectin- promotes np cell survival under conditions of oxygen deprivation. in np cells, suppression of galectin- activity promotes the expression of fasl, an inducer of apoptosis, suggesting that this hif- α-regulated lectin plays a role in np cell survival (zeng et al., ). hif- α and hif- α have also been shown to negatively regulate the expression of ank and thereby control local levels of pyrophosphate, an important inhibitor of tissue mineralisation (skubutyte et al., ). therefore, the hypoxic environment and the consequent role of hif transcription factors is critical to the np cell identify and function. the importance of low oxygen tension is further accentuated by recent investigations of tnmd-null mice. tnmd is an anti-angiogenic factor with robust af expression, especially by the outer annulocytes. its loss (tnmd−/−), as well as a double knockout with its homologue, chondromodulin i (tnmd−/−;chm −/−), results in vascular invasion of the af tissue, macrophage infiltration, and accelerated disc degeneration with hypertrophic cells. the double knockouts show greater progressive changes including ectopic bone formation (lin et al., ). central regulators of spinal development and skeletogenesis include a number of sox transcription factors. sox and sox / have been shown to cooperate via super-enhancers to drive chondrogenesis (liu and eronique lefebvre, ); hence, these three sox proteins are often referred to as the sox trio. the importance of the sox family members is made apparent by the various human skeletal diseases caused by their heterozygous mutations. mutation of a copy of sox or disturbance to its regulation causes campomelic dysplasia (wunderle et al., ); haploinsufficiency of sox causes lamshf, a neurodevelopmental disorder associated with variable skeletal abnormalities (lamb et al., ). while sox / are functionally redundant, their dual ablation prevents formation of the notochord sheath, evidenced by notochordal and peri-notochordal downregulation of collagen ii, versican, and aggrecan. these aberrations are also met by subsequent apoptosis of notochord cells and culminate in formation of a severely defective spine lacking np (smits and lefebvre, ). similarly, mouse embryos null for sox show notochord disintegration as early as e . (barrionuevo et al., ) and deletion of sox in the disc (acancreert sox fl/fl) results in degeneration (henry et al., ). early degeneration of the cep is the first conspicuous change seen in acancreert sox fl/fl mice, followed by degeneration of all disc compartments and severe disc collapse involving apoptosis and progressive loss of disc cells. importantly, transcriptomic profiling indicated that sox has distinct compartment- specific functions (tsingas et al., ). the sox trio also works with paired box transcription factors pax and pax , which are essential for af development (peters et al., ; sivakamasundari et al., ). despite the key importance of the sox genes in disc homeostasis and skeletogenesis, the precise roles that many of these transcription factors play in the adult disc remain elusive, representing a necessary avenue for future investigations. in addition to pax / and the sox trio, among others, the mkx and scx transcription factors are key to af development. lineage tracing studies have shown that an af multipotent progenitor population co-expressing sox and scx contribute to the formation of the inner and outer af (sugimoto et al., ). furthermore, lineage studies have revealed that scx-expressing cells drive af regeneration after annular puncture of neonatal discs. this finding offers an interesting direction for future disc regeneration therapies, highlighting the importance of genetic j melrose et al. murine spine models www.ecmjournal.org lineage tracing studies in mice (torre et al., ; torre et al., ). by a similar token, complete knockout of mkx results in smaller collagen fibril diameter in the outer af and early onset disc degeneration. transplantation of mkx-overexpressing mscs into the injured af of a tail-loop mouse model was shown to promote af regeneration with abundant collagen fibril formation (nakamichi et al., ). it is worth noting here that mice deficient in the transcription factor bach- are less impacted by annular puncture. bach- deficiency results in increased levels of ho- , which protects disc cells from oxidative stress (ohta et al., ). recent investigations by alvarez-garcia et al. revealed that all compartments of the ivd express foxo , foxo , and foxo . downregulation of foxo levels, notably foxo and foxo , was observed during aging, preceding major degenerative changes seen on histology (alvarez- garcia et al., ). simultaneous knocking out of these three foxo isoforms using col a cre resulted in a progressive increase in np cellularity, due to increased proliferation, and an associated increase in disc height. by and months, these discs began to show marked features of degeneration and a severe kyphosis. interestingly, analysis of acancreert driven triple knockout at skeletal maturity showed degenerative changes more conspicuous in the np than the af, while analysis of single gene knockouts showed that foxo and foxo are the dominant members, playing a role in mediating autophagy and antioxidant defences in np tissues (alvarez-garcia et al., ). development of the axial skeleton relies on the tight spatio-temporal control of hox transcription factors. the hox genes that encode these factors differentially control the proliferation rates of the mesenchymal condensations that give rise to the vertebral cartilages. for instance, mutations in the homeobox containing gene hoxb- (hox . ) causes overt changes in the axial skeleton that are characterised by a transformation of the second cervical vertebra from axis to atlas (ramfrez-solis et al., ). similarly, hoxd- gene (hox- . ) disruption causes anterior transformations of the atlas and axis and a drastically remodelled craniocervical joint (condie and capecchi, ). the hox and hox genes are also involved in the global patterning of the axial and appendicular skeleton. lumbar vertebrae fail to develop with loss of hox , while loss of hox results in formation of lumbar vertebrae in the place of sacral vertebrae (wellik and capecchi, ). cell signalling pathways an intricate balance of morphogenic signals is required for proper embryonic development of the ivd. a centrally important morphogen in this process is notochord-secreted shh, which not only patterns surrounding embryonic structures such as the neural tube and af anlagen, but is also required for maintenance of the notochord itself and subsequent formation of the np. hedgehog proteins interact with the , -disulphated non-reducing terminal glycans of cs chains in aggrecan and the hs chains of perlecan and this may localise shh in tissues, aid in the formation of shh gradients, and regulate shh cell signalling (bandari et al., ; cortes et al., ; ortmann et al., ). the necessity of shh for disc development was demonstrated by choi and harfe who removed shh signalling from shh-expressing cells, including the notochord and floorplate, using a floxed mouse allele of the shh receptor smo and shhgfpcre (choi and harfe, ). conditional ablation of smo during early embryogenesis resulted in defects in ivds and vertebrae formation; however, removal of smo once the notochord sheath had formed did not alter disc development, highlighting the importance of the notochord sheath during spinal patterning. the role of shh in ivd development and postnatal homeostasis has been investigated and reviewed by dahia and colleagues (rajesh and dahia, ). the function of wnt/β-catenin signalling in the regulation of ivd development and degeneration has been examined in wnt/β-catenin reporter (topgal) mice (dahia et al., ; kondo et al., ). it was noted that during embryonic stages, wnt signalling was active in the ceps and af but very low in the np. postnatally, however, wnt signalling by np cells was found to increase. overexpression of β-catenin in both col a and col a -expressing disc cells resulted in af disorganisation, hyperplasia, and osteophyte formation in adult mice (kondo et al., ; wang et al., ). deletion of β-catenin in col a -expressing cells in -day-old mice resulted in accelerated maturation of subchondral bony endplate by weeks of age. a later study using topgal mice showed that wnt signalling in the np declines with aging in both lumbar and caudal discs (holguin et al., ). of note, wnt signalling positively regulates shh, which activates the expression of differentiation factors and cell proliferation in np cells, but undergoes a decline with ivd maturation (winkler et al., ). wnt and shh are poorly soluble proteins and in order to establish gradients of these morphogenetic components in tissues, perlecan may have a transporter role. indeed, wnt binds to the ldl receptor-like domains of perlecan domain ii (matsuo and kimura-yoshida, ). growth factors stimulate matrix production and np cell proliferation. ctgf, aka ccn , serves key functions in this regard. ccn binds to ldl receptor lrp , which is homologous to domain ii of perlecan (segarini et al., ), as well as integrins α β and αvβ (tran et al., ). ccn modulates bmp, tgf-β, and wnt signalling to coordinate chondrogenesis and angiogenesis during skeletal development (abreu et al., ; mercurio et al., ), and more recently in the prevention of degenerative disc disease (matta et al., ). deletion of the ccn gene in notochord-derived cells results in age- associated degeneration of ivds, decreased levels www.ecmjournal.org j melrose et al. murine spine models of aggrecan and collagen ii, and increased levels of collagen i within the np (bedore et al., ; tran et al., ). the ability of ccn to regulate the composition of the ivd suggests that it may be a clinical target for the treatment of ivd degeneration. the tgf-β superfamily are secreted proteins that play crucial roles in the determination of the notochord lineage and in skeletal development, growth, and cell differentiation. the importance of these signalling proteins in ivd development was well-demonstrated by the constitutive conditional knockout of the tgf-β type ii receptor (col acre;tgfbr fl/fl). these mutant embryos showed vertebrae deformities and ivds that were either completely lost or reduced due to af defects (baffi et al., ; baffi et al., ). subsequent microarray analyses of the embryonic tgfbr -null discs revealed that the expression profiles were similar to that of vertebrae profiles (sohn et al., ), and identified the transcription factor, avian erythroblastosis virus e- oncogene homologue (erg), as a player in af differentiation. accordingly, the function of tgf-β in disc development is thought to involve the induction of af differentiation from the sclerotome while inhibiting chondrocyte differentiation of the presumptive ivd. more recently, acancreert ;tgfbr fl/fl mice were generated to study the role of tgfbr in adult tissue. deletion of tgfbr at weeks-of-age resulted in progressive degeneration underscored by disorganisation of af lamellae with thinning of af collagen bundles, delayed bony endplate formation, and dystrophic calcification of the disc by months of age (alkhatib et al., ). these studies highlight that tgf-β also plays a clear role in ivd homeostasis postnatally. tgf-β signals through smad and ap- , positively regulating ccn expression in the np and may represent a limited reparative response in ivd degeneration (tran et al., ). smad null mice are smaller in size, show spinal malformations and kyphosis, exhibit alterations in cep structure, and show decreased ivd proteoglycan and collagen content (li et al., ). tgf-β/smad signalling in np cells regulates the expression of β- , - glucuronosyltransferase- (glcat- ), an important regulator of gag synthesis, which may partly explain the reduced gag levels in smad knockout mice (wu et al., ). it may be concluded that ccn and tgf-β are actively secreted by notochordal cells and that these direct resident disc cell populations in the maintenance of ivd homeostasis. additional growth factors that have a key role to play in disc homeostasis include igf- , fgf, and gdf . igf- and its receptor (insulin-like growth factor- receptor, igf r) have regulatory roles over extracellular matrix (ecm) synthesis and crucial roles in the maintenance of ivd homeostasis. igf- and tgf-β both regulate mmp- production by np cells (pattison et al., ). the ivds of igf r+/− mice display greater histopathological scores of degeneration, reduced collagen ii and proteoglycan levels, and elevated mmp (li et al., ). aberrations to fgf-fgfr signalling are responsible for a diverse group of skeletal disorders including those that afflict the axial skeleton (table ). polymorphism in gdf has been associated with disc degeneration in humans (huang et al., ); accordingly, ivds in gdf knockout mice show decreased proteoglycan content and loss of water binding, evident from reduced t -weighted signal intensity of lumbar levels (li et al., ). mutations in genes that cause over-stimulation of signalling pathways involved in cell growth and differentiation often yield predispositions to oncogenesis and other clinical pathologies, including skeletal abnormalities. mutations in nf , which encodes neurofibromin, a gtpase-activating protein that downregulates the ras pathway, causes nf . nf is a disorder characterised by generalised focal bony lesions, dystrophic scoliosis, and tibial pseudoarthrosis. to investigate the aetiology of the skeletal abnormalities associated with nf , researchers used col a cre;nf fl/fl mice to silence nf in axial and appendicular osteochondroprogenitor cells. these mice displayed progressive scoliosis, kyphosis, short stature, and ivd defects, closely recapitulating the clinical features of nf in human patients. interestingly, inhibition of ras/erk by lovastatin mitigated the phenotype of these mice, suggesting that activation of the ras/erk pathway by nf loss-of-function is in part responsible for these spinal defects (wang et al., ). similarly, tuberous sclerosis complex (tsc) is an autosomal dominant disorder characterised by mutations in tsc or tsc that leads to hyperactivation of mtor. patients with tsc suffer from benign tumours known as tubers that affect several organ systems including sclerotic bone lesions. tsc null mice show congenital spinal defects marked by kyphosis and a degenerative disc phenotype (yang et al., ). recent studies of phlpp , a phosphatase that negatively regulates akt signalling, suggested that this axis may play a role in disc degeneration. disc injury in phlpp null mice lead to akt activation and cell proliferation and showed long-term positive effects on preserving cellularity and matrix homeostasis, implying that it can be explored as a therapeutic target (zhang et al., ). ulici et al. have also recently reported the skeletal phenotype of jnk and jnk double- knockout mice (col a cre; jnk fl/fl/jnk −/−). these mice showed a severe and early onset scoliotic phenotype and vertebral and disc fusions (ulici et al., ). a murine model of human progeroid syndrome was developed by genetic ablation of ercc , a gene that encodes a functional protein of the xpf-ercc nuclease, ercc (niedernhofer et al., ) and contributes to the repair of double stand breaks. haploinsufficient ercc show advanced degenerative changes in the vertebral bodies and ivds, including reduced proteoglycan content, increased apoptosis, and p positive cells, consistent with accelerated j melrose et al. murine spine models www.ecmjournal.org senescence and aging (vo et al., ). further studies linked nf-κb-mediated signalling to the ercc +/− phenotype (nasto et al., ). extracellular matrix and its turnover in a polyaxial diarthrodial joint, the disc allows the spine to flex, extend, and rotate, with the np functioning as a central fulcrum (shapiro et al., ). this system is made possible by the relationship between the swelling forces of the np due to its proteoglycan-rich matrix and opposing counter- forces provided by the concentric collagenous lamellae of the af. therefore, matrix changes and degradation often define degenerative disc pathology (table ). high concentrations of aggrecan and ha are characteristic features of the ivd. mice lacking has show prominent vertebral body defects underscored by a lack of endochondral ossification, decreased matrix deposition, and increased cartilage cellularity. perhaps counter to what one might expect, np cellularity was increased with copious vacuolated cells. since ha can interact with chondrocytes through cd , rhamm, and other cell surface receptors, it is possible that lack of ha induced a state of proliferation and differentiation in the targeted cells of these mice (roughley et al., ). chloe b mice have a knock-in mutation in the acan gene that changes the sequence in the igd from dipen↓ffg to dipen↓gtr for the purpose of blocking mmp-dependent cleavage of aggrecan (little et al., ). these mice do not show major alterations in skeletal development, and their ivds have no obvious developmental abnormalities. adamts- is the major aggrecan degrading metalloprotease in murine articular cartilage and disc (stanton et al., ), while adamts- is the major aggrecanase in murine growth plates (glasson et al., ). adamts- knockout mice, surprisingly, do not show any defects in skeletal development, growth, or remodelling, and no alterations in the growth of their long bones (glasson et al., ). likewise adamts- knockout mice have no skeletal developmental abnormalities, although deletion of adamts- effectively prevents cartilage destruction in a murine osteoarthritis model and is shown to protect from chronic tobacco smoke-induced disc degeneration (ngo et al., ). these findings are consistent with the view that adamts- is largely responsible for the turnover of murine aggrecan model phenotype references has knockout vertebral body defects, decreased matrix deposition, and increased cartilage and np cellularity. roughley et al., chloe b mice no obvious abnormalities. little et al., perlecan knockout shortened growth plates, defective endochondral ossification leading to dwarfism, severe chondrodysplasia, dyssegmental ossification of spine. generalised abnormalities in development of vasculature and musculoskeletal system, myotonia. arikawa-hirasawa et al., prg knockout increased torsional modulus and reduced transverse major diameter and height. teeple et al., bgn knockout premature osteoarthritis and early-onset disc degeneration involving both the np and af. furukawa et al., col a deficiency homozygous null: severe skeletal defects and inability to pattern the notochord during disc development. haploinsufficiency: early skeletal defects including shorter spines, thicker and irregular vertebral endplates, and lower gag levels in the af. aszódi et al., sahlman et al., col a knockout premature degeneration associated with physical impairment and degenerative changes in the disc including the cep. allen et al., boyd et al., goldring, adamts- knockout no obvious skeletal phenotype. glasson et al., adamts- knockout protective against cartilage destruction and chronic tobacco smoke induced disc degeneration. ngo et al., mt -mmp knockout inadequate collagen turnover, dwarfism, kyphosis, accelerated age-related osteoarthritic changes evident in axial skeleton. holmbeck et al., sparc knockout endplate calcification and sclerosis. elevated cell numbers in the af, greater incidence of af herniations. behavioural studies evidence pain. gruber et al., millecamps et al., thrombospondin- knockout impaired collagen fibrillogenesis, reduced levels of transglutaminase, fragile skin, and disorganisation of annular lamellae. gruber et al., table . mouse models involving mutations in spine ecm molecules. model mechanism phenotype references ectopic fgf- expression fgf- transgene skeletal dwarfism coffin et al., fgf- deficient mouse knockout mutation inhibition of bone formation/bone mass montero et al., apert syndrome fgf (+/s w) mouse fgf- knock-in abnormalities in cartilage and bone development wang et al., ectopic fgf- expression fgf- transgene achondroplasia like dwarfism garofalo et al., fgfr deficient mice knockout mutation skeletal overgrowth colvin et al., deng et al., fgfr knock-in k m mutation severe dwarfism iwata et al., fgfr knock-ins c mutation severe dwarfism chen et al., fgfr knock-in k e mutation achondroplasia like dwarfism li et al., fgfr knock-in k e mutation thanatophoric dysplasia like dwarfism iwata et al., fgfr knock-in g r mutation achondroplasia like dwarfism naski et al., fgfr knock-in g c mutation achondroplasia like dwarfism chen et al., fgfr deficient mouse knockout mutation dwarfism, abnormal spinal development yu et al., fgfr- deficient mouse knockout mutation osteoglophnic dysplasia abnormal long bone and skeletal development white et al., table . mouse models examining aberrant fgf-fgfr signalling effects on spinal development. www.ecmjournal.org j melrose et al. murine spine models in-vivo (glasson et al., ). adamts- -dependent aggrecanolysis predominates over adamts- in mouse cartilaginous tissues due to an absence of highly sulphated ks chains in the murine igd (stanton et al., ; stewart et al., ). these mutants suggest that preventing aggrecan turnover do not lead to major effects on skeletogenesis and disc health. naturally occurring and engineered mutations in the gene encoding perlecan (hspg ) show unequivocally that perlecan is essential for cell growth, differentiation, and the function of cartilaginous tissues (arikawa-hirasawa et al., ; arikawa-hirasawa et al., ). both the core protein and the gag chains confer perlecan’s ability to modulate these processes. when substituted with hs, perlecan domain i promotes binding to laminin- and collagen iv. perlecan can also interact with a number of fibrillar or cell attachment molecules in the ecm and thus plays important roles in its organisation (melrose et al., ). the hs side chains of domain i of perlecan act as low affinity co-receptors for growth factors, such as fgf- , - , - and - , and a core protein receptor for fgf- has also been reported (ghiselli et al., ; mongiat et al., ). this complex formation is important for the correct presentation of the fgfs to fgfrs, their subsequent oligomerisation, activation to initiate cell signalling through the cytoplasmic tail of the fgfrs, and subsequent downstream effects on cell proliferation and differentiation (chang et al., ; chuang et al., ; knox et al., ; knox and whitelock, ). perlecan contains multiple modules that are homologous to the ldl receptor (murdoch et al., ; noonan et al., ). when expressed on cells, domain ii of perlecan binds and internalises ldl in a similar manner to lrp (fuki et al., ). the development of perlecan gene knock-out mice has demonstrated the essential role played by perlecan in cartilage development and skeletogenesis. homozygous knockout mice, which survive to birth, display severe skeletal defects with short axial and limb bones, defects of vertebral ossification centres, cleft palate, and striking abnormalities in the growth- plates of their long-bones (arikawa-hirasawa et al., ). null mice for the proteoglycans prg and bgn have also been generated. biomechanical studies of prg knockout spines have revealed an increased torsional modulus, and disc dimension measurements suggest that null discs have a reduced transverse major diameter and height, with an np that takes up a relatively larger area of the disc (teeple et al., ). bgn is a slrp that contributes to collagen fibrillogenesis, control of the bioavailability of tgf-β activity, and cellular regulation. consequently, bgn knockout mice display premature osteoarthritis and early-onset disc degeneration involving both the af and np (furukawa et al., ). in addition to proteoglycans, collagens are major matrix constituents of the disc matrix. inactivation of col a leads to premature ossification and ivd degeneration. one-month-old col a (+/−) mice have shorter spines, thicker and irregular vertebral endplates that calcify prematurely, and lower gag levels in the af. by months, some compensation in these spinal changes occur (sahlman et al., ). homozygous transgenic mice lacking col a die at birth and show severe skeletal defects characterised by impaired endochondral ossification and an inability to pattern the notochord during disc development (aszódi et al., ). collagen ix is a nonfibrillar collagen composed of three gene products: alpha- (ix), alpha- (ix), and alpha- (ix). collagen ix molecules are localised on the surface of type ii-containing fibrils and consist of two arms. these include a long arm that is crosslinked to collagen ii and a short arm that projects into the perifibrillar space (diab et al., ). it has been proposed that collagen ix molecules are involved in the interaction of fibrils with each other or with other components of the ecm. a mouse lacking both isoforms of the alpha- (ix) chain has been developed (col a null). col a null mice do not show evident abnormalities at birth, but progressively develop marked joint degeneration as is seen in osteoarthritis. col a null mice also develop premature degeneration associated with physical impairment and degenerative changes in the disc, including the ceps. behavioural studies measuring reflexes, beam walking, pole climbing, wire-hanging, grip strength, sensorimotor skills, and mechanical and thermal pain sensitivity were all compromised in these knockout mice (allen et al., ; boyd et al., ; goldring, ). interestingly, while preventing aggrecan turnover in murine tissues does not result in major phenotypes, blocking collagen turnover in some mouse models can have severe effects on skeletogenesis (glasson et al., ; holmbeck et al., ; little et al., ). mouse strains deficient in mmp- , - , - , - , - , - , and - have been developed (bian et al., ; foley and kuliopulos, ; van hove et al., ; kato et al., ; robinson et al., ; wells et al., ; wilson et al., ). while some changes in haematopoiesis and angiogenesis associated with the maturation of long bone growth plates have been reported in some of these models, little or no impairment in skeletal development has been observed. the contributions of individual enzymes and functional overlap with other mmps is therefore important to take into consideration. in contrast, membrane type- mt -mmp (aka mmp- ) knockout mice display cervical kyphosis, disc degeneration, and accelerated age-dependent osteoarthritic changes in the axial skeleton. this is apparently due to inadequate collagen turnover, which emphasises the critical role mt -mmp plays in the conversion of mmps from their inactive precursors into their active forms to promote collagenolysis in-situ (holmbeck et al., ). likewise, mmp efficiently cleaves collagen ii. mmp knockout mice display significant accumulation of interstitial collagen in their growth j melrose et al. murine spine models www.ecmjournal.org plate cartilages and delayed endochondral ossification due to inefficient collagen turnover (inada et al., ; stickens et al., ). its abundant presence in severely degenerated discs also highlights the deleterious role mmp can play in pathological states. matricellular proteins have emerged as important regulators of cell-ecm interactions and a growing body of evidence has established roles for these proteins in disc homeostasis. sparc is a matricellular protein important in the maintenance of ivd integrity. radiological examination of spines from -month-old sparc knockout mice revealed wedging, endplate calcification, and sclerosis. at months onwards, sparc knockout mice showed elevated cell numbers in the af and a greater incidence of af herniations. aged sparc knockout mice mirrored aspects of low back pain as they displayed changes in cutaneous sensitivity to cold, heat, mechanical stimuli, and ambulation, indicating pain may be emanating from the disc (gruber et al., ; millecamps et al., ). similarly, mice with disruption of the gene encoding thrombospondin- , a multifunctional, anti-angiogenic matricellular protein, showed impaired collagen fibrillogenesis, reduced levels of the intermolecular cross-linking enzyme transglutaminase, fragile skin, and disorganisation of annular lamellae (gruber et al., ). ectopic calcification is a notable feature that is known to occur in several spinal disorders. mice lacking ent , a model of diffuse idiopathic skeletal hyperostosis, show reduced expression of ank, enpp , and alpl in discs, increased af cell proliferation, and progressive ectopic calcification of fibrous connective tissues along the spine (warraich et al., ). analyses of af tissue isolated from ent knockout mice has further revealed that the observed increased cell proliferation is associated with an upregulation of e f transcription factors, the cell cycle regulators rb and cdk , and stimulation of the jnk/mapk pathway (veras et al., ). notably, the importance of genetic background in the ectopic calcification process has been recently demonstrated by the study of lg/j inbred mice, which show an age- dependent increase in dystrophic mineralisation of discs (this mouse strain will be discussed later in the review) (novais et al., ). an evolving view of inflammation in disc degeneration an association between increased inflammation and ivd degeneration is well-described and most commonly attributed to the cytokines tnfα and il- β. nevertheless, investigations of human tnfα overexpressing mice (tg and htnfαtg) and il- α/β double knockout (il- ko) mice have led to questioning the understanding of the role inflammation plays in disc homeostasis. while polyarthritic tg-htnf mice show compromised vertebral bone parameters, af defects, and a greater propensity for herniations at the cep/ af junction, the presence of increased tnf-α in these mice did not show adverse effects on the np compartment. surprisingly, tg-tnf mice showed healthy-appearing np cells that assembled into an expanded cell band and the overall transcriptomic profile remained unaltered (gorth et al., ; gorth et al., ). this phenotype contradicts the existing view that chronic tnfα overexpression would cause pronounced disc degeneration, as the articular joints of these mice are severely degenerated by rheumatoid arthritis. plausible reasons for this phenotype could be that previous studies have exclusively used herniated human disc material with infiltrated immune cells as starting material for the analysis, shaping the understanding of the function of tnfα in the disc compartment. this phenomenon, in which differential effects of inflammation are observed in discs as opposed to articular cartilage, has also been noted in tonebp haploinsufficient mice. tonebp- deficient np cells downregulate pro-inflammatory molecules yet experience notable degeneration, while, on the other hand, tonebp-deficiency is protective against immune-driven arthritis (tessier et al., b). the differential effects of inflammation on these joints may be credited to the fact that the inner disc is largely avascular and immune privileged, unless penetrated by herniation. similarly, while conditional loss of p ink a (acancreert ; p ink af/f) shows lower np levels of il- β, il- , and mcp- , these mice are not protected from age-dependent degenerative changes (novais et al., ). global il- α/β double knockout mice also show higher degenerative grades with aging than wild-type counterparts, suggesting that loss of il- does not serve a protective role (gorth et al., ). seemingly contrary to the phenotype of these il- knockout mice, mice null for the il- rn gene were reported to develop spinal abnormalities (phillips et al., ). however, the discrepancies in these findings may be reflective of mouse strain-dependent effects (c bl/ , il- ko; balb/c, il- rnko), highlighting the complexity of inflammation on disc health. the cytoskeleton the cytoskeleton is fundamental to cell biology as it maintains intracellular organisation and cell shape, offers mechanical support, and links the cell to extracellular components by transmembrane proteins to enable functions such as cell adhesion and migration. although this critical component of the cell is largely understudied in ivd tissues, a few mouse models targeting the cytoskeleton have been developed. these include mice lacking arp / , the branched actin nucleator, and flnb, an actin-binding protein which forms a linking scaffold to coordinate signal transduction (table ). constitutive deletion of the arpc gene encoding a critical subunit of the arp / complex in collagen ii-expressing cells (col a -cre; arpc fl/fl) results in severe chondrodysplasia and spinal defects. these mice are dwarfed due to disorganised growth plates, present with kyphosis, and show dramatic changes to the ivds, some of which are fused. on histology, www.ecmjournal.org j melrose et al. murine spine models the growth plates are grossly expanded, the np is reduced in size, and the af is deformed and disorganised, containing rounded chondrocyte-like cells. embryonic and postnatal lethality in these mice led to the crossing of arpc f/fl with the inducible acan- creert allele to generate acan-creert ; arpc f/fl mice. resultant loss of arp / at skeletal maturity was shown to induce notable af degeneration marked by altered matrix composition. in vitro analyses further revealed that arp / controls tonebp-dependent osmoadaptation and cell-ecm interactions in np cells (tessier et al., a). similarly, the discs of flnb−/− mice show rapid and progressive degeneration during postnatal development. the af cells of these mice undergo differentiation into the chondrogenic lineage, acquiring the signature of hypertrophic chondrocytes and upregulating tgfβ and bmp signalling. consequently, af tissues show endochondral- like ossification, express collagen x, and evidence increased apoptosis, leading to vertebral fusions (zieba et al., ). loss-of-function of other factors known to influence the cytoskeleton such as n-cadherin and αvβ integrin have also been investigated in mice and are associated with altered disc cell morphology and degenerative phenotypes (bian et al., ; hwang et al., ). nuclear hs-proteoglycans such as perlecan have recently been identified in np cells. these may interact with cytoskeletal components and re- organise the nucleosome and chromatin organisation which may regulate the access of transcription factors to dna (hayes and melrose, ; kovalszky et al., ). nuclear hs-proteoglycans inhibit histone deacetylases resulting in chromatin compaction affecting dna accessibility to transcription factors. hs also inhibits dna topoisomerase i activity, which has important roles to play in ( ) the removal of dna supercoils during transcription and dna replication; ( ) the re-annealing of dna strands following strand breakage during re-combination and chromosomal condensation; and ( ) the disentanglement of intertwined dna strands during mitosis (champoux, ; wang, ). nuclear heparanase may have roles in the regulation of nuclear hs-proteoglycans (chen and sanderson, ). insights from inbred mice while genetically modified mice have offered important insights into the function of individual genes, recent investigations of inbred mouse strains (sm/j, lg/j, and c bl/ ) have provided invaluable lessons on the pathogenesis of disc degeneration. sm/j (small) and lg/j (large) mice, generated by crossing multiple inbred strains and selecting for body size, are models of choice for qtl analysis. these strains show differential cartilage healing capacities: sm/j is considered a poor healer strain whereas lg/j is considered a super healer. the sm/j is the first mouse model to show early onset and spontaneous disc degeneration without the need of overt, inflammation-causing injury such as annular puncture, tail looping, or mechanical overloading (choi et al., b; zhang et al., ). thus, the sm/j is proposed to more closely resemble the chronic disc degeneration seen in most humans. the disc phenotype of these mice has been characterised by matrix fibrosis, elevated markers of hypertrophic chondrocytes, increased np cell death, decreased wnt and vegf signalling, and dysregulated ion transport systems (choi et al., b; zhang et al., ). an extensive characterisation and comparison of these inbred mice, as well as the commonly used c bl/ j strain, during the aging process has been recently conducted by novais et al. ( ). an important insight derived from these studies is the observation that each mouse strain possesses a unique disc degeneration phenotype, with dissimilar morphological features, transcriptomic signatures, and onset of disease. strain-dependent differences at the gene expression and histological level following traumatic injury have also been recently demonstrated (brent et al., ). ultimately, these differences underscore the notion that disc degeneration is largely influenced by genetic background and therefore, when combined with environmental and mechanical factors, presents heterogeneously across individuals as sub-phenotypes. conclusions with the advances in knowledge provided by the completion of the human genome project and elucidation of the complete murine genome, the mouse represents the vehicle of choice for further examining the role of specific human gene abnormalities on spinal development and homeostasis in health and disease. while the mouse musculoskeletal system displays notable differences, including the persistence of notochordal-np cells, quadrupedalism, additional vertebrae, and some variations in the structure of proteoglycans, the mouse model nevertheless is an attractive experimental system to answer important questions in spinal pathobiology. due to these intrinsic differences, careful interpretation of experimental findings is indicated when attempting to make comparisons with the human musculoskeletal system. the described studies on the mouse ivd have identified many potential therapeutic targets worthy of further model phenotype references col a -cre; arpc fl/fl severe chondrodysplasia, spinal defects, dwarfism, growth plate expansion, deformation of af and np compartments, fused discs. tessier et al., a acan-creert ; arpc f/fl np cell-band expansion and af degeneration marked by altered matrix composition. tessier et al., a flnb knockout postnatal progressive disc degeneration, endochondral-like ossification of af, vertebral fusions. zieba et al., ta b l e . m o u s e m o d e l s w i t h m u t a t i o n s i n cytoskeleton genes. j melrose et al. murine spine models www.ecmjournal.org examination, not only in the mouse, but also in other animal models, to ultimately identify their roles in human disc degeneration. acknowledgements this study is supported by the grants from the national institute of arthritis and musculoskeletal and skin diseases (niams) r ar , r ar , and r ar . references abreu jg, ketpura ni, reversade b, de robertis em ( ) connective-tissue growth factor (ctgf) modulates cell signalling by bmp and tgf-β. nat cell biol : - 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( ) adamts deficiency protects mice from chronic tobacco smoking-induced intervertebral disc degeneration. spine (phila pa ) : - . niedernhofer lj, garinis ga, raams a, lalai as, robinson ar, appeldoorn e, odijk h, oostendorp r, ahmad a, van leeuwen w, theil af, vermeulen w, van der horst gtj, meinecke p, kleijer wj, vijg j, jaspers ngj, hoeijmakers jhj ( ) a new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. nature : - . noonan dm, fulle a, valente p, cai s, horigan e, sasaki m, yamada y, hassell jr ( ) the complete sequence of perlecan, a basement membrane heparan sulfate proteoglycan, reveals extensive similarity with laminin a chain, low density lipoprotein-receptor, and the neural cell adhesion molecule. j biol chem : - . novais ej, diekman bo, shapiro im, risbud mv ( ) p ink a deletion in cells of the intervertebral disc affects their matrix homeostasis and senescence associated secretory phenotype without altering onset of senescence. matrix biol : - 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- - . zhang y, xiong c, kudelko m, li y, wang c, wong yl, tam v, rai mf, cheverud j, lawson ha, sandell l, chan wcw, cheah kse, sham pc, chan d ( ) early onset of disc degeneration in sm/j mice is associated with changes in ion transport systems and fibrotic events. matrix biol : - . zieba j, forlenza kn, khatra js, sarukhanov a, duran i, rigueur d, lyons km, cohn dh, merrill ae, krakow d ( ) tgfβ and bmp dependent www.ecmjournal.org j melrose et al. murine spine models cell fate changes due to loss of filamin b produces disc degeneration and progressive vertebral fusions. plos genet : e . doi: . /journal. pgen. . discussion with reviewer reviewer : which mouse model, or which combination of the described mouse models, would you recommend for studying spontaneous disc degeneration? authors: spontaneity eludes to a disease process that is not initiated by intentionally made genetic or physical (i.e. af puncture, tail looping) manipulations. therefore, the selection of a mouse model that displays spontaneous disc degeneration must be limited to the inbred strains. furthermore, the acknowledgment that disc degeneration encompasses a diversity of degenerative phenotypes precludes the use of a single model. with that held into consideration, the sm/j and lg/j inbred strains are especially useful, as they have been extensively characterised and show similar degeneration characteristics to that of human disease. sm/j mice show degeneration at a relatively early age (choi et al., b), whereas lg/j mice evidence disc calcification with ageing (novais et al., ). in the case of sm/j mice, the early onset aspect facilitates experimental investigations when time constraints are imposed and helps to lessen the costly housing of mice for extended periods of time, as is done in aging studies. editor’s note: the scientific editor responsible for this paper was mauro alini. [pdf] a basic probe of the beale cipher as a bamboozlement | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . / - corpus id: a basic probe of the beale cipher as a bamboozlement @article{kruh abp, title={a basic probe of the beale cipher as a bamboozlement}, author={l. kruh}, journal={cryptologia}, year={ }, volume={ }, pages={ - } } 	l. kruh 	published 	computer science 	cryptologia view via publisher angelfire.com save to library create alert cite launch research feed share this paper citationsbackground citations methods citations view all topics from this paper 	beale ciphers 	cipher citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by most influenced papers sort by citation count sort by recency benford’s law in the beale ciphers 	viktor wase 	mathematics 	 save alert research feed the role of base in the beale papers 	viktor wase 	philosophy 	 	pdf 	view excerpt, cites background save alert research feed unsupervised training with applications in natural language processing 	m. nuhn 	computer science 	 	 	pdf save alert research feed a systematic review on author identification methods 	s. kale, r. prasad 	computer science 	int. j. rough sets data anal. 	 	 	view excerpt, cites methods save alert research feed a multi-disciplinary framework for cyber attribution 	ronald smyth 	computer science 	 	view excerpt, cites background save alert research feed authorship attribution and the digital humanities curriculum 	p. juola 	political science 	 	 save alert research feed authorship attribution 	i.n. bozkurt, o. baghoglu, e. uyar 	computer science 	 nd international symposium on computer and information sciences 	 	 	pdf save alert research feed authorship attribution 	p. juola 	psychology, computer science 	found. trends inf. retr. 	 	 	pdf save alert research feed the beale cipher as a bamboozlement - part ii 	l. kruh 	computer science 	cryptologia 	 	 	pdf save alert research feed references showing - of references sort bymost influenced papers recency reminiscences of a master cryptologist 	l. kruh 	art, computer science 	cryptologia 	 	 	view excerpts, references background save alert research feed the beale cipher: a dissenting opinion 	j. gillogly 	philosophy, computer science 	cryptologia 	 	 save alert research feed the beale cipher: a dissenting 	opinion. cryptologia 	 literary detection: how to prove authorship and fraud in literature and documents 	a. q. morton 	political science 	 	 save alert research feed the beale ciphers 	 style and vocabulary: numerical studies 	j. m. sinclair, c. williams 	history 	 	 save alert research feed signature simulation and certain cryptographic codes 	c. hammer 	computer science 	cacm 	 	 save alert research feed style and vocabulary: numerical studies 	m. dillon 	psychology 	 	 	view excerpt, references background save alert research feed the cryptogram 	the cryptogram 	 letter from john ingles to editor, flynn's weekly 	letter from john ingles to editor, flynn's weekly 	 ... ... related papers 	abstract 	topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue severe mucositis with bendamustine etoposide ara-c and melphalan (be-eam) as conditioning regimen in non-hodgkin lymphoma (nhl) patients undergoing autologous stem cell transplantation (autosct) table systems symptoms g-i nausea vomiting abdominal pain cramping respiratory cough dys/tachypnoea hypoxia sob trali cardiac hypo/hypertension brady/tachycardia arrhythmia chest heaviness/pain mi cardiac arrest neuro amnesia seizure stroke numbness uc other fever chills flushing headache hypothermia anxiety vertigo allergy visual neuropathy back pain cause of sciar is either the graft (dmso, cell content, volume, clumping) or the patient (age, gender, disease). abstracts / biol blood marrow transplant ( ) s es s objective: to acquaint transplant infusionists with sciar causative factors and associated symptoms to guard for ae during infusion. method: study of published literature as available on pubmed website in the last years. result: articles by authors from diverse nations were reviewed. only publication is from usa. reports are for autologous cryopreserved hpc-a (including few allogeneic or marrow products). studies reported sciar after dmso wash. data size is from - in- fusions. ae ranges from . to %. various symptoms are reported. discussion: minor ae are attributed to dmso, ae from washed cells to granulocyte or tnc content of graft. cordoba r et al have reported % sciar despite dmso wash. years ago, donmez a et al (turkey) suggested re- striction of infusion to < e+ tnc; and wang jw et al (china) advised fractionated infusions (vs. single infusion) in pediatric patients. khera n et al (usa) have compared groups over years reporting . % sciar on infusion of < . e+ tnc/kg/day, fractionating infusions on different days. conclusion: despite multiple variables, transplant centers can lower incidence of sciar by restricting graft dose. table article infusions ae % finding/symptoms feb donmez a, turkey allo non cardiac > cardiac apr wang jw, china ped x g-i jun mueller lp, germany cardiac ^dmso jul calmels b, france (washed) x nov foïs e, france (washed) x dec cordoba r, spain (washed) allergic > g-i > respiratory milone g, italy hpc-a hpc-m cardiac ^vol/kg & inf time non cardiac ^age & non-mnc jul bojanic i, croatia symptom % > % jul curcioli ac, brazil allo haplo dmso but not dmso vol oct martìn-henao ga, spain g-i respiratory seizure . % feb khera n, usa (comparative) - : - : . infusions increased fold severe mucositis with bendamustine etoposide ara-c and melphalan (be-eam) as conditioning regimen in non- hodgkin lymphoma (nhl) patients undergoing autologous stem cell transplantation (autosct) sunita nathan , antonio m. jimenez , alfonso d. moreno , john maciejewski , henry c. fung . section of bone marrow transplant and cell therapy, rush university medical center, chicago, il; rush university medical center, chicago, il; section of bone marrow transplantation and cell therapy, rush university medical center, chicago, il; bone marrow transplant program, temple university hospital/fox chase cancer center, philadelphia, pa introduction: bendamustine is effective for front-line or salvage therapy in patients (pts) with nhl. benda-eam conditioning has been used in heavily pre-treated relapsed/ refractory lymphoma pts undergoing autologous stem cell transplantation (autosct) and is noted to be a safe and effective regimen. we report our experience with using be- eam conditioning regimen for autosct with special note on the toxicity profile. methods: data from consecutive patients (pts), under- going autosct using the be-eam [bendamustine mg/m daily d- ,- , etoposide mg/m daily d- to - , ara-c mg/m q d- to - and melphalan mg/m on d- ], treated at our institution between and , were collected. demographics, indication for autosct, time to engraftment (te), side effect profile, tolerability and out- comes were analyzed. who oral mucositis score was used for grading mucositis. results: pts (average age . yrs, range: - yrs) were identified and analyzed as a retrospective cohort with a follow-up duration of . months (range - mos). ( %) pts were male and ( %) pts fe- male. . % were caucasian. ( . %) pts had � ae cause suggestion/conclusion vol infused dmso tnc � e+ tnc single vol infusion fractionated infusion neurotoxicity unrelated to dmso vol dmso safe in neurologic disease tnc improve apheresis quality tnc clumps ae ^tnc granulocyte clumping � . e+ granulocytes age non-mnc � . e+ non-mnc female gender multiple myeloma granulocyte ae ^graft composition & disease dmso good documentation required ae ^granulocyte x x � . e+ tnc/kg/day multiple infusions abstracts / biol blood marrow transplant ( ) s es s comorbidities. indication for autosct included relapsed/ refractory follicular lymphoma, diffuse large b cell lym- phoma and lymphoplasmacytic lymphoma and upfront consolidation for mantle cell lymphoma. ( . %) pts underwent autosct as consolidative therapy and ( . %) pts for relapsed/refractory disease. therapies prior to autosct were - regimens. time to engraftment was . � . days for neutrophils and . � . days for platelets. be-eam-related toxicities included nausea, emesis, diarrhea, neutropenic fever and mucositis. ( %) pts had severe mucositis (grade / ) with pts developing neutropenic enterocolitis including patient with pneumatosis intestinalis. overall, ( . %) pts were in cr and ( %) pts had minimal disease at d . ( . %) pts had relapsed disease. ( . %) pts died from relapsed or progressive disease. conclusion: bendamustine based conditioning is an effec- tive regimen in patients with nhl undergoing autologous stem cell transplantation as previously reported. it has the potential of causing severe mucositis irrespective of age, comorbidities, disease type or number of prior therapies. this regimen although moderately tolerated should be used cautiously especially in patients who have had prior thera- pies that can affect the gastrointestinal tract. pegfilgrastim and planned plerixafor for autologous stem cell mobilization is safer than and as effective as chemo-mobilization in patients with hematological malignancies manish sharma , sherilyn tuazon , tingting zhan , john wagner , margaret kasner , onder alpdogan , ubaldo martinez , dolores grosso , joanne filicko , thomas klumpp , barbara pro , matthew carabasi , neal flomenberg , mark weiss . medical oncology, thomas jefferson university, philadelphia, pa; medical oncology, thomas jefferson university, philadelphia, pa; department of pharmacology and experimental therapeutics, thomas jefferson university, philadelphia, pa; department of medical oncology, kimmel cancer center, thomas jefferson university, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; medical oncology, thomas jefferson university hospital, philadelphia, pa introduction: we have previously shown that as compared with chemo-mobilization (chm) cytokine mobilization (ctm) is associated with a better chance of table primary endpoint analysis chemo- mobilization (n[ ) cytokine mobilization (n[ ) p-value median total cd cells/kg collected (in millions/kg): myeloma . . . non-myeloma . . . median number of apheresis days (mean): myeloma ( . ) ( . ) . non-myeloma ( . ) ( . ) . target dose achieved: . yes ( . %) ( . %) no ( . %) ( . %) median day cd collection (in millions/kg): . myeloma na . non-myeloma na . achieving a target autologous stem cell dose for patients with multiple myeloma (mm). we now review our expe- rience of autologous stem cell mobilization using a similar strategy for all patients referred for an autologous trans- plant (auto-sct). methods: we analyzed consecutive patients who received an auto-sct for hematological malignancies at our center from july to june . chm was achieved with cyclophosphamide ( g/m ), pegfilgrastim ( mg) and plerixafor ( . mg/kg once daily until target dose collected or maximum of days apheresis). ctm was achieved with pegfilgrastim and plerixafor. we recorded the total cd + cells/kg collection, number of apheresis days, and if the prescribed dose of cd + cells/kg was achieved. the prescribed cell dose in patients with mm is . x /kg, and . x /kg for all other hematological malignancies. we compared the median total cd + cells/ kg dose collection (wilcoxon test), the mean number of apheresis days (poission), and target stem cell dose collection (non-inferiority test on two proportions). we also compared day stem cell collection in the ctm group based on disease (myeloma vs. non-myeloma) (wilcoxon test). finally, we analyzed the probability of successful stem cell dose collection if the target collection dose was higher than our own criteria. results: a total of patients were included. fifty-three patients had a diagnosis of mm and twenty-one patients had other hematological malignancies, non-hodgkin (n¼ ) and hodgkin lymphoma (n¼ ). there was no statistically signif- icant difference in age, gender, number of prior induction treatment, prior treatment with lenalidomide and time from diagnosis to transplant between the two groups. in the chm group, ( %) were hospitalized from complications of mobilization regimen, whereas no patients were hospital- ized in the ctm group (p< . ). there was no statistically significant difference in neutrophil or platelet engraftment between chm and ctm. multivariate analysis did not reveal predictive factors which lead to > apheresis attempts. table describes the primary outcomes. conclusion: cytokine-mobilization with pegfilgrastim and planned plerixafor is an effective strategy for stem cell mobi- lization in patients being considered for autologous transplant. pre-transplant serum biomarkers predict early relapse in classical hodgkin lymphoma patients undergoing autologous stem cell transplantation bryan trottier , holly miller , qing cao , jeffrey s. miller , michael r. verneris , daniel j. weisdorf , john levine , linda j. burns . blood and marrow transplantation, university of minnesota, minneapolis, mn; blood and marrow transplantation program, university of michigan, ann arbor, mi; biostatistics and bioinformatics, university of minnesota, minneapolis, mn; blood and marrow transplantation program, university of minnesota, minneapolis, mn; pediatric hematology and oncology, university of minnesota medical center, fairview, minneapolis, mn; university of minnesota medical center, minneapolis, mn; pediatric blood and marrow transplant program, university of michigan, ann arbor, mi background: serum biomarkers in classical hodgkin lym- phoma (chl) reflect both tumor biology and burden in the non-transplant setting. we sought to determine the prognostic value of chl serum biomarkers in predicting early relapse following autologous stem cell transplantation (asct). 	severe mucositis with bendamustine etoposide ara-c and melphalan (be-eam) as conditioning regimen in non-hodgkin lymphoma ( ... 	introduction 	methods 	results 	conclusion announcement vol. , no. february . ph o'farrell: high resolution two-dimensional electrophoresis of proteins. j cell bioi : - , . towbin h, staehelin t, gordon j: electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some application. proc nat! acad sci usa : - , . schiller d, franke ww, geiger b: a subfamily of relatively large and basic cytokeratin polypeptides as defined by peptides mapping is represented by one or several polypeptides in epithelial cells. embo j : - , . quinlan r, dorthea ls, hatzefeld m, achtstatter t, moll r, jorcano jl, margin tm, franke ww: patterns of expression and organiza- tion of cytokeratin intermediate filaments. ann new york acd sci : - , . baden hp, kubilus j: fibrous proteins of bovine hoof. j invest derma- tol : - , cellular properties of nail . baden hp, kubilus j: a comparative study of immunologic properties of hoof and nail fibrous proteins. j invest dermatol : - , . heid hw, moll i, franke ww: patterns of expression of trichocytic and epithelial cytokeratins in mammalian tissues. . concomitant and mutually exclusive synthesis of trichocytic and epithelial cyto- keratins in diverse human and bovine tissues. differentiation : - , . moll i, heid hw, franke ww, moll r: patterns of expression of trichocytic and epithelial cytokeratins in mammalian tissues. . hair a.~d nail formation during human fetal development. differentia- tion : - , . dhouailly d, xu c, manabe m, schermer a, sun t-t: expression of hair-related keratins in a soft epithelium. exp cell res : - , announcement the korean derm meeting will be held may - , in seoul, korea. the post-congress meeting will be held may - , in hong kong and may - , in macao. this symposium is sponsored by the departments of dermatology, yonsei university col- lege of medicine, seoul, korea and the jefferson center for international dermatology, thomas jefferson university, jefferson medical college, philadelphia, pa. for further infor- mation, please contact eileen o'shaughnessy, meeting coordinator, jcid, jefferson medical college, s. th street, room , philadelphia pa. tel. ( ) - ; fax ( ) - . book reviews there is a statistically-based portrait, but the author's findings are largely negative. the group was older (a natural consequence of their training and careers before politics) and initially they were more likely to identify with political parties of the left, until the whole character of the legislature itself shifted in that direction by the end of the century. but for the most part, the physician-legislators were more the representatives of their local constituencies than of their profession. this was especially the case with questions of food and drink regulation, health insurance, or industrial hygiene and housing which doctors usually viewed more from the perspective of local economic interests than that of health professionals. to emphasize the exceptions to this rule, the author concludes with an examination of medical and health related legislation that the doctors generally supported. utilizing the work of jacques leonard and margaret hildreth to establish the setting, he makes his case that the physicians in parliament not only supported but also played an important role in shaping such legislation as the law on the practice of medicine and the public health law. the faults of the book are few. methodologically, the author could have been more rigorous in his collective description of the physician-legislators to show which characteristics were typical of all legislators as opposed to just those who were doctors. also, the descriptions of the legislative campaigns sometimes read like a chronological list of bills presented, which only touch the surface of complex movements (tuberculosis, mental illness, etc.) whose main thrust lay outside parliament. finally, to those who might ask whether the main question posed by the author warrants a whole book to answer it, it must be admitted that the topic may be a relatively small niche in the history of modern medicine and politics, but the author fills it well. william h. schneider, indiana university carol trowbridge, andrew taylor still, - , kirksville, missouri, the thomas jefferson university press, , pp. xiv, , illus., $ . ( - - -x). biographies of the "founding fathers" of "the fringe" are typically more hagiographic than historical, more celebratory than critical. although the publication of this biography of the inventor of osteopathy has been timed to coincide with the th anniversary of the founding of the first school of osteopathy, in kirksville, missouri, the author manages to avoid the deification of her subject. instead, she provides an understanding of the world that shaped his thinking. drawing effectively on recent work in the history of popular science and medicine, as well as on the local history of society, politics and religion in the "bled" frontier states of kansas and missouri, carol trowbridge illuminates how still's peculiar therapeutic achievement was fully a product of its phrenological, mesmeric, thomsonian, eclectic, spiritualist and, above all, spencerian evolutionary times. on the whole, trowbridge is far more successful at elaborating the mind of still, than at accomplishing her book's other main mission, to fill in the narrative gaps left in still's autobiography of . particularly in relation to the practical realization of osteopathy, trowbridge fails to deliver the "new and important facts" promised on her dust-jacket. on the seemingly central question of how still came by his practice of bone-setting, for example, trowbridge has regrettably little to say-less in fact than norman gevitz in his much broader history of osteopathy. it seems a pity that in a study of this kind the opportunity was not seized to inquire into either the local or the national practice of bone-setting during the s and s when still was advertising himself as the "lightning bone setter". nor is it made clear why still's popularity should have "surged" at this point through this conceit. some attempt at a systematic study of the "hundreds of patients [who] now awaited still's arrival in various towns" (p. ) would not have come amiss. one is left still wondering how the cognitive and therapeutic worlds actually folded together in the invention of osteopathy. roger cooter, wellcome unit for the history of medicine, manchester available at https://www.cambridge.org/core/terms. https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core review began / / review ended / / published / / © copyright zavodnick et al. this is an open access article distributed under the terms of the creative commons attribution license cc-by . ., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. effect of a female external urinary catheter on incidence of catheter-associated urinary tract infection jillian zavodnick , caitlin harley , kelly zabriskie , yasmin brahmbhatt . department of internal medicine, thomas jefferson university, philadelphia, usa . department of nursing, thomas jefferson university, philadelphia, usa . department of infection control, thomas jefferson university, philadelphia, usa corresponding author: jillian zavodnick, jillian.zavodnick@jefferson.edu abstract background catheter-associated urinary tract infections (cautis) can be fatal, and are a source of avoidable expense for patients and hospitals. prolonged catheterization increases infection risk, and avoiding catheters is crucial for infection prevention. male external urinary catheters are recommended as a tool to prevent the need for indwelling catheterization. female external urinary catheters (feucs) have intermittently been marketed without wide adoption; one has recently become available but published data is limited. objective this retrospective observational study was conducted to investigate the effect of feucs on indwelling catheter use and female cautis. methods feucs were introduced to intensive care units. cauti rates and indwelling catheter days were obtained before and after the introduction of the devices. results cauti rates decreased from . per catheter days to . per catheter days (p= . ). female indwelling catheter days decreased, while overall intensive care patient days increased. conclusions introduction of a feuc was associated with a statistically significant decrease in cauti rate among female intensive care patients. the feuc may prevent the need for indwelling catheters in some situations. categories: internal medicine, infectious disease, quality improvement keywords: hospital acquired infection, cauti, external urinary catheter, female external urinary catheter, cauti prevention, infection control, nosocomial infection introduction indwelling urinary catheters (iuc) are commonly used in hospitals, and have a number of potential complications including catheter-associated urinary tract infections (cautis) [ ]. cautis increase mortality, length of stay, and costs, with the cost of a single cauti recently estimated to be over $ , for a patient in intensive care; prevention is therefore a major focus for hospitals [ - ]. longer duration of indwelling catheterization increases cauti risk, and avoidance of iucs when feasible is an important part of cauti prevention [ ]. educating hospital staff on the benefits of iuc avoidance and removal [ ], as well as restricting iuc use and increasing access to alternatives to catheterization, have been well-studied methods for decreasing cautis [ , ]. male external urinary catheters have long been available, and are recommended by multiple society guidelines and as part of a published preventive bundle to decrease cautis [ , - ]. female external urinary catheters (feucs) have intermittently been marketed but never widely adopted [ , - ]. the purewick feuc (bard and purewick, becton, dickinson and company, franklin lakes, new jersey) has recently become available, but published data is so far limited to a single case series without systematic outcomes, a limited local investigation showing a decrease in iuc utilization after implementation without a decrease in cauti, and one inpatient study demonstrating an initial decrease in cauti which was not sustained after one year [ , - ]. cauti rates at our institution decreased over the past ten years with the introduction of new prevention measures (e.g. nurse-driven catheter removal protocol), but then reached a plateau once these measures had open access original article doi: . /cureus. how to cite this article zavodnick j, harley c, zabriskie k, et al. (october , ) effect of a female external urinary catheter on incidence of catheter-associated urinary tract infection. cureus ( ): e . doi . /cureus. https://www.cureus.com/users/ -jillian-zavodnick https://www.cureus.com/users/ -caitlin-harley https://www.cureus.com/users/ -kelly-zabriskie https://www.cureus.com/users/ -yasmin-brahmbhatt been consistently adopted. we began performing root cause analysis on all cautis to determine factors leading to the infection, with a goal of targeting future interventions to further decrease cautis. among other findings, we recently learned that the majority of iucs were placed for the purpose of close monitoring of urine output. we hypothesized that the introduction of an feuc would decrease utilization of iucs, and that this would prevent cautis. as our outcome measure, we compared cauti rates in female icu patients before and after the product became available. we measured catheter days in female icu patients as a process measure, hypothesizing that feuc availability would decrease iuc use as the mechanism of decreasing cauti. materials and methods setting thomas jefferson university hospital (tjuh) is a large urban academic medical center closely associated with jefferson hospital for neuroscience (jhn); these hospitals report jointly for some measures. together these hospitals contain nine intensive care units. the hospitals have long had a nurse-driven iuc protocol enabling removal without a physician order when patients no longer meet criteria for iuc use, a practice shown to decrease cauti [ ]. jefferson’s standardized infection ratio, a measure of cauti prevalence, was . in the year prior to this study. study design we performed a retrospective observational study. participants included all adult icu patients from january , to december , , a total of , patient days. as our main outcome, we compared cauti rates in female icu patients in the year before (jan , to december , ) and the two years after (jan , to december , ) the feuc became available at our hospital using the national healthcare safety network (nshn) measure of cauti per , catheter days [ ]. when calculating cauti rates, iuc days, and hospital-acquired pressure injury (hapi) rates, male patients were excluded. the hypothesized mechanism for decreased cauti after feuc introduction was decreased iuc use. to confirm this, we examined iuc days in female patients, calculated as a count of the number of female patients with iuc presence charted by the nurse each day of the study period. a decrease in iuc days with the introduction of the feuc would suggest the avoidance of iuc use, while no decrease would suggest that the feuc was being adopted primarily in patients who would not have had an iuc. hapi was analyzed in the same population over the same time frame as a secondary outcome and balancing measure. the measure was defined as a pressure-induced mucosal injury, non-mucosal ulcer of stage one through four, unstageable ulcer, or deep tissue injury [ ]. if the pressure injury was related to a medical device, this was recorded as well. the adoption of the feuc for patients with moisture dermatitis or at risk of skin breakdown was not anticipated to decrease cauti rates as these patients would not otherwise have had iucs, but might be expected to decrease hapis, making hapi a useful secondary outcome. however, since our hapi data includes device-related pressure injuries, an increase in device-related hapi with the introduction of an feuc could be evidence of unintended consequences of device adoption. we did not measure moisture dermatitis rates directly. we were not able to directly measure feuc days or how many patients had an feuc placed. information on icu patient days was collected to control for the impact of patient volume on iuc days; information on female-only icu days was not available, so male and female patients are included in this measure. cauti data was obtained by infection control personnel from an epic data report of positive urine cultures, which infection control staff used to determine whether cauti criteria were met. it was then analyzed using the nhsn data reporting tool and microsoft excel. hapi data was obtained by staff nurses trained as “skin champions” during a monthly assessment of all icu patients, and was analyzed using microsoft excel and spss. the two-sided fisher’s exact test was used to determine statistical significance. intervention the purewick feuc was introduced to all icus in january of . the product consists of a urine collection segment positioned between the patient’s labia, which is attached to wall suction (figures - ). zavodnick et al. cureus ( ): e . doi . /cureus. of figure : schematic of the purewick urinary collection system © bd. used with permission. bard and purewick are trademarks and/or registered trademarks of becton, dickson and company or its affiliates. mmhg = millimeters of mercury zavodnick et al. cureus ( ): e . doi . /cureus. of https://assets.cureus.com/uploads/figure/file/ /lightbox_d a f eab c b e fef-figure- -resized.png figure : detailed image of the patient portion of the female external urinary catheter © bd. used with permission. bard and purewick are trademarks and/or registered trademarks of becton, dickson and company or its affiliates. patients cannot ambulate while the feuc is in place. the decision to use the feuc in a given patient was nursing-driven, with guidelines given for appropriate indications. the first indication was patients requiring strict monitoring of intake and output without other means of obtaining these measurements; using the feuc for this indication was anticipated to avoid the need for an indwelling catheter. the second indication was moisture dermatitis or potential for skin breakdown due to incontinence; this is not an indication for an indwelling catheter at our institution, although inappropriate use of catheters for this indication has been described [ ]. using an feuc for this indication was intended to decrease pressure injuries, and was not expected to decrease iuc use or cauti. the introduction was overseen by the cauti working group, an interprofessional hospital committee with joint nursing and physician leadership, and representation from infection control professionals. representatives from the manufacturer trained all icu nurses in the use of the product. a few nurse members for each unit underwent more in-depth training so that they could serve as “superusers” to continuously educate other staff. product representatives remained available for questions as nurses began using the feuc. the thomas jefferson university institutional review board categorized this intervention as work not zavodnick et al. cureus ( ): e . doi . /cureus. of https://assets.cureus.com/uploads/figure/file/ /lightbox_ c dd f eaafc bbf e-figure- -resized.png requiring review. results in the year prior to feuc introduction, there were cautis in female icu patients, a rate of . per indwelling catheter days. in the two years after feuc introduction there were cautis in this population ( . events per indwelling catheter days), p= . . a yearly breakdown shows a continued downward trend, with a cauti rate of . in the first post-intervention year, and a rate of . in the second post- intervention year. there was an . % decrease in icu female indwelling catheter days, from an average of monthly device days to monthly device days. during this same period, overall icu patient days increased from a monthly average of to (table ). before feuc (january , – december , ) after feuc (january , – november , ) p value number of cautis female cauti rate (events per catheter days) . . . number of female iuc days number of patient days (male and female) average monthly patient days average monthly female iuc days table : female cauti rate and number of female iuc days before and after introduction of feuc cauti = catheter associated urinary tract infection. iuc = indwelling urinary catheter. feuc = female external urinary catheter. there were hapis in female icu patients between january and december of (pre-feuc) out of patients sampled (prevalence . %). of these, ( . %) were related to medical devices. between january , and november , (post-feuc; a prevalence assessment was not completed for december of ) there were hapis in the female icu patients sampled (prevalence . %), ( . %) related to medical devices. neither the increase in hapi overall nor the increase in device-associated pressure injuries was statistically significant (p= . and . respectively) (table ). prevalence before feuc (january , – december , ) prevalence after feuc (january , – november , ) p value hapi . % (n= ) . % (n= ) . hapi monthly average . . device-associated hapi . % (n= ) . % (n= ) . table : female hapi and device-associated pressure injury prevalence before and after feuc hapi = hospital acquired pressure injury. feuc = female external urinary catheter. discussion the availability of a feuc was associated with a statistically significant decrease in cauti. after the feuc became available, iuc days decreased among female icu patients, even though the number of icu patient days increased overall. the decrease in iuc days alongside the increase in icu days suggests that there may be some adoption of the feuc in place of iucs for strict intake and output monitoring, a trend which would be expected to decrease cauti rates, and has been demonstrated in recently presented data [ ]. zavodnick et al. cureus ( ): e . doi . /cureus. of data on skin outcomes does not suggest that pressure injuries are being avoided through use of the feuc. we propose the measurement of skin outcomes during the introduction of this device for two purposes. first, this can serve as a secondary outcome measure for the use of a feuc in cases of incontinence alone without an indication for an iuc. second, device-related pressure injuries could be a useful balancing measure, demonstrating unintended consequences of feuc adoption. however, hapi is a heterogeneous and multifactorial measure and there are multiple variables besides feuc adoption which may have led to our increased rates. many patients at risk for hapi have no indication for an external or internal urinary catheter, and we expected that any effect of this product on hapi would be modest at best. hapi data collection does include device-associated pressure injuries, which are a useful balancing measure for feuc use; these did not significantly change during the intervention period. ongoing careful surveillance will be needed to ensure that the feuc is not associated with increased device-associated pressure injuries. informal feedback from patients and nursing has been positive, and prior to the availability of outcomes data, the product had been introduced to all units of the hospital. this was done at the request of non-icu nurses who were aware of the product, and after feedback from patients who had used the feuc while in the icu and were frustrated at the need to discontinue it when transferred to the floors. even before a statistically significant decrease in cauti rates was demonstrated, staff and patient feedback led the hospital to continue making the feuc available. there are some limitations to our analysis. we were not able to obtain specific data on feuc utilization. for the primary outcome of cauti, we used the process measure of iuc utilization as a proxy for feuc use. however, there could be other factors leading to the decrease in iuc use during this time frame. we also noted an increase in icu days for all patients alongside a trend toward fewer cautis in female icu patients, the only population expected to be affected by the availability of an feuc. from this we inferred that the decrease in iuc use was not driven purely by lower patient volumes. this inference depends on two assumptions: first, that female icu days did not decrease relative to male icu days over this time period; and second, that there was no difference in the number of patients with a potential iuc indication between the before and after periods. these assumptions are reasonable but cannot be demonstrated by our data. there are also significant limitations pertaining to skin outcomes. moisture-associated dermatitis would have been a useful outcome to directly track the effectiveness of the feuc when used for the indication of skin protection, but was not available. the use of hapi as a proxy measure ignores patients who might have moisture-associated dermatitis that does not progress to a pressure injury. data collection for hapi comes from monthly prevalence surveys and may underestimate device-associated pressure injury, which is an infrequent occurrence. this data is unable to distinguish between types of devices leading to pressure injury; pressure injuries resulting from tracheostomy devices, for example, would be unaffected by our intervention. hapi assessment was not performed in december of , which is expected to artificially lower the total number of hapi in the post-intervention period (monthly average and prevalence should remain unaffected). although we recommend that institutions adopting the feuc make an effort to measure skin outcomes, our hapi measurement procedures significantly limit this measure’s use for the purpose of evaluating this device. an feuc is a feasible, well-tolerated intervention that is associated with decreased iuc utilization and cauti rates. further study is needed with direct tracking of feuc utilization by indication, and with measurement of moisture dermatitis. a cost-benefit analysis would be useful in determining the total utility of this product. further investigation could consider the incorporation of the population cauti rate, cauti per , patient days, a measure proposed as an alternative to the nhsn definition in a low-prevalence environment [ ]. conclusions the number of iuc days decreased with the availability of the feuc despite a slight increase in patient days, suggesting that this product may prevent the need for iuc in some situations. there was a statistically significant decrease in cauti rate, a meaningful outcome which also further supports the conclusion that iuc use decreased. no change was noted in hapi, but this analysis was subject to significant limitations. further quality improvement initiatives that focus on female iuc, hapi and cauti rates with the feuc product are warranted. additional information disclosures human subjects: consent was obtained by all participants in this study. thomas jefferson university irb issued approval n/a. the thomas jefferson university irb categorized this research as quality improvement work not requiring irb review under tju office of human research form ohr . animal subjects: all authors have confirmed that this study did not involve animal subjects or tissue. conf licts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial zavodnick et al. cureus ( ): e . doi . /cureus. of relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. acknowledgements the authors would like to acknowledge garland hendrickson, lisa gillen, and charlotte sacksteder for their assistance with this manuscript. references . saint s, trautner bw, fowler ke, et al.: a multicenter study of patient-reported infectious and noninfectious complications associated with indwelling urethral catheters. jama intern med. , : - . . /jamainternmed. . . 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( ). accessed: september , : https://www.cdc.gov/nhsn/pdfs/pscmanual/ psccauticurrent.pdf. . national pressure ulcer advisory panel, european pressure ulcer advisory panel, pan pacific pressure injury alliance: prevention and treatment of pressure ulcers: clinical practice guideline . haesler e (ed): cambridge media, osborne park, western australia; . . jain p, parada jp, david a, smith lg: overuse of the indwelling urinary tract catheter in hospitalized medical patients. arch intern med. , : - . . /archinte. . . fakih mg, greene mt, kennedy eh, et al.: introducing a population-based outcome measure to evaluate the effect of interventions to reduce catheter-associated urinary tract infection. am j infect control. , : - . . /j.ajic. . . zavodnick et al. cureus ( ): e . doi . /cureus. of https://dx.doi.org/ . /jamainternmed. . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /jamainternmed. . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.jhin. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.jhin. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.idc. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.idc. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.ajic. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.ajic. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /nejmoa ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /nejmoa ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . / ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . / ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /bmjqs- - ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /bmjqs- - ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . / ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . / ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /won. ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /won. ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . / ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . / ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /m - ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /m - ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.ajic. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.ajic. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j. - . .tb .x?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j. - . .tb .x?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j. - . .tb .x?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j. - . .tb .x?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /s - ( ) - ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /s - ( ) - ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /won. ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /won. ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.ajic. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.ajic. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /won. ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /won. ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.ajic. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.ajic. . . ?utm_medium=email&utm_source=transaction https://www.cdc.gov/nhsn/pdfs/pscmanual/ psccauticurrent.pdf?utm_medium=email&utm_source=transaction https://www.cdc.gov/nhsn/pdfs/pscmanual/ psccauticurrent.pdf?utm_medium=email&utm_source=transaction https://www.ehob.com/media/ / /prevention-and-treatment-of-pressure-ulcers-clinical-practice-guidline.pdf?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /archinte. . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /archinte. . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.ajic. . . ?utm_medium=email&utm_source=transaction https://dx.doi.org/ . /j.ajic. . . ?utm_medium=email&utm_source=transaction 	effect of a female external urinary catheter on incidence of catheter-associated urinary tract infection 	abstract 	background 	objective 	methods 	results 	conclusions 	introduction 	materials and methods 	setting 	study design 	intervention 	figure : schematic of the purewick urinary collection system 	figure : detailed image of the patient portion of the female external urinary catheter 	results 	table : female cauti rate and number of female iuc days before and after introduction of feuc 	table : female hapi and device-associated pressure injury prevalence before and after feuc 	discussion 	conclusions 	additional information 	disclosures 	acknowledgements 	references images in copd journal.copdfoundation.org jcopdf © volume • number • for personal use only. permission required for all other uses. in press images in copd journal.copdfoundation.org jcopdf © volume • number • for personal use only. permission required for all other uses. chronic obstructive pulmonary diseases: journal of the copd foundation images in copd: idiopathic emphysema in a never smoker stephan s. leung, md patrick lee, md jessica e. most, md baskaran sundaram, md abbreviations: chronic obstructive pulmonary disease, copd; alpha- -antitrypsin deficiency, aatd; human immunodeficiency virus, hiv; hypocomplementemic urticarial vasculitis syndrome, huvs; alpha- -antitrypsin protein, aat; erythrocyte sedimentation rate, esr; forced expiratory volume per second, fev ; forced vital capacity, fvc; total lung capacity, tlc; residual volume, rv funding support: not applicable citation: leung ss, lee p, most je, sundaram b. images in copd: idiopathic emphysema in a never smoker. chronic obstr pulm dis. ; ( ):in press. doi: https://doi.org/ . /jcopdf. . . . images in copd keywords: emphysema; idiopathic address correspondence to: baskaran sundaram, md division of cardiothoracic radiology department of radiology thomas jefferson university hospital philadelphia, pennsylvania email: baskaran.sundaram@jefferson.edu telephone: ( ) - fax: ( ) - smoking is an important risk factor for the development of chronic obstructive pulmonary disease (copd). this risk includes exposure to secondhand smoking. however, it is estimated that % of patients with emphysema have either rarely or never smoked. in this population, depending on the clinical picture, further consideration should be given to other potential causes for emphysema such as idiopathic, alpha- -antitrypsin deficiency (aatd), heritable connective tissue disorders, intravenous drug abuse, human immunodeficiency virus (hiv), hypocomplementemic urticarial vasculitis syndrome (huvs), and environmental exposures. case history “g.s” a -year-old male with no history of smoking or exposure to secondhand smoke presented for introduction division of cardiothoracic radiology, department of radiology, thomas jefferson university hospital, philadelphia, pennsylvania division of pulmonology, department of medicine, thomas jefferson university hospital, philadelphia, pennsylvania evaluation of increasing limitation of physical activity with shortness of breath. at this time, he was diagnosed with asthma-copd overlap syndrome. he was medically managed with inhaled corticosteroids and a long-acting beta -agonist. he denied a history of intravenous drug abuse. blood work revealed an alpha- -antitrypsin protein (aat) level of mg/dl (normal – mg/dl). erythrocyte sedimentation rate (esr) was mm/hr (normal – mm/hr). c q complement levels were . mg/dl (normal . – . mg/dl). here are the images taken of patient g.s., along with spirometry results. (figures , , and ). imaging : - . doi: https://doi.org/ . /jcopdf. . . . images in copd journal.copdfoundation.org jcopdf © volume • number • for personal use only. permission required for all other uses. images in copd journal.copdfoundation.org jcopdf © volume • number • for personal use only. permission required for all other uses. this clinical presentation highlights a case of severe emphysema in a nonsmoker. while smoking remains the de facto risk factor for the development of emphysema, in a never smoker patient, other potential etiologies should be considered. it is estimated that aat accounts for approximately % of cases of emphysema. the rate of decreased lung function is strongly affected by cigarette smoking in aat patients. radiological evidence of emphysema is more prevalent in smokers (approximately %) than non-smokers (approximately %). aat should be suspected if the patient presents with emphysema at a young age (< years old), the emphysema is in a non- smoker, the emphysema is in a radiographical basilar predominant pattern, there is adult onset asthma or there is a family history of lung and liver disease (figure ). diagnosis is confirmed with a serum aat level < mg/dl along with genetic confirmation. heritable connective tissue disorders are a heterogenous group of diseases which include marfan syndrome, ehlers-danlos syndrome, and cutis laxa. structural changes from gene mutations which affect tissue elasticity may predispose to the development of emphysema. - intravenous drug use has been associated with early onset development of emphysema. talc, or hydrated magnesium silicate, is used in oral tablets such as methylphenidate and phenmetrazine to hold the discussion components of the medication together. injected talc can migrate to the lungs causing a granulomatous foreign-body reaction, which can continue to tissue destruction leading to apical bullous emphysematous changes. the relationship between hiv status and emphysema was first described in the s. in contrast to smoking- associated emphysema, which clinically occurs over decades, hiv-associated emphysema develops over a period of years. huvs is a rare disorder that is typically characterized by urticarial lesions, decreased complement levels, and vasculitis. emphysema in huvs has been thought to be secondary to vasculitis of the lung resulting in pulmonary damage. computed tomography typically shows bibasilar panacinar emphysema with bullous changes, air trapping, scattered ground-glass opacities, and minimal fibrotic and inflammatory changes at the lung bases. an elevated esr and decreased serum complement levels lead to a diagnosis of huvs. a variety of environmental factors, particularly from occupational or agricultural exposures, have been studied as possible causes of emphysema. although classically associated with lung fibrosis, some studies have suggested that these patients may be at higher risk for developing emphysema. , declaration of interest the authors have no conflicts of interest to declare. images in copd journal.copdfoundation.org jcopdf © volume • number • for personal use only. permission required for all other uses. fabro ds, frenia ds. emphysema in the nonsmoker. clin pulm med. ; ( ): - . doi: https://doi.org/ . /cpm. b e a lee p, gildea tr, stoller jk. emphysema in nonsmokers: alpha -antitrypsin deficiency and other causes. cleve clin j med. ; ( ): - . doi: https://doi.org/ . /ccjm. . . tobin mj, cook pj, hutchison dc. alpha antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for pi type z. a survey by the british thoracic association. br j dis chest. ; ( ): - . doi: https://doi.org/ . / - ( ) - miravitlles m, dirksen a, ferrarotti i, et al. european respiratory society statement: diagnosis and treatment of pulmonary disease in α -antitrypsin deficiency. eur respir j. ; ( ). doi: https://doi.org/ . / . - jessurun cac, bom dam, franken r. an update on the pathophysiology, treatment and genetics of marfan syndrome. expert opin orphan drugs. ; ( ): - . doi: https://doi.org/ . / . . beridze n, frishman wh. vascular ehlers-danlos syndrome: pathophysiology, diagnosis, and prevention and treatment of its complications. cardiol rev. ; ( ): - . doi: https://doi.org/ . /crd. b e berk dr, bentley dd, bayliss sj, lind a, urban z. cutis laxa: a review. j am acad dermatol. ; ( ): . doi: https://doi.org/ . /j.jaad. . . roberts wc. pulmonary talc granulomas, pulmonary fibrosis, and pulmonary hypertension resulting from intravenous injection of talc-containing drugs intended for oral use. proc (bayl univ med cent). ; ( ): - . doi: https://doi.org/ . / . . kuhlman je, knowles mc, fishman ek, siegelman ss. premature bullous pulmonary damage in aids: ct diagnosis. radiology. ; ( ): - . doi: https://doi.org/ . /radiology. . . wisnieski jj, baer an, christensen j, et al. hypocomplementemic urticarial vasculitis syndrome. clinical and serologic findings in patients. medicine (baltimore). ; ( ): - . doi: https://doi.org/ . / - - erkinjuntti-pekkanen r, rytkonen h, kokkarinen ji, tukiainen ho, partanen k, terho eo. long-term risk of emphysema in patients with farmer’s lung and matched control farmers. am j respir crit care med. ; ( ): - . doi: https://doi.org/ . /ajrccm. . . daniil z, koutsokera a, gourgoulianis k. combined pulmonary fibrosis and emphysema in patients exposed to agrochemical compounds. eur respir j. ; ( ): . doi: https://doi.org/ . / . . . . references . . . . . . . . . . received / / review began / / review ended / / published / / © copyright papanagnou et al. this is an open access article distributed under the terms of the creative commons attribution license cc-by . ., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. integrating telehealth emergency department follow-up visits into residency training dimitrios papanagnou , danica stone , shruti chandra , phillip watts , anna marie chang , judd e. hollander . emergency medicine, thomas jefferson university, philadelphia, usa . jeffconnect program, thomas jefferson university . department of emergency medicine, thomas jefferson university  corresponding author: dimitrios papanagnou , dimitrios.papanagnou@jefferson.edu disclosures can be found in additional information at the end of the article abstract introduction given the rapid expansion of telehealth (th), there is an emerging need for trained professionals who can effectively deliver th services. as there is no formal th training program for residents, the department of emergency medicine (dem) at thomas jefferson university (tju) developed a pilot training program for senior post-graduate-year three (pgy- ) residents that exposed them to th practices. the objective of the study was to determine the feasibility of developing a resident-led, post-emergency-department (ed) visit th follow-up program as an educational opportunity to ) address patient satisfaction; and ) expose senior residents to th delivery. methods during a one-month block in their third-year of training, em residents were exposed to and educated on th delivery and utility through on-the-job, just-in-time training. residents spent four hours per week evaluating patients previously seen in the ed within the last - days in the form of th follow-up visits. ed patients were screened to identify which patient chief complaints and presentations were appropriate for a follow-up visit, given a specific day and time for their th encounter, facilitated by a resident, and supervised by a faculty member trained in th. demographic patient and visit data were collected. residents then completed a brief survey at the end of the rotation to capture their educational experiences and recommendations for subsequent training improvement. results over months, th follow-up visits were performed by residents. one hundred twenty- six patients ( %) were female. top chief complaints included extremity pain ( . %); abdominal pain ( . %); upper respiratory infections ( . %); lacerations ( . %), and motor vehicle accidents ( . %). the average number of days between the ed visit and the th follow- up call was . days (iqr - ). . % of patients were compliant with their discharge instructions and medications. on a likert scale low ( ) to high ( )], average patient helpfulness rating was . (iqr . - ) and the average patient likelihood to recommend a th follow-up visit was . (iqr - ). ten residents completed the follow-up survey on the educational experience of the rotation (response rate %), of which seven described there is value to have a th rotation in the curriculum. thematic analysis of open-ended responses yielded constructive feedback for programmatic improvement. open access original article doi: . /cureus. how to cite this article papanagnou d, stone d, chandra s, et al. (april , ) integrating telehealth emergency department follow-up visits into residency training. cureus ( ): e . doi . /cureus. https://www.cureus.com/users/ -dimitrios-papanagnou- https://www.cureus.com/users/ -danica-stone https://www.cureus.com/users/ -shruti-chandra https://www.cureus.com/users/ -phillip-watts https://www.cureus.com/users/ -anna-marie-chang https://www.cureus.com/users/ -judd-e-hollander conclusion the authors propose a feasible th training opportunity integrated into em residency training to assist them with meeting a rapidly-growing demand for th and prepare them for diverse job opportunities. categories: medical education, emergency medicine, healthcare technology keywords: telehealth, telemedicine, graduate medical education, training, professional development introduction telehealth (th) has been shown to broaden access to healthcare [ ], increase efficiency while reducing costs [ - ], and enhance patient satisfaction and health outcomes. given its rapid expansion, there is an emerging need for trained professionals who will effectively deliver th services. more recently, th has been used as a direct connection to the patient, rather than a physician to physician consult. the direct-to-consumer th industry is growing rapidly with over million visits in [ ]. international healthcare organizations, practitioners, patients, families, policy makers, and legislators are increasingly recognizing the value added by the integrated use of telehealth. given the high impact potential of telehealth, it is predicted that there will be an . % annual growth of th services through , inevitably resulting in spiking demand for th training and coordination [ ]. the health report states that the introduction of new th and telemonitoring programs in healthcare will require a new subset of skills that will change the roles and responsibilities of health providers [ ]. to date, there are few academic programs that offer th training especially for post-graduate resident trainees [ ]. the university of alaska southeast (in partnership with alaska federal health care access network) is one of the few institutions in the country that offers a th certificate program (for continuing education, ce, contact hours). the university of arizona, university of california-davis health system, and waldo county general hospital (maine) also run similar programs. other non-accredited, short-term training and educational resources exist, most notably through the cal telehealth resource center (also for ce credit) and the american telehealth association (ata). there are no sizeable general th programs in the northeast united states [ ]. given telehealth’s growing market and trending demands in the united states and abroad, it is expected there will be significant implications and expectations for the emergency medicine (em) residency graduate. it was in response to this accumulating evidence that the department of emergency medicine (dem) at thomas jefferson university (tju) created and successfully integrated a th training program into its residency program in an effort of preparing its graduates for telehealth’s rapidly-growing demand. a major focus was placed on developing senior residents’ clinical and non-clinical skills that are essential to th delivery, such as the th physical exam, virtual doctor-patient communication, and troubleshooting technological challenges. the goal of this paper is to describe the first months of the program, including the resident and patient experience of a novel th follow-up encounter subsequent to the traditional ed visit. specifically, the authors aimed to determine if such a training program could be integrated into an em graduate medical education program to describe what patient complaints em residents would typically encounter through a th medium, and to survey residents on the educational value of th training. papanagnou et al. cureus ( ): e . doi . /cureus. of materials and methods our curriculum and quality improvement project was completed at tju, an academic medical center located in philadelphia, pennsylvania that has an enterprise-wide telehealth program (jeffconnect) including / / on-demand access to an emergency physician, a -hospital neurostroke network providing partner affiliate hospitals’ emergency physicians with telehealth access to neurovascular experts, and scheduled visit programs in clinical specialties. over , telehealth calls are completed annually. targeted learners the tju sponsors a -year (post-graduate year, pgy, through ), em residency training program, with total residents ( residents per year). the residency program is accredited by the accreditation council for graduate medical education (acgme). during the one-month emergency medicine administration and teaching (emat) block of the last year of training, pgy- residents were immersed in a multifaceted th experience which exposed, educated, and trained senior residents on the delivery and utility of telehealth in patient care. with regards to the goals of the rotation, residents were expected to develop both the clinical and non-clinical skills that are essential to telehealth care delivery, such as the th physical exam, virtual doctor-patient communication, and troubleshooting technological challenges. at the beginning of the rotation, residents were given an introductory orientation providing them with an overview of the th program. residents were provided with resources on telehealth principles. these resources included internally-developed modules that introduced telehealth, its applications, the telehealth physical exam, troubleshooting, and regulatory considerations; institution-specific clinical pathways; and video examples of successful th encounters. residents spent four hours per week performing follow-up visits on patients seen in the ed within the past five to seven days. ed patients appropriately identified for a follow-up visit were given a specific day and time for their virtual telehealth encounter, which was facilitated by the pgy- resident, and supervised by a faculty member credentialed in telehealth delivery. patient recruitment ed patients suitable for a telehealth follow-up visit were identified by a faculty member, resident, and/or research coordinator. patients were enlisted for a th follow-up visit only if the treating physician agreed that a timely follow-up visit would be helpful for the patient and would assist in the management of his/her chief complaint. chief complaints were low-acuity, and included upper respiratory infections, wound care concerns, lacerations, cellulitis, headaches, or minor trauma, as examples. if an ed patient was amenable to participate in a virtual visit, a research coordinator then scheduled the patient for the virtual appointment prior to his/her discharge. all patients were also contacted days after their th visit to assess whether their respective issues were resolved or further care was necessary, and to gauge their experience with the th encounter. assessment and supervision each resident was expected to complete hours of directly supervised th delivery over the four-week period ( hours per week x four weeks). evaluations of residents were performed by the supervising faculty member. all supervising faculty members hold a faculty appointment in the dem are trained in th and provide ongoing th coverage within the enterprise-wide jeffconnect program. formative feedback was provided to each resident during and at the completion of each th encounter. papanagnou et al. cureus ( ): e . doi . /cureus. of the telehealth visit prior to the th encounter, residents reviewed the patient’s ed note from their original visit to the hospital. all scheduled visits were conducted via video using a hipaa-compliant, secure, jeffconnect platform (www.jeffconnect.org), which can be conducted via the web, smart phone, or tablet device. at the time of scheduling, a coupon code was created, which made the follow- up visit free to the patient. when logging-on to the platform, patients entered structured clinical information, including any medications and allergies. once this information was successfully entered, patients clicked a button that immediately connected them to the physician. the average wait time for this process is one to three minutes. physicians and patients were then able to view one other, similar to a video call on skype or facetime. documentation was captured in the electronic medical record, identifying the encounter as a th visit, and linking it to the original ed visit as an addendum to the patient's medical record. data collection during the telehealth encounter, residents followed a standardized approach to collecting patient data, which included medication reconciliation, assessment of whether ed discharge follow-up instructions were followed, and an assessment of how the patient was doing since his/her discharge from the ed. any issues or questions that patients had were also addressed. data collected from each encounter included the number of patient visits to the ed, chief complaint, days between initial visit and telehealth visit, and an assessment of medication and discharge instruction compliance. patients who received a telehealth visit were sent a brief follow-up survey at days, which asked them ) how helpful the th visit was, ) if they would recommend a th follow-up to someone else, and ) if they required additional care since their ed visit (i.e., an additional ed or urgent care visit and/or hospitalization). at the end of the rotation, all pgy- residents completed a short survey, administered through survey monkey, which solicited feedback on the educational value of the th experience. open-ended questions were included in the survey to capture resident comments on the benefits of th training, ways in which the experience could be enriched, and residents' opinions on whether th training should be included in the formal em residency curriculum. data are presented as descriptive statistics. because of its focus on quality improvement, the study was exempt from review by the institutional review board (irb) of the sidney kimmel medical college of tju. educational and theoretical considerations the educational framework that informed the telehealth training program is rooted in experiential learning; furthermore, resident supervision by telehealth-trained faculty preceptors promoted reflection after telehealth clinical encounters. david kolb’s widely quoted ‘experiential learning cycle’ informed training program design. kolb originally represented four elements (i.e., concrete experience, observation and reflection, the formation of abstract concepts, and active experimentation) in an experiential learning circle that provides a flexible framework for instructional design [ ]. the model is derived from a model of social learning that connects variability of individual learning style to flexibility in learning context [ ]. in the context of the telehealth encounter, the senior resident is immersed in a concrete experience (i.e., the jeffconnect telehealth patient encounter), he/she then observes and reflects on himself/herself or others (i.e., debriefing with the faculty preceptor and/or observation of ‘modeled’ encounters by the faculty preceptor), the learner is then able to make inductive systematic conclusions or abstractions (i.e., refining frames for his/her clinical practice via the telehealth medium), which then allows the learner to empirically test the action plans that arise from the abstract concepts (i.e., applying this new practice to subsequent telehealth papanagnou et al. cureus ( ): e . doi . /cureus. of encounters) [ ]. results from august to may , ed follow-up visits were scheduled to be performed via telehealth. of these, patients conducted the visit ( %). visits were conducted by all pgy- residents. one hundred twenty-six patients ( %) were female, ( . %) patients were black. the top five chief complaints included extremity pain ( . %), abdominal pain ( . %), upper respiratory infection ( . %), lacerations ( . %), and motor vehicle accidents ( . %) (table ). the average number of days between the ed visit and the telehealth follow-up call was . (interquartile range, iqr, - ) days. patients reported that they were compliant with at least one part of their discharge instructions . % of the time, and with medications . % of the time. new prescriptions were provided in six follow-up visits ( . %). at the end of the call, encounters ( %) were “resolved,” meaning no further follow-up was necessary. papanagnou et al. cureus ( ): e . doi . /cureus. of demographic data n= % age . (mean) iqr ( - ) gender female . % male . % race black . % white . % other . % most common chief complaints extremity pain . % abdominal pain . % upper respiratory infection . % laceration . % motor vehicle collision . % back pain . % joint pain . % chest pain . % headache . % fall . % cellulitis / rash / abscess . % dizziness . % gynecologic-related complaint . % table : demographic and chief complaint data of patients receiving telehealth (th) follow-up visits after emergency department discharge (n= ) a total of patients were able to be reached for the -day follow-up ( %). on a likert scale from (low) to (high), the average patient helpfulness rating was . (iqr . - ), and the average patient likelihood to recommend a th follow-up visit was . (iqr - ). six patients ( %) were hospitalized within days, while patients ( %) had ed or urgent care visits. each resident completed an average of th visits (iqr - . ). ten of the residents papanagnou et al. cureus ( ): e . doi . /cureus. of completed the post-rotation survey (response rate %). seven residents ( %) agreed that there is educational value to have a th rotation in the em residency curriculum. residents commented that “the experience was valuable,” that “(they) liked it better than expected,” and that it appropriately “prepared (them) for telehealth in em,” specifically for specialized areas such as “remote and rural settings” and “assisting with ems services.” additional comments highlighted that the rotation “exposed them to a new medium that is in its infancy, but will likely dominate healthcare delivery in the near future.” three residents commented that they enjoyed the patient follow-up and the ability to assess their progress post discharge. with regards to areas for programmatic improvement in the rotation, eight residents submitted detailed descriptions on how the experience could be optimized. open axial coding was used to organize these comments into themes (table ). these included integrating th into other rotations, formalizing th training in residency, allowing residents to get exposed with being the first provider, and maximizing the educational value of their time when the patient does not show-up for the th encounter. qualitative themes specific details integrate th training into other rotations allow resident to use th during the ems rotation; use th in the urgent care setting; explore wilderness medicine applications create more formalized training integrate more lectures, didactics, best practices into the rotation; share more resources with residents; more detailed approach on how to incorporate th into direct patient care leverage the initial encounter find ways to allow the resident to be the first provider; if possible, residents could potentially follow-up on their own patients and procedures (i.e., lacerations) through th; have resident make decisions via th during the undifferentiated stage of patient presentation maximize down-time secondary to patient cancellations, there was idle time; find ways to maximize the educational value of this down-time during the th rotation table : areas for programmatic improvement in telehealth (th) training discussion in this evaluation of a first-ever, resident-operated program for th follow-ups of ed patient visits, we found that of the patients who completed a th encounter, over half of the issues were resolved by the follow-up th visit. patients found the th visits helpful, and would also recommend the service to others. many patients discharged from the ed or hospital lack timely outpatient follow-up with primary care providers [ ], and th may provide a new way to provide these services, and possibly prevent repeat ed visits and hospitalizations. in addition, the th follow-up provides patients the time to understand and review instructions and medication after their ed discharge. as th services become more common and accessible to patients [ - ], providers will need to have standardized training to teach how to appropriately and effectively provide these services. papanagnou et al. cureus ( ): e . doi . /cureus. of this is the first report of an integrated th curriculum within an em residency program. specific objectives of our program included the following: . introduce resident physicians to a professional ‘tele-presence,’ including appropriate attire, technological preparation, and environmental preparation. . develop the skills needed to effectively conduct th visits (i.e., camera positioning, eye contact, and documentation). . conduct appropriate histories and physical exams within the scope of th, under the supervision and guidance of a trained faculty member. . apply and critique peer-reviewed clinical pathways for th delivery for common patient complaints. . systematically troubleshoot computer and connectivity issues, and . educate patients on the utility and limitations of th. in this novel educational program, our first class of graduating pgy- residents successfully met these objectives through ‘on-the-job’ training and direct supervision from em faculty who were trained in th delivery. most residents agreed that th should be incorporated into the em curriculum, to some capacity. comments made by residents were also insightful, and highlighted areas where improvements could be easily made to maximize the educational value of the th experience, including better utilization of downtime. the healthcare sector has acknowledged the increasing value added by the integrated use of th [ - ]. its benefits are threefold: this new means of healthcare delivery has the potential to significantly broaden access to healthcare, increase efficiencies and reduce costs, and enhance patient safety, quality of care, and ultimately, patient outcomes. there are several limitations worth noting in our study. the sample size included in our training intervention was only limited to the pgy- cohort at our training site. future plans will aim to aggregate this data with yearly data of graduating senior residents working with th. if possible, there may be utility to compare and contrast the experience of em resident trainees with residents from other specialties and across other institutions. the authors also wish to acknowledge that the study was possible given the successful th program that currently exists at the host institution, to some extent, this may impact its reproducibility at other institutions. with regards to the overarching research question initially posed, our data supports that integrating th training into a graduate medical education program for senior em residents is quite feasible. in terms of program effectiveness, the kirkpatrick four-level training evaluation model was helpful to objectively analyze the impact of integrating th emergency department visits into residency training. trainees reacted well to training (level : reaction), the majority of residents enjoyed the program and agreed that it was of sound educational value. through successive th patient encounters, senior em residents were able to learn how to independently facilitate a supervised th encounter for a wide array of common patient presentations (level : learning) using specific skills to conduct the th visit and troubleshoot connectivity issues. senior residents were also able to apply their traditional patient care skills (i.e., extracting histories and conducting physical examinations) to the supervised th encounter (level : behavior). papanagnou et al. cureus ( ): e . doi . /cureus. of next steps for this program will include evaluating kirkpatrick’s level (results) on programmatic impact. specifically, the investigators plan to examine long-term outcomes on patients evaluated via th (i.e., hospitalization rates, patient satisfaction ratings). preliminary patient-specific data is encouraging: the majority of patients highly rated the th encounter, and the majority of patients would recommend a th visit to someone else. the investigators also plan to incorporate resident feedback into the th experience to further improve the training program’s impact. based on feedback provided, consideration will be made to expand the program to include first-time encounters of the undifferentiated patient via the th platform, and appropriately link learning outcomes to acgme milestones relevant to em. conclusions in response to the accumulating evidence in support of new th roles and education, we have created a feasible th training opportunity integrated within an em residency training that aligns with patient-centered care. in this first-year pilot program, both patients and resident providers were satisfied with this new service and new educational opportunity, respectively. successfully optimizing this rotation has the opportunity to create a unique training opportunity for em residents, which will help them become part of a skilled th workforce to meet a rapidly-growing demand, and, in the process, prepare them for diverse and future- oriented job opportunities. additional information disclosures human subjects: consent was obtained by all participants in this study. thomas jefferson university issued approval n/a. the study was exempt from review by the institutional review board (irb) of the sidney kimmel medical college of thomas jefferson university in philadelphia, pennsylvania, as it was part of a university-wide training program intervention for post-graduate trainees at our institution. no patient identifying information was collected. please note that the study did not involve animal or human tissue. . animal subjects: all authors have confirmed that this study did not involve animal subjects or tissue. conf licts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. references . singh r, mathiassen l, stachura me, astapova ev: sustainable rural health innovation: a public health case study. health serv res. , : - 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( ). accessed: march , : http://infed.org/mobi/david-a-kolb-on-experiential-learning/. . anderson ja, adams m: acknowledging the learning styles of diverse student populations: implications for instructional design. new directions for teaching and learning. l.l.b border, n.v.n. chism (ed): jossey-bass publishers, san francisco; . - . . /tl. . misky gj, wald hl, coleman ea: post-hospitalization transitions: examining the effects of timing of primary care provider follow-up. j hosp med. , : - . . /jhm. . pearl r: kaiser permanente northern california: current experiences with internet, mobile, and video technologies. health aff. , : - . . /hlthaff. . . dorsey er, topol ej: state of telehealth . n engl j med. , : - . . /nejmra . schwamm lh: telehealth: seven strategies to successfully implement disruptive technology and transform health care. health aff. , : - . . /hlthaff. . papanagnou et al. cureus ( ): e . doi . /cureus. of http://www. health.org/dms/ health/downloads/reports/ telehealthlow.pdf https://dx.doi.org/ . /heat. . -psh https://dx.doi.org/ . /heat. . -psh http://infed.org/mobi/david-a-kolb-on-experiential-learning/ http://infed.org/mobi/david-a-kolb-on-experiential-learning/ https://dx.doi.org/ . /tl. https://dx.doi.org/ . /tl. https://dx.doi.org/ . /jhm. https://dx.doi.org/ . /jhm. https://dx.doi.org/ . /hlthaff. . https://dx.doi.org/ . /hlthaff. . https://dx.doi.org/ . /nejmra https://dx.doi.org/ . /nejmra https://dx.doi.org/ . /hlthaff. . https://dx.doi.org/ . /hlthaff. . 	integrating telehealth emergency department follow-up visits into residency training 	abstract 	introduction 	methods 	results 	conclusion 	introduction 	materials and methods 	targeted learners 	patient recruitment 	assessment and supervision 	the telehealth visit 	data collection 	educational and theoretical considerations 	results 	table : demographic and chief complaint data of patients receiving telehealth (th) follow-up visits after emergency department discharge (n= ) 	table : areas for programmatic improvement in telehealth (th) training 	discussion 	conclusions 	additional information 	disclosures 	references untitled . couvillion ss, margolis r, mavrofjides e, hess d, murray tg. laser treatment of coats’ disease. j pediatr ophthalmol strabismus. ; ( ): - . . shapiro mj, chow cc, karth pa, kiernan df, blair mp. effects of green diode laser in the treatment of pediatric coats disease. am j ophthalmol. ; ( ): - . . nucci p, bandello f, serafino m, wilson me. selective photocoagulation in coats’ disease: ten-year follow-up. eur j ophthalmol. ; ( ): - . . pulido js, mieler wf, walton d, et al. results of peripheral laser photocoagu- lation in pars planitis. trans am ophthalmol soc. ; : - , discussion - . . early treatment for retinopathy of prematurity cooperative group. revised in- dications for the treatment of retinopathy of prematurity: results of the early treat- ment for retinopathy of prematurity randomized trial. arch ophthalmol. ; ( ): - . . goggin m, o’keefe m. diode laser for retinopathy of prematurity: early outcome. br j ophthalmol. ; ( ): - . . ling cs, fleck bw, wright e, anderson c, laing i. diode laser treatment for reti- nopathy of prematurity: structural and functional outcome. br j ophthalmol. ; ( ): - . . paysse ea, hussein ma, miller am, brady mccreery km, coats dk. pulsed mode versus near-continuous mode delivery of diode laser photocoagulation for high- risk retinopathy of prematurity. j aapos. ; ( ): - . . mizuno k. binocular indirect argon laser photocoagulator. br j ophthalmol. ; ( ): - . . mizuno k, takaku y. dual delivery system for argon laser photocoagulation: im- proved techniques of the binocular indirect argon laser photocoagulator. arch ophthalmol. ; ( ): - . . friberg tr. clinical experience with a binocular indirect ophthalmoscope laser delivery system. retina. ; ( ): - . . pulido js, folk jc. laser photocoagulation of the retina and choroid. san fran- cisco, ca: aao; . . oosterhuis ja, journée-de korver hg, kakebeeke-kemme hm, bleeker jc. transpupillary thermotherapy in choroidal melanomas. arch ophthalmol. ; ( ): - . . mainster ma, reichel e. transpupillary thermotherapy for age-related macular degeneration: long-pulse photocoagulation, apoptosis, and heat shock proteins. ophthalmic surg lasers. ; ( ): - . . reichel e, berrocal am, ip m, et al. transpupillary thermotherapy of occult sub- foveal choroidal neovascularization in patients with age-related macular degeneration. ophthalmology. ; ( ): - . . vogel a, birngruber r. temperature profiles in human retina and choroid during laser coagulation with different wavelengths ranging from - nm. lasers light ophthalmol. ; : - . . puliafito ca, deutsch tf, boll j, to k. semiconductor laser endophotocoagula- tion of the retina. arch ophthalmol. ; ( ): - . . shah pk, narendran v, kalpana n. large spot transpupillary thermotherapy: a quicker laser for treatment of high risk prethreshold retinopathy of prematurity. a randomized study. indian j ophthalmol. ; ( ): - . . iridex manual of products. mountain view, ca: iridex corp; . archives web quiz winner c ongratulations to the winner of our april quiz, juan d. arias, md, fun-dación oftalmológica de santander, clinica foscal, bucaramanga, colom- bia, and ocular oncology service, wills eye institute, thomas jefferson univer- sity, philadelphia, pennsylvania. the correct answer to our april challenge was foscarnet crystals. for a complete discussion of this case, see the research letters section in the may archives (martı́nez-castillo s, marı́n-lambı́es c, gallego- pinazo r, arévalo jf, dı́az-llopis m. crystallization after intravitreous foscarnet injections. arch ophthalmol. ; [ ]: - ). a b c t n s i t n s i be sure to visit the archives of ophthalmology website (http://www.archophthalmol .com) and try your hand at our clinical challenge interactive quiz. we invite visi- tors to make a diagnosis based on selected information from a case report or other feature scheduled to be published in the following month’s print edition of the archives. the first visitor to e-mail our web editor with the correct answer will be recognized in the print journal and on our website and will receive a -year com- plimentary online subscription to archives of ophthalmology. arch ophthalmol / vol (no. ), sep www.archophthalmol.com © american medical association. all rights reserved. downloaded from: https://jamanetwork.com/ by a carnegie mellon university user on / / thz paper nim version rev .doc production of high power femtosecond terahertz radiation george r. neil( )*, g. l. carr( ), joseph f. gubeli iii ( ), k. jordan( ), michael c. martin( ), wayne r. mckinney( ), michelle shinn ( ), masahiko tani ( ), and g. p. williams( ), x.-c. zhang ( ) ( )thomas jefferson national accelerator facility, jefferson avenue, newport news, va usa ( )national synchrotron light source, brookhaven national laboratory, upton, ny ( )advanced light source, lawrence berkeley national laboratory, berkeley, ca ( ) research center for superconductor photonics, osaka university, - yamadaoko, suita, osaka - , japan ( )physics department, rensselaer polytechnic institute, th st., troy, ny - ———————————————————————————————————————————————————————— abstract the terahertz (thz) region of the electromagnetic spectrum is attracting interest for a broad range of applications ranging from diagnosing electron beams to biological imaging. most sources of short pulse thz radiation utilize excitation of biased semiconductors or electro-optic crystals by high peak power lasers. for example, this was done by using an un- doped inas wafer irradiated by a femtosecond free-electron laser (fel) at the thomas jefferson national accelerator facility. microwatt levels of thz radiation were detected when excited with fel pulses at . µm wavelength and w average power. recently substantially higher powers of femtosecond thz pulses produced by synchrotron emission were extracted from the electron beamline. calculations and measurements confirm the production of coherent broadband thz radiation from relativistic electrons with an average power of nearly watts, a world record in this wavelength range by a factor of , . we describe the source, presenting theoretical calculations and their experimental verification. potential applications of this exciting new source include driving new non-linear phenomena, performing pump-probe studies of dynamical properties of novel materials, and studying molecular vibrations and rotations, low frequency protein motions, phonons, superconductor bandgaps, electronic scattering, collective electronic excitations (e.g., charge density waves), and spintronics. pacs codes: . .cr, . .ms keywords: linac, thz, recirculation ——— * neil, george r., jefferson lab, jefferson avenue, mail stop a, phone: - - , fax: - - . introduction the thz region, ( thz = cm- or mev), lies in the far infrared spectral range where conventional thermal sources are very weak. for example, a k blackbody source typically provides less than microwatt/cm- . while narrow band sources have been available using fel technology[ ], a significant advancement in broadband thz sources has occurred over the past decade with the advent of coherent thz radiation emission from photocarriers in a biased semiconductor or from optical rectification in an electro-optic crystal[ ]. an energy per pulse of about µj has been achieved, implying mw peak powers, but at repetition rates of khz such that average power levels are only mw[ ]. the jlab fel was used to produce such radiation from a semiconductor while operating in the third harmonic at micron[ ]. this work describes a different process for producing coherent thz radiation from accelerated electrons. this process also begins with pulsed laser excitation in gaas, but uses photoemission to produce bunches of electrons. using the energy recovery linac (erl) at the jefferson lab free electron laser[ ], electron bunches are brought to ~ mev in a linac and then transversely accelerated by a magnetic field to produce the thz emission as synchrotron radiation. this accelerator produces high average current (up to ma) by operating at a very high repetition rate (up to mhz) using superconducting rf cavities and recovering the energy of the spent electrons. electron bunches as short as ~ fs are produced by the technique of energy modulation followed by compression in the dispersive region of a magnetic chicane. like the thz emitter described above, the electrons experience a common acceleration. if the electron bunch dimensions are small (in particular, the bunch length is less than the wavelength of observation), one obtains a multiparticle coherent enhancement[ , ] of the form n[ - f(ω)]+n , where n is the number of particles in a bunch and f(ω)is the fourier transform of the normalized longitudinal particle distribution within the bunch. the power produced is given by larmor’s formula[ ] which in cgs units takes the form: e a power c γ= ( ) where e is the charge, a is the acceleration, c the speed of light and γ is the ratio of the mass of the electron to its rest mass. for a conventional auston switch thz emitter based on a laser pulse striking gaas, the voltage across the gap might produce an acceleration of the freed charges on the order of cm/sec . a similar acceleration results from a m radius magnetic bend but in our case γ is , yielding a considerable enhancement in radiated power. such coherent synchrotron radiation has been observed from electrons accelerated in linacs[ - ], and more recently it has been discussed and observed from electron bunches in storage rings[ - ], but not at thz frequencies or in a form stable enough for use as a light source although there are several development efforts in place in this area[ , ]. . calculations and results details of the theory have been presented elsewhere[ ]; in fig. we present calculations and measurements of the power emitted by a fsec fwhm electron bunch. we assumed the electron bunches had an energy of mev, a charge of pc, and that they passed through a m radius bend at a . mhz repetition rate. figure . calculated and measured spectral power. the measured spectrum suffers from diffraction losses at the long wavelength end. . . . . frequency (thz) measured calculated ( fs bunch length) w a tt s/ cm - frequency (cm - ) . diffraction losses . . . . frequency (thz) measured calculated ( fs bunch length) w a tt s/ cm - frequency (cm - ) . diffraction losses i = . ma polarizer vertical polarizer horizontal m e a s u re d i n te n s it y ( a rb . u n it s ) wavenumbers (cm - ) the spectral content of the emitted thz light was analyzed using a nicolet rapid-scan michelson interferometer and detected using a . k infrared laboratories bolometer. our collection angle was × milliradians and the extraction window was quartz. we were able to determine the absolute power in two ways, one using a calibrated pyro- electric detector, and one by comparing our spectra with that from a k thermal source. the data has been scaled on the basis of these absolute power measurements. the spectral onset of the super- radiant enhancement of the thz light is clearly seen on the high frequency side. the onset shape is also seen to match closely the theoretical predictions. note that there is a severe discrepancy on the lower frequency side due to diffraction effects from the small aperture at long wavelengths. we note that we were able to observe considerable changes in spectral weight depending on operating conditions, and were able to enhance certain spectral regions via the machine parameters. thus the electron bunch distributions were not purely gaussian but contained higher order components. since we measured the intensity, not field, of the emitted light, we were unable to determine uniquely the electron density distributions, but this might be possible in future experiments using coherent detection. this can in principle be a powerful technique for the analysis of linac performance. for example noise spectral measurements (figure ) can be utilized to uncover sources of beam fluctuations. figure . a measurement of noise on the thz signal was used to identify fluctuations in the drive laser power on the cathode. finally we measured the polarization of the emitted thz light. the intensity ratio for the horizontal to vertical polarization components is for synchrotron radiation in the long-wavelength limit. this assumes full collection of the emitted radiation. we note that the dominant intensity is near cm- , which has a natural opening angle of millirad. since the emission pattern is “clipped” by the mrad collection optics, the calculated ratio is expected to be higher, approaching a value of . using a wire-grid polarizer placed between the michelson interferometer and the detector, we measured a ratio of (see figure ). figure . spectral characteristics illustrating the structure that can result from electron density modulation at higher orders than the bunch length. the measured polarization ratio is in agreement with calculations. the intensity of the radiation can be gauged from figure , which is a real time image taken in thz radiation on a pyroelectric camera. although detailed thz images have previously been obtained by a number of research groups, it typically took minutes to hours to obtain an image. the present source should permit real time imaging over large areas and/or determination of spectral absorption in a broad wavelength band simultaneously. - - - - - - bolometer detector output into a spectrum analyzer. ftir scanning mirror turned off. db v frequency (hz) jlab thz beam beam blocked figure . a real time image of the thz emission taken using a pyroelectric camera illustrates the available power. . conclusion we are now installing an upgrade to the facility at jefferson lab (see neil, et al., in a separate talk at this conference) in which we will considerably improve the thz extraction aperture. thz radiation will be outcoupled through a port and delivered to an experimental facility for use independent of the fel. . acknowledgements this work was supported primarily by the u.s. dept. of energy under contracts de-ac - ch (brookhaven national laboratory), de- ac - sf (lawrence berkeley national laboratory) and de-ac - -er (thomas jefferson national accelerator facility). the jlab fel is supported by the office of naval research, the air force research laboratory, the commonwealth of virginia and the laser processing consortium. we are indebted to our colleagues at each institution for critical support. . references [ ] s. winnerl, et al., applied physics letters , - 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[ ] g. p. williams, rev. sci. instr. , ( ). the new world stamp corner robin wilson the new world tt he founders of american independence included several highly learned people who encouraged the study of mathematics and science in the late th century. benjamin franklin ( – ) invented the franklin stove, bifocal spectacles, the odometer, and the lightning rod. he also carried out experiments in electricity, such as his celebrated one on lightning conduction in which he flew a kite in a thunderstorm. although never claiming to be a mathematician, he was fascinated by magic squares, and constructed a remarkable square in which the numbers in any row, column, or sub-square, have the same sum. thomas jefferson ( – ), the third president of the united states, extolled the virtues of science and wrote of the importance of calculation (extracting roots, solving quadratic equations, and using logarithms). interested in classical archi- tecture, he designed his home, monticello, and the rotunda of the university of virginia. while ambassador in paris he became enthused by the metric system being proposed in france, and strongly advocated decimalising the american coinage, but it was not until that the united states con- gress passed a law legalising the use of metric measurements. benjamin banneker ( – ) was a self-taught mathe- matician and astronomer. when years old he designed and built an accurate striking clock, although he had never seen one previously. in later life he constructed accurate astronomical tables. in he compiled the first of several almanacs, as ‘the creation of a free man of the african race’, and sent it to jefferson with a plea to end slavery. banneker was appointed by george washington, himself a noted surveyor, to help with the surveying and layout of the new capital city. benjamin franklin thomas jefferson franklin’s lightning experiment virginia rotunda banneker and washington benjamin banneker � column editor’s address: robin wilson, mathematical institute, andrew wiles building, university of oxford, uk e-mail: r.j.wilson@open.ac.uk the mathematical intelligencer � springer science+business media new york doi . /s - - - 	the new world jefferson scale of patient’s perceptions of physician empathy: preliminary psychometric data aim to develop a brief scale for measuring patient’s perceptions of their physician’s empathic engagement and to provide preliminary evi- dence in support of aspects of the scale’s psychometrics. method study comprised patients, out of patients ( % re- sponse rate) seen by residents in the internal medicine residency program at the jefferson hospital ambulatory clinic as part of their ambulatory training at thomas jefferson university hospital. a -item questionnaire entitled the jefferson scale of patient’s perceptions of physician empathy was developed and administered to the study par- ticipants. its factor structure, item-total score correlations, and correla- tions with several relevant criterion measures were examined. results factor analysis indicated that the scale was measuring a single factor of emphatic engagement. item scores and total scores of the jefferson scale of patient’s perceptions of physician empathy yielded significant correlations with the american board of internal medicine patient ratings form and with selected items from other relevant instru- ments measuring physicians’ humanistic behavior and the appraisal of physicians’ performance. conclusions a brief scale for assessing physician empathy from the pa- tients’ perspective showed good psychometric characteristics and can be used for the assessment of patient outcomes. department of medicine, jefferson medical college of thomas jefferson university, philadelphia, pa, usa center for research in medical education and health care and department of psychiatry and human behavior, jefferson medical college of thomas jefferson university, philadelphia, pa, usa gregory c. kane , joanne l. gotto , salvatore mangione , susan west , mohammadreza hojat gregory c. kane department of medicine jefferson medical college walnut street, philadelphia, pa , usa gregory.kane@jefferson.edu > received: october , > accepted: december , > croat med j. ; : - > correspondence to: clinical scienceclinical science www.cmj.hr mailto: gregory.kane@jefferson.edu croat med j ; : - empathy has been described as an important el- ement of professionalism in medicine ( - ). the importance of empathy as the foundation for positive relationships between patients and physicians has been discussed in medical edu- cation and health care research ( - ). physi- cian empathy and effective communication skills increase patients’ satisfaction, improve patients’ compliance, and enhance physicians ability to diagnose and treat their patients ( , ). improved outcomes may be a result of better compliance or the activation of psycho- logical factors that are formed in trusting rela- tionships ( , ). viewed from the contrasting perspective, a lack of empathy can have negative effects on clinical outcomes. resident’s humanistic qual- ities, communication skills, and professional- ism are considered important components of the trainee’s evaluation by both the american board of internal medicine, which certifies in- ternists, as well as the accreditation counsel for graduate medical education, which accredits programs in american medical schools(http:// www.acgme.org/outcome/comp/comphome.asp). while the new outcomes project of the ac- creditation counsel for graduate medical edu- cation does not specifically call for an evaluation of physician empathic concern; interpersonal communication with patients, cultural sensitiv- ity, and professionalism are key components of the new evaluation process. specifically, residents are expected to form effective therapeutic rela- tionships with patients and families, to build re- lationships through listening, narrative or non- verbal skills, and to develop skill in education and counseling of patients and their families (http:// www.acgme.org/outcome/comp/comphome.asp), all of which are relevant to physician-patient em- pathic engagement. patients are considered as an important source for the assessment of these skills. therefore, it is important to develop an in- strument to assess patient’s perceptions of phy- sician empathic engagement. this study was de- signed to examine the psychometric properties of such an instrument. methods participants data for this study were collected in and for internal medicine residents at dif- ferent levels of training at thomas jefferson uni- versity hospital and from patient encounters in the resident ambulatory clinic, jefferson hospi- tal ambulatory clinic. complete data (with no missing responses) were available for patient encounters with residents. instruments based on a review of literature, we developed the jefferson scale of patient’s perceptions of physician empathy. this is a brief instrument ( - item) intended to measure patient’s perceptions of his/her physician’s empathic concern and un- derstanding (table ). patients were asked to re- spond to each item on their physicians by using a -point likert-type scale (from = strongly dis- agree to = strongly agree). it takes a few min- utes to answer the scale. to examine the validity of the jefferson scale of patient’s perceptions of physician empathy we used the american board of internal medi- cine patient rating form intended to measure as- pects of physician communication skills, human- istic qualities, and professionalism in medicine ( ). this form was developed by the american board of internal medicine to be used as part of a comprehensive evaluation for physician recertifi- cation and presents an opportunity to assess phy- sician-patient relationships at all levels of medi- cal education and practice. the american board of internal medicine patient rating form used in this study included items, each answered on a -point likert scale (from = strongly disagree to = strongly agree). a “not applicable” option was also available. http://www.acgme.org/outcome/comp/comphome.asp http://www.acgme.org/outcome/comp/comphome.asp http://www.acgme.org/outcome/comp/comphome.asp http://www.acgme.org/outcome/comp/comphome.asp kane et al: patient’s perception of physician empathy also, five items that were conceptually rele- vant to empathic physician-patient engagement were selected to be used as additional criterion measures for the validity study (table ). four of these items were adapted from the physicians’ humanistic behavior questionnaire developed by weaver et al ( ), and one item was adapted from a questionnaire intended to measure pa- tients’ appraisal of physicians’ performance de- veloped by matthews and feinstein ( ). finally, we used scores of the jefferson scale of physician empathy that was administered to a sub-sample of residents to examine the concor- dance between patient’s perceptions of physician empathy and physician’s self-reported empathy. the jefferson scale of physician empathy is a - item scale with sound psychometric support that measures physician empathic orientation and be- havior ( - ). procedures the approval of our institutional review board was obtained for this project. patients were ap- proached in the waiting room upon checkout after completing their visit with their resident physician at the jefferson hospital ambulatory clinic. patients were asked by a trained research assistant to voluntarily and confidentially com- plete the survey containing demographic ques- tions, plus survey items ( for the jefferson scale of patient’s perceptions of physician empa- thy, criterion measures, and for the american board of internal medicine patient rating form) as a part of a quality improvement project with- in the residency program at thomas jefferson university hospital (web-extra material). the resident’s name was printed on the survey that was anonymously completed by the patient. to maintain complete confidentiality, the patients were guided to a private location, away from the physician treatment areas to complete the survey. the research assistant would offer to read and re- cord the patient’s responses if this was requested by patients. additionally, patients were told that their participation or refusal would in no way in- fluence the care they received. statistical analyses principal component factor analysis was used to examine the dimensionality of the jefferson scale of patient’s perceptions of physician empathy. we calculated the pearson product-moment cor- relation coefficients for the validity study. results a total of patient rating forms were received. of these, ( %) were complete with no missing data that were used as the units of anal- yses in this study. in factor analysis of data, only one factor emerged with an eigenvalue greater than one (eigenvalue = . ), indicating that the jefferson scale of patient’s perceptions of phy- sician empathy is a uni-dimensional scale mea- suring only one underlying factor interpreted as “empathic engagement.” the factor coefficients are reported in table . the item-total score correlations were all pos- itive and statistically significant (p< . ), and ranged from a low of . to a high of . with table . factor coefficients, item-total score correlations, and correlations with american board of internal medicine patient rating form for the items of jefferson scale of patient’s perception of physician empathy* items factor coefficients item-total score correlations correlations with abim patient rating form understands my emotions, feelings and concerns. . . . seems concerned about me and my family. . . . can view things from my perspective (see things as i see them). . . . asks about what is happening in my daily life. . . . is an understanding doctor. . . . *the jefferson scale of patient’s perceptions of physician empathy items were answered on a -point likert-type scale ( = strongly disagree, = strongly agree). all correlations were statistically significant (p< . ). croat med j ; : - a median correlation of . , indicating that all items contributed substantially to the total score (table ). inter-item correlations ranged from a low of . to a high of . with a median of . (p< . ). the reliability coefficient (the cronbach α coefficient of internal consistency) for the jef- ferson scale of patient’s perceptions of physician empathy was . which is relatively low, but with only five items in the scale it can be consid- ered satisfactory. the score distribution of the jefferson scale of patient’s perceptions of physician empathy was skewed toward the upper tail of the distribu- tion reflected in the mean score of . on a scale with a maximum score of , indicating that pa- tients expressed an extremely positive view of the residents’ empathic engagement (table ). correlations between each item of the jef- ferson scale of patient’s perceptions of physi- cian empathy and the total scores of the amer- ican board of internal medicine patient rating form ranged from a low of . to a high of . (table ). all these correlations were statistically significant (p< . ) with a median of . , in- dicating that the items of the jefferson scale of patient’s perceptions of physician empathy were significantly related to the evaluation of physi- cians’ communication skills, humanistic qual- ities, and professionalism as measured by the american board of internal medicine patient rating form, thus providing support for the valid- ity of the items. also, correlations between the total scores of the jefferson scale of patient’s perceptions of physician empathy and scores for each item of the american board of internal medicine pa- tient rating form were examined. the highest correlation (r = . ) was obtained for the fol- lowing item of the american board of internal medicine patient form: “(this physician) is in- terested in me as a person; does not act bored or ignore what i have to say.” the lowest correla- tion (r = . ) was found for the following item: “(this physician) explains what you need to know about your problems and what to expect in plain language.” the median correlation was . , and all correlations were statistically significant (p< . ). the correlation between the total score of the jefferson scale of patient’s perceptions of phy- sician empathy and the average scores of the american board of internal medicine patient ratings was . (p< . ), providing support for the criterion-related validity of the jefferson scale of patient’s perceptions of physician em- pathy (table ). correlations between the total scores of the jefferson scale of patient’s perceptions of phy- sician empathy and the selected items from the physicians’ humanistic behavior questionnaire ( ) and from the patient’s appraisal of physi- cians’ performance ( ) were all statistically sig- nificant (p< . ; table ). the correlation be- table . descriptive statistics for the jefferson scale of patient’s perception of physician empathy descriptive statistics mean . standard deviation . possible range - actual range - cronbach α reliability . table . validity coefficients for the jefferson scale of patient’s perception of physician empathy expressed as correlation coef- ficient between scale result and six criterion measures*. criterion measures validity coefficients abim patient rating form† . shows concerns for my feelings and needs, not just my physical status.‡ . asks me how i feel about my problems.‡ . arranges for adequate privacy when examining or talking with me.‡ . is always in a hurry.‡ - . takes my wishes into account when making decisions.§ . *the jefferson scale of patient’s perceptions of physician empathy items were answered on a -point likert-type scale ( = strongly disagree, = strongly agree). all correlations were statistically significant (p< . ) †total scores on the american board of internal medicine (abim) patient rating form ( ). ‡adapted from the physicians’ humanistic behavior questionnaire ( ). §adapted from patients’ appraisal of physicians’ performance ( ). kane et al: patient’s perception of physician empathy tween scores of the jefferson scale of patient’s perceptions of physician empathy and the item that describes physician as being always in a hur- ry was expectedly negative, indicating that being in rush is not conducive to empathic engagement in the patient care context. these findings fur- ther support the criterion-related validity of the jefferson scale of patient’s perceptions of physi- cian empathy. data for both the jefferson scale of patient’s perceptions of physician empathy and the jef- ferson scale of physician empathy were available for a small number of residents (n = ). correla- tion coefficient of the two scales for this group of residents was . , which did not reach the level of statistical significance (p = . ). discussion several conclusions can be drawn from the find- ings of the present study. first, the results of fac- tor analysis suggest that the jefferson scale of patient’s perceptions of physician empathy mea- sures a single factor that can be entitled physi- cian’s empathic engagement as perceived by the patient. second, findings that each item of the jefferson scale of patient’s perceptions of phy- sician empathy and its total scale score were sig- nificantly correlated with the responses on the selected criterion measures, including the total scores of the american board of internal medi- cine patient rating form provide evidence for the criterion-related validity of the jefferson scale of patient’s perceptions of physician empathy. third, a lack of significant correlation between patient’s perceptions of physician’s empathic en- gagement and the resident’s self-reported empa- thy deserve further clarification. a lack of rela- tionship on empathic understanding between therapists and patients has been reported ( ) and explained by factors such as residents’ inabil- ity to communicate their empathic understand- ing to their patients, or patients’ viewing em- pathic engagement differently from physicians. in another study with residents in a family med- icine program, a significant correlation (r = . , p< . ) was observed between the jefferson scale of physician empathy and the jefferson scale of patient’s perceptions of physician em- pathy scores (data not shown). we expected to find a significant overlap between scores of the jefferson scale of patient’s perceptions of phy- sician empathy and the jefferson scale of physi- cian empathy in the present study. the non-sig- nificant correlation we observed between these two measures could be due to the skewed score distribution of the jefferson scale of patient’s perceptions of physician empathy, restriction of range, and the ceiling effect. we examined the distribution of scores of the jefferson scale of pa- tient’s perceptions of physician empathy for the residents who completed the jefferson scale of physician empathy and found that a great ma- jority ( %) of them obtained the maximum score on the jefferson scale of patient’s percep- tions of physician empathy, leading to a severe skewed distribution and an extreme ceiling ef- fect. the true relationship between variables can- not be fully captured with such an extreme ceil- ing effect. more empirical research is needed to examine factors that contribute to the relation- ships between physicians’ self-reported empathy and patients’ perceptions of their physicians’ em- pathy in clinical encounters. it is generally believed that patient’s percep- tions of a caregiver’s empathy is associated with a positive treatment outcome ( , ), but empirical evidence in support of this proposition is rarely available. one reason for the scarcity of empiri- cal evidence is the absence of a psychometrically sound instrument for measuring patients’ per- ceptions of their physicians’ empathic engage- ment when rendering care. although additional studies are needed to further examine different aspects of psychometrics of the jefferson scale of patient’s perceptions of physician empathy in groups of physicians in different specialties and patients in different settings (outpatient, hospi- croat med j ; : - talized), our preliminary findings suggest that it is feasible to use this scale to study predictors and outcomes of patients’ perceptions of physician empathy. the external validity (generalization of the findings) of this study is limited because of the convenient sampling that included only residents in one residency training program who were not necessarily the primary caregivers of the patients. in this study, we used patients rather than the residents, as the unit of observation. some of the residents were evaluated by more than one pa- tient. our analyses showed that the pattern of findings remained generally unchanged when residents were used as the unit of observation. despite the study limitations, the findings generally suggest that it is feasible to use patients’ ratings of residents’ humanistic attributes in a residency clinic setting. this is important for the accreditation counsel for graduate medical education outcome project that emphasizes the centrality of the patient in the evaluation of resi- dents. we believe that greater use of the patients’ assessments of their care provider’s empathy as part of the evaluation of residents could have a significant impact upon the enhancement of pro- fessionalism in medicine. acknowledgments we would like to acknowledge the following individu- als for their contributions to this project: kaye maxwell from the center for research in medical education for supplying data analysis; linda brooks from the jefferson hospital ambulatory practice for assisting with the fa- cilitation of survey completion in the resident’s clinic; and deborah tuitt for formatting and distributing pa- tients’ surveys. dorissa bolinski assisted us in editorial polishing. this project was supported in part by a grant (to dr hojat) from pfizer medical humanities initia- tive, pfizer inc. new york. references hojat m. empathy in patient care: antecedents, development, measurement, and outcomes. new york (ny): springer; . arnold l. assessing professional behavior: yesterday, today, and tomorrow. acad med. ; : - . medline: veloski jj, hojat m. measuring specific elements of professionalism: empathy, teamwork, and 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ll, leas bf, fortna gs. the value of patient and peer ratings in recertification. acad med. ; :s - . medline: weaver mj, ow cl, walker dj, degenhardt ef. a questionnaire for patients’ evaluations of their physicians’ humanistic behaviors. j gen intern med. ; : - . medline: matthews da, feinstein ar. a new instrument for patients’ ratings of physician performance in the hospital setting. j gen intern med. ; : - . medline: hojat m, mangione s, nasca tj, cohen mjm, gonnella js, erdmann jb, et al. the jefferson scale of physician empathy: development and preliminary psychometric data. educ psychol meas. ; : - . hojat m, gonnella js, nasca tj, mangione s, veloksi jj, magee m. the jefferson scale of physician empathy: further psychometric data and differences by gender and specialty at item level. acad med. ; ( suppl):s - . medline: hojat m, gonnella js, nasca tj, mangione s, vergare m, magee m. physician empathy: definition, components, measurement, and relationship to gender and specialty. 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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids= &dopt=abstrac http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids= &dopt=abstrac http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids= &dopt=abstrac http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids= &dopt=abstrac http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids= &dopt=abstrac wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ two-in-one: activation and inactivation at the intracellular gate of a kv channel sunday, february , a receptor x were transfected into cho cells. the cho transfectants were char- acterized by facs and then scaled up for kinexa binding studies. kinexa has been used to measure binding affinity of adnectin-a to the cell surface ex- pressed receptor x to measure the effect of avidity of the multivalent adnectin binding to receptor clusters. as controls for the functional activity of the adnectin-a and the affinity of the monovalent interaction, the same kinexa assay was used, substituting the soluble receptor x extracellular domain for the transfected cho cells. the binding avidity measured by kinexa for cho expressed receptor is pm for both species of receptor x. however, the affinity of adnectin-a for monovalent soluble receptor x was quite different between the species suggesting that avidity due to receptor clustering equilizes the functional avidity at the cell surface. platform: voltage-gated k channels: activation/ inactivation mechanisms -plat a-type kv channel closed-state inactivation is modulated by the tetramerization domain interacting with auxilary kchip a yi-quan tang , fan yang , jingheng zhou , jie zheng , kewei wang . peking university, beijing, china, university of california at davis, davis, ca, usa. a-type kv potassium channels undergo a conformational change towards a non-conductive state at negative membrane potentials, a dynamic process known as closed-state inactivation (csi). csi causes inhibition of channel ac- tivity without prerequisite of channel opening, thus providing a dynamic regu- lation of neuronal excitability, dendritic signal integration and synaptic plasticity. however, the structural determinants underlying kv csi remain largely unknown. we have recently demonstrated that auxiliary kchip a sub- unit contains an n-terminal kv inhibitory domain (kid) that directly interacts with kv . channels to enhance csi. in this study, we utilized the fret two- hybrid mapping and bifc-based screening combined with electrophysiology, and identified the intracellular tetramerization (t ) domain that functions to suppress csi and serves as a receptor for the binding of kid. disrupting kv . t -t interaction by mutating c a within the c h motif of t domain facilitated csi, and ablated the kid-mediated enhancement of csi. furthermore, replacing the characteristic c h motif of kv . t domain with the t domain from kv . without the c h motif or kv . with the c h motif resulted in channels functioning with enhanced or suppressed csi, respectively. taken together, our findings reveal a novel role of the t domain in suppressing kv csi with the c h motif functioning to stabilize the channel activation gate; and kchip a kid directly interacts with the t domain to relieve the stabilization, leading to facilitation of csi and inhibition of channel function. -plat two-in-one: activation and inactivation at the intracellular gate of a kv channel manuel covarrubias , jeffrey d. fineberg . neuroscience, jefferson medical college of thomas jefferson university, philadelphia, pa, usa, physiology and molecular biophysics, jefferson medical college of thomas jefferson university, philadelphia, pa, usa. n-type and p/c-type inactivation are firmly established mechanisms of inac- tivation in voltage-gated kþ (kv channels). however, kv .x channel com- plexes, which undergo fast preferential closed-state inactivation (csi; fineberg et al., , jgp . : - ), appear to use a distinct but un- known inactivation mechanism. previously, we hypothesized that a weak interaction between the voltage sensing domain and the intracellular activa- tion gate underlies csi (bähring & covarrubias, , j physiol : - ). thus, csi is essentially governed by the intracellular activation gate, which fails to open and adopts an inactivated conformation. to directly test this hypothesis, we investigated the heterologously expressed kv . ternary channel complex including accessory subunits kchip and dpp , and ex- ploited the ‘‘trap-door’’ paradigm of the activation gate. the results show that kv . inactivation traps intracellularly applied quaternary ammonium blockers (btbua and tbua) inside the channel’s pore. the trapped blockers can only escape if the channels are opened again by subsequent depolariza- tions. by contrast, inactivation cannot trap tea, whose binding kinetics is faster than that of channel gating. moreover, under identical conditions, a shaker kv channel (shb-t k) known to exhibit fast p/c-type inactivation cannot trap btbua. these findings conclusively suggest that the intracellular activation gate of the kv . ternary channel complex plays a novel dual role, controlling both activation and inactivation. supported in part by nih grant r ns (mc). -plat development and validation studies of universal pharmacophore models for herg channel openers serdar durdagi , , matthew patterson , sergei y. noskov . department of biophysics, bahcesehir university, faculty of medicine, istanbul, turkey, biological sciences, institute for biocomplexity and informatics, university of calgary, calgary, ab, canada. the intra-cavitary drug blockade of herg channel, a common off-target for many drugs, have been extensively studied both experimentally and theoreti- cally. structurally diverse ligands inadvertent blockade of rapid component of delayed rectifying kþ currents are potentially pro-arrhythmic and may lead to drug-induced long qt syndrome-lqts. there are a number of natural strategies for rational drug design; one dubbed the ‘‘passive’’ approach avoids block of herg whereas the ‘‘proactive’’ strategy designs treatments to acti- vate the channel. while ‘‘passive’’ approach has been developed for decades, studies of structural mechanisms of herg channel activation by small mole- cules are truly novel. accordingly, design of the herg openers or current ac- tivators may offer a momentum for modern anti-arrhythmia drug development. significant number of small molecules with capacity for herg activation was identified in mandatory herg screens. to establish possible correlation be- tween activators structure and reactivity, we attempted to construct a universal pharmacophore model for herg channel openers using phase protocol. the biochemical data on kþ channel activators are used in training and test sets. these compounds span a wide range of structurally different chemotypes with ~ ^ -fold variances in binding affinity, which is sufficient for statistically sound model. a developed five sites aahhr (a, hydrogen-bond accepting, h, hydrophobic, r, aromatic) pharmacophore model has showed reasonable high statistical results compared to other constructed models and was selected for steric and electrostatic contour maps analysis. the predictive power of the model was also tested with external test-set (as true unknowns) compounds. pharmacophore model is also combined with previously developed receptor- based homology model of herg k channel and novel activators are generated and screened. the developed ligand-based models may serve as a basis for the synthesis of novel potential therapeutic herg activators. -plat n-terminal regulation of herg kd channel deactivation steven j. thomson, angela hansen, michael c. sanguinetti. nora eccles harrison cardiovascular research and training institute, university of utah, salt lake city, ut, usa. slow deactivation of herg (kv . ) potassium channels maintains ikr dur- ing final repolarization of the cardiac action potential and opposes asynchro- nous early depolarization. inherited point mutations in herg that accelerate deactivation of ikr cause long qt syndrome (lqts), a disorder of ventricular repolarization that increases the risk of lethal cardiac arrhythmia. the intracellular n-terminal domain of herg is known to be essential for slow deactivation. deletion of the entire (~ residues) or just the initial residues of the n-terminus accelerates deactivation -fold. the same effect is achieved by neutralization of the charged residues, arg or arg . how many of the n-termini are required to slow channel deactivation is unknown. herg , like other kv channels, is a homotetramer. by repeatedly linking the c-terminal of one subunit to the n-terminal of the next subunit we constructed concatenated herg tetramers. a variety of homomeric and heteromeric concatenated tetramers were characterized (i.e., wtn/r a:r a( -n); where n = to ). the concatenated channel containing a single r a/r a subunit and wild-type subunits deactivated as fast as the concatenated channel con- taining only r a/r a subunits. the lqts-associated mutation r q, located in the n-terminal of herg was also studied. again, a concatenated tetramer containing a single mutant subunit deactivated as fast as channels with r q mutations in all four subunits. our results show that all n-termini are required to mediate slow deactivation in wild-type herg channels. -plat lipid affinity to the voltage-gated potassium channel kvap elise faure , christine thompson , rikard blunck , . physiology, université de montréal, géprom, montréal, qc, canada, physique, université de montréal, géprom, montréal, qc, canada. voltage-gated potassium channels (kv) are formed by a central conducting pore surrounded by four voltage sensor domains. functional studies have re- vealed that biophysical properties of lipid molecules in the channels environ- ment can have strong effects on the activity of kv channels. here, we investigated the influence of different lipids as well as their affinity to kvap channels. we carried out electrophysiology measurements by fusing vesicles containing purified channels into planar lipid bilayers with varied lipid compo- sitions. we found that kvap properties are mainly determined by the lipid 	a-type kv channel closed-state inactivation is modulated by the tetramerization domain interacting with auxilary kchip a 	two-in-one: activation and inactivation at the intracellular gate of a kv channel 	development and validation studies of universal pharmacophore models for herg channel openers 	n-terminal regulation of herg k+ channel deactivation 	lipid affinity to the voltage-gated potassium channel kvap _editor's choice.qxd usabmjprimary care medicine for the american physician bmj usa is published monthly by jobson publishing in conjunction with the british medical association. editor, bmj usa editor, bmj steven h woolf, md, mph dr. richard smith professor, department of family practice chief executive professor, department of preventive bmj publishing group and community medicine london, uk virginia commonwealth university fairfax, virginia associate editors paul s frame, md joanne c roberts, md, facp tri-county family medicine medical director cohocton, new york whatcom hospice clinical professor of family medicine center for senior health university of rochester school of st joseph hospital medicine and dentistry bellingham, washington rochester, new york jo ann rosenfeld, md rebekah wang-cheng, md, facp assistant professor of medicine clinical professor of medicine johns hopkins university school of medical college of wisconsin medicine milwaukee, wisconsin baltimore, maryland private practice, st helena, california editorial board margaret i aguwa, do, mph david atkins, md, mph chairperson center for practice and technology dept of family & community medicine assessment college of osteopathic medicine agency for healthcare research michigan state university and quality east lansing, michigan washington, dc regina m benjamin, md, mba klea d bertakis, md, mph assistant dean for chairperson rural health dept of family & community medicine university of south alabama school of medicine college of medicine university of california, davis mobile, alabama sacramento, california mark a kelley, md thomas e kottke, md, msph executive vice president and professor of medicine chief medical officer (cardiovascular diseases) henry ford health system mayo clinic detroit, michigan rochester, minnesota rosanne m leipzig, md, phd david c slawson, md associate professor b lewis barnett, jr, professor of dept of geriatrics & adult development family medicine mount sinai school of medicine university of virginia new york, new york charlottesville, virginia edward h wagner, md, mph director w a maccoll institute for healthcare innovation group health cooperative of puget sound seattle, washington bmj usa (issn - ) is published monthly by the bmj and jobson publishing, llc, avenue of the americas, new york, ny - . periodicals postage paid at new york, ny, and additional mailing offices. postmaster: send address changes to bmj usa, jobson publishing, llc, avenue of the americas, new york, ny - . subscription rates: $ per year in the us ($ per year for students). copyright © by bmj and jobson publishing, llc. printed in the usa. all rights reserved. no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior permission, in writing, from the publishers. circulation: , office-based physicians specializing in primary care or cardiology. bmj usa is a registered trademark. bmj usa volume may editor’s choice the first americans in an letter to congress, thomas jefferson wrote, “with our indian neighbors the public peace has been steadily maintained. some instances of individual wrong have, as at other times, taken place, but in nowise implicating the will of the nation…. and, generally, from a conviction that we con- sider them as part of ourselves, and cherish with sincerity their rights and interests, the attachment of the indian tribes is gaining strength daily—is extending from the nearer to the more remote, and will amply requite us for the justice and friendship practised towards them” (http://memory.loc .gov/ammem/mtjhtml/mtjhome.html). now, years later, it can hardly be said that native americans have been the beneficiaries of overabundant “justice and friendship.” one need not recount their bar- baric treatment in the th century and the vestiges that remain on today’s reservations, but the social injustice that modern society affords the first americans does weigh on the conscience. large numbers suffer from poverty, poor housing, loss of culture, and sickness. the high disease rates and poor health care experi- enced by native americans are not unique but appear to be part of a global phenomenon among indigenous peo- ples, as the new zealander mason durie writes in this issue (p ). the public health histories of new zealand’s maori, australia’s aborigines, norway’s saami, native ha- waiians, and the first nations of canada bear striking re- semblances to historical and modern patterns among na- tive americans. a companion editorial by charles grim, director of the us indian health service, paints a more positive picture, noting recent advances in the health care of native americans (p ). for example, their life ex- pectancy has increased by years since . tribes are more engaged in self-management of health affairs. this is certainly good news, but there is still too much bad news. rates of cigarette smoking, binge drinking, and illicit drug use remain higher among native americans than among whites. fully % of native americans lack health insurance (the same is true for only % of whites). one out of every native american youths has not been to a doctor within the year. infant, neonatal, and post- neonatal mortality rates are % higher than those of whites. among adults, % of whites—but % of native americans—rate their health as fair or poor. having a chronic disease limits activity for % of whites but for % of native americans. among women age and older, more than % of whites but only % of native americans have had a recent mammogram. society faces an ethical imperative to address the socio- economic deprivation of native americans that lies at the heart of these disparities if, as jefferson wrote, we “con- sider them as part of ourselves, and cherish with sincerity their rights and interests.” otherwise, it can be said that inaction is, indeed, “implicating the will of the nation.” ✦ —steven h woolf, md, mph o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .b m j.co m / b m j: first 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contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ editorial the second neurocritical care research conference jose i. suarez • peter d. leroux published online: april � springer science+business media new york one of the missions of the neurocritical care society (ncs) is to foster clinical, experimental, and outcomes research focused on developing innovative and cost-ef- fective medical and surgical interventions for acute neurological disorders. to achieve this mission, ncs cre- ated a research committee. this committee organized the neurocritical care research conference. the most im- portant outcome of the first neurocritical care research conference (september ) was the creation of the neurocritical care research network (ncrn) [ ]. fol- lowing the success of that first endeavor, the second neurocritical care research conference took place in houston, tx may – , . this symposium was funded by ninds ( r ns - , p.i. jose i. suarez), baylor st. luke’s medical center (neuroscience center) in houston, and the integra foundation and endorsed by the baylor college of medicine (bcm) and the ncs. the overall goal of this interdisciplinary scientific gathering was to bring together a diverse group of aca- demic scientists and physicians with a common interest in understanding and advancing research in multimodality monitoring in neurocritical care diseases, in large part be- cause monitoring patient disease and care is a fundamental aspect of neurocritical care. the need for the design of adequate clinical studies to test these monitoring techniques was addressed in the context of the recently created ncrn to facilitate collaboration and patient en- rollment. in addition, this conference provided a unique opportunity for trainees, junior faculty, and other scientists to interact with investigators in the field of neurocritical care. the conference opened with a discussion on new approaches to multifaceted therapeutic bundles in neuro- critical care followed by five scientific sessions: ( ) global brain monitoring in the neurocritical care unit; ( ) re- gional brain monitoring in the neurocritical care unit; ( ) data collection and interpretation; ( ) conventional clinical trial design of multimodality monitoring; and ( ) alternative clinical trial design. the meeting had registrants and attendees. this represents a % increase in attendance compared to our first research conference. attendees came from all parts of the world including the united states, canada, latin america, europe, japan, india, and the middle east. we had lively and interesting discussions throughout the meeting. the conference was successful and well received with % stating that it was fair and balanced. at the end of the meeting, there was consensus on two major points: ( ) we need a common language to describe the technology available and the information it provides to pursue further research to advance the field and ( ) technology alone will not impact upon clinical outcome without specific inter- ventions and pathways that can modify and ameliorate the biochemical cascade unleashed by brain insults. two pro- jects have since evolved from the second neurocritical care research conference: ( ) the international multidis- ciplinary consensus conference on multimodality monitoring in neurocritical care, a collaboration between the ncs, the european society of intensive care medicine, the society of critical care medicine, and the latin & jose i. suarez jisuarez@bcm.edu division of vascular neurology and neurocritical care, department of neurology, baylor college of medicine, houston, tx, usa lankenau medical center, thomas jefferson university, philadelphia, pa, usa neurocrit care ( ) : – doi . /s - - - http://crossmark.crossref.org/dialog/?doi= . /s - - - &amp;domain=pdf http://crossmark.crossref.org/dialog/?doi= . /s - - - &amp;domain=pdf american brain injury consortium [ ] and ( ) the com- mon data elements project in subarachnoid hemorrhage in collaboration with the subarachnoid hemorrhage interna- tional trialists collaboration [ ]. this issue of neurocritical care contains the summary statements that were prepared based on the presentations and discussions that followed during this second neuro- critical care research conference. similar to the first conference, the content of each manuscript reflects input from conference organizers, speakers, session moderators, and attendees. we have prepared five summary statements that mirror each of the sessions. in addition, we have listed the names and academic affiliations of all investigators who attended the meeting at the end of each manuscript. we are very grateful to all of them for their participation and enthusiasm. acknowledgments the second neurocritical care research con- ference was funded by the national institutes of health (ninds) (r ns , pi: suarez ji), the integra foundation, and the baylor st luke’s medical center in houston, tx. disclosures the content is solely the responsibility of the authors and does not necessarily represent the official views of the national institute of neurological disorders and stroke of the national insti- tutes of health. references . suarez ji, geocadin r, hall c, le roux p, smirnakis s, wijman cac, zaidat oo, for the first neurocritical care research conference investigators. the neurocritical care research net- work: ncrn. neurocrit care. ; ( ): – . . le roux p, menon dk, citerio g, vespa p, bader mk, brophy gm, et al. consensus summary statement of the international multidisciplinary consensus conference on multimodality monitoring in neurocritical care: a statement for healthcare professionals from the neurocritical care society and the euro- pean society of intensive care medicine. neurocrit care. ; : – . . macdonald rl, cusimano md, etminan n, hanggi d, hasan d, ilodigwe d, et al. subarachnoid hemorrhage international trialists data repository (sahit). world neurosurg. ; ( – ): – . neurocrit care ( ) : – 	the second neurocritical care research conference 	acknowledgments 	references meditation and yoga associated with changes in brain p h o t o : a v e s u n / is t o c k p h o t o october • vol issue s c i e n c e sciencemag.org meditation and yoga associated with changes in brain brain researchers have detected improvements in cognition and emotional well-being associated with meditation and yoga, as well as differences in how meditation and prayer affect the brains of those who believe in god and those who do not. at a september neuroscience & society event cosponsored by aaas and the dana foundation, neuroscientist sara lazar said that not only were the brain images in a study of people who meditated different from those who did not, other research showed that certain changes in performance such as improved scores on the graduate record exam (gre) occurred in controlled experiments involving mindfulness training. “this suggests neuroplasticity to me,” said lazar, associate researcher in the psychiatry department at massachusetts general hospital and an assistant professor in psychology at harvard medi- cal school, “the ability of your brain to change, to grow and adapt” in correlation with meditation. aaas and the dana foundation have collaborated on the neuro- science & society lecture series since , with events so far reaching attendees. the purpose of the series is to provide a public forum for experts to share the latest advances in brain research and what they might mean for individuals and society. in another presentation at the event, chris streeter, associate professor of psychology and neurology at boston university school of medicine, reported that the brain chemical gaba, a neurotrans- mitter associated with control of anxiety, peaked in experienced yoga practitioners after they executed minutes of postures. “that was the first time people could say there was a change in brain chemistry associated with yoga,” streeter said. in order to test whether yoga improved mood and lessened anxiety more than other physical exercise, study subjects were tested before and after a -week intervention in which they did yoga or walked. the activities were metabolically matched to involve the same amount of physical exercise. the yoga group consistently felt better, according to various mark- ers of mood and anxiety, streeter said. an hour after the yoga, acute changes—revitalization, tranquillity, positivity, and increases in gaba levels—were reported. in depressed patients, even those already on antidepressants, yoga was associated with improved sleep, increased positivity, and decreased suicidal ideation (although none of the participants had shown intent to commit suicide). all the measurements indicating mood began “moving in the right direction,” streeter said. in contexts involving meditation and prayer, brain scans show differences in how the brain reacts depending on whether a subject believes in god, said andrew newberg, director of research at the marcus institute of integrative health and a physician at thomas jefferson university hospital. according to one of newberg’s studies, when nuns contemplated god, activation was detected in images of the prefrontal cortex, the center of cognitive control, but there was no such activation in the brains of atheists. newberg also discussed brain chemistry changes associated with retreat experiences involving prayer, meditation, and silence. tests from before and after the retreat experience showed decreases in dopamine and serotonin transporter levels, which w ould allow the neurotransmitter chemicals to be stored in the brain for later use. finishing his presentation, newberg said the work of all three researchers could be seen as interconnected. “all of this work is coalescing and helping us to understand the overall nature of these experiences,” he said. neuroscientists describe improvements in cognition and mood at aaas event by michaela jarvis a a a s n e ws & n o t e s studies of meditation and yoga report changes in brain activation and chemistry. da_ aaasnewsnotes.indd / / : am published by aaas o n a p ril , h ttp ://scie n ce .scie n ce m a g .o rg / d o w n lo a d e d fro m http://science.sciencemag.org/ meditation and yoga associated with changes in brain michaela jarvis doi: . /science. . . ( ), . science article tools http://science.sciencemag.org/content/ / / permissions http://www.sciencemag.org/help/reprints-and-permissions terms of serviceuse of this article is subject to the is a registered trademark of aaas.sciencescience, new york avenue nw, washington, dc . the title (print issn - ; online issn - ) is published by the american association for the advancement ofscience science. no claim to original u.s. government works copyright © the authors, some rights reserved; exclusive licensee american association for the advancement of o n a p ril , h ttp ://scie n ce .scie n ce m a g .o rg / d o w n lo a d e d fro m http://science.sciencemag.org/content/ / / http://www.sciencemag.org/help/reprints-and-permissions http://www.sciencemag.org/about/terms-service http://science.sciencemag.org/ journal of applied mathematics and decision sciences, ( ), – copyright c© , lawrence erlbaum associates, inc. duals for classical inventory models via generalized geometric programming carlton h. scott† university of california irvine, graduate school of management, irvine, california usa thomas r. jefferson university of florida, gainesville, warrington college of business, decision and in- formation sciences department, gainesville, florida usa soheila jorjani california state university san marcos, college of business, high technology man- agement department, san marcos, ca usa abstract. inventory problems generally have a structure that can be exploited for computational purposes. here, we look at the duals of two seemingly unrelated inventory models that suggest an interesting duality between discrete time optimal control and optimization over an ordered sequence of variables. concepts from conjugate duality and generalized geometric programming are used to establish the duality. keywords: inventory models, conjugate duality, generalized geometric programming. . introduction geometric programming is now a well-established branch of optimization theory and has been instrumental in the solution of many nonlinear opti- mization problems occurring in such diverse areas as marketing, balachan- dran and gensch [ ], water pollution management, ecker and mcnamara [ ] production engineering, petropoulos [ ], transportation planning, jef- ferson and scott [ ], and machine maintenance, cheng [ ]. initially, geo- metric programming concerned itself with finite dimensional optimization problems where both the objectives and the constraints were in posynomial form (i.e. polynomial with positive coefficients). subsequently the theory was extended by peterson [ ] to any finite dimensional convex program- ming problem. this latter development is termed generalized geometric programming and it is with the so called “unconstrained” version of gen- eralized geometric programming that we will be concerned with in this † requests for reprints should be sent to carlton scott, university of california irvine, graduate school of management, irvine, california usa. c. h. scott, t. r. jefferson, and s. jorjani paper. various other extensions are possible such as to composite geomet- ric programming, jefferson and scott and wang [ ] which have particular application in tool replacement strategies, scott, jefferson and lee [ ]. generalized geometric programming is novel in its approach to mathe- matical programming in that it identifies and utilizes the following proper- ties: (i) convexity, (ii) linearity, (iii) separability, and (iv) duality. convex- ity and linearity are two very important functional forms in mathematical programming and they provide powerful results regarding optima. in ad- dition, powerful computational techniques are associated with these forms. separability, even if only partial, provides insight into the solution of a mathematical program and often contains the key to a successful decom- position. the dual problem, taken in the geometric programming sense often provides a much simpler problem to work with for the following two reasons: (i) the dual problem is optimized over the polar to the cone constraints in the primal. this means that if the primal cone is of high dimension, the polar cone is of low dimension – a computational bonus! (ii) the constraints in the primal problem are absorbed into the dual ob- jective function. in this way, while the primal program may have non- linear constraints, the dual may be simply an optimization over a poly- hedral set. joint utilization of the primal and dual objectives yields a powerful algo- rithmic stopping criteria; i.e. the sum of both objectives is less than some specified tolerance. finally, the dual often gives a different perspective to the problem which has useful interpretational insights. many examples are given in peterson [ ] and focused applications on location theory may be found in scott, jefferson and jorjani [ ]. as stated earlier, we will be concerned with the so called “unconstrained” version of generalized geometric programming which in conventional terms means a finite dimensional convex programming problem with the con- straint set being a cone. reason (ii) above refers to the constrained theory [ ]. in this paper, we present the theory pertaining to this particular prob- lem type and then we look at the application to two problems of inventory control, clark and scarf [ ], modigliani and hohn [ ]. these seemingly unrelated models are in fact, related in the sense of duality. duals for classical inventory models . generalized geometric programming we consider an optimization problem of the form: minimize f (x) over x ∈ c ∩ χ ( ) where χ is a cone in en and f is a closed convex function with domain c. this problem is termed the primal problem. we associate with the primal problem, another problem, called the dual problem, which is of the form: minimize g(y) over y ∈ d ∩ χ∗ ( ) where χ∗denotes the polar cone of χ in en and [g: d] is the conjugate transform of [f : c] with value g(y) = sup x∈ c (xt y − f (x)), ( ) d = {y ∈ en|xt y − f (x) < ∞} ( ) and χ∗ = {y |xt y ≥ ∀x ∈ χ} ( ) we note that the primal and dual problems are essentially of the same form and hence are termed symmetric. at optimality, the following relationships hold between the primal the primal and dual optimal points, x and y respectively. f (x ) + g(y ) = ( ) y ∈ ∂ f (x ) , x ∈ ∂ g (y ) ( ) xt y = ( ) these optimality conditions allow an optimal point for one program to be calculated from an optimal point of the other. here ∂ f (x ) denotes the subgradient set of f at x . that is, ∂ f (x ) = {y |f (x )+ < y, x − x >≤ f (x), ∀x ∈ c} ( ) for full details of the theory given in this section the reader is referred to peterson [ ]. c. h. scott, t. r. jefferson, and s. jorjani . a multi-echelon inventory model for a storage network, with n facilities in series, uncertain demand d, occurs at facility n only. shortages are passed up the line to n − , then n − if n − is out of stock, etc. facility n may be a retail store, whereas facility may be a distant warehouse where storage costs are much lower. let ui be the sum of stock on hand at facilities i, i = , . . ., n. hence u ≥ u ≥ ... ≥ un ( ) at the beginning of a planning period, each facility places an order with immediate delivery. let ci denote the amount by which the unit capital charge on ordering at facility i exceeds that at i− and c = . similarly let hi denote that amount by which the unit storage cost at facility i exceeds that at facility i − and h = . we note that ci ≥ , hi ≥ is reasonable since distant warehouses may have smaller holding and ordering costs than retail stores within a city. let pi denote the unit shortage cost at facility i. hence the total costs incurred are∑ i ciui + n∑ i= (pi e [d − ui]+ + hi e [ui − d]+) ( ) which represent the ordering cost, expected shortage cost and expected holding cost respectively and ζ+ = max[ζ, ]. hence we obtain the following optimization problem: minimize the convex function∑ i (ci − pi)ui + ∑ i (pi + hi)e[ui − d]+ + ∑ i pie[d] ( ) subject to equation ( ), ui ≥ ui+ i = , , ...., n- ( ) in the generalized geometric programming form, we have to minimize ∑ i aiui + bi d=ui∫ d= (ui − d)f (d)dd ( ) subject to the cone condition p u ≥ ( ) duals for classical inventory models where ai = (ci −pi), bi = (pi +hi), u = (u , ...., un)t and p is an (n− )×n matrix with elements pij = + for i = j and pij = − for j = i + . f denotes the probability density function of demand. for the dual problem, we require the conjugate transform of the objective function, equation ( ), and polar of equation ( ). taking the conjugate transform defined by equations ( ), of ( ) results in the supremum being attained when vi − ai − bif (ui) = ( ) where vi is the dual variable corresponding to ui and f is the cumulative distribution function of demand. hence, solving equation ( ) for ui we have that ui = f − ((vi − ai)/bi) hence the dual objective function is ∑ i (vi − ai)f − ((vi − ai)/bi) − bi d̂∫ d= (f − ((vi − ai)/bi) − d)f (d)dd − ∑ i pie[d] ( ) where d̂ = f − ((vi − ai)/bi). the polar cone is given by {v |v t u ≥ ∀ u s.t. p u ≥ } ( ) equation ( ) readily implies that v = p t z, z ≥ ( ) where z is an n − dimensional vector. expanding equation ( ), we have that v = z vi = zi − zi− i = , ..., n − vn = −zn− ( ) we note that the dual problem, i.e. the minimum of equation ( ) subject to equations ( ) and z≥ is a discrete time optimal control problem, c. h. scott, t. r. jefferson, and s. jorjani where zi, i = , ..., n − are the state variables and vi, i = , ..., n are the control variables. several other models which fit into this framework may be found in muck- stadt and roundy [ ] and a specialized algorithm has been given by scott and tang [ ]. a numerical example follows: suppose the demand d follows an exponential distribution with mean λ. hence f (d) = /λ exp(−d/λ), f (u) = − e−d/λ and f − (α) = −λ ln( − α) it follows that the primal objective given by equation ( ) is∑ i ((ai + bi)ui + biλe −ui/λ − hiλ) the corresponding dual objective is from equation ( ) ∑ i (λ(ai + bi − νi) ln( ai + bi + νi bi ) − ciλ + νiλ) where the primal and dual variables are related by ui = −λ ln( ai + bi − νi bi ) i = ,..,n we now particularize to the following data set. n = , λ = , c = ( , , ), h = ( , , , ), p = ( , , ). in this case, the minimal cost is . with optimal dual variables ν = ( , . , − . ) and corresponding primal variables u = ( . , . , . ).this implies that it is optimal to hold . units of inventory at facility and the remaining . at facility . . an inventory-production control model a well-known problem in inventory control is to select a set {xt ≥ t = , ..., t} of production levels to minimize, over a planning horizon of length duals for classical inventory models t, the sum of production and holding costs, while meeting demand. for- mally the problem may be posed as: minimize t∑ t= (c(xt) + htyt) ( ) subject to the inventory balance dynamics y = x − d yt − yt− = xt − dt t = , ..., t − −yt− = xt − dt ( ) and the non-negativity constraints yt ≥ t = ,..., t xt ≥ t = , ..., t ( ) here yt denotes the inventory level in period t, dt is the demand in period t, c(xt) is the production cost (assumed convex and strictly monotonically increasing) and ht is the holding cost per unit in period t. to invoke the theory of generalized geometric programming, we need to put the constraint equations ( ) and ( ) into a cone. hence we intro- duce a new variable αt, t = , ..., t and restrict it to a one point domain {dt}, t = , ..., t . this variable is then associated with an additive com- ponent of the objective function which is identically zero. hence we obtain a cone condition y - x + α = yt − yt− − xt + αt = t = , ..., t − −yt− − xt + αt = yt ≥ t = , ..., t ( ) it is convenient to treat the other non-negativity constraint xt ≥ , t = , ..., t as an implicit one. our problem is now in a form which is directly suitable for application of the theory. the dual objective is given by sup xt, yt, αt xt ≥ ∑ t (xtut + ytvt + αtβt − c(xt) − htyt) = sup xt≥ ∑ t (xtut − c(xt)) + sup αt ∑ t αtβt + sup yt ∑ t (ytvt − htyt) = ∑ t c∗(ut) + dtβt ( ) c. h. scott, t. r. jefferson, and s. jorjani where c∗(ut) = sup xt≥ (xtut − c(xt)) ut ∈ ∂ c(xt) and vt = ht ( ) usually c(xt) is a quadratic function and c∗(ut) is readily calculated. fur- ther we require the polar to the cone defined by equations ( ) i.e. {(ut , vt, βt)| ∑ t (utxt+vtyt+βtαt) ≥ ∀ xt, yt, αt satisfying equations ( )} a straightforward calculation shows that vt = pt − pt+ + qt t = , ..., t − ut = −pt t = , ..., t βt = pt t = , ..., t qt ≥ t = , ..., t hence the dual problem is to minimize t∑ t= (c∗(−pt) + dtpt) subject to pt − pt+ + ht ≤ t = ,...,t- for constant ht, we have a minimization over a monotonically increasing set of decision variables. a numerical example follows: suppose c(xt) = x t for t = and h = ( , ), d = ( , , ). in this case, c∗(pt) = p t / with pt = xt. the primal program is minimize ∑ t= x t + y + y subject to: y = x − y − y = x − − y = x − and x ≥ , y ≥ duals for classical inventory models the corresponding dual program is: minimize ∑ t= p t + p + p + p subject to : p − p − ≤ p − p − ≤ solving the dual program yields the optimal value of – , . with opti- mal solutions p = (− . , − . , − . ). the corresponding pri- mal program has minimal cost , . with optimal solution (rounded) x = ( , , ) and y=( , ). . conclusions the two inventory problems considered suggest an interesting duality be- tween certain problems of discrete time optimal control and static opti- mization over monotonic sequences. the multi-echelon inventory model considered in section is a static optimization over monotonic sequences and the geometric dual is a discrete time optimal control problem. the reverse is the case for the production planning problem treated in section . problems of both type arise naturally in inventory control. further, with a dual problem we are in a far better position to develop efficient computational algorithms that if only the primal is considered. references . balachandran, v. and gensch, h. ( ) solving the marketing mix problem using geometric programming, management science, , – . . cheng, t.c. ( ) optimal replacement of aging equipment using geometric programming, international journal of production research, , – . . clark, a. and scarf, h. ( ) optimal policies for a multi-echelon inventory problem, management science, , – . . ecker, j.g. and mcnamara, j.r. ( ) geometric programming and the prelim- inary design of industrial waste treatment plants, water resources research, , – . . modigliani, f. and hohn, f. ( ) production planning over time nature of the expectation and planning horizon, econometrica , – . . muckstadt, j. and roundy, r. ( ) analysis of multistage production systems. in handbooks in or &ms. s.c. graves et al., eds. north holland, amsterdam, – . . peterson, e.l. ( ) geometric programming, s.i.a.m. review, , – . . petropoulos, p.g. ( ) optimal selection of machining rate variables by geo- metric programming, international journal of production research, , – . c. h. scott, t. r. jefferson, and s. jorjani . scott, c.h. and jefferson, t.r. ( ) entropy and geometric programming in transportation planning, opsearch, , – . . scott, c.h., jefferson, t.r., and wang, y.p. ( ) composite geometric pro- gramming, journal of optimization theory and applications, , – . . scott, c.h. and tang, c.s. ( ) separable convex programs with ratio con- straints over a directed tree, operations research letters, , – . . scott, c.h., jefferson, t.r., and jorjani, s. ( ) conjugate duality in facility location. in facility location: a survey of applications and methods, z. drezner ed. springer verlag, new york, – . . scott, c.h., jefferson. t.r., and lee, a. ( ) stochastic tool management via composite geometric programming, optimization, , – . hp fda regulatory actions against misleading or unsubstantiated economic and quality-of-life claims: an analysis of warning letters and notices of violation abstracts medication (p = . ); more likely to become frustrated (p = . ) and annoyed (p < . ) with the patient for asking to try a medication; and less likely to provide samples (p = . ) or a prescription (p < . ) for a medication. conclusion: clinicians are amenable to patients asking for drug information and medications, but their level of receptiveness is associated with the source from which the patient’s questions originate. hp relationship of direct-to-consumer advertising spending and drug pricing for the top twenty drugs from to : an exploratory study parthan ag, anantharaman rt, shepherd md the university of texas at austin, austin, tx, usa there exists an ongoing debate regarding the effect of direct-to-consumer (dtc) advertising spending on drug prices. the two opposite views are: (a) increase in dtc advertising spending would be added to drug prices (b) dtc advertising would increase competition and thus reduce drug prices. objective: explore the relationship of dtc advertis- ing spending and drug pricing for the top twenty drugs from to . methods: top twenty drugs were selected on the basis of their dtc advertising spending (source: competitive media reporting, ny) for . for analysis, average wholesale price (awp) per unit was used from the blue book awp unit pricing. for each of the top twenty drugs, the following trend graphs were plotted for to : (a) the total dtc advertising spending and per unit price of the drug; (b) the percent changes in the dtc advertis- ing spending and drug price. the percent change in dtc advertising spending and drug price for a year was calculated as percent change from the previous year. results: only sildenafil (viagra) and sibutramine (meridia) showed an increase in the actual drug price with an increase in the dtc advertising spending. however, for these two drugs in year , the percent change in dtc advertising spending decreased and the percent change in drug price increased. no trend was evident from the graphs of the other eighteen drugs. on an average dtc advertising spending for most of the drugs decreased with time while drug prices continued to increase. conclusion: results indicate a very weak relation- ship between dtc advertising spending and drug prices. the increase in drug price in spite of the decrease in the dtc advertising spending contradicts both rationale i.e. dtc advertising spending reduces drug price through competition or increase in drug price is due to increase in dtc advertising spending. hp impact of direct to consumer advertising—the consumer search for information belazi dt , crawford a , pizzi l thomas jefferson university & abbott laboratories, philadelphia, pa, usa; thomas jefferson university, philadelphia, pa, usa objective: the purpose of this study is to identify factors associated with consumers’ seeking various infor- mation sources about medications sought in response to direct to consumer advertising. methods: in the spring and summer of , the fda, division of drug marketing, advertising, and commu- nication conducted a national telephone survey of adults regarding direct-to-consumer (dtc) promotion of prescription drugs and its effects on visits to the doctor. in addition to consumer attitudes, opinions and responses to direct to consumer advertising, the survey also elicited responses regarding consumer utilization of information sources such as reference books, -telelphone number, and health care providers. there were total respon- dents, of whom completed the required questions regarding information sources. chi square analysis was used to assess associations between consumer demographic information and the different types of informational resources that consumers used after exposure of direct to consumer advertising. results: the analysis showed significant associations (p £ . ) between gender, race, education, health status, self-perceived knowledge of health, prescription medication use, and internet use and many of the following information resources: reference books, asking friends/neighbors, -telephone number, primary doctor, pharmacist, specialist, and nurse. across all information sources, female gender, decreased health status, low education, and higher than average medica- tion use were the variables that had the strongest associ- ations. a model was developed depicting the associations between these findings. results pertaining to specific sources will be presented. conclusions: this study evaluated how different consumers seek information from different sources as a result of direct to consumer advertising. this study will assist those interested in identifying and further educat- ing consumers about their health and novel treatments or therapies. hp fda regulatory actions against misleading or unsubstantiated economic and quality-of-life claims: an analysis of warning letters and notices of violation stewart ka, neumann pj harvard school of public health, boston, ma, usa abstracts objectives: to examine the frequency and nature of fda regulatory actions against pharmaceutical compa- nies for unsubstantiated or misleading economic and quality-of-life (qol) claims. methods: review of publicly-available fda warning letters and notices of violation (n = ) sent to pharma- ceutical companies between january and november for inappropriate promotional claims. a standard data collection form was developed to capture the frequency and type of violation and the medium in which violations were found. we classified economic violations into several categories (e.g., “unsupported comparative claim of effectiveness, safety or interchangeability,” “claims of cost-savings when there are obvious additional costs that may affect cost savings,” “implied claims of cost-savings to a broader audience than applicable”). qol violations for false or misleading claims using the words improved ‘quality of life’ or ‘patient well-being’ were classified into the following categories: “lack of substantial evidence for qol claims,” “promoting qol claims in investigational or unapproved drug,” and “selective presentation of qol information”. results: ( . %) letters cited false and/or mislead- ing economic claims. the most common economic viola- tion was an economic claim containing an “unsupported comparative claim of effectiveness, safety or interchange- ability” (n = ). ( . %) letters cited qol violations ( letters contained both economic and qol violations). the most common qol violation was “lack of substan- tial evidence for qol claims” (n = ). violations were found most frequently in brochures and on websites. conclusions: a body of evidence is emerging that illustrates how the fda is regulating promotional mate- rial containing misleading or unsubstantiated economic and qol claims. knowing what constitutes an economic or qol violation remains unclear, because there are no formal guidelines about what constitutes a violation, nor what level of substantiating evidence is required. more guidance may be needed to ensure appropriate use in drug promotions. asthma & respiratory disorders/infections ar relationship between different measures of asthma severity: patient- perceived, symptom derived, and fev determined severity measures erickson sr, kirking dm, bria wf university of michigan, ann arbor, mi, usa objective: in health services research, obtaining objective measures of pulmonary function to classify asthma severity is often not possible. researchers must rely on methods such as frequency of self-reported symp- toms and patient perceived severity. this study examined the relationship between fev determined severity and severity determined by patient-reported information. methods: data from adult patients with asthma were obtained from a pulmonary clinic via chart review and patient self-report during a scheduled physician visit. patients in acute exacerbation were excluded. patient- perceived severity (pps) was determined by asking “how severe do you think your asthma is?” with a five-point likert scale from very mild to very severe. overall symptom-derived severity (oss) and nocturnal symptom-derived severity (nss) were determined from two separate questions regarding symptom frequency during the preceding four weeks. responses were based on the nhlbi asthma guidelines. pulmonary func- tion tests were obtained the same day as part of standard care. fev -determined severity (fev -ds) was derived by comparing the fev with the guideline classification of severity based on spirometry. three severity categories were derived for each severity method. percent agreement between fev -ds and each patient-reported severity was determined by constructing ¥ tables. correlations (spearman’s rho) were conducted between fev -ds and the patient-reported severity measures. results: patients with a mean fev percent predicted of . % ( . ) were studied. the percent agreement between fev -ds and pps was . % ( . % over-estimate, . % under-estimate); . % between fev -ds and oss ( . % over-estimate, . % under-estimate); and . % between fev -ds and nss ( . % over-estimate, . % under-estimate). the correlations between fev -ds and pps were . (p < . ); . with oss (p < . ); and . with nss (p = . ). conclusions: pps and oss demonstrated reasonable agreement and correlation to fev -ds, albeit opposite trends in over- and under-estimates. these two measures of asthma severity appear useful for population based studies when fev is unavailable. ar directly elicited preferences compared to preferences derived from the sf- in adult asthmatics lee ta , hollingworth w , sullivan sd hines va hospital, hines, il, usa; university of cambridge, cambridge, uk; university of washington, seattle, wa, usa objectives: several empiric algorithms have been developed to derive preference estimates from the sf- . the objective of this study was to compare the validity and responsiveness of sf- derived preference estimates to directly elicited preferences in persons with persistent asthma. methods: we used data from a one-year clinical trial of adult asthmatics to derive preferences from the sf- . preferences were estimated using five published algo- rithms for converting sf- scores to non-choice based preference estimates. derived preferences were compared to directly elicited visual analog scale (vas) values. dichotomy between mitochondrial ca + uptake and martix [ca +] in micu deficient cells sunday, february , a mitochondrial membranes which result in the dramatic increase of their perme- ability. this increase in permeability during necrosis is caused by the opening of a permeability transition pore - ptp in mitochondrial inner membrane. on the other hand apoptosis induces opening of a large non-selective channel (mito- chondrial apoptotic channel - mac) in the mitochondrial outer membrane. we used atomic force microscopy to study the structure and organization of native mitochondrial membranes isolated from necrotic and apoptotic cells. we com- plement our afm imaging with nanopatricle-based immnunoassays, where mi- tochondrial membranes are pretreated with nanoparticle-conjugated antibodies for recognition of specific proteins. we will present our data on morphological studies of these membranes and will discuss feasibility of this approach for visu- alization of mptp and mac channels in the native mitochondrial inner mem- branes (mim) and mitochondrial outer membranes (mom) using afm methods. -pos board b heterogeneity of cardiolipin regulation yi-fan lin, mei-jie jou. department of physiology and pharmacology, chang gung university, tao-yuan, taiwan. cardiolipin (cl), is a protective phospholipid located exclusively on the mito- chondrial inner membrane for stabilizing individual complex of mitochondrial respiratory chain for energy production, mitochondrial ca þ (mca þ) regula- tion and reactive oxygen spices formation. deficiency of cl has been associated with multiple mitochondrial dysfunctions upon pathological condition, diseases and aging. using fluorescence digital imaging microscopy this study investi- gated how cl is preciously regulated in rat brain astrocytes rba- . results demonstrate that at the resting stage, the distribution of cl is rather heteroge- neous within single cell. the perinulear mitochondria show lower cl than mi- tochondria from the peripheral area. heterogeneity of cl was observed even in single mitochondrion, which may affects mitochondrial fission and fusion mechanism. cl was found to be higher at the cross point area of mitochondrial network. thread-like mitochondria and granular-like mitochondria, however, contain similar level of cl. some of the thread-like mitochondria even contain lower cl than granular-like mitochondria. upon localized oxidative stress in- duced by nm laser irradiation, heterogeneous depletion of cl was observed among mitochondria populations within single cell. distribution of cl altered also mitochondrial dynamics that depletion of cl always occurred before fis- sion. intriguingly, although complete depletion of cl is irreversible upon high strength of laser irradiation, depleted cl recovered during lower strength of laser irradiation and occurred heterogeneously within mitochondria popula- tions. condensation of cl was observed upon various stresses including oxida- tive stress induced by nm laser irradiation, ionomycin-induced mca þ stress and arachidonic acid-induced lipid stress which crucially enhances pres- ervation of cl and its resistance to stress which may be of significance for mi- tochondrial protection and survival. unveiling pathophysiological regulation of cl thus may contribute significantly the prevention and treatment of cl asso- ciated pathological condition, diseases and aging. -pos board b mtdna t g mutation-induced mitochondrial complex v inhibition augments cardiolipin-dependent alterations of mitochondrial dynamics during oxidative, ca d and lipid insults in narp cybrids: a potential therapeutic target tsung-i peng , chia-wei hsiao , mei-jie jou . keelung chang gung memorial hospital, tao-yuan, taiwan, national tsing hua university, tao-yuan, taiwan, chang gung university, tao-yuan, taiwan. mitochondrial dynamics including morphological fission and mitochondrial movement are essential to normal mitochondrial and cellular physiology. this study investigated how mtdna t g (narp)-induced inhibition of mito- chondrial complex v altered mitochondrial dynamics in association with a pro- tective mitochondrial phospholipid, cardiolipin (cl), as a potential therapeutic target. narp cybrids harboring % of mtdna t g genes and its parental osteosarcoma b cells were studied for comparison, and protection provided by melatonin, a potent mitochondrial protector, was explored. we demonstrate for the first time that narp mutation significantly enhances apoptotic death as a result of three distinct lethal mitochondrial apoptotic insults including oxida- tive, ca þ and lipidstress. in addition, narpsignificantly augmented patholog- ical depletion of cl. narp-augmented depletion of cl results in enhanced retardation of mitochondrial movement and fission and later swelling of mito- chondria during all insults. these results suggest thatcl is a common and crucial pathological target formitochondrial apoptoticinsults. furthermore, cl possibly plays a central role in regulating mitochondrial dynamics that are associated with narp-augmented mitochondrial pathologies. intriguingly, melatonin, by differ- entially preserving cl during various stresses (oxidation > ca þ > lipid), res- cuesdifferentially cl-altered mitochondrial dynamics and cell death (oxidation > ca þ > lipid). thus, melatonin, in addition to being a mitochondrial antioxidant to antagonize mitochondrial oxidative stress, a mitochondrial permeability tran- sition modulator to antagonize mitochondrial ca þ stress, may stabilize directly cl to prevent its oxidization and/or depletion and, therefore, it exerts great po- tential in rescuing cl-dependent mitochondrial dynamics-associated mitochon- drial pathologies for treatment of narp-induced pathologies and diseases. -pos board b shuttling of membrane-bound cytochrome b between mitochondria and er david weaver , veronica eisner , peter varnai , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis medical university, budapest, hungary. cytochrome b type b has long been described as a tail-anchored protein of the outer mitochondrial membrane (cb -mito). using a fusion protein consisting of photoactivatable gfp fused to the c-terminus membrane-targeting segment of cb -mito, we have found that while this construct concentrates in the mitochon- drial membrane, it is continuously exchanged between the membranes of the mitochondrion and the endoplasmic reticulum. this effect does not depend on the presence of mitofusin or , as it occurs in mfn-null mefs as well as in wild type cells. interestingly, a point mutation in the hydrophobic, membrane-targeting sequence of cb -mito that was recently reported to prevent its association with autophagosome membranes, also eliminates its exchange with the er. while lipids and viral proteins have been shown to traffic from er to mitochondria, this is, to our knowledge, the first demonstration of such a back-and-forth shuttling, representing both a new aspect of the er- mitochondrial interface and an mfn-independent pathway for the exchange of an outer mitochondrial membrane protein. -pos board b dichotomy between mitochondrial ca d uptake and martix [ca d] in micu deficient cells tunde golenar , gyorgy csordas , fabiana perocchi , vamsi k. mootha , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. mitochondrial calcium uptake is central to cell physiology, but the underlying molecular mechanism remains elusive. recently, micu was identified as a mi- tochondrial protein required for ca þ uptake but dispensible for mitochondrial respiration or membrane potential generation. to study the specific role of micu in mitochondrial ca þ uptake, we used wild type hela cells (ctrl), micu knockdown by distinct shrnas (kd) and micu rescued cells (res- cue). first, we monitored the cytoplasmic and mitochondrial matrix [ca þ] ([ca þ]c and [ca þ]m, respectively) during store-operated ca þ entry. specif- ically, cells were preincubated in a ca þ-free buffer containing thapsigargin (tg), to deplete the er ca þ store, and then ca þ was added back and the en- suing [ca þ]c (fura ) and [ca þ]m (mitochondria-targeted pericams) changes were measured. in both ctrl and kd a [ca þ]c increase occurred that was asso- ciated with a [ca þ]m rise only in ctrl. the rescue behaved similarly to the ctrl. also, when ca þ was added to permeabilized cells, no [ca þ]m increase ap- peared in the kd. these results confirm that the shortage of micu causes sup- pression of the [ca þ]m signal. surprisingly, when the ca þ entry was followed byuncoupler additiontoreleasethemitochondrial ca þ content, ahuge[ca þ]c increase appeared in kd, however, when the uncoupler was added prior to ca þ entry, no [ca þ]c increase occurred. thus, mitochondria in the kd also accumu- lated ca þ during ca þ entry. mitochondrial ca þ uptake evoked by ca þ ad- dition was also documented in permeabilized kd by measurement of ruthenium red sensitive ca uptake and cytoplasmic ca þ clearance (fura ). thus, ca þ is accumulated by micu deficient mitochondria but it fails to result an increase in[ca þ]m.weare currentlyinvestigating, whether suppression ofthe [ca þ]m rise in the kd is due to enhanced matrix ca þ-buffering. -pos board b micu serves as a ca d-controlled gatekeeper for the mitochondrial ca d uniporter györgy csordás , tünde golenár , erin l. seifert , fabiana perocchi , vamsi k. mootha , györgy hajnózky . thomas jefferson university, philadelphia, pa, usa, department of systems biology, harvard medical school, boston, ma, usa. micu serves as a ca þ-controlled gatekeeper for the mitochondrial ca þ uniporter mitochondria are important targets and relay points of calcium signaling. ca þ is driven to the mitochondrial matrix via a low-affinity ca þ channel, the ca þ uniporter (mcu) that exhibits time-dependent 	heterogeneity of cardiolipin regulation 	mtdna t g mutation-induced mitochondrial complex v inhibition augments cardiolipin-dependent alterations of mitochondria ... 	shuttling of membrane-bound cytochrome b between mitochondria and er 	dichotomy between mitochondrial ca + uptake and martix [ca +] in micu deficient cells 	micu serves as a ca +-controlled gatekeeper for the mitochondrial ca + uniporter letters figure the computed tomography scan appearance of the orbit before treatment. one week later the patient complained of horizontal diplopia. on examination visual acuities were unchanged, but the conjunctiva was diffusely inflamed and chemosed bilater- ally. colour vision was reduced on both sides on testing with ishihara plates ( / right and / left). there was no proptosis but the eyes felt hard to retropulsion on both sides. the intraocular pressures were now mm hg and mm hg, increasing to mm hg and mm hg on upgaze. a diagnosis of dys- thyroid eye disease was made and the patient treated with acetazolamide mg three times daily and prednisolone mg daily. thyroid function tests, full blood count, erythrocyte sedimentation rate, urea and elec- trolytes were all normal. a computed tomo- graphy scan showed marked increase in size of all the extraocular muscles but particularly the medial rectus on both sides (fig ) with crowding of the orbital apex suggestive of dys- thyroid eye disease. over the next week there was gradual improvement in both symptoms and clinical signs. steroids were gradually reduced and at his last visit weeks after the episode the visual acuities had returned to / right and / left with all ishihara plates seen on both sides. the chemosis had resolved and there was a full range of extraocular move- ments. comment dysthyroid eye disease is described by duane' as an organ specific autoimmune disease with a tenuous link to thyroid disease. it is charac- terised histologically by inflammation, oedema, and secondary fibrosis and clinically by proptosis, eyelid oedema and retraction, conjunctival chemosis, extraocular muscle abnormalities, and optic neuropathy. the aetiology is thought to be an autoimmune process possibly due to an altered antigen on a follicular cell that stimulates antibody produc- tion which cross reacts with extraocular tissue. alternatively, the primary problem may be a deficiency in suppressor t cell function and a breakdown of the immune system's ability to recognise self tissue. extraocular tissue is thus recognised as foreign and an immune re- sponse mounted against it. amiodarone is a class iii antiarrhythmic and chemically a benzofuran derivative. it is extensively plasma protein bound and is structurally similar to thyroxine. amiodarone has been reported in the medical literature to cause both hypothyroidism and hyperthy- roidism' which ophthalmologists should be aware of. treament with amiodarone has also been shown to result in in the production of both antithyroid antibodies and anti- amiodarone antibodies. previous studies have shown a positive correlation between the pres- ence of anti-amiodarone antibodies and the development of amiodarone induced side effects suggesting an immunological basis of these side effects. these ocular side effects may occur in the presence of normal or increased thyroid function. we suggest that amiodarone induced an exacerbation of thyroid eye disease in our patient already suffering from hypothyroidism either by acting as a stimulus for the production of antibodies that cross reacted with extraocular tissue or by the direct stimu- lation of t cells and a breakdown of the self recognition process. s banerjee c b james the eye unit, stoke mandevile hospital, aylesbury, bucks correspondence to: mr c b james. accepted for publication april duane's clinical ophthalmology. vol . baltimore: jb lippincott, . wilson js, podrid pj. side effects of amiodarone. am heartj ; : - . fraunfelder ft. drug induced ocular side effects. th ed. philadelphia: williams and wilkins, : - . monteiro e, galvao-teles a, santos ml, mourao l, correia mj, lopo tuna j, et al. antithyroid antibodies as an early marker for thyroid disease induced by amiodarone. bmj clinical research edition ; : - . pichler wj, schindler l, staubli m, stadler bm, de weck al. antiamiodarone antibodies: detec- tion and relationship to the development of side effects. amjmed ; : - . carcinoid tumour metastatic to the choroid edrror,-uveal metastasis is believed to be the most common form of intraocular malig- nancy. rarely, however, do features of a meta- static lesion indicate the primary origin of the tumour. a case of multiple metastatic uveal carcinoid tumour is presented, in which the characteristic orange colour of the lesions was suggestive of the nature of the primary tumour. case report a -year-old white woman presented with a month history of bilateral floaters. eight years earlier, a left pneumonectomy with adju- vant radiotherapy had been performed for bronchial carcinoid tumour with mediastinal lymph node involvement. she had since remained well with no evidence of systemic recurrence. the visual acuity was / in both eyes and the anterior segments were nor- mal. in the right fundus there were three well circumscribed orange choroidal lesions in the posterior pole (fig ) and one inferonasal to the optic disc. in the left fundus, a similar orange choroidal lesion was identified nasal to figure fundus photograph of the right eye showing three orange choroidal metastases suggestive of carcinoid tumour. figure fundus photograph of the left eye showing a single orange choroidal lesion nasal to the optic disc. the optic disc (fig ). fluorescein angiogra- phy showed hyperfluorescence of the lesions in the arterial and laminar venous phases that persisted through the late stages (fig a and b). indocyanine green angiography revealed hyperfluorescence of the lesions in early and late frames with late dot hyperfluorescence (fig a and b). b scan ultrasonography docu- mented high internal reflectivity and a maxi- mum thickness of mm. a diagnosis of multi- ple metastatic uveal carcinoid tumour was made. systemic evaluation, including physical examination, liver enzymes, chest x ray, and brain magnetic resonance imaging showed no evidence of metastases elsewhere and she was visually asymptomatic. the lesions were care- fully observed and remained unchanged at months' follow up. comment choroidal metastases from carcinoid tumour are rarely described' and comprise approxi- mately only % of intraocular metastases. figure (a) laminar venous phase fluorescein angiogram of the right eye showing moderate hyperfluorescence of the choroidal lesions. (b) late phase fluorescein angiogram of the right eye showing continued hyperfluorescence of the choroidal lesions. o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://b jo .b m j.co m / b r j o p h th a lm o l: first p u b lish e d a s . /b jo . . . o n s e p te m b e r . d o w n lo a d e d fro m http://bjo.bmj.com/ letters figure (a) earlyframe indocyanine green angiogram of the right eye detailing mild homogeneous fluorescence of the choroidal lesions. (b) lateframe indocyanine green angiogram of the right eye showing isofluorescence of the three lesions and intrinsic dot hyperfluorescence of the largest tumour. the few reported cases suggest they fre- quently originate from bronchus in contrast with orbital carcinoid metastases which may originate from the gastrointestinal tract. they may have a characteristic orange appear- ance,' in contrast with most other choroidal metastases which have a creamy yellow colour.' the interval between diagnosis of the primary carcinoid tumour and uveal metas- tases may be as long as years (mean years) and in over % ofpatients the primary lesion is undiscovered at the time of ocular diagnosis. unlike breast and lung uveal metastases,' the mean survival after diagnosis of uveal carcinoid metastases approaches years. the occurrence of orange choroidal lesions should raise the possibility of carcinoid metastases and prompt an intense search for a primary lesion, directed principally at the lung, or if the primary is known, for systemic recurrence elsewhere. at least % of cases are likely to have other metastases at the time ocular involvement is diagnosed.' in this case, however, systemic evaluation was unre- markable. a urinary hiaa was not per- formed as this had not been helpful in previous cases.' close follow up is required to detect tumour activity, either growth or the development of subretinal fluid or haemor- rhage. external beam radiotherapy ( - cgy) caused effective tumour regression in six of eight treated cases,' and is advocated if activity occurs. support provided by the eye tumor research foun- dation, philadelphia, pa, usa. philip g hykin ocular oncology department and the retina service, wius eye hospital, thomas jefferson university, philadelphia, pa , usa jerry a shields carol l shields patrick v de potter ocular oncology department, wills eye hospital, thomas jefferson university, philadelphia, pa , usa william h kehrli northeastern eye institute, scranton, pa , usa correspondence to: jerry a shields, md, ocular oncology department, wills eye hospital, th & walnut streets, philadelphia, pa , usa. accepted for publication june shields ja, shields cl. intraocular tumors: a text and adas. philadelphia: wb saunders, ; - . harbour jw, de potter p, shields cl, shields ja. uveal metastases from carcinoid tumor. oph- thalmology ; : - . archer db, gardiner ta. an ultrastructural study of carcinoid tumor of the iris. am j oph- thalmol ; : - . fan jt, buettner h, bartley gb, bolling j. clini- cal features and treatment of seven patients with carcinoid tumor metastatic to the eye and orbit. amj ophthalmol ; : - . stephens rf, shields ja. diagnosis and manage- ment of cancer metastatic to the uvea: a study of cases. ophthalmology ; : - . o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://b jo .b m j.co m / b r j o p h th a lm o l: first p u b lish e d a s . /b jo . . . o n s e p te m b e r . d o w n lo a d e d fro m http://bjo.bmj.com/ _ _ _article .. physician empathy and diabetes outcomes alexander chaitoff, md, mph , michael b. rothberg, md, mph , and kathryn a. martinez, phd, mph cleveland clinic lerner college of medicine, case western reserve university, cleveland, usa; center for value-based care research , cleveland clinic, cleveland, oh, usa. j gen intern med ( ): doi: . /s - - -z © society of general internal medicine w e appreciate the response from hojat and colleaguesregarding our study. in our manuscript, we extensively outlined reasons why we might not have been able to replicate the original study’s findings. those that the authors proposed in their letter, however, are unlikely causes. they propose our findings may have differed due to the mandatory communication trainings at cleveland clinic. yet our methods stated the jefferson scale of empathy (jse) scores used in our study were collected prior to training exposure. it’s true we had a larger proportion of internal versus family medicine physicians and a moderately different case mix of patients, but our finding of no association between empathy and diabetes outcomes was consistent in all multi- variable and sensitivity analyses. whether using their empathy cut points, analyzing scores continuously to maximize statis- tical power, or looking at subsets of patients with poorly controlled diabetes, we found no relationship between jse and outcomes. as described in detail in our paper, our inability to repro- duce the original study’s conclusions is not unusual—research findings are often reversed. this is why it’s important to replicate studies. it may be true that empathy was associated with diabetic control among patients of family medicine physicians at thomas jefferson > years ago, but their conclusion that “physician empathy is an important factor associated with clinical competence and patient outcomes” is not true now, at least not at the cleveland clinic. finally, the authors cite our “error in judgment” for acknowl- edging that the two studies that found correlations between empathy and diabetes outcomes were conducted by the same group. we fear they felt we were impugning their integrity, which is not the case. research shows even when studying the same data, different researchers often come to different conclusions, highlighting the benefit of having multiple groups independently study similar topics. additionally, financial in- terests have been shown to lead to unconscious biases, and investigators that are professionally invested in a specific field may be more likely to see associations in data than impartial methodologists. these implicit phenomena are reasons that authors are required to disclose financial conflicts of interest, and less commonly, professional ones. we have no specific stake in the outcome of this study. we hope that others will also attempt to replicate this work and add to our knowledge about the impact of empathy on patient outcomes. corresponding author: kathryn a. martinez, phd, mph; center for value-based care research cleveland clinic, cleveland, oh, usa (e-mail: martink @ccf.org). compliance with ethical standards: conflict of interest: the authors declare that they do not have a conflict of interest. references . ioannidis jpa, chen j, kodell r, haug c, hoey j. why most published research findings are false. plos med. ; ( ):e . https://doi.org/ . /journal.pmed. . . silberzahn r, uhlmann el, martin dp, et al. many analysts, one data set: making transparent how variations in analytic choices affect results. adv methods pract psychol sci. ; ( ): – . . dana j. conflict of interest in medical research, education, and practice. vol (field mj, lo b, eds.). washington dc: national academies press; . . panagiotou oa, ioannidis jpa. primary study authors of significant studies are more likely to believe that a strong association exists in a heterogeneous meta-analysis compared with methodologists. j clin epidemiol. ; ( ): – . publisher’s note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. published online july , http://dx.doi.org/ . /journal.pmed. http://dx.doi.org/ . /journal.pmed. http://crossmark.crossref.org/dialog/?doi= . /s - - -z&domain=pdf 	physician empathy and diabetes outcomes 	references games:science:science_magazine_ - :root:data:science_ - :pdf: _v _n :p _ .pdf [ganino] ganino user tools 	register 	log in site tools search tools show pagesource old revisions backlinks recent changes media manager sitemap register log in > 	recent changes 	media manager 	sitemap trace: games:science:science_magazine_ - :root:data:science_ - :pdf: _v _n :p _ .pdf this topic does not exist yet you've followed a link to a topic that doesn't exist yet. if permissions allow, you may create it by clicking on create this page. page tools 	show pagesource 	old revisions 	backlinks 	back to top editorial office news and notes more editorial board members and kudos for the practice-based research network poster award in an ongoing effort to introduce our readers to the distinguished members of the editorial board that advises the journal of the american board of family medicine, in this issue we highlight drs. fenton, figueroa, and jimbo. dr. joshua fenton, md, mph, is a graduate of the university of california, san francisco, and completed residency at san francisco general hospital. subsequently he was a family physician on the navajo indian reservation at crownpoint, new mexico, and a robert wood johnson clinical scholar at the university of washington, where he received an mph in health services. dr. fenton is currently assistant professor of family and com- munity medicine at the university of california, davis. an american cancer society mentored re- search scholar, dr. fenton conducts research ex- amining the dissemination and accuracy of breast and colorectal cancer screening tests. dr. edgar figueroa, md, mph, is currently assistant professor of family medicine in medi- cine and director of student health at weill cor- nell medical college in new york city. a life-long new yorker, he earned his medical degree from weill cornell medical college and completed his residency at the family medicine residency pro- gram at new york presbyterian hospital—colum- bia university medical center. he subsequently completed a faculty development fellowship and earned his mph from columbia university. his academic interests include web-based education, narrative medicine, health promotion in urban un- derserved populations, and understanding issues of diversity in academic medicine. dr. masahito jimbo, md, phd, mph, is an associate professor of the departments of familyconflict of interest: the authors are editors and staff of the jabfm. dr. joshua fenton, md, mph dr. edgar figueroa, md, mph dr. masahito jimbo, md, phd, mph doi: . /jabfm. . . editorial office news and notes o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n m a rch . d o w n lo a d e d fro m http://www.jabfm.org/ medicine and urology at the university of mich- igan. he obtained his medical and doctorate de- grees from keio university school of medicine in japan, and after completing an internal medicine residency at the same institution he completed his residency in family medicine at the thomas jeffer- son university in philadelphia. he obtained a mas- ter’s in public health from the university of north carolina at chapel hill while serving as a medical director in rural north carolina. dr. jimbo prac- tices a wide range of clinical medicine, including primary care for the japanese population in south- eastern michigan, medical consultation for patients with urological problems, and hospital medicine. he is heavily involved in teaching the university of michigan family medicine residents in hospital medicine and is a member of the society of teach- ers of family medicine group on hospital medi- cine and procedural training. in addition, he teaches and lectures extensively in japan, where he is a visiting professor at several institutions, includ- ing okayama university and st. marianna univer- sity. the main focus of dr. jimbo’s research is patient-physician communication and cultural fac- tors in cancer screening and prevention. he has published in national family medicine and cancer journals and is currently a coinvestigator in the federally funded center of excellence in cancer communications research at the university of michigan. he also educates the japanese commu- nity about health and prevention through a monthly newspaper column, a bimonthly newslet- ter, and a monthly podcast. congratulations to dr. ely! we also would like to take this opportunity to congratulate editorial board member, dr. john w. ely, md, msph, who won the practice-based research network poster award at the agency for health care research and quality na- tional practice-based research network research conference for his poster entitled “primary care perceptions regarding community-acquired me- thicillin-resistant staphylococcus aureus infections.” dr. ely was previously featured in the september/ october issue of our editorial office news and notes section. th anniversary supplement be sure to see the journal of american board of family medicine supplement from the american board of family medicine’s symposium celebrating its th anniversary (journal of american board of family medicine, march , volume ). in , the american board of family practice (now the american board of family medicine) was approved and recognized as the th medical specialty in the united states by the american board of medical specialties. as usual, family medicine was in the forefront of innovation as it became the first med- ical specialty board to issue time-limited certificates and to mandate recertification every years. a number of interesting articles in this special issue discuss the past, present, and future of training and certification in our specialty. looking ahead please look for a special report in the may/june issue about the top journal of american board of family medicine articles and online reader- ship for . the july/august issue will be dedicated to practice-based research networks (pbrns). phillip lupo, mlis anne victoria neale, phd, mph marjorie a. bowman, md, mpa reference . lupo p, neale av, bowman ma. introduction of more editorial board members and new guest com- mentary feature. j am board fam med ; : – . john w. ely, md, msph jabfm march–april vol. no. http://www.jabfm.org o n a p ril b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://w w w .ja b fm .o rg / j a m b o a rd f a m m e d : first p u b lish e d a s . /ja b fm . . . o n m a rch . d o w n lo a d e d fro m http://www.jabfm.org/ gating interactions between the cytoplasmic t domain and pore of a kv channel sunday, february , a -pos board b access constraints and binding energetics of a potassium channel inactivation gate gaurav venkataraman, deepa srikumar, miguel holmgren. nih, bethesda, md, usa. voltage-activated potassium (kv) channels open an intracellular gate in re- sponse to changes in transmembrane voltage, allowing k þ to permeate at rates near diffusion. in some kv channels, permeation can be interrupted by the n-terminus of the protein acting as a blocking particle, binding at the intracel- lular cavity of the channel and physically obstructing the permeation pathway. despite being tetramers, kv channels require only one bound n-terminus to inactivate. in nature, inactivation is targeted by rna editing, which converts an isoleucine of the intracellular cavity into a valine. the functional conse- quence is a large increase in unbinding kinetics. how does each ‘‘wall’’ of the cavity contribute to the increase in unbinding kinetics of a single bound n-terminus? to address this question we made con- catenated shaker heterotetramers consisting of only one free n-terminus and a single isoleucine to valine mutation at position (i v), mimicking the rna editing site in humans and rodents. surprisingly, the rate of unbinding was the same for individual i v mutations in each wall; each corresponded to a decrease in binding energy of about . rt. in fact, the binding energy de- creased linearly as a function of the number of i v mutated subunits. these results suggest that despite being tethered to a particular subunit, the single in- activation particle has sufficient freedom to interact with position of each subunit with roughly equal probability. where does this freedom come from? it is expected that the inactivation gates enter the cavity through lateral ‘windows’, similarly to k þ . can our single tethered inactivation gate enter through each of the four windows of the protein? we will address this question by making individual cysteine mutations at each window and testing the inac- tivation gate’s binding kinetics after chemical modification. -pos board b gating interactions between the cytoplasmic t domain and pore of a kv channel brian urbani, manuel covarrubias. jefferson medical college of thomas jefferson university, philadelphia, pa, usa. whereas the gating roles of the voltage-sensing and pore domains of kv channels have been extensively investigated, much less is known about the mechanisms governing the regulation of gating by the cytoplasmic t domain. previous work from this lab strongly suggests that the kv . t domain un- dergoes conformational changes directly linked to gating (j. gen. physiol., : - , ); however, the structural basis of the communication between the activation gate and the t domain has remained elusive. to tackle this problem, we applied cysteine scanning mutagenesis, voltage- clamp electrophysiology, double mutant cycle analysis (dmca) and oxidizing reagents to probe specific interactions between the cytoplasmic t domain l helix, the s -s linker and s tail. the energetic impact of the mutations on activation gating is apparently small. by comparison, the energetic impact of the mutations on inactivation gating was significantly greater. dmca of k c(l )þa c(s ) revealed a significant interaction energy ( kcal/ mol), which suggests an interaction between k in the l helix and a in s . supporting this possibility, the currents induced by k c(l )þ a c(s ) are inhibited (~ % of control) by an oxidizing agent (tbuho ), whereas the single mutants are not; and the effect is reversed by the reducing agent dtt. these results indicate the formation of a disulfide bond between the interacting side chains, which is consistent with physical interaction between k (l ) and a (s ). overall, we conclude that regulation of inactivation gating by the t domain involves a physical interaction between the t l helix and the distal segment of s . supported by nih grant r ns (mc). -pos board b is the activation gate closed in kv channel closed-state inactivation? jeffrey d. fineberg, manuel covarrubias. thomas jefferson university, philadelphia, pa, usa. kv .x channel complexes including auxiliary subunits such as dpp -s and kchip undergo preferential closed-state inactivation (csi; baehring and covarrubias, , j physiol, . : - ; fineberg et al., , j gen physiol, in press). however, the molecular basis of csi in kv .x channels remains poorly understood. a key unanswered question of this problem is whether the channel’s activation is actually closed, as csi implies. we have previously proposed that csi results when the activated channel fails to open or simply prefers to close. this hypothesis specifically suggests that the intra- cellular activation gate may adopt a stable closed conformation, even under depolarized conditions that would initially favor the activated ‘‘up’’ state of the voltage sensors. to test this hypothesis, we are exploiting the trapping paradigm previously investigated by holmgren et al. to test the state of the intracellular activation gate ( , j gen physiol, : - ). essentially, if the activation gate closes behind a quaternary ammonium (qa) blocker inside the pore, the blocker cannot exit the pore; effectively, it is trapped. we are expressing the ternary kv . /i c channels (this mutation favors trap- ping) including dpp -s and kchip in xenopus oocytes. then, in the inside- out patch-clamp configuration, we are using a computer-controlled perfusion system to deliver the qa derivative decyltrimethylammonium bromide (c ) to the bath and probe the ability of the channel’s activation gate to trap c in the closed, open and inactivated states. preliminary results show that the trapping paradigm may yield an answer to the central question of this study. if the activation gate is indeed closed during csi, c trapping will only occur when the drug is applied to the conducting channel, but no trapping of c will be observed in the closed and inactivated states. supported by nih grant r ns (mc). -pos board b water at the potassium channel gate: quantum calculations show an oscillation in water structure alisher m. kariev, michael e. green. city college of the city university of ny, new york, ny, usa. quantum calculations on the open gate and the immediately surrounding re- gion of the kv . voltage gated potassium channel show that water adopts two conformations there, one when the ion is present, and another with no ion present. an energy minimum at the gate with no ion allows an ion to enter from the solution; from the gate it repels an ion in the channel pore cavity into the selectivity filter (essentially the ‘‘knock-on’’ mechanism). the pore cavity minimum can then be occupied by the ion moving from the gate minimum, leaving it available for anion from bulk, so the cycle continues. the arrange- ment of water, and the ion hydration, defines the gate energy minimum, and this in turn depends on the highly conserved prolines, especially p ( a pdb numbering), in the pvpv sequence in the gate. absent an energy minimum at the gate an ion entering from solution would be repelled back into solution by the ion in the cavity. furthermore, the ion remains hydrated by water molecules, at least more than in bulk, as it passes through the gate, based on optimizations with the ion at three different positions: ) at the gate position nearest p ) å above ) å below, this position. the open gate maintains very nearly the same protein atom positions throughout. additional calculations will be required to determine the exact interaction en- ergy with an ion in the cavity, and the amount of water that is present in the cavity. optimizations of the system configuration were done at hf/ - gsp level, with atoms ( with the ion). energy was determined using both b lyp/ - g* and bvp / - g*, but the system was too large for free en- ergy determination. -pos board b water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computational mutations, and the role of a histidine in gating alisher m. kariev, michael e. green. city college of the city university of ny, new york, ny, usa. conservation of the pvpv sequence at the potassium channel gate has not been well understood. quantum computations (optimization at hf/ - gsp level) of the gate of the kv . channel that are presented here show that the proline-proline distances (ring atoms) are preserved as the ion moves through the gate. this calculation is supplemented by mutating one of the prolines to valine (p v, a pdb numbering for all residues in this abstract) in the computation, producing a pvvv sequence. water structure changed dramati- cally, as the protein backbone moved inward nearly å, effectively closing the channel; the proline ring n-n distance between diagonally opposite pro- lines dropped from . å (distance from optimization: x-ray distance = . å) to . å, too small to allow passage of a hydrated k þ . this suggests that the prolines play a key structural role, modulating both protein and water structure. furthermore, protonation of h may close the channel. protonation of this histidine shows it moving toward the gate by about å, which should close the gate electrostatically, while deprotonation opens the gate. protonation was calculated with two added protons, the other being accepted by e of the t intracellular moiety. when deprotonated, the histidine does not move as much as å from the x-ray position in the optimization, and is linked to e ; this accounts for the known importance of the t segment in gating. e , also of t , could accept a third proton. there is a salt bridge structure including these residues similar to the one occupying a key position in the pro- ton pathway in the hv channel. 	access constraints and binding energetics of a potassium channel inactivation gate 	gating interactions between the cytoplasmic t domain and pore of a kv channel 	is the activation gate closed in kv channel closed-state inactivation? 	water at the potassium channel gate: quantum calculations show an oscillation in water structure 	water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computation ... vol. ı no. ı www.biotechniques.com ı biotechniques l ong, long ago, my father told me a story about the dinner president john f. kennedy hosted for american nobel prize winners in . “i think,” kennedy told his guests, “this is the most extraordinary collection of talent, of human knowledge, that has ever been gathered together at the white house—with the possible exception of when thomas jefferson dined alone.” unlike some of the tales we heard at our parents’ knee, this one seems to square with the historical record. the anecdote came to mind after watching an exchange be- tween host tom brokaw and president-elect barack obama on the dec. edition of nbc news’ “meet the press.” it was just a fleeting comment near the close of the hour-long interview, and passed so quickly i almost missed it, sandwiched as it was between two higher-profile items: the nomination of gen. eric shinseki to head the veterans administration and mr. obama’s pledge that, despite his own difficulty quitting smoking, he will see that no-smoking rules are obeyed in his white house. here is an edited transcript: brokaw: ...let me ask you as we conclude this program this morning about whether you and michelle have had any discussions about the impact that you’re going to have on this country in other ways besides international and domestic policies… who are the kinds of artists that you would like to bring to the white house? obama: …[ w ] e have thought about this because part of what we want to do is to open up the white house and… remind people…this is the people’s house. there is an incredible bully pulpit to be used when it comes to, for example, education. yes, we’re going to have an education policy. yes, we’re going to be putting more money into school construction. but, ultimately, we want to talk about parents reading to their kids. we want to invite kids from local schools into the white house. when it comes to sci- ence, elevating science once again, and having lectures in the white house where people are talking about traveling to the stars or breaking down atoms, inspiring our youth to get a sense of what discovery is all about. thinking about the diversity of our culture and, and inviting jazz musicians and classical musicians and poetry readings in the white house so that, once again, we appreciate this incredible tapestry that’s america… [o] ur art and our culture, our science…that’s the essence of what makes america special…and we want to project that as much as possible in the white house. scientific lectures at the white house. if i used exclama- tion points, i’d use one here. how long has it been since we thought of a president actually embracing and enjoying the challenge of science? are we really facing a time when american leadership once again accepts scientific inquiry as an integral part of our culture, and not an enemy of it? with regard to whom, exactly, mr. obama should invite to the white house, we have some obvious choices. the new president should hear rita colwell’s ( university of maryland and johns hopkins university) “climate, oceans, infectious disease, and human health: the saga of cholera.” [ we heard her in october at columbia university’s annual presidential lecture, and wrote about it for the online component of our december issue ( ). he and his administration would also benefit from visits by any of the participants in the extraordinary james l. waters symposium, including leroy hood ( institute for systems biology, seattle, wa) talk- ing about p medicine ( p stands for “predictive, preventive, personalized, and participatory” ), george church ( harvard university) discussing the means and applications of high- speed, low-cost individual sequencing, or richard wilson ( washington university in st. louis) explaining crop plant genomics or the history of the human genome. better yet, we would like to hear our readers’ suggestions for the white house lectures. so please post your suggestions on the “to the editor” section at the bottom of the biotechniques molecular biology forums page ( ). if you’re shy, write directly to douglas.mccormick@ informausa.com. tell us whom the people of the united states should invite to lecture at the people’s house, what we should ask them to talk about, and why the president should listen. references . mccormick, d. . washed in a microbial sea. biotechniques vol. , no. : ( dec. ), www. biotechniques.com . “to the editor,” molecularbiology.forums.biotechniques.com. from the editor who should speak at the people’s house? douglas mccormick editorial director, biotechniques douglas.mccormick@informausa.com the us president-elect hopes to make scientifi c lectures part of the white house social calendar. we ask biotechniques’ readers: who should be asked to speak, and why? fossils are for everyone kramer, jon m., georesearch department, earth museum, toledo ave. n., robbinsdale, mn , u.s.a. perhaps unlike any other field of science, paleontology is dependent upon the contributions of common everyday people. indeed, in many cases formal academic training is completely immaterial to making great scientific discoveries in paleontology. historically, earth science is replete with giants who had little or no academic background at all. in addition, the vast number of fossils in the world's institutions were discovered by amateurs and commercial collectors, not degreed professionals. the history of commercial fossil collecting is long and honorable. it began long before the advent of geologic sciences or such things as museums. europeans have commercially traded fossils for centuries. before the u.s. was a nation fossils were collected and bartered by indigenous peoples that lived here. even our founding fathers supported the fossil trade. thomas jefferson was a naturalist who bought and sold fossils on a regular basis. the contributions of commercial fossil collecting have not been small. every specimen of archaeopteryx, arguably one of the most important fossil species known, is the result of collection by commercial groups. the largest, most complete tyrannosaurus rex was found by a commercial party which, incidentally has discovered more t. rex specimens than any other group, public or private. even jack horner has a commercial shop to thank for his discovery of baby dinosaurs that launched him to the front of dinosaur science. and what paleontologist today hasn't held in their hand a fossil specimen from wards or carolina biological supply during their early education? or entered a limestone quarry, gravel pit, or coal mine to search for fossils under the auspices of the commercial owner? who will provide those specimens or access to them if commerce in fossils is restricted? paleontology is best served in a spirit of working together. cooperation between land owners and fos.sil collectors, government and industry, academics and amateurs, public institutions and private enterprise is all needed to the continued vitality of this science. there is no reason au concerned parties cannot work together and promote paleontology like never before. july-august • vol. , no. family medicine brief reports r acial and ethnic disparities in health persist in the unit- ed states. - these dispari- ties also exist in self-perception of health. african americans (aa) were less likely to describe themselves as overweight versus whites, were par- ticularly less likely to adopt healthy weight-related attitudes and behav- iors, and have worse obesity out- comes. health-specific self-efficacy is a strong predictor of health behav- iors. , recent research has shown efficacy for targeted, community- based interventions resulting in re- duced weight and cardiovascular risk factors for aa women in urban communities. , tailoring a weight- loss intervention to specific popula- tions may be a reasonable approach to reducing chronic disease in these groups. the stephen klein wellness cen- ter is a family medicine residency- affiliated federally qualified health center (fqhc) in north philadel- phia serving a predominantly aa community. the fqhc’s target population was determined to have significantly poorer health than phil- adelphia residents overall. sociocultural factors play an im- portant, positive role in exercise ad- herence ; therefore, a community needs survey was performed and identified nutrition, exercise, and physical activity (pa) as very impor- tant aspects of health and wellness to community members. respon- dents desired aerobic activities, spe- cifically indicating “urban” or “soul” (synchronized, choreographed, so- cial dance with cultural roots in af- rica and the caribbean) line dancing classes, , confirmed by additional community meetings. this study evaluated how partici- pation in a community-tailored, soul line dancing class with nutrition ed- ucation correlates with changes in background and objectives: the population surrounding an urban federally qualified health center (fqhc) in philadelphia has poorer health than philadelphia overall. community residents identified aerobics and dance classes as very important services or programs that an fqhc might provide. we sought to measure the impact of participation in a resident physician-led, patient-centered fitness and nutrition class on participants’ attitudes, knowl- edge, and self-efficacy regarding their health. methods: an urban line dancing class and brief healthy eating intervention for adults was held at a ymca adjacent to a residency-affiliated fqhc weekly for weeks. pre/postsurveys were administered to assess attitudes and con- fidence toward physical activity and healthy lifestyles. results: participants’ self-assessment of health and levels of physical activ- ity improved. confidence in performing everyday activities, doing regular exer- cise and exercising without making symptoms worse increased. a significant decrease in participants’ physical activity gratification was observed. partici- pants’ confidence improved in reading food labels for health, but confidence in eating a balanced diet did not improve. conclusions: a resident-led fitness and nutrition class, tailored to per- ceived community needs, generated significant interest and sustained par- ticipation. this pilot study furthered development of community infrastructure addressing health, nutrition, and overall fitness, and the results reflect oppor- tunities and challenges of engaging communities in physical fitness. (fam med. ; ( ): - .) doi: . /fammed. . attitudes surrounding a community-based fitness intervention at an urban fqhc krys foster, md, mph; john stoeckle, md; alexis silverio, mph; christine castellan, md; angela hogue, md; ayanna gouch, md, ma; lara weinstein, md, drph, mph from thomas jefferson university, department o f fa m i l y a n d c o m m u n i t y m e d i c i n e, philadelphia, pa (drs foster, stoeckle, castellan, hogue, and weinstein, and ms silverio); lewis katz school of medicine at temple university, philadelphia, pa (dr gouch); and stephen klein wellness center, philadelphia, pa (drs stoeckle, castellan, hogue, and weinstein). family medicine vol. , no. • july-august brief reports self-assessment of health, levels of pa, attitudes towards pa, and con- fidence to implement health promot- ing behavior. additionally, we aimed to understand adherence to this type of activity. methods setting and sampling participants were recruited by fqhc staff. flyers were posted throughout the fqhc and an adja- cent ymca. those under years old and who self-identified as physi- cally unable to participate were ex- cluded. individuals were consented by resident physicians to participate and signed a waiver of liability. par- ticipants who attended two or more classes were included. intervention a free, weekly, -minute line danc- ing class was offered for weeks with a -minute nutrition lesson at the end of class. a hired instruc- tor from a north philadelphia ymca directed the class and physician res- idents observed their engagement in the class, administered surveys, and taught the nutritional compo- nent of the class. residents were free to dance alongside participants, and often did, as a way to encourage re- lationship-building. the nutrition- al education was derived from the academy of nutrition and dietetics (table ). our budget was able to support the dance instructor and supplement the nutrition counseling sessions with food items/water. our nutrition content was online, free, and resident delivered. the cost per participant was estimated at $ . measures participants completed a preinter- vention survey at the first class they attended. postsurveys were adminis- tered at the final class; participants who did not attend the final class completed the final survey over the phone. the -item survey collected data about participant demographics, self- assessments of health, levels of pa, attitudes toward pa, confidence to implement health promoting behav- ior, and several program evaluation items (table ). the institutional review board of thomas jefferson university ap- proved this study. analysis a descriptive analysis was conduct- ed for participant demographics. for each survey section, paired samples t-tests were used to compare the means of continuous measurements pre- and postsurvey. results forty-seven individuals attended at least one class. sixty percent of participants attended six or more classes. twenty-eight completed both pre- and postsurveys. a com- plete descriptive analysis is shown in table . the mean number of classes at- tended was . (sd= . ). only three participants had attended the adjacent fqhc’s nutrition class. all respondents “would recommend the class to a friend,” and all were “totally satisfied” with the class. twenty-one wanted to learn more about nutrition. participants’ favor- ite nutrition topics were healthy table : nutrition topics week nutrition topic benefits of water healthy grocery shopping tips reading nutrition labels healthy postworkout snacks myplate overview portion control sodium awareness protein options table : sources for health-related survey questions survey question domain questions drawn/modified from* self-assessment of health (q , q , q ) the validated general health question promis global health survey physical activity behaviors (q , q , q ) behavioral risk factor surveillance system (brfss) physical activity attitudes (q , q , q , q , q ) physical activity enjoyment scale confidence towards exercise (q , q , q ) chronic disease self-efficacy scale confidence towards diet (q , q , q , q , q ) self-rated abilities for health practices scale * survey questions for the health-related themes were drawn from several published health surveys. july-august • vol. , no. family medicine brief reports postworkout snacks, the benefits of water, and healthy shopping tips. only two participants had a pri- mary care doctor at the fqhc prior to the class; by the end of the inter- vention, three additional participants had established care. sixty percent of participants had a ymca member- ship preintervention, and two joined during the study. there were no significant chang- es in self-assessment of one’s over- all health, physical fitness, ability to carry out physical activities or pa levels. a significant decrease in pa gratification from pre- to post- survey was observed. there were no significant differences across the remaining domain questions for pa enjoyment, pa confidence levels, nor the ability to consume a healthy diet (table ). discussion a resident physician-led pilot fit- ness and nutrition class generated significant interest and sustained participation. our homogeneous pop- ulation consisted predominantly of aa women ( %). it has been shown in the literature that social support is a motivating factor for aa wom- en regarding participation in group physical interventions. the social cohesion of our population could have contributed to the high adher- ence observed. gratification decreased signifi- cantly; this may reflect participants’ challenges with their experience of increased activity. participation did not decrease throughout the study. satisfaction was reported with mu- sic and the class instructor, which has been shown to correlate with table : demographics of stephen klein wellness center: healthy eating and line dancing project characteristics participants n (%) female ( ) age range (years) - ( ) - ( ) - ( ) - ( ) - ( ) race* white ( ) african american ( ) other ( ) hispanic ( ) marital status married ( ) never married ( ) divorced/separated ( ) widowed ( ) education some high school ( ) high school or ged ( ) some college or technical school ( ) college ( ) household income $ –$ , ( ) $ , –$ , ( ) $ , –$ , ( ) declined ( ) employment full time ( ) part time ( ) retired ( ) other ( ) covered by health insurance ( ) children under years old living in household ( ) * n= unless otherwise indicated. family medicine vol. , no. • july-august brief reports exercise adherence. sociocultur- al factors play an important role in exercise adherence, , and could be why it remained strong. our study suggests that using a culturally rel- evant, social model for pa may be effective at encouraging adherence. participants’ overall self-assess- ment of health and level of physi- cal fitness trended positively. global health self-assessments are strongly linked to mortality and other health outcomes, and longitudinal studies could demonstrate if a relationship exists between self-assessment of health and participation in exercise. nonsignificant gains were also noted in confidence towards pa. increased confidence improves an individual’s likelihood to main- tain pa, which is associated with improved quality of life and health outcomes. , inconsistent changes were noted in confidence to consume a healthy diet. although our study addressed nutritional education, it did not ad- dress disparities that play a role in access to healthy foods and super- markets, racial and ethnic dispar- ities in food deserts, socioeconomic status and placement of chain gro- cery stores. these should be consid- ered in future attempts to improve confidence in healthy eating. the intervention’s short length and small sample size limited our findings. our project was conduct- ed in a single neighborhood with largely older, female, aa participants limiting generalizability. a larger, more diverse sample over a great- er duration as well as determining motivational factors for participant sign up and attrition may be worth exploring. additionally, combining questions from multiple instruments limited the validity and reliability of measurement and the ability to compare findings to other studies. of note, the statistically significant find- ing of decreased gratification does not necessarily equate to meaning- ful clinical change in behaviors or motives for exercise participation. a qualitative approach would be an ap- propriate next step to determine if a decrease in gratification of physi- cal activity was clinically meaningful and why it occurred; this approach could also uncover barriers to partic- ipation in the class. finally, relation- ship development with participants and the impact of the study on resi- dent attitudes and behaviors with table : health-related domains: pre- and postsurvey mean responses health-related domain survey item pre post significance ( -tailed) grouped significance self-assessment of health overall healtha . . . p=. physical fitnessa . . . ability to perform adlb . . physical activity enjoymentc pleasurable . . . p=.   fun . . . gratifying . . . stimulating . . . refreshing . . physical activity confidence levelsd muscle strength and flexibility . . . p=. aerobic exercise . . . exercise without increased symptoms . . . abilities to consume a healthy dietd find healthy food p=. eat a balanced diet . . . understand fiber content in food . . . read food labels . . . consume recommended water intake . . . abbreviation: adl, activities of daily living. a self-assessment of health questions (rate overall health) and (rate physical fitness): excellent= , very good= , good= , fair= , poor= . b self-assessment of health question (ability to carry out adl): completely= , mostly= , moderately= , a little= , not at all= . c physical activity enjoyment: extremely “x”= , very “x”= , moderately “x”= , slightly “x”= , not at all “x”= . d physical activity confidence and abilities to consume health diet: completely confident= , fairly confident= , somewhat confident= , slightly confident= , not at all confident= . july-august • vol. , no. family medicine brief reports underserved populations are also two important factors that could be addressed in future studies. this project identified a commu- nity partnership with potential to improve the community’s ability to address health, nutrition, and overall fitness. the class increased ymca memberships and the number of pa- tients receiving primary care at the fqhc. we encourage this fqhc and ymca partnership to be mod- eled by others to foster active en- gagement in health and well-being. acknowledgments: the authors thank the women’s board of thomas jefferson uni- versity for financial support of this pilot in- tervention, as well as the faculty and staff at the ymca, tjuh and skwc for support of the project, assistance with recruitment, and guidance with analysis. this study was presented as “development of a community-tailored, resident-led, fitness and healthy eating intervention at an urban federally qualified health center,” at the society of teachers of family medicine annual spring conference, may - , , san diego, ca. corresponding author: address corre- spondence to dr krys foster, walnut st, suite , philadelphia, pa . - - . fax: - - . references . mensah ga, mokdad ah, ford es, greenlund kj, croft jb. state of disparities in cardiovas- cular health in the united states. circulation. ; ( ): - .   . keppel kg. ten largest racial and ethnic health disparities in the united states based on healthy people objectives. am j epi- demiol. ; ( ): - .   . national center for health statistics. health, united states, : with special feature on racial and ethnic health disparities. : - . . duncan dt, wolin ky, scharoun-lee m, ding el, warner et, bennett gg. does perception equal reality? weight misperception in rela- tion to weight-related attitudes and behaviors among overweight and obese us adults. int j behav nutr phys act. ; . : . . langellier ba, glik d, ortega an, prelip ml. trends in racial/ethnic disparities in overweight self-perception among us adults, - and - . public health nutr. ; ( ): - . . becker h, stuifbergen a, oh hs, hall s. self- rated abilities for health practices: a health self-efficacy measure. health values: the jour- nal of health behavior. education & promo- tion. ; ( ): - . . hibbard jh, greene j. what the evidence shows about patient activation: better health outcomes and care experiences; 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( ): - . development and validation studies of universal pharmacophore models for herg channel openers sunday, february , a receptor x were transfected into cho cells. the cho transfectants were char- acterized by facs and then scaled up for kinexa binding studies. kinexa has been used to measure binding affinity of adnectin-a to the cell surface ex- pressed receptor x to measure the effect of avidity of the multivalent adnectin binding to receptor clusters. as controls for the functional activity of the adnectin-a and the affinity of the monovalent interaction, the same kinexa assay was used, substituting the soluble receptor x extracellular domain for the transfected cho cells. the binding avidity measured by kinexa for cho expressed receptor is pm for both species of receptor x. however, the affinity of adnectin-a for monovalent soluble receptor x was quite different between the species suggesting that avidity due to receptor clustering equilizes the functional avidity at the cell surface. platform: voltage-gated k channels: activation/ inactivation mechanisms -plat a-type kv channel closed-state inactivation is modulated by the tetramerization domain interacting with auxilary kchip a yi-quan tang , fan yang , jingheng zhou , jie zheng , kewei wang . peking university, beijing, china, university of california at davis, davis, ca, usa. a-type kv potassium channels undergo a conformational change towards a non-conductive state at negative membrane potentials, a dynamic process known as closed-state inactivation (csi). csi causes inhibition of channel ac- tivity without prerequisite of channel opening, thus providing a dynamic regu- lation of neuronal excitability, dendritic signal integration and synaptic plasticity. however, the structural determinants underlying kv csi remain largely unknown. we have recently demonstrated that auxiliary kchip a sub- unit contains an n-terminal kv inhibitory domain (kid) that directly interacts with kv . channels to enhance csi. in this study, we utilized the fret two- hybrid mapping and bifc-based screening combined with electrophysiology, and identified the intracellular tetramerization (t ) domain that functions to suppress csi and serves as a receptor for the binding of kid. disrupting kv . t -t interaction by mutating c a within the c h motif of t domain facilitated csi, and ablated the kid-mediated enhancement of csi. furthermore, replacing the characteristic c h motif of kv . t domain with the t domain from kv . without the c h motif or kv . with the c h motif resulted in channels functioning with enhanced or suppressed csi, respectively. taken together, our findings reveal a novel role of the t domain in suppressing kv csi with the c h motif functioning to stabilize the channel activation gate; and kchip a kid directly interacts with the t domain to relieve the stabilization, leading to facilitation of csi and inhibition of channel function. -plat two-in-one: activation and inactivation at the intracellular gate of a kv channel manuel covarrubias , jeffrey d. fineberg . neuroscience, jefferson medical college of thomas jefferson university, philadelphia, pa, usa, physiology and molecular biophysics, jefferson medical college of thomas jefferson university, philadelphia, pa, usa. n-type and p/c-type inactivation are firmly established mechanisms of inac- tivation in voltage-gated kþ (kv channels). however, kv .x channel com- plexes, which undergo fast preferential closed-state inactivation (csi; fineberg et al., , jgp . : - ), appear to use a distinct but un- known inactivation mechanism. previously, we hypothesized that a weak interaction between the voltage sensing domain and the intracellular activa- tion gate underlies csi (bähring & covarrubias, , j physiol : - ). thus, csi is essentially governed by the intracellular activation gate, which fails to open and adopts an inactivated conformation. to directly test this hypothesis, we investigated the heterologously expressed kv . ternary channel complex including accessory subunits kchip and dpp , and ex- ploited the ‘‘trap-door’’ paradigm of the activation gate. the results show that kv . inactivation traps intracellularly applied quaternary ammonium blockers (btbua and tbua) inside the channel’s pore. the trapped blockers can only escape if the channels are opened again by subsequent depolariza- tions. by contrast, inactivation cannot trap tea, whose binding kinetics is faster than that of channel gating. moreover, under identical conditions, a shaker kv channel (shb-t k) known to exhibit fast p/c-type inactivation cannot trap btbua. these findings conclusively suggest that the intracellular activation gate of the kv . ternary channel complex plays a novel dual role, controlling both activation and inactivation. supported in part by nih grant r ns (mc). -plat development and validation studies of universal pharmacophore models for herg channel openers serdar durdagi , , matthew patterson , sergei y. noskov . department of biophysics, bahcesehir university, faculty of medicine, istanbul, turkey, biological sciences, institute for biocomplexity and informatics, university of calgary, calgary, ab, canada. the intra-cavitary drug blockade of herg channel, a common off-target for many drugs, have been extensively studied both experimentally and theoreti- cally. structurally diverse ligands inadvertent blockade of rapid component of delayed rectifying kþ currents are potentially pro-arrhythmic and may lead to drug-induced long qt syndrome-lqts. there are a number of natural strategies for rational drug design; one dubbed the ‘‘passive’’ approach avoids block of herg whereas the ‘‘proactive’’ strategy designs treatments to acti- vate the channel. while ‘‘passive’’ approach has been developed for decades, studies of structural mechanisms of herg channel activation by small mole- cules are truly novel. accordingly, design of the herg openers or current ac- tivators may offer a momentum for modern anti-arrhythmia drug development. significant number of small molecules with capacity for herg activation was identified in mandatory herg screens. to establish possible correlation be- tween activators structure and reactivity, we attempted to construct a universal pharmacophore model for herg channel openers using phase protocol. the biochemical data on kþ channel activators are used in training and test sets. these compounds span a wide range of structurally different chemotypes with ~ ^ -fold variances in binding affinity, which is sufficient for statistically sound model. a developed five sites aahhr (a, hydrogen-bond accepting, h, hydrophobic, r, aromatic) pharmacophore model has showed reasonable high statistical results compared to other constructed models and was selected for steric and electrostatic contour maps analysis. the predictive power of the model was also tested with external test-set (as true unknowns) compounds. pharmacophore model is also combined with previously developed receptor- based homology model of herg k channel and novel activators are generated and screened. the developed ligand-based models may serve as a basis for the synthesis of novel potential therapeutic herg activators. -plat n-terminal regulation of herg kd channel deactivation steven j. thomson, angela hansen, michael c. sanguinetti. nora eccles harrison cardiovascular research and training institute, university of utah, salt lake city, ut, usa. slow deactivation of herg (kv . ) potassium channels maintains ikr dur- ing final repolarization of the cardiac action potential and opposes asynchro- nous early depolarization. inherited point mutations in herg that accelerate deactivation of ikr cause long qt syndrome (lqts), a disorder of ventricular repolarization that increases the risk of lethal cardiac arrhythmia. the intracellular n-terminal domain of herg is known to be essential for slow deactivation. deletion of the entire (~ residues) or just the initial residues of the n-terminus accelerates deactivation -fold. the same effect is achieved by neutralization of the charged residues, arg or arg . how many of the n-termini are required to slow channel deactivation is unknown. herg , like other kv channels, is a homotetramer. by repeatedly linking the c-terminal of one subunit to the n-terminal of the next subunit we constructed concatenated herg tetramers. a variety of homomeric and heteromeric concatenated tetramers were characterized (i.e., wtn/r a:r a( -n); where n = to ). the concatenated channel containing a single r a/r a subunit and wild-type subunits deactivated as fast as the concatenated channel con- taining only r a/r a subunits. the lqts-associated mutation r q, located in the n-terminal of herg was also studied. again, a concatenated tetramer containing a single mutant subunit deactivated as fast as channels with r q mutations in all four subunits. our results show that all n-termini are required to mediate slow deactivation in wild-type herg channels. -plat lipid affinity to the voltage-gated potassium channel kvap elise faure , christine thompson , rikard blunck , . physiology, université de montréal, géprom, montréal, qc, canada, physique, université de montréal, géprom, montréal, qc, canada. voltage-gated potassium channels (kv) are formed by a central conducting pore surrounded by four voltage sensor domains. functional studies have re- vealed that biophysical properties of lipid molecules in the channels environ- ment can have strong effects on the activity of kv channels. here, we investigated the influence of different lipids as well as their affinity to kvap channels. we carried out electrophysiology measurements by fusing vesicles containing purified channels into planar lipid bilayers with varied lipid compo- sitions. we found that kvap properties are mainly determined by the lipid 	a-type kv channel closed-state inactivation is modulated by the tetramerization domain interacting with auxilary kchip a 	two-in-one: activation and inactivation at the intracellular gate of a kv channel 	development and validation studies of universal pharmacophore models for herg channel openers 	n-terminal regulation of herg k+ channel deactivation 	lipid affinity to the voltage-gated potassium channel kvap i n t e r - a m e r i c a n n o t e s chairman of the conference on latin american history of the american historical association. j. preston moore of louisiana state university, author of the cabildo in peru under the hapsburgs (durham, n . c , ), is at present in peru studying municipal documentation of the eighteenth century. e m i l i o rodriguez demorizi has been named rector of the university of santo domingo. robert c. mead of the university of connecticut is the new director of the review hispania, the official journal of the association of professors of spanish and portuguese of the united states. philip c. brooks of the national archives, san francisco branch, has been appointed director of the new truman library in independence, missouri. r e c e n t d e a t h s v i t o alessio robles died in mexico city in june, , at the age of years. h e was born in saltillo, coahuila, and concentrated his historical studies in the northern provinces of mexico, in particular, coahuila and texas. his coahuila y texas en la epoca colonial (mexico, ) is one of the most outstanding works to come from his pen. alessio robles edited editions of many works of fundamental importance for the history of northern mexico, such works as the viaje de indios and the diario de nuevo mexico of fray agustin de morfi (mexico, ); demostracion del vastisimo obispado de la nueva vizcaya by bishop don pedro tamaron romeral (mexico, ); the relacion del viaje of nicolas de lafora (mexico, ), and the diario y derrotero of pedro de rivera (mexico, ). claude g. bowers died in n e w york city in january, . h e was both a historian and a diplomat. as a historian he is considered a top authority on thomas jefferson. his books on lincoln and his era have won wide appreciation. as united states ambassador to spain ( - ) he wrote the controversial mission in spain. his diplomatic mission in chile ( - ) produced his chile through embassy eyes. gustavo otero munoz on august , , gustavo otero munoz, a permanent member of the colombian academy of history, archivist, librarian, and author of many books and articles on colombian history, died in bogota. h e was born in bucaramanga (department of santander) on february , . his copious bibliographic production up to — books, three pamphlets, five volumes of compilations, articles, two published reports, discourses and conferences, and ten prologues—can be seen detailed in the bibliografia academic a by enrique ortega ricaurte (bogota, ). powerpoint presentation  familial hypercholesterolemia (fh) is a common genetic disease that leads to substantially elevated levels of low- density lipoprotein cholesterol (ldl-c)  the acc/aha guidelines for treatment of blood cholesterol to reduce ascvd risk in adults denote an ldl-c level > mg/dl (suggestive of fh) as an independent high-risk feature.  individuals with fh have a -fold increase in risk of early cardiovascular disease.  despite its prevalence, fh remains largely underrecognized: an estimated . million individuals in the u.s. have fh, yet fewer than % have been formally diagnosed.  in , the fh foundation (a patient-led nonprofit organization) created the cascade-fh registry.  the cascade-fh registry is a national initiative to increase fh awareness, characterize trends in treatment, and monitor clinical and patient-reported outcomes over time.  cascade-fh represents a collaboration between the fh foundation, cardiologists, primary care providers, lipid specialists, and patients with fh. initial results from the cascade-fh registry: cascade screening for awareness and detection of familial hypercholesterolemia emily c. o'brien , emil m. degoma , patrick m. moriarty , macrae f. linton , michael d. shapiro , p. barton duell , christie m. ballantyne , william a. neal , zahid s. ahmad , danielle duffy , lisa c. hudgins , linda c. hemphill , james a. underberg , karol e. watson , samuel s. gidding , seth j. baum , katherine wilemon , dave pickhardt , iris kindt , daniel j. rader , matthew t. roe , joshua w. knowles duke clinical research institute, durham, nc; university of pennsylvania, philadelphia, pa; university of kansas, kansas city, ks; vanderbilt university, nashville, tn; oregon health and science university, portland, or; baylor college of medicine, houston, tx; fh foundation, south pasadena, ca; ut southwestern, dallas, tx; thomas jefferson university, philadelphia, pa; rogosin institute, new york, ny; mgh heart center, boston, ma; nyu langone medical center, new york, ny; ucla school of medicine, los angeles, california; nemours dupont hospital, wilmington, de; preventive cardiology, boca raton, fl; stanford school of medicine, stanford, ca  cascade-fh uses a multi-pathway enrollment strategy to ensure maximum availability to interested fh patients  registry participants may enroll in cascade-fh by one of two methods: ) enrollment by a provider in a specialized lipid clinic ) self-enrollment via an interactive online portal for participants meeting pre- specified ldl criteria consistent with fh. funding/disclosures the cascade fh registry has been supported by amgen, astra zeneca, regeneron, sanofi and aegerion. contact emily o’brien, phd medical instructor duke clinical research institute duke medical center pratt street durham, nc email: emily.obrien@duke.edu . . variable overall (n= ) online portal (n= ; . %) clinical sites (n= ; . %) median age, years . . . (iqr) ( . , . ) ( . , . ) ( . , . ) < years of age . --- . white race, % . . . female sex, % . . . formal fh diagnosis, % . . . family member with fh, % . . . prior mi, % . . . prior pci, % . . . prior cabg, % . . . diabetes . . . hypertension . . . current smoker . . . historical highest ldl-c (mg/dl) . ( . , . ) . ( . , . ) . ( . , . ) current ldl level (mg/dl) . ( . , . ) . ( . , . ) . ( . , . ) the cascade fh registry background methods results conclusions data elements • demographics • medical history and laboratory values • current lipid-lowering therapies • clinical events (hospitalizations, mortality) • patient-reported outcomes (qol, treatment satisfaction) data analysis • baseline characteristics presented as percentages for categorical variables and medians with interquartile ranges (iqrs) for continuous variables phase online patient self- enrollment • patient-reported information through online portal • medical release for comparison with clinical data phase retrospective clinical data collection • deidentified patient data abstracted and entered at each site phase prospective clinical data collection • longitudinal data collected at month intervals • information on quality of life, medication changes, and clinical events • the cascade-fh registry represents a collaboration between fh patients and clinical researchers who have partnered to address gaps in knowledge regarding fh screening, identification, and treatment. • cascade-fh will evaluate future longitudinal treatment patterns and outcomes in this high risk patient population abbreviations: mi=myocardial infarction; pci=percutaneous coronary intervention; cabg=coronary artery bypass graft *high-intensity statins defined as atorvastatin> mg or rosuvastatin> mg variable overall (n= ) online portal (n= ; . %) clinical sites (n= ; . %) currently treated with statins, % . . . currently treated with high- intensity statins*, % . . . number of llt . . . . . . . . . + . . . table . baseline characteristics of the cascade-fh patient population (september – february ). table . treatment patterns of the cascade-fh patient population (september – february ). *among patients treated with statins abbreviations: llt=lipid lowering therapy results (continued) . . . . . . . how fh can negatively affect my health current medication regimen available treatment options how fh increases risk of heart disease where i can go to get more information about fh your personal risk for events like heart attack and stroke why fh screening of family members is important not satisfied at all % mostly dissatisfied % somewhat dissatisfied % mostly satisfied % highly satisfied % i can't stop worrying about it % i often worry about it % i occasionally worry about it % i rarely worry about it % i never worry about it % figure . how satisfied are you that everything possible is being done to treat your fh?* figure . how often do you worry that you may have a heart attack or die suddenly?* figure . percent of patients reporting that they “completely understand” the following about fh* % *online portal patients only the provenance of the thomas jefferson papers paul g. sifton a striking lack of information concerning the provenance of his papers characterizes early works on thomas jefferson by such diverse figures as henry s. randall ( ), henry a. washington ( - ), paul leicester ford ( - ), and a. a. lipscomb and a. e. bergh ( - ), as well as more recent studies by claude g. bowers ( , ), bernard mayo ( ), marie kimball ( , , ), dumas malone ( - ), and julian p. boyd ( - ).' the deficiency was partially remedied in by worthington chauncey ford in an essay that still stands as the most authoritative provenance statement on many aspects of the history of the jefferson papers, both public and private. ford's essay was complemented by helen duprey bullock in her article stressing the origins of the jefferson collection at the university of virginia. beyond the insights in the ford and bullock essays, it should be recognized that jefferson himself attempted to remedy gaps in his correspondence; that a small but historically important group of manuscripts collected by jefferson came to the library of congress in ; and that there were several notable accretions to the library's holdings as recently as the - period. it is when one investigates the rather obscure figure of professor henry augustine washington that one gains new understanding of the tangled tale of the jefferson manuscripts after . none of these points are developed in the ford and bullock essays which, although models of their kind, require both a note of caution and these additional facts to set their information in proper perspective. paul g. sifton is specialist in early american history, manuscript division, library of congress. on october , , he presented a somewhat different version of this paper to the saa panel on revolutionary age material and modern methods, and another adaptation of it appears in the index to the thomas jefferson papers (washington: library of congress, ). henry s. randall, life of thomas jefferson, vols. (new york: derby & jackson, ); the writ- ings of thomas jefferson, henry a. washington, ed., vols. (washington: taylor & maury, - ); the writings of thomas jefferson, paul leicester ford, ed., vols. (new york: g. p. putnam's sons, - ); the writings of thomas jefferson, andrew adgate lipscomb and albert e. bergh, vols. (washington: thomas jefferson memorial association, - ); claude g. bowers, jefferson and hamilton: the struggle for democracy in america (boston: houghtonmifflinco., ) and jefferson in power: the death struggle of the federalists (boston: houghton mifflin co., ); jefferson him- self: the personal narrative of a many-sided american, bernard mayo, ed., (charlottesville: university of virginia press, ); marie kimball, jefferson, the road to glory, to (new york: coward- mccann, inc., ), jefferson, war and peace to (new york: coward-mccann, inc., ), and jefferson, the scene of europe, to (new york: coward-mccann, inc., ); dumas malone, jefferson and his time (boston: little, brown and co., - ); the papers of thomas jeffer- son, julian p. boyd, ed. (princeton: princeton university press, - ). worthington chauncey ford, "the jefferson papers," in thomas jefferson, architect, fiske kim- ball, ed. (boston: privately printed, ), pp. - . helen duprey bullock, "the papers of thomas jefferson," in jefferson papers of the university of virginia: a calendar, constance e. thurlow and francis l. berkeley, jr., eds. university of virginia bibliographical series no. (charlottesville: university of virginia library, ), pp. - . origi- nally published in the american archivist (october ). the american archivist vol. , no. january d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril the american archivist—january the beginning history of jefferson's papers is familiar enough to students of the third president's life. peter jefferson, thomas's father, was a surveyor, planter, and county colonel, and he had no more than a nominal interest in preserving a body of papers. the manuscripts he possessed passed to his son at his death in . undoubtedly, his father's papers meant little to thomas at the age of fourteen. soon thereafter the young jefferson went to williamsburg to pursue his collegiate and legal studies. as a student of the law, jefferson kept his commonplace books and a small library in his rented quarters in williamsburg. the remainder of his papers, as well as those of his father, were at his home, shadwell. in february , shadwell burned to the ground, and with it burned most of the papers of the two jeffersons. jefferson wrote to his friend, john page, that the fire involved "every paper i had in the world, and almost every book. on a reasonable estimate i calculate the cost of the books burned to have have been £ sterling. . . . of papers too of every kind i am utterly destitute. all of these, whether public or private, of business or amusement, have perished in the flames." other than a few items retrieved from the disastrous fire, thomas jefferson's small accumulation in williamsburg was all that remained of his youthful correspondence. the want of pre- manuscripts has, therefore, given historians an imperfect view of jefferson's formative years. a second catastrophe occurred when jefferson's letterbooks as governor of vir- ginia were lost during arnold's raid on richmond, in december . to fill in this gap, insofar as possible, jefferson borrowed, for copying, his gubernatorial letters to washington as commander-in-chief. to a similar end, jefferson in bor- rowed gen. horatio gates's letterbook to copy letters to correspondents writ- ten during the period june , , to october , . in both these actions, jeffer- son was consciously trying to fill in gaps in the gubernatorial correspondence for the last months of the revolution. additionally there is a mysterious gap in the s, commencing immediately after jefferson left office as secretary of state. worthington ford has stated that these particular papers were destroyed for political reasons; however, julian p. boyd disagrees, stating that "there is not a shred of evidence to support such a charge." fortunately, these are the only serious gaps in the extensive accumulation of man- uscript materials which jefferson left when he died on july , , exactly fifty years after the declaration of independence was adopted. three months before his death, jefferson executed a will which bore the follow- ing codicil: "my papers of business going of course to him [his grandson, thomas jefferson randolph] as my executor, all others of a literary or other character i give to him as of his own property." sarah nicholas randolph, in her charming and informative work the domestic life of thomas jefferson, has noted jefferson's relationship with his grandson: mr. jefferson had found the cares of his large estates too great a burden for him to carry in his advancing years, and gladly handed them over into the hands of the young grandson, in whose skill and energy he expresses such perfect confidence. . . . until the day of jefferson's jefferson to page, february , ; yale university library. quoted in boyd, ed., papers of tho- mas jefferson, vol. , p. . ibid., vol. , p. n. boyd, letter to john c. broderick, may , ; manuscript division, library of congress (lc). original holograph will, clerk's office, albemarle county, virginia; photocopy in thomas jefferson papers, series , manuscript division, lc. quoted in bullock, "papers of thomas jefferson," p. . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril thomas jefferson papers death, we . . . find this grandson interposing himself, as far as possible, between his grand- father and his financial troubles, and trying to shield him, at least during his life, from the financial ruin which the circumstances of his situation made unavoidable. thomas jefferson randolph, therefore, as a matter of course was given the important responsibility of guarding the papers of his illustrious grandfather. in , two important steps were taken under randolph's supervision. the library of congress acquired, in addition to printed books, several bound volumes and bundles of manuscripts concerned chiefly with virginia history. these items included the records of the virginia company of london ( - ), materials relat- ing to the general assembly, and other colonial records, as well as notes and com- mentaries on such subjects as history, philosophy, and the law. in addition, ran- dolph prepared and edited four volumes entitled memoir, correspondence, and miscellanies from the papers of thomas jefferson, which were to be only the first of several attempts to replicate, with varying degrees of success, the correspondence of the third president. the publication of randolph's work led henry lee ( - ) to revive the long-standing feud between his father, henry ("light-horse harry") lee ( - ), and jefferson. in , virginia governor lee had passed secondhand gossip on to washington about the president's advisers and pro-british sentiments which purportedly had been expressed at jefferson's dinner table; and, in , lee told washington that jefferson was involved in intrigue against his administration. jefferson's correspondence clearly indicates that he knew of and resented lee's machinations. in light-horse harry's son, henry lee, proceeded to publish the avowedly partisan observations on the writings of thomas jefferson, which did little to remove the stain from his father's escutcheon. the vivid partisanship which thus enveloped the first publication of jefferson's correspondence led thomas jefferson randolph to permit the political economist and author george tucker ( - ) to see "all the letters written" by jefferson so that he could prepare an impartial rebuttal to lee's work. as a youth, tucker had been sent from his native bermuda to the care of his distant relative, st. george tucker ( - ), who had succeeded jefferson's mentor, george wythe, as pro- fessor of law at the college of william and mary. the young man had, therefore, come to maturity among the leading antifederalists in the jefferson circle. in spite of this pro-jeffersonian background, tucker performed extensive independent research, held many conferences with james madison, and used a "selection of such letters and papers, never before published, as were thought to throw light on mr. jefferson's character." the result of tucker's research was the life of thomas sarah n. randolph, the domestic life of thomas jefferson ( ; d ed., cambridge: harvard uni- versity press, ), p. . report of the librarian of congress for the fiscal year ending june , (washington, ), p. ; handbook of manuscripts in the library of congress (washington, ), pp. - . these two listings include materials from both the and the acquisitions. published by f. carr and co., charlottesville, , dumas malone, jefferson and his time, vol. , jefferson and the ordeal of liberty (boston: little, brown and co., ), pp. - . the rumor was revived in ; ibid., p. . published by c. debahr, new york, . george tucker, the life of thomas jefferson, vols. (philadelphia: carey, lea blanchard, ), vol. , p. xv. see the discussion of tucker in dictionary of american biography, s.v. tucker, george. in his preface, tucker states that randolph allowed him "access to all the letters written" by jefferson and that nicholas p. trist, who had married randolph's sister, made the selection mentioned in the text. w. c. ford ("jefferson papers," p. ) suggests that trist's involvement with jeffersonian manuscripts may imply a "possible division of the papers within the family." however, there is no definitive evidence that this group of papers were returned either to the randolphs or the trists, or remained in tucker's hands. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril the american archivist—january jefferson, a remarkably impartial and fairly successful contribution to early ameri- can history. from until the sale of the jefferson papers to federal government in , no one is known to have made use of the manuscripts. in a letter which thomas jeffer- son randolph wrote to frederick augustus hall muhlenberg of franklin college, lancaster, pennsylvania, on september , , he explained the reason for declin- ing requests to examine the papers: you are perhaps not aware that mr jeffersons estate was greatly embarrassed under the extreme depression of the period of its sale fell far short of the payment of his debts. these debts have all been discharged by myself and the sale of his m.s.s. afford the only hope i have to protect my family from the effect of an act of filial duty. many applications are made for copies of letters; to comply would greatly impair their value and i have felt myself reluctantly compelled to decline a compliance. my contemplation is to dispose of the whole in mass where the[y] would be accessible to every one. randolph kept the jefferson collection intact because he was aware of contemporaneous sales of the george washington papers ( ) and the james madison papers ( ) to the government. later criticism of the incompleteness of the papers mrs. madison had sold to the government led secretary of state james buchanan to admonish randolph to include both public and private papers in the sale. in due course, the appropriation act of august , , providing for the civil and diplomatic expenses of the government for the fiscal year , contained the following item: for paying to thomas jefferson randolph, executor of thomas jefferson, deceased, the sum of twenty thousand dollars, for all the papers and manuscripts of the said thomas jefferson: provided, that said t.j. randolph shall deposit all the said papers and manuscripts of a public nature in the state department, and execute a conveyance thereof to the united states. t h e papers were deposited by randolph at the department of state for exam- ination, in order that the private papers might be separated from the public and returned to the family. shortly thereafter, in , randolph wrote a particularly informative description of the state of his grandfather's papers at the time of their sale to die federal government in : the letters written by mr. jefferson are all arranged together in chronological order. the pa- pers, documents, official correspondence, notes of transactions while secretary of state to gen washington, are bound in three volumes of marbled paper, marked a. b. c : the letters received are in three series alphabetically arranged—the first, received during his residence in paris; the second, during his residence in philadelphia as secretary of state, vice president and president at washington; the third after his return home. these are contained in paper boxes, open at top and back, the width and breadth of letter paper folded lengthwise; the name of the writer and date endorsed across the end, added to t. j. randolph to f. a. h. muhlenberg, september , ; muhlenberg family papers, manu- script division, lc. this is specifically noted in t. j. randolph's letter of august , , to h. a. washington, in the tucker-coleman papers, college of william and mary—hereafter cited as tcp. microfilm copy in henry a. washington collection, manuscript division, lc. the point is also repeated in randolph's letter, receipt stamped october , ; misc. letters, october , part ii, department of state rec- ords, national archives and records service. the department's records will be hereafter cited as r.g. , na. stat. l. . secretary of state james buchanan's letter of acceptance to t. j. randolph, dated at the department of state, october , , was acquired in and added to the buchanan collection. fair copy in domestic letters, vol. , p. , r.g. , na. the letter concludes: "your wish in regard to a return of such of the papers as are of a private nature, shall receive proper attention, as far as this department is concerned." d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril thomas jefferson papers these are packages with the contents endorsed on the wrapper. there is also an index contain- ing some , entries of letters written and received, partly in a bound volume and con- tinued on loose sheets stitched together. the arrangements for reference is very convenient and it would be desirable to preserve it. . . . his private family letters were in three square boxes and not intended to be sold, but the secretary of state mr. buchanan expressed a doubt as to the law and advised their deposit. . . . these i wish to reclaim as of no public value and interesting only his family. in , however, few could have predicted that henry a. washington, based in williamsburg, would rapidly go through the estimated , letters in his search for items suitable for a congressionally sponsored publication; that he would arbi- trarily divide the jeffersonian manuscripts into five series; that the personal papers would remain unexamined until ; that the federal government would fail to purchase thousands of manuscripts offered to it by other descendants at bargain pri- ces; that there would be a reappearance in of enough jeffersonian manuscripts to fill nineteen additional volumes; that major segments of jefferson's papers would be added to the library of congress's collections as late as ; or that defin- itive publication of the third president's outgoing and incoming correspondence would not commence until . randolph's letter, therefore, takes on retrospective importance in confirmation of the archival integrity jefferson main- tained throughout his lifetime in the control of his priceless collection of manu- scripts. it was this integrity which was to desert the collection, for a variety of rea- sons, for over a century after its receipt in the department of state by secretary james buchanan. on march , , virginia congressman james murray mason, of the joint committee on the library, asked henry augustine washington, of the college of william and mary, to edit the papers of thomas jefferson for publication by the government. as a grandson of george mason, congressman mason believed that it is of great importance to virginia that this duty should be performed by one of her own citizens whose integrity c capacity may be relied on, that no injustice shall be done to the fame of mr jefferson. the mason letter clearly indicates that only material deemed of a "public" nature was to be selected. further, "it is not expected or desired that any editorial matter should be incorporated." on july , , professor washington had the jefferson papers delivered to him in a room set aside for him in the department of state, where he worked on them for fifty-nine days at $ . per day. however, the most singular point of agreement, which was arrived at after some uneasiness on the part of the joint committee on the library, was the removal of the jefferson manu- scripts from the district of columbia to williamsburg. washington was deter- mined to maintain his full schedule of academic duties at the college of william and mary, and by late autumn of he had persuaded the committee members to agree to the mass removal. once the papers were in williamsburg, washington speedily set to work copying and collating the material. between october and august , he worked t. j. randolph to h. a. washington, august , ; tcp. thereupon designated series in the records of the bureau of rolls and library; see deed of transfer to i x , dated july , , r.g. , na. j. m. mason to h. a. washington, march , ; tcp. joint committee on the library, account book with the library, p. ; lc archives. h. a. washington to his father, lawrence washington, september , ; h. a. washington col- lection, manuscript division, lc. h. a. washington, undated draft memorandum, probably july ; tcp. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril t h e american archivist—january days and hours at $ . per day, as well as days (at $ . per day) in new york city editing the papers at the office of the publishers, taylor & maury. at this time, the professor had an even more surprising innovation to suggest: in this connection, i take the liberty of making a suggestion which, if adopted, will greatly diminish the expenses attending the publication of the jefferson papers. many of the papers are not originals, but press copies ir manuscript copies, carefully preserved by mr. jefferson. there is a large mass of this description of papers the expense of copying [which] would be considerable—my suggestion is that [the] editor be permitted to entrust these copies to the printer—this will save much expense and such being the case, why make copies from cop- ies? . . . it is not proposed that, in any case, an original paper shall pass from the hands of the editor. although the library committee did not permit washington to send the letter- press copies to the printer, he nonetheless left his mark on the letterpress and poly- graph copies, often important and u n i q u e copies rather than secondary versions. years later, librarian of congress ainsworth rand spofford reported to the library committee that professor washington was guilty of "inaccuracies, omissions, garbled extracts and evident tampering with letters, mss., and material in his hands." a twentieth-century editor has also commented: here and elsewhere in this and other press copies by tj, someone in the th century, proba- bly employing a sharp steel pen, traced over the faint and fading lines. the motive was laudable, but the execution was often demonstrably faulty. . . . h. a. washington was one of those who was responsible for retracing faded parts of press copies. working with all possible speed, and in response to pressing reminders from the j o i n t committee on the library, washington finished the editing by ; the nine volumes of the writings of thomas jefferson were published in - . in addi- tion to editing jefferson's papers for publication, however, washington had also agreed "to select all papers worthy of preservation among the national archives [at the state department], & arrange & index the same." on december , , assis- tant librarian of congress edward stelle wrote to inquire in behalf of the joint committee as to the length, duration, and cost of the publishing project. wash- ington temporized on the exact length, number of volumes, and possible costs of the publication of the letters and then summed u p his work on selecting and binding the papers for preservation: and, in discharge of . . . my duty, some one hundred & twenty five volumes of manuscripts have been selected, arranged, indexed, c are now ready for the hands of the binder—leaving in my possession a mass of refuse matter nearly twice as large as that which has been selected j o i n t committee account book with library, p p . a n d ; l c archives. h . a. washington to library committee, undated m e m o r a n d u m ; t c p . a later two-page, undated (ca. ) m e m o r a n d u m in the same collection indicates that the committee had rejected the sending of letterpress copies to the printer. w a s h i n g t o n nonetheless had marked u p a portion of the press and poly- g r a p h copies to render them more legible to his copyists. extracts, minutes of the j o i n t committee, march , , p . ; l c archives. see also the undated, four-page report in spofford's correspondence folder, l c archives. boyd, ed., papers of thomas jefferson, vol. , p . n. in discussing the m a n u s c r i p t description of jefferson's tour t h r o u g h h o l l a n d (ibid., vol. , p p . - ), boyd notes that " p o r t i o n s of ms have been marked or crossed o u t by h . a. washington, w h o used the original for printer's copy a n d indicated on it his directions to the compositor, a fact which may explain why a part of the ms is missing." t h e exten- sive footnotes detail w a s h i n g t o n ' s many changes, emendations, and omissions. see , , and correspondence to h . a. washington; t c p . h. a. washington to james a. pearce, june , ; tcp. librarian's letterbook, december , ; lc archives. another copy is in tcp. similar inquiries were directed to all editors of such projects. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril t h o m a s jefferson papers [i.e., "public" papers] for preservation among the national archives, & which will be placed at the disposal of the library committee. it should be noted that the volumes cited in january grew to vol- umes by late j u n e , and to volumes, including the index, by early september. on j u n e , , washington wrote to the joint committee chairman, james pearce: the whole mass of the manuscript, which i received from the state department, has been carefully examined by me, & every thing deemed worthy of preservation, has been selected, c . . . digested, arranged c indexed. . . . the manuscripts selected for preservation from the general mass amount to one hundred & thirty four volumes, which are now in the hands of the binder under authority received from you, & which will be, when bound, returned to the archive office, together with the general index to the whole. the refuse matter, constituting a mass considerably larger than the selected matter, has already been deposited in the state department in the same condition in which it was received by me. on j u n e , , therefore, s. le camp, a washington binder, acknowledged the receipt of "one hundred & thirty four volumes of the jefferson manuscripts, together with an index to the same," from professor washington. t h e next day, george chipman of the roll office in the department of state, received from the professor "three boxes containing all the jefferson papers, received by him from this dept. except that portion of the same now in the hands of the binder." what was not apparent at this time, however, was that a number of jeffersonian items may have remained in the hands of professor and mrs. washington; this would be suspected only in , when william k. bixby purchased , items of jefferson correspondence from a descendant of the two editors, george tucker and henry a. washington, a purchase to be discussed later. t h e selection of the private papers from the u n b o u n d manuscripts was apparently overlooked at the state department until , when thomas jefferson randolph wrote to complain to secretary of state hamilton fish: prior to the late rebellion i sold to the government, the letters and papers of president jefferson. . . . on the delivery of those papers, mr. buchanan, then secretary of state, required me to deliver his whole papers public and private: those which came under the purview of the act [august , ] and those which did not; submitting to a committee (i think the library committee) to determine. mr. buchanan after the delivery gave himself no further concern about it. it became impos- sible to get the committee to act, thus i lost private family papers of no use to any save mr jeffersons family, and obviously not included in the terms of the act. these if my memory does not deceive were contained in three square pine boxes marked private papers. these papers i desire to reclaim and you sir would lay me under great obligation could you facilitate this object. secretary fish replied to randolph on november , , that the act of august , , appeared to him "ambiguous" and also that an examination of the department's records disclosed nothing "to show mr. buchanan ever contemplated the return of any portion of the papers." fish closed by saying he had no legal au- thority to act, and that only congress could effect such a restitution. h. a. washington to edward stelle, january , ; tcp. s h. a. washington to pearce, june , ; tcp. see also the joint committee account book with the library, pp. - ; lc archives. s. le camp, signed receipt, june , ; tcp. george chipman, signed receipt, june , ; tcp. t . j . r a n d o l p h to secretary of state h a m i l t o n f i s h , receipt s t a m p e d o c t o b e r , ; miscellane- o u s letters, o c t o b e r , p a r t ii, r . g . , n a . f i s h to t . j. r a n d o l p h , n o v e m b e r , ; d o m e s t i c l e t t e r s , vol. , p p . - , r . g . , n a . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril the american archivist—january the joint committee on the library proved to be somewhat less dilatory, and on december , , voted to request that the secretary of state transmit the "three boxes of private papers" to the librarian of congress for his inspection. under congressional pressure, secretary fish wrote to the chairman of the joint committee, senator alexander g. cattel, on december , , a letter which was more forth- right than his earlier reply to randolph's plea for restitution. there are preserved in this department three boxes, two of which are marked "jefferson's manuscripts—refuse" and one "jefferson's manuscripts," which boxes contain bundles of papers, a number of which are labelled "private—examined." some are the letters addressed to private individuals and others are of a miscellaneous character. . . . the fact that these boxes of papers are not entered in the list of archives in the department printed in , it seemed not unlikely that the committee on the library intended to recommend the restitution of them to mr. randolph, but that the matter had been overlooked. at all events, for the last eight years, copies of papers in the regular five series have been called for by historians and others, but those in boxes not at all.' fish thereupon stated that he would deliver the three boxes to spofford or one of his agents if they bore the chairman's "official order therefor." the bound quarto volumes remained in the state department. on february , , the committee resolved that after librarian spofford's ex- amination of the papers he be "authorized to return to the executor of thomas jefferson such of the papers of the said jefferson as upon examination shall be deemed of a private character." in spite of the allegedly disorganized condition of the joint committee in the - period, the papers ajudged private by spofford were sent to the family. sarah n. randolph was able, therefore, to write in june : "jefferson's executor having a few months ago recovered from the united states government his family letters and private papers which had been exempted from the sale of his public manuscripts." she could print letters never before pub- lished. unfortunately, the - selection of public and private papers was inconsistent: spofford himself explained that those "papers which were unques- tionably private" were returned to the heirs, but those "of a public nature, or partly public and partly private," were retained by the government. the basic fallacy, of course, was the attempt to categorize given letters. if there is such a thing as an average jefferson letter, it might touch upon such disparate subjects as crops, poli- tics, violins, astronomy, diplomacy, and wines. in retrospect, it can be seen that any attempt to classify an entire letter was foredoomed to failure. thomas jefferson randolph died on october , , and papers in his possession passed to his daughter under a general bequest. at this point, tribute should be paid to the careful stewardship of jefferson's papers which had been the hallmark of randolph's life from to his death; his publication of the memoir; the sale to the library of congress in the same year of an irreplaceable extracts, minutes of the joint committee, p. ; lc archives. reports from the secretary to the president and the congress, vol. , pp. - , r.g. na. extracts, minutes of the joint committee, p. ; lc archives. spofford was paid $ per day for his work. o n a p r i l , , l . m . m o r r i l l , a m e m b e r of t h e c o m m i t t e e , w r o t e to m r s . m. c. s p a r k s , a legatee of t h e j a r e d s p a r k s p a p e r s , t h a t " c o n s i d e r i n g the u n - o r g a n i z e d c o n d i t i o n of t h e l i b r a r y c o m m i t t e e , " they w o u l d be o b l i g e d to refuse t h e offer of t h e s p a r k s m a n u s c r i p t s ; l i b r a r i a n ' s l e t t e r b o o k , l c archives. s a r a h n . r a n d o l p h , domestic life, p . vii. a i n s w o r t h r. spofford to secretary of state j o h n s h e r m a n , december , ; j o h n s h e r m a n p a - pers, m a n u s c r i p t d i v i s i o n , l c . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril thomas jefferson papers group of early virginia documents; his positive reaction to henry lee's partisan work in seeking out george tucker to write a new and impartial book on his grand- father; his care of the manuscripts until the sale to the government in ; and, finally, his valiant attempt in to convince professor washington to honor jef- ferson's original intentions in the preservation of his priceless collection. on february , , congressman daniel w. voorhees called the attention of the joint committee to the application of sarah n. randolph of baltimore to reedit the works of jefferson, which she said were improperly edited and, in their pub- lished form, "very inaccurate." t h e committee thereupon invited miss randolph to appear on march , . t h e witness cited numerous errors in professor wash- ington's nine volumes, including omissions, inaccuracies, neglect, and ignorance, not to mention "tampering" with the manuscripts. in addition to preparing a new, correct, and thorough edition, miss randolph proposed to include documents in her family's possession which would "throw much light upon the private and pub- lic life of the great statesman, and present him in many phases of life, heretofore unknown and therefore all the more interesting to the world." after the interested committee heard miss randolph's presentation, it directed librarian spofford to report to the committee at their next meeting. for his report at the march , , meeting, spofford prepared a four-page mem- orandum which largely supported miss randolph's contentions of the shortcom- ings of professor washington's work. additionally, spofford pointed out that the original letterpress copies "are gradually fading, and may hereafter become inde- cipherable." spofford's most devastating criticism was reserved for his summa- tion: the deficiencies of this edition are so great as to impair, and in some cases to destroy its value as an index to true opinions of mr. jefferson, and to his relation to the men and events of his time. . . . the fact remains that the writings of one of the foremost statesmen in american history have been given to the world in a most incomplete form, omitting far more than they contain. after hearing spofford's sobering report, the joint committee appeared to be con- vinced of the necessity of a new edition of jefferson's writings to be prepared by miss randolph under spofford's general direction. on april , , and again on january , , the joint committee came out in favor of sponsoring a new and comprehensive edition of jefferson's "correspondence sent and received," for prep- aration of which miss randolph was to receive $ , a year. however, by the committee was also considering the purchase of the papers in miss randolph's possession, none of which were duplicated in the state department collection. t h e debate in congress over the purchase continued for several years and in the mean- time the editorial project was shunted aside. sarah randolph died on april , , leaving the papers to her sister, caroline ramsey randolph. t h e joint committee had recognized the value of reuniting the public and private collections of jeffer- extracts, minutes of the joint committee, p. ; lc archives. ibid., p. . undated, unsigned report in spofford's correspondence folder, lc archives. e x t r a c t s , m i n u t e s of t h e j o i n t c o m m i t t e e , p . ; l c a r c h i v e s . ibid., pp. , . bullock, "papers of thomas jefferson," p. . although mrs. bullock calls her "carolina," she is identified as "caroline" in the randolphs of virginia, william randolph and mary isham. comps. (chicago: privately printed, ), entry . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril the american archivist—january sonian correspondence, but it was unable to persuade congress, and an outstanding opportunity to correct a failure of the previous generation was lost. in , some twenty-six years after the return of the private papers to the randolphs, those papers which had been retained by the government in came to light again during the move from the capitol of the library of congress to its new building across the street. as spofford explained in his letter of transmittal, december , , to secretary of state john sherman: these valuable papers have just been discovered by me in the clearance effected of a room next to the congressional library in the capitol, in which have been piled for many years (it being the only place under lock and key) the accumulations of manuscripts, rare books, etc. which could not be protected in the library proper. these jefferson papers were sent to the joint committee on the library, with others, upon an application of the heirs to have returned to them the papers of a private nature, which had been in possession of the government pending the selection of material to be published. an examination of all the papers resulted in the return by the committee of a selection of the pa- pers which were unquestionably private, to miss sarah n. randolph, representing the heirs, leaving all which were of a public nature, or partly public and partly private, in the hands of the committee. this deposit, with multitudes of others, was completely overlooked by me in the multiplic- ity of increasing cares and labors pressing upon the librarian in the copyright bureau and the library proper, and their discovery, after so many years, enables me to perform a most gratifying though tardy act of justice in restoring them to the department. they are believed to be wholly intact. t h e material was added to the jefferson holdings of the bureau of rolls and library at the department of state, which, according to an undated holograph list, already included: st series d " d " t h " t h " st" d, d, th & th series case no. jefferson papers letters from jefferson " rec'd by jefferson treasury, war & navy letters letters c notes rec'd while sec'y of state miscellaneous index to names index to names vols ° " " " " " " " " " " " " canons of etiquette with letter of rufus king to madison enclosed in book cover letters to jefferson concerning his administration package loose papers letters of jefferson from paris during — — bundle of papers diary of thomas jefferson (small m o calf binding) in envelope design of a monument to jefferson batture case—pamphlet with written notes by jefferson this is the sole characterization of the five, bound series as designated by henry a. washington in . the list is also important for noting the existence of a number of "loose" and unbound items. the material sent from the library of congress in december was bound in nineteen additional volumes and formed a sixth series of jefferson papers. by an a description of the material offered to the congress appears in w. c. ford, "jefferson papers," p. , note . see also joint committee on the library, report to accompany s. , st cong., sess, , s. report . spofford to sherman, december , ; john sherman papers, manuscript division, lc. quoted only in part in calendar of correspondence of thomas jefferson, u.s. department of state, bureau of rolls and library, bulletin no. (washington, ), p. . folder, "old lists of department's papers," p. ; bureau of rolls and library, r.g. , na. transmittal letter, department of state to lc, july , ; bureau of rolls and library, letters, vol. , p. , r.g. , na. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril thomas jefferson papers act of congress of february , , however, heads of government agencies were authorized to turn over to the library of congress "books, maps, or other material" n o longer needed in the conduct of their business. t h e jefferson papers formed one of the first groups to be transferred in accordance with this act, following an execu- tive order of march , . t h e library received them on july , . t h e depart- ment of state retained two groups of jeffersonian letters: transcripts of his parisian letters, may , —august , ; and his official letters as minister to france, to congress, and to j o h n jay, secretary for foreign affairs. in addition to the six series of bound papers, the library of congress received: the virginia almanack for the year , con- taining memoranda in jefferson's hand- writing relating to money matters. letters to jefferson, - . unbound mounted sheets. design of a monument to jefferson by larkin g. meade, . altogether, more than fifty-five years had elapsed before all the manuscripts obtained from t h o m a s jefferson randolph were reassembled in one place. t h e government had preserved all that had come to it, but its custody u p to that time had been marked by apparent confusion and seeming neglect. it should be noted in passing that, in , worthington c. ford wrote that an additional group of jefferson manuscripts was found "in , or " in spof- ford's office. t h i s is probably an incorrect assertion because such a discovery would have been reported in the librarian's letterbook and in other appropriate rec- ords. no such proof has been located. it is more likely that ford misconstrued the nature of a number of groups of u n b o u n d jefferson items either in the bureau of rolls and library or in the library of congress. we have previously noted the number of loose jeffersonian items listed in the holdings of the state department and in the transfer to the library of congress. there is n o conclusive proof of an additional discovery in of "upwards of two thousand pieces," in addition to the large group found in by spofford. helen duprey bullock has covered in some detail the fortunes of the private pa- pers returned to the randolph family. caroline r. randolph inherited the papers of her sister sarah in , and in t h o m a s jefferson coolidge, a great- grandson of t h o m a s jefferson, purchased from caroline r. randolph approximately , items, which he presented to the massachusetts historical society in j u n e of that year. a selection from these papers was printed in the society's collections. after the death of caroline randolph in , her remaining papers were bequeathed to three nieces, mrs. william mann randolph, cornelia j. taylor, and eliza ruffin. most of the papers owned by mrs. randolph were lost in a bureau of rolls and library, letters, vol. , pp. , , r.g. , na. these items now form part of the papers of the continental congress, r.g. , na. t r a n s m i t t a l letter, d e p a r t m e n t of s t a t e to l c , j u l y , ; b u r e a u of r o l l s a n d l i b r a r y , l e t t e r s , v o l . , p . , r . g . , n a . w . c . f o r d , " j e f f e r s o n p a p e r s , " p . . a n u m b e r of m i s c e l l a n e o u s g r o u p s of jefferson m a t e r i a l a r e m e n t i o n e d i n t h e calendar, b u r e a u of r o l l s a n d l i b r a r y , b u l l e t i n n o . , p . iii. i n a d d i t i o n , t h e p r e s e n c e of v a r i o u s t y p e s of jefferson " p a p e r s " is n o t e d i n t h e several u n d a t e d lists of m a t e r i a l in t h e c u s t o d y of t h e b u r e a u of r o l l s a n d l i b r a r y for t h e p e r i o d a n t e d a t i n g ; r . g . , n a . w h i l e n o n e of these lists a r e c o n c l u s i v e , they i n d i c a t e t h a t t h e e x i s t e n c e of u n b o u n d jefferson m a t e r i a l w a s k n o w n to f o r d a n d h i s c o n t e m p o r a r i e s . collections of the massachusetts historical society, seventh series (boston, ), vol. . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril the american archivist—january fire, and after miss ruffin's death in her portion was divided between the two survivors. after the death of miss taylor, her nieces olivia and margaret taylor inherited her share of the papers and transferred them, along with many papers of the randolph family at edgehill, to the university of virginia. following in his father's footsteps, thomas jefferson coolidge, jr., in located and purchased from mrs. william mann randolph and cornelia j. taylor a large group of jefferson's architectural drawings for monticello; these he sim- ilarly deposited in the massachusetts historical society. the drawings were subse- quently printed in . as heir of caroline r. randolph, wilson cary nicholas randolph gave sixty- two of jefferson's sketches and plans for its original buildings to the university of virginia; and upon her husband's death in , mrs. randolph presented drafts of letters by jefferson concerning the university of virginia to the library of congress. a final outstanding private purchase of jeffersonian letters took place in . the prominent st. louis collector william k. bixby acquired , pieces from george p. coleman of williamsburg and richmond, whose ancestor, george tucker, had edited the life of jefferson noted above. coleman's mother had mar- ried henry a. washington and, after his death in , charles w. coleman. it appears probable that the jefferson material in the coleman collection came from the papers of the two editors, tucker and washington. wishing to share his collection with the public, bixby distributed more than jeffersonian items to forty-six individuals and repositories, and , he presented to the missouri historical society. a selection of these he printed in , and the missouri histor- ical society has since printed another collection. also in , the library of con- gress acquired "inedited" letters at a sale in philadelphia. in the library acquired an important group of about three hundred jeffer- son letters dating from to , most of which were addressed to thomas mann randolph, together with several bound volumes and miscellaneous papers. the materials included jefferson's memorandum book and diary ( - ), two of his commonplace books, notes on religion, verses in greek, latin, and english, copies of early legal instruments and precedents, a holograph library catalog listing the books jefferson had accumulated after the sale of his first library to the govern- ment, and an annotated copy of the edition of the manual of parliamentary practice for the use of the united states senate. these randolph family papers no longer constitute a separate group: the jefferson-thomas mann randolph corre- bullock, "papers of thomas jefferson," p. . the edgehill-randolph papers were deposited in the university of virginia in april and were purchased from the two sisters in september . fiske kimball, ed., thomas jefferson, architect (boston: privately printed, ). memorandum by w. c. n. randolph, april , ; university of virginia files. mrs. randolph's gift to the library; report of the librarian of congress . . . for the fiscal year ending june , (washington, ), p. . thomas jefferson correspondence, printed from the originals in the collections of william k. bixby (boston: privately printed, ). "correspondence of thomas jefferson," in missouri historical society, glimpses of the past (april-june ): - . report of the librarian of congress . . . for the fiscal year ending june , (washington, ), p. . from henry burke, alexandria, virginia, acting in behalf of himself and other heirs; manusciipt division files, lc. report of the librarian of congress . . . for the fiscal year ending june , (washington, ), pp. - ; and manuscript division files, lc. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril thomas jefferson papers spondence has been chronologically interfiled in the jefferson papers; the other types of material are now in the jefferson collection, rare book and special collec- tions division, and follow the main correspondence series in the manuscript divi- sion's jefferson papers. also in , the library received from colonel jefferson kean three jefferson memorandum books of household and legal matters, - . bullock has noted the location of all the jefferson account books, and photostatic sets of the entire group are available to scholars in the university of virginia and in the library of congress. some eighteen years after the large transfer of , the department of state on january , , transferred in accordance with the provisions of executive order , dated december , , jefferson's annotated rough draft of the declaration of independence; his directions for his epitaph and gravestone; and a letter, dated september , , concerning the graff house in which he composed the declaration. of these, the treasure was the rough draft. its history belied its incomparable importance in national life. even the hard-pressed professor washington, in an undated draft memorandum (probably mid-july ), was struck by the poor con- dition of the document which had come with the papers thomas jefferson randolph sold to the government in : many of the papers are very valuable & should be by all means be carefully preserved. among them is the original draught declaration of independence as reported by mr. j. to the com- mittee appointed to prepare a declaration, with interlineations by mr. adams c dr. franklin in their own handwriting. . . . the original rough draught of the del. of in. to which i have alluded, is in a very frail state—since step[s] should be taken for its preservation without delay—i believe that the draught of the declaration should be joined together if the commit- tee so desires. according to a january report on the condition of the rough draft after its arrival in the library, the document had been "slightly repaired" and joined together while in the state department's custody. additionally, as julian boyd has pointed out, the rough draft has been subjected to facsimile reproduction sev- ibid. bullock, "papers of t h o m a s jefferson," p . n. t h e locations of the jefferson account books are as follows: - library of congress [lc] massachusetts historical society [mhs] mhs lc mhs h u n t i n g t o n - mhs - lc - mhs - new york public library - new-york historical society [nyhs] - nyhs - nyhs t h e massachusetts historical society also holds fourteen miscellaneous papers, of various dates between and , with an index. photostatic sets of all of the books are at the library of congress and the university of virginia. three receipts signed by charles moore, january , ; manuscript division files, lc. h. a. washington, to library committee, probably mid-july ; tcp. j o h n c . f i t z p a t r i c k , " c o n d i t i o n of t h o m a s j e f f e r s o n ' s o r i g i n a l d r a f t of t h e declaration of inde- pendence," j a n u a r y ; m a n u s c r i p t d i v i s i o n files, l c . d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril the american archivist—january eral times. the manuscript division holds at least five examples of such copies taken from the rough draft while it was in the custody of the state department. since its arrival in the library, the document has undergone additional preservation measures and has frequently been on display in the library's main building. the last important group of jeffersonian manuscripts was transferred from the department of state to the library on august , . this group of letters and pa- pers pertaining to the establishment of the district of columbia was an artificial collection created by the department from the manuscript collections of george washington, john adams, thomas jefferson, james madison, james monroe, and others. the ten bound-volumes of material also include the letters and papers of such figures as benjamin henry latrobe, pierre charles l'enfant, and andrew ellicott, and covered theperiod - . manuscripts in this grouping belonging to presidential collections in the manuscript division have been restored to their respective collections. the jefferson material has not been chronologically inter- filed in the jefferson papers, but remains a separate district of columbia series which follows the main chronological series in the collection. the library has since acquired other jefferson items as additions to the jefferson papers and other collec- tions, or as separate purchases or gifts. these, with the scattered holdings among what henry randall called a "multitude of inheritors," complete the record of the collection thomas jefferson bequeathed to thomas jefferson randolph in . from the four series of published writings of jefferson, edited in sequence by randolph, henry a. washington, paul leicester ford, and a. a. lipscomb and a. e. bergh, much of the public and some of the private life of the man was revealed. however, it was not until that the authoritative edition, the papers of tho- mas jefferson, was started, under the editorship of julian parks boyd; this will appear in a projected series of forty to fifty volumes. thus, for the first time, schol- ars will be able to read most of jefferson's incoming and outgoing correspondence in letterpress form. the boyd volumes will attempt, in printed form, to restore the jefferson papers to the archival care and historiographical thoroughness which they possessed when jefferson bequeathed them to his favorite grandson. julian p. boyd, the declaration of independence: the evolution of the text as shown in facsim- iles of various drafts by its author, thomas jefferson (princeton: princeton university press, ), p. . the , , , , and (?) examples are in the facsimile collection, manuscript divi- sion, lc. see subsequent annual reports of the librarian of congress; library of congress quarterly journal of current acquisitions; and quarterly journal of the library of congress. randall, life of thomas jefferson, vol. , p. vii. boyd, papers of thomas jefferson, vol. , p. xiv. the project was originally supported, starting in , by the trustees of princeton university and the new york times company. at the present time it is sponsored by princeton university under grants from the new york times company and the ford foundation, and with the assistance of the national historical publications commission. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . . u by c arnegie m ellon u niversity user on a pril big bone lick: the cradle of american paleontology (review) big bone lick: the cradle of american paleontology (review) james l. murphy ohio history, volume , , pp. - (review) published by the kent state university press doi: for additional information about this article [ this content has been declared free to read by the pubisher during the covid- pandemic. ] https://doi.org/ . /ohh. . https://muse.jhu.edu/article/ https://doi.org/ . /ohh. . https://muse.jhu.edu/article/ ohio history the fourth and most extensive section contains thirty-one interviews con- ducted between and . the bulk of these interviews represent a gen- eration of delawares who grew up without knowing many of their cultural traditions and language. for the most part their collective memories express a desire to learn more about their heritage and reconnect the songs, dances, clothing, and foods of their grandparents and great-grandparents. they also express a community effort not only to explore and restore their heritage but also a commitment to transmit that knowledge to the younger generation. for scholars this work is a tantalizing sampling of indian oral histories that continue to be underutilized. for the general reader the stories shared by the delaware people are lessons in the resilience and tenacity of a community. daw n m a r s h purdue university big bone lick: the cradle of american paleontology. by stanley hedeen. (lexington: university press of kentucky, . xviii, pp. cloth $ . , isbn - - - - .) kentucky’s first tourist attraction, big bone lick has long deserved a mod- ern account such as stanley hedeen provides. professor emeritus of biology at xavier university, hedeen does a fine job of interpreting the history and significance of the prehistoric and historic salt lick aptly termed “the cradle of american paleontology.” well-grounded in history, geology, and vertebrate paleontology, the au- thor for the most part ably deals with a historical problem compounded by a plethora of obscure and widely scattered references; but in some respects his study supplements rather than supplants the work of the same title by the indefatigable willard rouse jillson (published by the original big bone lick association). hedeen does clarify jillson’s mistaken date for charles de longueuil’s expedition and provides previously unknown nineteenth-century newspaper references. his account is more readable and benefits from more recent advances in our understanding of local geomorphology, paleoecology, and vertebrate taxonomy. he incorporates much unpublished or “underpublished” recent research. hedeen’s account is comprehensive but not quite complete, for both he and jillson omit two significant references to early visitors. in capt. william harrod, hastening to join col. john bowman’s expedition against the shawnee indians of ohio, encountered a group of men transporting a canoe-load of specimens from big bone lick to redstone old fort. some . “bowman’s expedition against chillicothe, may‒june, ,” ohio archaeological and historical publications ( ): ‒ . bo ok reviews of these men joined harrod and bowman on the unsuccessful ohio foray, and subsequently “capt. wm. harrod, with others, went up the ohio to red stone in the two keel boats &c. and took along several bones & tusks got at the big bone lick.” what became of these specimens remains unknown, but this was an important early effort at “mining” the deposits at big bone. similarly, neither jillson nor hedeen mentions thomas rodney’s well-doc- umented stop there on october , , less than a week after meriwether lewis’s collecting visit for thomas jefferson. rodney not only took measure- ments of several of the remaining fossil bones but speculated (incorrectly) that no animals larger than bison ever existed there, larger bones being “only fossil concretions.” rodney himself collected a mastodon tooth and a tusk fragment, but these were lost when his boat sank at natchez. curiously, hedeen merely reproduces without explanation a photograph of three paleo-indian points “collected” at big bone lick. elsewhere, he has written that these were discovered in the lowest level of the big bone de- posits during william clark’s excavations for thomas jefferson and are “now likely” housed at the cincinnati museum center. the significance of associated paleo-indian artifacts and megafauna at big bone lick should certainly be acknowledged but so too should the considerable debate exist- ing about the precise provenance and pedigree of these artifacts. such strictures aside, this book provides ample context for the present big bone lick state park museum and should remain a standard resource for many years. ja m e s l . m u r p h y the ohio state university mennonites, amish, and the american civil war. by james o. lehman and steven m. nolt. (baltimore: johns hopkins university press, . xiv, pp. cloth $ . , isbn - - - .) when war engulfed virginia in the summer of , mennonite christian good was conscripted into the state militia. after good experienced battle and failed to discharge his rifle, his perturbed captain asked him why he . henry hill, “bowman’s campaign— ,” ohio archaeological and historical publica- tions ( ): . . simon gratz, “thomas rodney,” pennsylvania magazine of history and biography . ( ): ‒ . . stanley hedeen, natural history of the cincinnati region. cincinnati museum center scientific contributions no. (cincinnati: the center, ), . in the same publication, these artifacts are captioned only as “most likely [discovered] during william clark’s expedition” (plate ). nwig . - _f _ - .indd book reviews napoleon’s atlantic: the impact of napoleonic empire in the atlantic world. christophe belaubre, jordana dym & john savage (eds.). leiden, the neth- erlands: brill, . xvi + pp. (cloth € . ) napoleon’s atlantic is the english translation of the proceedings of a sym- posium entitled “l’atlantique napoléonien” organized at the university of toulouse-le mirail in , which were first published in french in . as the french title—napoléon et les amériques: histoire atlantique et empire napoléonien—more accurately conveys, the book’s scope is not fully atlantic: apart from a mention of the egyptian campaign in the introduc- tion, africa is nowhere, and europe does not occupy center stage. instead, the collected essays focus on the impact of the napoleonic empire on the americas, already a fully legitimate and very ambitious project. napoleonic studies in france have been largely limited to the impact of the napoleonic empire in europe. in the same way, historians of latin american independence movements who are increasingly exploring the connections between the various revolutions in the atlantic world have paid little attention in recent times to the specific influence exercised by the napoleonic regime. thus, the book aims at changing both the spatial and the chronological framework of napoleonic studies and of atlantic history in the era of revolutions. it is also an attempt at connecting the two fields. the book’s title is also misleading in another way, since the collection of fourteen essays does not cover the whole napoleonic period, but focuses on the decades following , after napoleon’s imperial coronation and the quasi-disappearance of the french atlantic empire with the failure of the leclerc expedition, the louisiana purchase, and haitian indepen- dence. the extension of the chronological framework beyond , intended to demonstrate that the impact of the napoleonic regime endured after his fall, has been made to the detriment of the consulate. the book’s napole- onic empire thus has no colonial or postcolonial dimension: no chapter is devoted to saint-domingue/haiti, and the french lesser antilles are only briefly taken into account in john savage’s contribution. rather than “the direct and indirect consequences of france’s substan- tial retreat from an atlantic presence after / ” (p. ), the book is con- cerned above all with the direct and indirect consequences outside europe of the french invasion of the iberian peninsula, and with the influence of the napoleonic regime on latin american independence movements © cécile vidal doi: . / - this is an open-access article distributed under the terms of the creative commons attribution-noncommercial . unported (cc by-nc . ) license, http://creativecommons.org/licenses/by-nc/ . / downloaded from brill.com / / : : am via free access book reviews and subsequent republics. the whole would have been more coherent if the editors had not included the two chapters which have nothing to do with these questions: luca codignila’s contribution on the reactions of the “north atlantic catholic community” to napoleon’s policy toward the church and the pope, and jean-marc olivier’s essay on jean-baptiste ber- nadotte, who refused his appointment as governor of louisiana before the colony was sold to thomas jefferson. most of the other essays deal with brazil and spanish america or its (for- mer) borderlands. there is a strong emphasis on the greater caribbean, with half the contributions focusing on central america, gran colombia, cuba, louisiana, and texas. topics addressed by this collection of essays include the motivations of sugar planters in cuba or of indiano bureaucrats in spain to join or not to join napoleon’s side (dominique goncalvès and víctor peralta ruiz); the reporting of latin american events in the french press (felipe angulo jaramillo); the fear of french emissaries in central america (timothy hawkins); the political activism and cultural influence of french expatriates after napoleon’s fall (christophe beleaubre, rafe blaufarb, lilia moritz schwartz, and roderick barman); the intrusion of the militaries, following napoleon’s model, in the political field (mónica ricketts); and the impact of the napoleonic code (john savage). their insistence on the circulation of people, information, and ideas complies with atlantic his- tory’s methodology. apart from contributions by matt childs and nathalie dessens on the saint-domingue refugees’ expulsion from cuba and their relocation on louisiana, however, they all focus on white elites. in fact, childs’s essay on the little-known riots of free people of color against french émigrés in cuba in is one of the two best chapters of the book. it deconstructs the narratives by the state and the church to explain why the rioters who returned stolen goods were not prosecuted. the two institutions interpreted the event differently, but “both accounts deemphasized the role played by people of color in the riots and attempted to criminalize what might have developed into broader political activity” (p. ). if the rioters’ motivations are impossible to recover with certainty, the fact that one of their leaders later participated in the aponte rebellion in could be a sign of a real political and revolutionary agenda. another fascinating chapter is the one by john savage on the impact of napoleonic laws in the nineteenth-century atlantic world. drawing mostly on the two cases of gran colombia and louisiana, but alluding to chile, downloaded from brill.com / / : : am via free access book reviews argentina, haiti, and canada, savage explores the various domestic and international motivations in the recourse to the napoleonic legal model, emphasizing rupture with the colonial past and state consolidation. he also demonstrates that the adoption of napoleon’s civil code implied a process of accommodation initially and over time to fit the local political agendas and social and economic situations, especially regarding property, including property in humans. thus, far from being only the vehicle of lib- eral ideas, the napoleonic code in its atlantic expansion was also an instru- ment of imperial designs. globally, the book is an interesting attempt to draw attention to some neglected transatlantic dynamics in the late eighteenth and early nine- teenth centuries. it should be recommended to graduate students and scholars interested in napoleonic empire, atlantic revolutions, latin american independence movements, and caribbean studies. cécile vidal École des hautes Études en sciences sociales, centre d’Études nord-américaines paris, france cecile.vidal@ehess.fr downloaded from brill.com / / : : am via free access the teacher reordering american constitutional law teaching* scott d. gerber, college of william and mary constitutional law is the corner- stone of an undergraduate public law curriculum. political scientists will therefore want to teach consti- tutional law in the most effective manner possible. to that end, there is a welcome trend to offer consti- tutional law as a two-semester se- quence, a trend reflected by text authors and publishers who are in- creasingly dividing their constitu- tional law texts into two parts (mezey , ). i say welcome trend because, as anyone who has taught constitutional law knows, there is too much material to cover adequately in one semester. traditional constitutional law teaching: powers first invariably, constitutional law courses begin with constitutional powers issues: the origins and scope of judicial review, congress and the development of national power, the powers of the presi- dency, the modern administrative state, the states and american fed- eralism, and representation, voting, and electoral politics. in two-se- mester courses, these issues are addressed in the fall. in one-semes- ter courses, they are covered in the first part of the semester. after the powers issues have been addressed, attention is then turned to constitutional rights is- sues: property rights and economic liberty, freedom of expression, as- sembly, and association, freedom of the press, religious liberty and church-state relations, criminal jus- tice, personal autonomy and pri- vacy, and equal protection. in two- semester courses, rights issues are addressed in the spring. in one- semester courses, they are covered in the second part of the semester. the rationale for teaching consti- tutional powers before constitu- tional rights seems to be, first, that the bill of rights and the four- teenth amendment, the bases for the vast majority of rights ques- tions, were not part of the original constitution and, second, that stu- dents need a foundation in constitu- tional powers before they can un- derstand constitutional rights. in the spirit of more effective teach- ing, i would like to suggest that undergraduate teachers reverse the order in which constitutional law is taught. although this suggestion may strike many traditionalists as heresy, it has proved to be an ef- fective pedogogical technique in my courses. in fact, i have gone so far as to require the constitutional rights course as a prerequisite for the constitutional powers course. reordering constitutional law teaching: rights first the justification for reordering constitutional law teaching is sim- ple: students learn the material bet- ter if rights issues are taught first. this is because constitutional rights questions are more intuitive to stu- dents than constitutional powers questions. the american people— undergraduate students included— are imbued with the idea that indi- viduals have rights, an idea that is at the heart of the american politi- cal tradition. "we hold these truths to be self-evident," thomas jefferson wrote in the declaration of independence, "that all men are created equal, that they are en- dowed by their creator with certain unalienable rights; that among these are life, liberty and the pur- suit of happiness." with respect to constitutional law specifically, although for much of american history the supreme court's docket was dominated by powers questions—marbury v. madison ( ), m'culloch v. maryland ( ), gibbons v. ogden ( ), cooley v. board of wardens ( ), united states v. e.c. knight company ( ), and a.l.a. schechter poultry corpora- tion v. united states ( ), to name but a few of the classic cas- es—that changed in when the court, under the threat of president franklin d. roosevelt's infamous "court-packing" plan, stopped striking down the new deal and redirected its attention to protect- ing civil rights and liberties. in- deed, ever since the "switch-in- time-that-saved-nine," rights questions have far outnumbered powers questions on the court's docket (pacelle ). the late herbert j. storing made the point well a decade and a half ago. "[i]t seems quite plausible today," stor- ing remarked, "when so much of constitutional law is connected with the bill of rights, to conclude that the antifederalists, the apparent losers in the debate over the con- stitution, were ultimately the win- ners" (storing , ). as a con- sequence of the rights-oriented character of both american politi- cal culture and modern american constitutional law, i have found it easier to introduce students to the sometimes confusing subject of constitutional law, as well as to the daunting task of reading supreme court opinions, through issues with which they are more familiar and more comfortable: rights issues. december the teacher lessons from contracts law as strange as it may sound, my recommendation to reorder consti- tutional law teaching owes much to my former law school contracts teacher, stanley d. henderson. in his contracts course and accompa- nying casebook, henderson takes the bold step of teaching the rules governing remedies for breach of contract (e.g., damages, reliance, and restitution) before the rules governing contract formation (e.g., offer, acceptance, and consider- ation) (dawson, harvey, and henderson ). critics of hend- erson's approach argue that a con- tracts course must begin with the rules governing contract formation. after all, the argument goes, reme- dies questions cannot arise unless a contract is formed. according to henderson, however, it is easier for students to learn the complex world of contracts law through a remedy-centered approach. this is because students are more familiar from their everyday experience with what happens if they breach a contract than they are with the technical rules required for them to form a contract (ibid., xxii). as anyone who has had the good for- tune of taking henderson's con- tracts course or of using his top- selling contracts casebook can attest, henderson's unconventional approach, in which he teaches con- tracts law "backwards," works splendidly. although contracts law and con- stitutional law have little in com- mon substantively, they have much in common pedogogically. like the rules of contract formation, ques- tions of constitutional powers are frequently obscure and confusing to students. by contrast, like the rules governing remedies for breach of contract, constitutional rights ques- tions are quite familiar and under- standable to students, exposed as students are to discussions about abortion and the rights of those ac- cused of crime, for instance, in the everyday discourse of american life. indeed, i venture to say that, before students step into a constitu- tional law classroom, few, if any, have been exposed to questions like whether the legislative veto is constitutional, while many have heard about—and possibly even discussed—"hate speech," to name but two typical examples of the constitutional powers/rights dichot- omy. some suggestions for teaching the rights course my reordered constitutional law sequence does not simply entail teaching the material traditionally offered in a constitutional rights course before the material tradi- tionally offered in a constitutional powers course. although the vast my classroom discussion of the rights-oriented character of american political culture is not limited to the american founding. . . i also turn the class's attention to the contemporary debate over whether we are too rights-oriented in the united states. majority of what i teach in the con- stitutional rights course is tradi- tional constitutional rights materi- al—most notably, landmark cases like lochner v. new york ( ), schenck v. united states ( ), new york times v. sullivan ( ), wisconsin v. yoder ( ), everson v. board of education ( ), mapp v. ohio ( ), gideon v. wainwright ( ), furman v. georgia ( ), griswold v. con- necticut ( ), roe v. wade ( ), bowers v. hardwick ( ), brown v. board of education ( ), frontiero v. richardson ( ), and regents of the univer- sity of california v. bakke ( )— i spend the first several class ses- sions discussing the central place of rights in american political culture in the hopes of setting the appropri- ate mood for the course. i begin by examining the decla- ration of independence, the found- ing document of the american re- gime. indeed, in correspondence with james madison about the uni- versity of virginia's curriculum, thomas jefferson put the declara- tion at the top of his required read- ing list for government and law stu- dents (hellenbrand , ). while it is certainly not my objec- tive to turn the constitutional rights course into a political philosophy course, i try to give my students a general understanding of the politi- cal ideas of the declaration—and as the students quickly come to appreciate, rights are at the heart of those political ideas. i follow the discussion of the declaration of independence with a discussion of the debate over the ratification of the constitution. here, i remind the students that the absence of a bill of rights from the proposed constitution framed in philadelphia in nearly led to the constitution's defeat, a point i illustrate with some revealing quotes from leading antifederalists like mercy otis warren, luther martin, george mason, and patrick henry. i also invoke the name and forceful language of thomas jeffer- son, author of the declaration of independence. jefferson was ini- tially a reluctant supporter of the constitution, i explain, and one of his most famous letters to madison tersely said why. "[a] bill of rights," jefferson wrote, "is what the people are entitled to against government on earth, general or particular, and what no just govern- ment should refuse, or rest on in- ference" (peterson , ). i close my discussion of the rati- fication debate by explaining to the students that, in the end, the an- tifederalists prevailed in the debate over the bill of rights, and the constitution was ratified only be- cause the federalists promised to add a bill of rights at the first op- portunity. that promise soon was fulfilled by madison in the first congress, with madison's change of heart largely being attributable to his recognizing the importance to the american people of securing ps: political science & politics reordering american constitutional law teaching their rights. i quote madison's clos- ing remarks in his june , , speech to the u. s. house of rep- resentatives advocating the adop- tion of the bill of rights to demon- strate the point. " i think we should obtain the confidence of our fellow- citizens," madison argued, "in proportion as we fortify the rights of the people against the encroach- ments of the government" (meyers , ). my classroom discussion of the rights-oriented character of ameri- can political culture is not limited to the american founding, impor- tant as that period in our history is for defining who we are as a nation. i also turn the class's attention to the contemporary debate over whether we are too rights-oriented in the united states. i discuss both the provocative scholarship of con- temporary communitarians like amitai etzioni ( ) and mary ann glendon ( ) and the com- munitarianism of our current presi- dent, bill clinton. most significantly, i alert the class to the majoritarian and com- munitarian inclinations of today's conservative republican court. in stark contrast to the post- roosevelt and warren courts, i suggest, the republican court ap- pears to reject the idea that the constitution commissions the court as the institutional protector of in- dividual rights. i use the "peyote case," employment division v. smith ( ), as an example. there, justice antonin scalia, writ- ing for a sharply divided court, made the startling pronouncement that the values enshrined in the bill of rights—individual religious lib- erty, in particular—are not immune from definition by the political pro- cess. my objective at this point in the course is not to engage the stu- dents in an extended exegesis on religious liberty, but rather to use the case as a vehicle through which they can begin to acclimate them- selves to constitutional law, as well as to reading supreme court opin- ions. that foundation laid, the stu- dents are ready to enter the fasci- nating world of american constitutional law. conclusion in suggesting that constitutional law teaching needs to be reordered, i do not mean to imply that consti- tutional powers questions are less important than constitutional rights questions. my goal is simply to help students learn constitutional law better. in my experience, the order in which constitutional law is taught does not affect students' ability to learn the constitutional rights material. for the reasons dis- cussed above, students have little trouble with the rights material, regardless of whether that material is presented first or second. with respect to constitutional powers, however, students learn that material much better if they have had an opportunity to accli- mate themselves to thinking about constitutional law and to reading supreme court opinions through the more accessible constitutional rights material. hence, my ration- ale for teaching constitutional rights first. after all, our objective as teachers should be to help students learn—even if that means reorder- ing a subject as dear to political scientists as constitutional law. references dawson, john p., william burnett harvey, and stanley d. henderson. . cases and comment on contracts. th ed. min- eola: foundation press. etzioni, amitai. . the spirit of commu- nity: rights, responsibilities, and the communitarian agenda. new york: crown. glendon, mary ann. . rights talk: the impoverishment of political discourse. new york: free press. hellenbrand, harold. . the unfinished revolution: education and politics in the thought of thomas jefferson. newark: university of delaware press. meyers, marvin, ed. . the mind of the founder: sources of the political thought of james madison. revised ed. hanover: university press of new eng- land. mezey, susan gluck. . "introduction to the law and politics book review." law and courts newsletter. spring. pacelle, richard l., jr. . the transfor- mation of the supreme court's agenda. boulder: westview press. peterson, merrill d., ed. . the portable thomas jefferson. new york: penguin books. storing, herbert j. . "the constitution and the bill of rights." in essays on the constitution of the united states, ed. m. judd harmon. port washington: kenni- kat press. note •thanks to j. timothy collins for helpful comments. this article is dedicated to stanley d. henderson. about the author scott d. gerber is visiting assistant pro- fessor of government at the college of wil- liam and mary. he has published articles on constitutional in- terpretation, on clar- ence thomas, and on american political thought. his book, to secure these rights: the declaration of independence and constitutional interpreta- tion, will be published by new york uni- versity press in march . december bcl-xl increases bax mitochondrial localization and activation in non-apoptotic cells tuesday, february , a agent colchicine that is known to increase free tubulin, mitochondrial potential, as measured by tetramethylrhodamine methyester (tmrm) uptake, decreased. inhibition of pka activity with h increased mitochondrial potential and, fur- thermore, reversed mitochondrial depolarization induced by colchicine. to fur- ther explore a role vdac-tubulin interaction in cell proliferation and survival, we studied the effect of erastin, the selective anti-tumour agent involved in the ras-raf-mek signalling pathway, on vdac blockage by tubulin. we found that erastin reverses tubulin blockage of vdac isolated from hepg cells, pro- moting the unblocked state of the channel. our findings suggest a novel func- tional link between serine/threonine kinase signalling pathways, mitochondrial respiration, and highly dynamic microtubule network which is characteristic of carcinogenesis and cell proliferation. -plat the isoform specific n terminus of vdac is dispensable for tbid induced cytochrome c release shamim naghdi , peter varnai , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, department of pathology anatomy and cell biology, philadelphia, pa, usa, semmelweis university, faculty of medicine, department of physiology, budapest, hungary. vdac proteins represent a main component of the outer mitochondrial mem- brane (omm). the vdac family is composed of isoforms with more than percent similarity. although their primary role was known to be in ion and me- tabolite transport between mitochnodria and cytosol, it has been discovered that vdacs are involved in apoptotic pathways. we have recently found that spe- cifically the vdac isoform is needed for tbid-induced cytochrome c release, due to its role in supporting bak insertion to the omm (roy et al. . embo rep. : - ). sequence analysis of the mammalian vdac isoforms shows a unique n terminal end in vdac , which is likely to be exposed to the cyto- plasm. to test the functional significance of this n terminus, the first amino acids were removed from vdac or were added to vdac . vdac -/- mef cells that are resistant to tbid, were rescued with these constructs and cyto- chrome c release was monitored in permeabilized cells by single cell imaging and immunoblotting. these studies revealed that cytochrome c release upon tbid application is effectively supported by both full length vdac and the vdac n-terminal deletion mutant. furthermore, vdac extended by the n terminus of vdac failed to restore cytochrome c release in vdac -/- mefs. thus the n terminus of vdac seems to be dispensible for tbid- induced omm permeabilization. currently, we are designing different muta- tions which target some addititional unique sequences in vdac to find the specific domain that is essential for tbid induced cytochrome c release. -plat patch-clamp analysis of mitochondrial ca d uniporter in different tissues francesca fieni, yuriy kirichok. ucsf, san francisco, ca, usa. the mitochondrial ca þ uptake has been recognized as a central player in cel- lular pathophysiology for decades. pathways of ca þ transport across the inner mitochondrial membrane (imm) were investigated indirectly with biochemical techniques and most recently by applying the patch clamp technique to mito- plasts isolated from mammalian systems. patch-clamp recording of the imm have proved to provide an unambiguous picture of mitochondrial ca þ uptake under strictly controlled conditions. in this study, we evaluated and compared the biophysical properties of mito- chondrial ca þ uptake in different mouse tissues. freshly isolated mitoplasts from mouse heart, skeletal muscle, liver, kidney, spleen and brown adipose tis- sue were patch clamped in the whole-mitoplast configuration. voltage step and ramp protocols covering the whole range of physiological potentials were ap- plied to elicit the inwardly rectifying ca þcurrent sensitive to rur known as mcu. the distribution of mcu current densities between tissues was as fol- lows: spleen > brown adipose tissue z skeletal muscle > kidney > liver >> heart. interestingly, mcu current density in heart was about times smaller than in skeletal muscle. our results support the view of a differential tissue activity of mcu, which can be explained by either a different distribution of mcu channel and/or by a different expression of its regulatory subunits confer- ing various modes of physiological regulation. further on, in order to investigate the putative direct contribution of uncou- pling protein isoform and (ucp / ) to the uniporter, we investigated mcu properties in wild type (wt) mouse tissues where these two proteins have been found to have a major role and compared its properties in the corre- spondent tissues of ucp and ucp ko mice. we found no significant differ- ences in calcium currents of any of the wt tissues studied compared to their ucp / ko counterparts. -plat sr-mitochondrial ultrastructure in the heart of normal and ethanol-fed rats gyorgy csordas , david mankus , tanvir shaikh , xing meng , jan hoek , carmen mannella , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, wadsworth center, albany, ny, usa. chronic alcoholism causes various forms of stress in the heart, and this is often accompanied by mitochondrial dysfunction. a putative source of mitochondrial dysfunction is sr-mitochondrial stress and the ensuing mitochondrial ca þ overload. to test this possibility, first we isolated mitochondria from chronic ethanol-fed ( months) and paired control rats, and documented ethanol- dependent sensitization to ca þ and ros-induced permeabilization. to evalu- ate the ultrastructural basis of the mitochondrial impairments, we performed transmission electron microscopy (tem) and electron tomography studies of left ventricular muscle. the overall ultrastructure of the myocytes became less organized in the ethanol-fed condition. also, a considerable fraction of the mitochondria lost the highly ordered structure of the cristae and showed an increase in the cross-sectional area. however, the size of the sr- mitochondrial associations and the gap-width at the interface was unchanged. evaluation of the sr-mitochondrial tethers by electron tomography indicates that they occur in clusters and display heterogeneity in length, as previously re- ported for er-mitochondrial tethers in normal rat liver (csordas et al, , j cell biol, : ). overall tether length distribution appears to be unaltered by alcohol ingestion. analyses of effects of alcohol ingestion on tether membrane-surface density and structural classes (linear, v, y and more com- plex shapes) is in progress, as is d analysis of ser and mitochondrial inner- and outer-membrane topologies. (supported by nih grant rc aa .) -plat bcl-xl increases bax mitochondrial localization and activation in non- apoptotic cells laurent m. dejean , thibaud t. renault , oscar teijido , gisele velours , yogesh tengarai ganesan , nadine camougrand , bruno antonsson , stephen manon . california state university of fresno, fresno, ca, usa, cnrs, institut de biochimie et de génétique cellulaires, bordeaux, france, nih, nichd, bethesda, md, usa, memorial sloan kettering cancer center, new york, ny, usa, merck serrono s.a., geneva research center, geneva, switzerland. we report that, in non-apoptotic pro-lymphocyte cells, bcl-xl induced an in- crease of the mitochondrial localization of bax up to the level found in apopto- tic cells. furthermore bcl-xl stimulated both the active conformation of bax and increased the total amount of bax inserted in the outer mitochondrial mem- brane. in order to further investigate the molecular mechanisms involved in this effect, different bax and bcl-xl mutants were co-expressed in yeast. we found that wild-type bcl-xl increased the mitochondrial localization of both wild- type bax and of an active mutant bax-s d, while mutant bcl-xl-g a did not have this effect. further, wild-type bcl-xl protected bax-s d against proteolytic degradation. finally, we found that a c-terminally truncated mutant of bcl-xl, that lost its capacity to inhibit bax-induced release of cyto- chrome c, still increased the mitochondrial localization of wild-type bax, thus promoting the release of cytochrome c. these data suggest that bcl-xl, by act- ing as a modulator of mitochondrial bax localization, may play an active role along the pathway leading to bax activation. -plat the physiological response of intact ex vivo mitochondria upon apopto- tic stress: insight into the regulation of apoptosis at a mitochondrial level martin n. lidman , marcus wallgren , olivier keech , yong-zhi guo , tor ny , gerhard gröbner . chemistry department, umeå university, umeå, sweden, umeå plant science center, umeå, sweden, medical chemistry and biophysics, umeå university, umeå, sweden. apoptosis - programmed cell death - is vital for multicellular organisms to dis- pose of redundant, damaged or infected cells. this mechanism becomes dys- functional in cancer where tumor cells survive drug-induced death signals. reversely, upregulated apoptosis can induce premature neuronal cell death in amyloidogenic diseases such as alzheimer’s disease (ad) or amyotrophic lateral sclerosis (als). mitochondrion, the power plant of the cell, contains an arsenal of proteins which regulate programmed cell death. there, the pro- and anti-apoptotic bcl- proteins meet at the mitochondrial membrane to decide the fate of a cell. how the molecular activities of the anti-apoptotic 	the isoform specific n terminus of vdac is dispensable for tbid induced cytochrome c release 	patch-clamp analysis of mitochondrial ca + uniporter in different tissues 	sr-mitochondrial ultrastructure in the heart of normal and ethanol-fed rats 	bcl-xl increases bax mitochondrial localization and activation in non-apoptotic cells 	the physiological response of intact ex vivo mitochondria upon apoptotic stress: insight into the regulation of apoptosis a ... wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ diagnosing mr. jefferson: retrospectives on developmental disabilities at monticello. by: j. david smith smith, j.d. ( ). diagnosing mr. jefferson: retrospectives on developmental disabilities at monticello. intellectual and developmental disabilities., ( ), - . made available courtesy of american association on intellectual and developmental disabilities: http://dx.doi.org/ . / - ( ) [ :dmjrod] . .co; ***reprinted with permission. no further reproduction is authorized without written permission from american association on intellectual and developmental disabilities. this version of the document is not the version of record. figures and/or pictures may be missing from this format of the document. *** abstract: for a number of years, i have been intrigued by what might be termed the retrospective diagnosis of developmental disabilities. in my book minds made feeble: the myth and legacy of the kallikaks (j. smith, ), i expressed amazement that psychologist henry goddard in his study of the “good” and “bad” kallikak families pronounced that a woman who had an illegitimate child in was “feebleminded.” this was years after the birth of the child. in fact, goddard diagnosed entire generations of kallikaks who neither he nor anyone alive at that time had ever seen, let alone tested with even the most rudimentary of diagnostic techniques. yet when his study was published in , he asserted with confidence that he had found proof of a genetic basis for intellectual disabilities in these families. developmental disabilities | diagnosing disabilities | retrospective diagnosis | keywords: psychology article: for a number of years, i have been intrigued by what might be termed the retrospective diagnosis of developmental disabilities. in my book minds made feeble: the myth and legacy of the kallikaks (j. smith, ), i expressed amazement that psychologist henry goddard in his study of the “good” and “bad” kallikak families pronounced that a woman who had an illegitimate child in was “feebleminded.” this was years after the birth of the child. in fact, goddard diagnosed entire generations of kallikaks who neither he nor anyone alive at that time had ever seen, let alone tested with even the most rudimentary of diagnostic techniques. yet when his study was published in , he asserted with confidence that he had found proof of a genetic basis for intellectual disabilities in these families. retrospective diagnosis by rumor or legend was common during the eugenics movement's zenith in the earth th century. it continued as a practice in the united states and europe until well http://libres.uncg.edu/ir/uncg/clist.aspx?id= http://dx.doi.org/ . / - ( ) % b :dmjrod% d . .co; after world war ii (black, ). until recently, however, i mistakenly believed that retrospective diagnosis was now an historical artifact. i recognized how wrong i was when i happened on a book that proposed that a founding father belongs on the autism spectrum as well as on mount rushmore. autism at monticello in his book diagnosing jefferson: evidence of a condition that guided his beliefs, behavior, and personal associations, ledgin ( ) wrote with certainty that thomas jefferson was a person with autism (more specifically asperger's syndrome). three attributes are presented to support his argument that jefferson had this developmental disability. the first is the founding of the university of virginia. ledgin described jefferson's depth and intensity of involvement in designing the architecture, creating the curriculum, hand-picking the faculty, prescribing student housing, and personally cataloguing the more than , books in the original library of the university. according to ledgin ( ), jefferson actually referred to the university as “a tribute to his genius and, i have no doubt a monument to obsessive behavior linked strongly to traits of asperger's syndrome” (p. ). he described jefferson's library cataloging as a savant- like trait reminiscent of those often attributed to people with autism. the second characteristic of jefferson described by ledgin ( ) as being indicative of autism is his lack of money management skills. he reported that jefferson's inability to keep his income ahead of his debts is typical of individual's with asperger's syndrome and argued that this was “self-deluding … [with jefferson] believing somehow everything relating to money management would end well, [this] together with his keeping irreconcilable financial records—had evidently induced the situation” (p. ). the third attribute that ledgin ( ) discussed was perseveration. the evidence he presented for jefferson's “belaboring a topic endlessly” is his letter writing. ledgin pointed particularly to jefferson's letters to abigail adams after a very intense political dispute with her husband, john adams. his extensive correspondence with abigail began when jefferson's daughter polly died, and it continued for years. after jefferson and john adams reconciled, they resumed direct correspondence. these later letters are described by ledgin as “a treasure and a rich record of the outpourings of contrasting geniuses” (p. ). this is quite a different point of view from the “perseveration” he found in jefferson's earlier letters to abigail. ledgin ( ) also ascribed several of jefferson's personal relationship difficulties to autism. he argued that a lack of warmth toward his mother and jefferson's reported inability to show affection to his own children are clearly indicative of asperger's syndrome. ledgin even made a connection between jefferson's affair with sally hemings and his claim that the third president had asperger's. he wrote that when jefferson returned from france with sally and had established a romantic relationship with her, “he faced the dilemma of balancing at home a private benefit that was taboo against his public image of propriety as a respecter of law and custom” (p. ). explaining the connection, ledgin went on to describe people with asperger's: they live mentally and perhaps emotionally on two planes. they live in our world of nonautistics, but they carry with them a separate and otherworldly ‘reality’—their reality … autistics seem to convert it [their reality] into something palpable. (p. ) disabilities and “the sage of monticello” i am unconvinced by ledgin's ( ) arguments. i think that his thesis that jefferson had asperger's syndrome is fraught with the same weakness and dangers that characterized the family pedigree studies of the eugenics movement. i appreciate the fact, however, that ledgin's book led me to take another look at this remarkable individual and national icon. jefferson's actual experience with disability is documented in several sources. it was not the kind of personal experience portrayed by ledgin ( ); rather, it was a familial experience. thomas jefferson was the sibling of a sister and a brother with disabilities. his relationships with them reveal much about his character as a brother and, perhaps, the attitudes of his time and social class regarding disability. jefferson's younger sister elizabeth has been characterized by a number of scholars as having a serious and persisting disability (brodie, ; mapp, ). she was described by one researcher with the words “rather deficient in intellect” (randolph, , p. ). jefferson cared for his sister after the death of their father. he administered his father's estate and saw to it that elizabeth was attired and treated in a manner befitting a woman of her family's social status (brodie, ). jefferson's account book records that on february , , an intense nighttime earthquake forced all of the family to run outside their home at monticello. apparently, frightened by the darkness and confusion, elizabeth became separated from the rest of the family. she was found dead days later, and on march , he recorded his sister's funeral in his account book (brodie, ). in her biography of jefferson, brodie suggested that his feelings for elizabeth might best be symbolized by a clipping in one of his scrapbooks. it is entitled “elegy on the death of an idiot girl” and it includes the line: “poor guileless thing! … heaven took thee spotless to his own” (p. ). jefferson's only brother, randolph, has been described in jefferson biographies as “retarded” (richards & singer, ). it is clear, however, that he lived a life that was characteristic of southern planters in the th century. he married twice, had seven children and lived on a large plantation (p. smith, ; risjord, ). on the other hand, he had limited verbal skills. his letters, many to his brother, are filled with grammatical errors, poor spelling, and scrawled handwriting. he was clearly no match for the famed intellect of his brother thomas. still, there is no clear and convincing evidence of an intellectual disability. the evidence that does exist has lead two researchers to state that “we might best say that jefferson's brother would today be considered to have learning disabilities rather than mental retardation” (richards & singer, , p. ). although the nature of randolph's disabilities can only be the subject of speculation at this point, it is clear that he experienced difficulties in several areas of his personal and vocational life, that he frequently called on his brother for assistance and that he received the help he needed. thomas advised randolph on the running of his plantation and shared everything from dogs to vegetable seeds with him. he loaned him farming equipment and money, and took his brother's beloved watch to richmond for repair. he also wrote his brother's will for him (malone, ). in a deposition given in , thomas described his brother as “not possessing skill for the judicious management of his affairs” (cited in malone, , p. ). a man who lived as a slave at monticello later dictated his memoirs of those years in . among the recollections of the man who was identified only as isaac was a memory in which the former slave compared the intellect of randolph jefferson to his own in a self-deprecating manner. isaac said: “old master's brother, mass randall, was a mighty simple man: used to come out among black people, play the fiddle and dance half the night; hadn't much more sense than isaac” (cited in bear, , p. ). it may not be surprising that isaac's comment has been used to claim that it was not thomas but randolph jefferson who fathered sally hemings' children and that thomas was not involved sexually with her. in a book published by the thomas jefferson heritage society, coates ( ) wrote that it should be noted that randolph would be more likely to have a sexual encounter with sally than would thomas. randolph was known to socialize with the black slaves at monticello when he visited there. … and since randolph was a widower at the time, it is easy to understand how he could become involved with one of the beautiful house servants. … in addition, randolph was age when eston [a child claimed to be the son of thomas jefferson and sally hemings] was conceived while thomas was . randolph remarried a year after eston was born, and fathered an additional son in that marriage, so he was evidently still sexually active throughout that time period. (p. ) when the issue of randolph's possible paternity of the jefferson–hemings children was raised and questioned, a descendent of thomas jefferson remarked that it had not been discussed publicly before because good taste and respect for the privacy of others was the reason for this rarely mentioned topic. it was bad enough to be illegitimate, much less the illegitimate offspring of a half-witted no account, namely president jefferson's brother, randolph jefferson. (mcmurry, , p. ) the diagnosis: a good brother in a review of the treatment of people with intellectual disabilities in virginia from through , wickham ( ) offered an important perspective on the interaction of social class and “idiocy.” wickham found that a two-tiered system existed. poor and dependant people with intellectual disabilities often met with public scorn and rejection from even a place in virginia's public mental institutions. on the other hand, prominent families responded with “silent avoidance” and hiding of what was perceived to be a family weakness (wickham, ). thomas jefferson was a man of means and elevated public stature. he was also a good brother. in one instance he protected the dignity and well-being of a sister with a severe disability. in the second, he promoted the independence and social inclusion of a brother with a disability who needed his help. these are, indeed, additional reasons why his likeness rightfully belongs on mount rushmore. references bear, j. a. . jefferson at monticello. charlottesville: university press of virginia. black, e. . war against the weak: eugenics and america's campaign to create a master race. new york: four walls eight windows. brodie, f. . thomas jefferson: an intimate biography. new york: norton. coates, e. r. . the jefferson–hemings myth: an american travesty. charlottesville, va: thomas jefferson heritage society. ledgin, n. . diagnosing jefferson: evidence of a condition that guided his beliefs, behavior, and personal associations. arlington, tx: future horizons. malone, d. . the sage of monticello. boston: little brown. mapp, a. . thomas jefferson: a strange case of mistaken identity. latham, md: madison books. mcmurry, r. l. . paternity of sally heming's children. retrieved july , , from http://www.angelfire.com/va/tjtruth/mcmurry .html. randolph, s. . the domestic life of thomas jefferson. new york: frederick ungar. richards, p. and g. singer . . “to draw out the effort of his mind”: educating a child with mental retardation in early-nineteenth-century america. journal of special education : – . risjord, n. k. . thomas jefferson. madison, wi: madison house. smith, j. d. . minds made feeble: the myth and legacy of the kallikaks. austin, tx: pro- ed. smith, p. . jefferson: a revealing biography. new york: american heritage. wickham, p. . idiocy in virginia, – . bulletin of the history of medicine : – . pmh : change in health-related quality of life in patients with schizophrenia taking antipsychotic agents abstracts % when patients were rated as “improved,” and %, %, respectively when rated as “much better.” mean -point item scores improved by . points panss, . points qls for “improved” patients, and by . , . , respectively for “much better” patients. minimal changes were seen for all items when patients were rated as “unchanged.” the relationship between clinician rat- ings and score changes was stable over multiple assess- ments in this large sample. conclusion: these data describe the amount of change that represents clinically important improvement related to treatment based on commonly used symptom and qol scales. planning sample sizes for clinical trials can be based on percentage change in scores or mean item scores to aid clinicians and researchers in understanding meaningful treatment ef- fects. pmh translations of the migraine specific quality of life questionnaire (msq): a psychometric comparison between the english, finnish, dutch, hungarian, and spanish translations grossman pr, black lk, kwong j glaxo wellcome inc., research triangle park, nc, usa objectives: the msq (migraine specific quality of life questionnaire) measures migraine-related quality of life in three dimensions [role restrictive (rr), role pre- ventive (rp), and emotional function (ef)]. the objec- tive of this analysis was to compare the psychometric properties of the finnish (fn), dutch (hd), hungarian (hg), spanish (sp), and uk english translations with the original us english version of the msq. methods: one hundred and ninety-eight finns, dutch, hungarians, new zealanders, and spaniards, participated in a multinational migraine clinical trial in which the msq was completed at baseline and after a - month treatment period with customary therapy or naratriptan . mg. the distribution of item responses, item-discriminant validity and scale-level reliability for the msq translations were examined and compared to the previously published us english version results. re- sults: the distribution of responses for each item was negatively skewed for all translations. the full range of the response categories was used by migraineurs from all countries except for the fn version in the clinical trial. every translation of the msq possessed item-scale corre- lations that were higher for the hypothesized scale com- pared to competing scales. similar to the us english ver- sion results, baseline cronbach’s alpha coefficients for the three msq dimensions were greater than . for all translations. the msq translations were sensitive to de- tect intervention differences after months of naratrip- tan treatment for migraines. conclusions: the msq translations have demonstrated item-level discriminant validity, reliability, and sensitivity to detect treatment changes in quality of life and has cross-cultural empirical validity. the msq is an effective tool in assessing mi- graine-related quality of life across different cultures. pmh the impact of schizophrenia on health- related quality of life (hrql) for patients admitted to psychiatric units of general acute care hospitals durkin mb , edell ws , mody sh , adams be , repp ea janssen pharmaceutica, titusville, nj, usa; mental health outcomes, lewisville, tx, usa objective: to evaluate the impact of schizophrenia versus other chronic conditions on health-related quality of life (hrql). methods: patients who were admitted to a psychiatric inpatient unit at one of the � acute care hospitals using the cqi�sm outcomes measurement system were administered the sf- health status survey. all patients with a discharge diagnosis of schizophrenia who completed the sf- and were admitted to adult (n � ) or geropsychiatric (n � ) inpatient units were selected. randomly generated observations were drawn from general us population sf- data to con- struct two general population cohorts matching the adult and geriatric schizophrenia samples, respectively, in dis- tribution of age and gender. adult and geriatric schizo- phrenic cohorts were compared to their corresponding matched general population cohort on each of the eight sf- domains. comparisons were also made to three disease cohorts: hypertension, congestive heart failure (chf), and diabetes. independent sample t-tests were used to evaluate differences between the groups. re- sults: schizophrenic patients from both adult and geri- atric groups had significantly lower scores (p � . ) on virtually all mental and physical hrql domains when compared to the general us population and to patients with hypertension or diabetes. both groups of schizo- phrenics scored lower (p � . ) on mental health do- mains when compared to chf patients. adult schizo- phrenics scored higher in the physical health domains than chf patients (p � . ), while geriatric schizophren- ics were similar to chf patients in those domains. con- clusions: schizophrenia’s association with lower hrql extends beyond mental health to physical health status. the physical health status of schizophrenics is more impaired than those observed in patients with dia- betes and hypertension, and is comparable to patients with chf. pmh change in health-related quality of life in patients with schizophrenia taking antipsychotic agents edell ws , durkin mb , mody sh , adams be , white re , qiu az mental health outcomes, lewisville, tx, usa; janssen pharmaceutica, titusville, nj, usa abstracts the perceived health status of individuals with severe psychiatric illness, such as schizophrenia, is an important element of disease burden and quality of life. the effect of antipsychotic therapies on psychiatric symptoms is well-understood. however, more information about the effects of antipsychotics on health status is needed. ob- jective: to examine changes in health-related quality of life (hrql) from inpatient admission to follow-up of adult and geriatric patients with schizophrenia treated with conventional or atypical antipsychotic agents. methods: data were obtained from the cqi�sm out- comes measurement system, an oryx (jcaho) ac- cepted performance improvement system, which tracks patients admitted to adult or geropsychiatric inpatient programs in over general hospitals across states. health status was measured by the sf- at time of ad- mission and at three (geriatric) or six months (adult) post-discharge. patients with a primary discharge diagno- sis of schizophrenia (icd- -cm codes . – . ) who completed the sf- and were treated with antipsy- chotic agents were included. one sample t-tests were used to test the null hypothesis that the mean change is equal to zero. results: mean scores were higher (i.e., healthier) at follow-up, as compared to admission, on all eight domains of the sf- for the adult schizophrenic group (n � ) and seven of eight domains for the geriat- ric schizophrenic group (n � ). statistically significant improvements were noted on five of the eight scales. largest improvements were found on role physical (p � . ), role emotional (p � . ), and social func- tioning (p � . ). conclusions: marked improve- ment in diverse aspects of hrql among schizophrenic patients treated with conventional or atypical antipsy- chotic agents supports the humanistic value of antipsy- chotic medications beyond simple symptom ameliora- tion. pmh the impact of depression on health- related quality of life (hrql) mody sh , edell ws , durkin mb , adams be , repp ea janssen pharmaceutica, titusville, nj, usa; mental health outcomes, lewisville, tx, usa objective: to describe the effect of depression on health-related quality of life (hrql) utilizing the sf- health status survey. the scores of patients with depres- sion were compared to age and gender matched us popu- lation norms and contrasted to results of similar research on patients with other psychiatric disorders. methods: sf- scores were collected from patients admitted to adult (n � ) or geriatric (n � ) psychiatric pro- grams within acute care hospitals who had an icd- -cm discharge diagnosis of depressive disorder. adult and ge- riatric us population norms were simulated using data from the medical outcomes study manual and interpre- tation guide to match the age and gender distributions of the adult and geriatric depression groups. admission sf- scores for the adult and geriatric depression groups were compared to these age and gender matched us popula- tion norms using independent sample t-tests. the find- ings were then placed in context of sf- scores for other psychiatric conditions including schizophrenia, bipolar disorder, and cognitive disorder. results: hrql for both the adult and geriatric groups of depressed patients was significantly lower than the simulated us population norms for all eight domains of the sf- , for physical health as well as mental health (p � . ). the greatest differences were observed in the role physical, social functioning, and role emotional domains. adult inpa- tients with depression had similar scores on all domains to adult patients with the other psychiatric diagnoses studied. however, geriatric patients with depression had lower scores on hrql across all domains versus geriat- ric patients with other psychiatric illnesses. conclu- sions: depression has a strong negative association with both adult and geriatric patients’ perceived hrql. depressed patients not only had the expected decreases on mental health domains, but also scored significantly lower on physical health domains. finally, depression in geriatric patients is associated with greater decrements in hrql than other psychiatric illnesses examined. pmh quality of life differences between patients with episodic and transformed migraine meletiche dm , lofland jh , young wb , hopkins mm office of health policy and clinical outcomes, thomas jefferson university, philadelphia, pa, usa; jefferson headache clinic, thomas jefferson university hospital, philadelphia, pa, usa currently there are no published studies comparing the health-related quality of life (hrqol) of transformed and episodic migraneurs. objectives: the study objec- tive was to detect differences in hrqol between patients with transformed migraine (tm) and episodic migraine (em). methods: this retrospective study examined the hrqol of transformed and episodic migraneurs of the jefferson headache center during their first visit to the center. data collected included the short form (sf- ) and the migraine disability assessment (midas) questionnaires as well as demographic information. a t-test with bonferroni correction was used to test for sig- nificant differences in the sf- domains between the groups. results: to date, data has been collected on patients, from each group. there were no signifi- cant differences with respect to gender, race, age or the number of comorbid conditions between groups. over the last days prior to their first visit, patients with tm reported having a headache on an average of days compared to em patients who averaged days with headache (p � . ). compared to em patients, patients with tm had statistically and clinically significant (� point difference) lower mean scores on the mental com- wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ untitled  | cancer discovery�august www.aacrjournals.org news in brief precision medicine path for prostate cancer a mainstay of metastatic prostate cancer treatment is the suppression of hormones that fuel tumor cells. how- ever, almost all men with advanced prostate cancer develop resistance to these androgen-depleting therapies. recently, researchers showed that nearly % of patients with metastatic castration-resistant prostate cancer (mcrpc) have a genetic alteration that could be targeted by other clini- cal treatments. the fi ndings suggest individualized approaches for these patients (cell ; : – ). “this will have a major impact on how we move forward in [treating] this disease,” says johann de bono, md, a principal investigator in the study and head of the division of clinical stud- ies at the institute of cancer research in london, uk. “ninety-nine percent of our trials involve no patient prese- lection. with this information, we can now subdivide these patients, as we’ve done with breast and lung cancers.” in this fi rst multicenter, inter- national clinical trial, researchers conducted whole-exome and transcrip- tome sequencing of bone or soft-tissue biopsy samples from patients living with mcrpc. results showed that . % of the patients who had a genetic alteration had androgen recep- tor mutations, a fi nding in line with current understanding of the disease. more compelling, researchers found that of the nearly % of patients with genetic alterations, % had anoma- lies (other than androgen receptor mutations) that could be targeted by investigational or fda-approved drugs currently used for other cancers. among these alterations, almost % occurred in dna repair pathways. for instance, some tumors had brca or brca mutations, which, in ovarian and breast cancers, have shown sensi- tivity to parp inhibitors, drugs that interfere with dna repair and prevent tumor cells from dividing. in addition, researchers mapped more than a half dozen previously unknown genetic changes, such as mutations in the wnt signaling pathway, which leads to regulation of cell development and migration, and a pik cb mutation with cancer-activating effects similar to pik ca. they also found that % of patients with mcrpc had germline mutations. “this is a very important study on a number of fronts,” says karen knudsen, phd, director of the sidney kimmel cancer center at thomas jefferson university in philadelphia, pa, who was not involved in the study. “it’s the fi rst large study looking at the incurable stage of the disease, where the unmet clinical need is. the large cohort gives us confi dence and a much clearer picture of the drivers of disease, and they’ve uncovered new potential drivers that are targetable.” when the study is completed, research- ers will have mapped and sequenced the tumors of patients with mcrpc. amassing such data, says de bono, will lead to more targeted—and more afford- able—sequencing. “it will be critical to follow up with clinical trials that correlate clinical outcomes with molecular alterations,” says arul m. chinnaiyan, md, phd, a senior author on the study and direc- tor of the michigan center for trans- lational pathology at the university of michigan in ann arbor. “the longer- term goal is to have this information ahead of time and be able to direct patients in a more precise way to the best therapy.” ■ cellular backpackers deliver lymphoma drugs researchers have developed a new technique that enlists t cells to ferry chemotherapy drugs into tumors and that improves the effi ciency of drug delivery. cancer cells can elude chemo- therapy by hiding out in lymph nodes and other protected locations. even if a small amount of drug makes it to these refuges, it may not permeate the tissue to reach the tumor cells inside. researchers have tried to overcome these problems by having nanoparti- cles transport chemotherapy drugs, but not all tumors have the leaky blood vessels that enable the particles to leave the bloodstream and disperse into the tumor. people karen e. knudsen, phd, has been named director of the sidney kimmel cancer center at thomas jefferson university in philadelphia, pa, as well as chair of its department of cancer biology. she has been serving in these roles on an interim basis since january. an expert in the molecular basis of hormone-dependent prostate cancer, knudsen aims to prevent and treat the disease. her studies that identify tumor suppressor and hormone-receptor alter- ations have uncovered new targets for treating advanced disease and have led to innovative, biomarker-driven clinical trials. in addition, she is editor-in-chief of molecular cancer research. rolf apweiler, phd, and ewan birney, phd, have been appointed joint directors of the european molecular biology laboratory— european bioinfor- matics institute (embl-ebi), effective july . the european hub for big data in biol- ogy, embl-ebi is based on the wellcome trust genome campus in hinxton, uk. as part of embl, the institute collects, annotates, archives, and shares data from publicly funded life-science experiments with the global scientific community. apweiler and birney will continue to lead their respec- tive research groups. apweiler is involved in many internal col- laborations and initiatives, including the human proteome organization proteomics standards initiative. he has served on the editorial and advisory boards of several journals, and he has published more than papers and book chapters. birney played a vital role in annotating the genome sequences of the human, mouse, and other organisms. he led the analysis group for the encode project. his inter- ests include functional genomics and statisti- cal methods to analyze genomic information. e m b l -e b i e m b l -e b i rolf apweiler, phd ewan birney, phd on april , . © american association for cancer research. cancerdiscovery.aacrjournals.org downloaded from published onlinefirst june , ; doi: . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/ ; : . published onlinefirst june , .cancer discovery precision medicine path for prostate cancer updated version . / - .cd-nb - doi: access the most recent version of this article at: e-mail alerts related to this article or journal.sign up to receive free email-alerts subscriptions reprints and .pubs@aacr.org to order reprints of this article or to subscribe to the journal, contact the aacr publications department at permissions rightslink site. click on "request permissions" which will take you to the copyright clearance center's (ccc) .http://cancerdiscovery.aacrjournals.org/content/ / / . to request permission to re-use all or part of this article, use this link on april , . © american association for cancer research. cancerdiscovery.aacrjournals.org downloaded from published onlinefirst june , ; doi: . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/lookup/doi/ . / - .cd-nb - http://cancerdiscovery.aacrjournals.org/cgi/alerts mailto:pubs@aacr.org http://cancerdiscovery.aacrjournals.org/content/ / / . http://cancerdiscovery.aacrjournals.org/ outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion a wednesday, february , voltage-dependent anion channel isoform (vdac ). here, we show that hcc induced by carcinogenic compounds, aflatoxin or den is highly sensi- tized to tbid-induced omm permeabilization and cyto c release when com- pared to normal liver. expression levels of vdac and bak were also higher in hcc than in control liver. the role of the vdac -bak pathway in the differential tbid sensitivity was validated by overexpression of vdac in primary hepatocytes. in hcc cells, elevation of bak was also associated with an increased level of mcl- , an inhibitor of bak. furthermore, both constitutive and drug-induced genetic deletion of mcl- in mouse embryonic fibroblasts caused sensitization to tbid-induced omm permeabilization in the absence of a change in bcl-xl or bax . based on these results, we are evaluating the possibility of selective killing of hcc cells by the combination of a bak activator and an mcl- inhibitor. -pos board b which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c release? shamim naghdi , peter varnai , soumya sinha roy , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadlephia, pa, usa, semmelweis university, budapest, hungary. vdac proteins represent a main component of the outer mitochondrial membrane (omm). the vdac family is composed of isoforms with more than percent similarity. although their primary role was known to be in ion and metabolite transport between mitochondria and cytosol, it has been dis- covered that vdacs are also involved in apoptotic pathways. we have recently found that specifically the vdac isoform is needed for tbid-induced cyto- chrome c release, due to its role in supporting bak insertion to the omm (roy et al. . embo rep. : - ). to determine the domain(s) of vdac which supports bak insertion, vdac and vdac amino acid composition compared and the unique attributes of vdac sequencewereconsideredformutationalanalysis.totestfunctionalsig- nificance of the changes in vdac or vdac , vdac -/- mef cells that are resistant to tbid, were transfected with the mutants and insertion of bak to the omm and cytochrome c release were monitored in permeabilized cells by immunoblotting. previously, we showed that the vdac -specific n terminal tail and cysteins are dispensable for tbid-induced omm permeabilization. to approach the remaining differences four chimeras were prepared: vdac ( - )vdac ( - ), vdac ( - )vdac ( - )vdac ( - ), vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ). these studies revealed that tbid dependent omm permeabilization is only sup- ported by vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ), indicating that the first two third of vdac is required and sufficient for bak targeting to the omm and tbid induced cytochrome c release. -pos board b outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion david weaver , xingguo liu , veronica eisner , peter varnai , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary. cells and tissues deficient in mitochondrial fusion have been shown to have defects linked to the exchange of inner membrane (imm) and matrix compo- nents, particularly mitochondrial dna. outer membrane (omm) constituents originate in the cytoplasm, thus the role of intermitochondrial transfer of omm components by fusion remained unexplored. here we show that fibro- blasts lacking the gtpases responsible for omm fusion, mfn / , have a more heterogeneous distribution of omm proteins than wild-type cells, and in partic- ular that heterogeneity of pro-apoptotic bak leads to dysregulation of bid- dependent apoptotic signaling. homogeneous distribution of bak is partially rescued by introduction of mfn into mfn / -/- cells. furthermore, fusions be- tween mitochondria lacking and containing bak result in hybrids sensitive to bid. proteins with different modes of omm association display varying degrees of heterogeneity in mfn / /- cells and different kinetics of transfer during fusion in fusion-competent cells. efficient coupling of omm to imm fusion depends on the presence of both mfn isoforms and is antagonized by the mitochondrial fission protein, drp . thus, omm function depends on mitochondrial fusion and is a locus of dysfunction in conditions of fusion deficiency. -pos board b mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat veronica eisner , guy lenaers , gyorgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, inserm u- , institut des neurosciences de montpellier, montpellier, france. mitochondria are highly mobile and dynamic organelles in many cell types. however, in the muscle, mitochondria are crammed into the narrow space among the myofilaments. until now, it remained unclear if mitochondrial fusion occurs in and supports the contractile activity of skeletal muscle (sm). here we applied mitochondria matrix-targeted dsred and photoactiv- able gfp to study mitochondrial fusion in rat fdb sm fibers. in vivo electro- porated fibers were imaged by confocal microscopy. when we tagged the mitochondria in ~ % of cell area with twophoton photoactivation of gfp, rapid spreading of fluorescence showed subsets of interconnected mitochondria, mostly in longitudinal direction. matrix fusion occurred with a rate of . and . events/min in adult fibers and skeletal myotubes, respectively. expres- sion of autosomal dominant optical atrophy-causing mutants of the fusion protein opa or ethanol exposure caused suppression of fusion, which is fol- lowed by mitochondrial dysfunction and late onset myopathies. when chal- lenged by repetitive tetanic stimulation, ethanol exposed cells displayed intracellular ca þ dysregulation, appearing as a fatigue pattern. ethanol also induced a decrease in mfn protein levels, without significantly altering mfn , opa or deltapsi. depletion of mfn alone was sufficient to suppress mi- tochondrial fusion in fdb fibers. fusion inhibition was apparent before any cell dysfunction, suggesting that suppression of fusion is not secondary to other problems in the cells. to directly test the role of mfn in ca þ regulation, ryr -transfected control and mfn ko mefs were stimulated with caffeine. mfn ko cells showed oscillatory ca þ transients that decayed faster than that in the control. thus, fusion dynamically connects skeletal muscle mito- chondria and serves as a target mechanism of both mutations and environmen- tal cues to cause impaired excitation-contraction coupling. -pos board b bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action katarina stroffekova, lucia balogová, mária maslaňáková, lenka dzurová, pavol mi�skovský mi�skovský. safarik university, kosice, slovakia. apoptosis is a key process in the development and maintenance of tissue homeostasis. this process of controlled cell death is tightly regulated by a balance between cell survival and damage signals. we focused our attention towards the intrinsic mitochondrial apoptotic pathway, where bcl- family of proteins plays the major role. we were particularly interested in two pro- apoptotic players bak and bax. here we investigated their role in apoptosis triggered by photodynamic action. we show the localization of bax and bak in u- mg human glioma cells incubated with photosensitizer hypericin (hyp) before and after photodynamic action. apoptotic stimulus by hyp photodynamic action caused bax translocation into mitochondria. however our results suggest that under these condi- tions there are two populations of mito- chondria: one which contains bax and bak simultaneously, and is almost exclu- sively localized near the plasma mem- brane; the other which contains bax only and is distributed throughout the cell. the different protein content and spatial distri- bution of these two populations suggest that they can play different roles in re- sponse to apoptotic stimuli. -pos board b stimulation of bax mitochondrial localization by bcl-xl thibaud renault , oscar teijido , gisele velours , yogesh tengarai ganesan , florent missire , nadine camougrand , bruno antonsson , laurent dejean , stephen manon . ibgc-cnrs, bordeaux, france, nyu college of dentistry, new york, ny, usa, merck-serono sa, geneva research center, geneva, switzerland, california state university of fresno, fresno, ca, usa. cytochrome c release, the commitment step of apoptosis, is regulated at the mitochondria through protein-protein interactions between the bcl- family proteins. an imbalance of this interaction network due to the up-regulation of the proto-oncogenes bcl- and/or bcl-xl lead to a resistance to apoptosis and is associated with tumor formation. bcl-xl overexpression act at the level of the mitochondrial outer membrane (mom) by inhibiting bax-mediated apoptosis; more particularly mac formation and cytochrome c release. how- ever, the molecular mechanisms through which bcl-xl affect earlier steps of bax-mediated apoptosis are not fully understood. surprisingly, we found that mitochondrial bax redistribution and change of conformation were not inhibited but rather spontaneously increased in response of bcl-xl overexpres- sion. in order to further investigate the molecular mechanisms involved in this 	which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c re ... 	outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion 	mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat 	bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action 	stimulation of bax mitochondrial localization by bcl-xl doi: . / .wnl. . . ; ; - neurology injury locomotor trial (scilt) group dudley, r. elashoff, l. fugate, s. harkema, m. saulino, m. scott and the spinal cord b. dobkin, d. apple, h. barbeau, m. basso, a. behrman, d. deforge, j. ditunno, g. incomplete sci weight-supported treadmill vs over-ground training for walking after acute this information is current as of january , http://www.neurology.org/cgi/content/full/ / / located on the world wide web at: the online version of this article, along with updated information and services, is all rights reserved. print issn: - . online issn: - x. since , it is now a weekly with issues per year. copyright © by aan enterprises, inc. ® is the official journal of the american academy of neurology. published continuouslyneurology at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org/cgi/content/full/ / / http://www.neurology.org weight-supported treadmill vs over- ground training for walking after acute incomplete sci b. dobkin, md, frcp; d. apple, md; h. barbeau, phd; m. basso, edd; a. behrman, phd; d. deforge, md; j. ditunno, md; g. dudley, phd; r. elashoff, phd; l. fugate, md; s. harkema, phd; m. saulino, md; m. scott, md; and the spinal cord injury locomotor trial (scilt) group* abstract—objective: to compare the efficacy of step training with body weight support on a treadmill (bwstt) with over-ground practice to the efficacy of a defined over-ground mobility therapy (cont) in patients with incomplete spinal cord injury (sci) admitted for inpatient rehabilitation. methods: a total of subjects from six regional centers within weeks of sci were entered in a single-blinded, multicenter, randomized clinical trial (mrct). subjects were graded on the american spinal injury association impairment scale (asia) as b, c, or d with levels from c to l and had a functional independence measure for locomotion (fim-l) score � . they received weeks of equal time of bwstt or cont. primary outcomes were fim-l for asia b and c subjects and walking speed for asia c and d subjects months after sci. results: no significant differences were found at entry between treatment groups or at months for fim-l (n � ) or walking speed and distance (n � ). in the upper motor neuron (umn) subjects, % of asia b, % of asia c, and all asia d subjects walked independently. velocities for umn asia c and d subjects were not significantly different for bwstt ( . � . m/s, n � ) and cont ( . � . , n � ) groups. conclusions: the physical therapy strategies of body weight support on a treadmill and defined overground mobility therapy did not produce different outcomes. this finding was partly due to the unexpectedly high percentage of american spinal injury association c subjects who achieved functional walking speeds, irrespective of treatment. the results provide new insight into disability after incomplete spinal cord injury and affirm the importance of the multicenter, randomized clinical trial to test rehabilitation strategies. neurology ; : – annually, approximately , americans have a traumatic spinal cord injury (sci). for many pa- tients, the most visible lingering disability is the in- ability to walk or a slow spastic-paretic gait with high energy cost. a gait training strategy, using body weight support on a treadmill (bwstt), , has evolved from physiologic studies of the effects of the level and timing of limb loading during stepping and of stance and swing phase kinematics in spinal transected quadrupeds - and in patients with com- plete sci. - the experimental intervention received clinical support from nonrandomized studies of pa- tients with incomplete sci early and late after injury. , , - no randomized trials with blinded out- comes, however, had compared different physical therapy strategies aimed at the recovery of walking during initial inpatient and outpatient rehabilita- tion. further, no prospective trials in sci had col- lected measures related to functional walking, such as walking speed, distance, and the need for assis- tive devices. , the spinal cord injury locomotor trial (scilt) was a single-blinded, parallel-group, multicenter, randomized clinical trial (mrct) that compared two interventions for walking: bwstt vs a similar in- tensity of a defined control (cont) program of over- ground mobility training. subjects had an incomplete sci on admission to each site graded on the american spinal injury association impairment scale (asia) as b, c, or d. the functional indepen- dence measure locomotor (fim-l) walking scores, obtained at inpatient admission and discharge from the participating clinical units (cus) for the years and , were used to formulate the study design. these data showed that % of patients classified as asia b, % as asia c, and % as editorial, see page *see the appendix on page for a list of group members and clinical unit sites. from the department of neurology, university of california los angeles, neurologic rehabilitation and research program, reed neurologic research center, los angeles, ca. funded by the nih at the national institute for child health and human development grants ro h , r hd , and k hd ; la foundation quebequoise sur la moelle epiniere, and la fondation pour la recherche sur la moelle epiniere. disclosure: the authors report no conflicts of interest. received november july , . accepted in final form december , . address correspondence and reprint requests to dr. bruce h. dobkin, department of neurology, university of california los angeles, neurologic rehabili- tation and research program, reed neurologic research center, westwood plaza, los angeles, ca ; e-mail: bdobkin@mednet.ucla.edu copyright © by aan enterprises, inc. at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org asia d at the time of admission to the cu were able to walk feet at a supervised or better level of function at discharge. because of the divergence be- tween the asia b and c subjects compared to the asia d subjects, the level of walking independence and the walking velocity were chosen as separate primary endpoints. the primary hypotheses were ) asia b and c subjects in the bwstt group will recover supervised or independent walking on the fim-l with a reciprocal gait pattern for feet (fim-l � ) significantly more often compared to those in the cont group at months after sci and ) asia d subjects assigned to bwstt will walk over ground significantly faster than the cont group. methods. study design. the scilt mrct recruited potential subjects by screening all admissions to six cus, each a regional sci center, from june to january . coordination and central data management were carried out at the university of california los angeles. institutional review board approval was obtained from each site. written informed consent was obtained from each subject prior to inclusion. the design and methods for this trial, including efforts for training and standardizing thera- pies and data collection, have been reported in detail. a sum- mary of important features follows. subject selection and randomization. patients were entered within weeks of onset of incomplete sci and within week of admission for rehabilitation. subjects with a cervical to t /t lesion were designated as the upper motor neuron (umn) group. subjects with a t to l lesion were designated as the lower motor neuron (lmn) group if they had no umn neurologic signs. if subjects with a low thoracic lesion had umn signs on one side and lmn signs on the other, they were designated umn. inclu- sion and exclusion criteria are listed in table . subjects were excluded at time of randomization if they needed antispasticity medication other than overnight. after entry, use of medication was determined by the treating physician. subjects were assigned to their treatment group using a random, permuted block design with the factors umn-lmn and asia b-c-d across all cu sites and generated by the ucla statistical coordinating unit. treatment. all subjects received the cu’s standard inpatient and outpatient rehabilitation therapies for mobility and self-care skills. within this routine, the main component of their mobility training was weeks of either bwstt or cont therapy for walking. they did not receive any formal training for walking other than during these sessions. the bwstt group had its mo- bility training for up to hour each day of therapy. the specific amount of time spent standing or stepping depended on each subject’s level of exercise-induced fatigue. the physical therapists proceeded with stretching exercises for up to minutes, then step training on the treadmill using bws for to minutes in - to -minute increments. walking over ground was practiced, once feasible, for an additional to minutes each session. for bwstt, subjects wore a climbing harness (robertson harness, henderson, nv) attached to an overhead lift that used a gas cylinder to enable vertical displacement during the step cycle (vigor co., stevensville, mi). weight support and treadmill speed were adjusted to enable training at speeds greater than . m/s with a goal of over . m/s. stepping with partial weight sup- port as needed was expected to allow therapists to initiate therapy for walking before patients were able to fully bear weight, prior to developing adequate motor control for balance and stepping, as well as allow practice of reciprocal stepping at faster speeds with greater safety and less fear of falling than early over-ground reha- bilitation training would ordinarily permit. the trainers in the bwstt group concentrated, both on and off the treadmill, on assisting trunk and lower extremity kinematics, limb loading, and the cutaneous and proprioceptive feedback that would approach those used by healthy subjects during reciprocal stepping. the scilt trainer’s group intermittently monitored the technique of bwstt at each cu by videotape and provided help in solving training problems. the cont group also had its mobility training for up to hour each day of therapy. the specific amount of time spent standing or stepping depended on each subject’s level of exercise-induced fatigue. the physical therapists proceeded with stretching exercises for up to minutes, followed by a minimum of minutes of standing for those subjects who could not take steps. subjects who could take steps practiced in parallel bars or over ground with assistive devices, braces, and physical assistance from one or two therapists within their exercise tolerance for to minutes. the cont subjects were not allowed to use a treadmill or bws. the goals of bwstt were not discussed with the therapists assigned to treat the cont group. the two approaches were carried out at different locations within each cu. for both mobility interventions, practice aimed to progressively increase task difficulty, be repetitive, maintain the attention of subjects, and reinforce successful skill acquisition. subjects were permit- ted to stand and walk, if feasible, during other portions of their inpatient and outpatient care, such as during routine occupa- tional therapy and at home for daily activities. both groups were permitted to perform leg and trunk strengthening exercises. the maximum number of bwstt or cont sessions would have been if subjects had received five sessions weekly for weeks, or the equivalent of about hours of formal mobility training. the number of training sessions was expected to vary among subjects from a minimum of to the maximum of sessions of their respective intervention. treatment sessions could be stopped when individuals reached the highly func- table number of screened subjects excluded based on inclusion and exclusion criteria by inclusion criteria . ages – years (n � ) . traumatic sci within days of injury (n � ) . incomplete lesion (asia b, c, or d at time of randomization) from below c on at least one side of the body to no lower than l on either side of the body (n � ) . unable to ambulate over ground at randomization without at least moderate assistance (� fim locomotor score) (n � ) . mini-mental state examination score � (n � ) by exclusion criteria . symptomatic orthostatic hypotension or � -mm hg drop when upright in the bws apparatus (n � ) . subject with a spine-stabilizing device whose treating surgeon states that bwstt is contraindicated (n � ) . contraindication to weight bearing on lower extremities (pelvic or leg fracture, chronic joint pain) (n � ) . pressure sore stage or higher, located where a harness or treadmill training or standing could affect healing (n � ) . a debilitating disease prior to sci that caused exercise intolerance and limited mobility-related self-care and instrumental activities of daily living (n � ) . must use antispasticity medication at entry (initial use to prevent spasms that interfere with sleep allowed) (n � ) . premorbid major depression or psychosis; suicide attempt caused the sci (n � ) . unlikely to complete the intervention or return for follow-up (n � ) . participation in another research study (n � ) sci � spinal cord; asia � american spinal injury association impairment scale; fim � functional independence measure; bws � body weight support; bwstt � body weight support on a treadmill. february ( of ) neurology at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org tional walking speed of . m/s, even if the minimum ses- sions were not completed. after the assigned -week intervention (bwstt or cont), all subjects had the opportu- nity to receive conventional outpatient therapy if recommended by the treating physician. adverse training events were moni- tored and reviewed by the external safety and data monitoring committee. outcome measures. the primary outcome measures in- cluded the fim-l and over-ground walking speed. these tests were performed by trained, blinded observers at a site where they would not encounter subjects during treatment times. the internationally accepted standard for the fim-l uses a -foot walk for levels to but requires a -foot walk for levels and . a fim-l score of means the patient requires total physical assistance; , maximum assistance of person; , mod- erate assistance; , minimal assistance (hands on contact); , supervision (not safe alone, but no physical help); , indepen- dent with equipment; and , no need for assistive devices. walking speed was calculated for the faster of two -foot ( . - meter) walks in patients who were able to walk that distance with moderate or less assistance. patients were asked to walk as fast as safely possible. these outcomes were obtained at entry (baseline), every weeks for weeks, at the end of the training intervention ( months), and at and months after entry into the study. secondary outcomes were collected at baseline and at , , and months. they included the distance walked in minutes to assess endurance and fitness, the berg balance scale to assess trunk and leg motor control (range to ), the walking index for spinal cord injury (wisci) (range to ) to assess functional limitations that require braces and assistive devices, the lower extremity motor score (lems) (range to ) to assess strength, the ashworth scale for hypertonicity, and the sf- for self- perceived quality of life. changes and interrelationships among these measures will be reported in other publications. of the , forms with subject data expected from the coordinators and blinded observers at the cus, % were complete when received by the statistical coordinating unit. sample size. the fim-l on admission and discharge from the participating cus in to was used for a power analysis. we hypothesized a higher probability that asia b and c subjects receiving bwstt would obtain a fim-l score � than those re- ceiving cont. for a power of . with � � . and a two-sided test, a total sample size of asia b and asia c subjects with umn and lmn lesions was needed to demonstrate a difference in fim-l scores. for a power of . , a sample size of asia d subjects who achieved over-ground walking at months was ex- pected to be needed to detect a � % difference in walking speed. statistical analysis. a four-way design was employed with three stratification factors (umn, lmn, cu site), one treatment factor, a repeated-measure time factor (onset of sci to randomiza- tion), and the primary endpoint (fim-l or walking speed) for asia b, c, and d entries. the analyses at baseline were con- ducted on those patients who had performance data such as walk- ing speed available. for the intention-to-treat paradigm, the cus asked subjects at the time they voluntarily withdrew from the trial to return for - and -month visits, but the institutional review boards would not permit an investigator to contact a sub- ject who had withdrawn. the method of imputation was the last observation carried forward and included subjects who completed at least weeks of mobility intervention. permutation tests and modified fisher tests were used for the analyses of baseline data between the bwstt and cont groups. the -month analyses used a robust regression approach with a two-way design. where the distributions were bimodal, a logistic regression analysis was performed using the standard asymptotic (wald) or quasi-exact method. ordinal or quantitative scales were split at a predetermined value (fim-l score � or � , for exam- ple) and after examining histograms of the data distribution to derive a binary endpoint to carry out standard binary scale anal- yses. when data included outliers and influential points, we ap- plied the huber regression analysis to lessen the effects, for example, of the few very fast and very slow velocities in �outlier� subjects. results. recruitment and retention. figure shows the flow diagram for recruitment. of , screened pa- tients with sci admitted to the cus, potentially eligi- ble subjects signed a consent form to allow further assessment, were subsequently found to be eligible, eligible subjects refused; subjects were randomized into the mrct. table shows the number of subjects excluded by each inclusion and exclusion criterion. some individuals met more than one criterion that eliminated them from eligibility. the majority of excluded subjects had a complete sci, onset beyond weeks prior to admis- sion for rehabilitation, or a fim-l score � . at a mean of . weeks after onset of sci, umn and lmn sub- jects were randomized. eight umn subjects (bwstt, n � ; cont, n � ) and five lmn subjects (bwstt, n � ; cont, n � ) dropped out prior to completing weeks of intervention, mostly within the first week. two of the subjects in the bwstt group stopped because they felt the therapy was too taxing and two had a tendon or joint injury. sixteen subjects, umn (bwstt, n � ; cont, n � ) and six lmn (bwst, n � ; cont, n � ), did not meet the eligibility requirements because they had a fim-l score of at the time of randomiza- tion. they were inadvertently entered into the study and completed their respective mobility interventions. we carried out all analyses with these subjects included (n � ) and excluded (n � ) and found no differ- ence in the statistical outcomes. data are reported only for the latter group. figure . flow diagram of progress through the phases of screening, enrollment, allocation, follow-up, and data analyses of the scilt. umn � upper motor neuron group; lmn � lower motor neuron group; b, c, and d � asia classifications; bwstt � step training using body weight support on a treadmill group; cont � defined over-ground mobility control group. neurology february ( of ) at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org for the intent-to-treat analyses of those who com- pleted at least weeks of intervention, subjects were classified as umn and subjects were lmn. fourteen of the umn subjects (bwstt, n � ; cont, n � ) stopped before weeks of mobility training was com- pleted. reasons for refusal to continue at any time after entry included disappointment at assignment, rapid re- covery no longer requiring therapy, and rehabilitation therapy “too difficult.” no differences in rate or cause for withdrawal were observed between the bwstt and cont groups. the -month analyses for walking speed included subjects with an umn lesion initially graded asia c or d who completed their training and all outcome measures. the study fell short in recruiting asia d umn and lmn subjects. several cus reported that asia d subjects no longer were being referred to their regional centers by , instead going to commu- nity facilities. randomization. the baseline characteristics and out- come measures at the time of randomization are shown for subjects who had adequate data for the intention-to-treat analyses (n � ) including umn and lmn asia b and c subjects (n � , table ) and umn and lmn asia c and d subjects who were able to complete the -foot walk (n � , table ). the baseline characteristics of the bw- stt and cont groups revealed no differences in age, gen- der, race, days since injury, or spinal level. fim-l, lems, walking speed, walking distance, berg balance, and wisci measures were also comparable at baseline, reveal- ing that the subjects were highly disabled with only two of patients able to walk feet at entry, both who were in the cont group. futility analysis and change in primary analysis. the fim-l was originally planned for use in the primary outcome analysis of asia b and c subjects, whereas walking speed was planned for only asia d subjects, who were expected to become independent walkers re- gardless of assigned intervention. we did not enter a sufficient number of asia d subjects for this primary analysis. a comparison of bwstt and cont for walk- ing speed in asia c and d subjects who were able to perform the task was originally planned as a secondary analysis, however. the majority of asia c subjects in the bwstt and cont groups reached functional walk- table baseline measurements for umn and lmn subjects in intention-to-treat analyses b � c c � d bwstt cont p bwstt cont p no. age, y ( – ) ( – ) . ( – ) ( – ) . gender . . % male % female race % white . . % african american % hispanic % asian % other level % cervical . . % thoracic % lumbar randomization, d ( – ) ( – ) . ( – ) ( – ) . fim-l score ( – ) . ( – ) . ( – ) . . ( – ) . ( – ) . lems ( – ) . ( – ) . ( – ) . . ( – ) . ( – ) . speed, m/s — (n � ; . , . )* distance, m — — berg balance scale score ( – ) . ( – ) . ( – ) . . ( – ) . ( – ) . wisci ( – ) ( – ) ( – ) . ( – ) ( – ) . values are median (range). group b � c includes all subjects used for intent-to-treat analyses of fim-l score. group c � d includes all subjects used for intent-to-treat analyses that were able to walk. *two subjects were able to walk in the cont group. umn � upper motor neuron; lmn � lower motor neuron; bwstt � step training using body weight support on a treadmill group; cont � defined over-ground mobility control group; fim-l � functional independence measure locomotor; lems � lower extremity motor score; wisci � walking index for spinal cord injury. february ( of ) neurology at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org ing scores, far more than predicted by the pre-study data gathered from the cus. thus, a change in the primary analyses was required. we combined the asia c and d subjects who could walk for the primary analysis of walking speed. prior to stopping the trial, a conditional power analy- sis was undertaken at the direction of the safety and data monitoring committee. futility analyses based on available data revealed that to detect a conditional power of % for the primary outcome measure of fim-l, an additional , subjects would have been needed. for a conditional power of % to detect a % difference in walking speed, an additional , asia c and d subjects would have been needed. thus, we report the primary outcomes for those subjects enrolled by the time of the interim analyses for fim-l in the asia b and c subjects and for walking speed for asia c and d subjects who were able to walk. we did not recruit a sufficient number of lmn subjects to complete indepen- dent analyses for those with conus/cauda equina sci. we separately report the combined umn and lmn sub- jects within each experimental group in the primary planned analysis as well as each umn group as planned for a secondary analysis because mechanistic differences of the response to bwstt may exist between individu- als with umn and lmn lesions. primary outcome analysis: asia b and c for fim- l. the primary outcome measures were obtained at months after entry, which was months after bwstt or cont was completed. statistical analyses were per- formed for intention to treat on data from asia b and c subjects who completed at least weeks of intervention for umn and lmn groups combined (n � ) and for umn subjects only (n � ) (table ). no statistical difference was found between the two groups for fim-l score. thirty-three percent ( / ) of asia b subjects in the bwstt group were ambulatory at months and % ( / ) in the cont group. of the asia b subjects who reached an fim-l score � , of who achieved this score would have been randomized as asia c if entered at the maximum eligibility time of weeks after sci. the majority of asia c subjects recovered indepen- dent walking; % of bwstt and cont subjects ( / in each group) had a fim-l score � at months. asia c subjects were significantly more likely than asia b subjects to walk independently and both asia b and c subjects who were randomized earlier (� weeks after sci) had a greater probability of recovery to a fim-l score � (table ). primary outcome analyses: asia c and d for walking speed. intent-to-treat analyses were performed on data from umn and lmn subjects graded asia c and d who could walk over ground and completed at least weeks of intervention as well as on of the umn subjects (table ). no statistical differences between treatment groups were observed in walking velocity at months for the combined umn/lmn subjects or the umn subjects alone. the median measures for velocity in the asia c and d subjects demonstrated a remarkably high level of walk- ing ability and fell within the range of functional commu- nity ambulation. secondary outcome analyses: umn asia c and d at months. the median quartile walking velocities at months for umn asia c and d subjects were unexpect- edly high in both arms ( . m/s [table ]). these analyses were performed on the of bwstt and of cont subjects at months who could complete the walk- ing test. regardless of the method of statistical analysis carried out on the asia c and d groups, including the effect by cu and time since onset of sci, no significant differences were found between the two interventions for fim-l, walking speed, endurance, lems, berg balance scale score, or wisci score. figure shows the change in walking speed at months compared to months for asia b, c, and d subjects who were walking and illustrates the overlap in walking speeds for the two arms of the trial. this figure also illustrates the change from entry, when walking speed was zero for these subjects, to the velocities at- tained at or months. walking speed at the end of treatment was highly correlated (r � . ) with the speed at months, but speeds continued to increase between and months. earlier time of entry (� weeks) into the mrct after onset of sci was associated with faster walking speeds (p � . ) and longer walk- ing distances (p � . ) in both arms at months for each asia group compared to velocities attained in sub- jects in that group who were randomized � weeks after sci. this finding was primarily related to subjects who were entered at a lower asia level at � weeks after sci (e.g., asia b or c) and attained the next higher asia level (e.g., asia c or d) within the next to weeks. the number of treatment sessions was higher (p � . ) in the bwstt group ( . � . ) than the cont ( � ) for the intention-to-treat analysis of all umn and lmn subjects. this difference was found, however, only for the asia c subjects. the difference in the number of sessions was attributable in part to a higher number of individuals in the cont group who reached the maximum walking speed of . m/s prior to completion of the minimum sessions. either the subjects or their therapists deter- mined that they had no need to continue cont rehabilita- tion for gait training. an analysis of only the umn subjects, however, revealed no significant difference in number of treatment sessions for the combination of b, c, and d subjects or for the asia c subjects in each arm of the trial. adverse responses. no differences in adverse reactions were found between the two arms during treatment. most complications during rehabilitation were not related to the interventions. no excess muscle strain, joint pain, or other potential complications of mobility training were docu- mented from a list on one of the report forms. based on questions and about pain from the sf- , no differ- ences were found. based on the ashworth score, no differ- ences in tone of the lower extremities or frequency of spasms at or months were found for umn subjects randomized to each intervention. discussion. no significant differences were ob- served at months for the fim-l for asia b and c subjects or in walking velocity for asia c and d subjects between the bwstt and cont groups. these individuals represented incomplete sci pa- tients referred to the regional rehabilitation centers neurology february ( of ) at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org who fulfilled the inclusion/exclusion criteria and could not ambulate without human assistance. subjects were similar in demographics and out- come measures at baseline, suggesting successful randomization. the “median” umn subject who was initially graded asia c or d on admission to a scilt cu became able to walk independently by months after sci at velocities that usually allow unlimited community activity. for umn c and d subjects, the outcomes were internally consistent at the primary endpoint of months in terms of walking speed, distance, and level of indepen- dence, which occurred in parallel to gains in leg strength (lems) and berg balance scale score (ta- ble ). thus, both internal and external validity of the results is likely. for umn asia b subjects, neither treatment led to gains in over-ground walking. most of the subjects who did improve to have a measurable walking speed were entered as asia b soon after sci and converted to asia c within the -week entry period (but continued to be considered as asia b for data analysis). thus, patients who are still graded asia b at weeks after sci have a low probability of achieving functional walking with a fim-l score � when treated with either bwstt or cont. the asia c and d subjects in both treatment groups achieved walking abilities beyond what had been expected (figure ) based on the available literature at the start of scilt and the experience of the investigators. , based on data collected in from the scilt sites, no more than % of asia c patients were expected to walk at dis- charge from the inpatient service with a fim-l score � . at the interim analysis, % of asia c and d subjects in the cont group were able to walk and % performed at walking velocities greater than . m/s. the asia c and d subjects in the bwstt group also reached these levels of walking ability. the trial was stopped before the planned number of asia d subjects was recruited based on the outcome of the futility analyses; re- sults were reported on those subjects entered by the time of completion of the interim analyses. we did not enter enough subjects with conus/cauda equina sci, which represents about % of trau- matic sci, to be able to make an independent analysis of lmn subjects. for patients graded as asia c on admission for rehabilitation, the scilt revealed less disability related to walking by months after sci than had been assumed from studies performed at single sites. in scilt, most individuals graded asia c ( / bwstt; / cont) at entry became able to walk independently. attained velocities for umn asia c and d individuals also did not differ between bwstt and cont groups (median . and . m/s; table ). walking speeds were so much faster than expected that the hypothesized % increase using bwstt that was used for the statistical power analysis would not have been clinically meaningful even if present. no prior studies had reported the walking speeds achieved during rehabilitation. indeed, few data were avail- able in the literature about walking-related out- comes after sci. the sites that participated in table fim-l at months for asia b and c subjects (analysis of maximum likelihood estimates) bwstt cont no. fim no. fim p umn and lmn b, c ( – ) ( – ) . asia b � c � . shorter time of sci to randomization . umn b, c ( – ) ( – ) . asia b � c � . shorter time of sci to randomization . values for fim are given as medians (interquartile range). fim-l � functional independence measure locomotor; asia � american spinal injury association impairment scale; bwstt � step training using body weight support on a treadmill group; cont � defined over-ground mobility control group; umn � upper motor neuron; lmn � lower motor neuron; sci � spinal cord injury. table walking speed at months for asia c and d subjects (analysis of maximum likelihood estimates) bwstt cont no. m/s no. m/s estimate se % ci p umn, lmn c, d . ( . – . ) . ( . – . ) � . . � . to . . shorter time of sci to randomization � . . � . to . � . umn c, d . ( . – . ) . ( . - . ) � . . � . to . . shorter time of sci to randomization � . . � . to . � . values for walking speed are given as medians (interquartile range). asia � american spinal injury association impairment scale; bwstt � step training using body weight support on a treadmill group; cont � defined over-ground mobility control group; umn � upper motor neuron; lmn � lower motor neuron; sci � spinal cord injury. february ( of ) neurology at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org the model sci care systems (national institute on disability and rehabilitation research, www.spi- nalcord.uab.edu) did not routinely collect walking outcomes from to on their , sub- jects. one model systems site reported that only % of incomplete paraplegic and % of incom- plete tetraplegic patients ( subjects) regained the ability to walk meters or climb stairs, whereas another site reported that % ( / ) of incomplete asia c and d tetraplegic subjects could ambulate feet independently at dis- charge. the interaction between time of assign- ment of the asia score, the initial level of walking skill, and the functionality of ambulation in terms of speed and endurance, however, was not discern- ible from the reports. also, no information was available before the start of scilt about the use of standardized measures for walking speed and distance or need for assistive devices. the sygen mrct, published after the start of scilt, compared gm- ganglioside to placebo. modified benzel scores, which expand the asia grades, were assigned within hours of a umn sci. benzel grade v is defined as walking with or without physical assistance for feet, which has no equivalent to a fim-l measure. of interest, this benzel grade was achieved weeks after en- try by % ( / ) of sygen study subjects initially graded asia a, % ( / ) for asia b, and % ( / ) for asia c. in the latter group, / became unlimited walkers by the benzel system. walking speed and endurance were not reported. scilt subjects received their asia grade well be- yond hours after sci, so one might have ex- pected to have even fewer asia b and c subjects who still could not walk to weeks after sci to subsequently achieve an fim-l score � . thus, the natural history of disability after incomplete sci may be considerably different from what had been assumed prior to the sygen and scilt mrcts. the results did not support the expectation that bwstt would be more effective than cont ther- apy. studies published before and after the start of scilt reported positive results for similar bw- stt approaches. , , , - however, most of these studies found improvements in individuals with chronic sci. also, no alternative treatment or con- current control group was used. for example, wernig et al. showed that of ( %) wheelchair-bound patients with a recent myelopa- thy, most of whom had a traumatic sci, recovered the ability to walk at least five steps. in compari- son, only of of the site’s historical control subjects treated with conventional therapy accom- plished this level of walking. the subjects were not randomized to a comparison intervention other than bwstt and outcome measures were not blinded. walking speed and distance were not re- ported. the lems score of subjects at the start of treatment (median of to weeks after spinal cord table secondary outcome measures for umn c and d subjects who were able to walk at months baseline months measure bwstt cont p bwstt cont p no. fim-l ( – ) . ( – ) ( – ) . ( – ) ( – ) . speed, m/s — — . ( . – . ) . ( . – . ) . distance, m — — ( – ) ( – ) . lems ( – ) ( – ) ( – ) . ( – ) ( – ) . berg ( – ) ( – ) ( – ) . ( – ) ( – ) . wisci ( – ) ( – ) ( – ) . ( – ) ( – ) . values are given as median (interquartile range). umn � upper motor neuron; bwstt � step training using body weight support on a treadmill group; cont � defined over-ground mobility control group; fim-l � functional independence measure locomotor; lems � lower extremity motor score; wisci � walking index for spinal cord injury. figure . comparison of walking speed at end of interven- tion ( months) and at time of primary outcome analysis in asia b, c, and d subjects who were able to walk and had complete data at months. neurology february ( of ) at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org disease symptoms) ranged from to . most pa- tients with an lems score � will recover the ability to take steps for at least short distances. of the umn asia c and d subjects in scilt who were unable to walk at entry, % (bwstt / and cont / ) walked at least feet without assistance. thus, the wernig et al. study cannot be interpreted as showing that bwstt is more efficacious than training without bws on a treadmill. rehabilitation trials may fail to reveal a differ- ence between an experimental and control therapy because they do not provide the necessary dose of the experimental treatment or do not maintain sufficient differences between the experimental and control interventions. we standardized the cont mobility therapy to include similar intensi- ties of weight bearing for standing or, when feasi- ble, time spent training to walk. the number of mobility training sessions for the cont and bw- stt group aimed to be equal. this was achieved for the asia b and d subjects and the umn asia c subjects. although a trend was present for the bwstt groups to have received more therapy ses- sions than the cont, the two arms had equal outcomes. the ability of the cont and bwstt subjects to take steps over ground determined how much they would practice walking on level surfaces in each session. if patients developed the ability to take steps, usual rehabilitation care proceeded to try to improve over-ground walking skills. possibly, the intensity of therapy for walking in both treatment groups may have been greater than what some rehabilitation providers offer to their physically assisted walkers who are graded asia c. the scilt cannot directly address this possibility since other intensities of mobility-related activity were not studied. one of the rationales for bwstt was to allow earlier step training and a higher intensity of initial practice. the contrast in the amount of standing and stepping between the two groups, however, was probably less than antici- pated. subjects in the cont and bwstt groups were required to weight bear or practice walking, when feasible, for similar amounts of time. the mrct’s primary aim was to compare the potential advantages of bwstt to cont within similar practice durations, not to compare different amounts of therapy time. the early gains by asia c and d subjects in both arms by weeks after entry (data not shown) and by the end of weeks of training compared to the more modest addi- tional gains in walking speed by months (figure ), suggest that bwstt may, in effect, have be- come only a marginally different training strategy than cont during the intervention, at least in terms of intensity of early practice of walking. the trial, however, was designed to test two treatment strategies and found that they were equivalent for the outcomes measured. the better than expected walking velocity outcomes in asia c subjects in scilt may also be attributed in part to the em- phasis on task-oriented therapy for all subjects, the entry of subjects without serious comorbidities, and a preponderance of patients with cervical cen- tral cord injuries who have a fair prognosis for recovery of walking. given that bwstt and cont provided equivalent outcomes for subjects in scilt, clinicians and patients can base their use of each strategy on personal preferences, skill, availability of equipment, and costs. bwstt for asia b subjects with umn lesions did not improve outcomes over cont therapy. bwstt was expected to induce mechanisms of activity-dependent plasticity within the spinal cord, which would be reflected in locomotor gains. if mechanisms of spinal plasticity in humans are to be used for functional walking, greater su- praspinal input or other interventions that modu- late posture and spinal stepping oscillators will be necessary. the highly functional outcomes in most of the asia c and d subjects regardless of the intervention suggest that when some threshold of supraspinal input and segmental sensory feedback are available, task-specific training can lead to im- proved walking. interventions that meet criteria for success, such as training hind limb stepping in spinal transected cats and rats or employing a physical therapy strategy for walking in single-subject de- signs, are critical for the development of new reha- bilitation therapies to improve motor control. the results of these types of experiments may support further scientific study of a new intervention, but the experiments cannot stand alone as evidence of the efficacy of the approach. the results of scilt reemphasize the value of mrcts with blinded out- comes in rehabilitation research, especially to evaluate new and complex physical therapies. sta- tistically sound mrcts in neurorehabilitation with adequate numbers of subjects, distinctively defined interventions, blinded outcomes, and rele- vant outcome measures had only been attempted several times prior to scilt. , this study dem- onstrated that complicated physical therapy ap- proaches can be taught to therapists and implemented across sites. the scilt confirmed the feasibility of carrying out an ethical, scientifi- cally rigorous trial within the time and physical constraints of customary inpatient and outpatient services. the results also provided quantitative data about functional outcomes after sci that dif- fer from reports of volunteer subjects from a single site, which will improve power analysis calcula- tions for future trials that assess recovery of walking. future trials of bwstt may aim to improve outcomes in asia b subjects who have no motor control beyond weeks after sci and in asia c subjects who still cannot walk more than to months after sci. pilot studies of chronic asia c february ( of ) neurology at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org patients who cannot walk suggest that the combi- nation of bwstt with functional electrical stimu- lation or robotic assistive devices may improve stepping. , bwstt may be a valuable training adjunct in future trials of biologic interventions that promote axonal regeneration toward the lum- bar cord to physiologically incorporate this input because the technique may be less physically bur- densome on therapists and safer for assisting asia a and b subjects to stand and step than conventional physical therapy. testing these ap- proaches will require well-designed mrcts. acknowledgment the authors thank the staff of each rehabilitation center and the individuals who participated in this study. they also thank dr. walter hauck and dr. ralph marino for their suggestions on this manuscript. appendix the scilt group. principal investigator: bruce h. dobkin, md (ucla department of neurology). statistical coordinating unit: robert elashoff, phd (co-investigator); joanie chung; and xiaohong yan (ucla depart- ment of biomathematics). trainers group: susan harkema, phd (co-investigator, ucla); andrea behrman, pt, phd (co-investigator, university of florida); and d. michele basso, pt, edd (co-investigator, the ohio state university). safety and data monitoring committee: carolee winstein, pt, phd; ann xiang, phd (university of southern california); patricia nance, md (vamc long beach, ca); beth ansel, phd (nih/nichd). clinical unit sites. magee rehabilitation center/jefferson university: michael saulino, md (co-investigator); john ditunno, md (co-investiga- tor); amy bratta, mpt; mary schmidt-read, pt, ms. mcgill university/ institut de readaptation de montreal: hugues barbeau, pt, phd (co- investigator); christiane garneau, pt; michael danakas, pt; brigitte bazinet, md. the ohio state university: lisa fugate, md (co-investiga- tor); michele basso, pt, edd; leslie fischer rachel botkin, pt. univer- sity of ottawa rehabilitation hospital: dan deforge, md (co- investigator); jennifer nymark, pt; michelle badour, pt. rancho los amigos rehabilitation center: michael scott, md (co-investigator); jeanine yip-menck, pt; claire beekman, pt. shepherd rehabilitation center: david apple, md (co-investigator); gary dudley, phd (co- investigator, university of georgia); leslie vanhiel, pt; scott bickel, pt, phd. references . waters rl, adkins r, yakura j, sie i. donal munro lecture: functional and 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jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org corrections vascular events, mortality, and preventive therapy following ischemic stroke in the elderly in the article “vascular events, mortality, and preventive therapy following ischemic stroke in the elderly” by r.c. kaplan, d.l. tirschwell, w.t. longstreth, jr., et al., (neurology ; : – ), a data coding error led to incorrect classification of recurrent strokes into the categories of ischemic, hemorrhagic, or indeterminate etiology. the following correction in the results section (p. , first paragraph) is required: of recurrent strokes, . % (n � ) were ischemic, . % (n � ) were hemorrhagic, and . % (n � ) were of indeterminate etiology. in addition, two statements in the first paragraph of the discussion (p. ) are incorrect. the proportion of hemorragic strokes among recurrent stroke events should have been stated as . % rather than %. the authors also incorrectly stated that the study suggested a higher proportion of hemorrhagic strokes among recurrences than prior studies of stroke survivors. the authors regret the errors. plasma cells in muscle in inclusion body myositis and polymyositis in the article “plasma cells in muscle in inclusion body myositis and polymyositis” (neurology ; : – ) by s.a. green- berg, e.m. bradshaw, j.l. pinkus, g.s. pinkus, t. burleson, b. due, l. bregoli, k.c. o’connor, and a.a. amato, the author l. bregoli was incorrected listed as l.s. bregoli. the authors regret the error. february ( of ) neurology at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org doi: . / .wnl. . . ; ; - neurology injury locomotor trial (scilt) group dudley, r. elashoff, l. fugate, s. harkema, m. saulino, m. scott and the spinal cord b. dobkin, d. apple, h. barbeau, m. basso, a. behrman, d. deforge, j. ditunno, g. incomplete sci weight-supported treadmill vs over-ground training for walking after acute this information is current as of january , & services updated information http://www.neurology.org/cgi/content/full/ / / including high-resolution figures, can be found at: subspecialty collections http://www.neurology.org/cgi/collection/all_clinical_trials all clinical trials following collection(s): this article, along with others on similar topics, appears in the permissions & licensing http://www.neurology.org/misc/permissions.shtml or in its entirety can be found online at: information about reproducing this article in parts (figures, tables) reprints http://www.neurology.org/misc/reprints.shtml information about ordering reprints can be found online: at scott memorial library @ thomas jefferson university on january , www.neurology.orgdownloaded from http://www.neurology.org/cgi/content/full/ / / http://www.neurology.org/cgi/collection/all_clinical_trials http://www.neurology.org/misc/permissions.shtml http://www.neurology.org/misc/reprints.shtml http://www.neurology.org 	 ->get indirect treatment comparison of interventions for neovascular (wet) age-related macular degeneration (wet amd) va l u e i n h e a l t h ( ) a – a a according to psoriasis area and severity index (pasi) and dermatology life quality index (dlqi) scores. methods: all patients who stayed on the same active treat- ment for weeks were included. active treatments were subcutaneous secuki- numab mg (n= ) or mg (n= ) at weeks , , , , and , followed by dosing every weeks, and subcutaneous etanercept mg twice weekly for weeks and then once weekly (n= ). total aucs over the -week period by percentage of pasi- / / and dlqi- / (no impact on patient quality of life) responders—measuring overall controlled disease time—were determined using all responder numbers at all scheduled visits. results: total aucs for patients who received secukinumab and mg, and etanercept, respectively, were: . , . , and . (pasi- ); . , . , and . (pasi- ); . , . , and . (pasi- ); and . , . , and . (dlqi- / ). total auc ratios for secukinumab and mg, respectively, vs etanercept were . and . (pasi- ); . and . (pasi- ); . and . (pasi- ); and . and . (dlqi- / ). total auc ratios for secukinumab vs mg were . (pasi- ), . (pasi- ), . (pasi- ), and . (dlqi- / ). conclusions: in patients with moderate-severe plaque psoriasis, greater aucs by pasi- / / and dlqi- / responders were achieved with secukinumab mg, followed by secukinumab mg and etanercept. this analysis suggests that secukinumab mg resulted in the best overall disease control over time. pss knowledge and practice of pharmacy students regarding the use of skin whitening product ab hadi h., awadh a. international islamic university malaysia, kuantan, malaysia objectives: the aim of this study was to assess the knowledge and practice of international islamic university malaysia (iium) kuantan undergraduate pharmacy students on the use of skin whitening product. methods: a self- administered questionnaire on the use of skin whitening product was dis- tributed to iium kuantan undergraduate pharmacy students at iium kuantan malaysia. results: three hundred and nine ( ) of four hundred ( ) students responded ( % response rate). the highest percentage of participants is from year three students which is . % while year four students are the least which is . %. the mean of knowledge score, regardless of their year of study is . over . among the user and non-user of skin whitening products, user shows higher mean knowledge score which is . than non-user which is . .of the participants, . % ( / ) are using the skin whitening products. . % ( / ) of the respondent read the instruction of the products before using them. conclusions: it is proven that the user of skin whitening products has better knowledge about the product than the non-user. half of the participants are still practicing poor practice in using the skin whitening products. there is a need to educate the students about the proper usage of skin whitening products to avoid any misuse of these products. pss antidepressant use in patients with age-related macular degeneration and depressive symptoms: baseline results from the low vision depression prevention trial pizzi l.t. , karel l.i. , shang t. , casten r.j. , rovner b.w. thomas jefferson university, philadelphia, pa, usa, thomas jefferson university hospital, philadelphia, pa, usa, jefferson hospital for neuroscience, philadelphia, pa, usa, jefferson hospital for neuroscience, philadelphia, pa, usa objectives: characterize baseline utilization of antidepressant and psychotropic medications in older adults with age-related macular degeneration (amd) and depressive symptoms. methods: patients ≥ years with bilateral amd and subthreshold depressive symptoms were recruited from a large private retina practice affiliated with a tertiary eye care institution to participate in the low vision depression prevention trial testing a multi-component intervention that combined low vision rehabilitation (lvr), home-based occupational therapy, and behavioral activation versus supportive therapy with lvr. variables considered were age, sex, race, education, marital status, living situation, medical comorbid- ity, depressive symptoms, and medication use. medications of interest included prescription antidepressants and psychotropics. depressive symptoms were meas- ured using the patient health questionnaire- (phq- ). scores range from to , with higher scores indicating greater severity. scores ≥ indicate at least mild depression. results: of the participants, % were female, % caucasian, and the mean age was . the mean phq- score was . (sd . ), and % were taking at least one depression and/or psychotropic medication. for those reporting these medications, ( %) reported medication, ( %) reported medications, and one ( . %) reported medications. participants with higher phq- scores were more likely to report ≥ depression and/or psychotropic medication (p = . ). no significant associations were found between use of these medications and demographic or medical variables with the exception of cardiovascular dis- ease (p = . ). conclusions: individuals with amd are at risk for depressive disorders due to the substantial impact vision loss has on quality of life. in this study, about one third of patients reported depression and/or psychotropic medi- cation treatment. while this rate is higher than prior studies, findings suggest an opportunity to increase the number treated with medications and/or behavioral approaches. pss study of psychological stress and acne vulgaris among pharmacy students ab hadi h., awadh a. international islamic university malaysia, kuantan, malaysia objectives: acne vulgaris is described as a common skin disease involving block- age and inflammation of pilosebaceous unit such as hair follicles and sebaceous gland. as many factors may contribute to the formation of acne, this study attempt ( . %). approximately , ( . %) had a coded ae. of the ae patients, . % were persistent with treatment despite the ae, . % switched to another treatment within . days, and . % discontinued therapy within . days. ae patients incurred $ (medical: $ , pharmacy: $ ) in rosacea-related costs, while patients without aes incurred $ (medical: $ , pharmacy: $ ). conclusions: the majority of aes associated with current rosacea drugs/formulations resulted in treatment switch/ discontinuation. new drug/formulation may provide additional treatment options for patients with aes and lead to improved persistence and better symptom control. pss indirect treatment comparison of interventions for neovascular (wet) age-related macular degeneration (wet amd) malcolm w.a. , hodgson r. , glanville j. , barata t. , fleetwood k. novartis uk, frimley, uk, york health economics consortium, york, uk, quantics consulting ltd, edinburgh, uk objectives: to undertake a network meta-analysis (nma) to assess the effective- ness of licensed interventions (aflibercept q , ranibizumab prn, pegaptanib and photodynamic therapy (pdt)) in the treatment of neovascular (wet) age-related macular degeneration (wet amd). methods: a systematic review was undertaken to identify trials comparing any of the interventions to treat neovascular amd reporting change in best corrected visual acuity (bcva). a nma of the studies was carried out using winbugs. identified studies often reported results at multiple time points. hence, a number of models were applied accounting for the time structure in the data. the deviance information criterion (dic) was used to select the most appropriate model. multiple separate networks were applied to the data to account for the fact that posologies were equivalent at some time points. results: tri- als were included in the network. aflibercept and ranibizumab were found to be statistically superior to pdt and pegaptanib at and months. the mean change from baseline bvca estimated between ranibizumab and pdt at months was . [ . to . ] and at months was . [ . to . ]. the mean change from baseline bvca estimated between ranibizumab and pegaptanib at months was . [ . , . ] and at months was . [ . , . ]. results for afliber- cept were quantitatively similar. there was minimal difference in the effectiveness of ranibizumab and aflibercept at any time point: mean difference at months numerically favoured ranibizumab by . [- . to . ] and at months by . [- . to . ]. conclusions: aflibercept and ranibizumab are effective treatments for neovascular amd demonstrating a clinically and statistically significant differ- ence in bvca compared with pdt and pegaptanib. there were only minimal (non- statistically significant) differences in the relative effectiveness of aflibercept and ranibizumab at any time point. pss comparative effectiveness of bimatoprost . %/timolol . % preservative-free fixed combination for the treatment of open- angle glaucoma and oht; interpreting results from a large treatment network saunders o. , wong w. , collomb d. , stradwick s. bresmed, sheffield, uk, allergan inc, irvine, ca, usa, allergan ltd, marlow, uk objectives: a network meta-analysis (nma) evaluating the effectiveness of bimatoprost . %/timolol . % preservative-free (pf) fixed combination (pf btfc) solution in single-dose vials for the treatment of glaucoma/ocular hyper- tension (oht) compared to alternative therapies has been updated (harvey et al ). the outcome of interest was change from baseline (cfb) in intraocular pressure (iop). methods: systematic searches originally conducted in october were updated to identify additional randomized controlled trials investigat- ing the efficacy of glaucoma/oht therapies, where efficacy is defined as iop cfb. a bayesian model with random effects for trial, week and time of day was fitted to synthesize the resulting evidence base. results: in total, studies met the pre-determined mixed treatment comparison inclusion criteria, represent- ing unique treatment arms. pf btfc was numerically superior to all treat- ments (monotherapies and combination therapies; preserved and pf therapies) in lowering iop and statistically significant (p< . ) for all but seven of the comparisons. furthermore, despite some trials being adequately sized and the treatment effect showing similar levels of uncertainty to others in the network, the credible intervals (ci) for these treatments were among the widest in the network. conclusions: pf btfc was numerically but not statistically superior to all treatments in lowering iop. the sample size required to show statistically significant results in nmas is larger than for head-to-head randomized trials because the precision of comparisons made across a network is proportional not only to the size and uncertainty of individual trials but also to the number of nodes separating treatments (thorlund ). this is thought to be a key driver of the width of cis for some treatments within this network. results from the updated nma will be presented along with a discussion of the interpretation of results for large and complex networks. pss efficacy of secukinumab in patients with plaque psoriasis: area under the curve of treatment response rates armstrong a.w. , feldman s.r. , korman n.j. , meng x. , guana a. , nyirady j. , herrera v. , zhao y. university of colorado denver school of medicine, aurora, co, usa, wake forest university school of medicine, winston-salem, nc, usa, university hospitals case medical center, cleveland, oh, usa, novartis pharmaceuticals corporation, east hanover, nj, usa objectives: assessment of how therapies achieve cumulative disease control over time is critical. in two phase iii, -week trials (erasure and fixture), secukinumab—a human, anti–interleukin- a, monoclonal antibody—was an effective treatment for moderate-severe chronic plaque psoriasis. pooled analysis of these trials was performed to explore the cumulative efficacy of secukinumab by assessing area-under-the-curve (auc) of percentage of treatment responders wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm 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the site may not work correctly. 	doi: . / . . corpus id: hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data @article{zagar hyperthermiacw, title={hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data}, author={t. zagar and j. oleson and z. vujaskovi{\'c} and m. dewhirst and o. craciunescu and k. blackwell and l. prosnitz and e. jones}, journal={international journal of hyperthermia}, year={ }, volume={ }, pages={ - } } 	t. zagar, j. oleson, + authors e. jones 	published 	medicine 	international journal of hyperthermia hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. they often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. morbidity is… expand view on taylor & francis europepmc.org save to library create alert cite launch research feed share this paper citationshighly influential citations background citations results citations view all topics from this paper 	fever 	mammary neoplasms 	chest wall structure 	mastectomy 	therapeutic radiology procedure 	large 	morbidity - disease rate citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency hyperthermia for chest wall recurrence 	i. youssef, n. amin 	medicine 	 save alert research feed radiotherapy in conjunction with superficial and intracavitary hyperthermia for the treatment of solid tumors: survival and thermal parameters 	s. triantopoulou, e. efstathopoulos, k. platoni, n. uzunoglou, n. kelekis, v. kouloulias 	medicine 	clinical and translational oncology 	 	 	view excerpts, cites background save alert research feed the tolerance of reirradiation and hyperthermia in breast cancer patients with reconstructions 	m. linthorst, gerard c. van rhoon, + authors j. van der zee 	medicine 	international journal of hyperthermia : the official journal of european society for hyperthermic oncology, north american hyperthermia group 	 	 save alert research feed special cases for proton beam radiotherapy: re-irradiation, lymphoma, and breast cancer. 	j. plastaras, a. berman, g. freedman 	medicine 	seminars in oncology 	 	 save alert research feed hyperthermia and reirradiation for locoregional recurrences in preirradiated breast cancers: a single institutional experience. 	n. r. datta, e. puric, + authors s. bodis 	medicine 	swiss medical weekly 	 	 	pdf save alert research feed hyperthermia and radiation therapy in locoregional recurrent breast cancers: a systematic review and meta-analysis. 	n. r. datta, e. puric, d. klingbiel, s. gómez, s. bodis 	medicine 	international journal of radiation oncology, biology, physics 	 	 	highly influenced 	view excerpts, cites background save alert research feed microwave hyperthermia in conjunction with radiotherapy in superficial tumours: correlation of thermal parameters with tumour regression. 	v. kouloulias, s. triantopoulou, + authors n. kelekis 	medicine 	the west indian medical journal 	 	 	pdf 	view excerpts, cites background save alert research feed efficacy of hyperthermia in combination with radiation therapy for breast cancer 	d. yamamoto, c. yamamoto, s. iwase, h. odagiri 	medicine 	 save alert research feed superficial hyperthermia plus external beam radiation in the palliation of locally progressive chemoradiation-resistant breast cancer 	curt heese, p. lavagnini, pamela d mills, mark lewis, m. markman 	medicine 	case reports in oncology 	 	 	 save alert research feed hyperthermia is now included in the nccn clinical practice guidelines for breast cancer recurrences: an analysis of existing data 	v. kouloulias, s. triantopoulou, + authors j. kouvaris 	medicine 	breast care 	 	 	 save alert research feed ... ... references showing - of references sort byrelevance most influenced papers recency thermoradiotherapy for locally recurrent breast cancer with skin involvement. 	t. hehr, u. lamprecht, + authors m. bamberg 	medicine 	international journal of hyperthermia : the official journal of european society for hyperthermic oncology, north american hyperthermia group 	 	 save alert research feed recurrent tumors of the head and neck, pelvis, and chest wall: treatment with hyperthermia and brachytherapy. 	s. rafla, k. parikh, m. tchelebi, e. youssef, h. selim, s. bishay 	medicine 	radiology 	 	 save alert research feed radiation therapy for chest wall recurrence of breast cancer after mastectomy in a favorable subgroup of patients. 	r. a. hsi, a. antell, d. schultz, l. solin 	medicine 	international journal of radiation oncology, biology, physics 	 	 save alert research feed radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. international collaborative hyperthermia group. 	c. vernon, j. hand, + authors m. sherar 	medicine 	international journal of radiation oncology, biology, physics 	 	 	highly influential 	pdf 	view excerpts, references background, results and methods save alert research feed locally recurrent carcinoma of the breast. results of radiation therapy 	f. chu, f. j. lin, j. kim, s. huh, c. j. garmatis 	medicine 	cancer 	 	 	 save alert research feed prognostic significance of local recurrence in breast cancer after postmastectomy radiotherapy 	j. dunst, b. steil, + authors c. richter 	medicine 	strahlentherapie und onkologie 	 	 save alert research feed superficial hyperthermia and irradiation for recurrent breast carcinoma of the chest wall: prognostic factors in tumors. 	h. lee, a. antell, + authors m. lockett 	medicine 	international journal of radiation oncology, biology, physics 	 	 save alert research feed locoregional recurrence of breast cancer following mastectomy: always a fatal event? results of univariate and multivariate analysis. 	j. willner, i. kiricuta, o. kölbl 	medicine 	international journal of radiation oncology, biology, physics 	 	 save alert research feed superficial chest wall recurrences of breast cancer: prognostic treatment factors for combined radiation therapy and hyperthermia. 	h. seegenschmiedt, u. karlsson, + authors b. micaily 	medicine 	radiology 	 	 save alert research feed randomized phase iii study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors: final report by the radiation therapy oncology group 	c. perez, t. pajak, b. emami, n. hornback, l. tupchong, p. rubin 	medicine 	american journal of clinical oncology 	 	 save alert research feed ... ... related papers 	abstract 	topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue news in brief. | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /ns. . . .s corpus id: news in brief. @article{ newsib, title={news in brief.}, author={}, journal={nursing standard (royal college of nursing (great britain) : )}, year={ }, volume={ }, pages={ } } 	 	published 	medicine 	nursing standard (royal college of nursing (great britain) : ) a roundup of the latest nursing news.  view on pubmed jdc.jefferson.edu save to library create alert cite launch research feed share this paper related papers 	abstract 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue anti-hla antibodies predict graft failure, time to engraftment and umbilical cord unit dominance in double umbilical cord blood transplantation poster session i s conclusion: our results indicate an increased risk of acute gvhd in association with dpb mismatch regardless of the tce classifica- tion. tce classification did not correlate with any transplant out- come considered in our cohort. this analysis does not support the clinical relevance of ranking dpb mismatches based on the tce algorithm. a scoring system predicting outcome after unrelated donor stem cell transplantation in primary refractory acute mye- loid leukemia craddock, c.f. , labopin, m. , schmid, c. , mohty, m. , rocha, v. queen elizabeth hospital, birmingham, united kingdom; faculte de medecine st-antoine, paris, france; klinikum augsburg, germany; nantes hospital, nantes, france; hopital st louis, paris, france treatment options for adults with primary refractory aml (pref aml) are extremely limited. whilst sibling allogeneic stem cell transplantation can result in long term survival most pa- tients lack a matched family donor and are destined to die of refrac- tory disease. greater availability of unrelated donors and improvements in supportive care have increased the proportion of patients with pref aml in whom allografting is technically fea- sible but the outcome of unrelated donor transplantation in this population has not been extensively studied. we therefore analysed overall survival in patients with pref aml who underwent unrelated donor transplantation between and with a me- dian follow-up of months ( - ). patients received three or more courses of induction chemotherapy. the median percentage of bone marrow (bm) blasts at transplant was %. the -year overall survival for the whole group was %. in multivariate anal- ysis, fewer than three courses of induction chemotherapy, a lower percentage of bm blasts at transplant and patient cmv seropositiv- ity were associated with improved survival. we used the prognostic factors identified in multivariate analysis to develop a scoring sys- tem. this allowed the delineation of four prognostic groups with survival rates ranging between % and %. this study dem- onstrates an important role for unrelated donor transplantation in the management of selected patients with pref aml and confirms the importance of initiating an urgent unrelated donor search in pa- tients with no matched sibling donor who fail to respond to induc- tion chemotherapy. pre-transplant factors allow the identification of patients with pref aml who are likely to benefit from unre- lated donor transplantation. hla disparity and rapid immune reconstitution do not over- come propensity to relapse in patients undergoing haploi- dentical hematopoietic stem cell transplant (hsct) with persistent disease at the time of transplant grosso, d. , alpdogan, o. , carabasi, m. , colombe, b. , cornett farley, p. , filicko-o’hara, j. , flomenberg, p. , gitelson, e. , kasner, m. , martinez-outschoorn, u. , o’hara, w. , wagner, j.l. , weiss, m. , werner-wasik, m. , flomenberg, n. thomas jefferson university kimmel cancer center, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa while increasing hla disparity is known to be associated with increased risk of significant graft versus host disease (gvhd), there is less data as to whether increasing hla disparity is corre- lated with stronger, clinically significant graft versus leukemia ef- fects. we examined a group of patients with acute leukemia undergoing haploidentical hsct to assess whether ) there was a marked difference in relapse rates based on the degree of hla mismatch and ) if early recovery of donor lymphoid subpopula- tions was associated with less relapse after hla mismatched hsct. thirty-four adult patients with aml ( ) and all ( ) underwent haploidentical hsct between and using a step process which separates the infusion of the lymphoid and myeloid portions of the graft while attempting to render the lymphocytes tolerant utilizing cyclophosphamide. the patients re- ceived x e /kg donor cd cells (dli) after conditioning with either tbi gy (n ) or fludarabine mg/m � , thiotepa mg/m � , and tbi gy (n ). two days after the dli, all patients received cyclophosphamide (cy) mg/kg � followed by a cd selected donor product. the tbi based regimen was given to % of patients with all and % with aml. we exam- ined relapse rates based on the number of antigen mismatches at a, b, cw, and drb in the gvh direction. there were no discern- able differences based on degree of hla disparity with even the most haplodisparate group exhibiting high rates of relapse when disease was present at hsct. in contrast, the presence of active leukemia at the time of hsct had far more impact on subsequent relapse rates (see table). table . outcomes based on degree of hla disparity antigen antigen antigen antigen mismatch mismatch mismatch mismatch number of patients relapsed/ total relapsed/ total relapsed/ total relapsed/ total active disease at hsct ( %) / ( %) / ( %) / ( %) n/a cr at hsct ( %) / ( %) / ( %) n/a / ( %) total / ( %) / ( %) / ( %) / ( %) we also examined the impact of immune recovery on relapse. ab- solute numbers of nk, and cd and cd t cells were examined in the first months post hsct. t cell, mnc, and total chimerism was greater than % donor-derived at the time of the assessment. for patients who did or did not relapse post hsct the median numbers of lymphoid subsets (cells/ul) were: nk ( - ) vs ( - ), cd ( - ) vs ( - ), and cd ( - ) vs ( - ) respectively. in this small series of patients treated with the step transplant method, relapse was associated more with the presence of disease at hsct than with any discern- able trend in degree of hla disparity or early immunologic recov- ery. other approaches to treat resistant leukemia are required to substantially improve disease free survival in these high risk patients. anti-hla antibodies predict graft failure, time to engraft- ment and umbilical cord unit dominance in double umbilical cord blood transplantation cutler, c. , kim, h.t. , sun, l. , sese, d. , kao, g. , vasquez, m. , armand, p. , koreth, j. , ho, v.t. , alyea, e. , soiffer, r.j. , ballen, k. , ritz, j. , milford, e. , antin, j.h. dana-farber cancer institute, boston, ma; dana-farber cancer institute, boston, ma; brigham and women’s hospital, boston, ma anti-hla antibodies (hla-ab) predict graft failure in unrelated donor and single umbilical cord blood (ucb) transplantation. we measured hla-ab in double ucb transplantation (ducbt) with the hypothesis that hla-ab would predict time to engraftment, graft failure and ucb unit dominance. methods: patients with banked pre-transplant sera who under- went ducbt using / or better allelic hla-matched ucb units ( - ) were studied. labscreen (one lambda inc.) was used to capture class i/ii hla-ab and the luminex is system was used to detect fluorescent tagged binding of human igg. visual software was used to normalize results and to deter- mine the presence of mixed class i/ii hla-ab. positive samples were tested using single antigen-coated microbeads. beads with a mean fluorescent intensity above baseline were considered positive. chimerism was measured using str typing of informa- tive alleles. graft failure was defined as the absence of neutrophil engraftment days from ducbt or loss of ucb chimerism by day without malignant relapse. ucb dominance was defined as . % contribution to hematopoiesis by a single ucb unit at day . s poster session i results: patients with hla-ab against ucb unit ( ), ucb unit ( ) or both ucb units ( ) were identified. no differences in cell doses, viability or baseline characteristics were noted between patients with/without hla-ab. the presence of hla-ab was asso- ciated with an increased risk of graft failure (hla-ab against either ucb unit: or . , %ci . – . , p . ; hla-ab against both ucb units: or . , . – . , p . ). neu- trophil engraftment was delayed in the presence of hla-ab (median vs. days, p . ) and fewer patients engrafted platelets in the presence of hla-ab ( . % vs. %, p . ). hla-ab against ucb unit was associated with ucb unit dominance (or . , %ci . – . , p . ), while hla-ab against ucb unit was associated with a non-significant trend toward ucb unit dominance (or . , %ci . – . , p . ). overall survival was inferior in the presence of hla-ab against ucb unit (p . ) or both ucb units (p . ), but not with hla-ab against ucb unit only. conclusions: in dubct, the presence of hla-ab increases the risk of graft rejection, prolongs time to engraftment, predicts ucb dominance and is associated with inferior outcome. hla-ab screen- ing should be incorporated into ucb unit selection strategies in ducbt. ex vivo treatment of hematopoietic stem cells with , -di- methyl prostaglandin e (ft ) improves engraftment and hematopoietic reconstitution cutler, c.s. , desponts, c. , robbins, d. , north, t.e. , goessling, w. , kao, g. , ritz, j. , ballen, k.k. , antin, j.h. , spitzer, t.r. , soiffer- cheny.-b.a., r.j. , , ho, v.t. , armand, p. , koreth, j. , alyea, e. , mcafee, s. , dey, b.r. , shoemaker, d. , multani, p.s. dana-farber cancer institute, boston, ma; massachusetts general hospital, boston, ma; fate therapeutics, san diego, ca; beth israel deaconess medical center, boston, ma; brigham and women’s hospital, boston, ma; dana-farber cancer institute, boston, ma through an in vivo zebrafish screen for modulators of hematopoi- etic stem cell (hsc) development, a small molecule, , -dimethyl prostaglandin e (ft ) was identified (north, ). ft was shown to enhance the engraftment potential of hscs from mu- rine bone marrow (mbm) or human umbilical cord blood (hcb) in murine engraftment models through an increase in proliferation, survival, migration and homing after a brief ( to hr) ex vivo treat- ment (north, ; north, ; hoggatt, ; north, goessling, zon, unpublished data). we further optimized the ex vivo hcb incu- bation protocol using whole genome expression arrays and deter- mined that hsc-containing cell products should be incubated with mm ft for hrs at �c to obtain the optimal response. in addition, we observed that ft induces similar gene expres- sion changes in hbm- and mobilized peripheral blood-derived cd cells. subsequent functional studies demonstrated that in keeping with increases of up to -fold in cxcr gene expression, cell surface cxcr protein expression was also significantly in- creased. one hour after treatment with mm ft for hrs at �c, . % of cb cd cells expressed cxcr compared to . . % in dmso control (p\ . ). in vivo cfu-s anal- ysis showed that treatment of mbm cells with mm ft for hrs at �c resulted in greater proliferation with a statistically signif- icant increase in colony formation, . . , compared to . colonies with dmso control (p \ . ). this short-term ex vivo incubation protocol, mm ft for hrs at �c, has been in- troduced into an ongoing phase ib clinical trial in adults with hema- tologic malignancies receiving a nonmyeloablative conditioning (melphalan, fludarabine and atg) followed by double hcb trans- plantation, in which one of the two hcbs is incubated with ft prior to infusion. the primary objective of the study is to determine the safety of ft treatment of hcb. preliminary data demonstrate that this ex vivo incubation can be reliably per- formed at the clinical site on the day of infusion with good cell recov- ery and viability. subjects with a median age of years have been accrued to date, of which two have been treated using the optimized ex vivo incubation protocol. of patients have achieved an anc . before day . transplant related mortality has been low with one death at day from respiratory failure. patients are alive, of which are disease-free. accrual is ongoing. allogeneic transplantation using haploidentical donor ver- sus unrelated cord blood donor: a single center retrospec- tive study gonzalez-vicent, m., molina, b., andion, m., sevilla, j., ramirez, m., perez, a., lassaletta, a., diaz, m.a. ni~no jesus childre�ns hospital, madrid, spain we have performed a retrospective comparison of pediatric pa- tients with leukemia receiving a haplo transplant (n ) or ucbt (n ) in ni~no jesus children’s hospital since to . there were not significant differences in immunophenotype, disease status and antecedent of prior autograft. however, haplo re- cipients tended to be older and of male gender. engraftment failure was significantly higher following ucbt % compared to % in haplo transplants (p . ). median neutrophil engraftment were at days for haplo and days for ucbt (p . ) and platelet engraftment at days for haplo and days for ucbt (p . ). supportive care (transfusions, antibiotics, parenteral nutrition and hospitalization days) were sig- nificantly higher for cord blood transplants. trm and acute gvhd (more than grade ii) incidence was higher in ucbt compared to haplo transplants. there were not significant differences in chronic gvhd and relapse probability between the two groups. results are summarized in table . disease-free survival (dfs) with a median follow-up of months (range: - ) and months (range: - ) were of % and % (p . ) for haplo transplants and ucbt respectively. when we analyzed aml, there were not differences in dfs with both type of donor (p . ). however, dfs for all was better with haplo ( %) against cord blood ( %) (p . ). ac- cording to phase of disease, dfs was similar in early phase (p . ), but in advanced phase outcome was better with haplo ( %) ver- sus cord blood ( %) (p . ). multivariate analysis of dfs showed that the main prognostic fac- tors were disease status at transplant (hr . , p . ), chronic gvhd (hr . , p . ) and source of stem cells (hr . , p . ). in conclusion, our data suggest that haploidentical donor is a good alternative for patients lacking an hla identical donor. table . results. agvhd >ii trm relapse dfs haplo (n ) ± % ± % ± % ± % ucb (n ) ± % ± % ± % ± % p . . . . cd stem cell selection and cd addback for pediatric recipients of matched unrelated adult donor (mud) periph- eral blood stem cell transplantation (pbsct) preliminary re- sults of day trm, immune reconstitution (ir), ptld, systemic viral infections (svi), and invasive fungal infections (ifi) ricci, a.m. , geyer, m.b. , jacobson, j.s. , majzner, r. , satwani, p. , bhatia, m. , george, d. , bradley, m.b. , garvin, j.h. , harrison, l.a. , morris, e. , duffy, d. , semidei-pomales, m. , baxter-lowe, l.a. , daniel-johnson, j.a. , schwartz, j. , baxter- lowe, l.a. , cairo, m.s. , , columbia university, new york, ny; columbia university, new york, ny; columbia university, new york, ny; university of california san francisco, san francisco, ca; columbia university, new york, ny background: cd stem cell selection depletes t cells responsi- ble for severe agvhd (lang et al., blood, ). cd selected grafts have been associated with delayed ir (ball et al, bmt, , eyrich et al, bjh, ). delayed ir is a significant risk factor for 	a scoring system predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leu ... 	hla disparity and rapid immune reconstitution do not overcome propensity to relapse in patients undergoing haploidentical h ... 	anti-hla antibodies predict graft failure, time to engraftment and umbilical cord unit dominance in double umbilical cord b ... 	ex vivo treatment of hematopoietic stem cells with , -dimethyl prostaglandin e (ft ) improves engraftment and hemato ... 	allogeneic transplantation using haploidentical donor versus unrelated cord blood donor: a single center retrospective study 	cd + stem cell selection and cd + addback for pediatric recipients of matched unrelated adult donor (mud) peripheral blood ... [pdf] patient perceptions of telehealth primary care video visits | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /afm. corpus id: patient perceptions of telehealth primary care video visits @article{powell patientpo, title={patient perceptions of telehealth primary care video visits}, author={rhea e powell and jeffrey m henstenburg and grace cooper and j. hollander and kristin l. rising}, journal={the annals of family medicine}, year={ }, volume={ }, pages={ - } } 	rhea e powell, jeffrey m henstenburg, + authors kristin l. rising 	published 	medicine 	the annals of family medicine purpose telehealth is a care delivery model that promises to increase the flexibility and reach of health services. our objective is to describe patient experiences with video visits performed with their established primary care clinicians. methods we constructed semistructured, in-depth qualitative interviews with adult patients following video visits with their primary care clinicians at a single academic medical center. data were analyzed with a content analysis approach. results: of … expand view on aafp annfammed.org save to library create alert cite launch research feed share this paper citationshighly influential citations background citations methods citations results citations view all tables and topics from this paper 	 table 	primary health care 	telemedicine 	patient visit 	benefit 	experience 	academic medical centers 	patients 	physical examination paper mentions blog post patient perceptions of telehealth primary care video visits [original research] information for practice july news article cyber the subject of debate on the hill politico magazine june news article new research shows patients value the convenience of telehealth fierce health june citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency patient perceptions of video visits using veterans affairs telehealth tablets: survey study 	cindie slightam, a. gregory, + authors donna m. zulman 	psychology, medicine 	journal of medical internet research 	 	 	 	view excerpts, cites background save alert research feed patient satisfaction with telehealth services compared to in-office visits: a systematic literature review 	crystal l. fleischhacker, crystal l fleischhacker 	 	highly influenced 	view excerpts, cites background save alert research feed evaluating the patient experience with urological video visits at an academic medical center. 	steven thelen-perry, rohan ved, chad ellimoottil 	psychology, medicine 	mhealth 	 	 	 	view excerpt, cites background save alert research feed understanding the cost savings of video visits in outpatient surgical clinics. 	david s. portney, rohan ved, + authors chad ellimoottil 	medicine 	mhealth 	 	pdf 	view excerpt, cites background save alert research feed exploring the determinants and experiences of senior stroke patients with virtual care 	sophy chan, a. o’riordan, ramana appireddy 	medicine, psychology 	canadian journal of neurological sciences / journal canadien des sciences neurologiques 	 	view excerpts, cites background save alert research feed physicians’ experiences of video consultation with patients at a public virtual primary care clinic: a qualitative interview study 	cajsa björndell, a. premberg 	medicine 	scandinavian journal of primary health care 	 	 	view excerpts, cites background save alert research feed patient characteristics associated with choosing a telemedicine visit vs office visit with the same primary care clinicians 	m. reed, jie huang, + authors e. kim 	medicine 	jama network open 	 	 	pdf save alert research feed acceptability, benefits, and challenges of video consulting: a qualitative study in primary care 	e. donaghy, h. atherton, + authors b. mckinstry 	medicine 	the british journal of general practice : the journal of the royal college of general practitioners 	 	 	pdf save alert research feed telehealth provides a comprehensive approach to the surgical patient. 	kulvir nandra, g. koenig, andrea delmastro, elizabeth a mishler, j. hollander, c. yeo 	medicine 	american journal of surgery 	 	 save alert research feed “the more they know, the better care they can give”: patient perspectives on measuring functional status in primary care 	f. nicosia, m. j. spar, a. neumann, molly silvestrini, m. barrientos, r. brown 	medicine 	journal of general internal medicine 	 save alert research feed ... ... references showing - of references sort byrelevance most influenced papers recency patients’ satisfaction with and preference for telehealth visits 	j. polinski, tobias barker, nancy j. gagliano, a. sussman, t. brennan, w. h. shrank 	medicine 	journal of general internal medicine 	 	 	pdf 	view excerpt, references background save alert research feed patients and families experiences with video telehealth in rural/remote communities in northern canada. 	patricia sevean, s. dampier, m. spadoni, s. strickland, susan pilatzke 	medicine 	journal of clinical nursing 	 	 	pdf save alert research feed perceptions of video-based appointments from the patient's home: a patient survey. 	matthew r gardner, s. jenkins, dan o'neil, d. wood, b. spurrier, s. pruthi 	medicine 	telemedicine journal and e-health : the official journal of the american telemedicine association 	 	 	pdf save alert research feed client satisfaction with telehealth services in home health care agencies 	l. grant, t. rockwood, leif stennes 	medicine 	journal of telemedicine and telecare 	 	 save alert research feed virtual visits in a general medicine practice: a pilot study. 	ronald f dixon, j. stahl 	medicine 	telemedicine journal and e-health : the official journal of the american telemedicine association 	 	 save alert research feed patient satisfaction with video teleconsultation in a virtual diabetes outreach clinic. 	farhad fatehi, m. martin-khan, a. smith, a. russell, l. gray 	medicine 	diabetes technology & therapeutics 	 	 save alert research feed women's and providers' experiences with medical abortion provided through telemedicine: a qualitative study. 	k. grindlay, k. lane, d. grossman 	medicine 	women's health issues : official publication of the jacobs institute of women's health 	 	 save alert research feed how outpatient palliative care teleconsultation facilitates empathic patient-professional relationships: a qualitative study 	jelle van gurp, m. van selm, k. vissers, e. van leeuwen, j. hasselaar 	medicine 	plos one 	 	 	pdf save alert research feed a comparison of patient satisfaction with telehealth and on-site consultations: a pilot study for prenatal genetic counseling 	d. abrams, m. geier 	medicine 	journal of genetic counseling 	 	 save alert research feed the value proposition in the widespread use of telehealth 	caitlin m. cusack, eric j. pan, j. hook, adam g. vincent, d. kaelber, b. middleton 	medicine 	journal of telemedicine and telecare 	 	 save alert research feed ... ... related papers 	abstract 	tables and topics 	paper mentions 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators blog posts, news articles and tweet counts and ids sourced by altmetric.com terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue dynamic measurement of ca +-induced changes in organelle-specific redox microdomains a monday, february , core metadata, citation and similar papers at core.ac.uk provided by elsevier - publisher connector activates a novel, calcium-independent, pkca-dependent signaling pathway, which results in mitochondrial depolarization. as a result, mitochondrial dys- function is likely to be a key contributor to the pathophysiology of gas embo- lism injury. further, this connection between the endothelial surface layer and endothelial mitochondria may also play an important role in vascular homeo- stasis and disease. -plat calcium-induced ros generation during ischemia triggers mptp- dependent cell death during reperfusion lea k. seidlmayer, vanessa v. juettner, lothar a. blatter, elena n. dedkova. rush university medical center, chicago, il, usa. impairment of mitochondrial function is a central event of ischemia- reperfusion (i/r) injury leading to tissue damage and cell death. we studied the relationship between mitochondrial ca þ overload, reactive oxygen species (ros) generation, opening of the mitochondrial permeability transition pore (mptp) and cell death in rabbit ventricular myocytes exposed to simulated i/r. changes in mitochondrial ca þ ([ca þ]m) were measured with x-rhod- , ros generation with mito-sox red, mptp opening as mitochondrial calcein red release, and cell death as lactate dehydrogenase release. i/r was induced by exposing cells to glucose-free tyrode solution containing mm -deoxyglu- cose and mm nacn, ph . , followed by superfusion with standard tyrode solution. no cell death was observed after min of ischemia despite a signif- icant increase in [ca þ]m, ros and mptp opening, however cell death in- creased significantly after min of reperfusion. the ca þ uniporter blocker ru partially prevented [ca þ ]m increase and completely abolished ros generation and cell death when applied during i/r, however application of ru only during reperfusion did not protect from cell death. scavenging ros with superoxide dismutase mimetic mntbap or antioxidant trolox pre- vented reperfusion-induced cell death. blocking mptp during ischemia by cyclosporine a or depletion of mitochondrial inorganic polyphosphate did not provide protection against cell death during reperfusion, but instead led to increased mitochondrial ros accumulation. however, inhibiting mptp opening during reperfusion with cyclosporine a attenuated cell death. we con- clude that mptp-dependent cell death during reperfusion is mediated by ca þ- dependent ros generation during ischemia. moreover, our data suggest that mptp opening during ischemia could serve as ros escape pathway from mitochondria and thereby attenuate mitochondrial ros accumulation and ros-mediated cell damage during subsequent reperfusion. -plat dynamic measurement of ca d -induced changes in organelle-specific redox microdomains david m. booth , balázs enyedi , miklós geiszt , péter várnai , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary. multiple interactions between ca þ -signalling and reactive oxygen species (ros) production are thought to exist and be of both physiological and patho- physiological relevance. however, until recently, the study of ros in the con- text of ca þ-signalling has been hampered by ros probes limited in both specificity and targeting. to measure ros in discrete subcellular domains, we compared the genetically-encoded ratiometric h o sensor hyper with the redox de-sensitized derivative sypher to control for non-specific changes. these probes, targeted to the er lumen, er membrane (cytosolic face), cyto- sol, mitochondrial matrix and outer membrane (omm) and the ip -receptor, are positioned to assess redox changes at a local level. in resting conditions, the er lumen showed > -fold increased hyper ratio compared to the outside of the er membrane, bulk cytosol and mitochondrial matrix and omm. in the er lumen, ip -linked ca þ -mobilization induced a prounounced, downward shift in hyper ratio, whereas little or no change was detected in other compart- ments. in permeabilized cells, mitochondrial ca þ-overload was accompanied by substantial increase in h o detected in the matrix and at the omm. these data demonstrate that redox environments within individual cellular compart- ments constitute a complex and dynamic interrelationship with the concentra- tion of free ca þ . the er lumen is highly oxidized and exhibits profound decreases in h o concommitant with ca þ -release. interestingly, these changes are not transmitted to the outer leaflet of the er membrane or to other compartments. mitochondria resist redox changes under moderate stimulation, however, during mitochondrial ca þ-overload and collapsed membrane poten- tial, strong h o generation is detectible in the matrix and at the mitochondrial surface. the ros generated and detected at locations immediately apposed to ca þ -transport proteins, such as the ip -receptor, may modify their function at a local level and contribute to the feed-forward cycle of ca þ -dysregulation and subsequent cell death. -plat er-mitochondrial ultrastructure in the liver of normal and ethnaol-fed rats gyorgy csordas , david mankus , antony anil noronha , jan hoek , carmen mannella , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, wadsworth center, albany, ny, usa. chronic alcohol consumption causes severe pathology in liver, associated with altered metabolism and reduced atp production. liver mitochondria isolated from alcohol-fed animals show decreased capacity for electron transport and atp synthesis, impaired calcium handling, and increased ros. in parallel, the endoplasmic reticulum (er) also shows increased ros and a stress re- sponse. the close correlation between defects in mitochondria and er is matched by recent evidence of the functional integration of cellular responses (including calcium signaling) involving these organelles. to evaluate the ultra- structural basis of alcohol-induced changes, we performed transmission elec- tron microscopy and electron tomography studies of rat liver. hepatocytes showed a large number of mostly round mitochondrial cross sections, which oc- cupied ~ % of the cytoplasmic area. the cell cytoplasm in chronic ethanol- fed ( months) condition exhibited reduced particle density, indicative of cell swelling, and contained large lipid vesicles. the mitochondria were generally intact but showed narrower intermembrane spacings within cristae and at the organelle periphery, consistent with low-scale matrix swelling. in both control and ethanol-fed conditions, mitochondria were typically surrounded by exten- sive er, with cisternae sometimes sandwiched between neighboring mitochon- dria. in one case, er was prominent at a site of mitochondrial fusion/fission. as previously reported, regions of close er-mitochondrial association ( - nm) contained numerous ‘‘tethers’’ between outer mitochondrial membranes (omm) and adjacent er. while individual tethers were discernible, dense granular material (including ribosomes) within omm-er interfaces interfered with accurate quantitation of tethers. however, membrane spacings could be readily measured. it was found that the mitochondrial surface in close associ- ation with er was significantly reduced in the chronic ethanol-fed condition as compared to control ( . % vs. %). this might be expected to cause reduced calcium signaling between er and mitochondria in liver after chronic alcohol ingestion. -plat mitochondrial nm -h /ndpk-d is multifunctional: intermembrane cardiolipin transfer linked to apoptosis uwe schlattner , malgorzata tokarska-schlattner , sacnicte ramirez , yulia y. tyurina , andrew a. amoscato , zhentai huang , jianfei jiang , mathieu boissan , raquel f. epand , dariush mohammadsanyi , judith klein-seetharaman , richard m. epand , marie-lise lacombe , valerian e. kagan . joseph fourier university and inserm, grenoble, france, university of pittsburgh, pittsburgh, pa, usa, inserm, umpc université paris and hôpital tenon, paris, france, mcmaster university, hamilton, on, canada, inserm and umpc université paris , paris, france. nm -h /ndpk-d forms symmetrical homohexameric complexes in the mitochondrial intermembrane space. the well established function of the en- zyme is phosphotransfer activity as a nucleoside diphosphate kinase (ndpk), using mitochondrial atp to regenerate nucleoside triphosphates. nm -h is further known to strongly bind in vitro to anionic phospholipids, mainly cardi- olipin, and in vivo to inner mitochondrial membranes. we show here that such protein/lipid complexes inhibit ndpk activity but are necessary for nm -h to function in selective intermembrane lipid transfer. nm -h -deficient hela cells expressing either wild-type nm -h or a membrane-binding deficient mutant were analyzed by membrane fractionation and lc-esi-ms. data revealed that wild-type nm -h increased cardiolipin content in the outer mitochondrial membrane as compared to mutant enzyme. this correlated with higher susceptibility of wild-type enzyme expressing cells to rotenone-induced apoptosis as seen by increased annexin v binding, elevated caspase / activity and stimulated release of cytochrome c into the cytosol. molecular modeling of nm -h binding with cardiolipin reveals potential intermembrane transfer mechanisms. we propose that nm -h acts as a lipid-dependent mitochondrial switch with dual function, allowing either for phosphotransfer or for cardiolipin transfer, with a role in apoptotic signaling. https://core.ac.uk/display/ ?utm_source=pdf&utm_medium=banner&utm_campaign=pdf-decoration-v 	calcium-induced ros generation during ischemia triggers mptp-dependent cell death during reperfusion 	dynamic measurement of ca +-induced changes in organelle-specific redox microdomains 	er-mitochondrial ultrastructure in the liver of normal and ethnaol-fed rats 	mitochondrial nm -h /ndpk-d is multifunctional: intermembrane cardiolipin transfer linked to apoptosis volumen , nº  . páginas - idesia (chile) junio, soil erosion vulnerability in the southern part of the meia ponte watershed, goias, brazil vulnerabilidad erosiva del suelo en la parte sur de la cuenca media ponte, goias, brasil breno amaro da silva , pedro rogerio giongo *, patrick tomaz de aquino martins , thaís alves barbosa , victor hugo moraes , thomas jefferson cavalcante , angelina maria marcomini giongo abstract soil erosion is a serious environmental problem that can cause numerous types of damage to society and the environment, and thus require preventive measures. the objective of this study was to evaluate soil erosion vulnerability in the southern region of the meia ponte watershed, goias, brazil, considering two situations: natural and anthropic cover conditions. for the analysis, we used remote sensing data represented by several parameters: lithology, soil class, slope, rain intensity, vegetation index, vicinity of roads, and land use and occupation. for each variable, we established a scale of weights according to erosive susceptibility for natural and anthropogenic environments. multicriteria analysis, which allows the combination of qualitative and quantitative information in the analysis of erosive susceptibility, was used through the relationship between soil use and land occupation. in the southern part of the meia ponte river watershed, the anthropic factor showed greater influence. the factors that increase erosive susceptibility were soil use and occupation, low vegetation index, and high slope. the southern part of the meia ponte watershed presents medium natural erosive susceptibility in most of the study area. key words: remote sensing, gis, cerrado, anthropization. resumen la erosión de los suelos es un grave problema ambiental que puede ocasionar numerosos daños a la sociedad y al medio ambiente, siendo necesario la adopción de medidas preventivas. este estudio tuvo por objetivo evaluar la vulnerabilidad erosiva de los suelos en la región sur de la cuenca meia ponte, goiás, considerando dos situaciones: condiciones de cobertura natural y antrópica. para la realización de los análisis, se utilizaron datos de sensoriamiento remoto representados por diversos parámetros: litología, clase de suelo, declividad, intensidad de lluvia, índice de vegetación, cercanías de vías y uso y ocupación del suelo. se establecieron para cada variable, una escala de pesos de acuerdo con susceptibilidad erosiva para el medio natural y otra antrópica. se utilizó el análisis multicriterio, por medio de la relación entre las actividades de uso y ocupación del suelo, la cual permite combinar informaciones cualitativas y cuantitativas en análisis en cuanto a la susceptibilidad erosiva. en la parte sur de la cuenca del río meia ponte, el factor antrópico obtuvo mayor influencia. los factores que aumentaron susceptibilidad erosiva fueron el uso y ocupación del suelo, bajo índice de vegetación y la alta declividad. la parte sur de la cuenca media ponte, presenta susceptibilidad erosiva natural media en la mayor parte del área de estudio. palavras clave: detección remota, sig, cerrado, antropización. universidade estadual de goias, santa helena de goias, goias- brasil. instituto federal goiano, rio verde, gois, brasil * corresponding author: pedro.giongo@ueg.br fecha de recepción: marzo, . fecha de aceptación: abril, . a.  artÍculos de investigaciÓn / research papers introduction the central-west region of brazil has been undergoing an intense process of land occupation resulting from urbanization and mainly agricultural activities (lepsch, ). the change in land use from native vegetation to areas occupied by agriculture, pasture, and urban areas (moraes et al., ) has promoted changes in the pattern of biophysical variables, causing silting of reservoirs and water courses, loss of fertile soils (assis et  al., ), and finally contributing to soil erosion processes. soil erosion is a serious global environmental problem that can cause great damage to society idesia (chile) volumen , nº  , junio, and the environment. the erosion process is a phenomenon that may occur through millions of years, causing impacts and transformations in the topography of the surface soil and alteration in sedimentary rocks (ismael et al, ). preventive measures are necessary to ensure that there are no increases in the areas affected by erosion, which could possibly increase the risk of food shortages for the population depending on agricultural production (zanata, ). g e omo r p holog y c a n m a ke i m p o r t a nt contributions to the study and planning of urban and rural areas, because development has occurred at an accelerated pace and often does not obey the natural characteristics and limitations of the environment (christofoletti, ). considering the importance of knowing and seeking measures for erosion control, geomorphological analysis and geoprocessing techniques have become relevant in these studies. with the use of thematic mapping, it is possible to identify erosive features and areas prone to erosion and also to facilitate analysis of the natural or anthropogenic environmental variables that incur erosion. in conjunction with this type of analysis, it is important to verify or elaborate measures of control (nascimento, ; silva and machado, ). geographic information systems (gis), together with geoprocessing techniques, are an important technique for environmental studies with constant integration and updating of spatial and alphanumeric data. they also allow analysis of phenomena at different scales and simulation of situations and environmental planning for decision making (pina, ; zanata, ). in view of the above, this study aimed to evaluate soil erosion vulnerability in the southern region of the meia ponte watershed, goias, brazil, considering two situations: natural and anthropic cover conditions. material and methods this study was carried out in the southern part of the meia ponte river watershed, partially covering municipalities in the state of goias (figure  ). the climate of the region is classified as type aw (tropical subhumid) according to koppen-geiger classification. it has a rainy season in the winter figure  . geographic location of the municipalities and the southern part of the meia ponte, goias hydrographic watershed. soil erosion vulnerability in the southern part of the meia ponte watershed, goias, brazil and occasional drought. the average rainfall is mm (alvares et al., ). between october and april, the rainy season, there is an increase in the possibility of new erosion and the expansion of existing erosion because water erosivity tends to be more intense. for the analysis, we used remote sensing data providing several parameters: lithology, soil class, slope, rain intensity, vegetation index, vicinity of roads and land use, and occupation. the cartographic bases of the lithology and the classes of soils were made available by the state system of geoinformation (sieg, ). soil altimetry data were obtained through topodata (inpe, ), available in letters ( th to th, letter to the millionth), accessed through the national institute of space research. slope information was generated using the terrain altimetry data. precipitation data were obtained from the meteorological station registered under number of the national meteorological institute, which is under the responsibility of the state university of goias (campus morrinhos), located at latitude . ° s, longitude . ° w, and with an altitude of m. the rainfall intensity mapping was performed using annual precipitation data. the land cover and normalized difference vegetation index (ndvi) maps were obtained through images from the landsat- satellite (orbit /point ) with passage on january , , obtained from the inpe image catalog ( ). google earth images served as an aid for identifying land use and occupation. from the maps generated in the physiographic characterization of the study area, the final map was developed by integrating the lithology, soil class, slope, rain intensity, vegetation index, proximity of roads, and land use data. all of the information was analyzed in qgis software (qgis development team, boston, usa). for the determination of the variables that represent risks from erosion, multicriteria analysis was used through the relationship between the use and occupation of the soil in the southern portion of the meia ponte watershed. for each variable, we established a scale of weights according to erosive susceptibility for natural and anthropogenic environments. for the generation of areas susceptible to erosion, weights and variables proposed by silva and machado ( ) were adopted. to generate the final map of susceptibility, the variables were organized in matrix files and weights were assigned to the variables according to the following equations: a) natural erosive susceptibility (l × ) + (s × ) + (d × ) + (r × ) + (vi × ) , (equation ) where l is lithology, s is soil class, d is declivity, c is rainfall intensity, and v is vegetation index. b) anthropic erosive susceptibility (l × ) + (s × ) + (d × ) + (r × ) + (v × ) + (pp × ) + (su × ), (equation ) where l is lithology, s is soil class, d is declivity, c is rainfall intensity, v is vegetation index, pv is proximity of pathways, and su is soil use. for the components of each map, grades to were assigned according to characteristics that tend to favor the formation of erosive processes. for the elaboration of the maps with weights, it was necessary to convert the data into vector files and reclassify the images. the variables were adopted using the methodology proposed by assis et al. ( ) and adapted from silva and machado ( ). the final maps were converted into vector files for quantification of area and calculation of the percentage of each class of erosive vulnerability. results and discussion the mapping allowed the characterization of the southern part of the meia ponte river watershed in relation to geomorphological factors. the analyzed variables allow understanding of the aspects of the region in terms of agricultural fitness and areas susceptible to erosive processes with anthropic or natural action. the lithological formation of the southern part of the meia ponte river watershed presents aspects of having low influence on degradation, considering the areas classified as high and very high (figure  a). because the soil in this area is classified as latosol, the analyses allowed us to determine that the erosive susceptibility is to a greater extent classified as very low but classified as high or very high in other small portions of the area (figure  b). latosols are more resistant to the idesia (chile) volumen , nº  , junio, action of surface runoff due to their good permeability and drainage (valle junior et al., ). the declivity of the terrain presents classes of very low, low, medium, and high erosive susceptibility, considering that the slope is classified as low in most of this area (figure  c). this can be attributed to the predominance of relief being smoothly curled toward the banks of the streams. another factor that influences erosion susceptibility as a function of slope is areas located in hills top, with slopes ranging from to % (saraiva et al., ). the shape of the terrain constitutes a qualitative variable, and from its geometry, effects are attributed that can be ordered according to their intensity, while being passive about considering the values of vulnerability to soil loss (valeriano, ; silva neto, ). because the average precipitation in the region varies from to mm per year (oliveira and sousa, ) with good spatial distribution, low susceptibility to erosive processes was observed, avoiding new erosive processes (figure  d). the ndvi revealed that the vigor of the vegetation was low in most of the area but very low, medium, and high in some regions (figure  e). the areas that had high values of ndvi were areas in which the impact caused by the force of drops of precipitation was reduced beneath the soil surface, thus reducing the velocity of water flow and minimizing the removal and transport of aggregates. high values of ndvi also indicate high vigor of vegetation, which minimizes direct contact of precipitation particles with soil and thereby reduces the effects of laminar surface runoff (guerra, ). the absence of vegetation cover makes the soil more vulnerable to inclement weather processes, causing the processes to act more intensely on these areas and thereby weaken them (guerra, ). in the areas near highways, the influence for susceptibility was classified as high. as the distance from highway increased, erosive susceptibility decreased (figure  f). intense vehicle traffic tends to contribute to intensification of erosion processes. thus, the opening of highways is a contributing factor of erosive susceptibility (amaral et al., ). soil use was the factor that contributed most to erosive susceptibility, especially when there figure  . reclassification of variables for susceptibility to litology (a), soil class (b), declivity (c), rainfall intensity (d), vegetation strength (e), proximity of pathways soil (g), and landsat image , composition r g b (h). soil erosion vulnerability in the southern part of the meia ponte watershed, goias, brazil was exploitation through agricultural activities. this land use was identified as very low, low, and average (figure  g). variables such as declivity, soil type, and land use should be considered more important variables than terrain forms, because the latter is a qualitative variable in the dynamics of erosive processes (silva neto, ). the natural erosive susceptibility was classified as medium or low in the largest portion of the watershed (figure  a). however, in the north- central area of the watershed, the natural erosive susceptibility was classified as high or very high. the map of anthropic erosive susceptibility revealed changes in the natural landscape of the southern part of the meia ponte river watershed due to the processes and higher frequency of land use change and occupation by agricultural areas and pastures (figure  b). the main economic activities in these areas were dairy farming and soybean, corn, and sugarcane cropping. all of these activities require intense use of soil, which increases erosive susceptibility. among these agricultural activities, land use with pasture is considered to be the activity that most contributes to increased risk of erosive susceptibility (valle junior et al., ). the areas of natural susceptibility (figure  ) were concentrated in areas with medium and high susceptibility classes. anthropogenic susceptibility was mostly concentrated in medium and low classes. by means of these indicators, it can be affirmed that the anthropic action has greater influence on the erosive susceptibility of the hydrographic watershed of this study. conclusions the use of multicriteria analysis with gis tools allowed the combination of qualitative and quantitative variables for erosive susceptibility. in the southern part of the meia ponte river watershed, the anthropic factor had greater influence. the factors that increased the susceptibility class in certain areas were soil use and occupation, low vegetation index, and high slope. the southern part of the meia ponte river watershed has medium natural erosive susceptibility in most of the study area. this study and the mapping of the southern part of the meia ponte river watershed will serve as a basis for actions aimed at watershed planning, promote discussion of the erosive vulnerability of the region, and assist in management of the region through actions aimed at sustainable development and recovery and the prevention of the emergence of new erosion. figure  . map of the natural erosive susceptibility (a) and anthropic (b) for the southern part of the meia ponte watershed, goias, . figure . percentages of areas in the classes of natural and anthropic erosive susceptibility of the southern part of the meia ponte watershed, goias, . idesia (chile) volumen , nº  , junio, alvares, c.a.; 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postage prepaid to any address. volume ii, number printed in u.s.a. h tt p s: // d o i.o rg / . /s d o w n lo ad ed f ro m h tt p s: // w w w .c am b ri d g e. o rg /c o re . c ar n eg ie m el lo n u n iv er si ty , o n a p r a t : : , s u b je ct t o t h e c am b ri d g e c o re t er m s o f u se , a va ila b le a t h tt p s: // w w w .c am b ri d g e. o rg /c o re /t er m s. https://doi.org/ . /s https://www.cambridge.org/core https://www.cambridge.org/core/terms world politics vol. ii • published in april • no. contents france in defeat: causes and consequences saul k. padover a protest against a dilemma's two horns reinhold niebuhr the strategy of communist infiltration : czechoslovakia, - ivo duchacek i american wartime objectives in latin america edgar s. furniss, jr. the role of the united nations in the conduct of united states foreign policy daniel s. che ever review articles the problem of american intervention, : an historical retrospect richard w. leopold army and national socialism - : ; the responsibility of the generals gordon a. craig i ^research notes i standardized error and japanese character: a note on political interpretation john f. embree he contributors ii h tt p s: // d o i.o rg / . /s d o w n lo ad ed f ro m h tt p s: // w w w .c am b ri d g e. o rg /c o re . c ar n eg ie m el lo n u n iv er si ty , o n a p r a t : : , s u b je ct t o t h e c am b ri d g e c o re t er m s o f u se , a va ila b le a t h tt p s: // w w w .c am b ri d g e. o rg /c o re /t er m s. https://doi.org/ . /s https://www.cambridge.org/core https://www.cambridge.org/core/terms the contributors saul k. padover is dean of the school of politics of the new school for social research and was visiting professor last winter at the univer- sity of paris. he is the author of four books on thomas jefferson and five books on european politics and history. reinhold niebuhr is professor of applied christianity at union theo- logical seminary. his numerous publications include the nature and destiny of man, moral man and immoral society, christianity and power politics, and the children of light and the children of darkness. ivo duchacek is visiting lecturer in political science at yale university. in he was liaison officer between general patton's army and the czech government, and from liberation in s until the coup in he was chairman of the foreign relations committee of the czechoslovak parliament. edgar s. furniss, jr. is a member of the department of politics at princeton university/during - he served in the office of american republic affairs, department of state. daniel s. cheever is assistant professor of government at harvard university. he was formerly in the division of international security affairs of the department of state and was also a member of the inter- national secretariat at the san francisco conference. richard w. leopold is associate professor of history at northwestern university and specializes in american diplomacy. author of robert dale owen: a biography, he is engaged on a major study of the united states as a world power. gordon a. craig is a member of the department of history at princeton university. he was collaborating editor and contributor to makers of mod- ern strategy: military thought from machiavelli to hitler and is cur- rently engaged on a study to be entitled militarism and statecraft: the politics of the prussian army since . john f. embree is associate professor of sociology and director o\ graduate studies in the southeast asian field at yale university. his writ- ings include suye mura, a japanese village and the japanese nation. h tt p s: // d o i.o rg / . /s d o w n lo ad ed f ro m h tt p s: // w w w .c am b ri d g e. o rg /c o re . c ar n eg ie m el lo n u n iv er si ty , o n a p r a t : : , s u b je ct t o t h e c am b ri d g e c o re t er m s o f u se , a va ila b le a t h tt p s: // w w w .c am b ri d g e. o rg /c o re /t er m s. https://doi.org/ . /s https://www.cambridge.org/core https://www.cambridge.org/core/terms pancan- - -ver -li_ p .. open access duodenal adenocarcinoma in a patient with partial intestinal malrotation william t. li, sonia sethi, adrienne n. christopher, deepika koganti,* and charles j. yeo abstract background: small bowel cancers, specifically duodenal cancer, occur at very low rates but require aggressive surgical resection when diagnosed. an even rarer finding is the presence of intestinal malrotation. case presentation: we present the unique case of a patient with both duodenal cancer and partial intestinal malrotation undergoing pancreaticoduodenectomy. we discuss the challenges faced and techniques used to successfully perform a surgical resection in this circumstance. conclusion: understanding of intestinal malrotation and review of the imaging is crucial in preparing for a resection of a duodenal tumor in a patient with this condition. keywords: pancreaticoduodenectomy; intestinal malrotation; congenital anomaly background small bowel neoplasms are a rare form of cancer in the united states, with * , estimated new cases and estimated deaths per year. although the small bowel comprises % of the total surface area of the al- imentary tract, small bowel cancer comprises only . % of estimated new cases of alimentary tract cancers per year. another rare finding in adults is intestinal mal- rotation (im). a review of cases at the massachusetts general hospital found only confirmed diagnoses of im in adults for a -year period. in adults, im is often asymptomatic and found incidentally. we pres- ent a unique case of a -year-old male who presented with both duodenal cancer and incidental small bowel malrotation with associated radiological studies, pa- thology report, and a review of literature. presentation of case the patient is a -year-old caucasian male who initially presented with melanotic stools and anemia requiring mul- tiple blood transfusions. he had a medical history of hyper- tension, hyperlipidemia, chronic kidney disease, and a myocardial infarction that resulted in a cardiac stent place- ment. during his workup for anemia, he underwent an esophagogastroduodenoscopy (egd) and colonoscopy. his colonoscopy revealed no worrisome lesions in the colon. egd revealed a large malignant appearing mass – cm in size just adjacent to the ampulla, which was biop- sied. pathology analysis returned as invasive moderately differentiated adenocarcinoma. he had a computed to- mography to further delineate the mass and to assist with operative planning, which showed thickening of the duode- num as well as a partial malrotation at the third and fourth portions of the duodenum such that the ligament of treitz failed to cross the midline (fig. ). laboratories including serum tumor markers, carcinoembryonic antigen (cea) and carbohydrate antigen - (ca - ), were within normal limits. owing to his biopsy proven duodenal ade- nocarcinoma, its proximity to the pancreatic head, and the apparent structural anomalies, the patient was recommen- ded to undergo surgical resection through a pancreatico- duodenectomy. his imaging was carefully reviewed preoperatively, and the partial malrotation was noted. the patient was prepared for his whipple resection. surgical findings the patient was taken to the operating room for an open pancreaticoduodenectomy. upon exploration, the department of surgery, jefferson pancreas, biliary, and related cancer center, thomas jefferson university, philadelphia, pennsylvania. *address correspondence to: deepika koganti, md, department of surgery, jefferson pancreas, biliary, and related cancer center, thomas jefferson university, walnut street, suite , philadelphia, pa , e-mail: koganti.deepi@gmail.com ª william t. li et al. ; published by mary ann liebert, inc. this open access article is distributed under the terms of the creative commons license (http://creativecommons.org/licenses/by/ . ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. journal of pancreatic cancer volume . , doi: . /pancan. . journal of pancreatic cancer duodenum and head of the pancreas revealed a palpable mass at the level of the second part of the duodenum and extending close to the first part of the duodenum and fur- ther caudal. it was necessary to proceed with a classic whipple procedure since a pylorus-preserving pancreati- coduodenectomy would have compromised the duodenal margin. there was no evidence of carcinomatosis, malig- nant lesions in the liver, or omental implants. on explora- tion, various structures were abnormal. the duodenal c loop was vertical, and there was an ectopically located lig- ament of treitz; it was found on the right side and inferior to its typical location. in addition, the presence of malrota- tion in the setting of significant mesenteric adipose tissue warranted that a longer portion of his jejunum be resected to yield sufficient mobility of the retained proximal jeju- num to allow for a tension-free anastomosis of the jejunum to the pancreas remnant and biliary tree. the pa- tient had normal positioning of the mesenteric arteries, which facilitated normal dissection of the pancreas around the superior mesenteric vein (smv) and superior mesen- teric artery (sma). however, the presence of considerable mesenteric fat and bowel malrotation provided signifi- cant, although overcomable, challenges to our operation. the pancreaticojejunostomy, hepaticojejunostomy, and gastrojejunostomy anastomoses were completed without incident. the specimen was sent off to pathol- ogy analysis and the frozen section analysis revealed a duodenal adenocarcinoma, with all resection margins being negative for malignancy. postoperative care postoperatively, the patient experienced transient delir- ium and developed an international study group for pancreatic fistula (isgpf) grade b pancreatic leak that was drained percutaneously. he was discharged to a rehabilitation facility on postoperative day . pathological findings the pancreaticoduodenectomy specimen contained a . · . · cm exophytic tan pink to red firm granular mass within the duodenum, * cm from the proxi- mal gastric resection margin. the mass was adjacent to a normal ampulla of vater. upon sectioning, the mass grossly appeared to extend into the muscularis propria but did not involve the underlying pancreatic parenchyma. there was no dilation of the pancreatic duct. the mass was a moderately differentiated adeno- carcinoma of the duodenum with focal invasion of the subserosal fatty tissues. a microscopic neuroendocrine tumor was also identified within the duodenal wall. it was well differentiated, low grade, and mm in greatest dimension. all regional lymph nodes recovered were negative for metastatic disease. all resection mar- gins were also negative for neoplasm. the final staging of the duodenal adenocarcinoma was t n m . molecular testing a pan-cancer -gene mutation panel of the specimen was performed. analysis showed a g v mutation of the kras gene, as well as a t>g nucleotide change in fig. . a ct scan without iv contrast showed generalized esophageal wall thickening and mild duodenal (marked by ‘‘d’’) wall thickening (b). the duodenal sweep does not cross the midline (a–c), consistent with a malrotation. there is no obstruction identified. the transverse colon evaluation was limited due to motion blur. the smv (marked by ‘‘v’’) is anterior and to the right of the sma (marked by ‘‘a’’), as would be found normally. eus performed showed a duodenal mass in the second portion of the duodenum that measured – cm. ct, computed tomography; eus, endoscopic ultrasound; sma, superior mesenteric artery; smv, superior mesenteric vein. li, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . codon - of the tp gene. both of these changes were classified as pathogenic. no further mutations were identified in the other genes in the panel. discussion and literature review cancer of the small bowel is a rare entity and accounts for only about . % of gastrointestinal tract neoplasms. im is a congenital anomaly that occurs in in live births and very rarely presents in adults. , small bowel cancer occurring in the setting of im is a rare combina- tion and can pose unique surgical challenges as the ana- tomical variations can often be located in the pancreatic region. rittenhouse et al. performed a retrospective re- view of the incidence of gastrointestinal malrotation dis- covered incidentally on preoperative imaging before hepatobiliary surgery. they found an incidence of out of cases, or . %. in planning for these cases, the surgeon must be prepared to deviate from the classic surgical techniques utilized to ensure a safe resection. for example, in two cases reported in rittenhouse et al., the jejunal limb had to be brought up for the pan- creaticojejunostomy and hepaticojejunostomy in a par- acolic manner, as opposed to the standard retrocolic manner. in our case, we were required to divide the proximal jejunum cm below the ligament of treitz to create a tension-free anastomosis. this is a much longer proximal limb than is typically required. mateo et al. discuss the need to modify the approach to pan- creaticoduodenectomy secondary to the presence of ladds’ bands and the need to release these peritoneal extensions while exercising caution in avoiding the vas- cular arcades of the small bowel. it is also imperative to have an understanding of the vascular variants that may be present in a patient with malrotation. the presence of the smv found to the left of the sma, known as the smv rotation sign, may be indicative of im in the adult patient. although not the case in our patient, mateo et al. demonstrated sig- nificant vascular variation of the smv, sma, and celiac trunk in three patients with im undergoing pancreati- coduodenectomy. these vascular structures deliver most of the blood supply to the pancreas and midgut and are the centerpieces for dissection during pancrea- ticoduodenectomy. the presence of abnormalities in these critical vessels must be closely scrutinized on pre- operative imaging preoperatively to prevent uninten- tional injury or ligation of the vessels. finally, the ligament of treitz can often be found in an abnormal position or may be missing altogether in patients with im. – as the ligament of treitz is an im- portant landmark for identification of the mesenteric vein during pancreaticoduodenectomy, absence or ectopic placement of this structure carries with it the possibility of intraoperative injury or postoperative complications. in our case, the ligament of treitz was displaced from the normal location and somewhat inferior. we worked carefully along the plane between the uncinate process of the pancreas and the transverse mesocolon to identify and dissect the smv. conclusion we present a rare case of a patient with adenocarcinoma of the duodenum and im treated with pancreaticoduo- denectomy. close review of imaging and understanding of im helped us prepare for the challenging but ulti- mately successful resection of the tumor. author disclosure statement no competing financial interests exist. references . siegel rl, miller kd, jemal a. cancer statistics, . ca cancer j clin. ; : – . . helander hf, fändriks l. surface area of the digestive tract—revisited. scand j gastroenterol. ; : – . . nehra d, goldstein am. intestinal malrotation: varied clinical presentation from infancy through adulthood. surgery. ; : – . . torres am, ziegler mm. malrotation of the intestine. world j surg. ; : – . . dietz dw, walsh rm, grundfest-broniatowski s, et al. intestinal malrota- tion: a rare but important cause of bowel obstruction in adults. dis colon rectum. ; : – . . rittenhouse dw, pucci mj, brumbaugh jl, et al. congenital variants of gastrointestinal rotation found at desection fo hepatopancreaticobiliary tumors: a case series with review of the literature. case rep pancreat cancer. ; : – . . mateo r, stapfer m, singh g, et al. pancreaticoduodenectomy in adults with congenital intestinal rotation disorders. pancreas. ; : – . . nichols dm, li dk. superior mesenteric vein rotation: a ct sign of midgut malrotation. am j roentgenol. ; : – . . mizukami t, hyodo i, fukamizu h. free jejunal flap transfer for pharyng- oesophageal reconstruction in patients with intestinal malrotation: two case reports. microsurgery. ; : – . . saito y, miyamoto a, maeda s, et al. [a case of cholangiocarcinoma with intestinal malrotation treated with pancreaticoduodenectomy]. gan kagaku ryoho. ; : – . . hayashi t, takano s, kimura f, et al. [a case of cholangiocarcinoma with hepatomesenteric trunk and intestinal malrotation treated with pan- creaticoduodenectomy]. gan kagaku ryoho. ; : – . cite this article as: li wt, sethi s, christopher an, koganti d, yeo cj ( ) duodenal adenocarcinoma in a patient with partial intestinal malrotation, journal of pancreatic cancer : , – , doi: . / pancan. . . abbreviations used egd ¼ esophagogastroduodenoscopy im ¼ intestinal malrotation sma ¼ superior mesenteric artery smv ¼ superior mesenteric vein li, et al.; journal of pancreatic cancer , . http://online.liebertpub.com/doi/ . /pancan. . tyrosine phosphorylation of mitochondrial ca + uniporter regulates mitochondrial ca + uptake wednesday, february , a like ursodeoxycholic acid (udca) and tauroursodeoxycholic acid (tudca), are cytoprotective and inhibit cell death. the mechanisms associated with these distinct effects are not entirely clear. however, the effect of hydrophilic bile acids seems to be related with the blockage of a series of processes that converge on mitochondrial damage. bax is a pro-apoptotic protein that belongs to the superfamily of the bcl- proteins and is involved in mitochondrial pore formation. submicellar concentrations of cytoprotective bile acids have been shown to modulate bax concentration in mitochondria, suggesting that these molecules may interact directly with the protein. in this study, our objective was to evaluate the affinity of bile acids to recombinant bax protein, making use of fluorescence spectroscopy (fret and fluorescence anisotropy), as well as fluorescence correlation spectroscopy (fcs). our results show that the cytoprotective bile acids udca and tudca associate with recombinant bax protein with high affinity, while the cytotoxic bile acid dca only seems to be able to adsorb to the protein with much lower affinity. notably, the bind- ing site for udca seems to be located in a hydrophobic pocket of the protein. this interaction could be responsible for the disruption of bax translocation to the mitochondrial outer membrane in the presence of udca and/or tudca. supported from fct/portugal (projects ptdc/qui-biq/ / and reci/ctm-pol/ / ). t.s. and f.f. acknowledges fct grants sfrh/bd/ / and sfrh/ bpd/ / -pos board b mac inhibitors neutralize the pro-apoptotic effects of tbid pablo m. peixoto , oscar h. teijido , laurent m. dejean , evgeny pavlov , bruno antonsson , kathleen w. kinnally . natural sciences, baruch college - cuny, new york, ny, usa, national institute of child health and human development, baltimore, md, usa, chemistry, california state university of fresno, fresno, ca, usa, new york university college of dentistry, new york, ny, usa, merck serono, geneva research center, geneva, switzerland. since our initial characterization of the imacs, different di-bromocarbazole derivatives with anti-apoptotic function have been developed and tested in several mouse models of brain injury and neurodegeneration [ - ]. owing to the increased therapeutic potential of anti-apoptotic di-bromocarbazole de- rivatives, we sought to expand our knowledge of the mechanism of action of these small molecule inhibitors. we investigated the kinetics of mac inhibi- tion in mitochondria from wild type, bak, and bax knockout cell lines using patch clamp electrophysiology, fluorescence microscopy, elisa, and quantita- tive western blot analyses. our results show that imacs work through at least two mechanisms: ) by blocking relocation of the cytoplasmic bax protein to mitochondria and ) by disassembling bax oligomers in the outer membrane. a comparison of the inhibitory effects over channel conductance and cyto- chrome c release suggests that the imacs interacted with both bax and bak with similar kinetics. interestingly, wild type mitochondria were more suscep- tible to inhibition than the bak or bax knockouts. a quantitative western blot analysis showed that wild type mitochondria had lower steady state levels of bak, which suggests an uneven stoichiometry of the mac components. -pos board b tyrosine phosphorylation of mitochondrial ca d uniporter regulates mitochondrial ca d uptake jin o-uchi, stephen hurst, jyotsna mishra, xiaole xu, bong sook jhun, shey-shing sheu. depariment of medicine, center for translational medicine, jefferson medical college, thomas jefferson university, philadelphia, pa, usa. mitochondrial ca þ has a critical role for balancing cell survival and death. ca þ influx into mitochondrial matrix is mediated primarily by the mitochondrial cal- cium uniporter (mcu). however, the signaling pathways that regulate mcu channel functions via post-translational modifications of mcu are completely unknown. here we show that adrenergic signaling induces mcu tyrosine phos- phorylation and accelerates mitochondrial ca þ uptake in cardiac cells. adren- ergic signaling induces activation of proline-rich tyrosine kinase (pyk ) and translocation into the mitochondrial matrix; enhancing the interaction between pyk and mcu, which subsequently accelerates mitochondrial ca þ uptake via pyk -dependent mcu tyrosine phosphorylation. mcu contains tyrosine res- idues ( in the n-terminus, in the pore-forming region, in transmembrane do- mains and in the c-terminus), which are conserved across all eukaryotic species. among them, only of these tyrosine residues (y at n-terminus, y , and y at c-terminus in mouse mcu) remained as potential phosphor- ylation candidate sites for protein tyrosine kinases using phosphorylation predic- tion programs. we mutated these tyrosine residues to phenylalanine and generated non-phosphorylation mimetic mcu mutants (mcu-yfs). we confirmed that only two tyrosine sites were phosphorylated in response to adren- ergic stimulation in situ using cell lines stably expressing mcu-yfs. in addi- tion, overexpression of these mcu-yfs failed to increase mitochondrial ca þ uptake in response to cytosolic ca þ elevation by thapsigargin, whereas wild- type mcu transfection dramatically accelerates mitochondrial ca þ uptake compared to non-transfected cells. in summary, mcu contains pyk -specific phosphorylation site(s) and pyk -dependent tyrosine phosphorylation of mcu can modulate its channel functions and regulate mitochondrial ca þ uptake. -pos board b cardioprotective roles of neuronal ca d sensor- during stress tomoe y. nakamura-nishitani , shu nakao , shigeo wakabayashi . molecular physiology, natl.cer.cardiovasc.ctr., suita, japan, cardiac physiology, natl.cer.cardiovasc.ctrwakabayshi, suita, japan. dysregulation of ca þ homeostasis in cardiomyocytes often results in heart fail- ure. identifying molecular targets that regulate cardiomyocyte survival is of ther- apeutic importance. neuronal ca þ -sensor- (ncs- ) is an ef-hand ca þ - binding protein, which is important for excitable cell functions. we previously found that ncs- -deficient (ncs �/�) mice had excess neonatal mortality (circ. res. ).the aim ofthe present study isto examinewhether ncs- plays beneficial roles in cardiac survival during stress and the possible mechanisms un- derlying these effects. neonatal mouse ventricular myocytes orwhole hearts from wild-type (wt) and ncs �/� mice were subjected to stressors, and the resistance to stress was evaluated. ncs �/� mouse hearts were more susceptible to stress induced by oxidative impairment and ischemia-reperfusion injury. stress- inducedactivationofphosphatidylinositol -kinase (pi k)/akt signaling, a major survival pathway, was substantially reduced in the ncs �/�group, and overex- pressionofncs- ortheconstitutiveactive formofakt increased the survivalrate of ncs �/� myocytes. cellular atp levels, as well as mitochondrial respiration rates (both basal and maximal o consumption) were significantly depressed in ncs �/� myocytes; especially with oxidative stress. furthermore, intracellular ca þ handling was more easily dysregulated in stressed ncs �/� myocytes than wt myocytes. since ncs- levels were increased by stress, the data suggest that ncs- is a survival-promoting factor, which is upregulated by stress stimuli. interestingly, however,supra-physiological ncs- expression was toxic to cells. taken together, our data suggest that moderate ncs- expression during stress promotes cardiomyocyte survival by maintaining proper ca þ handling, which is required for activation of akt survival pathways and mitochondrial function. -pos board b initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart development gisela beutner, george a. porter, jr. pediatrics, university of rochester medical center, rochester, ny, usa. mitochondria in early embryonic hearts are not thought to produce atp, yet they do produce reactive oxygen species (ros) that regulate myocyte differen- tiation. to assess changes in atp and ros generation in the developing heart, we measured mitochondrial oxygen consumption, the activity of the complexes (cx) and of the electron transport chain (etc), etc supercomplex assem- bly, and ros in embryonic mouse hearts. at embryonic day (e) . , mitochon- drial etc activity and oxidative phosphorylation (oxphos) are not coupled, even though the etc complexes are present. we show that cx- is able to accept electrons from the krebs cycle, but enzyme assays that specifically mea- sure electron flow to ubiquinone or cx- show no activity at this early embry- onic stage. at e . , mitochondria appear functionally more mature; etc activity and oxphos are coupled and respond to etc inhibitors. in addition, the assembly of highly efficient respiratory supercomplexes containing cx � , � , and � , ubiquinone, and cytochrome c begins at e . , the exact time when cx- becomes functional activated. at e . , etc activity and oxphos of embryonic heart mitochondria are indistinguishable from adult mitochon- dria. in contrast, generation of reactive oxygen species (ros), as measured with amplex red, is high at e . and drops significantly by e . , coinciding with activation of the etc. in summary, our data suggest that between e . and e . dramatic changes occur in the mitochondria of the embryonic heart, which result in a decrease of ros generation and an increase in oxphos due to the activation of cx- and the formation of supercomplexes. -pos board b the stoichiometry between micu and mcu determines the different mitochondrial ca d uptake phenotypes in heart and liver melanie paillard, györgy csordás, tünde golenár, cynthia moffat, erin seifert, györgy hajnóczky. mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa. mitochondrial ca þ uptake is central to oxidative metabolism and cell death signaling. the first clues to its molecular mechanism have emerged from the recent identification of the mitochondrial ca þ uniporter’s pore forming protein (mcu) as well as its regulators. among the regulators, micu shows striking 	mac inhibitors neutralize the pro-apoptotic effects of tbid 	tyrosine phosphorylation of mitochondrial ca + uniporter regulates mitochondrial ca + uptake 	cardioprotective roles of neuronal ca + sensor- during stress 	initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart de ... 	the stoichiometry between micu and mcu determines the different mitochondrial ca + uptake phenotypes in heart and liver few-body syst ( ) : – doi . /s - - -x f o r e w o r d tobias frederico · giovanni salmè · michele viviani foreword received: december / accepted: december / published online: february © springer-verlag this special issue of few-body systems collects original efforts of the community in the field of “relativistic description of two- and three-body systems in nuclear physics” (october – , , ect∗). while we were completing the editorial and reviewing processes, we were shocked by the sad news that our outstand- ing colleague prof. john alexander tjon, suddenly passed away on september in bilthoven, the netherlands. for his great achievements and leading role, tjon has to be considered one of the “fathers” of modern few-body physics. he was a skilled and innovative scientist, with an outgoing and cheerful personality. he was extremely interested not only in various physics matters, but also in the lives, expectations, and fortunes of his colleagues and collaborators working in the same field. we have met him several times, especially at the conferences on few-body physics. just spending a few minutes with john was sufficient to appreciate his acuteness and sensitiveness. the research activity for extending the realm of investigation of the accurate non relativistic approaches, by including, possibly in a non perturbative way, the fulfillment of general properties, as the poincaré invari- ance, or even full covariance by dealing with antiparticle degrees of freedom, has been greatly influenced by his creative ideas. his interests covered a wide range of topics, from the calculations of the three-body faddeev equations, to the bethe–salpeter equation investigated both through three-dimensional reductions and the advanced and original application of the feynman–schwinger approach, always taking into great account the phenomenology. his scientific journey could be ideally started from the solution of the faddeev equations for the three-nucleon bound state, by using local two-body interactions (different from the stan- dard and simplified choice of separable interactions, mainly used at that time). this work quickly became a benchmark in the few-body community. the next steps, driven by the advent of accurate experiments on the electromagnetic interactions of very light nuclei at high momentum transfers, were the investigation of possible relativistic generalizations of the faddeev equations and the quasi-potential equations for generating solutions of the bethe–salpeter equation for the two-nucleon system. noticeably, he was the first to apply the feynman–schwinger representation for comparing ladder and generalized ladder sums in scalar field the- ories, providing a numerical demonstration of the relevance of crossed ladder diagrams in nonperturbative calculations. in the s and s, he investigated the relativistic treatment of the proton scattering by nuclei, and by exploiting his previous researches on the nucleon–nucleon interaction, he was able to shed light on t. frederico ita, são josé dos campos, brazil g. salmè (b) infn, sezione di roma, rome, italy e-mail: giovanni.salmeg@roma .infn.it m. viviani infn, sezione di pisa, pisa, italy t. frederico et al. the theoretical basis of the potential adopted in the relativistic calculations of that process. among his latest interests, of particular relevance was the very intriguing experimental result obtained at the thomas jefferson national accelerator facility, on the ratio between the electric and magnetic form factors of the proton, in sharp contrast with the values extracted from the slac data. he brightly noticed that the standard description in terms of one-photon exchange could be inadequate, and moving beyond the born approximation, he per- formed, with several co-workers, calculations of the two-photon exchange amplitude, obtaining a remarkable reduction of the discrepancy between new and old data. in his latest paper, he dealt with the same issue, but for the electric form factor of the pion. from this short description of the scientific life of tjon, one can immediately realize that the few-body community has been strongly influenced by his activity, and many of the topics discussed in the present ect∗ conference are just the continuation of the original ideas laid out by john in his seminal works. as a matter of fact, on the one hand, there already exists a number of challenging experimental puzzles (e.g., the neutron-deuteron analyzing power at low-energy or the detailed behavior at high momentum transfer of the electromagnetic deuteron form factors); on the other hand, new experimental facilities are forthcoming (as the approved gev upgrade of the electron accelerator at the thomas jefferson national accelerator facility) and this makes desirable the relativistic treatment of the nuclear systems involved in the proposed experiments. in view of this, the compelling motivation for organizing the ect∗ conference has been to set up an appropri- ate place for both discussions and cross-fertilizations between the non relativistic few-body community and the relativistic one. indeed, this motivation, fully in line with the john’s scientific legacy, is reflected in the editorial choice of putting mini reviews close to research papers, pointing to the fruitful interaction between experts in the different topics and younger colleagues, in order to widen their expertise, and to acquaint them with the most accurate and/or recent approaches. finally we would thank the people, who made it possible to organize the conference and to disseminate what has been achieved. first of all, we are pleased to express our gratitude, for both the financial support and the warm and generous hospitality, to the “european centre of theoretical studies in nuclear physics and related areas”, in trento. in particular, we acknowledge prof. achim richter, director of ect∗, the scien- tific board, and the staff. secondly we are very indebted to few-body systems, that offered the possibility of publishing this special issue, with a particular mention of the passion, the continuous help and advice of dr. bernard bakker, editor in chief. last but not least, we would like to warmly acknowledge all the partic- ipants, since, thanks to them, the discussions and the presentations were alive and fruitful, and this issue has come into the world. 	foreword << /ascii encodepages false /allowtransparency false /autopositionepsfiles true /autorotatepages /none /binding /left /calgrayprofile (gray gamma . ) /calrgbprofile (srgb iec - . ) 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setdistillerparams << /hwresolution [ ] /pagesize [ . . ] >> setpagedevice games:science:science_magazine_ - :root:data:science_ - :pdf: _v _n :p _ .pdf [ganino] ganino user tools 	register 	log in site tools search tools show pagesource old revisions backlinks recent changes media manager sitemap register log in > 	recent changes 	media manager 	sitemap trace: games:science:science_magazine_ - :root:data:science_ - :pdf: _v _n :p _ .pdf this topic does not exist yet you've followed a link to a topic that doesn't exist yet. if permissions allow, you may create it by clicking on create this page. page tools 	show pagesource 	old revisions 	backlinks 	back to top pms utility and quality of life of patients with osteoarthritis treated with the cyclooxygenase inhibiting nitric oxide donator (cinod) naproxcinod abstracts a symptom). the health assessment questionnaire (haq) was used to measure func- tional status (scores – ). qol was measured by the mental (mcs) and physical (pcs) component summary scores of the short form- (sf- ). work/productivity loss was measured by the work productivity and activity impairment (wpai) instrument. comparisons were made between patients who currently use sc biologics versus those who discontinued treatment. results: of the , survey respondents ( % female; average age . years), ( . %) used sc biologics. the average dura- tion of ra was . years, with % reporting severe disease. the patient-reported mean scores were: morning stiffness . , fatigue . , pain . , haq . , mcs . and pcs . . patients reported . % work impairment and . % impairments in daily activity. patients who had discontinued sc biologic therapy (n , . %) reported signifi cantly worse scores in morning stiffness, fatigue, pain, and pcs (all p . ) versus patients currently treated with sc biologics (n , . %). patients who discontinued therapy had more work/activity loss; only activity impair- ment was statistically signifi cant (p . ). there was no signifi cant difference in haq scores between groups. conclusions: ra patients using current sc biolog- ics still suffer from serious impairments in symptoms, functional status, qol, and work/productivity. however, patients who discontinued sc biologic therapy have sig- nifi cantly worse symptom scores, physical functioning, and activity impairment com- pared with those currently being treated. both fi ndings indicate there is still an unmet medical need in ra patients. pms utility and quality of life of patients with osteoarthritis treated with the cyclooxygenase inhibiting nitric oxide donator (cinod) naproxcinod jonsson b , pfi ster p , holmstrom s , kobelt g uppsala university, uppsala, sweden, nicox, sophia antipolis cedex, france, nicox, sophia antipolis, france, european health economics, speracedes, france objectives: to estimate changes in quality of life (sf ) and utility (sf ) in patients treated with naproxcinod, naproxen or placebo for weeks, and to explore the effect of different disease measures on utility. methods: sf was available from international ph clinical trials in patients with knee or hip osteoarthritis comparing doses of naproxcinod ( and mg bid) to naproxen ( mg bid) and placebo. effi cacy was based on the pain, function and composite scales of the womac™ osteoarthritis index. co-morbidity measures included hypertension (ht) which increases with nsaid therapy, body mass index (bmi) and diabetes. changes in sf and individual sf domains were compared between the groups using anova and dunett’s -sided test. the effect of the womac™ indices, bp, bmi and diabetes on utility scores was explored using multiple regression analysis. results: all sf subscales except mental health as well as utility changed signifi cantly from baseline for all groups, and were correlated with changes in the womac™ indices (p . ). the change in the active groups was signifi cantly better than placebo for pain and physical function ( . ), but not signifi cantly different between treatments. however, absolute changes in utility, pain, physical function and general health were generally larger for naproxcinod mg than naproxen mg by around %. utility scores correlated signifi cantly with womac™, and patients with high bmi and bp or diabetes had lower utility scores and worse womac™ indices. increase in utilities were larger for patients with mg naproxcinod than for the other groups. conclusions: the slightly larger utility and quality of life changes with naprox- cinod mg despite a similar effect as naproxen on womac™ may be explained by a different side-effect profi le and a neutral blood pressure effect. pms an assessment of self reported outcomes in a nationally representative sample of elderly person diagnosed with rheumatoid arthritis rajpura jrjp j st. john’s university, fresh meadows, ny, usa objectives: to utilize webtv technology as a tool to measure hrqol in elderly persons having rheumatoid arthritis (ra) in a nationally representative sample and to describe their socio-demographic characteristics, medication use and other treat- ment choices. methods: a cross- sectional online survey research design. random digit dialing (rdd) survey procedures were used to draw a sample of elderly arthritic individuals from us households across states. a subsample of individu- als previously diagnosed with ra completed sf- v survey, as part of a larger study. eight sf- domain scores and physical and mental component summary (pcs and mcs) scores were computed and compared with cross-sectional norms for general us population. results: compared to the general population, our study sample per- formed poorly with respect to all the sf- domains except mental health (mh) and social functioning (sf) domains. ra is more prevalent in whites ( %) and males reported higher scores for all the eight sf- domains than females. about % of the sample reported the use of at least one available otc arthritic medication; % of the sample was taking prescription drugs, while about % reported having used natural/herbal remedies for arthritis. a signifi cant difference (p . ) was found between males and females with respect to only pcs scores. age was found to correlate negatively (p . ) with pcs and mcs summary measures, particularly for indi- viduals years and older. conclusions: webtv is an effective survey administra- tion tool for measuring hrqol. as expected, elderly perform poorly on three of the sf- domains (pf, rp, bp) having the most physical factor content. prescription drug use is fairly prevalent and use of otc medications and other forms of treatment is popular in the population under study. pms the effect of lifestyle choices on the risk of impairment in rheumatoid arthritis patients: an analysis of aerobic exercise and cigarette smoking shah a , plumb j , brawer r , tang b thomas jefferson university, philadelphia, pa, usa, centocor ortho biotech, inc, horsham, pa, usa objectives: through data analysis we will examine and identify the lifestyle factors that impact clinical outcomes of rheumatoid arthritis (ra) patients. methods: patients’ self-reported data was collected from the ra patient survey, an internet survey of ra patients. we studied the effects of aerobic exercise ( minutes a day per month), and cigarette smoking on ra patients. sign and symptom scores for morning stiffness, fatigue, and pain are defi ned from (no symptom) to (severe symptom) within the survey. the health assessment questionnaire (haq) was used to measure functional status scores ( – ). quality of life was measured by the mental component score (mcs) and physical component score (pcs) of the short-form (sf- ). productivity was measured by the work productivity and activity impairment (wpai) scale. there were no non-ra controls included in the study. results: a total of respondents were included in the analysis patients exercised and patients smoked cigarettes. the average age was . years and average ra duration was . years. patients’ mean mcs and pcs scores in the exercise ( . , . ) and non-smoking groups ( . , . ) were signifi cantly higher, than in the non- exercise ( . , . ) and smoking groups ( . , . ). overall work and productivity impairment was . % (exercise) versus . % (non-exercise), and . % (smoking) versus . % (non-smoking). signs, symptoms, and haq scores were signifi cantly better in the exercise and non-smoking groups (all p . ). conclusions: ra patients who exercise regularly have higher quality of life scores and clinical outcomes. those that smoke cigarettes have lower quality of life scores and higher symptom/ haq scores suggesting that this habit may be detrimental to their clinical outcomes. these results suggest that these lifestyle choices infl uence the overall risk of impairment in ra patients. pms is the health utilities index valid and responsive in assessing patients with ankylosing spondylitis? gooch k , feeny dh , wong r , pangan a , revicki d , van der heijde d abbott laboratories, abbott park, il, usa, kaiser permanente center for health research, portland, or, usa, abbott laboratories, parsippany, nj, usa, united biosource corporation, bethesda, md, usa, leiden university medical center, leiden, netherlands objectives: qalys are an important outcome used in cost-effectiveness analysis. the health utilities index mark (hui- ) is a self-reported measure covering attri- butes of health status. our objective was to assess construct validity and responsiveness of hui- in ankylosing spondylitis (as). methods: data were derived from the adalimumab trial evaluating long-term effi cacy and safety in as (atlas). we speci- fi ed a priori hypotheses regarding the direction and magnitude of associations expected between overall and single-attribute hui- scores and other health status and quality of life measures—sf- , asqol, bath as functional index (basfi), bath as disease activity index (basdai), and patient’s global assessment (pga). using baseline data, we calculated correlation coeffi cients and interpreted them via guidelines suggested by guyatt for negligible, weak, moderate, and strong associations. responsiveness was assessed by calculating standardized response means (srms) of hui- scores from baseline to week for patients meeting the minimum clinically important differences (mcid) for the asqol ( . ). responsiveness analysis was limited to patients with -week hui- scores. results: a total of of the patients enrolled in atlas were included in the analysis. mean age was years, . % were male, and mean duration of as was years. correlation coeffi cients between hui- scores and other instruments confi rmed . % of the a priori hypothesis, with an additional . % being under- or over-estimated by only one category. results of responsiveness analysis demonstrated that there were signifi cant differences in overall hui- (srm . ) and most single-attribute change scores for patients whose changes were greater than the asqol mcid vs. those whose changes were mcid. conclusions: these results suggest that hui- constructs are related to similar constructs in other measures, as expected. this study provides evidence of cross-sectional and longitudinal construct validity of the hui- for deriving utility scores for as patients. pms validation of the multi-attribute health utility (mahu) derived from a computer adaptive instrument, cat- d-qol, in osteoarthritis kang wg , sayre ec , steininger g , doerfl ing p , ratzlaff c , esdaile j , kopec j university of british columbia, vancouver, bc, canada, arthritis research centre of canada and simon fraser university, vancouver, bc, canada, arthritis research centre of canada, vancouver, bc, canada objectives: we aimed to validate the multi-attribute health utility (mahu) derived from the cat- d-qol, a computer-adaptive instrument composed of domains (walking, handling objects, daily activities, pain/discomfort, and feelings) in people with self-reported osteoarthritis (oa), and to compare it with womac_hui , the utility derived from the standard disease-specifi c measure in oa. methods: data were collected from participants (age ) who completed questionnaires cat- d- qol in two waves and womac in one wave of a canada-wide online survey. to assess construct validity, we used multivariable regression to examine the associations /home/www/ftp/data/hep-lat/dir_ / .dvi physics development of web-based tools for use in hardware clusters doing lattice physics p. dreheramit]mit laboratory for nuclear science, massachusetts institute of technology, cambridge, ma ∗† ‡, w. akersbjlab]thomas jefferson national accelerator facility, newport news, va §, j. chenc[jlab]§, y. chend[jlab]§, c. watsone[jlab]†§ a[ b[ abstract: jefferson lab and mit are developing a set of web-based tools within the lattice hadron physics collaboration to allow lattice qcd theorists to treat the computational facilities located at the two sites as a single meta-facility. the prototype lattice portal provides researchers the ability to submit jobs to the cluster, browse data caches, and transfer files between cache and off-line storage. the user can view the configuration of the pbs servers and to monitor both the status of all batch queues as well as the jobs in each queue. work is starting on expanding the present system to include job submissions at the meta-facility level (shared queue), as well as multi-site file transfers and enhanced policy-based data management capabilities. . the meta-facility concept the next generation of computers for lattice calculations and other grand challenge type nu- merical simulation problems will be constructed with multi-teraflops computing capabilities. such machines dedicated to a particular grand chal- lenge problem may not be geographically located at a single site. the thomas jefferson national accelerator facility and the mit laboratory for nuclear science have undertaken a joint project to develop a meta-facility for lattice physics cal- culations at a geographically dispersed facility. a “meta-facility” for lattice physics will consist of a set of tools and utilities that allow for the effi- cient distribution of of data and computing tasks among multiple lattice gauge facilities. the goals ∗support provided through the u.s. department of en- ergy cooperative agreement de-fc - er †member, lattice hadron physics collaboration ‡poster presenter §this work was supported by the u.s. department of energy contract de-ac - er , under which the southeastern universites research association (sura) operates the thomas jefferson national accelerator fa- cility of the meta-facility will provide a central location for users to submit and monitor these jobs, collect and distribute data generated from these comput- ing activities, and status of the overall status of the hardware interconnected to the meta-facility. the full implementation of the meta-facility will have the capability of providing a primary routing mechanism to provide users with the abil- ity to run jobs at one of several sites according to the resources currently available at any given time. at each site, there will be a batch system that accepts jobs from the central routing queue. a distributed batch system at each site will queue the job(s) sent to each site and control the exe- cution of the jobs on the machines at that site. the distributed batch system at each site will also communicate with the central routing queue pro- viding job status and control information to the routing queue. . the present jlab-mit facil- ity at the present time, jlab and mit have devel- oped an initial set of web-based tools and utilities that have been installed at both sites. this ini- tial software deployment will become part of the design toward an eventual full implementation of a meta-facility at both sites. these web based tools have installed to monitor the clusters of machines at both jlab and mit. these machines currently have a mix of different capabilities and configurations. jefferson lab presently has two clusters oper- ational. the first cluster consists of xp nodes from compaq. the xp is a bit alphaa processor ( mhz)with a mb l cache and kb on chip cache, a mhz sdram subsystem and integrated gb wide- ultra scsi ( rpm) disk subsystem with dual independent / bit pci buses. eight of the xp nodes are have myrinet cards installed, the nodes are connected to a myrinet switch. the second cluster consists of dual processor up from api labs. the up- systems have dual mhz processors with mb caches, mb memory, and an gbide disk ( rpm) at mit, the are twelve compaq es ma- chines. each es machine has four ev- mhz alpha processors and gbyte of memory in an smp configuration within each box. the twelve es s are connected by both myrinet hardware and fast ethernet. there are also ad- ditional intel based pcs that serve as backup, file and batch servers at this site. this entire set of machines is positioned behind an intel based front-end machine. this front end machine serves the functionality of a firewall and as a repository for the web-based tools and utilities the current capabilities of the present sys- tem allow users at either the jlab or mit sites to launch and monitor batch jobs and examine batch queue parameters and machine status. the jlab site also has the capability to allow users to browse the tape file catalog and initiate file trans- fers from to and from the jlab tape storage fa- cilities. at the present time there is a certificate server operational at jlab with the capability of issuing a personal web certificate for enhanced se- curity for users submitting jobs to that site. . future plans and enhance- ments the present configuration that is operational at jlab and mit has demonstrated a proof of concept. the batch system execution queues at both the jlab and mit sites operate properly and a web based link has been established be- tween both sites that provides information on the status and batch jobs running on all clusters. the project will be moving forward with two ma- jor upgrade tasks scheduled over the next several months. - at the present time, batch job submission via the web is limited to the jlab site. web services for batch submission of jobs at the mit site will be installed in the fall of . - tape transfers at both jlab and mit involve a two-stage process because of the front-end ma- chines acting as firewalls at both sites. work is ongoing to develop full tape file transfer capabil- ity at both sites after these immediate tasks have been com- pleted and are operational, there are several longer term activities planned for development and implementation of a fully functional meta- facility. at both the mit and jlab sites, only the exe- cution queues have been configured in the batch queuing system at each site. the ultimate goal is to develop and install a separate node in the meta-facility that will be dedicated to the func- tionality of a routing queue. the routing queue would not be attached to any of the individual clusters in the meta-facility but would rather view all of the execution queues on every cluster at all sites throughout the meta-facility. the routing node will act as a separate communications and traffic manager. users would only submit jobs to the node that was running the routing queue system software. the routing queue would have the configuration parameters of each execution queue and commu- nicate with all of the various execution queues located throughout the entire system. based on the job requirements, the routing queue would examine systems loads and available resources throughout the entire meta-facility and direct the job to the execution queue on the cluster with the most available resources. at this point additional sites beyond the jefferson lab and mit locations would be added. finally, the routing queue will be integrated with future data grid software currently being developed using java and xml-based web ser- vices [ ]. the final system will be a web-based distributed data grid that is site independent. it will include a distributed batch system aug- mented with various monitoring tools and man- agement options to deliver a full production level meta-facility for lattice physics. references . w. watson, i. bird, j. chen, b. hess, a. kowalski, y. chen, a web services data analysis grid, submitted to concurrency and computation: practice and experience wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ la révolution de haïti vue par deux personnages contemporains: le scientifique prussien alexander von humboldt et l'homme d'état américain thomas jefferson la révolution de haïti vue par deux personnages contemporains: le scientifique prussien alexander von humboldt et l'homme d'état américain thomas jefferson sandra rebok french colonial history, volume , , pp. - (article) published by michigan state university press doi: for additional information about this article [ this content has been declared free to read by the pubisher during the covid- pandemic. ] https://doi.org/ . /fch. . https://muse.jhu.edu/article/ https://doi.org/ . /fch. . https://muse.jhu.edu/article/ · · · · · · sandra rebok studied sociology and anthropology in heidelberg, madrid, and paris. in she completed her ph.d. at the university of heidelberg with a dissertation entitled “alexander von humboldt and spain in the th century: analysis of the reciprocal perceptions” (vervuert, ). since she has been working at the history of science department of the spanish council for scientific research in madrid (csic), in a research project about alexander von humboldt’s stay in spain in and his posterior relationship to this country. the results of this research have been, besides numerous publications, the translation and edition of several documents previously unknown in spain. furthermore, together with her colleague dr. miguel Ángel puig-samper, she is the curator of a traveling exhibit about humboldt and spain, which was organized by the cervantes institute of madrid and has been presented in berlin, munich, bremen, manchester, london, and vienna. additional research includes the study of the perceptions of german travelers in america and the new world, and transatlantic communication during the enlightenment, particularly between alexander von humboldt and thomas jefferson. for the past three years, rebok has also been working on a project on scientific german and french travelers in spain in the nineteenth century. french colonial history, vol. , , pp. – . issn - . © french colonial historical society. all rights reserved. la révolution de haïti vue par deux personnages contemporains: le scientifique prussien alexander von humboldt et l’homme d’état américain thomas jefferson sandra rebok the haitian revolution was a historical event that immediately provoked numerous and very different reactions in the new as well as the old world. it can be regarded as an ideological laboratory for enlightenment actors, in which they tested how far their principles of liberty, equality, fraternity, and the right to revolt against oppression extended. their reactions were tightly linked to their personal interests and convictions and their relationship to the political system they inhabited. this study analyzes the different points of view of two personalities with a significant influence on the events and the spirit of their time: the famous traveler and prussian scientist alexander von humboldt ( – ) and the sandra rebok virginian statesman thomas jefferson ( – ). emphasis will be on their perception of the incidents in saint-domingue and their impact on the outer world, the way they referred to these events in their writings and their personal correspondence, and finally the position they took regarding the new situation of this caribbean island. i. introduction la révolution de saint-domingue, la première révolution menée par une société noire et esclave, constitua un événement dont l’impact fut immédiat dans la région. la population esclave y trouva un exemple de ce qu’elle était capable d’obtenir. les habitants blancs s’aperçurent, quant à eux, du résultat auquel pouvait aboutir le colonialisme établi par eux et, en particulier, l’inhumain sys- tème d’esclavage tellement répandu à cette époque. la conséquence principale fut un grand sentiment de peur parmi les blancs, mais elle fut aussi à l’origine de réflexions sur la manière de prévenir de semblables développements dans la région, c’est-à-dire, sur la création de mesures ou des réformes pour obtenir un système d’esclavage moins inhumain, plus efficace et surtout plus stable. ces événements provoquèrent ainsi de nombreuses réactions et des réponses différentes, non seulement au nouveau monde, affecté d’une façon plus im- médiate, mais aussi sur l’ancien continent. la révolte de saint-domingue (ou de haïti, nom pris par le pays lors de sa déclaration d’indépendance à partir de ) attira ainsi beaucoup l’attention, car elle réunissait des thèmes divers très discutés à cette époque et sujets à polémique: le colonialisme comme institution européenne étendu au reste du monde, les mouvements indépendantistes qui se développèrent en réaction, le système de l’esclavage, les buts et les résultats de la révolution française ainsi que la réalisation ou la mise en pratique des idéaux humanistes du siècle des lumières. on peut dire que la révolution haïtienne se présentait comme une provocation idéologique pour les hommes éclairés, un test pour voir jusqu’où vont leurs principes de liberté et d’égalité ainsi que le droit de se révolter contre une situation d’abus de pouvoir. les différentes réactions étaient donc étroitement liées à des intérêts et à des convictions personnelles comme aux relations entretenues avec le système politique dans lequel ils vivaient. la présente étude analyse les regards différents de deux personnages qui ont eu une influence remarquable sur les événements et sur l’esprit de l’époque: le la révolution de haïti vue par deux personnages contemporains fameux voyageur et scientifique prussien alexander von humboldt ( – ) et l’homme d’état virginien thomas jefferson ( – ). nous nous intéressons à la manière dont ils perçurent la révolution de saint-domingue et son impact sur le reste du monde, à la manière dont ils y firent référence dans leurs écrits ou dans leurs lettres et à la position ou l’action qu’ils développèrent concernant la nouvelle situation de cette île des caraïbes. après son expédition à travers l’amérique espagnole durant les années à , alexander von humboldt, accompagné de son collègue français aimé goujand bonpland, visitait les États-unis du mai au juin , ou il ren- contra plusieurs fois le président américain thomas jefferson et les membres de son cabinet. les motivations et les intérêts de humboldt pour sa visite aux États-unis reposaient sur deux intentions. tout d’abord, il voulait connaître personnellement jefferson, connu pour être un scientifique et un philosophe. ensuite, après avoir voyagé durant des années à travers les colonies espagnoles du nouveau monde et observé les différentes sociétés coloniales, dont cer- taines possèdent des caractéristiques critiquables, humboldt était intrigué par l’opportunité de se familiariser avec un pays libre en amérique. durant son séjour aux États-unis, humboldt resta principalement au con- tact d’hommes politiques et de l’élite scientifique du pays. il passa tout d’abord une semaine à philadelphie, où il s’entoura principalement de membres de la american philosophical society. ensuite, il voyagea à washington, où il resta du er au juin. il visita également alexandria et mount vernon durant cette période. humboldt rencontra jefferson la première fois probablement le juin, et durant ce séjour, il fit la connaissance de james madison, gilbert stuart, william thornton et albert gallatin. lorsque humboldt retourna à philadelphie, il y resta encore dix jours avant de repartir pour l’europe. antérieurement à cette première rencontre, humboldt écrivit une lettre à jefferson et exprima son admiration et respect pour son intellect développé, son travail, et ses idées libérales. influencé par son identification à des idéaux du mouvement indépendant américain, ainsi qu’aux buts de la révolution française, humboldt fut très impressionné par la forme démocratique de la société américaine, qu’il percevait comme une possibilité pour d’autres régions américaines ainsi que pour des nations européennes. jefferson, pour sa part, pensa également que humboldt pouvait lui apporter quelque chose de particulièrement intéressant. la documentation et les cartes des archives coloniales espagnoles contenant des données jusqu’alors inconnues sandra rebok sur les frontières entre les États-unis et le nouvel espagne pourraient en effet avoir beaucoup de valeur. cette information pourrait être très importante à cause du fait de l’acquisition récente du territoire de louisiane. humboldt se conforma au désir de thomas jefferson de voir cette documentation, lui permet- tant de connaître les dernières informations géographiques et statistiques de la nouvelle espagne. a partir de cette brève entrevue, une amitié de longue date se développa entre les deux hommes, marquée par des échanges d’idées dans leur correspondance, ainsi que dans leurs ouvrages. l’attitude de alexander von humboldt sur le colonialisme est connue grâce à cette unique expédition dans les colonies espagnoles. dans ces régions il put appréhender le système colonial avec tous ses inconvénients et ses problèmes pour la population opprimée ou rendue esclave, juste avant que les mouvements indépendantistes n’apparaissent dans ces territoires. dans ses nombreux ouvrages, et plus encore dans ses journaux de voyage, il offre des élaborations scientifiques détaillées sur cette exploration, mais aussi des réflexions plutôt critiques sur les diverses facettes du système colonial. en raison de ses propres convictions humanistes, humboldt n’était pas du tout d’accord avec cette institution, comme il l’exprime dans ses journaux: d’où vient ce manque de moralité, d’où viennent ces souffrances, ce malaise dans lequel tout homme sensible se trouve dans les colonies européennes? c’est que l’idée de la colonie même est une idée immorale, c’est l’idée d’un pays qu’on rend tributaire à un autre, d’un pays dans lequel on ne doit parvenir qu’à un certain degré de prospérité, dans lequel l’industrie, les lumières ne doivent se répandre que jusqu’à un certain point [ . . . ] tout gouvernement colonial est un gouvernement de méfiance. on y distribue l’autorité non selon que la félicité publique des habitants l’exige, mais selon le soupçon que cette autorité peut s’unir, s’attacher trop au bien de la colonie, devenir dangereux aux intérêts de la mère patrie. ces lignes témoignent des convictions de humboldt, connu comme un farouche adversaire du système d’esclavage, sa réaction aux événements qui se produisirent à haïti nous intéresse donc tout particulièrement. la révolution de haïti vue par deux personnages contemporains le regard de thomas jefferson sur ces événements nous fournit un point de vue issu du nouveau monde. avec lui on voit la réaction du prési- dent des États-unis—c’est-à-dire de la première république indépendante de cet hémisphère—au moment crucial de la révolution haïtienne, et dans les premières années après la déclaration d’indépendance de haïti en . dans sa fonction d’un des founding fathers et auteur de la déclaration d’indépendance des États-unis, jefferson était convaincu de la nécessité des futures révolutions non seulement dans les régions coloniales d’amériques, mais aussi dans les monarchies absolutistes en europe. il était, d’une certaine façon, considéré comme un promoteur ou inspirateur de ces mouvements. ses préoccupations se manifestent dans ses écrits, notamment dans sa vaste correspondance. en parlant de la situation tumultueuse en hollande et france, dans une lettre à tench coxe, le juin , il constate: this ball of liberty, i believe most piously, is now so well in motion that it will roll round the globe, at least the enlightened part of it, for light & liberty go together. it is our glory that we first put it into motion & our happiness that being foremost we had no bad examples to follow. pourtant, jefferson était aussi un grand propriétaire d’esclaves; il profitait donc lui aussi de cette institution inhumaine. l’esclavage aux États-unis fut cependant pour lui et durant sa vie une telle préoccupation, qu’il présenta plusieurs propositions pour le supprimer. la révolution menée par les noirs à saint-domingue était un test crucial pour le droit à la révolution de chaque peuple, droit qu’il défendait lui-même. il est finalement intéressant de voir jusqu’à quel point ces deux personnages représentent le regard du nouveau continent sur ces événements comparé à celui de l’ancien continent. c’est de notoriété publique que humboldt et jefferson étaient des supporteurs des idéaux éclairés existants au début de la révolution française, même s’ils n’étaient pas du tout d’accord avec ses réper- cussions sanglantes. ils partageaient donc un point de départ idéologique com- mun; pourtant, comme on le verra par la suite, les deux hommes appartenaient à des contextes sociopolitiques différents, qui déterminaient sans doute leur argumentation et leur action. sandra rebok ii. deux regards différents sur la révolution haïtienne alexander von humboldt en général, on peut dire que alexander von humboldt représentait la tradition du siècle des lumières et à plusieurs occasions lui-même reconnaît qu’il portait « les idées de dans son cœur », c’est-à-dire, qu’il conserva toute sa vie une conscience spéciale des principes fondamentaux de liberté, d’égalité et de fraternité, sur lesquels il construisit sa propre philosophie. pourtant, il faut souligner claire- ment qu’il n’a jamais approuvé l’intransigeance révolutionnaire des jacobins. la terreur de la révolution française comme les événements en haïti et d’autres révoltes d’esclaves l’inquiétaient beaucoup, si bien qu’en plusieurs occasions il avertit du danger de réactions violentes en amérique. selon les convictions de humboldt, ces réactions ne pouvaient jamais mener à la construction d’une société progressive. bien que critiquant sévèrement le colonialisme, en faisant mention des possibles conséquences qui pouvaient résulter de la situation sociale et politique de cette époque, il ne se montre en aucune façon en faveur d’une solution militaire. il rejette toute forme de révolution violente comme moyen politique. cependant il fait des propositions détaillées sur des gouvernements et des institutions établies par de possibles réformes, car il était convaincu que l’origine de beaucoup de ces problèmes se trouvaient dans l’administration: les gouvernements européens ont si bien réussi à répandre la haine et la désunion dans les colonies qu’on n’y connaît presque pas les plaisirs de la société; du moins tout divertissement durable dans lequel beaucoup de familles doivent se réunir est impossible. de cette position naît une confusion d’idées et de sentiments inconcevables, une tendance révolutionnaire générale. mais ce désir se borne à chasser les européens et à se faire après la guerre entre eux. il faut dire que humboldt était plutôt prudent dans ses commentaires en ce qui concernait la situation politique des régions qu’il visitait en amérique. comme scientifique il ne voulait pas trop se mêler de ce terrain compliqué et éviter de possibles conflits avec les autorités locales. mais c’est aussi sans doute en remerciement de l’autorisation généreuse qui lui était concédée par le roi espagnol carlos iv. dans ses journaux de voyage, on trouve également peu de commentaires explicites qui montrent son opinion sur les premiers signes de la demande de liberté dans les régions visitées. sa conviction que les colonies espagnoles pourraient être dans une situation économique beaucoup plus la révolution de haïti vue par deux personnages contemporains favorable si elles obtenaient leur indépendance vis-à-vis des intérêts financiers de la métropole, peut seulement être dérivée d’une analyse économique détaillée des statistiques du commerce. aussi à l’égard des événements en haïti, on ne trouve aucun commentaire dans la partie de ses journaux déjà publiée—un fait qui peut paraître étonnant, car l’expédition de humboldt était justement réalisée dans les années qui cor- respondent à la proclamation de liberté et d’indépendance de l’état de haïti en . un espoir subsiste néanmoins de découvrir des documents. ulrike leitner a récemment découvert pages avec des annotations inconnues faites par humboldt sur cuba, document trouvé à la biblioteka jagiellonska de cracovie. ce matériel portant le titre « isle de cuba. antilles en général » n’a pas encore été publié—et n’a donc malheureusement pu être consulté pour cette recherche. selon michael zeuske, il contient aussi des informations en relation avec saint-domingue. dans les oeuvres publiées par humboldt, on ne trouve pas de traité ou de longues réflexions sur les événements en haïti qui puissent révéler son attitude à l’égard de ce sujet, seules quelques références à saint-domingue avec de brefs commentaires sur l’influence possible ou le danger que cela pouvait avoir pour le reste de l’amérique coloniale. les deux ouvrages qui contiennent ces remarques sont les deux essais régionaux sur la nouvelle espagne et celui sur cuba; en revanche on n’en trouve aucune trace dans son récit de voyage voyage aux régions équinoxiales du nouveau continent. dans le premier essai, celui sur la nouvelle espagne, il mentionne les «  événements tragiques  » de la révolution de saint-domingue et regrette qu’apparemment la peur de ces événements prenne le pas dans la société sur les considérations morales, les principes philanthropes et ceux de justice qu’ils auraient pu susciter: [ . . . ] tant il est vrai que la crainte des maux physiques agit plus puissamment que les considérations morales sur les vrais intérêts de la société, ou les principes de la philanthropie et de justice, si souvent énoncés au parlement, à l’assemblée constituante et dans les ouvrages des philosophes! vers la fin de cette oeuvre il prévoit les futurs changements en amérique et se montre en cette occasion plutôt optimiste, car il voyait dans ces incidents haïtiens une influence positive sur la réduction du trafic de la population noire. sandra rebok a part ces commentaires, c’est surtout dans son traité sur cuba qu’il intègre les résultats de la révolution haïtienne dans sa propre argumentation. il faut d’abord rappeler que humboldt avait consacré beaucoup d’effort à la lutte contre l’esclavage, spécialement à cuba mais aussi aux États-unis. il proposa de nom- breuses réformes pour réduire et finalement supprimer cette institution atroce, qui contredisait pour lui tous les idéaux du siècle des lumières. parfaitement conscient que ses arguments humanistes n’emportaient pas la conviction de tous, il fait porter son argumentation sur le terrain économique. son étude sur cuba, et en particulier le chapitre sur l’esclavage, contient de nombreux avertissements sur ce qui pourrait se passer à cuba, au cas où on ne saurait pas interpréter les signes de haïti: si la législation des antilles et l’état des gens de couleur n’éprouvent pas bientôt des changements salutaires, si l’on continue à discuter sans agir, la prépondérance politique passera entre les mains de ceux qui ont la force du travail, la volonté de s’affranchir et le courage d’endurer de longues privations. cette catastrophe sanglante aura lieu comme une suite nécessaire des circonstances, et sans que les noirs libres de haïti s’en mêlent aucunement, sans qu’ils abandonnent le système d’isolement qu’ils ont suivi jusqu’ici. il continue son argumentation en critiquant la position de la population blanche, qui selon lui, n’était pas consciente de l’urgence de résoudre ce problème: toute similarité d’action de la part des noirs leur paraît impossible; tout change- ment, toute concession accordée à la population servile, un signe de lâcheté. rien ne presse: l’horrible catastrophe de saint-domingue n’a été que l’effet de l’inhabileté des gouvernants. on voit dans ces deux citations que humboldt considérait les incidents en haïti comme « l’horrible catastrophe » ou comme une « catastrophe sanglante ». avec ce jugement il ne se réfère pas aux résultats de ce mouvement, car il le considère comme « une suite nécessaire des circonstances », mais au processus violent qui leur a donné lieu et qui devait être évité à tout prix. comme on l’a déjà vu, il s’exprime toujours contre une solution violente, et croit en revanche profondément à la force des idées éclairées et humanistes. par conséquent, il valorise fortement la reconnaissance de l’état de haïti par le gouvernement français: la révolution de haïti vue par deux personnages contemporains espérons que la force de l’opinion publique, le progrès des lumières, l’adou- cissement des mœurs, la législation des nouvelles républiques continentales, et le grand et heureux événement de la reconnaissance d’haïti par le gouvernement français, exerceront, soit par des motifs de prévoyance et de crainte, soit par des sentiments plus nobles et plus désintéressés, une influence heureuse sur l’amélioration de l’état des noirs dans le reste des antilles, dans les carolines, les guyanes et le brésil. humboldt expose très clairement l’influence de cette révolution sur la situation des esclaves dans d’autres régions. pour lui ce thème est tellement important qu’il le reprend à la fin de son essai sur cuba et finit cet ouvrage avec des réflexions au sujet de haïti. il rappelle la situation de haïti comme « centre de grandes agitations politiques », qui menaçait de susciter dans les autres îles des luttes sanglantes que humboldt réprouvait: ces menaces et ces craintes n’ont heureusement pas été accomplies; l’orage s’est apaisé dans les lieux mêmes qui l’ont vu naître, et une population noire libre, loin de troubler la paix des antilles voisines, a fait quelques progrès vers l’adoucissement des mœurs et l’établissement de bonnes institutions civiles. finalement, humboldt se montre content du développement de ce proces- sus pendant les ans qui ont suivi la première révolution de haïti, pour les habitants de cette île, mais aussi pour les hommes blancs des îles espagnoles et anglaises. il prévenait cependant d’une « funeste sécurité qui s’oppose avec dédain à toute amélioration dans l’état de la classe servile », car comme le rappelle la conclusion de son livre, « la crainte du danger arrachera des concessions que réclament les principes éternels de la justice et de l’humanité. » il ne s’agit pas d’une étude approfondie sur cette question, ni de considérations sur les causes et les conséquences de ces événements, mais plutôt d’une application des résultats de la révolution haïtienne sur la situation de cuba. de cette manière, il inclut ces incidents, et la peur qu’ils ont provoquée parmi la population blanche, dans sa lutte contre l’esclavage, c’est-à-dire, qu’il les intègre à sa démonstration. selon zeuske, la clé de l’intérêt de humboldt pour l’esclavage ne se trouve ainsi pas directement à cuba, mais dans la révolution sandra rebok de saint-domingue. pour cela, les réflexions de son essai cubain peuvent être entendues comme un appel aux personnes éclairées et instruites parmi l’élite cubaine qu’il avait connue personnellement dans cette île, comme par exemple francisco de arango y parreño ( – ). thomas jefferson dans le cas de thomas jefferson, son attitude au sujet des événements de haïti est beaucoup plus complexe et davantage conditionnée par son statut de prési- dent des États-unis. son opinion personnelle, sur ce point, fait se rejoindre différents thèmes très importants à ses yeux: l’institution de l’esclavage, sa rela- tion à la population noire, la révolution comme moyen politique, ses idées pour l’avenir du nouveau monde, etc. ce sont ces différents aspects qui font du sujet haïtien un sujet assez compliqué pour lui. de plus, étant donné qu’il occupait dans les années – la tête du gouvernement, son opinion ne pouvait pas seulement être guidée par ses convictions personnelles, mais était en fonction d’un réseau d’intérêts divers. ces années virent de grands changements dans la politique intérieure et extérieure de son pays, changements qui eurent également une influence sur la position de jefferson. par conséquent, pour comprendre l’évolution de la politique de jefferson à l’égard de haïti, il est nécessaire de la replacer dans son contexte historique. a partir de , avec les premiers signes de cette révolte, jefferson commença à s’inquiéter du possible danger haïtien. sa réaction fut d’abord d’émettre des propositions pour une émancipation graduelle, comme on peut le voir dans une lettre de destinée à james madison où il parle du danger d’une insurrection inspirée par saint-domingue et où il conclut: « against this there is no remedy but timely measures on our part to clear ourselves by degrees of the matter on which that lever can work. » comme président, jefferson proposa un accord des puissances contre le régime de toussaint louverture, mais quand il devint conscient des vastes ambitions de bonaparte en amérique, il changea d’avis et refusa de tenir sa promesse d’aider les français. pendant les années de guerre de – , il suivit officiellement une politique de neutralité, mais en réalité cette posture cau- sait des problèmes aux français, car ils ne disposaient pas sur place des moyens suffisants pour cette expédition militaire et dépendaient de l’aide des américains. cette « neutralité » constituait, de fait, une aide considérable au régime haïtien. la révolution de haïti vue par deux personnages contemporains de cette manière, jefferson encourageait l’indépendance de saint-domingue à l’égard de la france, mais il refusa néanmoins en de reconnaître le nouveau régime, craignant l’influence de la révolution des esclaves haïtiens sur ceux qui se trouvaient aux États-unis. il proclama même un embargo sur le commerce avec l’île caraïbe, qui n’avait donc pas de légalité, jusqu’en . quand, avant la proclamation d’indépendance haïtienne en juin de , le général en chef de l’armée de saint-domingue, jean-jacques dessalines, lui envoya une lettre pour essayer de renouer les relations commerciales avec les États-unis et continuer les relations cordiales établies par john adams, il préféra ne pas répondre et de cette manière refusa l’opportunité d’établir des liens entre les deux pays. cette posture contredit son attitude comme secrétaire d’état en , quand il défendait la reconnaissance du gouvernement révolutionnaire français. elle est, de plus, en opposition avec les principes de la déclaration d’indépendance américaine en qui fixait le droit des peuples à changer un gouvernement oppresseur: that whenever any form of government becomes destructive of these ends, it is the right of the people to alter or to abolish it, and to institute new government, laying its foundation on such principles and organizing its powers in such form, as to them shall seem most likely to effect their safety and happiness. [ . . . ] but when a long train of abuses and usurpations, pursuing invariably the same object evinces a design to reduce them under absolute despotism, it is their right, it is their duty, to throw off such government, and to provide new guards for their future security. un point très important pour comprendre l’attitude de jefferson en ce qui concerne haïti concerne donc les rapports entre les États-unis et la france, et plus particulièrement, les intérêts de la république nord-américaine dans cette relation. au sujet de l’embargo, l’opinion publique était divisée sur l’opportunité et le bien-fondé d’entretenir des relations commerciales avec cette île. les sympa- thies de jefferson pour napoléon et le peuple français l’inclinaient à renoncer aux principes de neutralité qu’il avait énoncés comme un des axiomes de la politique nord-américaine. mais cette neutralité était par ailleurs très avantageuse pour les États-unis, car entre et ils étaient le plus important fournisseur de l’île, surtout en produits alimentaires. un autre aspect qui influe sur les relations avec la france, et par conséquent sur le sujet haïtien, concerne les intérêts du sandra rebok gouvernement nord-américain pour la louisiane et après l’achat de cette région en , ses ambitions pour obtenir la floride. l’embargo a été renouvelé d’une façon systématique jusqu’en , c’est-à-dire, le moment où les perspectives d’acquisition de la floride devenaient plus certaines. après cette date, le soutien de france ne lui paraissait plus indispensable, donc les commerçants pouvaient reprendre leur fructueux trafic avec haïti. les réactions des propriétaires d’esclaves du sud des États-unis sont un autre facteur dans la politique de jefferson face à haïti, surtout après les conspirations d’esclaves dans la région de richmond en et (gabriel plot et easter plot). la découverte de préparatifs pour une insurrection pro- voqua une grande peur parmi la population blanche de virginie, et déclencha en réaction une campagne de terreur contre les rebelles ou ceux soupçonnés tels. la loyauté de jefferson envers les planteurs de virginie était très forte; il pouvait comprendre leur peur et leurs phobies raciales—surtout qu’il était lui aussi un planteur des États du sud—et il se sentait donc obligé de défendre leurs droits. cela se manifeste dans une lettre à rufus king, où jefferson soulignait la vulnérabilité du sud de son pays, en disant: the course of things in the neighboring islands of the west indies appears to have given a considerable impulse to the minds of the slaves in different parts of the us. a great disposition to insurgency has manifested itself among them, which, in one instance, in the state of virginia broke out into actual insurrec- tion. this was easily suppressed, but many of those concerned, (between . & . i believe) fell victims to the laws. le président était obligé de prendre en considération les intérêts des expan- sionnistes, surtout après l’achat de la louisiane. sa politique face à l’esclavage dans les nouveaux territoires, et le fait qu’en il ne s’opposa finalement plus à l’extension de cette institution dans cette région, est un autre facteur lié à son attitude à l’égard de l’île caraïbe. jefferson était conscient que son attitude envers haïti n’était pas très cohérente et même plutôt ambivalente, mais souvent ses options étaient limitées et, dans autre cas, les changements dans sa politique étaient dictés par des considérations domestiques. la question de haïti montre clairement comment jefferson était la révolution de haïti vue par deux personnages contemporains tiraillé entre ses propres convictions et les conditions politiques de son époque, essayant de réconcilier les intérêts antagonistes existants aux États-unis—celui de maintenir l’esclavage dans le sud et les ambitions mercantiles du nord—pour ne pas risquer l’unité de son pays, tout en défendant les intérêts nord-américains au niveau géopolitique international. en conséquence, les convictions éclairées et les principes humanistes de jefferson se trouvaient subordonnés à des intérêts nationaux. ses convictions devaient s’effacer devant les ambitions économiques ou l’expansion de son pays. iii. analyse: le regard du vieux monde vers le regard du nouveau monde il serait très intéressant pour nous de savoir si alexander von humboldt et thomas jefferson discutèrent des événements de haïti quand ils se rencontrèrent à washington au printemps de ; malheureusement nous ne disposons pas de documents sur les thèmes qu’ils discutèrent pendant leurs réunions. il n’y a pas de référence non plus à ce sujet dans les lettres qu’ils échangèrent pendant les années suivantes, jusqu’à la mort de jefferson en , où ils commentent certains développements politiques. cela peut paraître étonnant, mais il faut savoir qu’il y a pas mal de thèmes « polémiques » comme par exemple l’esclavage, sur lesquels nous ne trouvons pas de commentaires dans leur correspondance. on peut supposer que tenant des positions très différentes en cette matière, ils préféraient éviter de se trouver dans un débat conflictuel. par contre, dans sa correspondance avec l’architecte william thornton ( – ), humboldt fait des références à l’esclavage échangeant informations et opinions. dans une lettre de juin il lui dit qu’il avait lu son mémoire sur les esclaves et dans ce contexte il se réfère à haïti où il constate que: « plus que les événements récents de s[an] domingue ont offusqué la vérité et plus il paraît du devoir de tout homme moral de replacer le problème dans son vrai jour ». afin de pouvoir comparer les positions de humboldt et jefferson, il faut d’abord être conscient des contextes différents dans lesquels ces deux personnages se trouvaient. humboldt comme scientifique pouvait approuver les buts et les résultats politiques de la révolution haïtienne—en refusant tous ses sandra rebok aspects violents—et faire état librement et publiquement de son opinion, puisque ces buts et ces résultats concordaient avec ses propres convictions humanistes. jefferson, par contre, dans sa fonction politique était obligé de réfléchir et de peser tous les conséquences de ses mesures en fonction de l’intérêt de son pays, des possibles réactions de ses adversaires, et finalement de l’influence de ses ac- tions sur les élections suivantes. humboldt regardait ainsi la révolution de haïti dans le contexte et en relation avec ses intérêts à cuba; jefferson, pour sa part, les reliait avec ses projets pour les États-unis, son intérêt lié avec la france, et particulièrement avec la situation des propriétaires d’esclaves. ces différences dans leur situation personnelle sont également évidentes dans leurs regards très distincts sur l’institution de l’esclavage. pour humboldt c’est l’antithèse de ses convictions personnelles, et à de nombreuses occasions il exprime son aversion pour cette institution inhumaine, particulièrement dans le septième chapitre de son oeuvre sur cuba qui est entièrement consacré à ce sujet. en ce qui concerne thomas jefferson ses commentaires sont assez ambivalents et souvent contradictoires, ce qui fait que le sujet a été beaucoup débattu parmi les historiens et a été source d’interprétations divergentes. son attitude évoluait avec le temps, comme on peut voir dans un grand nombre de ses lettres, dans son oeuvre notes on the state of virginia, et dans son autobiographie écrite en . a part ses premières initiatives pour l’affranchissement des esclaves et sa conviction ultérieure que cela pouvait résoudre les problèmes pour les générations futures, on peut également trouver dans ses ouvrages certaines affirmations qui peuvent être interprétées comme racistes ou supportant l’esclavage. finalement, il était lui-même un des plus grands propriétaires d’esclaves en virginie, et au lieu de l’interdire, il approuva plus tard l’expansion de cette institution dans le missouri et dans d’autres états. la complexité et la difficulté de ce sujet sont exprimées par lui dans la fameuse citation de son autobiographie: nothing is more certainly written in the book of fate, than that these people are to be free; nor is it less certain that the two races, equally free, cannot live in the same government. nature, habit, opinion have drawn indelible lines of distinction between them. humboldt pouvait voir et évaluer le système de l’esclavage d’un point de vue extérieur, puisque ni sa vie privée ni sa vie professionnelle n’étaient connectées avec cette institution. jefferson était né dans ce système et il était étroitement la révolution de haïti vue par deux personnages contemporains lié avec l’esclavage de plusieurs manières. pour lui il s’agissait d’une institution établie depuis longtemps sur laquelle était basée la vie des planteurs en virginie. les esclaves constituaient de plus une partie significative de sa richesse person- nelle et de cette façon lui assuraient ses revenus et sa liberté économique, ce qui lui permettait de se dédier à ce qui était important pour lui. la décision de supprimer l’esclavage aurait donc eu des conséquences majeures non seulement dans son futur d’homme politique, mais aussi dans sa vie personnelle. quant aux idéaux humanistes du siècle des lumières et à l’égalité des hom- mes, ils témoignent de différences remarquables entre les représentants des deux continents. de nouveau jefferson semble montrer une compréhension plus pragmatique et limitée de ses propres valeurs. il est connu—bien que beaucoup débattu—que la fameuse phrase de la déclaration de l’indépendance, « all men are created equal » n’incluait pas d’autres personnes que les hommes blancs ayant propriété de la terre. il ne s’agissait pas d’une égalité politique, sociale ou économique, mais plutôt d’un droit divin à la vie, à la liberté et par suite à la félicité. donc, c’est dans les commentaires, à caractère privé, de jefferson sur la situation de la population noire, sur le système d’esclavage en particulier, mais aussi sur sa position à l’égard des indiens d’amérique et finalement dans ses réflexions sur la révolution haïtienne, qu’il manifeste ses convictions. humboldt appliquait en revanche ses revendications éclairées à tous, comme cette citation sur l’égalité des hommes, tirée de son oeuvre kosmos, l’illustre clairement: indem wir die einheit des menschengeschlechtes behaupten, widerstreben wir auch jener unerfreulichen annahme von höheren und niederen menschenracen. es giebt bildsamere, höhere gebildete, durch geistige cultur veredelte, aber keine edleren volksstämme. alle sind gleichmäßig zur freiheit bestimmt; zur freiheit, welche in roheren zuständen dem einzelnen, in dem staatenleben bei dem genuß politischer institutionen der gesamtheit als berechtigung zukommt. en conclusion, la révolution en haïti et les différentes réactions que cet événement a provoquées dans le vieux comme dans le nouveau monde ne peuvent pas être regardées indépendamment des autres thèmes mentionnés. les réactions peuvent manifester des convictions personnelles, mais elles sont également liées à des conditions historiques et politiques ou à des intérêts privés, comme on a pu le montrer avec l’exemple de ces deux personnalités. finalement sandra rebok on pourrait dire que dans le cas présent humboldt représente une perspective plus européenne et une position plus idéaliste, tandis que jefferson était plus pragmatique; pour lui, c’était la réalité qu’il se présentait, puisqu’il s agissait de créer une société nouvelle aux États-unis et pour cela, beaucoup des aspects étaient à prendre en compte. dans la comparaison de ces deux regards il faut être conscient de la fonction différente qu’ils occupaient dans leurs sociétés respectives: humboldt comme scientifique, philosophe et autorité morale, et jefferson, comme scientifique, mais surtout comme homme politique, respons- able de l’avenir de sa jeune république. notes ce travail a été réalisé dans le cadre d’un contrat post-doctoral i p du csic. mes remerciements aux robert h. smith international center for jefferson studies à charlottesville, virginia, États-unis pour une bourse de quatre mois afin d’effectuer mes recherches à monticello. je remercie également jean-françois guennoc du centre de recherche sur la littérature de voyages (crlv, paris iv) et marie ange minh trang do cao pour leur aide linguistique. . sur ce sujet voir par exemple léon-françois hoffmann, frauke gewecke, ulrich fleisch - mann (éds.), haïti —lumières et ténèbres: impact et résonances d’une révolution (madrid: iberoamericana; frankfurt am main: vervuert, ); alain yacou (éd.), saint-domingue espagnol et la révolution nègre d’haïti ( – ): commémoration du bicentenaire de la naissance de l’État d’haïti ( – ) (paris: karthala, ); david patrick geggus, « the naming of haiti », new west indian guide/nieuwe west-indische gids , nos. / ( ): – ; david patrick geggus (éd.), the impact of the haitian revolution in the atlantic world (columbia: university of south carolina press, ); david patrick geggus, haitian revolutionary studies (bloomington/indianapolis: indiana university press, ); alfred n. hunt, haiti’s influence on antebellum america: slumbering volcano in the caribbean (baton rouge: louisiana state university press, ). . aimé goujand bonpland ( – ) était un botaniste et un médecin français. . sur le séjour de humboldt aux États-unis en et sa correspondance avec thomas jefferson dans les années suivantes voir ingo schwarz, « alexander von humboldt’s visit to washington and philadelphia, his friendship with jefferson, and his fascination with the united states », proceedings: alexander von humboldt’s natural history legacy and its relevance for today, northeastern naturalist, special issue ( ): – ; sandra la révolution de haïti vue par deux personnages contemporains rebok, «  two exponents of the enlightenment: transatlantic communication by thomas jefferson and alexander von humboldt », southern quarterly , no. ( ): – ; sandra rebok, « enlightened correspondents: the transatlantic dialogue of thomas jefferson and alexander von humboldt », virginia magazine of history and biography, vol. , n. ( ):  - ; peter schoenwaldt, « alexander von humboldt und die vereinigten staaten von amerika », in heinrich pfeiffer (éd.), alexander von humboldt: werk und weltgeltung (munich: r. piper & co., ), – ; ingo schwarz, « from alexander von humboldt’s correspondence with thomas jefferson and albert gallatin », berliner manuskripte zur alexander-von-humboldt-forschung ( ): – ; helmut de terra, « alexander von humboldt’s correspondence with thomas jefferson », proceedings of the american philosophical society ( ): – ; helmut de terra, « motives and consequences of alexander von humboldt’s visit to the united states ( ) », proceedings of the american philosophical society ( ): – . . concernant le regard comparatif entre les différentes régions américaines se référer à l’ouvrage ingo schwarz, « alexander von humboldts bild von latein- und angloamerika im vergleich », in wolfgang reinhard, peter waldmann, (éds.), nord u. süd in amerika: gegensätze. gemeinsamkeiten. europäischer hintergrund, vol. (freiburg: rombach, ), – . . une bonne description du voyage de humboldt pour les États-unis se trouve en: hermann r. friis, « alexander von humboldts besuch in den vereinigten staaten von amerika vom . mai bis zum . juni  », in joachim h. schultze (éd.), alexander von humboldt: studien zu seiner universalen geisteshaltung (berlin: walter de gruyter & co., ), – . une version anglaise qui se limite seulement à son séjour à washington est proposée dans l’ouvrage: hermann r. friis, « baron alexander von humboldt’s visit to washington », records of the columbia historical society ( ): – . . humboldt to jefferson, may (dlc: thomas jefferson papers), publié en ingo schwarz, alexander von humboldt und die vereinigten staaten von amerika: briefwechsel (berlin: akademie verlag, ), – . voir aussi des divers commentaires sur cet rencontre sur la page web: www.ku.edu/~maxkade/humboldt/subwashington.htm. . les informations détaillées sur les documents échangés apparaissent dans jaime labastida, humboldt, « méxico y estados unidos: historia de una intriga », in jaime labastida (éd.), atlas geográfico y físico del reino de la nueva españa (méxico: siglo veintiuno editores, ), – ; ingo schwarz, « “shelter for a reasonable freedom” or cartesian vortex », debate y perspectivas: alejandro de humboldt y el mundo hispánico, no. (madrid: fundación histórica tavera, ), – . . la correspondance de humboldt avec jefferson ainsi qu’avec d’autres politiciens, sandra rebok intellectuels ou scientifiques nord-américains se trouve publiée dans schwarz, alexander von humboldt und die vereinigten staaten von amerika. la traduction en anglais des lettres de humboldt, originellement écrites en français, la traduction en terra, « humboldt’s correspondence with jefferson ». . une excellent vue d’ensemble des ouvrages de humboldt ainsi que des différentes éditions et traductions est proposée dans horst fiedler, ulrike leitner, alexander von humboldts schriften: bibliographie der selbstständig erschienenen werke (berlin: akademie verlag, ). . voir les différentes éditions réalisées par le centre de recherche alexander von humboldt de l’académie des sciences de berlin. ces éditions gardent la langue choisie par humboldt; les descriptions sont donc en français et en allemand: margot faak (éd.), lateinamerika am vorabend der unabhängigkeitsrevolution: eine anthologie von impressionen und urteilen aus den reisetagebüchern, vol. (berlin: akademie verlag, ); margot faak (éd.), alexander von humboldt: reise auf dem rio magdalena, durch die anden und durch mexiko, vol. (berlin: akademie verlag, ); margot faak (éd.), alexander von humboldt: reise auf dem rio magdalena, durch die anden und durch mexiko, vol. (berlin: akademie verlag, ); margot faak (éd.) alexander von humboldt: reise durch venezuela, vol. (berlin: akademie verlag, ); ulrike leitner (éd.), alexander von humboldt: von mexiko-stadt nach veracruz. tagebuch (berlin: akademie verlag, ). a part ces publications, il y a une très grande partie de ces documents qui ne sont pas encore édités: margot faak, alexander von humboldts amerikanische reisejournale: eine Übersicht (berlin: alexander-von-humboldt-forschungsstelle, ). . faak, lateinamerika am vorabend der unabhängigkeitsrevolution, – . . sur ce sujet voir philip s. foner, alexander von humboldt on slavery in the united states (berlin: humboldt-universität, ); ingo schwarz, « ‘shelter for a reasonable freedom’ or cartesian vortex », in miguel Ángel puig-samper (éd.), debates y perspectivas: alejandro de humboldt y el mundo hispánico, vol. (madrid: fundación histórica tavera, ), – ; ingo schwarz, « alexander von humboldt—socio-political views of the americas », in ottmar ette, walther l. bernecker (éds.), ansichten amerikas. neuere studien zu alexander von humboldt (frankfurt a. main: vervuert verlag, ), – ; michael zeuske, « alexander von humboldt y la comparación de las esclavitudes en las américas », humboldt im netz: http://www.uni-potsdam.de/u/romanistik/ humboldt/ hin/ hin /inh_zeuske_ .htm, vii ( ), ; michael zeuske, « humboldt, esclavitud, autonomismo y emancipación en las américas, –  », in mariano cuesta domingo, sandra rebok (éds.), alexander von humboldt: la estancia en españa y su viaje americano (madrid: real sociedad geográfica, consejo superior de investigaciones científicas, ), – . la révolution de haïti vue par deux personnages contemporains . pour connaître la position d’autres founding fathers des États-unis face à haïti, voir gordon s. brown, toussaint’s clause: the founding fathers and the haitian revolution (jackson: university press of mississippi, ); james sidbury, « saint domingue in virginia: ideology, local meanings, and resistance to slavery, –  », journal of southern history , no. (august ): – ; tim matthewson, « george washington’s policy towards the haitian revolution  », diplomatic history ( ): – ; tim matthewson, « john adams and the independence of haiti », manuscrit non publié, arlington, virginia, . . lettre manuscrite, library of congress, washington d.c., États-unis. voir lettre tran- scrite: http://www.loc.gov/exhibits/jefferson/ .html. . il serait trop long d’entrer ici dans le débat complexe sur l’attitude de jefferson envers l’esclavage, et de plus inutile au vu des nombreuses publications traitant de ce sujet, parmi lesquelles: lucia c. stanton, « “those who labor for my happiness”: thomas jefferson and his slaves », in peter s. onuf (éd.), jeffersonian legacies (charlottesville: university press of virginia, ), – ; paul finkelman, « jefferson and slavery: treason against the hopes of the world, » in ibid., – ; hartmut wasser, « zwischen herrenrecht und menschenrecht: thomas jefferson und das “amerikanische dilemma”», in hartmut wasser, thomas jefferson: historische bedeutung und politische aktualität (paderbonn, münchen, wien, zürich: schöningh, ), – ; garry wills, negro president: jefferson and the slave power (boston: houghton mifflin, ); peter s. onuf, «to declare them a free and independent people: race, slavery, and national identity in jefferson’s thought», journal of the early republic , no. (spring ): – ; john c. miller, the wolf by the ears: thomas jefferson and slavery (charlottesville: university press of virginia, ); winthrop d. jordan, white over black: american attitudes toward the negro, – (new york: norton, ). . faak, lateinamerika, s. . ibid., . . ulrike leitner, « “anciennes folies neptuniennes!” Über das wiedergefundene “journal du mexique à veracruz” aus den mexikanischen reisetagebüchern a. v. humboldts », humboldt im netz, http://www.uni-potsdam.de/u/romanistik/humboldt/hin/hin /leitner. htm, berlin/potsdam, iii, no. ( ). . ulrike leitner de l’académie des sciences de berlin et michael zeuske de l’université de cologne préparent une édition de ce document. . voir les explications sur ces documents de zeuske, , ch. « el diario perdido », – . . apparemment humboldt utilise ces deux termes sans connotation politique. sandra rebok . alexandre de humboldt, essai politique sur le royaume de la nouvelle-espagne du mexique, vols. (paris: schoell, – ). . alexandre de humboldt, essai politique sur l’ile de cuba, dir. charles minguet, amos segala et jean-paul duviols (nanterre: Éditions erasme, ). . alexandre de humboldt, a. bonpland, voyage aux régions équinoxiales du nouveau continent, fait en , , , , et , vols. (paris, gide: smith, – ). . humboldt, essai politique sur le royaume de la nouvelle-espagne, vol. , – . . humboldt, essai politique sur l’ile de cuba, . . ibid.. . ibid., . . ibid., . . sur ce sujet voir aussi maria dolores gonzalez-ripoll, consuelo naranjo et al., el rumor de haiti en cuba: temor, raza y rebeldia, – (madrid: consejo superior de investigaciones científicas, ). . michael zeuske, « alexander von humboldt y la comparación de las esclavitudes en las américas », humboldt im netz: http://www.uni-potsdam.de/u/romanistik/ humboldt/ hin/ hin /inh_zeuske_ .htm, vii, no. ( ): . . maría dolores gonzález-ripoll navarro, vínculos y redes de poder entre madrid y la habana: francisco arango y parreño ( – ), ideólogo y mediador (madrid: consejo superior de investigaciones científicas, ). . les publications suivants donnent des informations très détaillées sur la situation politique et les différents intérêts des États-unis envers la france et saint-domingue ainsi que sur l’attitude de jefferson pendant toutes ces années: tim matthewson, a proslavery foreign policy: haitian-american relations during the early republic (westport, conn.: praeger, ); donald r. hickey, «america’s response to the slave revolt in haiti, – », journal of the early republic , no. (winter ): – ; tim matthewson, « jefferson and the nonrecognition of haiti », proceedings of the american philosophical society , no. (mars ): – ; tim matthewson, « jefferson and haiti », journal of southern history, , no. (mai ): – ; yves auguste, « jefferson et haiti », revue d’histoire diplomatique ( ): – ; wills, negro president, – ; brown, toussaint’s clause, – . . jefferson à james madison, février , publié en julian p. boyd, charles t. cullen, john catanzariti, barbara b. oberg et al. (éds.), the papers of thomas jefferson [ –], vol. ( ) : – . . voir aussi les conversations de jefferson avec le représentatif français à washington louis andré pichon sur ce sujet en : brown, toussaint’s clause, ss. . il est intéressant de noter dans ce contexte les positions opposées de jefferson et timothy la révolution de haïti vue par deux personnages contemporains pickering, qui reproche à jefferson son double standard face à la révolution française et la révolution en haïti (wills, negro president, chapitre «  pickering vs. jefferson: toussaint », – ). voir aussi donald r. hickey, « timothy pickering and the haitian slave revolt: a letter to thomas jefferson in », essex institute historical collections (july ): – . . matthewson, « jefferson and the nonrecognition of haiti », . mes remerciements à lisa francavilla du robert h. smith international center for jefferson studies pour m’aider à consulter quelques citations de jefferson. . cette lettre est publiée dans auguste, « jefferson et haiti », – . . « the declaration of independence » : http://www.ushistory.org/declaration/document/ index.htm. . auguste, « jefferson et haiti », . . ibid., . . jefferson à rufus king, juillet , jefferson papers, library of congress, washington, d.c. . lettre de humboldt à william thornton, juin , publié en schwarz, « alexander von humboldt’s visit », – . . bernard bailyn, « jefferson and the ambiguities of freedom », proceedings of the american philosophical society , no. ( ): – . . frank shuffelton (éd.), jefferson, thomas: notes on the state of virginia (new york: penguin books, ). . publié en adrienne koch, william peden (éds.), the life and selected writings of thomas jefferson (new york: modern library, ). . koch/peden, life and selected writings, . . une analyse détaillée sur les similarités et les différences entre humboldt et jefferson se trouve en rebok, « two exponents of the enlightenment, – . . la connexion entre l’attitude de jefferson et humboldt avec le siècle des lumières américaine versus l’européenne est présentée en ibid., – . . alexander von humboldt, kosmos: entwurf einer physischen weltbeschreibung, édité par ottmar ette et oliver lubrich (frankfurt a. m.: eichborn, ), . . traduction en français: « en affirmant l’unité du genre humain, nous nous opposons à l’hypothèse fâcheuse de races supérieures et inférieures. certains peuples sont plus cul- tivés, ont une éducation plus haute, et peuvent s’ennoblir de leur histoire intellectuelle, mais aucun n’est plus noble qu’un autre. tous sont également destinés à la liberté; une liberté qui, si elle revient dans l’état de nature à l’individu, est dans l’état civilisé un droit garanti à l’ensemble de la communauté par les institutions politiques. » knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november jvib november • volume • number research report knowledge and use of low vision services among persons with age-related macular degeneration robin j. casten, eileen k. maloney, and barry w. rovner this research was supported by grant ag from the national institute on aging geriatric academic career leadership award, entitled "research program to promote optimal aging in place," to laura n. gitlin, at the jefferson college of health professions, thomas jefferson university. visual impairment (blindness or low vision) is a leading cause of disability among older adults and is most often due to age-related macular degeneration (amd). the prevalence of amd is rapidly increasing with the aging of the population; from to , it increased from . % to . % in a cohort of medicare beneficiaries (crews, ; lee, feldman, ostermann, brown, & sloan, ). it is predicted that . million people will have amd by (eye diseases prevalence research group, ). http://www.afb.org/jvib/jvib .asp ( of ) / / : : pm http://www.afb.org/jvib/jvib_main.asp# http://www.afb.org/jvib/jvib toc.asp knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november compared to older people with typical vision, those with amd report greater difficulty with a variety of daily activities (williams, brody, thomas, kaplan, & brown, ). for example, in a community sample of older people, those with amd were . times more likely to have impairments in instrumental activities of daily living (such as taking medication and shopping) than were people with typical vision (rovner & ganguli, ). unfortunately, there is no cure for amd, nor can lost vision be restored. although there are interventions to slow the progression of the condition, treatment is primarily rehabilitative. services for people with low vision include low vision rehabilitation, occupational therapy, social support programs, and orientation and mobility training. assistive devices include magnifiers, large-print materials (such as books, clocks, and calculators), audio materials (such as books and magazines), electronic reading devices, and speech-output systems. despite the availability of these rehabilitative services and devices, they are underutilized. a series of focus groups that were conducted by the national eye institute (nei) indicated that many older persons with low vision have little or no awareness of these services, and, as a consequence, few take advantage of them (national eye institute, ). similar findings were reported in the lighthouse national survey on vision loss (lighthouse international, ). among adults with low vision, only % were using optical devices, % were using large-print reading materials, and % received rehabilitation. the most common reason for the lack of utilization of low vision devices and services was the participants' unawareness of them. ophthalmologists may not be informing and educating their http://www.afb.org/jvib/jvib .asp ( of ) / / : : pm knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november patients about these resources. some studies have reported that ophthalmologists refer only %- % of appropriate patients to low vision rehabilitation services (greenblat, ). leinhaas and massof ( ) found that only % of ophthalmologists and % of optometrists "always or often" prescribed low vision devices, and only % of ophthalmologists and % of optometrists "always or often" referred patients for low vision services. the goal of the current study was to obtain more detailed information on the use of low vision services and devices by older adults with amd and to determine whether knowledge and use of such services are related to the severity of vision loss. methods sample we studied consecutive patients who were evaluated at the retinovitreous clinic of wills eye hospital, philadelphia, from september to july . the patients who were included in the study had a diagnosis of amd (atrophic or neovascular), were aged or older, had no cognitive impairment, and were residing in the community. all procedures were approved by the internal review board of thomas jefferson university. of the patients whom we contacted for possible participation, were enrolled in the study. of the nonenrolled patients, ( %) refused to participate, ( %) could not be reached, ( %) were cognitively impaired, ( %) had severe hearing impairments that precluded telephone interviews, ( %) were hospitalized, ( %) was residing in a nursing home, and the remaining ( %) were not included for other reasons. the participants http://www.afb.org/jvib/jvib .asp ( of ) / / : : pm knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november did not differ from the nonparticipants in visual acuity of the better eye or gender but were somewhat older [ . (sd = . ) versus . (sd = . ) years; f ( , ) = . , p < . ]. measures a research assistant obtained demographic data on the participants--their age, sex, marital status, education, race, and whether they lived alone--by telephone. the research assistant also obtained information from medical records on the participants' clinical characteristics--bilateral versus unilateral amd, visual acuity of the better eye (snellen chart), and duration of the amd. an expert panel compiled a comprehensive list of services and devices. this panel was comprised of a retinologist, a geriatric psychiatrist with expertise in research on the emotional impact of vision loss, a clinical psychologist who treats people who are visually impaired, and two leaders of a local amd support group. the principal investigator of this study (casten) presented the panel with a working list of services and devices for amd patients and asked them to comment on the suitability of the language of each item (such as "talking books" versus "books on tape") and to edit the list as appropriate. the final list consisted of devices and services, and for each, the participants were asked whether they were aware of it (yes or no), their past and current use of it, and if they would like to use it (yes or no). frequency distributions were computed to characterize the rates of awareness, use, and interest for each service and device. one-way analyses of variance (anovas) determined whether the use of a resource was related to the severity of the participants' visual impairment. http://www.afb.org/jvib/jvib .asp ( of ) / / : : pm knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november results the average age of the sample was . years (sd = . ); % of the participants were female, and % were caucasian. the mean number of years of education was . (sd = . ). almost half the participants ( %) were married, and % were living alone. the majority ( %) had bilateral amd. the mean visual acuity of the better-seeing eye was . (sd = . ); a logmar of . corresponds to an acuity of / . the average duration of amd was . years (sd = . years). table shows the rates of awareness and use of and interest in each service and device and demonstrates two important findings. first, awareness and use rates were low relative to the high rates of expressed interest. for example, although only % of the participants knew of low vision rehabilitation, % expressed their desire to receive this intervention. second, although more than % reported using a magnifier or telescope, only % had magnifiers that were prescribed by an ophthalmologist or optometrist; most had purchased their devices at a pharmacy or obtained them from relatives. we next examined whether the use of devices and services was related to the severity of the participants' vision loss. we grouped the participants according to whether the acuity in their better-seeing eye was above the median for the sample ( / ). using this criterion, we found that ( %) participants had "better" vision, and ( %) had "worse" vision. for each participant, we computed the number of low vision services and devices that he or she used. a one-way anova with better versus worse vision as the grouping variable indicated that those with worse vision used more http://www.afb.org/jvib/jvib .asp ( of ) / / : : pm http://www.afb.org/jvib/jvib tab intro.asp knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november services and devices. the average number of services and devices for the worse group was . (sd = . , range - ), compared to . (sd = . , range - ) for the better group [f ( , ) = . , p < . ]. a series of chi-square analyses determined which services or devices were more likely to be used by those with worse vision. because of the large number of statistical comparisons, alpha was set at ≤ . . the results indicated that those with worse vision were more likely than those with better vision to use magnifiers ( % versus %, p = . ). discussion the results of this study confirm the findings of other studies that have demonstrated low rates of use of services and devices by older people with low vision. however, a large percentage of older people with low vision want to use low vision resources but are unaware of them (lighthouse international, ). this finding suggests that health care professionals may either be unaware of rehabilitation options or fail to discuss them with their patients for other reasons. although the participants with worse vision appeared to use more resources, the overall rates of usage were low even in this group. this situation is unfortunate because low vision rehabilitation can lead to the better-informed use of optical devices, a faster reading speed, and an enhanced mood (horowitz, reinhardt, & travis, ; raasch, leat, kleinstein, bullimore, & cutter, ). all the participants were aware of magnifiers, and most ( %) were using them. however, few had prescription magnifiers, which calls into question whether they were using the best possible magnification for them. only % had ever seen a low vision optometrist. that % of the http://www.afb.org/jvib/jvib .asp ( of ) / / : : pm knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november participants expressed a desire for low vision rehabilitation indicates that, with proper education and referrals, many could benefit from this intervention. this study indicates that people with amd are underutilizing available rehabilitation interventions that hold the promise of improving their visual function and quality of life. efforts to educate them about available resources need to be increased, and removing obstacles, such as reimbursement and transportation issues, are needed as well. what is perhaps most important is that increasing ophthalmologists' awareness of the value of rehabilitation treatments and of their patients' desire to use them may be the first step in this process. references crews, j. ( ). the demographic, social, and conceptual contexts of aging and vision loss. journal of the american optometric association, , - . eye diseases prevalence research group. ( ). prevalence of age-related macular degeneration in the united states. archives of ophthalmology, , - . greenblat, s. l. ( ). physicians and chronic impairment: a study of ophthalmologists' interactions with visually impaired and blind patients. social science medicine, , - . horowitz, a., reinhardt, j. p., & travis, l. a. ( ). the influence of health, social support quality and rehabilitation on depression among disabled elders. aging and mental health, , - . http://www.afb.org/jvib/jvib .asp ( of ) / / : : pm knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november lee, p. p., feldman, z. w., ostermann, j., brown, d. s., & sloan, f. a. ( ). longitudinal prevalence of major eye diseases. archives of ophthalmology, , - . leinhaas, m. m., & massof, r. w. ( ). clinical management of patients with low vision in the u.s. health care system. in r.w. massof & l. lidoff (eds.), issues in low vision rehabilitation: service delivery, policy, and funding (pp. - ). new york: afb press. lighthouse international. ( ). the lighthouse national survey on vision loss: the experience, attitudes, and knowledge of middle-aged and older americans. new york: author. lighthouse international. ( , february). statistics on vision impairment: a resource manual. new york: author. national eye institute ( ). life with low vision: a report on qualitative research among people with low vision and their caregivers [online]. available: http://www.nei.nih. gov/nehsep/execsum.htm raasch, t. w., leat, s. j., kleinstein, r. n., bullimore, m. a., & cutter, g. r. ( ). evaluating the value of low- vision services. journal of the american optometric association, , - . rovner, b. w., & ganguli, m. ( ). depression and disability associated with impaired vision: the movies project. journal of the american geriatric society, , - . williams, r. a., brody, b. l., thomas, r. g., kaplan, r. http://www.afb.org/jvib/jvib .asp ( of ) / / : : pm knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november m., & brown, s. i. ( ). the psychosocial impact of macular degeneration. archives of ophthalmology, , - . robin j. casten, ph.d., assistant professor, department of psychiatry and human behavior, jefferson medical college, jefferson hospital for neuroscience, walnut street, philadelphia, pa ; e-mail: <robin.casten@jefferson. edu>. eileen k. maloney, m.s., clinical research coordinator, department of psychiatry and human behavior, jefferson hospital for neuroscience, thomas jefferson university; e-mail: <eileen.maloney@jefferson.edu>. barry w. rovner, m.d., department of psychiatry and human behavior, jefferson hospital for neuroscience, thomas jefferson university; e-mail: <barry.rovner@jefferson.edu>. previous article | next article | table of contents jvib, copyright © american foundation for the blind. all rights reserved. search jvib | jvib policies | contact jvib | subscriptions | jvib home if you would like to give us feedback, please contact us at jvib@afb.net. http://www.afb.org/jvib/jvib .asp ( of ) / / : : pm mailto:robin.casten@jefferson.edu mailto:robin.casten@jefferson.edu mailto:eileen.maloney@jefferson.edu mailto:barry.rovner@jefferson.edu http://www.afb.org/jvib/jvib .asp http://www.afb.org/jvib/jvib .asp http://www.afb.org/jvib/jvib toc.asp http://www.afb.org/jvib/jvib_search.asp http://www.afb.org/jvib.asp http://www.afb.org/jvib/contact_jvib.asp http://www.afb.org/store/journal_view.asp?name=journal+of+visual+impairment+% +blindness&mscssid= http://www.afb.org/jvib/main.asp mailto:jvib@afb.net knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november www.afb.org | change colors and text size | contact us | site map | site search about afb | press room | bookstore | donate | policy statement please direct your comments and suggestions to afbinfo@afb.net copyright © american foundation for the blind. all rights reserved. http://www.afb.org/jvib/jvib .asp ( of ) / / : : pm http://www.afb.org/default.asp http://www.afb.org/myafb.asp http://www.afb.org/section.asp?sectionid= &topicid= http://www.afb.org/site.asp http://www.afb.org/section.asp?sectionid= http://www.afb.org/section.asp?sectionid= http://www.afb.org/store http://www.afb.org/donate_bks_jnls_dir.asp http://www.afb.org/section.asp?documentid= mailto:afbinfo@afb.net 	afb.org 	knowledge and use of low vision services among persons with age-related macular degeneration - jvib - november 	jbapoopogfcnanoigmdjcdencfpkceam: 	form : 	x: 	f : 	f : go 	f : tf-cmte .. full terms & conditions of access and use can be found at https://www.tandfonline.com/action/journalinformation?journalcode=imte medical teacher issn: - x (print) - x (online) journal homepage: https://www.tandfonline.com/loi/imte medical student perceptions of hospital discharge transitions in care beth careyva, danielle snyderman & gretchen diemer to cite this article: beth careyva, danielle snyderman & gretchen diemer ( ) medical student perceptions of hospital discharge transitions in care, medical teacher, : , - , doi: . / x. . to link to this article: https://doi.org/ . / x. . published online: apr . submit your article to this journal article views: view related articles citing articles: view citing articles https://www.tandfonline.com/action/journalinformation?journalcode=imte https://www.tandfonline.com/loi/imte https://www.tandfonline.com/action/showcitformats?doi= . / x. . https://doi.org/ . / x. . https://www.tandfonline.com/action/authorsubmission?journalcode=imte &show=instructions https://www.tandfonline.com/action/authorsubmission?journalcode=imte &show=instructions https://www.tandfonline.com/doi/mlt/ . / x. . https://www.tandfonline.com/doi/mlt/ . / x. . https://www.tandfonline.com/doi/citedby/ . / x. . #tabmodule https://www.tandfonline.com/doi/citedby/ . / x. . #tabmodule ; : – letters to the editor medical student perceptions of hospital discharge transitions in care dear sir improved coordination of care after hospitalizations is essential to decrease readmissions and costs, and most importantly, to prevent undesirable patient outcomes. changes in care plans may be lost through ineffective communication to the patient or providers, making this transition particularly critical (kripalani et al. ). third- year medical students are frequently involved in discharges though rarely have opportunities to follow patients after the hospitalization and receive little formal training in transitional care. students’ self-assessed competency in transitional care has been shown to increase after introducing curriculum designed to focus on discharge planning (bray-hall ). this study aims to assess third-year medical student perceptions of transitional care following an educational exercise. students identified a patient and completed a semi- structured telephone interview within – days after discharge to assess patients’ adherence with discharge instructions. the survey involved questions about the discharge process guiding the students to: assess the patient’s understanding of perceived need, benefit and disadvantages of the hospitaliza- tion, reconcile medications, determine adherence to home services and follow-up appointments, and ascertain if the patient returned to the ed. students were then asked to comment on their experiences in order to provide an opportunity for reflection. three independent reviewers analyzed the qualitative data from the students’ reflections for emerging themes. themes included coordination of care, empathy and patient relationships, in addition to recognition of logistical challenges in patient continuity. students articulated many components of the discharge process in which difficulties arise and noted that they were more thoughtful in preparing discharge-related documentation when they knew they would be contacting the patient. several students also high- lighted continuity of care and patient relationships as the aspects of this exercise that they found to be most valuable. this exercise serves as an innovative model for incorporating discharge planning into the curriculum of inpatient clerkships and was found to increase insight into the complexities of transitional care. transitional care is pivotal in decreasing adverse events and readmission, and we recommend that this education be incorporated into undergraduate medical training. beth careyva, lehigh valley health network, bethlehem, pennsylvania, usa. e-mail: beth.careyva@gmail.com danielle snyderman, gretchen diemer, thomas jefferson university, philadelphia, usa references bray-hall s. . toward safe hospital discharge: a transition in care curriculum for medical students. j gen intern med ( ): – . kripalani s, jackson at, schnipper jl, coleman ea. . promoting effective transitions of care at hospital discharge: a review of key issues for hospitalists. j hosp med ( ): – . patient participation in, and attitudes towards, community-based medical education dear sir the training of future doctors relies on their learning in real clinical environments. in australia the dominant clinical training sites are public teaching hospitals, however commu- nity-based medical education is increasingly recognised as an alternative to in-hospital training. australian health care is provided through either publically- funded teaching hospitals, or privately provided services in specialist and general practice. private health services attract a government (medicare) rebate, but often require a patient co-payment. this public–private divide has created an ethos that private (i.e. paying) patients would not accept the presence of medical students, despite previous studies reporting positive patient perceptions. the authors surveyed patients attending for private health care to determine whether there was a basis for this ethos. we found that % of respondents either had agreed or would agree to the presence of a student, and . % said that issn – x print/issn – x online/ / – � informa uk ltd. doi: . / x. . received / / review began / / review ended / / published / / © copyright zhang et al. this is an open access article distributed under the terms of the creative commons attribution license cc-by . ., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. the zoom picture book game: a creative way to promote teamwork in undergraduate medical education xiao chi zhang , arjun balakumar , carlos rodriguez , anthony sielicki , dimitrios papanagnou . emergency medicine, thomas jefferson university, philadelphia, usa corresponding author: xiao chi zhang, xzhang @gmail.com abstract effective team building and leadership are crucial in running an effective and safe healthcare system with improved patient care and clinical outcomes. currently, there is a great demand for formal leadership training throughout the extensive medical education curriculum. we constructed an interactive team-building activity utilizing gamification-theory with the zoom game. the zoom activity requires a team of learners to organize a set of sequential images, each of which contains a “zoomed out” section from the previous image, into the correct order within a set time frame. given the unique and approachable nature of this team-based activity, we propose the following: ) to introduce the zoom game as a team-building and communication fostering exercise in undergraduate medical education and ) to assess baseline teamwork skills of first-year medical students through an immersive gaming experience. with this in mind, first-year medical students (class of ) at an urban-city medical school were enrolled in the zoom team building activity as part of their orientation. the students were randomly assigned to teams, comprising - students and two faculty facilitators per team and completed the activity in the allotted time frame. the average time to complete the zoom game was minutes, and all the teams successfully placed the pictures in the correct order. facilitators noted that the zoom game strongly encouraged friendly interactions, intercollegiate high values, mutual respect, confidence, and trust among each other. students observed take-home points such as selecting a leader, designating specific roles, and encouraging closed-loop communication. overall, the zoom activity game is an interactive, fun, and easily accessible team-building and communication fostering exercise in undergraduate medical education. further studies on the zoom game exercise would be essential to determine whether it has a continuous and enduring effect on developing team building among medical students. categories: medical education, other keywords: team building, gamification, undergraduate medical education introduction team building and leadership are two critical features in running an effective and safe healthcare system. studies have indicated that effective leadership correlates with improved patient care and clinical outcomes [ - ]. as medical students graduate to become resident physicians, they are tasked with newfound responsibilities of simultaneously managing their patient care, communicating treatment plans, and coordinating care from the nurses, techs, consultants, and supervising physicians. despite robust scientific literature supporting the importance of effective teamwork and leadership in promoting student learning, healthcare performances, and improved patient outcomes, there is still a great demand for formal open access technical report doi: . /cureus. how to cite this article zhang x, balakumar a, rodriguez c, et al. (february , ) the zoom picture book game: a creative way to promote teamwork in undergraduate medical education. cureus ( ): e . doi . /cureus. https://www.cureus.com/users/ -xiao-chi-zhang https://www.cureus.com/users/ -arjun-balakumar https://www.cureus.com/users/ -carlos-rodriguez https://www.cureus.com/users/ -anthony-sielicki https://www.cureus.com/users/ -dimitrios-papanagnou- leadership training throughout the extensive medical education curriculum [ - ]. in order to address the leadership gap between resident and attending physicians, we posit that leadership and team-building training should begin at the undergraduate medical education setting, rather than delaying it until residency training. while teaching and leadership skills are formally taught during residency, we believe that junior learners, such as first-year medical students may benefit from interactive, innovative, and low-stake teaching strategies. a review of team building and leadership training suggests that retreats and other forms of dedicated leadership exercises have been shown to engage the learners and simultaneously improve leadership and teamwork skills [ , ]. the zoom team building activity is a well-regarded game based on a picture book, “zoom”, by istvan banyai and repurposed as a team-building and leadership exercise [ , ]. the activity requires a team of - players to organize a set of sequential images, each of which contains a “zoomed out” section from the previous image, into the correct order within minutes. for example, a person is seen on a pool deck, which zooms out to be on a cruise ship, which again zooms out to be an advertisement for a cruise ship on a bus in sequential pictures. the caveat is that players are not allowed to look at other players’ pictures, but must describe the pictures’ contents among the team to determine the correct order. once the final order is decided by the team, all of the players will display their pictures and compare their order with the correct sequence. given the unique and approachable nature of this team-based activity, we propose the following: ) to introduce the zoom game as a team-building and communication fostering exercise in undergraduate medical education and ) to assess baseline teamwork skills of first-year medical students through an immersive gaming experience. technical report study setting the zoom activity was conducted at a conference room at the sidney kimmel medical school, associated with thomas jefferson university, philadelphia, pa. the conference-room setting allowed all players to move around the room with ease to communicate the details of their pictures. study-participant selection study inclusion criteria were as follows: ) participants should be years and older; ) they should be first-year medical students attending thomas jefferson university. individuals who were unable to consent (e.g., due to altered mental status, dementia, or developmental delay) were excluded. we did not anticipate community attendants to be intoxicated, incarcerated, or in clinical distress during this study. all incoming first-year medical students were required to attend this activity as part of their mandatory orientation training. this study was deemed exempt from institutional review board (irb) approval by the jefferson irb. materials/personnel requirements in order to play the game, each group, consisting of - students, is required to cut out and separate a set of pictures from the zoom game (with one picture on every individual sheet). two facilitators are responsible for organizing the activity, handing out the pictures, and evaluating the team performance. detailed activity description preparation (five minutes) the facilitators first select the number of sequential pictures in play for the activity. the zhang et al. cureus ( ): e . doi . /cureus. of number of active pictures must be equal to the number of total players (a maximum of pictures). if there are fewer than players, all pictures must be in the correct sequence to avoid lapsing photographs. the picture order is then shuffled before distribution. introduction (five minutes) the facilitators explain the zoom activity to the group and then hand out the sequential pictures facedown to each participant. each participant is given a few moments to thoroughly examine his or her pictures. activity ( minutes) the group communicates with each other about the order they believe the pictures to be in without showing each other the pictures. the group is then instructed to put the pictures in order as efficiently as possible (with no information given about what the “order” is). once they believe they have put the images in order, the images are revealed sequentially to see if the order is correct. if one image is not correct, the game continues until everything is in the correct order. participants are not allowed to show each other their images but can demonstrate/describe their image through actions and words. the entire game is expected to last minutes in total. debrief ing (five minutes) after the completion of the zoom game, all players participate in a brief facilitator-led debriefing to discuss the overall observed teamwork during the activity. players are encouraged to disclose take-home points of the activity. activity evaluation following the end of the activity, the facilitators are expected to complete two separate, blinded evaluations of the participants’ leadership, preparation, participation, communication, and listening skills through the institutional jefferson teamwork observation guide (jtog) [ ]. the jtog is a validated, user-friendly, -item likert-scaled ( = strongly agree, = strongly disagree) evaluation instrument based on learner and clinician feedback for interprofessional education, primarily designed to assess teamwork [ ]. results in our activity, first-year medical students in the graduating class of at sidney kimmel medical school of thomas jefferson university, philadelphia, pa participated as part of their orientation. the students were randomly assigned to teams, comprising - students and two faculty facilitators per team. the average time to complete the zoom game was minutes and all the teams successfully placed the pictures in the correct order. the mean jtog scores were calculated based on the blinded assessment of each team’s two facilitators. facilitators noted that the zoom game strongly encouraged friendly interactions (likert score: . ), intercollegiate high values (likert score: . ), and mutual respect, confidence, and trust (likert score: . ) among each other (table ). in contrast, areas of improvement were noted in the identification of a team leader (likert score: . ), understanding the roles and responsibilities of each member (likert score: . ), and the overall activity preparation (likert score: . ). comments captured from the jtog for first-year medical students were evaluated through open-axial qualitative analysis performed by the authors, who have extensive experience with qualitative research (table ). according to the students, the primary take-home points from the zoom activity centered on the following: ) selecting a leader ) designating specific roles ) zhang et al. cureus ( ): e . doi . /cureus. of eliciting specific directions; ) recognizing the challenges of macro- and micro-managing siloed teams, and ) encouraging closed-loop communication. jtog assessment mean likert score* sd there appeared to be a team leader that coordinated the discussion . . the team leader facilitated the discussion rather than dominating it . . members of the team who came prepared to discuss the case/situation contributed to the discussion . . members of the team who were involved in the case/situation contributed to the discussion . . discussion points were distributed among all team members . . member of the team appeared to understand the roles and responsibilities of other members of the team . . team members appeared to have respect, confidence, and trust in one another . . team members listened and paid attention to each other . . team members listened to and considered the input of others before pressing their own ideas . . team members added other supporting pieces of information from their profession-specific perspective regarding the case/situation . . the opinions of team members were valued by other members . . team members appeared to feel free to disagree openly with each other's ideas . team members sought out opportunities to work with others on specific tasks . . team members engaged in friendly interaction with one another . . table : jtog assessment of the zoom activity for first-year medical students jtog: jefferson teamwork observation guide; sd: standard deviation * = strongly agree, = strongly disagree zhang et al. cureus ( ): e . doi . /cureus. of jtog feedback themes positive impacts leadership: naturally emerging leadership, proper instructive techniques; calm; leader-requested debriefing communication: asking for help, suggestions, and counter-arguments; frequent timeouts; acknowledging others; hand-raising. organization: preferred one person in charge; initial delegation, using dry-erase boards knowledge: quick pattern recognition negative impacts location: small rooms and cluttered desk leadership: ranging from too many leaders to absent leadership communication: disruptive side conversation; interruptions; siloed communication between small groups organization: tribal mentality; lack of initial system; resistant to movement knowledge: lack of thought flexibility take-home points listeners can be leaders; teamwork; specificity is important; clear role definition; importance of micro- and macro- management table : themes developed from responses to jtog assessment by the participants jtog: jefferson teamwork observation guide discussion the investigators were successful in utilizing the zoom game as an effective team building and leadership training activity and assessing the baseline teamwork skills for first-year medical students. the zoom activity allowed first-year medical students to engage in a low-stake, controlled, interactive, and immersive activity that transcended their training, expertise, and educational background. facilitators noted that the first-year medical students exemplified friendly and respectful intercollegiate skills, but were less adept at selecting leaders, assigning roles, and preparing for the activity challenges. the open-axial qualitative assessment of the jtog response also demonstrated that the participants recognized the important aspects and challenges of team building and leadership. additional common themes included a preference for larger rooms and recognizing the detrimental effects of disruptive side conversions, interruption, and lack of closed-loop communication. in order to prepare medical students for residency, the association of american medical colleges (aamc) has issued a set of guidelines and expectations, known as core entrustable professional activities (epas), for graduating medical students to learn, develop, and ultimately be able to perform without supervision by graduation [ ]. in accordance with the aamc core epas, the zoom game also affords the learners to be exposed to specific components of epa : collaborate as a member of an interprofessional team - interpersonal and communication skills (ics : work effectively with healthcare team; ics : communicate zhang et al. cureus ( ): e . doi . /cureus. of effectively with colleagues within the same profession), professionalism (p : demonstrate compassion, integrity, and respect), and interprofessional collaboration (ipc : work with other health professional to maintain mutual respect, dignity, and trust). we recognize that there were several limitations to our study. this was a feasibility study at a single medical school, assessing the baseline teamwork skills for the first-year medical students during orientation. while there are numerous published studies on teaching teamwork in undergraduate medical education, most involve case scenarios or role-playing within a non- acute healthcare setting or simulation centers with high-fidelity mannequins [ - ]. our study focused primarily on assessing and reflecting on unique aspects of teamwork and leadership of first-year medical students before they began their medical training, making it unique compared to previous studies. while the jtog was a useful assessment tool, an additional test is warranted to see how the early implementation of the zoom activity can affect the realization of epa guidelines during the students' training period. furthermore, due to a large number of students, we required a large number of facilitators to evaluate and supervise the students. additionally, more iterations and advanced statistical software will be required to calculate inter-rater reliability between the facilitators' scores in the future. conclusions the zoom activity game is an interactive and easily accessible team-building exercise that can be used to assess baseline teamwork skills of first-year medical students through an immersive gaming experience. by engaging first-year medical students in the zoom game, we were able to highlight the aspects of teamwork necessary among the students to succeed as collaborative and supportive future physicians. further studies on the zoom game exercise would be essential to determine whether it can have a continuous and lasting effect on instilling team-building qualities among medical students. additional information disclosures human subjects: consent was obtained by all participants in this study. thomas jefferson university irb issued approval not applicable. this study meets the jefferson irb exemption criteria. animal subjects: all authors have confirmed that this study did not involve animal subjects or tissue. conf licts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. references . bohmer r: designing care: aligning the nature and management of health care . harvard business review press, boston, ma; 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stemcyte taiwan national cord blood center, linkou, taiwan; duke university medical center, durham, nc nucleated cell (nc), cd cell (cd ), and colony forming unit (cfu) doses have been proposed to measure cb potency - important for engraftment potential prediction and transplantation product selec- tion.thoughtnciswidelyusedforcbselection,itspredictivevalueis not as robust as the progenitor cell measurements. cfu and cd suf- fer from high inter-laboratory coefficient of variance (cv) - decreasing the clinical utility as potency measures. recently, the duke group pro- posed a cb apgar scoring system composed of (a) a pre-cryopre- served score (pcs) reflecting pre-freeze cfu, cd , nc, and cb collected volume, as well as a (b) composite score (cs) which combines the pcs score with post-thaw nc, cd , cfu and mononuclear cell dose. based on single, myeloablative and first (smf) transplants of largely pediatric patients performed at duke and using mostly red cell reduced (rcr) cb, the pcs and cs scores were shown to be predictive of graft failure, neutrophil and platelet engraftment. with cibmtr- auditedoutcomedataoftransplantedcbproductsfromamulti-national cbbank, wesought tovalidatethecbapgarsystemon apatient pop- ulationwithmostlyadults,heavyrepresentationofminorityandinterna- tional patients, and on both smf transplants, and all transplants (all) using plasma depleted/reduced (pdr) cb products. the pcs and cs table below shows the day neutrophil engraftment cumulative inci- dence (anc ) and graft failure probability (gf) comparisons of the duke data with pdr transplants for both smf and all transplants. for each of the pcs and cs strata compared, anc and gf ap- peared to be similar among the duke smf, stemcyte smf and all co- horts. we conclude that the cb apgar score, especially the pcs, is an easy-to-use and reproducible potency measurement for cb selection by transplant centers that is highly predictive of anc engraftment and gf for ( ) rcr as well as pdr cb, ( ) for mostly pediatric patient pop- ulationaswellasformixedpopulationsofadultsandchildren,and( )for minority and international patients. whether the methodcanbeapplied to double, non-myeloablative and repeat cb transplants remains to be seen.lastly,forthesamepcsorcsstrata,pdrcbappeartohavesim- ilar engraftment and gf probabilities as rcr cb; therefore, the duke cb apgar is applicable to cb products with or without rbc reduc- tionandreflectspotencyofcbproductsprocessedandstoredbyvarious methods at different cb banks. table . anc engraftment cumulative incidence & graft failure probabilities anc duke smf pdr smf pdr all pcs$ . % ( - %) ± % ± % pcs< . % ( - %) ± % ± % hr . ( . - . ) . ( . - . ) . ( . - . ) cs$ . % ( - %) ± % ± % cs< . % ( - %) ± % ± % hr . ( . - . ) . ( . - . ) . ( . - . ) graft failure probability duke smf pdr smf pdr all pcs$ . % ( - %) ± % ± % pcs$ . & < . % ( - %) ± % ± % pcs$ . & < . % ( - %) ± % ± % pcs< . % ( - %) ± % ± % in-vivo expansion of t regulatory cells by rapamycin in a calcineurin-inhibitor free gvhd prophylaxis in unmanipu- lated haploidentical stem cell transplantation (sct) peccatori, j. , clerici, d. , forcina, a. , bondanza, a. , messina, c. , giglio, f. , mastaglio, s. , crotta, a. , lupo stanghellini, m.t. , marcatti, m. , crocchiolo, r. , assanelli, a. , bernardi, m. , corti, c. , noviello, m. , olek, s. , ferraro, a. , battagglia, m. , roncarolo, m.g. , locatelli, f. , bonini, c. , ciceri, f. san raffaele scientific institute, mi- lan, italy; san raffaele scientific institute, milan, italy; epiontis gmb, berlin, germany; san raffaele scientific institute, milan, italy; san raf- faele scientific institute, milan, italy; irccs ospedale pediatrico bambino ges�u, roma, italy background: tregs are attractive candidates for clinical modulation of excessive immune responses. in sct mouse models, the adoptive transfer of purified natural tregs has been shown to prevent gvhd, while sparing a significant gvl effect. tregs’ suppressor function has been demonstrated to be critically dependent on il- , therefore cya significantly reduces the function of allostimulated tregs. aim: to address the role of tregs in human sct, we focused on a calcineurin inhibitor-free gvhd prophylaxis. we tested this hy- pothesis in haploidentical peripheral blood stem cells sct without any in-vitro manipulation. patients and methods: since , pts underwent allo-sct for aml ( ), all ( ), mds ( ), mpd ( ), nhl ( ) or hd ( ). median age was years (range - ). at sct all but pts were in advanced phase. conditioning included treosulfan ( g/m for ), fludara ( mg/m for ) and an in-vivo t and b-cell depletion, by atg- fresenius ( mg/kg for ) and mabthera (a single mg dose). all pts received allogeneic pbsc from an hla-haploidentical related donor without any in-vitro positive selection. gvhd prophy- laxis consisted of rapamycin (target level - ng/ml, till day ) and mmf ( mg/kg tid till day ). results: all pts but had neutrophil engraftment. ci of grade - , grade - agvhd and cgvhd were %, % and %. days trm and relapse incidence at year were % and %. projected os at year is %. immunoreconstitution was fast and sustained witha median circulating cd cells/ml on day . we detected high levels of cd cd cd - foxp tregs (up to % of circulating cd t lymphocytes) on day . these cells were able tosuppressinvitroproliferationofautologouseffectorcells.thisobser- vation was further reinforced at a molecular level. we applied a quanti- tative rt-pcr based methylation assay that enables a specific and sensitive determination of t regs numbers by measuring demethylated foxp att regspecific demethyletedregion (tsdr).anexpansion of cells carrying foxp demethylation was evident in our pts, but not in a control group of pts receiving mismatched sct and cyclosporine. conclusions: rapamycin-mycophenolate-atg are effective as gvhd prophylaxis in unmanipulated haploidentical peripheral sct andareassociatedwith anearlyt-cellimmunoreconstitutioncharacter- ized by the in-vivo expansion of tregs. further studies are warranted to gain insight correlations between tregs expansion and sct outcome. / high-resolution hla match rate: the impact of race dehn, j. , buck, k. , yang, s.y. , schmidt, a. , hartzman, r. , maiers, m. , setterholm, m. , confer, d. national marrow donor program, minneapolis, mn; histogenetics, inc., ossining, ny; dkms, tuebingen, germany; c.w. bill young marrow donor re- cruitment and research program, rockville, md aim: calculation of the / (hla-a, b, c, drb ) high-resolution (hr) match rate using real patient unrelated donor (urd) searches presents a biased sample for reasons including access to treatment, fi- nancial barriers and incomplete donor testing. a study was designed to estimate the true match rate for caucasian (cau), hispanic (his), asian/pacific islander (api), and african american (afa) groups, representing the four largest race groups in the us population. methods: urd searches were performed for pseudopatients (pp) who were randomly selected, previously hr tested donors in the nmdp’s be the match registry (btmr). searches were based on a fixed btmr file as of january . search results from cau, his, api, and afa pp were classified as follows: oral presentations s ) at least one / hr matched donor exists on btmr ) no potential / hr donors exist ) potential / hr donors exist pp searches falling into category (accrued until n per race) then had an hla search strategy expert rank potential donors within btmrinorder oftheirmatchinglikelihood.previouslystoreddonor samples were hr hla tested in order of ranking and evaluated to de- termine match status. consecutive rounds of donor sample testing were performed until either an / matched donor was identified or no potential donors with stored samples remained. results: the table below shows the / hr match rate of cases to be % for cau, % for his, % for api, and % for afa. careful review of the cases ‘‘pending further testing; no stored sample’’ sug- gests that few additional cases would yield / hr matches. cau pp his pp api pp afa pp / hr matched ( %) ( %) ( %) ( %) pending further testing; no stored sample ( %) ( %) ( %) ( %) no / hr match ( %) ( %) ( %) ( %) total conclusions: thisstudyprovidesatrue / hrmatchrateestimatefor cau, his, api, and afa patients through btmr, which has not been accomplished previously. these results demonstrate the racial disparity in hla match rates and can be used to inform patients searching btmr.thisstudyalsoprovidesvitalinformationfordonorrecruitment and availability efforts. results provide a baseline match rate that can be further supplemented using the additional worldwide urd inventory. a step approach to myeloablative haploidentical hemato- poietic stem cell transplanation (hsct): report of a phase ii trial with months of follow-up for all patients grosso, d. , carabasi, m. , colombe, b. , cornett farley, p. , flomenberg, p. , filicko-o’hara, j. , kasner, m. , o’hara, w. , wagner, j.l. , weiss, m. , werner-wasik, m. , flomenberg, n. thomas jefferson kimmel cancer center, philadelphia, pa; thomas jef- ferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, phila- delphia, pa; thomas jefferson university hospital, philadelphia, pa; thomas jefferson university hospital, philadelphia, pa haploidentical hsct using post transplant cyclophosphamide (cy) for elimination of alloreactive lymphocytes has been reported as a safe option for patients lacking an hla identical donor. we re- port an alternate approach with the following salient differences: mye- loablative vs non-myeloablative conditioning, peripheral blood rather than marrow stem cell source, no exposure vs exposure of hsc to cy- clophosphamide, higher fixed number of cd cells versus a lower var- iable number of cd cells in each graft. results are reported now with a followed up of - months. table . patient characteristics- step approach age ( - ) aml remission resistant/pif biphenotypic leukemia (active disease) all cr (ph-) persistent disease (ph+) mds nhl resistant saa hla mm (gvh direction) patients received gy of total body irradiation (tbi), followed by a donor lymphocyte product (dli) containing � e cd cells/kg (step ). this large dose of haploidentical lymphocytes re- sulted in fever (median temperature . �f), diarrhea and rash. cy mg/kg was given on days - and - resulting in resolution of symp- toms. tacrolimus and mmf were begun on day- . a cd selected donor product was infused on day (step ). two of the patients died of toxicity and infection before day . of the remaining pa- tients, had complete engraftment while two with pre-existing anti-donor hla antibodies failed to engraft. only of ( %) pa- tients developed severe acute gvhd, of ( %) developed limited chronic gvhd, and no patient died of gvhd. only two of pa- tients ( %) died of infection. of disease-free patients surviving months from hsct, median cd count at day was cells/ ml (range - ). eight of ( %) patients relapsed after hsct. probability of survival (os) at and years post transplant is % and % respectively. all surviving patients are disease-free. os at years is % for patients transplanted in cr, but only % for patients transplanted with active disease. kir mismatching was not correlated with relapserates. incontrast, child tomother transplants for aml ap- pear to be relapsing at higher rates than other combinations ( % vs %). in the context of cy tolerization, a dose of � e /kg t-cells resultedinconsistentengraftment,prompt immunereconstitution,lit- tle severe gvhd, acceptable toxicity, and encouraging overall sur- vival, particularly in patients transplanted in cr. using this -step platform allows us to explore the use of alternate agents for the elimi- nationofalloreactive lymphocytes,increase the lengthoftime between dliand cy, and toemploytwo donor strategies toimprove outcomes in high risk patients. unmanipulated haploidentical stem cell transplantation using myeloablative or reduced-intensity preconditioning regimen ikegame, k., yoshihara, s., kaida, k., taniguchi, k., inoue, t., kato, r., fujioka, t., tamaki, h., okada, m., soma, t., taniguchi, y., ogawa, h. hyogo college of medicine, nishinomiya, hyogo, japan background: related haploidentical donors, as cord blood, can be alternative donor sources in stem cell transplantation (sct). severe gvhd, however, has interfered the progress of haploidentical sct (haplosct). to deal with this strong gvhd, t cell depletion has usually been used in us and european countries. in order to pursue the controllable gvl effect by t cells, we have performed unmanip- ulated haplosct using myeloablative or reduced intensity precondi- tioning regimen accompanied with intensified gvhd prophylaxis. in this meeting, we will summarize our experience of haplosct for more than ten years. patients: from august to september , we have performed cases of haplosct (all cases were hla - antigen mismatched in gvh direction). patients’ characteristics are sex: male , female , age: - years old (median ), disease: aml/mds , all , ml , others . % of cases underwent sct in non-complete remission (non-cr) state. patients under years old underwent mye- loablative preconditioning regimen consisting of flu/ca/cy/ tbi gy (haplo-full, n ), and patients over years old or with comorbidities or repetitive sct (including second to fifth sct) underwent reduced intensity preconditioning regimen consist- ing of flu/(ca)/bu/atg or flu/(ca)/mel/atg (haplo-mini, n ). high dose ara-c (ca) was optional to reduce tumor burden. as atg, atg (fresenius) mg/kg, or thymoglubulin (genzyme) - mg/kg were used. gvhd prophylaxis consisted of taclolimus (tac), methylprednisolone (mpsl) mg/kg/day, short term mtx, and mycophenolate mofetil (mmf) mg/kg/day in haplo-full, and tac, mpsl mg/kg/day in haplo-mini, respectively. for elderly pa- tients over years old in haplo-mini, mmf was added. results: hematopoietic engraftment in haplosct was as rapid as that in hla-identical sct, except ten cases of graft rejection. acute gvhd (grade ii-iv) was observed in %. overall survival in five years is % in haplo-full and % in haplo-mini, respectively. if limited to cr cases, overall survival reached over % in haplo- mini. there is no difference in survival rate among patients’ diseases. discussion: unmanipulated haplosct is feasible and effective for refractory diseases. atg dose used in haplo-mini is critical, and rather low compared with that of european cases reported so far. 	cord blood (cb) apgar score is predictive of neutrophil engraftment and graft failure probabilities for plasma depleted/red ... 	in-vivo expansion of t regulatory cells by rapamycin in a calcineurin-inhibitor free gvhd prophylaxis in unmanipulated hapl ... 	 / high-resolution hla match rate: the impact of race 	a step approach to myeloablative haploidentical hematopoietic stem cell transplanation (hsct): report of a phase ii trial ... 	unmanipulated haploidentical stem cell transplantation using myeloablative or reduced-intensity preconditioning regimen eta and two-pion electroproduction with clas james a. muellera for the clas collaboration a department of physics and astronomy, university of pittsburgh in the mass region above . gev many overlapping baryon states are present and some of them are not well known. there are also many baryon resonances predicted to be in this mass range which have never been observed. to fully understand the fundamental properties of baryon structure, the nucleon excitation spectrum must be measured in a variety of reaction channels. in this paper, we present results on the reactions ep → epπ+π− and ep → epη obtained with the clas detector at the thomas jefferson national laboratory. in the two-pion channel, the data show resonant structures not visible in previous experiments. phenomenological predictions based on available information on known n∗ and ∆ states fail to match our results. in the η channel, results from clas have already been published[ ]. now we present results from the an order of magnitude more statistics, yielding a precise measurement of the proton-s ( ) photocoupling over a wider range in q than any previous experiment. we also observe structure in the differential cross section that is not predicted by current phenomenological models. in both of these channels the observed discrepancies either indicate the presence of new baryon resonances[ ] or a significant revision of the properties of known states in the models. references [ ] r. thompson, et al., (the clas collaboration), phys. rev. lett. ( ) . [ ] b. saghai and z.p. li, eur. phys. j. a ( ) , s. capstick, et al., phys. rev. c ( ) . potent inhibition of human immunodeficiency virus type in primary t cells and alveolar macrophages by a combination anti-rev strategy delivered in an adeno-associated virus vector authors’ correction ( articles) nuclear preservation and cytoplasmic degradation of human immunodeficiency virus type rev protein satoshi kubota, lingxun duan, rika a. furuta, masakazu hatanaka, and roger j. pomerantz the dorrance h. hamilton laboratories, section of molecular retrovirology, division of infectious diseases, department of medicine, jefferson medical college, thomas jefferson university, philadelphia, pennsylvania, and institute for virus research, kyoto university, sakyo-ku, kyoto - , japan volume , no. , p. – . binding of intracellular anti-rev single chain variable fragments to different epitopes of human immunodeficiency virus type rev: variations in viral inhibition yong wu, lingxun duan, minghua zhu, baocheng hu, satoshi kubota, omar bagasra, and roger j. pomerantz the dorrance h. hamilton laboratories, center for human retrovirology, division of infectious diseases, department of medicine, jefferson medical college, thomas jefferson university, philadelphia, pennsylvania volume , no. , p. – . targeting human immunodeficiency virus type reverse transcriptase by intracellular expression of single-chain variable fragments to inhibit early stages of the viral life cycle farida shaheen, lingxun duan, minghua zhu, omar bagasra, and roger j. pomerantz the dorrance h. hamilton laboratories, section of molecular retrovirology, division of infectious diseases, department of medicine, jefferson medical college, thomas jefferson university, philadelphia, pennsylvania volume , no. , p. – . intracellular expression of single-chain variable fragments to inhibit early stages of the viral life cycle by targeting human immunodeficiency virus type integrase pnina levy-mintz, lingxun duan, huizhong zhang, baocheng hu, geethanjali dornadula, minghua zhu, joseph kulkosky, diane bizub-bender, anna marie skalka, and roger j. pomerantz dorrance h. hamilton laboratories, center for human virology, division of infectious diseases, department of medicine, jefferson medical college, thomas jefferson university, philadelphia, pennsylvania , and fox chase cancer center, philadelphia, pennsylvania volume , no. , p. – . o n a p ril , a t c a r n e g ie m e l l o n u n iv l ib r h ttp ://jvi.a sm .o rg / d o w n lo a d e d fro m http://jvi.asm.org/ potent inhibition of human immunodeficiency virus type in primary t cells and alveolar macrophages by a combination anti-rev strategy delivered in an adeno-associated virus vector roger t. inouye, bin du, deborah boldt-houle, anthony ferrante, in-woo park, scott m. hammer, lingxun duan, jerome e. groopman, roger j. pomerantz, and ernest f. terwilliger divisions of experimental medicine and hematology/oncology and infectious disease, beth israel deaconess medical center and harvard institutes of medicine, boston, massachusetts , and dorrance h. hamilton laboratories, center for human virology, division of infectious disease, thomas jefferson university, philadelphia, pennsylvania volume , no. , p. – . the following correction pertains to all of the above articles. the heavy chain of the d anti-rev single-chain variable fragment (sfv) has been reanalyzed and demonstrated to be an aberrant heavy chain sequence. this heavy chain sequence is very close to the aberrant heavy chain sequence published by p. thammana (molecular immunology : – , ), who derived it via rt-pcr directly from the rna of the ns cell line which is commonly used as a fusion partner to construct mouse hybridomas. therefore, it is likely that the aberrant d sfv heavy chain was derived from a gene originating from the fusion partner cell line used to make the original d hybridoma and not from the heavy chain gene expressed by the b-cell precursor to this hybridoma. this aberrant heavy chain has a deletion in the framework region (fr ) leading to a frameshift in cdr and downstream regions of the heavy chain gene. in addition, there were some individual nucleotide changes, on reanalysis, that brought the heavy chain sequence even closer to that described by thammana. it should also be noted that the function of the aberrant heavy chain in the d sfv is not known. as well, the initial amino acids in the d sfv represent a portion of the vk leader sequence. the possible effects, if any, of this segment on subcellular localization and/or secretion have not been investigated. there was noted to be rather minimal binding data for the d sfv available to be reevaluated at this time, including only a single elisa for the d sfv to recombinant rev and a single binding study of the activation domain peptide of rev. comparisons to the original d monoclonal antibody are not obtainable since the characteristics of the original monoclonal antibody are not fully demonstrated at the present time. as well, complete original data dealing with anti-rev d sfv binding to peptides of rev are not available at the present time. on reanalysis, inaccuracies in the d sfv sequence were noted. d sfv on resequencing showed the following differences compared to the published sequence: t to a (aca to gca), t to s (acg to tcg), and g to a (ggt to gct). nucleotide changes which did not alter the amino acid sequence were: c to t, g to c, t to a, and t to a (numbering started at initial atg codon). a nucleotide was demonstrated to be missing at position (g) (l ), compared to the original sequence, altering the remaining amino acids (dywgqgtsvtvssakttpppvyplapgs). on reevaluation, the originally reported d sequence would connote a frameshift in the cdr of vh, but now, as resequencing revealed the missing nucleotide, the frameshift is shown not to be present. thus, d sfv is, in fact, an appropriate antibody sequence. although further studies are planned, these additional findings do not alter the previous conclusions that intracellular d and d sfvs inhibit hiv- . we regret any difficulties these inaccuracies in the original publications may have caused. authors’ correction j. virol. o n a p ril , a t c a r n e g ie m e l l o n u n iv l ib r h ttp ://jvi.a sm .o rg / d o w n lo a d e d fro m http://jvi.asm.org/ the stoichiometry between micu and mcu determines the different mitochondrial ca + uptake phenotypes in heart and liver wednesday, february , a like ursodeoxycholic acid (udca) and tauroursodeoxycholic acid (tudca), are cytoprotective and inhibit cell death. the mechanisms associated with these distinct effects are not entirely clear. however, the effect of hydrophilic bile acids seems to be related with the blockage of a series of processes that converge on mitochondrial damage. bax is a pro-apoptotic protein that belongs to the superfamily of the bcl- proteins and is involved in mitochondrial pore formation. submicellar concentrations of cytoprotective bile acids have been shown to modulate bax concentration in mitochondria, suggesting that these molecules may interact directly with the protein. in this study, our objective was to evaluate the affinity of bile acids to recombinant bax protein, making use of fluorescence spectroscopy (fret and fluorescence anisotropy), as well as fluorescence correlation spectroscopy (fcs). our results show that the cytoprotective bile acids udca and tudca associate with recombinant bax protein with high affinity, while the cytotoxic bile acid dca only seems to be able to adsorb to the protein with much lower affinity. notably, the bind- ing site for udca seems to be located in a hydrophobic pocket of the protein. this interaction could be responsible for the disruption of bax translocation to the mitochondrial outer membrane in the presence of udca and/or tudca. supported from fct/portugal (projects ptdc/qui-biq/ / and reci/ctm-pol/ / ). t.s. and f.f. acknowledges fct grants sfrh/bd/ / and sfrh/ bpd/ / -pos board b mac inhibitors neutralize the pro-apoptotic effects of tbid pablo m. peixoto , oscar h. teijido , laurent m. dejean , evgeny pavlov , bruno antonsson , kathleen w. kinnally . natural sciences, baruch college - cuny, new york, ny, usa, national institute of child health and human development, baltimore, md, usa, chemistry, california state university of fresno, fresno, ca, usa, new york university college of dentistry, new york, ny, usa, merck serono, geneva research center, geneva, switzerland. since our initial characterization of the imacs, different di-bromocarbazole derivatives with anti-apoptotic function have been developed and tested in several mouse models of brain injury and neurodegeneration [ - ]. owing to the increased therapeutic potential of anti-apoptotic di-bromocarbazole de- rivatives, we sought to expand our knowledge of the mechanism of action of these small molecule inhibitors. we investigated the kinetics of mac inhibi- tion in mitochondria from wild type, bak, and bax knockout cell lines using patch clamp electrophysiology, fluorescence microscopy, elisa, and quantita- tive western blot analyses. our results show that imacs work through at least two mechanisms: ) by blocking relocation of the cytoplasmic bax protein to mitochondria and ) by disassembling bax oligomers in the outer membrane. a comparison of the inhibitory effects over channel conductance and cyto- chrome c release suggests that the imacs interacted with both bax and bak with similar kinetics. interestingly, wild type mitochondria were more suscep- tible to inhibition than the bak or bax knockouts. a quantitative western blot analysis showed that wild type mitochondria had lower steady state levels of bak, which suggests an uneven stoichiometry of the mac components. -pos board b tyrosine phosphorylation of mitochondrial ca d uniporter regulates mitochondrial ca d uptake jin o-uchi, stephen hurst, jyotsna mishra, xiaole xu, bong sook jhun, shey-shing sheu. depariment of medicine, center for translational medicine, jefferson medical college, thomas jefferson university, philadelphia, pa, usa. mitochondrial ca þ has a critical role for balancing cell survival and death. ca þ influx into mitochondrial matrix is mediated primarily by the mitochondrial cal- cium uniporter (mcu). however, the signaling pathways that regulate mcu channel functions via post-translational modifications of mcu are completely unknown. here we show that adrenergic signaling induces mcu tyrosine phos- phorylation and accelerates mitochondrial ca þ uptake in cardiac cells. adren- ergic signaling induces activation of proline-rich tyrosine kinase (pyk ) and translocation into the mitochondrial matrix; enhancing the interaction between pyk and mcu, which subsequently accelerates mitochondrial ca þ uptake via pyk -dependent mcu tyrosine phosphorylation. mcu contains tyrosine res- idues ( in the n-terminus, in the pore-forming region, in transmembrane do- mains and in the c-terminus), which are conserved across all eukaryotic species. among them, only of these tyrosine residues (y at n-terminus, y , and y at c-terminus in mouse mcu) remained as potential phosphor- ylation candidate sites for protein tyrosine kinases using phosphorylation predic- tion programs. we mutated these tyrosine residues to phenylalanine and generated non-phosphorylation mimetic mcu mutants (mcu-yfs). we confirmed that only two tyrosine sites were phosphorylated in response to adren- ergic stimulation in situ using cell lines stably expressing mcu-yfs. in addi- tion, overexpression of these mcu-yfs failed to increase mitochondrial ca þ uptake in response to cytosolic ca þ elevation by thapsigargin, whereas wild- type mcu transfection dramatically accelerates mitochondrial ca þ uptake compared to non-transfected cells. in summary, mcu contains pyk -specific phosphorylation site(s) and pyk -dependent tyrosine phosphorylation of mcu can modulate its channel functions and regulate mitochondrial ca þ uptake. -pos board b cardioprotective roles of neuronal ca d sensor- during stress tomoe y. nakamura-nishitani , shu nakao , shigeo wakabayashi . molecular physiology, natl.cer.cardiovasc.ctr., suita, japan, cardiac physiology, natl.cer.cardiovasc.ctrwakabayshi, suita, japan. dysregulation of ca þ homeostasis in cardiomyocytes often results in heart fail- ure. identifying molecular targets that regulate cardiomyocyte survival is of ther- apeutic importance. neuronal ca þ -sensor- (ncs- ) is an ef-hand ca þ - binding protein, which is important for excitable cell functions. we previously found that ncs- -deficient (ncs �/�) mice had excess neonatal mortality (circ. res. ).the aim ofthe present study isto examinewhether ncs- plays beneficial roles in cardiac survival during stress and the possible mechanisms un- derlying these effects. neonatal mouse ventricular myocytes orwhole hearts from wild-type (wt) and ncs �/� mice were subjected to stressors, and the resistance to stress was evaluated. ncs �/� mouse hearts were more susceptible to stress induced by oxidative impairment and ischemia-reperfusion injury. stress- inducedactivationofphosphatidylinositol -kinase (pi k)/akt signaling, a major survival pathway, was substantially reduced in the ncs �/�group, and overex- pressionofncs- ortheconstitutiveactive formofakt increased the survivalrate of ncs �/� myocytes. cellular atp levels, as well as mitochondrial respiration rates (both basal and maximal o consumption) were significantly depressed in ncs �/� myocytes; especially with oxidative stress. furthermore, intracellular ca þ handling was more easily dysregulated in stressed ncs �/� myocytes than wt myocytes. since ncs- levels were increased by stress, the data suggest that ncs- is a survival-promoting factor, which is upregulated by stress stimuli. interestingly, however,supra-physiological ncs- expression was toxic to cells. taken together, our data suggest that moderate ncs- expression during stress promotes cardiomyocyte survival by maintaining proper ca þ handling, which is required for activation of akt survival pathways and mitochondrial function. -pos board b initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart development gisela beutner, george a. porter, jr. pediatrics, university of rochester medical center, rochester, ny, usa. mitochondria in early embryonic hearts are not thought to produce atp, yet they do produce reactive oxygen species (ros) that regulate myocyte differen- tiation. to assess changes in atp and ros generation in the developing heart, we measured mitochondrial oxygen consumption, the activity of the complexes (cx) and of the electron transport chain (etc), etc supercomplex assem- bly, and ros in embryonic mouse hearts. at embryonic day (e) . , mitochon- drial etc activity and oxidative phosphorylation (oxphos) are not coupled, even though the etc complexes are present. we show that cx- is able to accept electrons from the krebs cycle, but enzyme assays that specifically mea- sure electron flow to ubiquinone or cx- show no activity at this early embry- onic stage. at e . , mitochondria appear functionally more mature; etc activity and oxphos are coupled and respond to etc inhibitors. in addition, the assembly of highly efficient respiratory supercomplexes containing cx � , � , and � , ubiquinone, and cytochrome c begins at e . , the exact time when cx- becomes functional activated. at e . , etc activity and oxphos of embryonic heart mitochondria are indistinguishable from adult mitochon- dria. in contrast, generation of reactive oxygen species (ros), as measured with amplex red, is high at e . and drops significantly by e . , coinciding with activation of the etc. in summary, our data suggest that between e . and e . dramatic changes occur in the mitochondria of the embryonic heart, which result in a decrease of ros generation and an increase in oxphos due to the activation of cx- and the formation of supercomplexes. -pos board b the stoichiometry between micu and mcu determines the different mitochondrial ca d uptake phenotypes in heart and liver melanie paillard, györgy csordás, tünde golenár, cynthia moffat, erin seifert, györgy hajnóczky. mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa. mitochondrial ca þ uptake is central to oxidative metabolism and cell death signaling. the first clues to its molecular mechanism have emerged from the recent identification of the mitochondrial ca þ uniporter’s pore forming protein (mcu) as well as its regulators. among the regulators, micu shows striking a wednesday, february , co-expression and co-evolution with mcu. micu has been demonstrated to be a ca þ -sensing protein, which both sets a threshold for low ca þ concentration while it assures cooperative activation during high ca þ rises. mitochondrial ca þ uptake shows tissue specific differences and interestingly, mrna level for micus and mcus also displays tissue specificity. we set out to investigate if the stoichiometry between micu and mcu could account for the previously described differences between heart and liver in mitochondrial ca þ uptake. immunoblotting showed higher expression for all micu , micu and mcu in mouse liver versus heart mitochondria, and a . fold higher micu to mcu ratio in liver. in fluorometric measurements of mitochondrial ca þ uptake, heart mitochondria displayed a decreased threshold and lesser cooperativity compared to liver mitochondria. additionally, nad(p)h elevation was detect- able after exposure to moderate [ca þ ] elevations only in heart mitochondria. overexpression of micu in the heart using aav -micu tail-vein injection significantly increased the micu protein level without any changes of micu or mcu. this increased the micu to mcu ratio in the heart and led to increased thresholding and cooperativity, reproducing the liver-like mito- chondrialca þ uptakephenotype.viceversamicu downregulationintheliver has been shown to lower the threshold and cooperativity of mitochondrial ca þ uptake in hepatocytes. thus, heart and liver mitochondria show different levels of ca þ threshold and cooperative activation of ca þ uptake, which seem to result from differential quantitative relationship between micu and mcu. -pos board b er calcium release is tuned by mitochondrial redox nanodomains david m. booth , balázs enyedi , miklós geiszt , péter várnai , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, department of physiology, semmelweis university, budapest, hungary. spatially and temporally controlled increases of h o emerge as an intracellular signal. we hypothesized that ros and ca þ interact locally, in the restricted vol- ume of the er-mitochondrial interface. these physically tethered structures host enrichments of ion transport proteins such as the ip receptor, which support elevated nanodomains of ca þ during signalling events and are sensitive to h o . we used the genetically encoded h o sensor hyper incorporated into an inducible linker system to probe the redox environment at the er- mitochondrial interface in hepg cells. we found a moderately elevated h o nanodomain which developes into a h o transient following ip receptor- mediated er ca þ release and mitochondrial ca þ uptake. pharmacological in- hibition showed that the transient was dependent upon er ca þ, mitochondrial membrane potential and functional electron transport chain. hyper measure- ments of the mitochondrial intermembrane space revealed significantly elevated h o within this volume. using electron microscopy we found that hepg mito- chondria possess a cohort of dilated cristae, which disappeared following ip - linked ca þ release. paxilline that inhibits mitochondrial bkca channels blocked the cristae reshaping and also abolished the h o transient at the inter- face. furthermore, paxilline caused suppression of the ip -linked calcium signal, whereas interface targeted killer red, a photoactivated h o source, induced sensitization to the ip -linked agonist. we conclude that the intermembrane/ cristae volume of mitochondria represents an oxidized pool fed by the electron transport chain. ca þ -uptake stimulates expansion of the mitochondrial matrix via kþ and concomitant water uptake, squeezing the oxidized volume of the cristae to the interface. here, a transient h o nanodomain sensitizes ip recep- tors to further stimulation. we demonstrate a physiological setting where ca þ release may autoregulate using mitochondrial h o released from the cristae. -pos board b reactive oxygen species (ros) suppress mitochondrial motility valentina debattisti, masao saotome, sudipto das, gyorgy hajnoczky. mitocare center, thomas jefferson university, philadelphia, pa, usa. mitochondrial distribution and transport play pivotal roles for many cellular functions, including cell differentiation, cell division to ensure proper inheri- tance, apoptosis, atp supply at the local sites of demand, ca þ buffering for intracellular ca þ homeostasis. we previously showed that mitochondrial motility (mito-motility) is regulated by the cytosolic ca þ concentration ([ca þ]c), providing the basis for a homeostatic circuit in which the organelles decrease their movements along microtubules to locally buffer high [ca þ ]c and contribute to atp supply. mito- chondria are also a major site for production and scavenging of ros that serve as both a messenger and regulator of calcium signaling and are particularly rele- vant for the control of mitochondrial function. here we tested the hypothesis that ros target mito-motility to control mitochondrial function. h c myoblast cells were transfected with a mitochondrial matrix targeted yfp and then loaded with fura , to monitor the mito-motility simultaneously with [ca þ ]c. h o ( mm) caused a decrease in mito-motility ( %) and an elevation in [ca þ ]c (from to nm) at the same time. when the cells were incu- bated in a ca þ -free medium and were pretreated with thapsigargin to prevent ca þ entry and intracellular ca þ mobilization, respectively, h o continued to inhibit the mito-motility dose-dependently without any changes in [ca þ]c. these results indicate that h o can cause suppression of mito-motility through a ca þ independent mechanism we are currently analyzing. -pos board b miro is dispensable for calcium-mediated inhibition of mitochondrial movement david b. weaver , agnieszka lewandowska , tammy t. nguyen , valentina debattisti , janet m. shaw , gyorgy hajnoczky . mitocare center, dept of pathology, anatomy and cell biology, thomas jefferson university, philadelphia, pa, usa, biochemistry, university of utah school of medicine, salt lake city, ut, usa. miro and are (rhot and ) are two highly similar gtpases that are bound to the surface of mitochondria and possess ef-hand calcium binding motifs. several groups have reported that miro is involved in mitochondrial motility and inheritance, and particularly its calcium regulation, but the roles of the two isoforms have not been established. genetic deletion of miro in mouse is lethal at birth (nguyen et al., ) and fibroblasts (mefs) derived from miro ko em- bryos show abnormal mitochondrial distribution, but the calcium-dependent in- hibition of motility is unaffected and the respiratory and calcium buffering capacities are normal. neuron-specific knockout of miro leads to progressive deficits of upper motor neuron function, however mitochondria in processes of cortical neurons from miro ko and wild-type embryos showed comparable calcium-sensitive motility inhibition. while no significant increase in miro pro- tein was observed in miro ko mefs, these data raise two possibilities: miro and are interchangeable with regard to calcium regulation of mitochondrial motility or miro is the key player in this regard. to finally resolve this question, we are in the process of generating miro ko and miro / ko cell lines. -pos board b mitochondrial fusion dynamics in the heart veronica eisner , ryan cupo , erhe gao , györgy csordás , lan cheng , jessica ibetti , j. kurt chuprun , walter j. koch , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, center for translational medicine, temple university school of medicine, philadelphia, pa, usa, center for translational medicine, thomas jefferson university, philadelphia, pa, usa. heart physiology depends on oxidative metabolism that likely requires dy- namic and permanent reorganization of mitochondria by fusion and fission. to directly evaluate mitochondrial fusion dynamics in cardiomyocytes (cm), mitochondrial matrix-targeted photoactivatable gfp and dsred were intro- duced either in vitro or in vivo by adenovirus and were followed by confocal microscopy. four conditions were analyzed: to h cultured neonatal and in vitro transduced adult cm, and cm from in vivo infected rat hearts. in the latter case, cm were isolated - days after infection and were imaged promptly or - h post harvesting. neonatal cm mitochondria form a highly connected network, whereas both in vitro and in vivo transformed cultured cm displayed only some connectivity. impressively, in vivo transduced adult cm that were imaged promptly after harvesting, unveiled a significantly higher con- nectivity among mitochondria than the - h cultured adult cm. furthermore, fusion events (f.e./ square micrometers/min) were almost absent in cultured in vitro transduced cm, meanwhile in vivo transduced and cultured cm showed . . f.e./min, whereas isolated, freshly-imaged cm displayed . . f.e./min. imaging in perfused whole heart ex vivo, showed consider- able mitochondrial continuity and fusion activity in ventricular cm. to study more directly the role of cm’s contractile activity in mitochondrial fusion, cm were incubated with verapamil ( mm), that blocked spontaneous contrac- tion and partially suppressed the fusion activity of mitochondria. also, mito- chondrial fusion activity appeared to be higher after spontaneous contraction or short term field stimulation in isolated freshly-imaged cm. thus, mitochon- dria are dynamic in both neonatal and adult cm, but under culture conditions, adult cm lose mitochondrial fusion activity. this might be at least in part, because cardiomyocyte contractile activity is altered in culture and contractions likely provide some factors to support mitochondrial fusion activity. -pos board b mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide venkat r. pannala, ranjan k. dash. bioengineering and biotechnology, department of physiology, medical college of wisconsin, wauwatosa, wi, usa. the thioredoxin system plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (h o ). specifically, 	mac inhibitors neutralize the pro-apoptotic effects of tbid 	tyrosine phosphorylation of mitochondrial ca + uniporter regulates mitochondrial ca + uptake 	cardioprotective roles of neuronal ca + sensor- during stress 	initiation of electron transport activity and a decrease of oxidative stress occur simultaneously during embryonic heart de ... 	the stoichiometry between micu and mcu determines the different mitochondrial ca + uptake phenotypes in heart and liver 	er calcium release is tuned by mitochondrial redox nanodomains 	reactive oxygen species (ros) suppress mitochondrial motility 	miro is dispensable for calcium-mediated inhibition of mitochondrial movement 	mitochondrial fusion dynamics in the heart 	mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide water at the potassium channel gate: quantum calculations show an oscillation in water structure sunday, february , a -pos board b access constraints and binding energetics of a potassium channel inactivation gate gaurav venkataraman, deepa srikumar, miguel holmgren. nih, bethesda, md, usa. voltage-activated potassium (kv) channels open an intracellular gate in re- sponse to changes in transmembrane voltage, allowing k þ to permeate at rates near diffusion. in some kv channels, permeation can be interrupted by the n-terminus of the protein acting as a blocking particle, binding at the intracel- lular cavity of the channel and physically obstructing the permeation pathway. despite being tetramers, kv channels require only one bound n-terminus to inactivate. in nature, inactivation is targeted by rna editing, which converts an isoleucine of the intracellular cavity into a valine. the functional conse- quence is a large increase in unbinding kinetics. how does each ‘‘wall’’ of the cavity contribute to the increase in unbinding kinetics of a single bound n-terminus? to address this question we made con- catenated shaker heterotetramers consisting of only one free n-terminus and a single isoleucine to valine mutation at position (i v), mimicking the rna editing site in humans and rodents. surprisingly, the rate of unbinding was the same for individual i v mutations in each wall; each corresponded to a decrease in binding energy of about . rt. in fact, the binding energy de- creased linearly as a function of the number of i v mutated subunits. these results suggest that despite being tethered to a particular subunit, the single in- activation particle has sufficient freedom to interact with position of each subunit with roughly equal probability. where does this freedom come from? it is expected that the inactivation gates enter the cavity through lateral ‘windows’, similarly to k þ . can our single tethered inactivation gate enter through each of the four windows of the protein? we will address this question by making individual cysteine mutations at each window and testing the inac- tivation gate’s binding kinetics after chemical modification. -pos board b gating interactions between the cytoplasmic t domain and pore of a kv channel brian urbani, manuel covarrubias. jefferson medical college of thomas jefferson university, philadelphia, pa, usa. whereas the gating roles of the voltage-sensing and pore domains of kv channels have been extensively investigated, much less is known about the mechanisms governing the regulation of gating by the cytoplasmic t domain. previous work from this lab strongly suggests that the kv . t domain un- dergoes conformational changes directly linked to gating (j. gen. physiol., : - , ); however, the structural basis of the communication between the activation gate and the t domain has remained elusive. to tackle this problem, we applied cysteine scanning mutagenesis, voltage- clamp electrophysiology, double mutant cycle analysis (dmca) and oxidizing reagents to probe specific interactions between the cytoplasmic t domain l helix, the s -s linker and s tail. the energetic impact of the mutations on activation gating is apparently small. by comparison, the energetic impact of the mutations on inactivation gating was significantly greater. dmca of k c(l )þa c(s ) revealed a significant interaction energy ( kcal/ mol), which suggests an interaction between k in the l helix and a in s . supporting this possibility, the currents induced by k c(l )þ a c(s ) are inhibited (~ % of control) by an oxidizing agent (tbuho ), whereas the single mutants are not; and the effect is reversed by the reducing agent dtt. these results indicate the formation of a disulfide bond between the interacting side chains, which is consistent with physical interaction between k (l ) and a (s ). overall, we conclude that regulation of inactivation gating by the t domain involves a physical interaction between the t l helix and the distal segment of s . supported by nih grant r ns (mc). -pos board b is the activation gate closed in kv channel closed-state inactivation? jeffrey d. fineberg, manuel covarrubias. thomas jefferson university, philadelphia, pa, usa. kv .x channel complexes including auxiliary subunits such as dpp -s and kchip undergo preferential closed-state inactivation (csi; baehring and covarrubias, , j physiol, . : - ; fineberg et al., , j gen physiol, in press). however, the molecular basis of csi in kv .x channels remains poorly understood. a key unanswered question of this problem is whether the channel’s activation is actually closed, as csi implies. we have previously proposed that csi results when the activated channel fails to open or simply prefers to close. this hypothesis specifically suggests that the intra- cellular activation gate may adopt a stable closed conformation, even under depolarized conditions that would initially favor the activated ‘‘up’’ state of the voltage sensors. to test this hypothesis, we are exploiting the trapping paradigm previously investigated by holmgren et al. to test the state of the intracellular activation gate ( , j gen physiol, : - ). essentially, if the activation gate closes behind a quaternary ammonium (qa) blocker inside the pore, the blocker cannot exit the pore; effectively, it is trapped. we are expressing the ternary kv . /i c channels (this mutation favors trap- ping) including dpp -s and kchip in xenopus oocytes. then, in the inside- out patch-clamp configuration, we are using a computer-controlled perfusion system to deliver the qa derivative decyltrimethylammonium bromide (c ) to the bath and probe the ability of the channel’s activation gate to trap c in the closed, open and inactivated states. preliminary results show that the trapping paradigm may yield an answer to the central question of this study. if the activation gate is indeed closed during csi, c trapping will only occur when the drug is applied to the conducting channel, but no trapping of c will be observed in the closed and inactivated states. supported by nih grant r ns (mc). -pos board b water at the potassium channel gate: quantum calculations show an oscillation in water structure alisher m. kariev, michael e. green. city college of the city university of ny, new york, ny, usa. quantum calculations on the open gate and the immediately surrounding re- gion of the kv . voltage gated potassium channel show that water adopts two conformations there, one when the ion is present, and another with no ion present. an energy minimum at the gate with no ion allows an ion to enter from the solution; from the gate it repels an ion in the channel pore cavity into the selectivity filter (essentially the ‘‘knock-on’’ mechanism). the pore cavity minimum can then be occupied by the ion moving from the gate minimum, leaving it available for anion from bulk, so the cycle continues. the arrange- ment of water, and the ion hydration, defines the gate energy minimum, and this in turn depends on the highly conserved prolines, especially p ( a pdb numbering), in the pvpv sequence in the gate. absent an energy minimum at the gate an ion entering from solution would be repelled back into solution by the ion in the cavity. furthermore, the ion remains hydrated by water molecules, at least more than in bulk, as it passes through the gate, based on optimizations with the ion at three different positions: ) at the gate position nearest p ) å above ) å below, this position. the open gate maintains very nearly the same protein atom positions throughout. additional calculations will be required to determine the exact interaction en- ergy with an ion in the cavity, and the amount of water that is present in the cavity. optimizations of the system configuration were done at hf/ - gsp level, with atoms ( with the ion). energy was determined using both b lyp/ - g* and bvp / - g*, but the system was too large for free en- ergy determination. -pos board b water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computational mutations, and the role of a histidine in gating alisher m. kariev, michael e. green. city college of the city university of ny, new york, ny, usa. conservation of the pvpv sequence at the potassium channel gate has not been well understood. quantum computations (optimization at hf/ - gsp level) of the gate of the kv . channel that are presented here show that the proline-proline distances (ring atoms) are preserved as the ion moves through the gate. this calculation is supplemented by mutating one of the prolines to valine (p v, a pdb numbering for all residues in this abstract) in the computation, producing a pvvv sequence. water structure changed dramati- cally, as the protein backbone moved inward nearly å, effectively closing the channel; the proline ring n-n distance between diagonally opposite pro- lines dropped from . å (distance from optimization: x-ray distance = . å) to . å, too small to allow passage of a hydrated k þ . this suggests that the prolines play a key structural role, modulating both protein and water structure. furthermore, protonation of h may close the channel. protonation of this histidine shows it moving toward the gate by about å, which should close the gate electrostatically, while deprotonation opens the gate. protonation was calculated with two added protons, the other being accepted by e of the t intracellular moiety. when deprotonated, the histidine does not move as much as å from the x-ray position in the optimization, and is linked to e ; this accounts for the known importance of the t segment in gating. e , also of t , could accept a third proton. there is a salt bridge structure including these residues similar to the one occupying a key position in the pro- ton pathway in the hv channel. 	access constraints and binding energetics of a potassium channel inactivation gate 	gating interactions between the cytoplasmic t domain and pore of a kv channel 	is the activation gate closed in kv channel closed-state inactivation? 	water at the potassium channel gate: quantum calculations show an oscillation in water structure 	water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computation ... in this issue: communicable disease omar a. khan, md, mhs; and timothy e. gibbs, mph . president, delaware academy of medicine / delaware public health association; editor-in- chief, delaware journal of public health . executive director, delaware academy of medicine / delaware public health association this is truly a milestone moment for the delaware academy of medicine / delaware public health association. at our annual meeting this year (the th), our keynote address was delivered by david heymann, m.d., d.t.m.&h., c.b.e., speaking about a lifetime combating global communicable diseases. the entire collection of images from this event is available online at https://delamed.org/images-from-the- th-annual-meeting-of-the-academy-dpha/. immediately before dr. heymann’s presentation, we recognized the extraordinary work of the william j. holloway community program at christiana care health system. now expanded to include sites throughout the state, their efforts have been a part of the success story regarding hiv—seeing it go from being a fatal illness, to a manageable chronic disease. the award was accepted by dr. susan szabo and arlene bincsik r.n., m.s., c.c.r.c., a.c.r.n. arlene was thanked in particular, for her years of advocacy, care, and education. for more on the story, see: https://news.christianacare.org/ / /william-j-holloway-program-honored-by-delaware- academy-of-medicine/ the timing of this issue on communicable disease could therefore not be better. it follows the day-long holloway infectious disease symposium and the spectacular events and awards above. we are indebted to our expert guest editors, neal goldstein, ph.d. and deborah kahal, m.d. for their guest editorship of this issue. we also recognized the work of sherman l. townsend, chair of the delaware institute for medical education and research (dimer), with the lewis b. flinn president’s award. his leadership of dimer, which along with the delaware branch campus at christiana care acts as delaware’s medical school, has been assuring spots for delaware students at our philadelphia medical school partners for nearly years. we take this opportunity to thank the sidney kimmel medical college of thomas jefferson university and the philadelphia college of osteopathic medicine for their continued partnership in helping serve delawareans’ health needs through a well-trained workforce. to those of you who have read the delaware journal of public health from the start in , you’ll notice a change in the layout and readability of this issue. this is a result of reader feedback; as a result we have improved viewability and readability of graphics and text on mobile devices. we hope that you like the change, and as always, keep the comments coming! 	in this issue: communicable disease erratum evaluation of a scaling approach for the bioequivalence of highly variable drugs sam h. haidar, , fairouz makhlouf, donald j. schuirmann, terry hyslop, barbara davit, dale conner, and lawrence x. yu published online september the affiliations listed in the pdf and online version of this article for donald j. schuirmann and terry hyslop were incorrect. the correct affiliations for these authors are: ( ) division of biostatistics, thomas jefferson university, chestnut st., suite m , philadelphia, pennsylvania, usa ( ) office of biostatistics, cder/fda, new hampshire ave, silver spring, maryland, usa - / / - / # american association of pharmaceutical scientists the aaps journal, vol. , no. , september (# ) doi: . /s - - -y the online version of the original article can be found at http://dx.doi. org/ . /s - - - . office of generic drugs, cder/fda, standish place, hfd- , rockville, md , usa. office of biostatistics, cder/fda, new hampshire ave, silver spring, md, usa. division of biostatistics, thomas jefferson university, chestnut st., suite m , philadelphia, pa, usa. to whom correspondence should be addressed. (e-mail: sam. haidar@fda.hhs.gov) http://dx.doi.org/ . /s - - - http://dx.doi.org/ . /s - - - 	evaluation of a scaling approach for the bioequivalence << /ascii encodepages false /allowtransparency false /autopositionepsfiles true /autorotatepages /none /binding /left /calgrayprofile (gray gamma . ) /calrgbprofile (srgb iec - . ) /calcmykprofile (iso coated v % \ eci\ ) /srgbprofile (srgb iec - . ) /cannotembedfontpolicy /error /compatibilitylevel . /compressobjects /off /compresspages true /convertimagestoindexed true /passthroughjpegimages true /createjdffile false /createjobticket false /defaultrenderingintent /perceptual /detectblends true /detectcurves . /colorconversionstrategy /srgb /dothumbnails true /embedallfonts true /embedopentype false /parseiccprofilesincomments true /embedjoboptions true /dscreportinglevel /emitdscwarnings false /endpage - /imagememory /lockdistillerparams true /maxsubsetpct /optimize true /opm /parsedsccomments true /parsedsccommentsfordocinfo true 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popcþpope. -pos board b hiv fusion peptide perturbs membrane structure in a cholesterol dependent fashion alex liqi lai, jack h. freed. acert, cornell university, ithaca, ny, usa. the fusion between viral envelopes with host cell membranes is required for viral entry and infection, which is mediated by special glycoproteins anchored on the viral membrane. fusion peptide (fp) is the domain that initiates mem- brane fusion. however, the mechanism of membrane fusion is still unclear. we previously found that the influenza hemagglutinin fp increases the order of dmpc lipid bilayer. we hypothesize that inducing lipid ordering might be a critical step in fusion caused by a variety of fusion proteins. hiv gp fp plays a similar role as influenza ha fp. however, gp fp is polymorphic and changes from alpha helix to beta aggregation as cholesterol concentration in lipid increases. we used pc spin labels on the lipid head group and different positions on the acyl chain to detect the perturbation by gp fp to popc/ popg lipid bilayers with different cholesterol concentration ( % to %) by cw-esr. our data show that ) gp fp affects the lipid order in the same pat- tern as ha fp does, i.e., a cooperative effect vs. lipid/peptide ratio, thus sup- porting our hypothesis; ) gp fp induces membrane ordering in all tested lipid compositions, consistent with promoting membrane fusion in these com- positions; ) in the high cholesterol containing lipid bilayers, whereas gp fp is in the beta aggregation conformation, its effect on the lipid ordering reaches deeper into the bilayer, consistent with deeper membrane insertion for gp fp in this conformation. we are extending the esr studies to look for coexisting membrane microdomains induced by different conformations of fps and the fp partitioning between them and for precise separation of the effects of ordering and molecular motion. -pos board b cd binding induces an asymmetric transition of hiv- env from its native conformation into the prehairpin intermediate state mukta d. khasnis, konstantine halkidis, anshul bhardwaj, michael root. thomas jefferson university, philadelphia, pa, usa. hiv- membrane fusion is mediated by sequential binding of the viral homo- trimeric env (gp /gp ) to cellular cd and chemokine receptor (cxcr or ccr ). these binding events coordinate conformational transitions of the gp trimer from its native conformation into a prehairpin intermediate state (phi) and, subsequently, into its fusogenic trimer-of-hairpins structure (toh). in the phi, the gp trimer assumes an extended conformation that bridges the viral and cellular membranes, and exposes the n-hr and c-hr do- mains which are targeted by hiv- fusion inhibitors t and -helix, respec- tively. our previous work suggests that the phi-to-toh transition occurs in a concerted (symmetric) fashion. here, we investigate the transition from the native state to the phi using a functional complementation strategy that em- ployed heterotrimeric envs containing only one or two functional cd - and chemokine receptor-binding sites. additionally, by incorporating t - and -helix- resistance mutations into individual env protomers, we were able to interrogate exposure of discrete gp n-hr and c-hr domains. our data indicate that a single cd binding to an env trimer is sufficient to promote fusion. moreover, the first cd binding event appeared to expose only one of three possible binding sites for each fusion inhibitor, suggesting an asymmetric transition into the phi. this asymmetry was significantly more pronounced in the gp n-hr region compared to the gp c-hr region. these results can be used to explain the multiphasic titration of mutant env homotrimers that naturally form asymmetric n-hr domain structures. taken together, these data suggest that the native state-to-phi transition of env occurs in a multistep (asymmetric) fashion. -pos board b evolution of hiv- resistance to a cholesterol-linked d-peptide fusion inhibitor amanda e. siglin , nicholas francis , michael s. kay , micheal j. root . thomas jefferson university, philadelphia, pa, usa, university of utah, salt lake city, ut, usa. during hiv- entry, the n-hr and c-hr regions of the gp viral glycoprotein associate to form a trimer-of-hairpins critical for membrane fusion. the n-hr region contains a highly conserved hydrophobic pocket that is the target for a multivalent, d-peptide fusion inhibitor, pie -trimer. recently, a modified form of this inhibitor with a conjugated cholesterol (chol-pie -trimer) was shown to possess up to -fold increased potency, presumably due to mem- brane targeting. here, we determined the resistance profile of chol-pie - trimer starting from either inhibitor-naı̈ve or pie -trimer-resistant hiv- (nl - strain). viral propagation in increasing inhibitor concentrations pro- duced hiv- populations with - to -fold reduced sensitivity chol- pie -trimer. these viruses were also resistant to the parental, unconjugated inhibitor pie -trimer. using hiv- fusion inhibitors di-c and -helix, we were able to interrogate the effect of escape mutations on the exposure of the gp n-hr and c-hr regions, respectively. resistance to chol-pie - trimer resulted in a slight decrease in the temporal window of n-hr exposure, regardless of the starting viral population. exposure of the c-hr region was unchanged for resistant viruses generated from the inhibitor-naı̈ve viral pool. by contrast, the temporal window of c-hr exposure was significantly increased (> -fold) for resistant viruses that were generated from the pie -trimer-resistant viral pool. efforts to identify the mechanisms of chol- pie -trimer resistance and the decoupling of n-hr and c-hr exposure are underway. -pos board b fusogenic activity of the hiv- gp mper-tmd region: mechanism and targeting by immunogens and inhibitors jose l. nieva , beatriz apellaniz , carmen domene , nerea huarte , eneko largo . biophysics unit (csic-upv/ehu) and dept. of biochemistry, university of the basque country (upv/ehu), bilbao, spain, chemistry research laboratory, university of oxford, oxford, united kingdom. fusion of the viral envelope with the cell membrane marks the beginning of the hiv- replicative cycle. this event is targeted by inhibitors currently in clinical use and by preventive vaccines under development. antibodies e and e bind to the gp membrane proximal external region (mper)- transmembrane domain (tmd) junction and block fusion. these antibodies display the broadest viral neutralization known to date, which underscores the conservation and functionality of the mper-tmd region. in recent work, we have described that peptides representing this region have potent membrane-destabilizing effects. here, based on the outcome of vesicle assays, atomic force microscopy studies and molecular dynamics simulations, we propose a mechanism for the involvement of the mper-tmd region in hiv- fusion. in addition, we provide evidence that underpins the poten- tial use of its activity as a new target for inhibitor and immunogen development. -pos board b studies on the membrane-active behavior of outer membrane vesicles from a gram negative bacterium william bartos, rensa chen, donald y. kobayashi, paul r. meers. rutgers, the state university of new jersey, new brunswick, nj, usa. gram-negative bacteria are known to produce small ~ - nm vesicles by ‘‘blebbing’’ of their outer membranes. these outer membrane vesicles (omv) have been implicated in activities such as transmission of virulence fac- tors, horizontal gene transfer and development of biofilms. in this investigation, the interactions of omv from lysobacter enzymogenes (strain c ) with other membranes have been monitored using fluorescent assays for association and/or fusion. defined composition large unilamellar vesicles labeled with the fluorescence resonance energy transfer (fret) pair , -dipalmitoyl-sn- glycero- -phosphoethanolamine-n-( -nitro- - , -benzoxadiazol- -yl) (nbd- pe) and , -dipalmitoyl-sn-glycero- -phosphoethanolamine-n-(lissamine rho- damine b sulfonyl) (rh-pe) were incubated with isolated omv to observe the interaction via the fret ratio of donor/acceptor. omv substantially increased this ratio over the course of about an hour (t / ~ - min.) at �c, when added directly to vesicles comprising disordered or fluid lipids, such as -palmitoyl- -oleoyl-sn-glycero- -phospho-( ’-rac-glycerol) (popg), -pal- mitoyl- -oleoyl-sn-glycero- -phosphoethanolamine (pope) or -palmitoyl- - oleoyl-sn-glycero- -phosphocholine (popc). this apparent fusion was much more limited or absent with liquid ordered membranes of , -dipalmitoyl-sn- glycero- -phosphocholine/cholesterol (dppc/chol). in the case of popg/ pope / vesicles, apparent fusion was also confirmed by testing vesicles with exclusively inner monolayer fluorescent probes to diminish any fluores- cence changes from external interactions of outer monolayer fluorophores. when the omv were labeled with the fluorophore , -dioctadecyl- , , , - tetramethylindocarbocyanine, and incubated with a natural host, yeast cells (strain s ), association and/or fusion was observed by co-sedimentation of the omv label with yeast cells. these studies may help to elucidate the mech- anism of natural host-pathogen interactions and define the lipid specificity for 	hiv fusion peptide perturbs membrane structure in a cholesterol dependent fashion 	cd binding induces an asymmetric transition of hiv- env from its native conformation into the prehairpin intermediate state 	evolution of hiv- resistance to a cholesterol-linked d-peptide fusion inhibitor 	fusogenic activity of the hiv- gp mper-tmd region: mechanism and targeting by immunogens and inhibitors 	studies on the membrane-active behavior of outer membrane vesicles from a gram negative bacterium case report a -year-old male with fever and persistent lung infiltrate tajender s vasu md, rodrigo cavallazzi md, amyn hirani md, and paul e marik md acute fibrinous and organizing pneumonia is a newly recognized pattern of lung injury. it may be idiopathic or secondary to a variety of lung injuries. in this case report we describe a -year-old male with acute fibrinous and organizing pneumonia caused by decitabine. he had substantial clinical and radiological improvement after the discontinuation of decitabine and a course of corticosteroids. key words: acute respiratory distress syndrome, ards, acute lung injury, ali, decit- abine, myelodysplastic syndrome, drug induced pneumonitis, acute fibrinous and organizing pneumonia. [respir care ; ( ): – . © daedalus enterprises] introduction a wide variety of drugs can cause pulmonary injury and should be considered during the evaluation of lung infil- trate. early diagnosis is important because unrecognized toxicity can be progressive and even fatal. drug-induced lung injury may manifest in a variety of histological pat- terns. acute fibrinous and organizing pneumonia is a dis- tinct pattern of reaction of the lung to injury. it is char- acterized by intra-alveolar fibrin balls and organizing pneumonia. the absence of hyaline membranes, granulo- matous inflammation, and eosinophilic deposition are im- portant distinguishing features. case report a -year-old male came to our hospital with dry cough, fever, and chills, of weeks duration. he had a history of myelodysplastic syndrome, developing after the successful treatment of acute myelogenous leukemia. four weeks earlier he had received mg of intravenous decitabine daily for days. at the time of hospitalization he had just completed a second course of decitabine. on examination his temperature was °f, blood pressure was / mm hg, heart rate was beats/min, oxygen saturation was % on room air, and respiratory rate was breaths/ min. his lung examination had inspiratory crackles in the left lung base. the rest of his physical examination was unremarkable. he had pancytopenia, with white-blood-cell count of . � cells/l (normal range of – � cells/ l), hemoglobin of . g/dl (normal range of – g/dl), and platelets of , cells/l (normal range of , – , cells/l). his differential count showed % neu- trophils, % lymphocytes, and % monocytes. his se- rum sodium, potassium, creatinine, magnesium, calcium, and liver function test were all within normal limits. blood and urine cultures were negative. the chest radiograph showed an ill-defined left-lower-lobe infiltrate. he was started on broad-spectrum antibiotics, including an anti-fungal agent. the computed tomography scan of his chest (fig. ) revealed a left-lower-lobe consolidation. computed-tomography-guided needle aspiration of the left lower lobe was non-diagnostic. he underwent bronchos- copy with bronchoalveolar lavage, which was non-diag- nostic. his bronchoalveolar lavage fluid showed % mac- rophages, % neutrophils, and % lymphocytes. he remained febrile despite treatment with antibiotics. a re- peat computed tomography of the chest (fig. ) days later showed worsening of the left-lower-lobe consolida- tion. the patient underwent video-assisted thoracoscopic wedge biopsy of the left lower lobe. the open-lung biopsy from the left-lower lobe (fig. ) showed patchy areas of organizing pneumonia with fibrin balls within the alveoli and air spaces. there was no hyaline membrane. the di- agnosis of acute fibrinous and organizing pneumonia sec- tajender s vasu md, rodrigo cavallazzi md, amyn hirani md, paul e marik md are affiliated with the division of pulmonary and critical care medicine, thomas jefferson university, philadelphia, pennsylva- nia. the authors have disclosed no conflicts of interest. correspondence: tajender s vasu md, division of pulmonary and crit- ical care medicine, thomas jefferson university, walnut street, suite , philadelphia pa . e-mail: tajender.vasu@ jeffersonhospital.org. respiratory care • september vol no ondary to decitabine was established. he was started on methylprednisone mg intravenously, every hours, fol- lowed by mg of oral prednisone daily. he had substan- tial clinical and radiological improvement after discontin- uation of decitabine and a course of corticosteroids. discussion acute fibrinous and organizing pneumonia was first de- scribed by beasley et al in . in their paper they noted several conditions associated with acute fibrinous and or- ganizing pneumonia, including collagen-vascular disease, lymphoma, amiodarone, and infections caused by hae- mophilus influenzae and acinetobacter baumannii. re- cently, acute fibrinous and organizing pneumonia has also been reported in patients with dermatomyositis, acute lym- phocytic leukemia, severe acute respiratory syndrome, and secondary to drugs, including abacavir and busulfan. patients with acute fibrinous and organizing pneumonia may have an acute or subacute clinical course. the pattern of the acute form resembles the clinical picture of acute lung injury. decitabine is a hypomethylating agent that was recently approved by the food and drug administra- tion for the treatment of myelodysplastic syndrome. the major adverse effect of decitabine is myelosuppression. other adverse effects, including fever, nausea, vomiting, diarrhea, bone aches, hyperbilirubinemia, and skin rash, have also been described. to the best of our knowledge this is the first case describing acute fibrinous and orga- nizing pneumonia pattern of lung injury secondary to de- citabine. the classic histological findings of acute fibrinous and organizing pneumonia include intra-alveolar fibrin balls with organizing pneumonia. this pattern must be distin- guished from diffuse alveolar damage, bronchiolitis oblit- erans organizing pneumonia, and eosinophilic pneumo- nia. fibrin deposits are found in diffuse alveolar damage and bronchiolitis obliterans organizing pneumonia, but, fig. . computed tomogram shows a left-lower-lobe consolida- tion. fig. . repeat computed tomography days later shows wors- ening of the left-lower-lobe consolidation. fig. . micrograph from the open-lung biopsy of the left-lower lobe shows patchy areas of organizing pneumonia with fibrin balls in the alveoli and air spaces. a -year-old male with fever and persistent lung infiltrate respiratory care • september vol no unlike acute fibrinous and organizing pneumonia, these deposits do not represent the major findings. the air-space involvement in acute fibrinous and organizing pneumonia is patchy in distribution, as opposed to diffuse involve- ment in diffuse alveolar damage. hyaline membranes, gran- ulomatous inflammation, and eosinophilic infiltrates are absent in acute fibrinous and organizing pneumonia. the retrospective review by beasley et al demonstrated that approximately % of patients with acute fibrinous and organizing pneumonia required mechanical ventila- tion. notably, all those patients who needed mechanical ventilation died. the acute fibrinous and organizing pneu- monia pattern portends a poor prognosis, with a mortality rate of more than %. the clinical course of these pa- tients is similar to those with diffuse alveolar damage, and, indeed, acute fibrinous and organizing pneumonia may be a fibrinous variant of diffuse alveolar damage. treatment with corticosteroids and discontinuation of the underlying drug may be attempted. references . erasmus jj, mcadams hp, rossi se. drug-induced lung injury. semin roentgenol ; ( ): - . . beasley mb, franks tj, galvin jr, gochuico b, travis wd. acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage. arch pathol lab med ; : - . . prahalad s, bohnsack jf, maloney cg, leslie ko. fatal acute fi- brinous and organizing pneumonia in a child with juvenile dermato- myositis. j pediatr ; ( ): - . . kim bc, servi r, sucai bi, ramsey r. acute lymphoblastic leuke- mia presenting with an acute fibrinous and organizing pneumonia. j respir dis ; : - . . hwang dm, chamberlain dw, poutanen sm, low de, asa sl, butany j. pulmonary pathology of severe acute respiratory syndrome in toronto. mod pathol ; ( ): - . . yokogawa n, alcid dv. acute fibrinous and organizing pneumonia as a rare presentation of abacavir hypersensitivity reaction. aids ; ( ): - . . colby tl, yousem sa, kitaichi m. atlas of pulmonary surgical pathology. philadelphia: wb saunders; . . kantarjian hm, o’brien s, shan j, aribi a, garcia-manero g, jab- bour e, et al. update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors asso- ciated with outcome. cancer ; ( ): - . . epler gr, colby tv, mcloud tc, carrington cb, gaensler ea. bronchiolitis obliterans organizing pneumonia. n engl j med ; ( ): - . . liebow aa, carrington cb. the eosinophilic pneumonias. medi- cine (baltimore) ; ( ): - . a -year-old male with fever and persistent lung infiltrate respiratory care • september vol no pms an assessment of self reported outcomes in a nationally representative sample of elderly person diagnosed with rheumatoid arthritis abstracts a symptom). the health assessment questionnaire (haq) was used to measure func- tional status (scores – ). qol was measured by the mental (mcs) and physical (pcs) component summary scores of the short form- (sf- ). work/productivity loss was measured by the work productivity and activity impairment (wpai) instrument. comparisons were made between patients who currently use sc biologics versus those who discontinued treatment. results: of the , survey respondents ( % female; average age . years), ( . %) used sc biologics. the average dura- tion of ra was . years, with % reporting severe disease. the patient-reported mean scores were: morning stiffness . , fatigue . , pain . , haq . , mcs . and pcs . . patients reported . % work impairment and . % impairments in daily activity. patients who had discontinued sc biologic therapy (n , . %) reported signifi cantly worse scores in morning stiffness, fatigue, pain, and pcs (all p . ) versus patients currently treated with sc biologics (n , . %). patients who discontinued therapy had more work/activity loss; only activity impair- ment was statistically signifi cant (p . ). there was no signifi cant difference in haq scores between groups. conclusions: ra patients using current sc biolog- ics still suffer from serious impairments in symptoms, functional status, qol, and work/productivity. however, patients who discontinued sc biologic therapy have sig- nifi cantly worse symptom scores, physical functioning, and activity impairment com- pared with those currently being treated. both fi ndings indicate there is still an unmet medical need in ra patients. pms utility and quality of life of patients with osteoarthritis treated with the cyclooxygenase inhibiting nitric oxide donator (cinod) naproxcinod jonsson b , pfi ster p , holmstrom s , kobelt g uppsala university, uppsala, sweden, nicox, sophia antipolis cedex, france, nicox, sophia antipolis, france, european health economics, speracedes, france objectives: to estimate changes in quality of life (sf ) and utility (sf ) in patients treated with naproxcinod, naproxen or placebo for weeks, and to explore the effect of different disease measures on utility. methods: sf was available from international ph clinical trials in patients with knee or hip osteoarthritis comparing doses of naproxcinod ( and mg bid) to naproxen ( mg bid) and placebo. effi cacy was based on the pain, function and composite scales of the womac™ osteoarthritis index. co-morbidity measures included hypertension (ht) which increases with nsaid therapy, body mass index (bmi) and diabetes. changes in sf and individual sf domains were compared between the groups using anova and dunett’s -sided test. the effect of the womac™ indices, bp, bmi and diabetes on utility scores was explored using multiple regression analysis. results: all sf subscales except mental health as well as utility changed signifi cantly from baseline for all groups, and were correlated with changes in the womac™ indices (p . ). the change in the active groups was signifi cantly better than placebo for pain and physical function ( . ), but not signifi cantly different between treatments. however, absolute changes in utility, pain, physical function and general health were generally larger for naproxcinod mg than naproxen mg by around %. utility scores correlated signifi cantly with womac™, and patients with high bmi and bp or diabetes had lower utility scores and worse womac™ indices. increase in utilities were larger for patients with mg naproxcinod than for the other groups. conclusions: the slightly larger utility and quality of life changes with naprox- cinod mg despite a similar effect as naproxen on womac™ may be explained by a different side-effect profi le and a neutral blood pressure effect. pms an assessment of self reported outcomes in a nationally representative sample of elderly person diagnosed with rheumatoid arthritis rajpura jrjp j st. john’s university, fresh meadows, ny, usa objectives: to utilize webtv technology as a tool to measure hrqol in elderly persons having rheumatoid arthritis (ra) in a nationally representative sample and to describe their socio-demographic characteristics, medication use and other treat- ment choices. methods: a cross- sectional online survey research design. random digit dialing (rdd) survey procedures were used to draw a sample of elderly arthritic individuals from us households across states. a subsample of individu- als previously diagnosed with ra completed sf- v survey, as part of a larger study. eight sf- domain scores and physical and mental component summary (pcs and mcs) scores were computed and compared with cross-sectional norms for general us population. results: compared to the general population, our study sample per- formed poorly with respect to all the sf- domains except mental health (mh) and social functioning (sf) domains. ra is more prevalent in whites ( %) and males reported higher scores for all the eight sf- domains than females. about % of the sample reported the use of at least one available otc arthritic medication; % of the sample was taking prescription drugs, while about % reported having used natural/herbal remedies for arthritis. a signifi cant difference (p . ) was found between males and females with respect to only pcs scores. age was found to correlate negatively (p . ) with pcs and mcs summary measures, particularly for indi- viduals years and older. conclusions: webtv is an effective survey administra- tion tool for measuring hrqol. as expected, elderly perform poorly on three of the sf- domains (pf, rp, bp) having the most physical factor content. prescription drug use is fairly prevalent and use of otc medications and other forms of treatment is popular in the population under study. pms the effect of lifestyle choices on the risk of impairment in rheumatoid arthritis patients: an analysis of aerobic exercise and cigarette smoking shah a , plumb j , brawer r , tang b thomas jefferson university, philadelphia, pa, usa, centocor ortho biotech, inc, horsham, pa, usa objectives: through data analysis we will examine and identify the lifestyle factors that impact clinical outcomes of rheumatoid arthritis (ra) patients. methods: patients’ self-reported data was collected from the ra patient survey, an internet survey of ra patients. we studied the effects of aerobic exercise ( minutes a day per month), and cigarette smoking on ra patients. sign and symptom scores for morning stiffness, fatigue, and pain are defi ned from (no symptom) to (severe symptom) within the survey. the health assessment questionnaire (haq) was used to measure functional status scores ( – ). quality of life was measured by the mental component score (mcs) and physical component score (pcs) of the short-form (sf- ). productivity was measured by the work productivity and activity impairment (wpai) scale. there were no non-ra controls included in the study. results: a total of respondents were included in the analysis patients exercised and patients smoked cigarettes. the average age was . years and average ra duration was . years. patients’ mean mcs and pcs scores in the exercise ( . , . ) and non-smoking groups ( . , . ) were signifi cantly higher, than in the non- exercise ( . , . ) and smoking groups ( . , . ). overall work and productivity impairment was . % (exercise) versus . % (non-exercise), and . % (smoking) versus . % (non-smoking). signs, symptoms, and haq scores were signifi cantly better in the exercise and non-smoking groups (all p . ). conclusions: ra patients who exercise regularly have higher quality of life scores and clinical outcomes. those that smoke cigarettes have lower quality of life scores and higher symptom/ haq scores suggesting that this habit may be detrimental to their clinical outcomes. these results suggest that these lifestyle choices infl uence the overall risk of impairment in ra patients. pms is the health utilities index valid and responsive in assessing patients with ankylosing spondylitis? gooch k , feeny dh , wong r , pangan a , revicki d , van der heijde d abbott laboratories, abbott park, il, usa, kaiser permanente center for health research, portland, or, usa, abbott laboratories, parsippany, nj, usa, united biosource corporation, bethesda, md, usa, leiden university medical center, leiden, netherlands objectives: qalys are an important outcome used in cost-effectiveness analysis. the health utilities index mark (hui- ) is a self-reported measure covering attri- butes of health status. our objective was to assess construct validity and responsiveness of hui- in ankylosing spondylitis (as). methods: data were derived from the adalimumab trial evaluating long-term effi cacy and safety in as (atlas). we speci- fi ed a priori hypotheses regarding the direction and magnitude of associations expected between overall and single-attribute hui- scores and other health status and quality of life measures—sf- , asqol, bath as functional index (basfi), bath as disease activity index (basdai), and patient’s global assessment (pga). using baseline data, we calculated correlation coeffi cients and interpreted them via guidelines suggested by guyatt for negligible, weak, moderate, and strong associations. responsiveness was assessed by calculating standardized response means (srms) of hui- scores from baseline to week for patients meeting the minimum clinically important differences (mcid) for the asqol ( . ). responsiveness analysis was limited to patients with -week hui- scores. results: a total of of the patients enrolled in atlas were included in the analysis. mean age was years, . % were male, and mean duration of as was years. correlation coeffi cients between hui- scores and other instruments confi rmed . % of the a priori hypothesis, with an additional . % being under- or over-estimated by only one category. results of responsiveness analysis demonstrated that there were signifi cant differences in overall hui- (srm . ) and most single-attribute change scores for patients whose changes were greater than the asqol mcid vs. those whose changes were mcid. conclusions: these results suggest that hui- constructs are related to similar constructs in other measures, as expected. this study provides evidence of cross-sectional and longitudinal construct validity of the hui- for deriving utility scores for as patients. pms validation of the multi-attribute health utility (mahu) derived from a computer adaptive instrument, cat- d-qol, in osteoarthritis kang wg , sayre ec , steininger g , doerfl ing p , ratzlaff c , esdaile j , kopec j university of british columbia, vancouver, bc, canada, arthritis research centre of canada and simon fraser university, vancouver, bc, canada, arthritis research centre of canada, vancouver, bc, canada objectives: we aimed to validate the multi-attribute health utility (mahu) derived from the cat- d-qol, a computer-adaptive instrument composed of domains (walking, handling objects, daily activities, pain/discomfort, and feelings) in people with self-reported osteoarthritis (oa), and to compare it with womac_hui , the utility derived from the standard disease-specifi c measure in oa. methods: data were collected from participants (age ) who completed questionnaires cat- d- qol in two waves and womac in one wave of a canada-wide online survey. to assess construct validity, we used multivariable regression to examine the associations pin the clinical and economic burden of complicated skin and skin structure infections due to staphylococcus aureus: findings from a national database a abstracts analyses were conducted from both the societal and health care system perspective. sensitivity analyses were performed. results: reduction in disease outcomes, disease sequelae and cost-of-illness by health state was observed in the time period post-prevnar®, across all age groups. the total cost of the vac- cination program to the canadian health care system (including herd immunity effects), from a payer perspective amounted to $ , , ; this decreased to $ , , from a societal per- spective. the total number of illnesses avoided was , . the incremental cost-effectiveness ratio (icer) was $ , and $ , per additional qaly from the health system and soci- etal perspectives, respectively. when herd immunity effects were excluded from the analysis, the icer increased to $ , and $ , per qaly, respectively. sensitivity analysis indicated that total cost and icer results were most sensitive to changes in the epidemiology and cost of otitis media. however, these changes did not considerably impact the results, indicating a robust model. conclusion: consistent with previous find- ings, vaccination with prevnar® is cost-effective. administration of prevnar® results in a substantial reduction in pneumococcal disease in vaccinated children and unvaccinated adults. pin cost-effectiveness of gargling for prevention of upper respiratory tract infections shimbo t , omata k , takahashi y , satomura k , kitamura t , kawamura t international medical center of japan, shinjyuku-ku, tokyo, japan, kyoto university, kyoto, kyoto, japan, osaka saiseikai senri hospital, suita, osaka, japan objectives: to investigate the cost effectiveness of gargling to prevent upper respiratory tract infections (uri) from a societal perspective. methods: the effectiveness of gargling for pre- venting uri has been demonstrated in a randomized controlled trial in which the participants recorded the frequency of gargling, incidence and severity of uri and duration of daily medicine. costs of gargling, visiting physicians, medicine, and lost pro- ductivity were considered. the cost of gargling was estimated as the opportunity cost of the time required. the utility of severe and moderate uri was also considered. average costs and utility during days of observation in the trial were estimated as the sum of the average daily cost and utility of the participants remaining staying in the trial. the incremental cost effectiveness ratio (icer) of gargling when compared with the absence of gar- gling was calculated, and bootstrap sampling generated an acceptability curve. results: the estimated unit cost of gar- gling was . yen. assigned participants gargled . times per day on average. the gargling group had higher costs and utility than the group that did not gargle. the incremental cost and effectiveness for days were yen and . quality- adjusted life days respectively. the gargling group required yen more for gargling, but saved yen by preventing uri for days. this showed that the icer of gargling was . million yen/qalys ( , us$/qalys). the acceptability curve showed . % was less than million yen/qalys, and . % less than million yen/qalys. conclusion: although it can prevent uri, gargling is more costly than not gargling because the cost of gargling exceeded the savings derived from uri prevention. however, the icer of gargling was comparable with that of other widespread medical technologies. pin pharmacoeconomic analysis of severe community- acquired pneumonia treatment kulikov a, krysanov i moscow medical academy, moscow, russia objectives: selection of the most cost-effective treatment regimen of severe community-acquired pneumonia. methods: direct medical expenditure on courses of treatment with lev- ofloxacin and ceftriaxone were evaluated during this trial. “cost minimization” analysis was chosen as a pharmacoeconomic method, and a “lost opportunities” index was calculated when using less cost-effective drugs. results: direct medical costs in the group of patients who received levofloxacin amounted to , . rubles, and in the group of patients who were treated with ceftriaxone they totaled , . rubles per patient. they were made up of levofloxacin and ceftriaxone antibacterial drug treatment costs and the costs of patients’ hospital stay. the cost of the drug treatment course amounted to , . rubles for the first group (levofloxacin) and to , . rubles for the second group (ceftriaxone); the cost of hospital stay amounted to , rubles and , rubles respectively. in the break- down of expenditure on treatment of community-acquired pneu- monia with levofloxacin, patients’ hospital stay accounted for % of expenses, whereas drug treatment accounted for only % thereof; when treating with ceftriaxone, the expenditure on patients’ hospital stay amounted to % and that on drug treat- ment—to %. the “lost opportunities” index equaled one and thus indicated that when using a more cost-effective drug (lev- ofloxacin) for the treatment of one patient compared to a less cost-effective drug (ceftriaxone) it is possible to theoretically treat an additional patient, taking into account the difference in the costs of treatment with the drugs compared, provided the profile of antibiotic resistance is congruent with that under the conditions of the clinical study used herein. conclusion: antibacterial treatment of severe community-acquired pneumo- nia with levofloxacin is more cost-effective, enabling the reduc- tion of costs by , rubles per patient compared to treatment with ceftriaxone owing to lower expenditure on drugs. pin the clinical and economic burden of complicated skin and skin structure infections due to staphylococcus aureus: findings from a national database marton jp , menzin j , sussman m , friedman m , philburn rt , rothermel cd pfizer global pharmaceuticals, pfizer inc, new york, ny, usa, boston health economics, inc, waltham, ma, usa objectives: complicated skin and skin structure infections (csssis) are a common complication among hospitalized patients. there are limited national data on the costs of csssis due to staphylococcus aureus, a common hospital-acquired pathogen. methods: this retrospective cohort study used data from the health care cost and utilization project nationwide inpa- tient sample (hcup-nis). patients with s. aureus csssis were identified based on icd- -cm diagnosis codes and compared to patients without skin infections. excess mortality, length of stay (los), and costs were estimated for both groups. multivariate models (with log transformation) were used to adjust costs for potential confounding factors, including age, gender, mortality, hospital region, and comorbidity. results: we identified , hospitalized patients with csssis due to s. aureus. the compari- son cohort consisted of , , patients without skin infec- tions. the mortality rates were similar for the s. aureus csssi and comparison cohorts ( . % and . %, respectively). for com- a abstracts parison purposes, the mortality rate of all inpatients with s. aureus infections was . %. patients with s. aureus csssis were older (mean age years vs. years for the comparison group) and were more likely to have congestive heart failure, diabetes with chronic complications and bacteremia/septicemia. relative to the comparison group, patients with s. aureus csssis had significantly (p < . ) longer mean length of stay ( . vs. . days) and higher average costs per stay ($ , vs. $ , ). after con- trolling for potentially confounding factors, the excess mean costs associated with s. aureus csssis were estimated to be $ , . conclusion: our findings suggest that the clinical and eco- nomic burden of complicated skin and skin structure infections (csssis) due to staphylococcus aureus among hospitalized patients is substantial. pin impact of s. aureus infections on expenditures and length-of-stay in u.s. hospitals noskin g , rubin r , schentag j , kluytmans j , hedblom e , jacobson c , smulders m , gemmen ek , bharmal m northwestern university feinberg school of medicine, chicago, il, usa, georgetown university, washington, dc, usa, university at buffalo school of pharmacy, buffalo, ny, usa, amphia hospital and vumc medical university, amsterdam, rk, the netherlands, m medical, st paul, mn, usa, quintiles, falls church, va, usa, quintiles strategic research & safety, falls church, va, usa objectives: evaluate the incremental impact of s. aureus infection stays on hospital charges and length-of-stay in u.s. hospitals in . methods: the nationwide inpatient sample data were analyzed. hospital discharges were classified as either a s. aureus–related infection stay or a non-s. aureus- related infection stay using a combination of several icd- codes. incremental effect of s. aureus infection on hospital charges and length-of-stay was estimated using multivariate regression models adjusting for hospital fixed effects and patient variables including age, gender, race, payer, diagnosis-related grouping and concomitant conditions including diabetes, dialy- sis and lung disease. results: s. aureus infection was reported as a discharge diagnosis for . % of all hospital inpatients, or , stays, in . s. aureus infection hospital stays were significantly more likely among male, older patients, stays that were paid by medicare, white or non-hispanics and hospital stays among individuals with diabetes, lung disease or dialysis. after adjusting for covariates, the mean incremental impact of s. aureus infection on hospital charges and length-of-stay was $ , ( % confidence interval (ci): $ , –$ , ) and . days ( % ci: . – . ) among all inpatient stays, $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among surgical stays, $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among invasive cardiovascular stays, $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among invasive orthopedic stays and $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among invasive neurosurgical stays. conclusion: s. aureus infections present a considerable economic burden to u.s hospitals. based on the prevalence of s. aureus infection and its incremental impact, the total economic impact of s. aureus among all hospital admissions was estimated at $ . billion in u.s. dollars. pin determinants of total hospital costs among inpatients with candidemia lee sp , bunz t , gagne jj , maio v , goldfarb ni , horn dl , swanson r thomas jefferson univeristy, philadelphia, pa, usa, thomas jefferson university, philadelphia, pa, usa, pfizer inc, new york, ny, usa objectives: to identify factors associated with total hospital costs among patients with candidemia in a large, urban, tertiary care, teaching hospital. methods: this retrospective cohort study examined hospitalizations during calendar years and at thomas jefferson university hospital in philadelphia, pa, using data from various hospital systems. candidemia cases were identified via the microbiological laboratory information system as those patients with at least one confirmed positive blood culture for any candida species at any point during the study period. demographic, economic, and clinical data, includ- ing length-of-stay (los), payer types, total costs, and diagnosis related group (drg) assignments were collected from the hos- pital cost accounting system. pharmacy data (i.e. medications administered and associated costs) were retrieved from the phar- macy electronic information system. a multivariate regression analysis, using the natural logarithm of total hospitalization costs as the dependent variable, was conducted. independent variables included demographic information, relative drg weights, and candida species. results: among , total hospitalizations during the study period, cases were con- firmed positive for candidemia. the mean age of cases was years, % were female, and % were caucasian. the mean los was . days and the average inpatient cost for candidemia cases was $ , (sd = $ , ; median, $ , ). the most common candida species was c. albicans (n = ; %). the most commonly used antifungal treatment was fluconazole (n = , %). age, and relative drg weights (p < . ) were significantly positively correlated with total hospital costs. older patients with higher relative drg weights were associated with the higher total costs. race, gender, and marital status were not associated with total costs. conclusion: relative drg weights, as well as age are associated with total hospital costs among patients with candidemia. candidemia is expensive to treat and results in lengthy hospital stay. early detection and treatment may significantly reduce resource use as well as improve outcomes. pin the economic impact of methicillin resistance in staphylococcus aureus bacteremia in korea park ej , lee ek , chae s korea institute for health and social afffairs, seoul, south korea, sookmyung women’s university, seoul, south korea, korea institute for health and social affairs, seoul, south korea objectives: the objective of this study is to examine the eco- nomic outcome of methicillin resistance in staphylococcus aureus bacteremia in korea, where mrsa is endemic in major- ity of hospitals. methods: we conducted retrospective case- control study of patients admitted to three university-based teaching hospitals in seoul, korea in . cases were defined as patients with methicillin-resistant s. aureus (mrsa) bac- teremia and controls were methicillin- susceptible s. aureus (mssa) bacteremia selected according to a priori matching cri- teria. cases and controls were identified. hospital charges were collected from hospitals’ billing system. results: the median hospital charge after the development of bacteremia was higher for cases with mrsa bacteremia ($ ) than for con- trols with mssa bacteremia ($ ). the median hospital doi: . /j.bpj. . . tuesday, march , a -pos board b regulation of mitochondrial motility by milton-like proteins, oip and grif sudipto das, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. regulation of mitochondrial motility by milton-like proteins, oip and grif grif and oip are mammalian homologs of milton, a kinesin-binding protein that forms a complex with miro gtpase, an integral outer mitochon- drial membrane ef-hand protein. kinesin, milton and miro have been proposed to function together in the movement of mitochondria along the mi- crotubules. we report here the influence of overexpression of oip and grif on mitochondrial motility and its inhibition by agonist-induced cyto- plasmic [ca þ] ([ca þ]c) signals in h c cells. ha-tagged oip and grif were overexpressed at similar level and were localized to the mito- chondria as detected by immunocytochemistry. in oip and grif overex- pressing cells, elongated mitochondria with varied degree of aggregation were visualized both in live and in fixed, immunostained samples. mitochondrial motility at resting ca þ (< nm) was greatly enhanced by oip and to a lesser extent by grif ( . . and . motility units, respec- tively against a control value of . . motility units). furthermore, the ca þ-dependent inhibition of motility during stimulation by vasopressin ( nm) was suppressed by overexpressed oip ( . . %), whereas grif ( . . %) had no significant effect compared to control ( . . %). overexpression of oip or grif did not alter either basal [ca þ]c or agonist-induced [ca þ]c levels measured by fura . collectively, these data show that both oip and grif can modulate mitochondrial motility presumably, by promoting the association of mitochondria with the motor proteins. furthermore, oip seems to have greater efficacy in the control of mitochondrial movements. -pos board b mitochondrial localization and function relationship gyorgy csordas , sudipto das , peter varnai , tamas balla , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, school of medicine, budapest, hungary, nichd, nih, bethesda, md, usa. mitochondrial contribution to cell signaling and function relies on the associ- ation and local communication of mitochondria with the er and the plasma membrane (pm). we have recently shown that the local ca þ communication between er and mitochondria is supported by interorganellar tethers, and cre- ated synthetic linkers that connected the outer mitochondrial membrane (omm) to the er and sensitized mitochondria to er ca þ release. to study the kinetics and short-term effects of the linkage formation, we have now de- vised fluorescent protein pairs targeted to the omm and er or pm containing fkbp or frb domains. rapamycin causes heterodimerization of these pro- teins to form omm-er or omm-pm bridges. confocal imaging of the induc- ible fluorescent linker pairs revealed increased association of er or pm-patches with the mitochondria within minutes of rapamycin exposure. the linkage formation between the er and mitochondria was followed by a decrease in mi- tochondrial motility (> % in min) and by sensitization of mitochondria to ip receptor-mediated ca þ release. linkage formation between pm and mitochondria also suppressed mitochondrial motility. the initial kinetics and spatial distribution of linkage formation could be followed via recording fret between cfp-and yfp-containing linker partners. a longer version of the linker was found to show faster increase of the fret signal, supporting the idea that the rate of linkage formation positively correlates with the tight- ness of the er-mitochondrial contacts. currently, we are using the fret kinet- ics to visualize the areas of close er-mitochondrial interface and study its relevance in the ca þ signal propagation to the mitochondria. thus, inducible interorganellar linkers provide a tool to assess the distance between organelles in live cells, to establish rapid changes in the subcellular distribution and dynamics of the organelles and to evaluate the ensuing changes in organellar and cell function. -pos board b bak/bax-dependent apoptotic signaling in vdac -/- cells soumya sinha roy , william j. craigen , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, baylor college of medicine, houston, tx, usa. bid, a pro-apoptotic bcl- family protein, upon activation forms truncated bid (tbid) that binds to the outer mitochondrial membrane (omm) and engages bak/bax-dependent release of cytochrome c (cyto c) and other intermembrane space proteins from mitochondria to the cytosol to induce apoptosis. the volt- age-dependent anion channel (vdac) is the major permeability pathway for metabolites and ions in the omm but its role in the tbid-induced omm perme- abilization remains controversial. previously we reported that among the vdac isoform-specific knockout mouse embryonic fibroblasts (mefs), only vdac -/- mefs lack tbid induced complete cyto c release and loss of djm. here we show by single cell fluorescence imaging that permeabilized vdac -/- mefs expressing cyto c-gfp were resistant to tbid ( nm)-induced cyto c-gfp release. furthermore, by rescuing vdac -/- mefs with vdac the tbid-induced cyto c-gfp release was restored. in addition, tbid adenovirus infection caused less cell death in intact vdac -/- mefs than in wildtype (wt) mefs. it has been reported that vdac is required for proper targeting of bak in omm. indeed, bak did not appear in the membrane fraction of vdac -/- mefs. along this line we show that permeabilized bak -/- cells were more resistant to tbid induced cyto c release and loss of djm than wt and bax-/- mefs. strikingly, washout of the cytosol further desensitized the bak-/- mefs to tbid. unlike vdac -/- mefs, the bak-/- mefs constitutively overex- pressed bax that was primarily localized in the cytosol. however, recombinant bax ( nm) could induce cyto c release and depolarization in vdac -/- mefs and also supported the tbid-induced cyto c release. thus, in vdac -/- cells bak does not localize to the mitochondria and fails to interact with tbid and does not allow a compensatory increase in bax. the combination of these two mechanisms greatly attenuates tbid-induced omm permeabilization and apoptosis. -pos board b mitochondrial fusion-fission dynamics during hypoxia/reoxygenation xingguo liu, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. structural, biochemical, and functional abnormalities of mitochondria during hypoxia/reoxygenation (h/r) are widely believed to be important pathogenic factors that underlie cell injury. however, mitochondrial fusion-fission dynam- ics responses to h/r are unclear. we investigated the effect of h/r and chem- ical hypoxia evoked by kcn on cellular atp, djm, and on mitochondrial morphology and fusion. sixty min h caused cellular atp decrease to %. djm showed progressive decrease during h, gradually improved in the first minutes r and decreased again during longer r. mitochondrial fusion activity decreased to % during h and to % during r. in addition, anomalous fusion (autofusion and fusion at multiple sites among - mitochon- dria) produced donut-shaped mitochondria during r. cyclosporine a (csa), an inhibitor of the permeability transition pore (ptp) relieved the fusion inhibition ( %) and prevented donut formation during r. five mm and mm kcn could induce cellular atp decrease to % and %, and djm decrease to % and %, respectively. depolarized mitochondria were associated with donut-formation in mm kcn, and with massive swell- ing in mm kcn. fusion activity decreased to % in mm kcn and % in mm kcn, respectively. neither h nor kcn evoked cleavage of opa , the mitochondrial inner membrane fusion protein. thus, both physical and chem- ical h induced respiratory inhibition to gradually lower djm and cellular atp level, and caused fusion inhibition that was not dependent on opa cleav- age. this is sharp contrast of the uncoupler-induced fusion inhibition that has been attributed to the rapid djm dissipation-induced opa cleavage. a conse- quence of ptp opening, the matrix swelling seems to be a key to donut forma- tion since this could be evoked by both mastoparan, a potent ptp activator and by valinomycin, a potassium ionophore. -pos board b governing respiration: tubulin’s c-terminus interaction with vdac kely l. sheldon , dan l. sackett , claire monge , valdur saks , sergey m. bezrukov , tatiana k. rostovtseva . lpsb, nichd, the national institutes of health, bethesda, md, usa, limb, nichd, the national institutes of health, bethesda, md, usa, joseph fourier university, grenoble cedex , france. mitochondria have long been known to localize within and move along the tu- bulin-microtubule network. it was shown that tubulin binds to isolated mito- chondria with high-affinity and specifically associates with the mitochondrial voltage-dependent anion channel (vdac). we found that nanomolar concen- trations of dimeric tubulin vastly increase vdac sensitivity to voltage allow- ing for vdac blockage at low transmembrane potentials. tubulin interaction with vdac requires the presence of anionic c-terminal tails (ctt) on the in- tact protein. tubulin with proteolytically cleaved ctts does not block the channel. actin, also an acidic protein but lacking ctts, does not induce vdac blockage. two synthetic peptides with the sequences of mammalian a and b brain tubulin ctt do not induce detectable channel closure up to mi- cromolar concentrations. these results suggest a completely new role for 	regulation of mitochondrial motility by milton-like proteins, oip and grif 	mitochondrial localization and function relationship 	bak/bax-dependent apoptotic signaling in vdac -/- cells 	mitochondrial fusion-fission dynamics during hypoxia/reoxygenation 	governing respiration: tubulin’s c-terminus interaction with vdac [pdf] linear relation between structure and function. | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /iovs. - corpus id: linear relation between structure and function. @article{wegner linearrb, title={linear relation between structure and function.}, author={a. wegner and a. erben}, journal={investigative ophthalmology & visual science}, year={ }, volume={ }, pages={ ; author reply - } } 	a. wegner, a. erben 	published 	mathematics, medicine 	investigative ophthalmology & visual science the main limitation of the study by danesh-meyer et al. was neither discussed nor mentioned. the time axis was not taken into account. the functional change after an acute event such as anterior ischemic optic neuropathy (aion) is immediate, but there is a delay before the anatomic changes take place. in this study, most of the patients with nonarteritic anterior ischemic optic neuropathy (naion) or arteritic anterior ischemic optic neuropathy (aaion) were tested a short period after the acute… expand view on pubmed iovs.arvojournals.org save to library create alert cite launch research feed share this paper topics from this paper 	optic neuropathy, ischemic 	retinal ganglion cells 	nervous system disorder 	glaucoma, open-angle 	disorder of the optic nerve 	papilledema 	nonarteritic anterior ischemic optic neuropathy (naion) 	glaucoma 	eye 	ganglion cell 	retina 	tomography, optical coherence 	optic disk 	perimetry 	layer of the ophthalmic nerve fibers 	abnormal degeneration 	axon 	tomography references showing - of references retinal nerve fiber structure versus visual field function in patients with ischemic optic neuropathy. a test of a linear model. 	d. hood, s. anderson, + authors r. kardon 	medicine 	ophthalmology 	 	 	 save alert research feed non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy 	s. hayreh, m. zimmerman 	medicine 	graefe's archive for clinical and experimental ophthalmology 	 	 	 save alert research feed optic disc morphology in open-angle glaucoma compared with anterior ischemic optic neuropathies. 	h. danesh-meyer, michael v. boland, + authors h. quigley 	medicine 	investigative ophthalmology & visual science 	 	 	highly influential 	pdf 	view excerpts, references results and methods save alert research feed effect of ruboxistaurin on the visual acuity decline associated with long-standing diabetic macular edema. 	a. sahu, a. majji 	medicine 	investigative ophthalmology & visual science 	 	 save alert research feed smoking and corneal biomechanics. 	f. hafezi 	medicine 	ophthalmology 	 	 	pdf save alert research feed effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. 	l. aiello, m. davis, + authors x. zhi 	medicine 	ophthalmology 	 	 save alert research feed cigarette smoking is negatively associated with keratoconus. 	e. spoerl, f. raiskup-wolf, e. kuhlisch, l. pillunat 	medicine 	journal of refractive surgery 	 	 save alert research feed nitrite-induced cross-linking alters remodeling and mechanical properties of collagenous engineered tissues 	d. paik, l. y. saito, dorcas d sugirtharaj, j. holmes 	chemistry, medicine 	connective tissue research 	 	 save alert research feed advanced maillard reaction and crosslinking of corneal collagen in diabetes. 	c. sady, s. khosrof, r. nagaraj 	medicine, chemistry 	biochemical and biophysical research communications 	 	 save alert research feed advanced glycation endproducts and cigarette smoking. 	i. d. nicholl, r. bucala 	medicine, biology 	cellular and molecular biology 	 	 save alert research feed related papers 	abstract 	topics 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about 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g. s. mutchler, p. stoler, d. p. weygand, p. ambrozewicz, m. anghinolfi, g. asryan, h. avakian, h. bagdasaryan, n. baillie, j. p. ball, n. a. baltzell, v. batourine, i. bedlinskiy, m. bellis, , n. benmouna, b. l. berman, a. s. biselli, s. bouchigny, s. boiarinov, r. bradford, d. branford, w. j. briscoe, w. k. brooks, s. bültmann, v. d. burkert, c. butuceanu, j. r. calarco, s. l. careccia, d. s. carman, s. chen, e. clinton, p. l. cole, p. coltharp, d. crabb, h. crannell, j. p. cummings, d. dale, e. de sanctis, p. v. degtyarenko, a. deur, k. v. dharmawardane, c. djalali, g. e. dodge, j. donnelly, d. doughty, , m. dugger, o. p. dzyubak, h. egiyan, ,* k. s. egiyan, l. elouadrhiri, p. eugenio, g. fedotov, h. funsten, m. y. gabrielyan, l. gan, m. garçon, a. gasparian, g. gavalian, , g. p. gilfoyle, k. l. giovanetti, f. x. girod, o. glamazdin, j. goett, j. t. goetz, e. golovach, a. gonenc, c. i. o. gordon, r. w. gothe, k. a. griffioen, m. guidal, n. guler, v. gyurjyan, c. hadjidakis, r. s. hakobyan, j. hardie, , f. w. hersman, k. hicks, i. hleiqawi, m. holtrop, c. e. hyde-wright, y. ilieva, d. g. ireland, b. s. ishkhanov, m. m. ito, d. jenkins, h. s. jo, k. joo, h. g. juengst, ,† j. d. kellie, m. khandaker, w. kim, a. klein, f. j. klein, a. v. klimenko, m. kossov, l. h. kramer, , j. kuhn, s. e. kuhn, s. v. kuleshov, j. lachniet, j. m. laget, , j. langheinrich, d. lawrence, t. lee, ji li, k. livingston, b. mckinnon, b. a. mecking, j. j. melone, m. d. mestayer, c. a. meyer, t. mibe, k. mikhailov, r. minehart, m. mirazita, r. miskimen, v. mochalov, v. mokeev, l. morand, s. a. morrow, , p. nadel-turonski, i. nakagawa, r. nasseripour, , s. niccolai, g. niculescu, i. niculescu, b. b. niczyporuk, r. a. niyazov, m. nozar, m. osipenko, , a. i. ostrovidov, k. park, e. pasyuk, c. paterson, j. pierce, n. pivnyuk, d. pocanic, o. pogorelko, s. pozdniakov, j. w. price, , y. prok, ,‡ d. protopopescu, b. a. raue, , g. riccardi, g. ricco, m. ripani, b. g. ritchie, f. ronchetti, g. rosner, p. rossi, f. sabatié, c. salgado, j. p. santoro, , v. sapunenko, r. a. schumacher, v. s. serov, y. g. sharabian, e. s. smith, l. c. smith, d. i. sober, a. stavinsky, s. s. stepanyan, s. stepanyan, b. e. stokes, i. i. strakovsky, s. strauch, ,x m. taiuti, d. j. tedeschi, a. teymurazyan, u. thoma, ,k a. tkabladze, s. tkachenko, l. todor, c. tur, m. ungaro, , m. f. vineyard, a. v. vlassov, l. b. weinstein, m. williams, e. wolin, m. h. wood, ,{ a. yegneswaran, l. zana, j. zhang, and b. zhao (clas collaboration) istituto nazionale di fisica nucleare, sezione di genova, and dipartimento di fisica, universitá di genova, genova, italy rensselaer polytechnic institute, troy, new york - , usa thomas jefferson national accelerator facility, newport news, virginia , usa rice university, houston, texas - , usa arizona state university, tempe, arizona - , usa university of california at los angeles, los angeles, california - , usa california state university, dominguez hills, california - , usa carnegie mellon university, pittsburgh, pennsylvania , usa catholic university of america, washington, district of columbia , usa cea-saclay, service de physique nucléaire, f gif-sur-yvette, france christopher newport university, newport news, virginia , usa university of connecticut, storrs, connecticut , usa edinburgh university, edinburgh eh jz, united kingdom florida international university, miami, florida , usa florida state university, tallahassee, florida , usa the george washington university, washington, district of columbia , usa university of glasgow, glasgow g qq, united kingdom idaho state university, pocatello, idaho , usa infn, laboratori nazionali di frascati, frascati, italy institut de physique nucleaire orsay, orsay, france institute for high energy physics, protvino, , russia institute of theoretical and experimental physics, moscow, , russia james madison university, harrisonburg, virginia , usa kharkov institute of physics and technology, kharkov , ukraine prl , ( ) p h y s i c a l r e v i e w l e t t e r s week ending february - = = ( )= ( )$ . - © the american physical society kyungpook national university, daegu - , south korea university of massachusetts, amherst, massachusetts , usa moscow state university, general nuclear physics institute, moscow, russia university of new hampshire, durham, new hampshire - , usa norfolk state university, norfolk, virginia , usa ohio university, athens, ohio , usa old dominion university, norfolk, virginia , usa university of richmond, richmond, virginia , usa university of south carolina, columbia, south carolina , usa union college, schenectady, new york , usa virginia polytechnic institute and state university, blacksburg, virginia - , usa university of virginia, charlottesville, virginia , usa college of william and mary, williamsburg, virginia - , usa yerevan physics institute, yerevan, armenia university of kentucky, lexington, kentucky , usa university of north carolina, wilmington, north carolina , usa north carolina agricultural and technical state university, greensboro, north carolina , usa the institute of physical and chemical research, riken, wako, saitama - , japan (received october ; published january ) the exclusive reaction �p ! �k k�n was studied in the photon energy range between . and . gev searching for evidence of the exotic baryon ��� �! nk�. the decay to nk� requires the assignment of strangeness s �� to any observed resonance. data were collected with the clas detector at the thomas jefferson national accelerator facility corresponding to an integrated luminosity of pb� . no evidence for the �� pentaquark was found. upper limits were set on the production cross section as function of center-of-mass angle and nk� mass. the % c.l. upper limit on the total cross section for a narrow resonance at mev was found to be . nb. doi: . /physrevlett. . pacs numbers: . .mk, . .rj, . .jn, . .�j following the announcement by the leps collaboration [ ] in , many experiments [ – ] reported evidence of a new exotic baryon with strangeness quantum number s �� and valence quark structure udud�s. the renewed interest in pentaquarks was motivated by a prediction within the chiral soliton model [ ] for a s �� baryon at a mass of mev and width of less than mev. if it exists, this would be the first observation of a baryon state that is not made up of a simple -quark (qqq) valence configuration. the observation of a second pentaquark, the ��� with dsds �u structure, was reported by the na collaboration [ ] and the first evidence for an anticharmed pentaquark, �c, was found by the h collaboration [ ]. on the other hand, in the past year reanalyses of data collected in high-energy experiments [ – ] show no evidence for pentaquarks, casting doubt on their existence. the experimental evidence, both positive and negative, was obtained from data previously collected for other purposes in many reaction channels and under very differ- ent kinematic conditions, which likely involved dissimilar production mechanisms. thus, direct comparisons of the results of the different experiments are very difficult, pre- venting a definitive conclusion about the pentaquark’s ex- istence. a second generation of dedicated experiments, optimized for pentaquark searches, was undertaken at the thomas jefferson national accelerator facility. these photo-production experiments cover the few gev beam energy region where most of the positive results have been reported, and collect at least an order of magnitude more statistics than any of the previous measurements. the mass resolution is of the order few mev and the accuracy of the mass determination is approximately – mev, allowing precise determination of any possible narrow peaks in the decay distributions. this letter presents the first result from this program. we searched for the �� in the �p ! �k k�n reaction, where the k�n decay mode identifies a baryon with strangeness � . this channel was previously investigated at elsa by the saphir collaboration [ ] in a similar photon energy range, finding positive evidence for a narrow �� state with m � mev and full width at half maximum (fwhm) � < mev. a total production cross section on the order of nb (reduced later to nb as reported in ref. [ ]) was reported. for the first time, our new results put previous positive findings to a direct test. this measurement was performed using the clas [ ] detector at jefferson lab in the experimental hall-b with a bremsstrahlung photon beam produced by a primary continuous electron beam of energy e � : gev. a bremsstrahlung tagging system [ ], which measures the energy of each interacting photon with resolution of . % e , was used to tag photons in the energy range . – . gev. the target consisted of a cm long cylindrical cell containing liquid hydrogen. outgoing hadrons were detected and identified in clas. momentum information for charged particles was obtained via tracking through three regions of multiwire drift chambers [ ] inside a prl , ( ) p h y s i c a l r e v i e w l e t t e r s week ending february - http://dx.doi.org/ . /physrevlett. . toroidal magnetic field (� : t), which was generated by six superconducting coils. the clas momentum resolu- tion is on the order of . – % (�) depending on the kinematics. the detector geometrical acceptance for each positive particle in the relevant kinematic region is about %. it is somewhat less for low-energy negative hadrons, which can be lost at forward angles because they are bent out of the acceptance by the toroidal field. the field was set to bend the positive particles away from the beam into the acceptance region of the detector. time-of-flight scintilla- tors were used for hadron identification [ ]. the interac- tion time between the incoming photon and the target was measured by the start counter [ ], consisting of a set of . mm thick plastic scintillators surrounding the hydrogen cell. coincidences between the photon tagger and two charged particles in the clas detector triggered the re- cording of the events. an integrated luminosity of about pb� was accumulated in days of running. in total, about tb of data were collected. the reaction �p ! �k k�n was isolated as follows. the k� was detected directly, and the ks component of the �k was reconstructed from its ���� decay. the momentum of the neutron was reconstructed from the known incident photon energy and measurements of all other particles in the event. calibrations of all detector components, and especially the tagger system, were performed achieving a precision of – mev in the nk� invariant mass determi- nation. the quality of the channel identification is shown in fig. where the �k and the missing neutron peaks are seen above a small background. reactions involving hyperon decays also contribute to the same final state. the most significant are �p ! k���� �! k� �k n, �p ! ��k���, and �p ! ��k���. these backgrounds are easily removed in our analysis with cuts around the known masses. they also serve as checks of our analysis procedure, e.g., by compar- ing their production cross sections with the world data. figure shows the background peaks: ��� � in the k� missing mass spectrum and the �� and �� peaks in the n�� and n�� invariant mass spectra, respectively. the mass region of each of these peaks was excluded from the final data set. after all cuts, the data sample contained approximately : � events out of the � in the original data set. the resulting nk� invariant mass distri- bution is shown in fig. . the spectrum is smooth and structureless. in particular, no evidence for a peak or an enhancement is observed at masses near mev, where signals associated with the �� were previously reported. to enhance our sensitivity to a possible resonance signal not visible in the integrated distribution, we considered the two-body reaction �p ! �k ��� � and selected differ- ent ks ( �k ) center-of-mass angle intervals. monte carlo studies of the clas acceptance for this reaction showed that we could detect events over the entire angular range ( 	 – 	), with some reduction of efficiency at forward angles (�c:m:�k < 	). no structures were found in the dis- tribution when specific angular ranges were selected. since no signal was found, an upper limit for the �� production cross section in this reaction channel was ex- tracted. the unbinned nk� mass spectrum was fit in the range . – . gev using a maximum likelihood proce- dure, with the sum of a narrow gaussian function and a th-order polynomial that parameterizes, respectively, the �� contribution and a smooth background. to derive the corresponding event yields, the fitted functions were inte- grated over � around a fixed mass position. the fit procedure was repeated varying the resonance position from to mev in mev steps while the width � was fixed at . mev. this value was derived by monte carlo simulation assuming a negligible intrinsic width as suggested from recent analyses of kn scattering data [ ] and therefore dominated by the clas experi- mental resolution. the validity of the monte carlo simu- lations in reproducing the experimental data was checked by comparing the predicted with measured widths of nar- row states such as the �� and ��. the data set was independently analyzed by three groups, each one deriving an estimate of the �� and background yields. the three analyses differ in the reaction selection cuts, in the back- ground rejection criteria, and in the fit to the mass spectra. the three results were found to be consistent. they were combined by taking the average of both the signal and background yield, assuming totally correlated measure- ments. these values were then used to evaluate an upper . . . . . m = . gev σ = . gev mπ+π- (gev) c ou n ts /m ev m = . gev σ = . gev mx(γp → k k+ x) (gev) c ou n ts /m ev _ . . . fig. . top: ���� invariant mass and the �k peak. bottom: missing mass for the reaction �p ! �k k�x after �k selection showing a peak at the neutron mass. the mass positions and widths of the measured peaks are given. for comparison, the arrows indicate the accepted value [ ] for the mass position. the shaded area corresponds to the events used in the analysis. prl , ( ) p h y s i c a l r e v i e w l e t t e r s week ending february - limit at % c.l. on the �� yield using the feldman and cousins approach [ ]. the upper limit on the yields was then transformed into an upper limit on the �� production cross section taking into account the luminosity of incident photons and target, the clas detection acceptance, the �k ! ks ! � ��� branching ratios of % � % [ ], the assumed �� branching ratio to nk� of %, and several models for the production mechanism. the clas acceptance for the detection of the �� in this reaction was obtained by means of detailed monte carlo studies which included knowledge of the detector geometry and response to traversing parti- cles. in the simulation the �p ! �k �� ! ����k�n distributions were generated assuming five different �� production mechanisms: t-exchange dominance (the �k is mainly produced at forward angles in the center-of-mass system), u-exchange dominance (at backward angles), uni- formly distributed, and using the predictions of the model in ref. [ ] (with and without k� exchange process). for the t-exchange hypothesis we used the same angular dis- tribution as for �p ! k���� � production, which ex- hibits a typical t-channel forward peaking behavior [ ]. the u-exchange distribution was generated the same way but interchanging the center-of-mass angles of the �k and ��. the clas overall detection efficiencies obtained with different production mechanisms varied between . % for the t-exchange hypothesis and . % for the angular distribution of ref. [ ] when no k� exchange process is included. all the upper limits reported in this article were derived in the most conservative scenario, i.e., in the t-exchange hypothesis. the upper panel in fig. shows the upper limit on the total cross section as a function of the �� mass. an upper . . . . . . . . . . . . mΘ (gev) σ ( n b ) + % cl upper limit cosθcm d σ (n b )/ d co sθ c m % cl upper limit - - . - . - . - . . . . . fig. . the % c.l. upper limit on the total cross section as a function of the �� mass (top) and on the differential cross section d�=d cos� �k c:m: (bottom) for the reaction �p ! �k �� for an assumed �� mass of mev. the dotted line in the top plot is to guide the eye. Θ+( )? mnk (gev) c ou n ts / m ev + . . . . . . . fig. . the nk� invariant mass distribution after all cuts. it is smooth and no narrow structures are evident. the arrow shows the position where evidence for the �� was found by previous experiments. the inset shows the nk� mass distribution with specific cuts to reproduce the saphir analysis [ ] as described in the text. . . . . . . . . . . m = . gev Γ = . gev mx(γp → k + x) (gev) c ou n ts /m ev m = . gev σ = . gev +mnπ (gev) c ou n ts /m ev m = . gev σ = . gev mnπ (gev) c ou n ts /m ev - . . . . fig. . top: k� missing mass distribution with the ��� � peak. bottom: n�� (left) and n�� (right) invariant mass dis- tributions with ��� � and ��� � peaks. the mass posi- tion and width of the measured peaks are indicated. for comparison, the arrows indicate the accepted value [ ] for the mass position. the shaded area corresponds to the events used in the analysis. prl , ( ) p h y s i c a l r e v i e w l e t t e r s week ending february - limit of . nb was found for m � mev. the process to extract the yield was repeated for each angular bin to derive the % c.l. upper limit on the ��� � differ- ential cross section d�=d cos� �k c:m:. the result is shown in the lower panel of fig. . the cross section upper limit remains within about – nb for most of the angular range and rises at forward angles due to the reduced clas acceptance. as a check on our procedure, we extracted the differential and the total cross section for several known reactions from the same data set, finding overall good agreement within experimental uncertainties with the existing world measurements. these results will be re- ported elsewhere. another measure of the strength of the pentaquark signal is to compare the upper limit on the yield to the number of ��� � events produced in the reaction. the % c.l. upper limit on the number of �� events at a mass of mev for our data sample is events. the number of observed ��� � events, shown in the upper panel of fig. , was determined using a breit-wigner resonance shape fit to be k. thus, the ratio is less than = k � : % ( % c.l.). our upper limit on the cross section is in clear disagree- ment with the findings of ref. [ ] which reported a �� signal of events at a mass of mev corresponding to the published total cross section of nb. in order to better compare with that experiment, we repeated the analysis applying the same cuts reported in that paper: the photon energy was limited to . gev, only events with a forward-emitted �k (� �k c:m: > 	) were used and no cuts were made to exclude hyperons. the resulting mass distribution is shown in the inset of fig. : it remains smooth and structureless. another way to show the incon- sistency of the two experiments is to compare the ratio of the upper limit of the number of �� with the number of the observed ��� �. applying again the same specific cuts to reproduce the saphir analysis, we evaluated a % c.l. limit on the �� yield of less than events. in the same photon energy range ( . – . gev) we observed � ��� �’s, compared with a �� yield of and ��� �’s, respectively, reported in ref. [ ]. the ratios obtained in the two experiments differ by more than a factor . in conclusion, this is the first result of a dedicated set of high-statistics and high-resolution experiments undertaken at jefferson lab to elucidate the debate on the existence of the pentaquark. the reaction �p ! �k k�n was studied in search for evidence of the �� pentaquark in the nk� decay channel. the final state was isolated detecting the k�, the �k by its ���� decay, and identifying the neutron by means of the missing mass technique. the direct mea- surement of the k� allows one to define the strangeness of any baryon resonance observed in this final state. the nk� mass distribution was found to be smooth and structureless. no evidence for a narrow resonance was found in the mass range – mev. an upper limit of . nb ( % confidence level) on the total production cross section for a �� mass of mev was set. this is in disagreement with previously reported evidence for a resonance in the same reaction channel, and sets stringent upper limits on the models which predict these long-lived pentaquark states. we would like to acknowledge the outstanding efforts of the staff of the accelerator and the physics divisions at jefferson lab that made this experiment possible. this work was supported in part by the italian istituto nazionale di fisica nucleare, the french centre national de la recherche scientifique and commissariat à l’energie atomique, the u.s. department of energy and national science foundation, and the korea science and engineering foundation. the southeastern universities research association (sura) operates the thomas jefferson national accelerator facility for the united states department of energy under contract no. de- ac - er . *current address: university of new hampshire, durham, nh - , usa †current address: old dominion university, norfolk, va , usa ‡current address: massachusetts institute of technology, cambridge, ma - , usa xcurrent address: university of south carolina, columbia, sc , usa kcurrent address: physikalisches institut der universität gießen, giessen, germany {current address: university of massachusetts, amherst, ma , usa [ ] t. nakano et al., phys. rev. lett. , ( ). 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[ ] d. barber et al., z. phys. c , ( ). prl , ( ) p h y s i c a l r e v i e w l e t t e r s week ending february - 	university of massachusetts amherst 	from the selectedworks of michael williams 	january , 	search for theta(+)( ) pentaquark in high-statistics measurement of gamma p ->(k)over-bar( )k(+)n at clas 	untitled “we hold these truths to be self-evident” “we hold these truths to be self-evident” monumental error: writing wrongs on the thomas jefferson memorial by martin antony parlett m.a., university of oxford a thesis submitted in partial fulfillment of the requirements for the degree of master of arts in the faculty of graduate and postdoctoral studies (english) the university of british columbia (vancouver) april © martin antony parlett ii abstract detailed analysis of the inscriptions found upon the walls of the thomas jefferson memorial (tjm), in washington d.c. reveals an astonishing rhetorical secret, hidden in plain sight in the form of one of america’s most visited, and high-profile, national monuments. upon the marbled interior of this washingtonian pantheon, brass lettered quotations from jefferson’s works, epistles, and legislation, purport to communicate an accurate and accessible facsimile version of the third president’s intellect, philosophy, and politics. comparison of the quinquepartite panels to the original documents authored by jefferson, however, exposes a systematic and purposeful series of textual and semantic alterations, giving rise to a highly manipulated form of us national history, presidential memorialization, and public understanding. this thesis moves in three parts: ) to establish the existence and extent of these manipulations; ) to interrogate the means and agents of jefferson’s mediation; and ) to assess the material and symbolic consequence of the tjm’s continued presence in extant form. in so doing, this thesis - informed by rhetorical theory, studies in public memory, and intensive archival research - finds that the inscriptions of the jefferson memorial were knowingly edited to function not only as a subjective commemoration of a national political hero, but also as an item of contemporary progressive propaganda, communicating messages consistently sympathetic to roosevelt’s new deal and wartime agendas. accordingly, the monument becomes an important locus for investigating the specific rhetorical formation and consequence of a single (and highly motivated) public memory space, whilst also providing a replicable case study methodology for a broader derivation of the workings of “technologies of memory” (as defined by sturken, ), as they function at political mnemonic sites in the u.s. and beyond. iii preface this thesis is original, unpublished, independent work of the author, martin a. parlett. iv table of contents abstract ....................................................................................................................................... ii preface ........................................................................................................................................ iii table of contents ....................................................................................................................... iv acknowledgements ...................................................................................................................... v introduction: errors carved in stone ....................................................................................... chapter : the rhetoric – from parchment to marble, jefferson reclaimed ..................... thomas jefferson memorial panel a (tjmpa) ........................................................................ thomas jefferson memorial panel b (tjmpb) ...................................................................... thomas jefferson memorial panel c (tjmpc) ...................................................................... thomas jefferson memorial panel d (tjmpd) ...................................................................... thomas jefferson memorial panel e (tjmpe) ....................................................................... chapter : the rhetors – the thomas jefferson memorial commission and franklin delano roosevelt as inventors of public memory.................................................................. jefferson (un) remembered .................................................................................................... fdr: a th century jefferson ................................................................................................ chapter : the consequence – material rhetoric, public mis-memory, and the broken enthymeme ............................................................................................................................... what is the significance of the text.......................................................................................... what are the apparatuses and degrees of durability displayed by the text? ............................ what are the text’s modes or possibilities of reproduction or preservation? .......................... what does the text do to (or with, or against) other texts? ...................................................... how does the text act on person(s)? ........................................................................................ epilogue ................................................................................................................................... bibliography .............................................................................................................................. appendix a ................................................................................................................................ appendix b................................................................................................................................. appendix c ................................................................................................................................ appendix d ................................................................................................................................ appendix e................................................................................................................................. appendix f ................................................................................................................................. appendix g ................................................................................................................................ appendix h ................................................................................................................................ appendix i ................................................................................................................................ v acknowledgements it would be impertinent not to begin by expressing unerring gratitude to my supervisor, dr judy segal, whose generosity and patience have no discernable earthly horizon. this thesis, interrupted as it was by the unexpected award of a book contract (on an entirely different subject) and my subsequent return to the uk, has benefitted immeasurably from a unique brand of candid trans- atlantic supervision. furthermore, i would like to thank dr jeff severs for providing his enviable precision to the scope of this thesis’ inquiry, to dr vin nardizzi for his open-handed navigation of various long distance graduate study dilemmas, and to louise soga for having the default philosophy that “nothing is too much trouble.” the following pages would remain blank were it not for a throwaway reference made by dr paul kraus to the thomas jefferson memorial during a seminar on african american studies in , which kindled the flame of my ensuing archival investigation. i would like to recognize the national archives of the united states government for allowing full access to the absorbing records of the thomas jefferson memorial commission and the roosevelt administration. i remain indebted to the university of british columbia, the faculty of english and to the canadian rhodes scholarship foundation for my election. to friends and family who have been too often neglected and supportive in equal measure, i am hopeful for swift reunion. and finally, to lydia, who remains in all ways a memorial to everything that is good, thank you. introduction: errors carved in stone detailed analysis of the inscriptions found upon the walls of the thomas jefferson memorial (tjm), in washington d.c. reveals an astonishing rhetorical secret, hidden in plain sight in the form of one of america’s most visited, and high-profile, national monuments. upon the marbled interior of this washingtonian pantheon, brass lettered quotations from jefferson’s works, epistles, and legislation, purport to communicate an accurate and accessible facsimile version of the third president’s intellect, philosophy, and politics. comparison of the quinquepartite panels to the original documents authored by jefferson, however, exposes a systematic and purposeful series of textual and semantic alterations, giving rise to a highly manipulated form of us national history, presidential memorialization, and public understanding. this thesis moves in three parts: ) to establish the existence and extent of these manipulations; ) to interrogate the means and agents of jefferson’s mediation; and ) to assess the material and symbolic consequence of the tjm’s continued presence in extant form. in so doing, this thesis finds that the inscriptions of the jefferson memorial were knowingly edited to function not only as a subjective commemoration of a national political hero, but also as an item of contemporary progressive propaganda, communicating messages consistently sympathetic to roosevelt’s new deal and wartime agendas. accordingly, the monument becomes an important locus for investigating the specific rhetorical formation and consequence of a single (and highly motivated) public memory space, whilst also providing a replicable case study methodology for a broader derivation of the workings of “technologies of memory” (as defined by sturken, ), as they function at political mnemonic sites in the u.s. and beyond. informed by rhetorical theory, studies in public memory, and intensive archival research, this investigation forms a rhetorical criticism of the tjm, with particular emphasis on the unearthed the thomas jefferson memorial commission: general records, - . record group : records of the national park service, - . ( files) arc: (national archives, md) fallacies of the inscriptions as one element of that material and symbolic rhetoric. the archive provides hitherto unreported documentary evidence of the role, motivations and consequence of the thomas jefferson memorial commission (tjmc) and its most senior and energetic patron, president franklin delano roosevelt, acting together as the rhetorical agents of jefferson’s reconceptualization, and codifiers of his public voice and history. an assessment of the tjmc’s method of textual selection indicates the extent to which the monument formed a potentially partisan and activist presidential memorialization, to the detriment of public understanding. evidence suggests that the memorial, and its constituent inscriptions, was appropriated to form a contemporary rhetorical object that ventriloquized jefferson to suit the political philosophy of roosevelt’s administration and an interpreted narrative of s- s america. the tjm is rhetorical attestation of jefferson’s continuous re-situatedness and of the forced malleability of his contested historical persona over time by those claiming (parts of) his legacy at tendentious moments (adams, ; ellis ). given the celebrity status of jefferson as a founder of american political thought, it is not surprising that he has been variably borrowed by academics, biographers, and politicians over the centuries as the historical prime mover of particular causes or movements. at the time of the memorial’s creation, roosevelt and the progressive movement adopted jefferson as the standard bearer of civic humanism and government-led social reform. according to paul zummo ( ), for example, “[t]he great depression, franklin roosevelt’s ascendancy, and the new deal reawakened the progressive impulse, and the spirit of the progressive movement – itself a manifestation of the jeffersonian political philosophy” ( ). the memorial commission, populated almost exclusively by democratic representatives – and acting as rhetorical sub-agents with political allegiance to roosevelt – were presented with an opportunity to write jefferson-the-progressive into the material and cultural fabric of the united states commemorative narrative. the discovery of the memorial’s de facto inaccuracy will be, for many, a matter of prima facie scholarly and public significance, under the unspoken, but persistent, motto of academic discourse: omne ignotum pro magnifico. yet that conversation gets only to the physical act of the memorial’s creation and its partiality, not to the more interesting (and rhetorical) question of the motives involved in the particular ways the memorial was rendered so. this study might loosely align itself with the dramatistic methodology of kenneth burke, in understanding the creation of the memorial (and its inscriptions) as a high-profile communicative action – or text – with complex and powerful motivational provenance and consequence (burke, ).the interpretative philosophy of the dramatistic pentad – burke’s principal construct for the investigation of human motivation – moves us beyond the monadic declaration of misquotation and into the interrogation of act, as well as scene, agent, agency, and purpose (burke, xv). the memorial can be understood as (evidence of) the rhetorical act itself, whilst the remaining elements of the dramatistic pentad can be derived from a thorough analysis of the archival material of the tjmc. here, exhaustive correspondence among members of the commission, agencies, the white house and others, alongside commission minutes, memoranda, designs, and submissions, reveals multivariate motivational forces and their interaction with the scene of mid-twentieth century socio-political attitudes. the memorialisation, therefore, is recognised as a product of a tangled cultural remembering; its (un)reliability forms the keystone for fathoming the interactive “desires, needs, and self-definitions” (sturken, ) of an american culture that created, and continues to validate, it. this study employs the lens of marita sturken, who (invoking foucault’s technologies of the self) defines memorialising objects, from monuments to yellow ribbons, as “technologies of memory” ( ), shifting the emphasis from the nature of the technology itself, to the process and source of that technology’s instrumented deployment by agents within a material (and invariably political) context. memorials are unavoidably – and axiomatically – rhetorical. studies in public memory, visual art and rhetorical theory (in response to the “discursive turn” ) have, following burke, established ‘everything unknown appears magnificent.” the “discursive turn” (also “rhetorical turn”) is widely understood as a challenge to the objective or scientific interpretation of the rhetorical form. in short, the core proposition of the discursive turn is that rhetoric is always meaning-making, effecting and memorials, museums and collective memory spaces as rhetorical acts (or texts), upon scenes, by recognised agents with discernible motivations. ehrenhaus ( ) recognises memorials as legitimate rhetorical texts because they are used for persuasion and propaganda, sponsored, endorsed or constructed by governments or their proxies, so that they might be read as inventions of institutional authority, or the expressions of political bodies in (re)conceptualising historical events. ( - ). gallagher ( ) writes, “[s]uch artifacts are intended by their creators and/or perceived audiences to perpetuate values, admonish us to future conduct, and affirm or challenge existing power relations” ( ). conversely, carruthers ( ), whilst recognising that “memorials are rhetorical…powerfully so,” notes that they are so “whether or not their designers and patrons intended them to have such rhetorical power.” according to her, “it is unlikely that the designers of the lincoln or vietnam [and we can assume other major] memorials thought in terms of rhetoric at all; probably they would be offended at the very idea” ( ). this thesis, with evidentiary support from the archive, aligns itself with the theories of agential purpose espoused by ehrenhaus and gallagher, whilst severely departing from carruthers’ claims of mediators’ rhetorical naiveté or innocuous political agency. part of the power wielded by the rhetors, or creators, of a public memorial is the manipulation not only of what a society remembers, but also of what it forgets, as referenced by sturken ( ), dacres, ( ) and ehrenhaus ( ). this is achieved, according to biesecker ( ), perelman and olbrechts-tyteca ( ), young ( ) and griswold ( ), as memorials function in epideictic or didactic rhetorical modes. by invoking the blame and praise dichotomy recognised by aristotle in his very definition of epideictic rhetoric, commemorations can “function rhetorically as civic lessons for a generation beset by fractious disagreements about the viability of u.s. culture and identity” (biesecker, affecting the realities and culture(s) of its participants. jack selzer ( ) and other have challenged the “discursive turn” and its concentration on the ephemeral, to underscore that an object’s material aspect is a dynamic component of rhetoric, meaning and culture. ). memorials such as the tjm are explicitly epideictic vehicles for employing national patriotic stories of “ennobling events” (young, ) for modern repossession. this thesis also follows the recent re-consideration of a material rhetoric (by sturken et al), whereby recognising rhetoric as substantial in itself – and not simply attending to the materiality of the rhetorical context – moves us to consider the memorial as a legitimate text outside of the narrow definitions of written and oral discourse. much of the intellectual space for a material rhetoric as applied to public memory in physical space was chartered by carole blair in the wake of the fifteenth penn state conference on rhetoric and composition ( ). having identified the postmodern, post- structuralist era as the kairotic moment for a material rhetoric, blair applies five modes of inquiry to her (admittedly curtailed) case studies from a post- memorialising culture. first, what is the significance of the text’s materiality? second, what are the apparatuses and degrees of durability displayed in the text? third, what are the text’s modes or possibilities of reproduction or preservation? fourth, what does the text do to (or with, or against) other texts? fifth, and most importantly for the heuristic of materiality, blair asks how does the text act on person(s) ( ). such questions, sufficiently adapted, will be deployed in the final chapter to assess the consequence of the misleading jefferson epigraphs upon the material and cultural context. in places of public memory ( ), dickinson, ott, and blair situate modern memory studies in a post-halbwachs, post-foucault context, in which memory is broadly understood as an operation of collectivity, “rather than individuated cognitive work” ( ). following hattenhauer ( ), dickinson, blair and ott argue that interaction with a site’s materiality “predisposes its visitors to respond in certain ways, enthymematically prefiguring the rhetoric of the place as worthy of attention, investment, and effort (at the very least)” ( ). arguably, the tjm engages in a fallacious rhetorical relationship griswold has similarly identified the lincoln memorial as a site of epideictic rhetoric, rendered in the traditional “pattern of a hero,” conveying the lincoln-as-saviour motif for replication among the american public. throughout her chapter in rhetorical bodies and other scholarship, blair has avoided the substantial washington memorials (lincoln, jefferson and washington) of the late-nineteenth and early-twentieth centuries. with its audience, enacting a betrayal by subverting the expectation of an accurate and authentic presidential memorialisation. finally, this thesis recognises the important observation of james loewen in underlining the tripartite historic dimension of objects of public memory, such as the thomas jefferson memorial. the first phase is the “manifest narrative” of the original event or person, that is to say the historical genesis to which the object refers ( - ). the second phase is the story of the site’s own creation, the historical circumstance of the object’s mediation which “reflect[s] the attitudes and ideas of the time when americans put them up, often many years after the event” ( ). the final historical moment is that of a visitor’s own contemporary experience, by which the manifest narrative is activated within the confines of a particular context. in summary, this thesis understands memorials such as the tjm to be legitimate texts subject to rhetorical motivational forces, used for political propaganda, and constructed for discrete remembrances and amnesias. they employ national stories for modern repossession. they are materially consequential objects which act upon audiences and influence other texts and interpretative discourses over time. memorials are also acts of collective cognitive work that predispose their audiences to receive accurate and authentic information. these characteristics of memorial objects provided the rhetorical mechanics for the thomas jefferson memorial commission to engineer a version of jefferson’s legacy to agree with the agenda of his democratic inheritor and primary commemorative sponsor: franklin delano roosevelt. in chapter , close analysis of the five inscriptions and the archival record reveals that the thomas jefferson memorial commission embarked upon a series of purposeful and recontextualizing revisions. in each case, the editing process achieves some level of alignment between the memorial’s subject and its patron. examples include the generalisation of jefferson’s political philosophy to serve as an apposite war cry against tyrannical injustice and religious oppression, the use of selective quotation to suggest jefferson’s support for the scope of governmental overhaul represented by roosevelt’s new deal, and the extrapolation of a comment jefferson made on educational provision to an unequivocal endorsement of universal public education. during the consideration of one panel, the commission simplifies and ameliorates jefferson’s complicated relationship to the abolition of slavery, while also wrestling with the question of whether any reference to jefferson and civil rights might be problematic for roosevelt’s administration (which, whilst contributing significantly to the advancement of african americans, also compromised parts of its civil rights agenda to maintain the political support of southern white democrats). chapter examines the competing motivational forces behind the mediation of jefferson via the manipulation of the memorial’s epigraphical content. specifically, archival research exposes the motivations of the commission and the sub-committee on inscriptions in (re)creating the historical voice of jefferson for public commemoration. this historicizing project competes with the direct intervention of president roosevelt to ensure a parallelism between his contemporary agenda and the legacy of jefferson as a progressive icon. chapter examines the memorial from a material-rhetoric perspective in order to understand how it achieves the goals of its rhetors, as well as a variety of unintended (or unforeseen) consequences in shaping public memory. the memorial engages its users in an enthymematic deceit, which presents an inauthentic version of jefferson as a supposedly elite, accurate and authentic object of public memory, worthy of attention, investment, and effort. chapter : the rhetoric – from parchment to marble, jefferson reclaimed thomas jefferson, who had designed his own modest tombstone during his lifetime, could hardly have imagined the scope of his eventual posthumous memorialisation. rising feet higher than the obelisk of coarse stone he had envisaged, the thomas jefferson memorial upon the south bank of the tidal basin is today an extravagant, brobdingnagian shrine to the third president of the united states and his interpreted ideals (appendix a). the design, informed by the roman pantheon and jefferson’s own architectural tastes, is unashamedly neo-classical, modelled by leading antiquarian architect john russell pope. facing the washington monument and the white house beyond, the main entrance of the memorial consists of sweeping marble steps leading to a portico with a circular colonnade of ionic order columns rising feet high to support a pediment containing a sculptured representation of the signing of the declaration of independence, crowned by a shallow dome. the interior of the monument is demarcated by four great stone panels on the northeast, northwest, southeast, and southwest walls, as well as a carved panel that encircles the base of the dome’s interior. each quadrant features a prominent brass-lettered epigraph, apparently taken from jefferson’s own writings, communicating a concentrated and accessible version of jefferson’s intellect, philosophy and politics. the content of these panels is illustrated in appendix b. this chapter recognises these inscriptions as part of the grammar of the memorial’s rhetorical whole, functioning as examples of the classical concept of “relative inscription” – i.e., epigraphical content bearing relationship to other rhetorical features of memorialisation to communicate a particular narrative or theme. those responsible for the creation of the tjm relied upon the manipulation of these inscriptions to fashion a reality of jefferson’s thinking which corresponded with – if not historically validated – a number of the policy decisions and rhetorical frameworks of the roosevelt administration itself. by number alone, analysis reveals that a total of (at least) ten separate textual sources were marshalled by the commission to compile only five panels, demonstrating the extent of creative license at work. the nature of this rhetorical manipulation is distinct for each panel, but the overall intent is largely consistent and well-evidenced: that is, to extract from jefferson’s often context-dependent, nuanced and problematic source texts, quotations that are generalised and aphoristic; applicable to world war ii dichotomies; and supportive of the new deal philosophy. the commission edited the inscriptions to simplify jefferson’s enigmatic qualities as an historical actor, by, for example, christianizing his voice (where greater theological complexity exists) and – most significantly – transforming the ideological minefield of jefferson’s record on slavery into declarations of unwavering and prophetic abolitionism. the story of each inscription’s formation is detailed in turn below, demonstrating the cumulative mechanistic and ideological manipulation of the source text material to effect an opportunistic interpretation of jefferson for the benefit of his rhetorical agents and their context. whilst it is clear that any truncation of jefferson’s language is a fraught experiment of semiotics, the commission’s accommodation of roosevelt’s presidential license leads to a codification of jefferson’s character that, at times, is both opportunistic and counter-historical. thomas jefferson memorial panel a (tjmpa) the quotation on the panel of the base of the interior dome (hereafter tjmpa) is, in fact, the only engraving of the five major quotations found within the memorial room, with the other four consisting of individually laid brass letters. comprising only twenty words, “i have sworn upon the altar of god eternal hostility against every form of tyranny over the mind of man,” the quotation runs around the entire circumference of the circular chamber, emerging from the right side of jefferson’s statue; its end and beginning points are demarcated only by three engraved saltire crosses – exaggerated terminal punctuation for greater legibility. as archival analysis reveals, the quotation against tyranny was selected, on the one hand, as an interpretative keystone for the entire memorial. the sentence functions as the generalising and encompassing parent-thought of american freedom to encircle and unify the quadrants’ endorsement of a variety of human freedoms. on the other hand, the commission significantly and knowingly recontextualized what was originally a private remark on personal electoral and theological rivalries, making it a cosmically proportioned proclamation of liberty. the commission therefore concentrated jefferson’s original subtlety and specific concern into an aggrandising aphorism that a) distilled jefferson’s historical persona as the prime mover of america freedoms, b) supported the current western response to the existential threat of nazism’s rise, and c) roused and comforted an american public by re-emphasising the existential semantic of is founding democratic philosophy. the quotation is taken entirely from a private letter written by jefferson (in monticello) to dr benjamin rush, dated september , , in which he defends his philosophical rebuttal to the enshrinement of state religion (boyd : ). the missive was written at a crucial point in american political history, on the eve of the antagonistic presidential election in which jefferson and his running mate, aaron burr, (on a democratic-republican ticket) campaigned against the incumbent federalist, john adams. the election was bitterly fought, with divisions on foreign policy – particularly attitudes towards the virtue or villainy of the french revolution – looming large in public debate. jefferson’s ultimately successful campaign was also dogged by accusations surrounding his religious (deistic) beliefs. his numerable critics voiced concern that his abstraction from mainstream christian orthodoxy made jefferson unfit to hold the highest office, and a threat to their congregations. this letter, from which the prominent quotation is taken, is, in fact, a response to a warning from rush – written august – about the strength of anti-jeffersonian feeling among the philadelphian clergy (and others) who continued to cast the candidate as a dangerous atheist. the wall of separation between rush was no doubt reading the same arguments captured in an article from the new england palladium: “should the infidel jefferson be elected to the presidency, the seal of death is that moment set on our holy religion, our churches will be prostrated and some infamous prostitute,…will preside in the sanctuaries now devoted to the worship of the most high.” church and state – a philosophy articulated by jefferson, and acted upon through his work in virginia to disestablish religion – had garnered extreme opposition and was becoming a partisan and theological issue. in the third paragraph of this letter, jefferson counters the logic of his pennsylvanian foes by interpreting their opposition to him as a misunderstanding of the “clause of the constitution, which, while it secured the freedom of the press, covered also the freedom of religion” and “had given to the clergy a very favourite hope of obtaining an establishment of a particular form of christianity thro’ the u.s.” jefferson’s potential election to the presidency threatened to thwart such an enshrinement, as his enemies believed that “any portion of power confided in me, will be exerted in opposition to their schemes.” it is here, at the crest of a political riposte, that the tjmpa quotation is found: and they believe rightly; for i have sworn upon the altar of god, eternal hostility against every form of tyranny over the mind of man. but this is all they have to fear from me: & enough too in their opinion & this is the cause of their printing lying pamphlets against me (boyd, : ). the quotation, as it appears upon the memorial frieze, is arguably the most faithful textual replication of jefferson’s words within the epigraphical whole. while it omits the sentence’s beginning, the quotation does not otherwise deviate significantly from the primary source, nor is it combined with any other source material. grammatically, the comma from the initial clause has been removed, and the lowercase “god” is rendered imperceptible by the total capitalisation of the sentence, as is customary for the majority of memorial inscriptions to maintain aesthetic balance (and also potentially convenient for avoiding theological controversy). instead the commission’s formation of tjmpa exemplifies a number of rhetorical fallacies under the broad terminology of recontextualization, a process defined by per linell as “the dynamic transfer and transformation of something from one discourse/text in context . . . to another” ( ). the commission abstracts jefferson and his language (the historical manifest narrative) – with intent – from an original context and, via the rhetor-agency of an early-twentieth century commission supported by the president, into a discrete alternative milieu. the inscription of tjmpa is a significant event of fallacious contextomy, or quoting out of context, in order to wrench the words away from their realpolitik, epistolary and theological context towards a new kairotic moment of generalising twentieth-century american resistance to oppressive regimes and tyrannical ideologies. the original letter, with its climactic rebuttal to jefferson’s political enemies, is a deeply context-dependent document, rich in reference to late eighteenth- and early nineteenth-century presidential politics, international affairs and constitutional philosophy. the letter forms part of a dialogic correspondence between two of the nation’s founding fathers on the subject of christianity and political strategy. recontextualized by the commission as it is – and dislocated from the realm of private discourse to public and international consumption – the statement is denuded of complexity and emphasis, so that the words are rendered as a stand-alone affidavit of the unerring philosophy of divinely witnessed american freedom. while there is no doubt that this sentiment exists in jefferson’s original, the quotation erases the constitutional backdrop that provokes it. rather the quotation drapes jefferson in a cloak of heroic christianity as some miles christi – potentially the antithesis of his original intent. under the agential influence of the tjmc, the oath sworn upon the altar is no longer the rhetorical retort to the oppressive potential federalist pamphleteers, but the sober religious staging for jefferson’s rejection of (now ill-defined, and thus potentially reclaimable) general tyranny. the inscription, installed upon the memorial as an isolated maxim, demonstrates the potential for the logical fallacy of contextomy to effect an entirely false attribution of values, to provide the phrase with a philosophical pregnancy not present within the source text. these words have significant bearing upon the interpretative framework of the memorial, and its constituent inscriptions, arguably serving as a keystone of misremembering. the commission archives illuminate the complex of motivational forces working upon the rhetor-agents who moved to adopt the frieze quotation. dr fiske kimball first suggested the use of the rush letter quotation at the meeting of the commission on march , , bolstering his selection of the frieze statement with an intriguing appeal to informal presidential authority and approval, suggesting that roosevelt had in some way already commended the quotation for the outlined application: i found one which you have seen before that i know the president would like very much. “i have sworn upon the altar of god eternal hostility to every form of tyranny over the mind of man.” i would like to see it run along the frieze (tjmc- ). on october , , the tjmc met to debate the wording for the frieze quotation, eventually moving to adopt the rush-letter phrase as the memorial’s banner epigraph. it was propelled to debate at this moment by contractual impetus, prior to the establishment of the formal sub-committee responsible for later inscription selection. from the beginning, the quotation was conceived by the commission as a purposefully undefined axiom, extracted from the particulars of jefferson’s electoral context to serve as a grandiloquent universal proclamation on liberty, under which each of the other quadrant panels could find a unifying theme. dr kimball made the generalizing stratagem clear, understanding the phrase as having the “advantage over all other excerpts, in that while he has elsewhere expressed his hostility to political tyranny, or religious tyranny or other forms of tyranny, in those words he covered all forms of tyranny” (tjmc- october , ). the leaflet prepared to attend the public opening of the memorial affirmed the quotation’s generalising properties in summarising the “creed of [jefferson’s] political and social philosophy” (tjmc- ). senator thomas, an appointed member of the tjmc, heaped praise upon the inscription in october for its potential to be an all-encompassing headline: “i do not know what better quotation you could get to show what an american democracy stands for” (tjmc- ). the commission transforms the electoral and constitutional threat of christian federalist activists, which jefferson describes as a form of tyranny within the complex of his own political battle, into the altruistic, statesmanlike remonstration of individual oppression. the recontextualization causes the twenty-word phrase to serve metonymically for the jefferson corpus and a rooseveltian brand of american foreign policy. tjmpa might be understood less as a signification of the historical object (and his unorthodox religious views), and more a means of deploying that historical object within the circumstantial zeitgeist of cultural memory. in the words of sturken (writing on other sites of commemoration), the memorial’s “authenticity is derived not from its revelation of any original experience but from its role in providing continuity to a culture” ( ). at the moment of the memorial’s creation, the continuity of american culture and democracy faced its greatest existential threat from the rise of european fascism. correspondingly, the archives reveal that the intent of the quotation was less to remember who jefferson was for posterity, and more to ensure that a public did not forget what america meant for interbellum modernity. the quotation was brought to the commission’s attention by dr fiske kimball, with the potency of implied presidential authorization. almost one year later roosevelt contacted chairman gibboney by memorandum, proposing the very same quotation from the benjamin rush letter for the dome inscription, forwarding a supporting letter from secretary harold ickes – a key implementer of the new deal agenda. “what do you think of this idea?” the president asked, before underscoring, “it seems pretty good to me. fdr” (tjmc- december , ). gibboney reassured roosevelt that “this has already been done, as mr ickes can see if he visits the memorial,” before inviting further involvement from the sitting president, “to select the most suitable quotations for these panels, and we should be most happy to receive from you any suggestions you might care to make in this connection (tjmc- december , ). whether roosevelt was merely measuring the potency of his earlier implicit endorsement of the sentence, or his general sway with the commission, (or indeed even if the entire matter had been coincidence) his preference for the tjmpa was secured, along with his power as an interceding rhetor with demonstrative agency in a project of jeffersonian recontextualization. the motivation behind roosevelt’s intervention was to memorialise a contemporary brand of american liberty, against the current context of hitlerism’s rise, via the abstraction of jefferson’s words. throughout his world war ii rhetorical output, roosevelt relied upon the re-interpretation of jefferson as an historical antecedent to his own administration and its challenges. when speaking about the protection of the american maritime borders from german invasion in , for example, roosevelt called upon the exemplar of jefferson’s order to the navy to end the attacks on american ships by the corsairs of the north african nation ( ). the alignment of jeffersonian liberty with roosevelt’s contemporary protection of it was repeated throughout the s, and in the president went so far as to adopt and redefine the interpretative framework of jefferson’s “four freedoms” within his state of the union address (pederson, ). in the words of katherine scarborough, the frieze quotation was “selected for perpetuation before the eyes of the world at an hour when the right of human beings to think for themselves has been denied to millions, and, where it survives, is challenged more seriously than ever before in history” (december , ). the sentence is recontextualized (with discernible intent) from jefferson’s political battle against religious intolerance, to an international struggle against fascism and dictatorships, and from an audience of one in , to a global audience of millions during the uncertainty of international warfare. in , senator thomas – referring to the frieze quotation – exclaimed: “i only hope that they will charge this sentence up to each member of the commission, and we can all take credit for writing it.” beneath the jocularity of this statement is a self-revelatory truth. the commission members, as well as roosevelt, rewrote jefferson’s political statement through the formation of their own rhetorical object, forgetting, and forcing others to never properly understand, the intent, context and scope of the manifest object. thomas jefferson memorial panel b (tjmpb) the engraving on the quadrant panel of the southwest interior wall (hereafter tjmpb) is similarly derived entirely from a single source, namely the american declaration of independence ( ). widely recognised as the most influential document in the history of the united states, and ubiquitous in every classroom as the originary rhetoric of the republic’s freedom, the declaration is the metonym for the american consciousness – an “expression of the american mind” (jefferson ) as its author described it – and understood as the centrepiece of jeffersonia. it is perhaps evermore striking, then, as central as these words are to the foundation of american democracy and the formation of public memory surrounding jefferson, that in their quotation there is evidence of significant truncation and deviation, leading to false attribution, contextomy, and the fallacy of incomplete evidence, when compared against the source text. archival evidence suggests that the manipulations of the declaration of independence involved the selective redaction of those clauses least transferrable to contemporary foreign policy challenges. roosevelt directly intervened to emphasise a (wartime-friendly) statement on the sacrifice of life required to protect american freedoms. this is achieved to the detriment of the document’s context and innate artistry. the changes made to the declaration for the purposes of inscription are perhaps not the most egregious textual manipulations of the five panels, but they are certainly the most audacious when one considers the eminence of the original. when compared with the signed parchment version housed in despite their ease with their own misquotations of jefferson, the commission attempts to tightly control the interpretation of the jefferson memorial and to limit the multiplicity of individual readings. when deciding upon the frieze quotation, for example, senator thomas forensically examined the collocation of the inscription’s letters to assess what alternative readings might be made from various starting points. “let us see,” he said without irony, “what they [the public] could twist it into” (tjmc- – october , ). the national archives, the memorial text (tjmpb) includes quotations from only two of the five main sections of the declaration. incorporating the language from the preamble and the conclusion, the quotation omits any reference to the introduction, the indictment of george iii, and the denunciation of the british people. it is a quotation of the declaration’s ceremonial and more generic bookends, avoiding the more specific and enumerative contents of the text’s middle section, so as to maximize the applicability of its theoretical principles. comparative analysis reveals a number of (signalled and hidden) alterations made by the commission in their attempts to adapt the source text for maximal relevance. at the end of the first phrase in line , for example, “self-evident” is followed by a colon (rather than the comma used in the source text) providing a more revelatory pause to the subsequent enumeration of natural rights. in line , the subordinating conjunctive “that” preceding the enumeration of life, liberty, and the pursuit of happiness, is eradicated, disrupting the anaphoric flow of the opening sentence. at line , the tjmpb version denudes “these colonies” of the modifying “united.” in the antepenultimate line, the conclusive declaration (“we mutually pledge our lives”) omits the specification that this pledge was made “to each other,” arguably molding it for roosevelt’s era of international conflict and military sacrifice. similarly, line marks the transition between the preamble and conclusion of the declaration, yet despite the significance of this textual discontinuity, there is no explicit ellipsis in the southwest panel. the transition between the two sections is problematized further by the terminalisation of the preamble, which excludes the right of revolution argument at the very heart of the declaration’s rejection of tyrannical rule. these changes, invisible on the memorial inscription, are a means to an end in drawing out applicable messages, and expunging others. for the current administration, reliant upon internal cohesion of the democratic party, the erasure of the revolution principle is a potentially calculated act of self-preservation. as the quotation moves to incorporate language from the declaration’s concluding paragraph, the textual alterations continue, including the omission indicated by the line ellipses. in the commission’s recontextualization of the source text for modern repossession, the plural pronoun “we” loses its original reference to congressional representatives: we, the representatives of the united states of america, in general congress, assemble…do, in the name, and by authority of the good people of these colonies, solemnly publish and declare. consequently, and rhetorically, the specific contextual strings to which the declaration was anchored – and which were complemented by the current debate and congressional vote – are cut from the memorial version. the inscription is subject to a process of broad generalisation, through which moral principles (freedom, equality, just government and personal and states’ rights) are extracted and decontextualized, in order that they can be successfully resituated in any future american period as embodying the strength of the imperative, yet redacted of george iii and his specific tyrannies. in the quotation, the identity of the american enemy is anonymized and the potential for historical resonance expanded, such that the tyranny of an english king is made relatable to the oppositional frameworks not only of world war ii, but, for example, the cold war, vietnam, and the modern war on terror. as a new re-interpretative object of public memory, the quotation is made available for generational reclamation, so that portions of jefferson’s political philosophy are (or can be) effectively ventriloquized for the posthumous events which extend beyond the scope of his biography. from the earliest inception of the memorial, the commission considered the declaration as having a prima facie right of inclusion. it had the virtue of being the primary document that jefferson included in his modest self-memorialisation at monticello, and it was identified in foley’s jeffersonian cyclopedia as one of his most substantial legacies. as the commission archives reveal in startling – and hitherto unreported – detail, the gross manipulation of the source document and the consequent distortion of jefferson’s voice was the sole result of the interruptive force of roosevelt and the commission’s subsequent attempt to accommodate that high-profile agent’s power. if roosevelt’s influence upon the selection of the quotation for tjmpa had to be inferred, his involvement in the composition of tjmpb is overt and well-evidenced. in mid-december , roosevelt was invited to initiate the construction project at the site of the prospective memorial. prior to the official ground-breaking, the president spoke of (and accordingly framed) jefferson’s meaning to his contemporary american public with direct reference to the declaration: jefferson… has been recognized by our citizens not only for the outstanding part which he took in the drafting of the declaration… not only for his authorship of the virginia statute for religious freedom, but also for the services he rendered in establishing the practical operation as a democracy and not an autocracy (washington herald, december , ). this statement pre-empts the ultimate inclusion of both the declaration and the virginian statute as permanent memory prompts within the textual corpus of the memorial room. posing the democratic ideals of jefferson against that final antonymic word – “autocracy” – would have undoubtedly resonated with a listening public upon the precipice of autocratic incursions in europe. less than a year later and speaking at the cornerstone-laying ceremony, roosevelt made the elision of jefferson’s political environment and his own era of power explicit: “he lived as we lived in the midst of struggle between rule by the self-chosen individual or the self-appointed few, and rule by the franchise and approval of the many” (tjmc- november , ). roosevelt’s attempts to publicly parallel jefferson with his own presidency were matched by private machinations that sought to influence the commission to do the same via the rhetoric of tjmpb. in may , gibboney wrote to roosevelt, making good on a promise that “i would send you a copy of the proposed inscriptions for your suggestions... we should be very glad to have your criticism at your convenience” (tjmc- ). though roosevelt received the letter only two weeks before he was to declare an unlimited national emergency, he responded immediately, giving his approbation to the work achieved so far whilst indicating a preference for amending tjmpb: i do miss the last paragraph of the declaration of independence. it seems to me that that is so familiar and so important that it should appear somewhere. it could be condensed somewhat as follows: “we . . . solemnly publish and declare, that these united colonies are, and of right ought to be, free and independent states . . . and for the support of this declaration, with a firm reliance on the protection of divine providence, we mutually pledge to each other our lives, our fortunes, and our sacred honor” (tjmc- may , ). here, roosevelt goes so far as to model the quotation, with ellipses and editing, to ventriloquize jefferson in an era of echoic competition between the values of american democracy and those of european autocracy. a number of days later, general kean responded to the intercession with mixed feelings, agreeing that the addition would “round it out very nicely” whilst being surprised at the “continued interest which the president takes in the memorial in spite of the tremendous responsibilities which he is facing on matters in which the whole world awaits decisions” (tjmc- may , ). indeed, the physical act of war and the rhetorical act of the memorial’s might be interpreted as thematically contemporaneous in roosevelt’s thinking, each functioning as defensive statements of the american ideal. practically, however, roosevelt’s suggested alteration to the panel’s length, emphasis and continuity, delivered under the seal of the president, sparked fractious debate among the tjmc members and the architectural firm, eggers and higgins. in particular, the changes to the content already agreed upon by the sub-committee on inscriptions, threatened to distort the visual balance of the four quadrants. the commission faced a genuine quandary of priorities, between effectively memorialising jefferson in accordance with their collective reasoning, and acquiescing to the power- laden intercession of his th century successor. in august , the architect’s design team revised tjmpb “to show the arrangement under these circumstances,” but eggers explicitly disapproved: “i have a feeling that the memorial might in part fail in its purpose if the inspiring words of jefferson were not read and absorbed by the majority of visitors… this would mean that substantial additions would have to be made to the other three panels if the president’s suggestion is carried out (tjmc- september , ). over the next few weeks, gibboney manoeuvred the commission out of a potentially embarrassing impasse. invisible to commission minutes and the papers of tjmc archives, the panel was significantly revised to accommodate the president’s suggestion. general kean praised the “very clever and satisfactory” compromised arrangement, which “met the president’s wishes, got rid of those troublesome words “or abolish it” and gives a satisfactory length for mr eggers” (tjmc- , october , ). the president subsequently approved of the resolution, adding “i like the way you have worked out the inscription” (tjmc- , october , ). demonstrably, almost all of the major textual deviations were incurred and documented as a cost of obliging presidential intercession. senator thomas viewed the concession as a consequence of short-sighted politicking via the back door of jefferson’s memorialisation, codifying the moral rightness of the incumbent rather than his predecessor: i… am loth to disagree with the president’s wishes, but the last words of the declaration which we have added on panel one are merely an appeal to support a cause – a great cause, of course, but there is not a bit of political theory in it. men fighting on hitler’s side today have mutually pledged their lives, their fortunes, and their sacred honour, and are giving them! that was america as a war cry, not jefferson as a political philosopher (tjmc- october , ). the consequence of roosevelt’s attempted historical parallelism is significant also for what it effects upon the public remembering of jefferson as a meticulous political author. roosevelt’s panel, adopted by the commission, is injurious to the modern interpretation of the declaration as an exemplum of eighteenth-century constitutional prose, wrought with rhetorical precision and enlightenment style. the declaration is a paragon of concentration and restraint, with individual propositions, phrases, and words irreducibly essential to the document’s force and meaning. it is a treatise brought to the scale of paragraph. on the artistry of the declaration, stephen lucas writes the following: each word is chosen and placed to achieve maximum impact. each clause is indispensable to the progression of thought. each sentence is carefully constructed internally and in relation to what precedes and follows…one word follows another with complete inevitability of sound and meaning. not one word can be moved or replaced without disrupting the balance and harmony of the entire preamble ( ). illustrative of this point is the way in which the preamble was conceived as an extended deployment of an elaborate rhetorical device – an ascending pentacolon– through which the compounding of five sequentially dependent propositions (cola) ascend towards a powerful and inevitable conclusion. jefferson was au fait with the eighteenth-century periodic style of rhetorical construction – including an informal sorites, or polysyllogistic construction – whereby “sentences are composed of several members linked together, and hanging upon one another, so that the sense of the whole is not brought out till the close” (blair , ). embedded within the preamble are five interconnected and progressively dependent propositions that move to justify the emphatic climax of revolution. throughout these propositions, the structure is dependently chronological – perhaps even biblically so, moving from an act of creation, to the implementation of order, to chaos (rebellion), and to the institution of a new redeeming governmental order. the pentacolon then, writes the fates of american readers in a fabled five-part chronology of american history. to this considered filigree, the commission take a metaphorical butcher’s cleaver, whereby incorporating the president’s wishes forestalls the ascent of the pentacolon, strips away the climactic conclusion, and eradicates any trace of polysyllogistic phrasing which speaks not only to the intended rhythm and progress of jefferson’s authorship, but also to the stylistic age to which he is intrinsically wed. the removal of the anaphorically related “that” at line – which would demarcate the third proposition, for example, – effectively neuters the polysyllogistic sense of purposeful expectation in the original, and in place of the fifth proposition (“whenever any form of government becomes destructive of these ends, it is the right of the people to alter or abolish it”), the commission instead appends the final lines of the declaration, rendering the ascent towards george iii’s tyranny as a nondescript affirmation of general freedom. not only is the jump to the document’s conclusion injurious to the rhetorical intricacy of the preamble, but the alterations made to this new conclusion further detract from another celebrated section of the declaration as a paradigm of jefferson’s writing. assessing the lexical incorruptibility of the declaration’s final sentence, carl becker suggests the words almost have an innate grammatical sanctity: how much weaker if he had written “our fortunes, our lives, and our sacred honour”! or suppose him to have used the word “property” instead of “fortunes”! or suppose him to have omitted “sacred”! consider the effect of omitting any of the words, such as the last two “ours” – “our lives, fortunes, and our sacred honour.” no the sentence can hardly be improved ( ). the commission evidently thought otherwise, consistently privileging the accommodation of roosevelt’s tendentious reclamation of the declaration for his contemporary rhetorical framework of american democracy versus fascist autocracy. by stripping away any specific context-dependent enumerations from the declaration, and showing a disregard for jefferson’s lexical artistry, the commission ensured that jefferson’s voice was spoliated for the modern audience. together, roosevelt and the commission use the founding document to restate the authoritative position of the american superpower at a moment of existential crisis, inhabiting the plural pronoun of the quotation affirming protected liberty, and relying upon the modal and infinitive verb sense of the inscription (“ought to be free and independent states”) to bring jefferson – and his defining document – to an object of perpetuating cultural memory and, potentially, rooseveltian activism. thomas jefferson memorial panel c (tjmpc) if tjmpb is controversial as a result of the commission’s decision to deviate from a source text of national celebrity for contemporary rhetorical application, tjmpc is doubly so because of the sheer number of sources – some famous and some less so - harnessed to furnish a panel of only ninety-seven words. the full scope of the panel’s misleading rhetorical composition is illustrated in appendix c. as a consequence, the inscription upon the northeast interior quadrant wall is potentially the most contentious example of the manipulation of jefferson’s words for the evocation of his public memory. the patch-work panel recontextualizes five separate sources and knits them into a singular expression of jeffersonian liberty, with an emphasis upon god-given freedom, anti-slavery, and general education. though presented as a pure and uninterrupted quotation, without ellipsis, the content is drawn from disparate sources spanning forty-seven years of the author’s life. the panel includes words taken from a political tract, a summary view of the rights of british america ( ); his only full length book, notes on the state of virginia, ( ); his personal narrative, jefferson’s autobiography, ( ); correspondence with his mentor, letter to george wythe (august , ); and an epistle to the first american president, letter to george washington (january , ). through chaining together variously extracted elements of jefferson’s writing and presenting them as the direct product of the memorialised, the commission perpetrates the fallacy of contextomy leading to a false attribution of a complete statement which jefferson never intended to be written in particular, the archival record relating to the selection process of this quotation reveals the tense negotiation of jefferson’s variable reputation relating to the institution of slavery and the abolitionist movement. while it is clear that a number of the commissioners were uncomfortable with a simplified caricature of jefferson’s record, others were more concerned about the comparative effect of such a quotation being memorialised in the age of roosevelt. like jefferson’s, roosevelt’s performance in the arena of civil rights was mixed, especially at the time of the memorial’s conceptualisation. though african americans certainly benefited through the institution of the new deal economic framework and improved labor laws, they were often deliberately excluded from specific programmes and their advantages. roosevelt’s reliance upon the southern white democratic caucus meant that he resisted a comprehensive civil rights agenda and, prior to world war ii, failed to institute anti-lynching legislation. to remember jefferson in the context of slavery was to invite a comparison with the extant racial inequalities under the roosevelt administration. the decision to reduce and embed the reference to abolition in this panel was arguably informed by the perceived imperfection of both men as proponents of african american progress, proving the rhetorical symbiosis of past and present at work. tjmpc- . a summary view of the rights of british america, . “still less let it be proposed that our properties within our own territories shall be taxed or regulated by any power on earth but our own. the god who gave us life gave us liberty at the same time; the hand of force may destroy, but cannot disjoin them” (boyd, : ). the first eight lines of tjmpc are taken from the penultimate sentence of jefferson’s summary view, a political tract “intended for the inspection of the present delegates of the people of virginia now in convention” (i.e. the inaugural continental congress). it is a document expressing both contemporary concerns and jefferson’s political philosophy, forming an embryonic argument for the dislocation of the underlined section indicates the text used in the thomas jefferson memorial panel american colonies from the control of great britain. throughout the summary view, jefferson decries george iii’s authoritarian grip over his native state’s ability to make fundamental fiduciary and political decisions, hampered as it was by the monarch’s “inattention to the necessities of his people.” jefferson levels a series of grievances at the british crown ranging from king george’s response to the boston tea party, to the restrictions placed upon the colonies in effectively dismantling the institution of american slavery. “the abolition of domestic slavery is the great object of desire in those colonies,” jefferson writes, “where it was unhappily introduced in their infant state.” extracted from a complex , -word long treatise on the numerous rights of british virginia, these eight words do not capture the essence of jefferson’s catalogue of political opposition, but are rather deployed in the sense of the beginning of a prayer or supplication to god. it is clear, from examination of the source text, that the quotation creates a new complete and simple sentence out of an elaborate construction, eliminating the initial determiner and impacting the statement’s parallel arrangement. extrication of the preceding sentences, which level attacks on taxation and exclusion from commodity markets, as well as removal of the complementary parallel section of the quoted sentence “the hand of force may destroy, but cannot disjoin them,” essentially neutralises the pointed and contextually-anchored criticism of british policy. jefferson’s concluding and embedded political argument is fundamentally transformed into the simple religious framing for tjmpc. . . . tjmpc- a. notes on the state of virginia, c. - "for in a warm climate, no man will labour for himself who can make another labour for him. this is so true, that of the proprietors of slaves a very small proportion indeed are ever seen to labor. and can the liberties of a nation be thought secure when we have removed their only firm basis, a conviction in the minds of the people that these liberties are the gift of god? that they are not to be violated but with his wrath? indeed i tremble for my country when i reflect that god is just: that his justice cannot sleep for ever" (ford, : ). the proceeding words are derived entirely from jefferson’s influential book-length work, notes on the state of virginia. the text originated in in response to the secretary of the french delegation – francois barbe marbois – who, during his posting in the temporary capital philadelphia, circulated a questionnaire requesting information on each of the thirteen colonies. jefferson was responsible for responding to the questionnaire on behalf of virginia, and it was this transcript which ultimately provided the basis for notes and gave it its overall sense of a directory or chronicle. jefferson’s work is not narrative, but rather a compilation of key state data points regarding rivers, seaports, mountains, population, religion, public revenues, laws, customs, and history. the document remains noteworthy for exposing jefferson’s views on the separation of church and state (fuelling federalist calls of “atheist”) and controversial for what it reveals about his policy on slavery and miscegenation (complicating jefferson’s already entangled relationship with the cause of abolition). this portion of the panel is derived exclusively from the second paragraph of section xviii of notes, on the topic of “manners.” extracted as they are, however, these words form less an objective summary of the attitudes of the virginian people, and more a glimpse into the religious and patriotic psychology of the author. the statement – selected, in part, no doubt, for its lexical continuity with the god-given freedoms of the summary view quotation (demonstrating the deliberate guise of a singular text) – serves as an expression of jefferson’s perceived crisis of national faith, but makes no reference to the main point of jefferson’s original: the injustice of american slavery. though jefferson uses the entire section on “manners” exclusively to address the issue of slavery and its pejorative effect upon virginian behaviour, the excerpted quotation instead presents a self-contained religious responsorial through careful redaction. the removal of the conjunction “and” at the beginning of the statement cuts all grammatical ties to the previous discussion of slave-owner immorality, and thus erases the primary object of jefferson’s religiously stated despair. this particular example of deliberate recontextualization is one of the clearest examples of calculated misrepresentation, but it is also peculiar for suppressing the theme of slavery to which the panel subsequently returns. his proximate criticism of black subjugation is circumvented in this quotation only to be revivified in concentrated form in the subsequent seven words of the panel, taken from the very same section of notes. tjmpc- b. notes on the state of virginia, c. - “the whole commerce between master and slave is a perpetual exercise of the most boisterous passions, the most unremitting despotism on the one part, and degrading submissions on the other. our children see this, and learn to imitate it...” (ford, : ). where the first quotation from notes’ section on manners evades reference to jefferson’s argument for abolition, these seven words state it with the force of a paternal and moral categorical imperative. distorting the order of the original, this quotation reverts to the first paragraph of the section and, without any formal ellipses, pretends to be a statement of climactic subsequence. the words are recontextualized from a complex grammatical composition, stripping back the ornate jeffersonian vocabulary and undoing the rhetorical balance of the final phrases. the “unremitting despotism” of the masters, for example, is associated syntactically, visually, semantically and rhythmically with “degrading submissions” of the slave community. the erasure of the latter part of that parallel construction removes the equalizing emphasis upon the condition of the subjugated. the quotation as extracted presents jefferson’s attitude toward slavery as one of unremitting, indignant opposition to an institutional despotism. however, the recontextualization oversimplifies and attempts to ameliorate jefferson’s historical position in the cause of abolition. whilst jefferson briefly decries the institution of slavery in the section on “manners” in notes, he does so less as a moral necessity and more in racist reaction to its observed “unhappy influence” upon virginian behaviour. “the man must be a prodigy,” jefferson remarks, “who can retain his manners and morals undepraved by such circumstances” (ford, : ). jefferson’s stated outrage is couched within an a posteriori argument informed by a moral relativist observation, re-worked by the commission to feature as a bellowing a priori objective morality. the act of contextomy enforces an unequivocal certainty that denies the less forward-thinking elements of jefferson’s ruminations on slavery in the same source text. in section xiv of notes on “laws,” for example, jefferson devotes a significant portion of his survey to the potential consequences of post-emancipation america. with the detachment of a prejudice-laden anthropologist, jefferson sees “deep rooted prejudices entertained by the whites; ten thousand recollections, by the blacks, of the injuries they have sustained; new provocations; the real distinctions which nature has made; and many other circumstances,” which threaten to “divide us into parties, and produce convulsions which will probably never end but in the extermination of the one or the other race.” racial integration is made problematic because of the irreconcilability of the “physical and moral” differences represented by colour, which is “the foundation of a greater or less share of beauty in the two races.” whites have “flowing hair, a more elegant symmetry of form” – so fair that even the black man shows “judgment in favour of the whites…as uniformly as is the preference of the oranootan for the black women over those of his own species.” blacks have, according to jefferson, “less hair on the face and body” and “secrete less by the kidnies, and more by the glands of the skin which gives them a very strong and disagreeable odour.” jefferson proposes that black people have the potential to love, but that “love seems with them to be more an eager desire than a tender delicate mixture of sentiment and sensation.” he promulgates that blacks feel less pain and discomfort (“those numberless afflictions…are less felt, and sooner forgotten with them”); they are musically gifted but whether they are “equal to the composition of a more extensive run of melody, or of complicated harmony, is yet to be proved”); “their disposition is to sleep;” and “in memory they are equal to the whites; in reason much inferior…in imagination they are dull tasteless and anomalous.” jefferson concludes, with the caveat that his ideation is more “a suspicion only,” that the black people “whether originally a distinct race, or made distinct by time and circumstances, are inferior to the whites in the endowments both of body and mind” (ford v. ). reconciling this self-revealed character of jefferson with the author of the very same work that argues passionately for the future emancipation of slaves, remains a point of academic disputation, befuddlement and evasion. whilst it is clear that one can find a race inferior and still advocate for the fair treatment of its members, the sphinx-like (ellis ) historical persona of jefferson – on this issue in particular – oscillates between a visionary of freedom (e.g. peterson , ferling , malone ) and a man anchored to the racisms and practices of his age (e.g. wiencek , finkleman ). through this quotation the commission attempts to clarify this interpretative confusion by capturing a single snapshot of jefferson’s oscillation, but in doing so they memorialise a caricatured and ameliorated political position, resolving the difficult and debated subject of jefferson’s reputation on slavery, and excising the quite significant prejudicial overtones of jefferson’s work tjmpc- . jefferson’s autobiography, "nothing is more certainly written in the book of fate than that these people are to be free. nor is it less certain that the two races, equally free, cannot live in the same government. nature, habit, opinion has drawn indelible lines of distinction between them" (boyd, : ). the commission’s attempts to navigate jefferson’s contradictions on the issue of slavery are also evident in the extraction of the above eighteen words from jefferson’s autobiography, which elaborate and sustain the memorial’s interpretation of the third president as a prophetic trailblazer in the march towards emancipation. jefferson’s work is not a traditional autobiography, but rather a concise summary of notable life works – a form of self-memorialisation. this quotation is taken from the middle section of the text, as jefferson surveys the major legislation of the late s, and specifically a “bill on the subject of slaves,” which he describes as “a mere digest of the existing laws respecting them, without any intimation of a plan for a future of general emancipation.” the law avoids explicit reference to the manumission of slaves, jefferson explains, “as the public mind would not bear the proposition…yet the day is not distant when it must bear and adopt it.” the quoted words, however, do not convey any of jefferson’s equivocation or contextualisation surrounding the proposed policy of emancipation. the unconditional tone (“nothing is more certainly written”), absolute concepts (“to be free”), as well as the semantic of inevitability (“book of fate”) renders jefferson’s phrase – in isolation – as a trumpet call for social action, and it is this clarion voice that the commission extracts and adopts to speak from the walls of their eventual memorial. these quoted lines eradicate the dissoi logoi of the statement’s original context. like notes on the state of virginia, jefferson’s autobiography is a receptacle for jefferson’s expressed contradictions on the matter of manumission – principled in argument, but cautious in practicality. the antithetical sentiments in the autobiography, moreover, are so proximate to the quoted statement (as exemplified above) that their extraction is at best misguided and, at worst, purposefully misleading. the quotation deliberately mutes jefferson’s indulgence in the racist terminology of his age, and distils his legacy on emancipation into one of seeming chapter-closing – and positive – singularity. tjmpc- . letter to george wythe, august , "preach, my dear sir, a crusade against ignorance; establish & improve the law for educating the common people." tjmpc- . letter to george washington, january , "it is an axiom in my mind that our liberty can never be safe but in the hands of the people themselves, and that too of the people with a certain degree of instruction. this it is the business of the state to effect, and on a general plan." the final twenty-three words of tjmpc are taken from two letters authored by jefferson in , whilst he was the us minister to france: one written to george wythe (his former law professor at the college of william and mary), and the other written to george washington (before he assumed the presidency), each representing distinct epistolary contexts. without formal ellipsis, the produced quotation is a pretended continuous, contemporaneous statement on universal educational provision as the addendum to a panel that refers to a diverse range of political positions. the imperative phrase extracted from the wythe letter for the institution of public education is found at the conclusion of the correspondence in which jefferson identifies the establishment of a new political republic as an opportunity for implementing improved education, redirecting public monies that had traditionally supported nobles, priests and kings. jefferson advocates an american (and specifically anti-european) educational brand, explaining to wythe that “i think by far the most important bill in our whole code is that for the diffusion of knowledge among the people.” grammatically, the quotation excises the sentence’s opening and, without ellipsis, also removes the second verb (“improve”) and with it jefferson’s belief in the continuous evolution required at the heart of a first class system of education. the quotation taken from the letter to washington re-emphasizes the preceding words of the inscription by underlining public education as explicit state business. there is no internal damage done to the syntax or balance of the sentence, though the detail of the contemporary debate around jefferson’s proposals is suppressed in the recontextualization. if the quotation suggests legislative certainty, jefferson’s letter acknowledges the multiplicity of educational proposals under consideration, including the use of charity schools as proposed by his addressee. the quotation also strips away jefferson’s belief in public education as a means to effect social change by passing the baton of democratic leadership to the common populace: “[l]iberty can never be safe,” he writes, “but in the hands of the people themselves, and that too of the people with a certain degree of instruction.” what is retained, if not exaggerated, is the sense of jefferson’s pro-governmental position, that the state has a the letter to wythe (written in august) postdates the letter to washington (written in january) further demonstrating the commission’s acceptance of distorted textual chronology. positive and transformational role and interest in promoting social mobility – particularly among the political elite. through the amalgamation of two private letters, the commission created an aphoristic proclamation on educational reform that jefferson would not recognise as his own. the commission expanded jefferson’s musings into a statement that endorses universal public education – a policy that jefferson never strictly recommended, but that comported with the pedagogical focus of roosevelt’s new deal, and, for example, his federal appropriations for national school relief following the impact of the great depression. as richard hamowy pointed out in his review of jeffersonian reclamation, “jefferson’s admonition that an educated electorate was essential if liberty were to be preserved is transmuted into a call for universal public education.” in totality, tjmpc represents a memorial panel designed by committee, culminating in false quotation born of the contestation of commission egos, historical (re)interpretations, theories of epigraphical memorialisation, and a variety of motivational forces at play over its years-long formation. the breadth of this compromise is demonstrated by the range of topics covered in the tapestried quotation, spasmodically transitioning from the nature of human creation, to theological justice, to slavery, and to universal education, giving the sense of aphoristic compilation. the leaflet produced by the commission to attend the official opening of the memorial in , described the formation of tjmpc as a deliberative process whereby quotations were carefully researched and selected to resound with established interpretations of the cornerstones of jeffersonian philosophy, “to his concepts of freedom of the body and to his beliefs in the necessity of educating the masses of the people” (tjmc- ). this presentation of a clean and undisputed exercise of quotation-as-value-memorialization, however, belies the ideological conflict and compromise at the heart of this tangled rhetorical construction of memory – over the meaning of the four freedoms, over the appropriateness (and rooseveltian relevance) of slavery as a memorialised subject, and over jefferson’s role in the history of emancipation. kean first introduced his argument for a panel exclusively devoted to slavery in a letter to senator thomas on october , . kean identified “freedom of the slaves” as one of jefferson’s core philosophical freedoms, and justified its commemoration in the memorial as a means to revive the issue in the public’s imagination. in his attempts to write the pro-abolitionist jefferson into the book of national consciousness, kean called upon british liberal historian francis hirst and his life of jefferson, in which jefferson is described as “the only powerful statesman of his day in america who was willing to risk political future and social favour in an active effort to remove this dark blot from the institutions of this native land” (tjmc- october , ). employing a somewhat positive interpretation of jefferson’s anti-slavery legacy, kean defended the memorialised, writing that whilst “he was unable to get the law which he and chancellor george wythe had prepared for the gradual abolition of slavery to be passed by the virginia legislature, he did succeed in getting acts forbidding the slave trade passed both by the virginia legislature in and by congress in .” kean not only presented an academic case to thomas at this early juncture, but also appended three separate proofs setting out the alternatives for a panel on slavery. these suggestions, included as appendix d, positioned jefferson as a pioneering abolitionist in three different forms to maximise the agreeability of the proposal for the onward approval of the diverse commission membership. at the subsequent meeting of the commission on january , , two of the most significant members – chairman gibboney and senator thomas – initially favoured kean’s recommendation of a panel devoted to the subject of emancipation whilst kimball sought a less overt reference. kean was emphatic that the subject of slavery deserved a panel to itself: “it does not seem to have been brought out by american historians and seems to be little known or appreciated by the general public today,” kean implored, “yet it had a large influence on our national life” (january , ). as dawned, however, a panel on slavery faced renewed challenge from a large constituency of the commission – including the once-supportive chairman, stuart gibboney. this mood change intersected with, and was perhaps precipitated by, a sharp increase in roosevelt’s direct interest in the progress of the memorial’s inscriptions. on th december , roosevelt asked the librarian of congress, archibald macleish, to compile a series of quotations for potential inclusion in the memorial’s quadrants. macleish provided a series of textual testimonies to jefferson’s achievements, covering a diverse range of topics including the constitution, education, free speech, liberty, political economy, agriculture and democracy. roosevelt forwarded his dossier to the commission with the explicit endorsement of the presidential seal. crucially, macleish’s suggestions made no reference to the issue of slavery, implicitly rejecting the nearing consensus of the inscription committee’s panel on jefferson’s role in american emancipation. the president’s interjection drove an ideological schism in the process. simultaneously, the chairman made his telling u-turn, rejecting the entire notion of the four freedoms as a vehicle for the memorial’s rhetoricity. in place of the slavery- themed drafts under consideration, gibboney suggested an entirely new source and thematic focus based upon a letter from jefferson to samuel kercheval on constitutional adaptability. a number of arguments emerged from the commission in resistance to a panel that raised the controversy of jefferson’s position on slavery. gibboney and ryan were concerned about complicating the legacies of jefferson and lincoln. tumulty was wary that the panel might be interpreted as an attempt “to rouse resentment” in the post-emancipation era, asking, “are we not opening up the old sores?” (tjmc- february , ). dr kimball said that whilst he could not hear kean’s suggestion “without feeling a tingling up my spine,” the sentiment seemed to be captured in the equality clause of the declaration: “i would not want to see slavery neglected but i feel it is there as part of civil liberty.” mr culkin believed the “slavery proposition would be a mistake.” the chairman agreed, stating that “i think some members of the commission thought it would be somewhat like waving a bloody shirt.” the archive is littered with such statements of resistance to a panel addressing slavery on the basis that such a topic was politically inauspicious and electorally inert in the age of roosevelt. the compromises of this particular panel exemplify the discrete indulgence of two competing forces of contemporary parallelism and historical (re)interpretation. the compromised draft for tjmpc was brought to the final full commission meeting on september , , at which the inscriptions were debated. despite the dilution of the slavery issue within a panel that now expressed a more general sentiment on human liberty, even this weaker concentration on the subject was under threat. senator andrews objected to many of the quotations selected, including one relating to the commerce between master and slave. “i think it should be left out. it means nothing to anybody. it is not impressive and i would rather not hear about it.” exposing the anti-historical ethos of some commission members, andrews lamented any reference to slavery in tjmpc as contrary to modernity (and the rhetorical agenda of the commission) because it did not speak to government “as it exists now.” kean replied: this makes it all the more obligatory for the commissioners charged with the duty of bringing to the knowledge of future generations his great words and deeds to point the finger of history at this particular panel…i for one would feel that i had failed in the duty placed upon me by the president if i should be a party to any conspiracy of silence with regard to it (tjmc- ). the revised panel with reference to slavery (appendix e) was eventually put to a vote, leading to a dramatic tie. chairman gibboney – who had consistently objected to an inscription on the subject – was the unexpected redeemer of kean’s compromised panel, endorsing it for architectural submission on october , . the fractious deliberations surrounding tjmpc, and the unsatisfactorily constructed nature of the panel itself, supplies evidence for the rhetorical argument of this thesis. unlike expressions of generalized liberty, democracy-over-autocracy, progressive government or religious tolerance, the specific issue of slavery was not only complicated by jefferson’s biography, but also contested by the commission because of its lack of relevance to the america of roosevelt’s inheritance. slavery, as an institution, had been abolished and was no longer a cause for political reclamation. furthermore, a recontextualized quotation of racial freedom from the eighteenth century risked inviting comparison with roosevelt’s own record as an advocate of african american rights. while roosevelt’s numerous relief efforts benefitted many black americans – and eleanor roosevelt gained a reputation as an outspoken defender of racial equality – jim crow policies of de jure segregation persisted throughout the s. furthermore, a number of the new deal initiatives, such as the fair labor standards act ( ), which protected wages and hours, and the national labor relations act, which protected employee rights and unionization, specifically excluded the majority black professions of domestic service and farm labor, as appeasement to roosevelt’s southern democratic allies. the archives reveal that the rhetorical agents of jefferson’s memorial were sensitive to the inclusion of an inscription referencing slavery during roosevelt’s administration, with commission members describing the panel as a “bloody shirt” that would “arouse resentment” and open “old sores.” a statement on slavery provided no opportune tendentious parallel between the founding father and the ethic of roosevelt’s programme, and lacked the broader international resonance offered by other panels. as a consequence, tjmpc is a panel of tangled motivations which ultimately suppresses the complexity and sometimes ugliness of jefferson’s (and by rhetorical extension, roosevelt’s) racial politics, and edits jefferson’s own writings to perform as a mouthpiece for federal educational intervention. thomas jefferson memorial panel d (tjmpd) the engraving on the panel of the southeast interior wall (hereafter tjmpd) is derived entirely from jefferson’s letter to samuel kercheval on june , . the selected quotation advocates intellectual advancement and implores institutional and legal adaptability – a proposition that might be read as the foundational statement of progressivism itself. this is achieved through the compilation of various proximate phrases and sentences from the letter’s penultimate paragraph (without ellipses). the original tone of self-reflection is excised and much of the first person pronoun is suppressed in order to extend jefferson’s individual musings to the level of a national, and reclaimable, pronouncement or recommendation. according to richard hamowy, the result is a very un-jeffersonian “justification for a new theory of government in keeping with the social-democratic principles that animated the new deal.” the leaflet prepared for the memorial’s dedication corroborated that intent, claiming, “jefferson’s vision in matters of government is demonstrated by the fourth panel. by this statement which appeared in a letter to a friend, we know that he recognised the necessity for change in the laws and institutions of a democracy as opinions altered, new discoveries were made, and circumstances changed” (tjmc- ) the memorial aligns this philosophy with the sentiment and practice of roosevelt’s paradigmatic shift in legal, societal and economic affairs, under the broad umbrella of the new deal. following the exhaustive debates and compromise over tjmpc, the kercheval letter (which had not yet been considered seriously for any of the memorial’s quadrants) gained the admiration of lanham, culkin and other commission members who successfully moved to substitute all other source texts for tjmpd with the chairman’s proposal (may , ). jefferson was responding to kercheval’s request for his perspective on the nature of equal representation within the united states. having extensively outlined the inequalities of representation in the congress, senate, executive and judiciary, jefferson promoted a number of advisory steps to improve the administration of government, including general suffrage, equal representation in the legislature, ward divisions and – importantly – periodical amendments of the constitution. the lexicon marshalled by the tjmpd inscription (change, progress, new discoveries, new truths, enlightened, advance, pace) is a relatively faithful concentration of the original’s call for generational governmental pragmatism, albeit extracted from a private epistolary context that jefferson insisted upon remaining so. jefferson could have little imagined that such a source might be recontextualized to form an entire quadrant of his public memorialisation, nor that it might one day be understood as a partially activist justification for the institutional transformations associated with the post- second new deal, which systemized the structural reforms of the era. once more, jefferson’s historical remembrance through this inscription seems intertwined with a parallel process of ventriloquization in a discrete political context of modernity that relies upon the historical object’s temporal translucence. thomas jefferson memorial panel e (tjmpe) the engraving on the panel of the northwest interior wall (hereafter tjmpe) is compiled from an excerpt from “the virginia statute for religious freedom” (drafted , enacted ) and a statement taken from a letter to james madison, dated august , . the highly selective quotation includes a pronouncement on the freedom of religious thought with an addendum on universal morality. freedom of religion was one of the so-called four freedoms of jefferson’s political thought, which came to be embraced and reinvigorated by roosevelt’s own rhetorical repertoire. in his state of the union address, roosevelt modernized jefferson’s four freedoms as a framework for his speech on the threat posed to american national security and democracy everywhere by world war ii. in roosevelt’s version, freedom of religion becomes the freedom of worship, with a particularly international emphasis: “the second [of the four freedoms] is freedom of every person to worship god in his own way – everywhere in the world.” passed by the virginia general assembly in january , jefferson’s statute disestablished the church of england as the preferred state religion, paving the way for the constitutionally enshrined right to religious liberty and intellectual freedom of the first amendment. the recontextualization of the statute involves the selective quotation from the preamble and the conclusion, eradicating any evidence that the source text was – in tone and structure – a legislative document. the panel utilises only one of the statute’s many premises, delimiting the compound sense and rhetorical dependency of the original. jefferson’s embedded clauses, and more florid language from the preface, are recontextualized to create a significantly more dogmatic text than the original. the inscription also eradicates the centre of jefferson’s ascending tricolon, forestalling its full effect whilst, unlike the earlier quotation, presenting no ellipses to indicate the manipulation by the commission. the final sentence of tjmpe is appended from a substantial letter from jefferson to james madison (august , ) in which the author gives credence to the notion of objective morality. the statement, however, is derived from a personal epistolary context, resulting in the panel’s inelegant transition from the identity-neutral language of the virginian statute to personal revelation. the compound quotation also suffers from a very un-jeffersonian thematic leap from a paragraph on religious freedom to a dogmatic affidavit on universal singular and collective morality. two primary suggestions for a panel expressing the freedom of religion (one of jefferson’s four freedoms) were considered throughout the memorial’s construction. kean’s initial proposal (appendix f) was a quotation taken entirely from the concluding section of the statute (the preamble would be added later), whilst senator thomas’ proposal (appendix g) was yet another composite quotation, referencing constitutional change, the populace’s responsibility for liberty, freedom of religion and morality. thomas relied upon the statute for the central component of this inscription, before concluding with a sentence on morality extracted from jefferson’s letter to james madison. over the next year, kean’s panel was broadly favoured, and at the meeting of the commission in february , his proposal included a section from the statute’s preface on the recommendation of dr kimball. the chairman described the source text as “one of the finest bits of language in the world” prior to the panel’s unchallenged endorsement. thomas highlighted that this decision resulted in the loss of his final quotation from the madison letter on morality, leading to members smith and lanham proposing that they be retained and incorporated within kean’s scheme. this motion to amalgamate the wording was seconded and carried, yet kean questioned the resultant integrity of the overall quotation, stating “that will introduce a thing that is not in the preamble or the law.” kimball responded that “we are satisfied in doing that” because “i do not think the statute on religious freedom is so well memorized by the public as a whole that they will know whether or not it is extraneous.” this stunning admission revealed by the tjmc archives, provides an important insight into the commission’s optioneering process, demonstrating not only an irreverent attitude toward the state of the public intellect, but also an explicit awareness of the rhetorical manipulation of memory, exacted without the fear of public consequence or challenge. the eventual panel met the intent to memorialise one of jefferson’s central four freedoms, and to remember that “[h]e had already, in virginia, separated the church from the state, guaranteeing freedom of religion” (tjmc- april , ). the quotation not only refers to the legacy of jefferson’s ideal of free religious thought (a luxury not afforded to jefferson during the contentious theological debates surrounding his own candidacy) but also reflects his reticence to discuss personal faith within public discourse. the inscription also functions rhetorically, however, to echo the rooseveltian connection between religious freedom and american democracy: the lessons of religious toleration - a toleration which recognizes complete liberty of human thought, liberty of conscience - is one which, by precept and example, must be inculcated in the hearts and minds of all americans if the institutions of our democracy are to be maintained and perpetuated. there can be no true national life in our democracy unless we give unqualified recognition to freedom of religious worship and freedom of education (march , ). the tjmpe inscription was undoubtedly selected because of its resonance with an era that feared the twinned rise of fascist ideology and religious intolerance, symbolized by the nazi-led genocide of europe’s jewish population. jefferson’s statute had disestablished the church of england in order that all protestant congregations, catholics and jews could enjoy the practice of faith without incrimination. a century and a half later, jefferson’s principle of the wall of separation between church and state was re-inscribed to strengthen a culture that was witnessing the nightmare consequence of abandoning that principle. chapter : the rhetors – the tjmc and fdr as inventors of public memory deriving the motive forces that compel the creation of a single memorial is, at first glance, as idiosyncratic and qualitative a process as defining the impulses driving the pen of a particular novel, the provocation of a brushstroke, the intent of a chisel. as adam gopnik ( ) has recently complained, for example, the interpretation of a memorial’s motive(s) is so often complicated by a “broadly unsatisfactory language of commemoration,” which – in isolation – can be “confusingly laconic in its architectural grammar.” unlike the private consolation of imagination or the internalised motives of the individual artist, however, the creation of a national memorial is an act of rhetorical communality, leaving behind a partial record of the interaction and competition of motives among the various agents, agencies, scenes and purposes working upon those entrusted with its execution. the memorial therefore, understood as a legitimate rhetorical product, text or act, has the advantage of some form of motivational testimony, against which the a posteriori interrogation of the historical object’s mediation (understood through kenneth burke’s pentad and sturken’s technologies of memory, for example) can be conducted with a rare measure of evidentiary support. consequently, the scope of this thesis’ analysis is indebted to a decision taken in by the executors of the commission chairman stuart gibboney’s estate “to see that all the papers relating to the conduct of the affairs of the commission should be put away safely and kept for a reasonable length of time” (tjmc- july , ). almost seventy years later, this archive reveals the significant multivariate motive forces upon the selection and manipulation of the memorial’s inner chamber inscriptions, as well as jefferson’s overall re- situatedness at the hands of the commission. this chapter focuses upon two essential motivational currents at work, as a brief (and by no means comprehensive) illustration of the evidence available to examine the praxis of jefferson’s individuated commemoration in s america. first, the commission archives uncover the competing intentions at work to remember (and forget) aspects of the historical person of jefferson (section . ), to establish in stone and brass his pre- eminence as an american and democratic hero, and to assert his place amongst the capital’s main geographical memory complex, alongside lincoln and washington. the archive reveals the entanglement of the commission members’ various mythologies and personal interpretations of jefferson’s historical character, as well as competing theories of public commemoration. second, the archives demonstrate the extent to which the commemoration of jefferson was summoned as a witness of the progressive agenda of roosevelt and his new deal (see section . ). as the primary agent of the memorial’s creation, roosevelt exerted and maintained a level of interpretative influence throughout the commission’s existence, in order to force or emphasise the compatibility of the monument’s rhetoric with his own. by appropriating the words of jefferson – and using the (overwhelmingly democratic) commission as his agency – roosevelt ventriloquized the memorial for maximum personal effect in his th century political context, historicizing his own legacy, whilst also distilling jefferson’s for modernity. the thomas jefferson memorial commission: jefferson (un) remembered the thomas jefferson memorial commission comprised multiple and often competing agents of rhetorical formation, shaping the commemorative object and its inscription content, through a complex and years-long negotiation of ego, differing historical interpretations, various reclamations of jefferson for tendentious applications, and alternate theories of acceptable levels of quotation fidelity. at the time of its appointment, the commission consisted of the following membership: rhoads ( ) has identified roosevelt’s “deep and direct” involvement with governmental commissions. appointed by the speaker of the house hon. john j. boylan hon. howard w. smith hon. francis d. culkin appointed by jefferson memorial foundation mr stuart gibboney dr fiske kimball dr george ryan appointed by president hon. thomas jefferson coolidge hon. joseph p. tumulty mr hollins s. randolph appointed by vice president hon. elbert d. thomas, utah. hon. augustine lonergan, conn. hon. charles l. mcnary, ore. despite the multiplicity of agents and attendant motives, all members were broadly aligned to the memorial’s overall purpose to commemorate jefferson as a representative of american liberty and constitutional democracy. “the worthy concept represented in this memorial,” explained louis ludlow in the house of representatives, is to embody “in visual form a nation’s love for the man who, above all others, created the ideals of popular government in the western hemisphere” (tjmc- june ). more specifically, the commission considered the four internal memorial panels upon which the inscriptions would be laid as potential sites for immortalising the specific concept of the so-called “four freedoms” of jefferson’s making and legacy. this concept – written into the very quadrant design of the memorial’s interior – was embedded within the initial programme of competition for the construction of the pantheon-style monument to jefferson: his fundamental achievement was in the apostleship of the “four freedoms” of america: abolition of feudal tenure of land – freeing the earth; abolition of human slavery – freeing the body; establishment of universal education and freedom of speech – freeing the mind; establishment of religious liberty – freeing the soul. all are summed up in his words: “i have sworn on the altar of god eternal hostility to every form of tyranny over the mind of man” (tjmc- ). this interpretative framework, which influenced the textual selection process (until its abandonment midway through), is doubly problematic because of its post-jeffersonian formulation. the concept of the four freedoms is an act of secondary historical interpretation, made tertiary by the commission’s later subjective application of it as the interpretative framework for commemorative inscription selection. while recommending the four freedoms as a thematic structure, kimball noted: jefferson himself did not formulate the four freedoms…although they are all mentioned in the course of his first inaugural and in many other places. the formulation which i followed was made by dr alderman, president of the university of virginia….he based it on a series of bills offered by jefferson in the virginia legislature, proposing reforms which were afterwards incorporated also in the work of the revisors of the virginia laws. (tjmc- oct , ). alderman’s interpretation of jefferson’s legacy, bound the members of the sub-committee on inscriptions to manipulate jefferson’s words into this contemporary quarto. kean recorded that “i have written out proposed inscriptions for four freedoms which comply with these very narrow limitations” (oct , ), and thomas “worked rather hard trying to make four suitable quotations limiting the panels to something equivalent to what we might call jefferson’s four freedoms” (tjmc- dec , ). so firmly were the four freedoms revived as an american conceptual framework that president roosevelt made it the rhetorical theme and structure of his annual message to congress on the state of the union in . senator thomas, who during his commission tenure was writing a full-length book on jefferson, thomas jefferson: world citizen ( ), approached the task of quotation selection with an unparalleled expansionist attitude. restricted as he was by the thematic quartet and the legibility of the brass letters, thomas struggled with the task of condensing the character of jefferson from his full- length volume into the short paragraphs of his remembrance. whereas kean and gibboney developed panels in thematic isolation, using one panel for one thought or “freedom,” thomas prepared a single prosaic statement that was subsequently divided into four length-appropriate sections. as a result, thomas’ panel drafts, parts of which were adopted, were less about remembering jefferson through textual fidelity, and more about amassing and re-contextualising dozens of jeffersonian quotations in an acrobatic display of topical erudition. thomas explained: jefferson did not write an inscriptive language . . . i wondered if we could not take jefferson’s words and adhere entirely to jefferson’s words and get a small, complete statement of jefferson . . . by starting the process of arrangement, leaving out the elements of time, and then just by eliminating all of the unnecessary words. i began to count the various american political concepts that were represented in this simple little statement and i counted something like forty-eight (tjmc- february , ). thomas’ approach is one of simultaneous rhetorical creation and destruction – dependent on a cavalier approach to the textual integrity of jefferson’s original, the collocation of his statements, and the chronology of ideas – in order to provide a densely concentrated version of almost individual political concepts. thomas’ concentration (and “elimination”) of the source texts in fact dilutes an accurate memorialisation of jefferson’s words, sacrificing quality for quantity. that thomas was the chair of the sub-committee on inscriptions speaks to the mechanism of the textual misremembering and tonal misrepresentation of jefferson through his own language. in commemorating jefferson conceptually (and anti-textually) this way, thomas also enacts a form of modern reparation, inducing the reader to (invisibly) forget the distinct source, style and context of jefferson’s original, in favour of a streamlined version. justifying his approach, thomas cited the grammatical weaknesses of the third president’s corpus: if jefferson had been writing the panels he would not have had great difficulty…his most choice sayings and most significant sentences sometimes are found in long paragraphs with dangling, incomplete and almost colloquial wording…i have taken sentences and eliminated unnecessary words and i have put sentences out of their original order in respect to time, place and circumstance. no violence is done to jefferson’s thought and no violence is done to jefferson’s expression and i am sure no violence can be done in the interpretation of jefferson (tjmc- dec , ). thomas’ modern reclamation of jefferson as a philosopher of succinctness and concision, necessitated the rhetorical annihilation of jefferson’s voice for the memorial’s recipient culture(s). the opinion that no injury had been done to jefferson as a result of thomas’ method was challenged even by his contemporaries. judge smith worried that “it is entirely possible that by taking three or four sentences from four or five different things and putting them all in one place that you may get a document that jefferson never thought about” (tjmc- may ). kimball also feared that thomas’ approach “may make jefferson sound more dogmatic, because when you shorten the sentence by eliminating words it is more acrostic,” with the potential consequence that “the sentences are not recognised,” or that his historical character is not rhetorically legible. arguably, thomas set the precedent for the commission’s well-evidenced lack of textual fidelity throughout the memorial’s inscription selection process. if thomas influenced the method or philosophy of quotation, kean’s singular attempt to reclaim jefferson as a hero of the african american community demonstrated the subjectivity of the third president’s remembrance within the scene of s america – as well as the individual motives of commissioners at work to objectively define jefferson’s mercurial historical character for a discrete purpose. whilst “freedom of the body” had been accepted by the commission as a facet of the memory-framework of the memorial, the explicit commemoration of jefferson’s work associated with the abolition of slavery was not well agreed upon. kean was, however, a direct descendent of jefferson and consistently urgent in the need to parallel him with the great emancipator, abraham lincoln: when jefferson wrote his sentiments and prophecy with regard to slavery in his contemporaries, far from sharing them, were not concerning themselves at all about the matter...they expunged from the declaration the paragraphs referring to the slave trade which jefferson had written in his draft. likewise the framers of the constitution inserted into it a proviso forbidding congress to interfere with the slave trade for years. jefferson was president when this period expired and sent a message to congress asking for its abolition. in he signed with joy the law which drive this infamous traffic from the seas. (tjmc- september , ). the scene upon which kean wished to exact this rhetorical memory, however, was still the america and washington of jim crow, of segregation, of racial inequality and political exclusion. in essence, the freedom of the (american) body was not an enacted concept at the time of the memorial’s conceptualisation or unveiling, and to include jefferson’s (disputed) work to improve the future of african americans was a troubling prospect for other rhetor-agents of the commission. mr culkin thought “the slavery proposition would be a mistake” (may , ), whilst fellow northerner, mr tumulty objected to a large-scale record of anti-slavery work within the inscription content: i think it will look as if we were attempting to arouse resentment, and why go back to and dig out these ghosts of the past except for a noble reason? my people were on the northern side, but i just think it is going back to a past that we ought to try to forget, and people are so sensitive when they look at those things. it just arouses that old feeling again. (feb , ). senator andrews’ speech against the use of the phrase “created equal,” from the declaration, also laid bare the commission’s unease with referring to anti-slavery in the racial milieu of roosevelt’s era (tjmc- september , ). the objections to kean’s slavery panel – as discussed in chapter – resulted in the suppression of emancipation as a secondary theme within a broader series of quotations regarding human liberty. the result is an entanglement of remembrance and amnesia relating to jefferson’s contribution to civil liberties. as petrina dacres has written on the subject of representing slavery and emancipation within heterogeneous societies, “[i]n the public-historical sphere visual arts and monuments are important to the evocation and denial of memory, a nexus of reclamation and invention significant to the making of history and identity” ( ). the complicated racial scene of roosevelt’s era, the all-white status of the memorial commission, the mixed evocations and denials of the various rhetors, the non-existence of true bodily freedom, and the contemporary memory of jim crow evils, together led to the obscuration and revelation of existing social fissures that we find in the compromised panel on slavery, and within the pages of the commission archives. in the following section, i further assess the extent to which the archives reveal that roosevelt himself effected the advantageous parallelisation of jefferson with the contemporary political scene of s america. franklin delano roosevelt: a th century jefferson roosevelt established his primary agency in the memorial’s creation at an early stage, with the commission of fine arts receiving a memorandum from him in seeking legislative support to erect a memorial to jefferson in washington d.c. (tjmc- may ). soon after the president’s intervention, the thomas jefferson memorial commission was established by an act of congress to direct the erection of a memorial to the third president of the united states. reflecting the roosevelt landslide of , the commission was populated with a majority of democratic representatives – rhetorical sub-agents of political allegiance. the commission consisted of members, three of whom were appointed each by the president, the speaker of the house of representatives, the vice president, and the president of the thomas jefferson memorial foundation. at the time of the commission’s appointment, only two of the commission members – charles l. mcnary and francis d. culkin – were identified republicans. the sub-committee on inscriptions, established on october , , consisted entirely of democratic representatives (gibboney, thomas, and kean). indeed, there were as many republicans on the commission as there were direct descendants of thomas jefferson himself. if almost omnipotent, roosevelt was also an omnipresent agent in forming the rhetorical object of memory and its inscription content. as early as the first recorded meeting of the commission in june , then-chairman john boylan underscored the commission’s fiduciary dependency upon presidential endorsement, stating, “i had in mind that we would not want to do anything positively without consulting the president because he has to help us out with the appropriation and we would not want to run counter to him.” the financial necessity of securing the funds to complete the memorial additionally, the director of the national park service acted as executive agent for the commission. arguably laid the precedent for the commission’s close consultation with the white house and their accommodation of the administration’s preferences. yet roosevelt’s influence went far beyond the issue of economic dependency. throughout the often controversial conceptualization and construction of the memorial, roosevelt’s interventions punctuated key decision points, provided advice, instruction, media cover, self-promotion, and, at times, pointed aesthetic judgement. as the prime mover of the jefferson memorial project, roosevelt received all plans and sketches of the memorial’s progress at the white house in march (tjmc- , february , ), commissioned the re- competition of the monument’s architectural design, privately studied the presented alternatives, endorsed the pantheon scheme (despite disagreements within the commission), and requested the appropriation of $ , from the bureau of the budget to initiate the project. roosevelt interrupted the open competition for jefferson’s statue by reporting to gibboney, “i do not like any of them!” (tjmc- january , ) and urging the committee to “reject them all.” while appealing to gibboney to run a new statue competition, roosevelt was reticent to publicise the evident capacity of his agency upon the rhetorical formation of the jefferson memorial: “under no circumstances,” he wrote, “should it leak out that i have had anything to do with the choice or non-choice of a statue.” roosevelt did, however, publicly rebut criticisms of the memorial’s design and location, and demonstrated singular disregard for the “embattled clubwomen of washington d.c.” whom threatened to chain themselves to site’s japanese cherry blossom trees in order to thwart the construction work. “if they chained themselves,” roosevelt warned, “they would be removed along with the trees” (tjmc- , november , ). roosevelt’s interventions can be understood as attempts to fuse the memorialised with the memorialiser, and to maximise opportunities to parallel of the era of jefferson’s existence and the scene of his th century commemoration. in this sense, the archives provide evidence of the deployment of political commemoration to bolster the legacy of both the manifest object and the sponsoring agent of the cherry tree controversy, and its rhetorical implications for the tjm, is explored on pages - below. its invention. primarily, roosevelt and the committee understood the memorial as having the broad capacity to translate jefferson’s symbolic properties of liberty, independence, democracy, progressivism, and american-ness, into a metonymic rejoinder from the current roosevelt administration towards the growing threat of nazism and fascism in europe. consequently, the memorial becomes an object of rhetorical and temporal duality, performing both as a long-term memory space for the national consideration of jefferson and his life’s achievement (as interpreted by the commission), and as a temporary war-time banner within the international rhetorical space of world war ii, providing that generation and its president with a rallying touchstone for the foundational principles of freedom which, in that moment, the united states was forced to defend. senator thomas recognised his own participation in a commemoration which was both historical and contemporary in : when democracy is being questioned in some parts of the world, it seems to me this will be a good influence to bring up at this time with the world on fire as it is, and the one great question in the world today is whether you are going to have government by force or coercion or government by common consent and liberty. this is a monument to those last two ideas (tjmc- march , ). making remarks in the house of representatives, louis ludlow concurred with thomas’ interpretation, elevating the memorial as an object involved in a project of remembering jefferson promotionally: at a time when tyrannical dictatorships are rising to the zenith all over the world and popular government is sinking to the nadir everywhere . . . i wish devoutly that the erection of this jefferson memorial might bring to every human being in the world a mental picture of the difference between dictatorships and rule by the people – between tyrants like napoleon and patriots like jefferson (tjmc- june , ). at key moments throughout the memorial’s creation, the president used his own rhetorical agency to cement the historical parallelism between jefferson’s age and his own. in , in preparation for the ground-breaking ceremony at the memorial construction site, roosevelt “requested this commission to arrange for a nation-wide hook up so that his remarks may be broadcast throughout the nation” (tjmc- december , ). roosevelt spoke as he was seated in his car, surrounded by members of the commission and beside his wife, eleanor. in the background, the secretary of war, harry woodring, “paced up and down, hands in pockets, in the cold,” energizing the scene with an acute atmospheric parallelism between the current and historical travails to establish american democratic principles. “jefferson,” roosevelt began, “has been recognized by our citizens not only for the outstanding part which he took in the drafting of the declaration of independence itself, not only for his authorship of the virginia statute for religious freedom, but also for the services he rendered in establishing the practical operation as a democracy and not an autocracy” (tjmc- december , ). at the memorial’s cornerstone-laying ceremony, roosevelt appropriated the symbolic parallels with jefferson with even greater zeal, stating: “he lived as we lived in the midst of struggle between rule by the self-chosen individual or the self-appointed few, and rule by the franchise and approval of the many. he believed as we do that the average opinion of mankind is in the long run superior to the dictates of the self-chosen” (tjmc- november , ). the surrounding press coverage confirmed the success of roosevelt’s strategy of aligning himself with the talismanic power of jefferson and the progressive ideal. under the heading “apostle of democracy,” the washington post underscored the memorial’s binary function to twin executive personalities and presidential eras: president roosevelt will be…participating in an act of rededication and consecration of profound significance to our troubled times. democracy was a frail and feeble plant when jefferson was alive. and outside the united states, governments almost everywhere were in the hands of despots. over a large part of the world that is now, unhappily, true again… long before hitler was born he saw the tragic fallacy of the fuehrer principle. long before the rise of the fascists, nazis and communists he exposed the tragic consequences of dictatorship… (tjmc- november , ). the rhetorical coordination of the memorial with roosevelt’s agenda was so overt that the washington daily news editorial, “jefferson on war,” remarked, “the president and his literary amanuenses might have done worse than commandeer old thomas jefferson himself as ghost-writer for the occasion.” so orchestrated was the echoic atmosphere that roosevelt tapped the cornerstone with “a gavel made from an elm which jefferson planted at monticello” (tjmc- november , ). if roosevelt’s partisan and contemporary arrogation of the jefferson myth was so visible to contemporary audiences, it has since faded from public memory. at the time of the memorial’s creation however, roosevelt was willing to risk short term reputational damage in order to secure a political legacy through the associative value of the memorial. “most monuments,” petrina dacres explains, “participate in establishing the legitimacy and authority of the state,” but, in the case of political monuments, it is clear that they can also promote the stability of contested partisan agendas under the veil of national accord. as demonstrated throughout chapter , the memorial’s quotations were perhaps the most subversive rhetorical technology available to roosevelt and his commission in order to legitimate and stabilize the contested progressive proposals underpinning the new deal. whether it is the transformation of jefferson’s specific statements on natural rights into aphorisms consistent with roosevelt’s wartime oratory; or the conversion of jefferson’s musings on educational roosevelt also orchestrated the eventual unveiling of the memorial for maximal rhetorical resonance, recommending that the date be postponed for one year so that it has “the advantage of the two hundredth anniversary of jefferson’s birth, thereby giving a sort of springboard on which to focus attention” (tjmc- january , ). gibboney endorsed the re-schedule, claiming that the memorial should become a pantheon of celebration, precisely because of the context of war: “we are fighting for democracy, so let us magnify and celebrate the founder of american democracy, not less, but more” (tjmc- january , ). the washington herald, for example, reminded readers that, whilst jefferson had designed his own modest tombstone during his lifetime, any elaboration of it is an act of third party aggrandisement: “one of the oldest examples of political flim-flam we ever saw is being circulated around town, belatedly, as the reason for this marble mass on the tidal basin. it runs about like this: ‘well, look here. lincoln was a republican. he has a memorial. and it cost plenty, too. what about jefferson? he founded the democratic party and what has he got?’ that’s the rather crass level on which to set even the monstrosity which is scheduled to go up as a ‘thomas jefferson memorial’” (tjmc- ). freedom into a trumpet-call for universal public education; or the transmutation of jefferson’s endorsement of constitutional evolution into a supporting affidavit of the radical overhaul of the new deal portfolio, roosevelt found in jefferson a nationally-cohesive icon for the celebration of his own partisan legacy, during the very era of its continuing implementation. chapter : the consequence – material rhetoric, public mis-memory, and the broken enthymeme building upon the demonstration of the nature and extent of the manipulations involved in the selection of the memorial’s quotations in chapter , and the analysis of the motivational forces working upon the rhetorical agents of the commission in chapter , this chapter grapples with the rhetorical consequences of the memorial’s continued existence. as such, this chapter calls upon a consideration of loewen’s final temporal stage of public memory: the visitor’s individual and collective experience of accessing the historical jefferson in the present. more specifically, the following analysis examines the memorial from a material rhetoric perspective, in order to understand how the memory object achieves the goals of its rhetors, as well as a variety of unintended (or unforeseen) consequences, in shaping public memory. accordingly, the memorial is subjected to the analytical framework for commemorative rhetorical objects proposed by carole blair, with a necessary limitation of focus upon the implications of the inscription controversy, namely: ( ) what is the significance of the text’s materiality? ( ) what are the apparatuses and degrees of durability displayed in the text? ( ) what are the text’s modes or possibilities of reproduction or preservation? ( ) what does the text do to (or with, or against) other ‘texts’? and, ( ) how does the text act on persons? finally this chapter proposes that the memorial engages its users within an enthymematic prefiguration, in which the major assumed premise (the tjm is an elite, accurate and authentic object, worthy of attention, investment and effort) encourages significant touristic visitation and the internalisation, acceptance and reproduction of the inscriptions as a material structure of public memory. arguably, the commission relied upon the subversive quality of the authenticity premise, creating a memorial which serves the aims of a s political philosophy, to the ongoing detriment of modern visitation and public knowledge. what is the significance of the text’s materiality? by this question, blair ( ) means to discuss how the appearance of a rhetorical text within a specific context moves upon or changes that context. that is, “what is different as a result of the text’s existence, as opposed to what might be the case if the text had not appeared at all?” ( ) memorials can mark changes in cultural contexts, they can establish issues, persons and events worthy of remembrance, and they can provide places to form communities missing, or lacking, in the public sphere. furthermore, the material installation of new monuments within particular landscapes has the potential to distract from, or enhance, the established interdiscursive qualities of a given community of memorial spaces. in washington d.c. in particular (where more than memorials exist), the act of memorialisation has been open to questions of commemorative saturation (e.g. savage ), whereby the introduction of new rhetorical sites has the potential to compete with, and weaken the impression of, existing material objects. the erection of a significant commemorative memory structure in washington d.c., devoted entirely to the works of thomas jefferson, (re)legitimized the third president as worthy of national prominence, cultural persistence and international visitation. in the words of the commission, “in a sense, we are erecting a $ , , billboard to advertise jefferson and everything connected with him” (tjmc- april , ). as an entirely created physical space, in the form of a classical pantheon, the memorial provides a destination of american pilgrimage for the singular remembrance of jefferson and his significance within the landscape of the nation’s founding and psyche . the memorial now functions as an unavoidable structure of the washingtonian skyline, “rising, as it appears to do, right out of the water which becomes its reflecting pool, exercis[ing] its glistening white tyranny over the eyes of all who stroll ‘round the tidal basin” (scarborough ). through its physical inscriptions, “in connection with this monument there should be something in an imperishable form in a separate memorial to preserve those writings that everyone likes to read… i do not refer to the preservation of the originals. i want to see the outstanding works preserved in bronze or marble. the monument that commands the attention of the thoughtful people above all other monuments in the world that i have ever seen is the monument to confucius, “the hall of the classics,” in peiping, where men come and remain not by the hour but by the day to study and be captivated by the writings. in your whole range of american history jefferson is the only man that can lend himself to that kind of commanding position.” (tjmc- june , ). the memorial purports to vocalize jefferson within a new public memory space and new physical rhetorical context. visitors experience jefferson’s words not in a public library or singular source document, but via the unique collocation, arrangement and form of the brass lettered quadrants of the memorial commission’s selection. the memorial’s materialization, two centuries after the historical object’s birth, communicates jefferson’s posthumous national celebrity and a presumed consensus of meritorious contribution. the memorial’s material existence interacts with the physical and symbolic characteristics of washington d.c.’s architectural complex in a number of meaningful ways. firstly, the memorial is purposefully located upon spatial coordinates which were marked out for exceptional utilisation from the moment that washington was selected as the seat of government. pierre charles l’enfant was appointed to design the new capital in by george washington, and was subsequently instructed by jefferson to provide a modest blueprint for planning sites for federal and public buildings (see appendix h). the city would be based on a series of grids, with streets running east to west and north to south. diagonal avenues created points of intersection for key buildings or plazas, including the “president’s house” and congress, connected by what would later become the national mall. l’enfant’s conception was extended and modernised by the mcmillan plan ( ) which re- emphasized the national mall complex as a monumental core of cruciform structure. the jefferson memorial occupies the same axis as the white house and the washington monument with the lincoln memorial to the north-east, and capitol hill to the north-west. the archives reveal that the memorial’s location was recognised by the commission as a crucial vehicle for the creation of automatic meaning and rhetorical significance, placing jefferson “on the last of the five cardinal points of the l’enfant plan conceived during the time of washington and jefferson who visualised and selected the shore of the potomac as the site of our great capitol city” (tjmc- november , ). as four of the cardinal points were already occupied, the materialisation of a memorial to jefferson completed washington’s core memory space. mr h.p. caemmerer of the fine arts commission called the location “the greatest site for a memorial in washington today,” concluding that “jefferson is worthy of that site” (tjmc- january , ). the commission concluded that “the american visiting his nation’s capital cannot help but sense the meaning of this arrangement” (tjmc- ). the siting of the memory structure places jefferson within a specific constellation of american presidential heroes: the orion belt of thomas jefferson, abraham lincoln and george washington. the creation of the memorial completed a conceptual triumvirate of celebrated early presidential characters, consistently recognised as the pre-eminent leaders of the united states. jefferson, lincoln and washington are each remembered through gargantuan classical stone formations – a roman pantheon, a doric temple and obelisk, respectively – historicizing their eras of power far beyond the actual geo-history of their own civilizations, and raising them (architecturally) to demi-god status within their republic. the commission consistently echoed this theological semantic when discussing the memorial’s proximity to the extant monuments. “[w]e are building something very much bigger than a memorial to thomas jefferson,” thomas wrote, “we are actually about to add another cornerstone in the formation of a structure which we may call the american national cult” (tjmc- , june ). hollins randolph envisaged the memorial as completing a mystical triptych of three presidential protagonists: “jefferson and washington and lincoln, all of them, should sit as near together as the law allows and the topography allows and the original plan of the city allows. they are together. they are the trinity. those are the three” (june , ). the faux classical temple design of the memorial, suggestive of national infallibility, comports with such an ethic of material beatification, but also architecturally denies the internal fallacies of the brass lettered inscriptions which are given the sense of jeffersonian scripture. the memorial’s material design also replicates and remembers jefferson’s personal architectural achievements and proclivities for the greco-roman form. despite his reputation for receiving “foreign diplomats in homespun boots” (tjmc- april , ), jefferson was undeniably a classicist, describing the roman pantheon as “the most perfect example of spherical architecture” in the world (scarborough ). jefferson used the design during his own architectural forays, including the design of his home at monticello and the significant rotunda at the head of the university of virginia, which he built as a hobby in his old age (also inspired by the villa rotunda near vienna). at william and mary college, jefferson, along with his associates chancellor wythe, dr william small and governor fauquior, “became absorbed no less with the perfection of classic architectural forms than with the government that gave rise to those forms” (april , ). whilst in france, he visited nimes and “gazed worshipfully for hours” at the maison carree “like a lover at his mistress” (tjmc- may , ). for jefferson, such architecture corresponded with the very fabric of the democracy he sought to establish, “realizing (as he pointed out himself) that our government was founded upon a greek concept of statesmanship – he found classic architecture to be the most suitable expression of his ideals for the republic’s buildings” (tjmc- , april , ) the memorial’s material rhetoric is also informed by the original conflict evoked by its proposed creation. objections cited the design’s lack of originality, the future usability of the tidal basin space, effects upon traffic flow, the lack of a utilitarian function and (most contentiously) the destruction of an established living memorial of cherry trees donated by the japanese government as a symbol of bilateral cooperation (tjmc april , ). some complained that the design was a mere replication of the national art gallery, whilst others suggested that the memorial was a cheap corollary to the republican iconophilia of the lincoln memorial. the commission was lampooned in the press, set back by initial congressional disapproval, and, at one point, subjected to a highly coordinated professional negative publicity campaign orchestrated by an alumnus of the university of virginia (tjmc september , ). in august , the commission was on the brink of resignation and plans were discussed to reserve the location for a future memorial to theodore roosevelt. the single- mindedness of the commission, and the personal agency of the incumbent president, ensured that jefferson alone secured the right to this privileged nexus of washington’s architectural and symbolic core – the automatic kudos of which contributes somewhat to its protection from serious critical deconstruction and distrust. what are the apparatuses and degrees of durability displayed by the text? blair’s second question seeks to differentiate material commemorative objects through the analysis of their respective durability and vulnerability. the fabric of rhetorical texts varies from site to site, and it is possible that such compositional qualities can communicate something of the text’s endurance and perceived importance. the memorial is materially, deliberately and durably, american. alabaster white danby marble from vermont was sourced to construct the monument’s exterior as well as the twenty-five marble columns (each made from six separate drum sections) with molded bases and carved ionic style capitals at a height of feet. “each column, before it was shipped to washington,” katherine scarborough writes, “was matched under supervision of the architect at the marble producer’s plant in vermont for color, tone and veining characteristics in order to secure a perfect harmony of material. over carloads were required, incidentally, to haul the stone to washington,” (december , ). tennessee pink marble was laid for the interior flooring space; white georgia marble was selected for the interior panels of the memorial room; grey missouri marble was selected for the statue pedestal; and bronze was chosen as the material for both the nineteen-foot statue of jefferson by rudolph evans and the quadrant lettering. due to metallic rationing during world war ii, a mock plaster statue, painted to look like bronze was initially installed prior to installation of the bronze version in . spanning the such conclusions are not altogether simple, however, as blair makes clear that whilst stone or metallic structures are ostensibly more stable and permanent than written or spoken discourse, they are often more vulnerable to attack, erosion, vandalism etc. the sourcing of the memorial’s composite materials is equally rhetorical. specifically, the debates over the suppliers of the memorial’s white marble, and the wartime priority acquisition of bronze for the inscription’s lettering and the central statue, communicates the importance of geography as well as the perceived importance of jefferson’s memorialisation despite the overt wartime preoccupation of the nation. a text’s durability and permanence is particularly important for our discussion in which composite materials ‘conspire’ with the perpetuation of error. to make alterations to a memorial, or to correct it, is to shade the quality of that permanence, and make vulnerable a text’s materiality – however durable. natural resources, and electoral map, of both the north and south of the nation, all of the construction materials harnessed for the memorial were deliberately “as native to american soil as jefferson himself” (scarborough ). the quotations of the memorial’s interior walls were cast in bronze, which had to be appropriated during a national war crisis and a scarcity of metallic materials. eggers warned chairman gibboney that “on account of the national defense program there is a demand for all kinds of metal and it is becoming harder and harder to get these bronze castings” (tjmc- february , ); accordingly, in january the priority on the bronze for the letters was withdrawn due to the declaration of war” (tjmc- january , ). the white house was eventually lobbied for assistance and a new priority gained, so that the installation of the bronze lettering was completed in april . that the visage of jefferson himself and his words share material durability is a meaningful and poetic parallelism between the memory of the man and the recollection of his language. the context of the metal’s procurement gives its use here particular cachet and material consequence, suggesting that the memorialization of jefferson was significant enough to draw upon the rationed resources of an america at war. bronze, since horace’s ode, has been recognized as a material of renowned strength, durability and artistic potential, and was pursued here, despite restrictions, to raise jefferson’s words and memory to a level of material endurance. to memorialise the selected quotations of jefferson in bronze was to suggest that this use of the restricted metallic compound was as important as (and connected to) the protection of american sovereignty by the deployment of the same material in weaponised form. as blair points out, however, durable materials such as stone and metal can be ironically “more vulnerable to destruction by hostile forces” ( ). indeed, jefferson had himself asked for his modest memorial obelisk at monticello to be “of the course stone…that no one might be tempted hereafter to destroy it for the value of the materials” (tjmc- ). today, the memorial, which is open to the public the substantial quantity of bronze required for the statue of jefferson ( tonnes) was not made available until the end of the war. hours a day, has fallen victim to material vulnerabilities. in , the memorial was vandalised with oil that was sprayed in crosses by religious groups upon the white marble interior panels, which left permanent staining (kilian ). in - , the tidal basin seawall was repaired to save it sinking amongst “primordial porridge” (ruane ). in october , a five-foot long portion of the limestone ceiling collapsed within the memorial room due to water damage caused by a leaking gutter (wtopstaff ). according to megan nortrup ( ), science communicator for the national capital region of the national park service, acid precipitation is causing significant degradation of the marble within the memorial, specifically “the loss of silicate mineral inclusions in the marble columns as the calcite matrix holding them together is dissolved.” due to the weakening effects upon the stone, ties were installed to prevent sections falling from the volutes, and restoration work in removed accumulated “black crusts.” most significant is the inevitable degradation of the bronze lettering which has succumbed to the green pigmentation of verdigris, caused by the exposure of the brass to half a century of weathering. today, the patina staining can be seen running down the white marble quadrants beneath the raised letters leaking into the fabric of the building as the words themselves have the capacity to corrupt the public remembrance of jefferson. the paradox of the memorial’s durability and vulnerability, therefore, offers opportunities to remedy the misrepresentation or slanted re- contextualization of jefferson via the bronze inscriptions. the detrimental effects of acidic precipitation, vandalism of the panels and the bronze verdigris might offer an opportune moment for the replacement of bronze lettering to correct some of the most egregious fallacies of the extant inscriptions, as a mode of the memorial’s material preservation. what are the text’s modes or possibilities of reproduction or preservation? “reproduction,” blair insists, “is an intervention in the materiality of the text, and it is important to grapple with the degrees and kinds of change wrought by it” ( ) reproduction can increase the public access and experience of texts, but in the case of material rhetorical objects – such as monuments – reproduction (via guidebooks, photographs, three-dimensional postcards etc.) can provide an inauthentic, incomplete or re-interpreted version of that text. the jefferson memorial is an object of diverse and numerous replications. the commission, which had already preserved its own brand of reproducing jefferson’s texts through the memorial, also authorized the publication of a four-page leaflet replicating some of the included quotations, whilst providing a commentary that supported the interpretative bent of the commission’s specific re- contextualization(s) (tjmc- january , ). a more substantial -page booklet was also drafted, providing an entire section that reprinted the inscriptions as they appear in the rotunda, prefaced with the paralleling statement that “however true they were at the time of writing, they are more significant at this critical moment in world history” (tjmc- ). the quotations are reproduced, and repackaged to purposefully underline their contemporary reclamation. the modern visitor is similarly exposed to facsimile reproductions of the memorial and its textual content. “the words of thomas jefferson” (appendix i) is a one-page replication of the inscriptions available from the memorial bookstore, and countless leaflets, such as those produced by the national park service reiterate select quotations as accurate and direct jeffersonian statements. the memorial’s prominence as a symbol of americana has led to its replicative omnipresence in popular culture. the memorial features in the opening credits to news programming, such as msnbc’s morning joe, to immediately establish a national political context. it is deployed during scene transitions and sweeping cutaways to establish geographical context in political dramas such as house of cards, scandal, and the west wing. the frieze quotation performs a narrative function in the satirical films bob roberts, and billy jack goes to washington, and the inscriptions spur discussions of what democracy means in born yesterday. so ubiquitous is the memorial that it featured in an episode of the simpsons (season , episode ), in which jefferson’s statue complains that lisa simpson has only visited his monument because the lincoln memorial is overcrowded. the memorial has appeared on postage stamps, such as that designed by dean ellis in ; pillowcases, mugs, tote bags, mouse pads, and all of the usual souvenir ephemera have featured the monument and its textual content. a cursory search on google.com provides over , , individual results for “thomas jefferson memorial.” in the process of reproduction, blair writes, “[s]ometimes what appears to be the rhetorical text is not the rhetorical text, but an altogether different one” ( ). that point is even more acute when the original rhetorical text is demonstrably inaccurate prior to its reproduction or preservation. indeed, where memorials include inscriptions of previously spoken or written discourses, the quality of reproduction is multiplied. at the moment of inscription a text has often traversed a series of significant publication reproductions. when dealing with the issue of error perpetuation, the modes and possibilities of a text’s reproduction or preservation are issues of some importance. fallacious quotations reproduced or preserved have consequence for those who receive them, and signify the intention of the rhetors involved in their materialisation. the reproduction of these texts through repeated visitation, gift shop reproductions and the national appropriation of the memorial as a symbol of justice, equality and democracy in various media, advances the dangers of a material commemorative rhetoric when its constituent texts are made to be simultaneously durable and misleading. what does the text do to (or with, or against) other texts? blair admits that this “is one of the more difficult questions to address because the linkages among texts can be so varied and numerous” ( ). in light of this unquantifiability, blair is sensible to limit these linkages or conversations to those among memorial sites and between memorial sites and their “immediate contexts.” according to blair, memorial texts can be “enabling, appropriating, contextualizing, supplementing, correcting, challenging, competing and silencing” towards others, though they can surely engage in other relationships too. washington d.c., as a physical centre of enlightened western democracy, american independence and the seat of government, also poses some of the most tangled and incestuous relationships among sites of memorialisation. the jefferson memorial supplements and appropriates the established vernacular of washington’s greco-roman architectural examples, connecting itself to their imposing statues, words upon walls, ascending stairways, domes, pediments and reflective pools. the memorial relies upon the audience’s familiarity with washington’s commemorative syntax and encourages an intertextual reading among the cardinal points. the assumption of this material vocabulary performs a number of functions: it connects utilitarian buildings with the purely commemorative, aligns contemporary government with historical presidencies, and importantly provides the memorial – and its inscriptions – with a sort of automatic authenticity amongst its architectural neighbours. the jefferson memorial’s inscriptions, however, have the potential to challenge the authenticity of the washington constellation, or to blemish the very symbolism of transparent democratic government that it purports. its perpetuation exacts reputational damage to an already maligned washington, famous as a topography of mistruth, partisan manipulation, and low standards of accuracy. the memorial’s creation not only involved the appropriation of the authenticity of surrounding sites, but also necessitated the partial and controversial silencing of a highly motivated memory space. prior to the monument’s construction, the tidal basin was already home to almost , japanese cherry trees that had been donated to the united states from mayor yukio ozaki of tokyo (encouraged by jokichi takamine, a japanese chemist). these cherry trees became a living symbol of the friendship between the two nations and, accordingly, the united states responded with a donation of blossoming dogwoods to the japanese nation, placing the memorials within a transactional diplomatic context. this “outstanding monument of international good will around the tidal basin” is the focal point of the national cherry blossom festival, which has taken place since . the proposal to construct the memorial was met with its strongest opposition from those who objected to the potential destruction or interruption of the tree-lined shore of the tidal basin. newspapers magnified the issue to a level of national controversy, with editorials petitioning the white house to reconsider the plans: “substantial damage will be done to this community if the simple beauty of the cherry trees is impaired... they are literally assets of great worth to the business of washington, and material, substantive damage will be inflicted…if those trees are touched” (tjmc- ). according to critics, the president was complicit in a macbeth-like drama, orchestrating “the scandalous workings of a gang” in a “distinctly skulking” process: “as things stand now…a world-famous spectacle of natural beauty will be shattered…by an invasion of men with picks, steam shoves, trucks and axes, unless the people force one public official to exercise his absolute power to restrain their vandalism” (tjmc- , april , ). as the embattled clubwomen of washington d.c. chained themselves to cherry trees in protest, the commission and the president dismissed the hype. the commission reported that only trees were potentially affected (tjmc- , november , ) and installed a billboard illustrating that the increased land would provide space for the planting of a large number of new trees (tjmc- december , ). thomas remarked that “if cutting those cherry trees was a declaration of war on japan, i should not do it, but there are plenty of them along the western boundaries and at haines point where they can be placed with the others” (tjmc- june , ). the memorial and its highly motivated inscriptions, therefore, materially disrupted a national symbol of us-japanese friendship. if jefferson’s memorial was shaped by an activist ethic to showcase american freedoms against the rise of international tyrannies, then its impact upon the cherry tree memorial might be read as a highly motivated parallel rhetorical act. prior to pearl harbor, the possibility of war with japan had existed since the s. the invasion of manchuria in and japan’s subsequent encroachments into china, as well as the axis alliance with nazi germany and italy, strained the very signification of the cherry tree memorial. due to emerging sensitivities, the cherry blossom festival was suspended during world war ii; the trees were temporarily labelled as “oriental” rather than explicitly japanese, and in response to pearl harbor a small number of trees were cut down by protesters. the material interjection of the tjm and its brass lettered quotations, within an already complicated and motivated memory space, provided an immediate world war ii conversational context for jefferson’s voice to oppose international aggression, restricted liberties and anti-american values. if the inscriptions were manipulated to form contemporary vocalizations of roosevelt’s foreign policy, the tidal basin provided an unparalleled material and metaphorical diplomatic arboreal space for that ventriloquization. how does the text act on person(s)? fifth, and most importantly for the heuristic of materiality, blair asks how the text acts on person(s). a material approach recognises that a rhetorical text, as a destination, can make particular demands upon the visitor’s body, intruding into our material existence. “memorials do perhaps even more obvious work on the body,” blair writes, as “they direct the vision to particular features, and they direct – sometimes even control – the vector, speed, or possibilities of physical movement” ( ). surrounded by a mass of cherry blossoms against the shore of the tidal basin, the startling white superstructure of the pantheon-style jefferson memorial immediately summons visitation as an aesthetic destination. upon arrival, the visitor traverses a series of steps leading to the interior memorial room which, with its central idol and panels of “scripture,” has the sense of a spiritual space, or temple. accordingly, as i observed on each of my several visits, the interior of the memorial induces the majority of visitors to a state of noticeable – and respectful – hush. the physical reflection of the memorial within the tidal basin gives rise to a contemplative atmosphere, with internal benches and the surrounding steps offering on-site locales for rumination upon its contents. the visitor experiences each of the memorial’s panel inscriptions in relative isolation, spaced as they are between the four compass-point entrances to the memorial room. the inscription-entrance- inscription-entrance architectural pattern demarcates the quotations as discrete textual wholes, connected by the continuous overhead frieze quotation. the archives reveal supporting evidence that the commission attempted to prescribe the order for experiencing the recontextualized inscriptions, calling upon psycho-spatial studies. kimball “assumed that no. (from the declaration of independence) would be the first one on the right as you enter…in accordance with the psychological studies that at least % of [test subjects] turn to the right, following our habit of walking and driving” (tjmc- , oct , ). eggers agreed that the “majority of the people do turn right on entering a place to view what may be exhibited on the walls,” proposing the arrangement of tjmpb on the southwest quadrant, tjmpe on the northwest quadrant, tjmpc on the northeast quadrant, and tjmpd on the southeast quadrant. this arrangement ensured that the declaration of independence panel retained primacy in the visitor’s reading (tjmc- november , ). the order of the memorial’s inscriptions invokes the declaration’s celebrity to initiate a sense of textual familiarity and also encourages the visitor to presume the fidelity of subsequent panels, despite their lesser renown and fallacious content. a consideration of the memorial from the perspective of blair’s rhetorical inquiry, demonstrates the various ways in which the monument’s materiality provides significance, endurance, and replication to the fallacious and inauthentic apparatus of the memorial’s inscriptions, which, in turn, have intended (and unintended) effects on their audiences. sites of public memory are also bordered within material and symbolic contexts. a memory place such as the jefferson memorial is constructed within the larger memory field of the monumental core of washington d.c., a city that exists as a real and imagined place and that metonymically expresses ideas far beyond its mere geography. such memorials are not just any interventions in public memory. memory places are self-consciously constructed by and for persons with individual and group interpretations of particular events. they are, in their sheer manifestation, partisan, and as a result of this partisanship they are rendered, by virtue of their rarity, as supposedly accurate, authentic and worthy objects of public consumption. that a memorial exists in the nation’s capital defines it as a hyper-rhetorical object of settled public memory, with the most elite forms of partisanship and authenticity. a memorial in washington d.c. demands a touristic commitment in exchange for the transmission of approved, nationally consequential and trustworthy information. in a sweeping survey of american attitudes towards methods of history learning, for example, rosenzweig and thelan found that museums and physical sites of public memory were the most trusted sources of historical information ( ). such sites score more highly for authenticity than direct conversations with family members, eye witnesses, history professors, teachers, books and visual media: americans put more trust in history museums and historic sites than in any other sources for exploring the past...approaching artifacts and sites on their own terms, visitors could cut through all the intervening stories, step around all the agendas that had been advanced in the meantime, and feel that they were experiencing a moment from the past almost as it had originally been experienced – and with none of the overwhelming distortions that they associated with moves and television, the other purveyors or immediacy...many respondents felt there was nothing between them and the reality of the past...museum visitors could form their own questions by imagining that they were re-experiencing for themselves – without mediation – moments from the past ( ). the public’s qualitative assessment of memorials as devoid of agenda, distortion and mediation runs entirely counter to the archival evidence of motivated historical manipulation. through the lens of material rhetoric, interaction with a site’s materiality “predisposes its visitors to respond in certain ways, enthymematically prefiguring the rhetoric of the place as worthy of attention, investment, and effort (at the very least)” (dickinson, blair and ott, ). this prefiguration is part of the mode of often invisible mediation, appropriated by the authors of particular memory places as a foil for historical immediacy. the complete structure might be presented as follows: sites of public memory are elite, accurate and authentic objects, worthy of attention, investment and effort. major premise – assumed the thomas jefferson memorial is a site of public memory. minor premise – assumed the thomas jefferson memorial is an elite, accurate and authentic object worthy of attention, investment and effort. conclusion - stated the thomas jefferson memorial engages its users in a fallacious rhetorical relationship, enacting a betrayal by subverting the expectation of an accurate and authentic memorialisation of the third president of the united states. the major assumed premise of this first order enthymeme has been found to be false in its assumption and, if the panels are left unchanged, the memorial appropriates the kudos of public memory objects in order to advance an inauthentic (yet trusted) version of american history. “epistemologically, memory places are frequently understood as offering a unique access to the past,” dickinson, blair and ott find, “but authenticity isn’t something that places just have. a sense of authenticity is a rhetorical effect, an impression lodged with visitors by the rhetorical work the place does” ( - ). the jefferson memorial is a single, high profile public commemorative object, invented in part as propaganda, wrapped in a pantheon, gifted to the world as a signification of fact, and received by its visitors as a heretofore largely un-interrogated and pure revivification of the thomas jefferson. the memorial commission relied upon the material nature of the memorial itself to acculturate its public with the highly motivated characterisation of the founding father as a leading light of rooseveltian progressivism. the “rhetorical work” of the commission was to smuggle statements supportive of world war ii intervention, new deal programmes, federal enlargement, and educational reform, into a memory space orchestrated to frame such words in a material cocoon of historical authenticity and consensus. as part of their material rhetoricity, these quotations can be demonstrated to be culturally significant, permanent, durable, replicable, corruptive to surrounding material memory sites, and disruptive to the relationship between america’s past and her public. with each day of the memorial’s persistence, the opportunistic reclamation of jefferson (by a sitting u.s. president no less) is given a greater cachet of commemorative authenticity. as a case study, this thesis has attempted to lay the groundwork for the identification of commemorative rhetorical fallacy, the utilisation of archival records to ascertain the footsteps of memorialising motive, and the deployment of a material rhetoric framework to qualify a (misleading) memorial’s consequence within a physical culture and zeitgeist. a comparative analysis of the rhetorical formation of other political memorials within the monumental core of washington d.c. is recommended to examine the extent to which the thomas jefferson memorial is either emblematic or anomalous in so explicitly serving the agenda of partisan proselytization. epilogue despite the inscriptions’ exponential detrimental impact upon jefferson’s public memory, awareness surrounding the concoction of the memorial’s inscription content is negligible. ronald hamowy, a professor emeritus in intellectual history, is a rare proponent of the theory of the memorial’s partisan appropriation, claiming that it is “perhaps the most egregious example of invoking jefferson for purely transient political purposes” ( ). hamowy +has criticized the cumulative effect of the quotations which suggests that “jefferson advocated positions consistent with the aims of the new deal – with which he would, in fact, have had little sympathy.” despite the force and clarity of hamowy’s claims, however, they exist only as a tangential point in an obscure book review, on the periphery of academic discourse. historian garry wills has bemoaned the slavery panel, in particular, as “misleadingly truncated” for its eradication of jefferson’s clear vocalisation of the slaveholder interest. the only serious journalistic intervention on the subject was that of nicholas kristoff (new york times) who, in , focussed his opposition on tjmpb and the misquotation from the declaration of independence: “[t]hat sentence is one of the greatest in american history, and it’s a disgrace that it’s improperly written on the wall of the jefferson memorial.” the intent of the preceding pages has been to provide comprehensive archival and rhetorical substantiation to the whispered accusations of deliberate misquotation which have yet to gain traction in the public sphere. at the risk of tinging a thesis with advocacy, one might ask whether any action should be performed to mitigate or revise such an elite object of misleading national memorialisation. the exigence for such an intervention is supported by a recent appetite for correcting the so-called errors of extant memorials. in , for example, one of the two engraved quotations of the martin luther king memorial in washington d.c. (“i was a drum major for justice, peace and righteousness”) drew heavy criticism for its misrepresentation of king as a rhetorician and historical character. this selective quotation from king’s drum major instinct sermon neutered the anaphoric ascension of king’s peroration, and removed the initial conditional phrase which in turn expunged the essential self- effacement of the original. the truncation led to an overall tonal change that maya angelou said made king sound like “an arrogant twit” (weingarten and ruane ). when dedicating the monument in october , president obama felt it necessary to gloss the engraving: “what he really said was that all of us should be a drum major for service, all of us could be a drum major for justice, and there’s nobody who can’t serve” (siddiqui and brower ). following considerable objection to the engraved quotation, ken salazar, secretary of state for the interior agreed that the inscription should be altered, tasking the king memorial foundation to find a substitution. “this is important,” salazar said in early , “because dr king and his presence on the mall is a forever presence for the united states of america, and we have to make sure we get it right” (manteuffel ). the episode was speared by television satirist stephen colbert, who described the monument as “to the point. not dr king’s point, but still. brevity is the soul of saving money on chiselling fees.” in august , the sculptor erased the disputed inscription from the statue but did not replace it, and instead reworked the side of the memorial with a new, inscription-less finish (in what might be understood as a richly rhetorical act in itself, proffering silence in place of controversy). importantly, the martin luther king example suggests that a culture exists which is prepared to upend “carved in stone” permanence and to interrogate the material consequences of fallacious mnemonic content in washington’s monumental district. this responsiveness, however, sits in contra- distinction to the veritable obliviousness surrounding the errors of the jefferson memorial, which are demonstrably more deleterious and far-sweeping than a single truncation and alteration of tone. in attending to the material consequence of an inauthentic historical narrative, however, and cognisant of the enthymematic prefiguration of a memorial’s role in public understanding, a number of practical options for the partial remediation of the thomas jefferson memorial might be considered, as follows:  the replacement of the current inscriptions with quotations from identifiable single sources, selected via committee or public/academic consultation.  the re-presentation of the current quotations, recording the extent of textual manipulation through standard typography.  the inclusion, within the memorial room, of clear source attribution for each panel via additional plaques, engravings or moveable signage.  the training of national park service steward staff in order to provide contextual information, relating to the composition, motivation and consequence of the selected quotations, to the memorial’s visitors.  the addition of a section in the jefferson memorial museum space relating specifically to the work of the thomas jefferson memorial commission, the process of inscription selection and the reclamation of jefferson for contemporary rhetorical deployment.  the provision of enhanced educational materials that underline the nature of the textual content and its role in creating a highly motivated and tendentious jeffersonian memorial. each of these options for modification, however, is subject to the same complications of agency and motive as those faced by the memorial’s original rhetorical creators, such that our corrective actions might be read by future generations as merely additive to the commemorative object’s already contested rhetorical formation. bibliography the thomas jefferson memorial commission: general records, - . record group : records of the national park service, - . 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(proquest, ) appendix a: the thomas jefferson memorial jefferson memorial seen across the tidal basin at dusk in washington, d.c., usa. courtesy of joe ravi (cc-by-sa . ) appendix b: the inscriptions of the thomas jefferson memorial tjmpa i have sworn upon the altar of god eternal hostility against every form of tryanny over the mind of man. appendix b (cont'd): the inscriptions of the thomas jefferson memorial tjmpb we hold these truths to be self- evident: that all men are created equal, that they are endowed by their creator with certain inalienable rights, among these are life, liberty and the pursuit of happiness, that to secure these rights governments are instituted among men. we … solemnly publish and declare, that these colonies are and of right ought to be free and independent states … and for the support of this declaration, with a firm reliance on the protection of divine providence, we mutually pledge our lives, our fortunes and our sacred honour. appendix b (cont’d): the inscriptions of the thomas jefferson memorial tjmpc god who gave us life gave us liberty. can the liberties of a nation be secure when we have removed a conviction that these liberties are the gift of god? indeed i tremble for my country when i reflect that god is just, that his justice cannot sleep for- ever. commerce between master and slave is despotism. nothing is more certainly written in the book of fate than that these people are to be free. establish the law for educating the common people. this it is the business of the state to effect and on a general plan. appendix b (cont’d): the inscriptions of the thomas jefferson memorial tjmpd i am not an advocate for frequent changes in laws and constitutions. but laws and institutions must go hand in hand with the progress of the human mind. as that becomes more developed, more enlightened, as new disoveries are made, new truths discovered and manners and opinions change, with the change of circumstances, institutions must advance also to keep pace with the times. we might as well require a man to wear still the coat which fitted him when a boy as civilized society to remain ever under the regimen of their barbarous ancestors. appendix b (cont’d): the inscriptions of the thomas jefferson memorial tjmpe almighty god hath created the mind free. all attempts to influence it by temporal punishments or burthens … are a departure from the plan of the holy author of our religion … no man shall be compelled to frequent or support any religious worshipor ministry or shall otherwise suffer on account of his religious opinions or belief, but all men shall be free to profess and by argument to maintain, their opinions in matters of religion. i know but one code of morality for men whether acting singly or collectively. appendix c: the composition of thomas jefferson memorial panel c (tjmpc) summary view notes on state of v… notes (earlier section) autobiography wythe letter washington letter god who gave us life gave us liberty. can the liberties of a nation be secure when we have removed a conviction that these liberties are the gift of god? indeed i tremble for my country when i reflect that god is just, that his justice cannot sleep for- ever. commerce between master and slave is despotism. nothing is more certainly written in the book of fate than that these people are to be free. establish the law for educating the common people. this it is the business of the state to effect and on a general plan. appendix d: kean’s “freedom of the slave” proposals for tjmpc; the thomas jefferson memorial commission: general records, - . record group : records of the national park service, - . ( files) arc: (national archives, md). appendix e: compromised version of tjmpc; the thomas jefferson memorial commission: general records, - . record group : records of the national park service, - . ( files) arc: (national archives, md). appendix f: kean’s tjmpe proposal; the thomas jefferson memorial commission: general records, - . record group : records of the national park service, - . ( files) arc: (national archives, md). appendix g: thomas’ tjmpe proposal; the thomas jefferson memorial commission: general records, - . record group : records of the national park service, - . ( files) arc: (national archives, md). appendix h: pierre l’enfant’s plan of the city of washington, march l'enfant, pierre charles, - . plan of the city of washington / thackara & vallance sc. [philadelphia : s.n., ] scale [ca. : , ]. map ; x cm., on sheet x cm. g .l . library of congress: http://lccn.loc.gov/ . appendix i: “the words of thomas jefferson” factsheet, washington d.c. greco. a.qxp_. thomas jefferson on private property: myths and reality maurizio valsania abstract • thomas jefferson is sometimes presented as a radical egalitarian—the same figure upon which early nineteenth-century american socialists built their theories. but he did not condemn private property. by the same token, he did not advocate redistribution. in the declaration of independence, jefferson omitted to list property among inalienable rights because he had good reasons to do so. for him, property neither fostered a society of self-seekers, nor promoted a purely instrumental and ad- versarial relationship between individuals and the political community. jefferson was no utopian, either in the sense that he wanted redistribution, or in the sense the he was nostalgic about the “simpler” societies of the past. rather, jefferson’s sole “utopianism” was enticed by the thought that in america, after the revolution, there was no urgent need of further redistribution. keywords • thomas jefferson; john locke; private property; declaration of independence; re- publicanism. in chapter , section , of his second treatise, john locke famously wrote that “the state of nature has a law of nature to govern it, which obliges everyone: and reason, which is that law, teaches all mankind, who will but consult it, that being all equal and independent, no one ought to harm another in his life, health, liberty, or possessions.” albeit in the declaration of inde- pendence thomas jefferson ( - ) omitted locke’s mention of property and replaced it with the phrase “pursuit of happiness,” property has never been for him an obstacle to republicanism, a hindrance to egalitarianism, and a moral embarrassment. on the contrary, property was an es- sential facet of jeffersonian political thought. according to jefferson, property neither fostered a society of self-seekers, nor promoted a purely instrumental and adversarial relationship between individuals and the political community. those who think that in principle property must be incompatible with jefferson’s egalitarianism and the very spirit of the declaration are prey to a prejudice of precisely definable lineage. nineteenth-century european social thought, notably the so-called hegelian left (which in- cluded karl marx and friedrich engels), keenly insisted on the intrinsic injustice of “private prop- erty.” furthermore, the hegelian left was so successful in its line of reasoning that a great deal of locke, two treatises on government, . word count does not allow a thorough analysis of the topic of the “pursuit of happiness.” but see conklin, pursuit of happiness in the founding era. i thank the two anonymous reviewers for their constructive comments. ricognizioni. rivista di lingue, letterature e culture moderne, • (vii) maurizio valsania twentieth-century social theory considered it obvious that property must, one way or another, be treated as scandalous and a perversion of the natural order. perhaps hegelians were too successful in their argument inculcating in the historical profession itself the anti-historical dogma that all intelligent, responsible, and morally upright persons, no matter where and when they could have lived, must have acknowledged the plain fact of the undesirability of acquisitiveness. that a worship of private property was dangerous was ingrained in the idea that georg wil- helm friedrich hegel had of the american society. the “fundamental character of the [american] community,” as he put it in his lectures on the philosophy of history, is “the endeavor of the in- dividual after acquisition, commercial profit, and gain.” scandalous, for hegel, was “the prepon- derance of private interest, devoting itself to that of the community only for its own advantage.” property has corrupted morality and undermined the ethical state. american society is a political community in which “the state [is] merely something external for the protection of property.” the property, that is, of its “atomic constituents.” hegel’s vision inspired his disciples, especially karl marx and friedrich engels. for their part, they certainly have been correct in their denunciations of the shortcomings of a society built on private property and deliberately ignoring the moral imperative that property must always be under the regulation of the civil society. hegel’s complaint has a noble pedigree. it resonates with jefferson’s rebukes of luxury and adam ferguson’s famous jeremiad about the “refinements” of the civilized age: “the boasted refinements, then, of the polished age, are not divested of danger. they open a door, perhaps, to disaster, as wide and accessible as any of those they have shut. if they build walls and ramparts, they enervate the minds of those who are placed to defend them; if they form disciplined armies, they reduce the military spirit of entire nations; and by placing the sword where they have given a distaste to civil establishments, they prepare for mankind the gov- ernment of force.” hegel reenacted an old republican song, almost a foreboding of impending doom, dating back at least to cicero. according to all republicans of all times, attachment to one’s country would be undermined by unbridled acquisitiveness, the calculus of profit and loss, and private property. that america could lose its soul and become that kind of aggregate of private properties de- nounced by hegel represented, in fact, jefferson’s worst nightmare. but this does not authorize any “marxian” reading of jefferson. jefferson did not consider property as scandalous. some his- torians and political scientists, of course, take a different view. richard matthews, for example, correctly argues that for jefferson “positive law, not natural right, creates property rights.” he insists on “jefferson’s explicitly rejecting property as a natural right.” for matthews, jefferson was a downright positivist in the matter of property: “property is merely an institution created by society to help men gain ‘life, liberty, and the pursuit of happi- ness’.” however, using the positivist argument to conjure up jefferson as a radical egalitarian—the same figure upon which early nineteenth-century american socialists built their theories—is in many ways problematic. matthews abides by staughton lynd’s hypothesis that in jefferson’s prin- hegel, philosophy of history, , . ferguson, an essay on the history of civil society, - . “ferguson’s closest reader would be wilhelm friedrich hegel, who incorporated many of ferguson’s ideas and even phrases into his own philosophy of history, which karl marx would take up and develop.” herman, scottish enlightenment, . matthews, radical politics of jefferson, , . itinerari thomas jefferson on private property ciple that “the earth belongs in usufruct to the living” the american revolution “approached most nearly the socialist conception that living labor has claims superior to any property rights.” jeffer- son, lynd’s argument continued, “seemed to imply that, in the absence of remedial state action, the unemployed might rightly take the land they needed.” jefferson, matthews is convinced, wanted “to institutionalize revolution in order to keep the spirit of perpetually alive.” he did not hurry, as matthews allows, but “perpetual transition is precisely what jefferson wants.” matthews arrives at his conclusion that jefferson wanted to institutionalize revolution via a close reading of the “usufruct” letter to madison of september , . one passage in particular strikes matthews in a special way: “but the child, the legatee, or creditor takes it [the parcel of land], not by any natural right, but by a law of the society of which they are members, and to which they are subject.” discussing the question of inheritance laws, as matthews recognizes, jefferson wanted to clarify that the church, hospitals, colleges, orders of chivalry, and so on, have no natural right to the appropriation of land. assessing the traditional mechanisms of appropriation of land and hence of power, jefferson wryly denounced this ancient habit of appropriation that allotted power “to hereditary offices, authorities and jurisdictions; to hereditary orders, distinctions and appellations; to perpetual monopolies in commerce, the arts and sciences; with a long train of et ceteras.” we can easily agree with matthews in every point and admit that, for jefferson, every living society should reaffirm all its statutes, institutions, and laws approximately every twenty years, including the inheritance laws. were this reenactment omitted, some types of property might result in an usurpation based on “an act of force, and not of right.” true as this is, however, the letter cannot be construed in a way that proves that jefferson considered property per se to be a usurpa- tion to be counteracted by a perpetual transition of assets. any socialist reading of jefferson is biased. the focus of the letter is whether or not “one generation of men has a right to bind another.” when a society “has formed no rules for the ap- propriation of it’s lands in severalty, it will be taken by the first occupants.” this is a natural right. if rules and laws exist, they can either sanction an act of force, or of right. in the first case, a gen- eration is binding another, as happens especially in europe and everywhere unnatural aristocracy, ibid., , . lynd quoted at - , . see lynd, intellectual origins, , , . for instance, we can easily remove from the context of the shays’ rebellion what jefferson said in a famous letter to james madi- son, jan. , papers of thomas jefferson (henceforward ptj), : , to give a further boost to matthews’s radical jefferson: “i hold it that a little rebellion now and then is a good thing, and as necessary in the political world as storms in the physical.” tj to james madison, sept. , ptj, : - , passim. see also matthews, radical politics of jef- ferson, . for a very convincing interpretation of this remarkable letter, see sloan, principle and interest, - . like all complex documents, sloan argues, the letter can be read in a number of ways. over time, jefferson would find new applications for the ideas he expressed at the end of . nonetheless, “debt is the key, and whatever else this insistence ‘that the earth belongs in usufruct to the living’ means, it is first and foremost a confession of what debt meant to thomas jefferson.” ( ) burstein and isenberg admit the centrality of debt. in addition, they also stress the character of a mental experiment: jefferson “hazarded a new and experimental view”; he “was not prescribing policy so much as opening a conversation about an issue he and madison both cared about: possible ways to fix limits on public debt.” burstein and isenberg, madison and jefferson, - . upon his return from france, jefferson was especially excited by the possi- bility of a fresh start, not corrupted by history: “he imagined being able to reshape society.” ( ) by no means did such a philosophical discourse on possibilities imply that he was “preparing to unleash social and political chaos.” ( ) itinerari maurizio valsania including orders, distinctions, and appellations, thrives. (this means that orders, appellations, and so on, take advantage of outdated laws, not reaffirmed by the living generation.) in the second case, the living generation reenact laws and institutions “as they please”: the living generation can transform the laws that were about to become a mere act of usurpation into something rightful and legitimate. the living generation can rewrite these laws, or adjust them, or even, willingly, take them as they are. unsympathetic though he was to the atomization of society, what jefferson was arguing is more limited and more circumstantial: “from the nature and purpose of civil institutions, all the lands within the limits which any particular society has circumscribed around itself, are assumed by that society, and subject to their allotment only. this may be done by themselves assembled collectively, or by their legislature to whom they may have delegated sovereign authority: and, if they are allotted in neither of these ways, each individual of the society may appropriate to himself such lands as he finds vacant, and occupancy will give him title.” the thesis, as stated, is that dis- assembled individuals and single laborers have the right to appropriate individually and according to their personal interests only such land as society has chosen not to allot. no mention is made of the nature of property in general as subordinate to the rights of labor. society, not laborers as such, has the superior right. finally, matthews’s biggest mistake is drawing on the declaration to demonstrate that jef- ferson’s failure to mention property among the inalienable rights translates automatically into a judgment of value. “the omission is significant. while locke views property as a natural right … jefferson does not.” why should it be so “significant”? as garry wills demonstrated, “pursuit of happiness” was a better and more precise phrase than property. “pursuit of happiness,” in the period, signified the right of american citizens to cul- tivate themselves, to pursue the realization of a proper end, in this way rising above the level of brute existence. as wills made clear, few used it vaguely, and certainly not jefferson. his most likely “sources” were in turn very precisely identifiable: hutcheson, ferguson, lord kames, burla- maqui, james wilson, george mason in “virginia declaration of rights” ( ), and locke in chapter , “of power,” of essay concerning human understanding ( ). the phrase did not evoke a vague aspiration (happiness was the realization of a proper end), and jefferson would have been quite an eccentric to list a fanciful wish among the rights that governments should pro- tect. as wills writes, “jefferson meant to state scientific law in the human area—natural law as human right. … man pursues happiness as the stone falls. … the stone must fall, but it does not— the illustration is diderot’s … . only when one recognizes the law of man’s nature as his right does one remove the obstacles and let him move free, knowing this is consonant with the order of nature.” in the declaration, jefferson omitted to list property among inalienable rights because he had good reasons to do so. by their nature, in a necessary way, humans pursue life, freedom, and happiness, while property is obviously alienable. property helps to make me the individual i am. but i can easily bequeath all my properties, or part of them, to somebody. i can run into debts. i matthews, radical politics of jefferson, , . on jefferson’s “bold innovation,” see . tj, summary view, ptj, : . according to matthews, jefferson was “inform[ing] the king of the rela- tionship between property and labor.” matthews, radical politics of jefferson, . ibid., . see wills, inventing america, - , quotation at . on mason’s declaration, see also maier, american scripture, - . itinerari thomas jefferson on private property can gamble and lose. war can rob me of my estate. after all, humans are very vulnerable beings. similarly, the living generation might rightfully reform all the extant laws concerning property. that jefferson did not list property among those rights does not make property something despicable; and it does not make perennial revolution a desirable condition. the mistake is that matthews associates the term “inalienable” with predicates such as “significant,” “important,” and “morally correct.” each society, as matthews allows, certainly has “a right to govern itself in terms of property usage.” the declaration’s omission may well signify that “property is merely an in- stitution created by society to help men gain ‘life, liberty, and the pursuit of happiness.” but this does not imply any reproof. admitting that jefferson was a positivist in the matter of property rights, that he believed property laws should be altered and refined every twenty years or so, that property was “merely” a convention, does not mean that, for jefferson, property in the long run becomes a hindrance to the realization of social happiness. matthews approves of charles wiltse’s argument that jefferson’s political theory conveys “an organic conception of society.” but jefferson’s “organic conception” must not be confused with socialism, that property is either a theft or a phase to be dialectically outstripped in the his- torical process that would restore the natural rights of laborers. when matthews stresses that jef- ferson’s view of property was “similar to that held by rousseau,” he closes his circle. he was sure from the outset that rousseau was the neglected source of jefferson’s social thinking. as far as the origin of property is concerned, rousseau was the main advocate for the moral reprobation of private property: “the first man who, having enclosed a piece of ground, bethought himself of saying ‘this is mine’, and found people simple enough to believe him, was the real founder of civil society.” according to rousseau, private property was the upshot of an act of usurpation of the propertied against the rights of the un-propertied. schooled in the eighteenth- century idea of a natural sociability and natural sympathy among individuals, jefferson could not have consented in rousseau’s hypothesis. for him, the history of civil institutions, at least in amer- ica, was not a perversion of the natural pre-historical order. let us consider jefferson’s most seemingly rousseauian explanation of the origin of property. unquestionably, he admitted of property as not founded in nature but in human laws. how earth- shaking this opinion was, however, is still to be determined. in discourse on political economy ( ) rousseau himself called property a “sacred right” without ever regarding it as a natural right. to isaac mcpherson, jefferson wrote: “it is a moot question whether the origin of any kind of property is derived from nature at all … it is agreed by those who have seriously considered the subject, that no individual has, of natural right, a separate property in an acre of land, for instance. by an universal law indeed, whatever, whether fixed or moveable, belongs to all men equally and in common, is the property, for the moment, of him who occupies it; but when he relinquishes the occupation the property goes with it. stable ownership is the gift of social law, and is given late in the progress of society.” it is a “moot” question, first of all, and, in addition, it is hard to discern any trace of moral reprobation in what jefferson said. provided that society is a second-order nat- ural occurrence, a gift of social law sanctioned by the living generation can be as sacred as a law matthews, radical politics of jefferson, , . for a more convincing discussion of jefferson and property as alienable, see yarbrough, “jefferson and property rights,” especially - . wiltse, jeffersonian tradition, . quoted in matthews, radical politics of jefferson, . on jefferson and rousseau, see . rousseau, discourse on inequality ( ), part , incipit. itinerari maurizio valsania that comes directly from nature herself. the social order to which the living agree, at least the american order, is not in principle an unnatural perversion, even when it admits “separate prop- erty.” another jeffersonian document makes the point still clearer: a right of property in moveable things is admitted before the establishment of government. a separate property in lands not till after that establishment. the right to moveables is acknowledged by all the hordes of indians surrounding us. yet by no one of them has a separate property in lands been yielded to individuals. he who plants a field keeps possession till he has gathered the produce, after which one has as good a right as another to occupy it. government must be established and laws provided, before lands can be separately appropriated, and their owner protected in his possession. till then, the property is in the body of the nation, and they, or their chief as trustee, must grant them to individuals, and determine the conditions of the grant. once again, there is no trace of moral reprobation. the myth of redistribution the key point of the whole discussion of property is not whether jefferson deemed property of land and other immovable things as directly or indirectly founded in nature. more important is how he considered the social consequences of what we would call private property. did he frown upon inequality? did he consider stable property a theft perpetrated against the rights of laborers? did he see in private property an obstacle to the full expression of human subjectivity? we have to keep in mind that the living generation, not laborers per se, were for jefferson sovereign. like every other “class,” laborers relinquish their power as they enter society. classes, that typical european staple, should not exist in america. furthermore, the “self-evident truth” tells that the earth belongs in usufruct to the living. when an individual dies, his property “reverts to the society” which means “a whole generation of men,” not a specific class. the earth belongs to them, jefferson says, “fully, and in their own right.” individuals, groups, and classes, we have to remember, are “parts only of a society, subject to the laws of the whole.” each time we contem- plate this whole, we must also acknowledge that “there is no superior.” this is the plainest meaning of the phrase “self-government.” we are dealing with a “whole nation itself assembled” or with its representatives. the laws that have been emanated flow, jefferson said, from the “will of the society.” every generation is “independant.” they, the living generation, are the sole legal subject that can manage the earth and property “as they please.” no other subject is allowed to do that. not classes; not even laborers. the living are the sole “masters,” as jefferson made clear, “of their own persons, and consequently may govern them as they please.” tj to isaac mcpherson, aug. , ptj, retirement series, : - . tj, the batture at new orleans (published as the proceedings of the government of the united states, in maintaining the public right to the beach of the missisipi, etc., ), writings of thomas jefferson, : - . on jefferson considering property of land sanctioned by the “laws of civil society” for the en- couragement of industry (also shorn of any moral reprobation), see tj to thomas earle, sept. , writ- ings of thomas jefferson, : - . tj to james madison, sept. , ptj, : - , passim. on the class conflict afflicting english, not american society, see tj to thomas cooper, sept. , ptj, retirement series, : - . i will return to this letter shortly. itinerari thomas jefferson on private property obviously, the “will of the majority” can rarely be obtained “fairly and without impediment.” the people cannot easily “assemble themselves.” the representation may be “unequal and vi- cious.” factions may “get possession of the public councils.” “personal interests” lead represen- tatives “astray from the general interests of their constituents.” but these hindrances only prove that laws should be of limited duration, not that the living whole has no real and absolute authority. against the true and living community, no part, no class, no group should consider itself “inde- pendant.” the issue of property and its relationship to labor must be assessed within this communitarian framework. it would be an open betrayal of the living generation if a part decided on its own to pursue its interests, however noble and just they might appear. similarly, redistributing and so- cializing property would not necessarily be an act of justice made in the interest of the whole com- munity. jefferson, in effect, was against redistribution. “to take from one, because it is thought that his own industry and that of his fathers has acquired too much, in order to spare to others, who, or whose fathers have not exercised equal industry and skill, is to violate arbitrarily the first principle of association, ‘the guarantee to every one of a free exercise of his industry, and the fruits acquired by it.’“ in a similar spirit, he also wrote: “the first foundations of the social compact would be broken up were we definitely to refuse to it’s members the protection of their persons and property, while in their lawful pursuits.” tj, prospectus introducing tracy’s treatise on political economy, appended to tj to joseph milligan, april , writings of thomas jefferson, : ; tj to james maury, april , ptj, retirement series, : . on jefferson’s defending the “state of property, equal or unequal, which results to every man from his own industry, or that of his fathers,” see tj, second inaugural address, march , works of thomas jefferson, : . lance banning agrees that jefferson wanted not just to protect the industry of each man, but in particular “that of his fathers.” despite his acceptance of the general abstract principle that the right to earn a subsistence may have priority over positive laws and the wishes of the rich, jefferson was not immune from a mode of reasoning à la burke. consequently, we have to resist representing jefferson “as more radical than he was.” see banning, jefferson and madison, - , n. . in a stimulating essay, michael kammen argues that, against the common perception of the sacredness of private property in amer- ica (strongly supported by the last clause of the fifth amendment, part of the bill of rights of : “… nor shall private property be taken for public use, without just compensation.”), american constitutional history abounds in “unsettling complexities and ambiguities.” the preamble to the constitution, in fact, does not mention property. “my point here,” kammen writes, “is quite simply that farrand’s four volumes of records of the federal convention are amazingly silent concerning the status and protection of property per se. they contain … little pertaining to government’s role in safeguarding private property.” kammen, “rights of property,” . true as it is, jefferson supported the bill of rights and unequivocally wanted private property to be protected. the living and loving community must be secured against any government that could become merely exterior. for jefferson’s defense of the bill of rights, see for example tj to james madison, dec. , ptj, : - ; tj to james madison, july , ptj, : - ; and tj to noah webster, dec. , ptj, : - . for jefferson’s support of the bill of rights with an explicit reference to the issue of property, see for instance tj to a. coray, oct. , writings of thomas jefferson, : : “i have stated that the constitutions of our several states vary more or less in some particulars. but there are certain principles in which all agree, and which all cherish as vitally essential to the protection of the life, liberty, property, and safety of the citizen.” in the letter to james madison of aug. , ptj, : , a younger jefferson proposed a list of “alterations and additions.” but he did not mention article fifth. approving reference to article fifth can be found in tj, message on the act for the defence of rivers and harbors, march , writings of thomas jefferson, : . itinerari maurizio valsania jefferson was always faithful to this principle. “i am conscious that an equal division of prop- erty is impracticable,” he wrote in . of course, in france especially, there was an “enormous inequality” that produced “so much misery to the bulk of mankind.” this unbalance notwithstand- ing, a general principle applied that “legislators cannot invent too many devices for subdividing property.” they should take care of their constituents and “let their subdivisions go hand in hand with the natural affections of the human mind.” jean yarbrough captures this point when, following stanley katz, she insists that it was not jefferson’s intention to involve government in any radical scheme of redistribution: “jefferson was not seriously troubled by the inequality of wealth in republican america.” elsewhere, she also writes: “in contrast to many of today’s rights advocates, jefferson is more inclined to accept the social and economic inequalities that result from the formal possession of equal rights. … jeffer- son’s conception of rights favors equality of opportunity over equality of condition, and liberty over equality.” the reason was perhaps that jefferson had the impression that in america the rich were “few, and of moderate wealth.” after all, america was neither france, nor england. keeping these qualifications in mind, we can return to the issue of labor. richard matthews is correct in stressing that, for jefferson, property was subordinate to labor. property, according to jefferson, was founded in labor. “the earth is given as a common stock for man to labour and live on. if, for the encouragement of industry we allow it to be appropriated, we must take care that other employment be furnished to those excluded from the appropriation. if we do not the funda- mental right to labour the earth returns to the unemployed. … [i]t is not too soon to provide by every possible means that as few as possible shall be without a little portion of land. the small landholders are the most precious part of a state.” this, of course, is a description of an ideal and hypothetical condition (“the earth … given as a common stock”) and involves a sound heuristic maxim. it should not be read as a declaration of jefferson’s commitment to redistribution, socialization, and his rejection of the market values. yet, the fact remains that jefferson considered labor a fundamental and natural right, and appro- priation as a grant consented to by society—albeit one that has to be protected taking into account real historical circumstances. labor is the foundation of property in the sense that, to be able to work and satisfy their wants, everyone should have access to a parcel of land. in this sense, property also is implicitly natural. “a right to property is founded in our natural wants, in the means with which we are en- dowed to satisfy these wants, and the right to what we acquire by those means without violating the similar rights of other sensible beings.” labor is the natural means through which we satisfy our natural wants. property, in turn, is a natural means through which we can put into effect the natural means we have (labor) to satisfy our natural wants. everybody, in an ideal state, should be placed in the condition to go successfully through this round of wants, work, property, and satis- faction. good governments should strive to fulfil this maxim as much as they can. tj to james madison, oct. , ptj, : . yarbrough, “jefferson and property rights,” , and see ; yarbrough, american virtues, . see also katz, “jefferson and the right to property.” on jefferson’s aversion to progressive taxation, see yarbrough, american virtues, - . on jefferson’s impression that in america the rich were “few, and of moderate wealth,” see tj to thomas cooper, sept. , ptj, retirement series, : . tj to james madison, oct. , ptj, : . tj to du pont de nemours, april , works of thomas jefferson, : . itinerari thomas jefferson on private property jefferson’s claim about societal responsibility must not be mistaken for socialism and a cen- sure of real american society. as yarbrough writes, “stable ownership of property, which comes about with agriculture, and is rooted in labor, can only be justified if it promotes greater industry. when it does not, as in the enclosure of royal estates for mere pleasure, the property laws are un- just.” jefferson was aware that if property cannot be justifiable on philosophical grounds, it remains totally unjustifiable. each time the political theorist spoke out, he had no other choice but to ac- knowledge that “whenever there is in any country, uncultivated lands and unemployed poor, it is clear that the laws of property have been so far extended as to violate natural right.” on a normative theoretical level, stable ownership should benefit society as a whole, while the government should make sure that no one is wronged. no program of effective redistribution is entailed here. it would make no sense to push societal responsibility toward a utopia of communion and collectivization. the term “common stock” refers only to a hypothetical ideal condition: “that, on the principle of a communion of property, small societies may exist in habits of virtue, order, industry, and peace, and consequently in a state of as much happiness as heaven has been pleased to deal out to imperfect humanity, i can readily conceive, and indeed, have seen its proofs in various small societies which have been constituted on that principle. but i do not feel authorized to con- clude from these that an extended society, like that of the united states, or of an individual state, could be governed happily on the same principle.” jefferson’s political vision was neither a socialist, nor a classical republican utopia. as yarbrough admits, his view of property was “decidedly modern and democratic.” that is, while classic republicanism put emphasis on the civil use of property and disparaged the acquisition of wealth as contrary to virtue, “modern political philosophy, beginning with machiavelli and con- tinuing through the seventeenth and eighteenth centuries, looks at acquisitiveness in a more positive light.” revitalizing an old argument already presented by the satirist bernard mandeville, adam smith proclaimed to the entire world of enlightenment that the selfish and the social passions pro- moted the same end. it was an eighteenth-century commonplace, as lord kames put it in a famous aphorism that jefferson entered in his commonplace book, that “property gives life to industry, and enables us to gratify the most dignified natural affections.” jefferson’s vision of property was modern and did not denounce a moral scandal. as a con- sequence, his idea that the earth is given as a “common stock” for humans to labor and live on must be approached via locke and via those intellectuals who were more reconciled to the present “as it is,” not via rousseau or, worst, via marx. jefferson and many other of his contemporaries could but agree with the sound realism and theoretical clarity of locke’s ideas: “though the earth, and all inferior creatures, be common to all men, yet every man has a property in his own person: this no body has any right to but himself. the labour of his body, and the work of his hands, we may say, are properly his. whatsoever then he removes out of the state that nature hath provided, and left it in, he hath mixed his labour with, and joined to it something that is his own, and thereby yarbrough, “jefferson and property rights,” ; tj to james madison, oct. , ptj, : . for an- other example of the political theorist pointing to the “equal right of every citizen, in his person and property, and in their management” as “the true foundation of republican government,” see tj to samuel kercheval, july , works of thomas jefferson, : . tj to cornelius camden blatchly, oct , writings of thomas jefferson, : . yarbrough, american virtues, ; tj, commonplace book, - , from henry home (lord kames), historical law-tracts ( ), tract , “history of property.” itinerari maurizio valsania makes it his property.” locke set out the theoretical principles with clarity, but he did not comple- ment them with a program for universal liberation. ideally, land should be granted to every individual. additionally, jefferson went beyond locke and many other philosophers in the sense that, in his role as a policy maker, he strove to distribute fifty acres of land to some un-propertied to make them propertied and hence “free.” but jefferson did not fall into despair or indignation at the thought that many others, like enslaved per- sons, were not allowed to own and work land and that still many others, like native americans, refused to own and work it for cultural reasons. he did not criticize american society. conclusion jefferson was no utopian, either in the sense that he wanted redistribution, or in the sense the he was nostalgic about the “simpler” societies of the past. rather, jefferson’s utopianism was enticed by the thought that in america, after the revolution, there was no urgent need of further redistri- bution. jefferson’s utopianism bordered on a conservative utopia, so to speak, overlapping with the belief that the victorious american nation was different from europe. the rich, here, were “few, and of moderate wealth.” as a consequence, “our people,” need not “to labor sixteen hours in the twenty-four.” english workers “have no time to think, no means of calling the mismanagers to ac- count.” europeans, not americans, were those who had no independence of heart and mind and who desperately needed redistribution. jefferson was sure that american society was homogeneous in comparison to europe. he saw no latent class conflict: “the great mass of our population is of laborers; … most of the laboring class possess property, cultivate their own lands, have families, and from the demand for their labor are enabled to exact from the rich and the competent such prices as enable them to be fed abundantly, clothed above meer decency, to labor moderately and raise their families.” jefferson’s utopianism rested in the conviction that america was in excellent shape, and that only details had to be readjusted. while fancying “a cordial fraternization among all the american nations” old jefferson openly yielded to a biblical dream: “the lion and the lamb, within our re- gions, shall lie down together in peace.” after achieving the presidency and accomplishing the “revolution of ,” jefferson had already confessed his conviction that “the storm we have passed through proves our vessel indestructible.” this kind of utopianism, insisting on uncritical optimism and emphasizing “our” greatness, made jefferson in some way blind to the ordeal of american under-classes, natives, enslaved individuals, women, or laboring children. he did not have the same perception we have about the fact that in america rights were actually violated. locke, second treatise, chapter , section . on jefferson’s theory of property as essentially locke’s, see griswold, “agrarian democracy of jefferson.” i consider the following passage a stunning criticism of every rousseauian perspective: “he who is permitted by law to have no property of his own [like slaves, for example], can with difficulty conceive that property is founded in any thing but force.” tj to edward bancroft, jan. , ptj, : . on the rich being “few, and of moderate wealth,” see tj to thomas cooper, sept. , ptj, retirement series, : . on “our people,” not needing “to labor sixteen hours in the twenty-four,” see tj to samuel kercheval, july , works of thomas jefferson, : . tj to thomas cooper, sept. , ptj, retirement series, : . tj to william short, aug. , writings of thomas jefferson, : - ; tj to lafayette, march , ptj, : . itinerari thomas jefferson on private property in america “we” had achieved a condition in which, as he said to thomas cooper, the great mass of the laboring class possessed property. property, for jefferson, did not just mean owning things and land to till. it meant having families and having gained position and self-respect. those who own property, he said, could “exact from the rich and the competent such prices as enable them to be fed abundantly, clothed above meer decency.” property entailed weltweisheit. property is a semantically comprehensive concept implying strong cultural values. locke’s understanding of property, for example, has been criticized for being “exceedingly comprehensive, referring not so much to things in themselves but to the act or conditions of possession.” such a comprehensiveness and multivocality, however, was hardly an embarrassment for an eighteenth- century mind. james madison’s essay “property,” for instance, expanded the notion of property not just to include the “means of acquiring property,” but to the point of defining conscience as “the most sacred of all property.” in its larger and juster meaning, it embraces every thing to which a man may attach a value and have a right; and which leaves to everyone else the like advantage. … if there be a government then which prides itself on maintaining the inviolability of property; which provides that none shall be taken di- rectly even for public use without indemnification to the owner, and yet directly violates the property which individuals have in their opinions, their religion, their persons, and their faculties; nay more, which indirectly violates their property, in their actual possessions, in the labor that acquires their daily subsistence, and the hollowed remnant of time which ought to relieve their fatigues and soothe their cares, the inference will have been anticipated, that such a government is not a pattern for the united states. for lord kames and for his followers as well, including hume and adams smith, property was more than just material objects. it was a part of one’s sense of self. without property, persons were missing an important dimension of their personality together with their grasp on the society around them. they had little or no chance to be publicly acknowledged. as arthur herman has noticed, in eighteenth-century english “property meant the same as propriety: those things that are proper to me, and to me alone. … to own things is in fact to own myself. property makes me a whole and complete human being.” besides its material connotation, property was also a condition of the mind, the best intel- lectual device to counteract “dependence.” to some extent, it was an anthropological category, dependent men being those who have lost propriety, namely, honor, agency, control, position, and affiliation. jefferson may have felt sorry for all those who, for historical or biological reasons, fell into the category of the un-propertied. he also honestly sought to enlarge the opposite group. but, realistically, he expressed no moral embarrassment, let alone indignation or desperation, that an increasing number of american individuals without propriety, the “private,” would never be in- cluded in the american community. instead of showing desperation or indignation, jefferson found refuge in his conservative utopia. this was most likely his way to compensate for the reality that virginia also was dramat- ically changing. before the revolution, almost every white male had property (in both senses of the word) and was qualified. every male was the center of a little universe. in the colony, land kammen, “rights of property,” . madison, “property,” the national gazette, march . herman, scottish enlightenment, . itinerari maurizio valsania ownership had been widespread. perhaps as many as eighty or ninety percent of white males either had sufficient property of their own or could claim protection from a propertied friend or relation. the trend in post-revolution virginia was toward an increase in the white un-propertied popula- tion, landless and dependent. the sheer number of virginians was advancing at a steady and dis- quieting pace. although it was not immediately a natural right, jefferson regarded property as a fundamental tool. it was an instrument, a social invention, to “augment” the self, notably, to increase individual efficacy. it was an effective means for getting a foothold in reality while winning acknowledgement from other fellows as a man of position. bibliography banning, lance ( ), jefferson and madison: three conversations from the founding, rowman & lit- tlefield publishers, lanham, md. burstein, andrew, and nancy isenberg ( ), madison and jefferson, random house, new york. conklin, carli n. ( ), the pursuit of happiness in the founding era: an intellectual history, university of missouri press, columbia, mo. ferguson, adam ( ), an essay on the history of civil society, orig. pub. , ed. t. cadell, london. griswold, a. whitney, “the agrarian democracy of thomas jefferson,” american political science review ( ): - . hegel, georg wilhelm friedrich ( ), the philosophy of history, orig. pub. , trans. j. sibree, dover publications, new york. herman, arthur ( ), the scottish enlightenment: the scots’ invention of the modern world, harper- collins, london. jefferson, thomas ( ), the commonplace book of thomas jefferson: a repertory of his ideas on gov- ernment, ed. gilbert chinard, johns hopkins press, baltimore. ———. the papers of thomas jefferson ( to date), ed. julian boyd et al., vols. to date, plus vols. in the retirement series, princeton university press, princeton, n.j. ———. the works of thomas jefferson ( - ), ed. paul leicester ford, vols., g.p. putnam’s sons, new york. ———. the writings of thomas jefferson ( ), ed. andrew a. lipscomb and albert ellery bergh, vols., thomas jefferson memorial association of the united states, washington, d.c. kammen, michael, “‘the rights of property, and the property in rights’: the problematic nature of ‘prop- erty’ in the political thought of the founders and the early republic,” in paul and dickman, liberty, property, - . katz, stanley n., “thomas jefferson and the right to property in revolutionary america,” journal of law and economics ( ): - . lewis, jan ( ), the pursuit of happiness: family and values in jefferson’s virginia, cambridge uni- versity press, new york. locke, john. two treatises of government ( ), orig. pub. , ed. thomas hollis, london. lynd, staughton ( ), intellectual origins of american radicalism, pantheon books, new york. maier, pauline ( ), american scripture: making the declaration of independence, vintage books, new york. on eighty or even ninety percent of propertied in virginia in the s, see lewis, pursuit of happiness, . in , according to mullin, flight and rebellion, , virginia’s population was , divided equally between black and white. in notes, jefferson gave the figures of , blacks out of a total population of , . see tj, notes, query , works of thomas jefferson, : . itinerari thomas jefferson on private property matthews, richard k ( ), the radical politics of thomas jefferson: a revisionist view, university press of kansas, lawrence, kan. mullin, gerald w ( ), flight and rebellion: slave resistance in eighteenth-century virginia, oxford university press, new york. paul, ellen frankel, and howard dickman, eds. ( ), liberty, property, and the foundations of the amer- ican constitution, suny press, albany, ny. sloan, herbert e. ( ), principle and interest: thomas jefferson and the problem of debt, oxford uni- versity press, new york. wills, garry ( ), inventing america: jefferson’s declaration of independence, doubleday, boston. wiltse, charles m. ( ), the jeffersonian tradition in american democracy, university of north carolina press, chapel hill, n.c. yarbrough, jean m., “jefferson and property rights,” in paul and dickman, liberty, property, - . ———. ( ), american virtues: thomas jefferson on the character of a free people, university press of kansas, lawrence, kan. maurizio valsania • is professor of american history at the university of turin, italy. author of the limits of optimism: thomas jefferson’s dualistic enlightenment (uva press, ), nature’s man: thomas jefferson’s philosophical anthropology (uva press, ), and jefferson’s body: a corporeal biography (uva press, ), he is the recipient of several fellowships from leading aca- demic institutions, including the american antiquarian society, the gilder lehrman institute of amer- ican history, the library company, the john d. rockefeller library, the daad (germany), and the international center for jefferson studies. he has written for the oup blog (oxford university press’s academic insights for the thinking world) and collaborated with the bbc world service. e-mail • maurizio.valsania@unito.it itinerari _layout key words: breast cancer, follow-up care, abdominal echogram, bone scan. financial disclosure: this work was supported by funding from the agen- zia sanitaria e sociale regionale, re- gione emilia-romagna, italy. correspondence to: maurizio leoni, ospedale s maria delle croci, via ran- di , ravenna, italy. tel + - - ; fax + - - ; email m.leoni@ausl.ra.it received march , ; accepted august , . variation among local health units in follow-up care of breast cancer patients in emilia-romagna, italy maurizio leoni , , radha sadacharan , daniel louis , fabio falcini , carol rabinowitz , luca cisbani , rossana de palma , elaine yuen , and roberto grilli ospedale civile ravenna, ravenna, italy; jefferson medical college, thomas jefferson university, philadelphia, pa, usa; registro tumori, forlì, italy; jefferson school of population health, thomas jefferson university, philadelphia, pa, usa; agenzia sanitaria e sociale regionale, regione emilia-romagna, italy abstract aims and background. this study examines the patterns of follow-up care for breast cancer survivors in one region in italy. methods and study design. this retrospective analysis included , surgically treated women, with incident cases of breast cancer in the years - who were alive months after their incidence date. rates of use of follow-up mammograms, abdominal echogram, bone scans and chest x-rays were estimated from administra- tive data and compared by local health unit (lhu) of residence. logistic regression analyses were performed to assess possible “overuse”, accounting for patient age, cancer stage, type of surgery and lhu of residence. results. a total of ( . %) women received a mammogram within months of their incidence date, while ( . %) had an abdominal echogram, ( . %) had a bone scan and ( . %) had a chest x-ray. the rates of use of abdominal echograms, bone scans and chest x-rays were substantially higher in the population of breast cancer survivors than in the general female population. taking account of patient age, cancer stage at diagnosis and type of surgery, multivariate analyses demonstrated significant variation in the use of these tests by lhu of residence. conclusions. the observed variation in the use of abdominal echograms, bone scans and chest x-rays supports the conclusion that there is substantial misuse of these tests in the population of postsurgical breast cancer patients in the emilia-romagna region in italy. in the absence of a documented survival benefit, overtesting has both a human and financial cost. we recommend additional review of the methods of fol- low-up care in breast cancer patients in the lhus of emilia-romagna, with the aim of developing, disseminating and evaluating the implementation of specific guidelines targeting primary care physicians and oncologists providing care to breast cancer survivors. patient education materials may also help to reduce unnecessary testing. tu mo ri, : - , hospital risk of data breaches mended screening to women years or older. our findings are largely consistent with a survey of pcps from clinical networks where similar proportions of physicians recommended screening with higher rates noted among gynecologists. we also found sharp differences in recommen- dations based on which guidelines physicians trusted most, which may suggest that current practices reflect both varying adherence to guidelines as well as differences in which guide- lines are trusted. the results provide an important bench- mark as guidelines continue evolving and underscore the need to delineate barriers and facilitators to implementing guide- lines in clinical practice. archana radhakrishnan, md, mhs sarah a. nowak, phd andrew m. parker, phd kala visvanathan, md, mhs craig evan pollack, md, mhs author affiliations: division of general internal medicine, johns hopkins university, baltimore, maryland (radhakrishnan, pollack); rand corporation, santa monica, california (nowak); rand corporation, pittsburgh, pennsylvania (parker); department of epidemiology, johns hopkins bloomberg school of public health, baltimore, maryland (visvanathan); department of oncology, johns hopkins school of medicine, baltimore, maryland (visvanathan); johns hopkins bloomberg school of public health, baltimore, maryland (pollack). corresponding author: archana radhakrishnan, md, division of general internal medicine, johns hopkins university, e monument st, ste - c, baltimore, md (aradhak @jhu.edu). published online: april , . doi: . /jamainternmed. . author contributions: dr radhakrishnan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. study concept and design: radhakrishnan, nowak, parker, pollack. acquisition, analysis, or interpretation of data: radhakrishnan, nowak, parker, visvanathan, pollack. drafting of the manuscript: radhakrishnan. critical revision of the manuscript for important intellectual content: nowak, parker, visvanathan, pollack. statistical analysis: radhakrishnan, parker. obtained funding: nowak, parker, pollack. administrative, technical, or material support: pollack. study supervision: pollack. conflict of interest disclosures: none reported. . oeffinger kc, fontham eth, etzioni r, et al; american cancer society. breast cancer screening for women at average risk: guideline update from the ameri- can cancer society. jama. ; ( ): - . doi: . /jama. . . siu al; u.s. preventive services task force. screening for breast cancer: u.s. preventive services task force recommendation statement. ann intern med. ; ( ): - . doi: . /m - . american college of obstetricians-gynecologists. practice bulletin no. : breast cancer screening. obstet gynecol. ; ( , pt ): - . doi: . /aog. b e c e . peterson eb, ostroff js, duhamel kn, et al. impact of provider-patient communication on cancer screening adherence: a systematic review. prev med. ; : - . doi: . /j.ypmed. . . . haas js, sprague bl, klabunde cn, et al; prospr (population-based research optimizing screening through personalized regimens) consortium. provider attitudes and screening practices following changes in breast and cervical cancer screening guidelines. j gen intern med. ; ( ): - . doi: . /s - - - hospital risk of data breaches as the adoption of electronic record and health information tech- nology rapidly expands, hospitals and other health providers increasingly suffer from data breaches. a data breach is an im- permissible use or disclosure that compromises the security or privacy of the protected health information and is commonly caused by a malicious or criminal attack, system glitch, or hu- man error. , policy makers, hospital administrators, and the public are highly interested in reducing the incidence of data breaches. in this retrospective data analysis, we use data from the department of health and human services (hhs) to exam- ine what type of hospitals face a higher risk of data breaches. methods | under the health information technology for eco- nomic and clinical health act of , all heath care providers covered by the health insurance portability and accountabil- ity act must notify hhs of any breach of protected health in- formation affecting or more individuals within days from the discovery of the breach. the department of health and hu- man services publishes the submitted data breach incidents on its website, with the earliest submission date as october , . we were able to link acute care hospitals to their fiscal year medicare cost reports filed with the centers for medi- care and medicaid services (cms). the unlinked hospitals in- clude long-term care hospitals, veterans affairs and military hos- pitals, hospital systems, and hospitals unidentifiable in the cms data set. we applied multivariable and regression analyses to compare these hospitals with other acute care hospitals to understand what type of hospitals face a higher risk of breaches. statistical analysis was performed with sas . (sas institute inc) and stata (statacorp llc). for statistical analysis, t tests were used, and p < . was considered significant. results | between october , , and december , , data breaches were reported. among them, breaches figure . proportion of physicians who recommend breast cancer screening categorized by which guidelines physicians report trusting the most - - ≥ - ph ys ic ia ns , % - acs acog uspstf guidelines a a a age group, y acog, american congress of obstetricians and gynecologists; acs, american cancer society; uspstf, us preventive services task force. adenotes statistically significant (p < . ) differences based on most trusted organizational guideline. letters jama internal medicine june volume , number (reprinted) jamainternalmedicine.com © american medical association. all rights reserved. downloaded from: https://jamanetwork.com/ by a carnegie mellon university user on / / mailto:aradhak @jhu.edu http://jama.jamanetwork.com/article.aspx?doi= . /jamainternmed. . &utm_campaign=articlepdf% utm_medium=articlepdflink% utm_source=articlepdf% utm_content=jamainternmed. . http://jama.jamanetwork.com/article.aspx?doi= . /jama. . &utm_campaign=articlepdf% utm_medium=articlepdflink% utm_source=articlepdf% utm_content=jamainternmed. . http://dx.doi.org/ . /m - http://dx.doi.org/ . /aog. b e c e http://dx.doi.org/ . /aog. b e c e http://dx.doi.org/ . /j.ypmed. . . http://dx.doi.org/ . /s - - - http://www.jamainternalmedicine.com/?utm_campaign=articlepdf% utm_medium=articlepdflink% utm_source=articlepdf% utm_content=jamainternmed. . were reported by health care providers and the remaining by business associates, health plans, or health care clearing houses. there were breaches reported by hospitals in the data, with median (interquartile range [iqr]) ( - ) affected individuals per breach; hospitals that had been breached at least twice and many of which are large ma- jor teaching hospitals (table ). table lists hospitals with more than total affected individuals. for the acute care victim hospitals linked to their cms cost reports, the me- dian (iqr) number of beds was ( - ) and ( %) were major teaching hospitals. in contrast, among acute care hospitals not identified as having breaching incidents, the me- dian (iqr) number of hospital beds was ( - ), and ( %) were major teaching hospitals. hospital size and major teaching status were positively associated with the risk of data breaches (p < . ). discussion | a fundamental trade-off exists between data secu- rity and data access. broad access to health information, es- sential for hospitals’ quality improvement efforts and re- search and education needs, inevitably increases risks for data breaches and makes “zero breach” an extremely challenging objective. the evolving landscape of breach activity, detec- tion, management, and response requires hospitals to con- tinuously evaluate their risks and apply best data security prac- tices. despite the call for good data hygiene, little evidence exists of the effectiveness of specific practices in hospitals. identification of evidence-based effective data security prac- tices should be made a research priority. this study has important limitations. first, data breaches affecting fewer than individuals were not examined. sec- ond, since each victim hospital was matched to cms cost re- port based on the name and state, the matching might be in- complete or inaccurate for some hospitals. finally, our analysis is limited to the hospital industry. future studies that exam- ine the characteristics of other types of health care entities that experienced data breaches are warranted. ge bai, phd, cpa john (xuefeng) jiang, phd renee flasher, phd, cpa author affiliations: the johns hopkins carey business school, washington, dc (bai); eli broad college of business, michigan state university, east lansing (jiang); miller college of business, ball state university, muncie, indiana (flasher). table . hospitals breached more than once between october , , and december , hospital name state frequency montefiore medical center ny university of rochester medical center & affiliates ny brigham and women's hospital ma cook county health & hospitals system il mount sinai medical center fl st vincent hospital and healthcare, inc in advocate health and hospitals corporation il aventura hospital and medical center fl beth israel deaconess medical center ma children's medical center of dallas tx children's national medical center dc florida hospital fl georgetown university hospital dc henry ford hospital mi holy cross hospital fl hospital for special surgery ny jersey city medical center nj jewish hospital ky kern medical center ca long beach memorial medical center ca lucile packard children's hospital ca martin army community hospital ga massachusetts general hospital ma mercy medical center redding ca mount sinai medical center ny nyu hospitals center ny phoebe putney memorial hospital ga rady children's hospital - san diego ca riverside county regional medical center ca st elizabeth's medical center ma thomas jefferson university hospitals, inc pa titus regional medical center tx uc davis medical center ca table . breached hospitals with more than total affected individuals hospital name state total affected individuals advocate health and hospitals corporationa il ahmc healthcare inc and affiliated hospitals ca jacobi medical center ny providence hospital mi st vincent hospital and healthcare, inca in cincinnati children’s hospital medical center oh montefiore medical centera ny kaiser foundation hospital- orange county ca methodist dallas medical center tx seton family of hospitals tx jersey city medical centera nj santa rosa memorial hospital ca cook county health & hospitals systema il integrity transitional hospital tx st luke's cornwall hospital ny gibson general hospital in blount memorial hospital, inc tn jamaica hospital medical center ny our lady of peace hospital ky thomas jefferson university hospitals, inca pa children's national medical centera dc reid hospital & health care services in florida hospitala fl rady children's hospital - san diegoa ca a hospitals that experienced at least breach occurring between october , , and december , . letters jamainternalmedicine.com (reprinted) jama internal medicine june volume , number © american medical association. all rights reserved. downloaded from: https://jamanetwork.com/ by a carnegie mellon university user on / / http://www.jamainternalmedicine.com/?utm_campaign=articlepdf% utm_medium=articlepdflink% utm_source=articlepdf% utm_content=jamainternmed. . corresponding author: ge bai, phd, cpa, the johns hopkins carey business school, bernstein-offit bldg , massachusetts ave nw, washington, dc (gbai@jhu.edu). published online: april , . doi: . /jamainternmed. . author contributions: dr bai had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. study concept and design: all authors. acquisition, analysis, or interpretation of data: bai, jiang. drafting of the manuscript: all authors. critical revision of the manuscript for important intellectual content: all authors. statistical analysis: bai, jiang. administrative, technical, or material support: all authors. supervision: bai, jiang. conflict of interest disclosures: none reported. additional contributions:we acknowledge the valuable comments from gerard f. anderson, phd, and technical support from jianbo liu, phd; they did not receive compensation. . liu v, musen ma, chou t. data breaches of protected health information in the united states. jama. ; ( ): - . . us department of health and human services. breach notification rule. https://www.hhs.gov/hipaa/for-professionals/breach-notification. accessed december , . . ponemon institute. sixth annual benchmark study on privacy & security of healthcare data. http://www.ponemon.org/blog/sixth-annual-benchmark -study-on-privacy-security-of-healthcare-data- . accessed december , . . bai g, anderson gf. a more detailed understanding of factors associated with hospital profitability. health aff (millwood). ; ( ): - . . the us department of health and human services. breaches affecting or more individuals. https://ocrportal.hhs.gov/ocr/breach/breach_report.jsf. accessed december , . . blumenthal d, mcgraw d. keeping personal health information safe: the importance of good data hygiene. jama. ; ( ): - . experience and outcomes of hepatitis c treatment in a cohort of homeless and marginally housed adults approximately % of homeless adults are hepatitis c virus (hcv)-infected. - historically, homeless and marginally housed (hmh) adults have faced barriers to hcv treatment. new, interferon-free therapies have excellent cure rates and improved tolerability, reducing barriers for treatment. to our knowledge, no published studies have documented the treat- ment of hmh populations with these therapies. the boston health care for the homeless program (bhchp) began treat- ing hmh adults with oral agents in . methods | we retrospectively describe the experience and outcomes of oral direct acting antiviral agents for hcv in a cohort of hcv-infected hmh adults. the study protocol was approved by the institutional review board at massachu- setts general hospital and deemed to meet minimal risk cri- teria. patients received treatment at bhchp, a federally qualified health center providing integrated primary care services via a patient-centered medical home approach to more than individuals in the boston area annually. patients were not compensated for their participation. the hcv treatment team (a c are coordinator [ . full-time equivalent], nurse [ . full-time equivalent], and primary care clinicians [ nurse practitioner, . full-time equiva- lent, and primary care physicians— . full-time equivalent combined]) provided care. patients had an initial evaluation table. baseline characteristics of the cohort of hepatitis c virus (hcv)-infected homeless and marginally housed adults treated with oral therapy characteristic sustained virologic response, no. (%) not achieved (n = ) achieved (n = ) age, mean (sd), y . ( . ) . ( . ) sex male ( ) ( ) race nonwhite ( ) ( ) ethnicity hispanic ( ) veteran ( ) education <high school graduate or ged ( ) ( ) employment part-time ( ) ( ) full-time ( ) unemployed ( ) disability ( ) insured ( ) ( ) history of incarceration ( ) homeless ( ) hiv coinfected ( ) genotype mixed ( ) ( ) ( ) ( ) ( ) ( ) fibrosis- value, mean (sd) . . ( . ) metavir stage f ( ) f ( ) f ( ) f ( ) f ( ) ( ) reactive hepatitis a virus ( ) ( ) hepatitis b virus ( ) alanine aminotransferase level, u/l, mean (sd) . ( . ) . ( . ) hcv treatment experience ( ) hcv treatment regimen sofosbuvir-ribavirin ( ) ( ) simeprevir-sofosbuvir ( ) ledipasvir-sofosbuvir ( ) ( ) ledipasvir-sofosbuvir-ribavirin ( ) history of idu ( ) ( ) used drugs (including marijuana) during hcv treatment ( ) abbreviations: ged, general educational development test; hiv, human immunodeficiency virus; idu, injection drug use. si conversion factor: to convert alanine aminotransferase to microkatals per liter, multiply by . . letters jama internal medicine june volume , number (reprinted) jamainternalmedicine.com © american medical association. all rights reserved. downloaded from: https://jamanetwork.com/ by a carnegie mellon university user on / / mailto:gbai@jhu.edu http://jama.jamanetwork.com/article.aspx?doi= . /jamainternmed. . &utm_campaign=articlepdf% utm_medium=articlepdflink% utm_source=articlepdf% utm_content=jamainternmed. . https://www.ncbi.nlm.nih.gov/pubmed/ https://www.hhs.gov/hipaa/for-professionals/breach-notification http://www.ponemon.org/blog/sixth-annual-benchmark-study-on-privacy-security-of-healthcare-data- http://www.ponemon.org/blog/sixth-annual-benchmark-study-on-privacy-security-of-healthcare-data- https://www.ncbi.nlm.nih.gov/pubmed/ https://ocrportal.hhs.gov/ocr/breach/breach_report.jsf https://www.ncbi.nlm.nih.gov/pubmed/ http://www.jamainternalmedicine.com/?utm_campaign=articlepdf% utm_medium=articlepdflink% utm_source=articlepdf% utm_content=jamainternmed. . pii: s - x( ) - Ž .matrix biology ] analysis of coding sequences for tissue inhibitor of ž / ž /metalloproteinases timp and timp in patients with aneurysms xiaoju wang a, gerard trompa, c. william coleb, alain verloesc, natzi sakalihasand, sungpil yoona, helena kuivaniemi a,u a center for molecular medicine and genetics, and department of surgery, wayne state unï ersity, school of medicine, gordon h. scott hall of basic medical sciences, east canfield a¨enue, detroit, mi , usa bdalhousie unï ersity, halifax, no¨a scotia, canada c wallonia center for human genetics, liege unï ersity, liege, belgium` ` d department of cardio¨ascular surgery, sart tilman unï ersity hospital, liege, belgium` received september ; accepted october abstract aneurysms are characterized by dilation, i.e. expansion and thinning of all the arterial wall layers, which is accompanied by remodeling of the connective tissue. genes involved in the regulation of tissue remodeling are therefore candidate genes. we Ž .analyzed timp and timp coding sequences in individuals with abdominal aortic aneurysms aaa , one individual with Ž .aaa and intracranial aneurysms ia , four individuals with ia and two clinically unaffected individuals. we identified two nucleotide variants in both the timp and the timp coding sequences. all differences occurred in the third base positions of codons and were neutral polymorphisms. a significant difference was observed in the frequency of timp nt polymorphism between alleles from aaa patients and control alleles. q elsevier science b.v.rinternational society of matrix biology. all rights reserved. keywords: aortic aneurysms; connective tissue; direct sequencing; intracranial aneurysms; polymorphism . introduction Ž .rupture of an abdominal aortic aaa or intracra- Ž .nial ia aneurysm is a significant cause of mortality and morbidity, and ] % of the population in the usa and other industrialized countries harbor Ž .aneurysms see verloes et al., . despite the u corresponding author. abbre¨iations: aaa, abdominal aortic aneurysm; cdna, comple- mentary dna; ia, intracranial aneurysm; pcr, polymerase chain reaction; timp , tissue inhibitor of metalloproteinase ; timp , tissue inhibitor of metalloproteinase ; nt, nucleotide major advances in surgical treatment, the survival rate after a ruptured aneurysm is low. early diagnosis of aneurysms is, therefore, important. if it were possible to predict who is at risk for developing an aneurysm, Ždiagnostic efforts ultrasonography, computerized to- .mography and magnetic resonance imaging could be directed towards those at risk. familial predisposition to both aaas and ias is Žnow well recognized see verloes et al., ; .ronkainen et al., . the possible genetic factors involved in the development of aneurysms include Ž . Ž .see verloes et al., : a structural components Ž .of arteries; b enzymes degrading the structural Ž .molecules; and c inhibitors of the proteolytic process. - xr r$ - see front matter q elsevier science b.v.rinternational society of matrix biology. all rights reserved. Ž .pii: s - x - ( )x. wang et al. r matrix biology ] dna sequencing of aortic aneurysm patients Ž .tromp et al., and ia or carotid artery Ž .dissection patients kuivaniemi et al., revealed that mutations in type iii procollagen are an infre- quent cause of aneurysms. the development of aneurysms is associated with remodeling of the extracellular matrix, including breakdown of structural components of the vascular Ž .wall see verloes et al., . collagenase activity Ž .and production of -kda gelatinase mmp are Žincreased in ruptured aneurysmal aorta see verloes .et al., . the increased proteolytic activity could be due to overexpression of the enzymes or down-reg- ulation of their inhibitors. in fact, decreased levels of Ž .tissue inhibitors of metalloproteinases timps in Ž .aaas have been reported see verloes et al., . furthermore, the ratio of matrix metalloproteinase Ž .mmp mrna amount to timp mrna was higher Ž .in aaa than in normal aortas tamarina et al., . the relative timp deficiency could be due to local tissue conditions inhibiting the expression or muta- tions in the primary structure of the timp genes. there are at least four members in the timp family, all of which were cloned, sequenced and mapped onto Ž .human chromosomes see olson et al., . we studied the coding sequences of timp and timp in patients with aaa andror ia to determine whether mutations in the timp genes are associated with aneurysms. . materials and methods this study was initiated at thomas jefferson uni- versity and was approved by the institutional review committees of thomas jefferson university and wayne state university school of medicine. skin biopsies obtained after written informed consent were used to establish fibroblast cultures. rna was isolated, cdna synthesized, pcr products purified and Žgenomic dna isolated as described previously tromp .et al., . oligonucleotide primers based on the Žcdna sequences of timp timp -i, cgc- gaattcagatccagcgcccagagag; timp - ii, cg cg g atccg g aag aaag atg g g ag - . Žtggg; docherty et al., and timp timp -ii, tttattcatgctgtttccaggaaggg; timp - vi, cggccccgcccgcccagc; stetler-stevenson .et al., were used in pcr to amplify all the coding sequences. because of the high gc content in the end of the timp , many pcr conditions failed, but q-solution and qiagen pcr kit were used Ž .successfully qiagen inc., santa clarita, ca, usa . the pcr products were sequenced directly using w Žeither sequenase us biochemical corporation, . w xc le ve la n d , o h , u s a a n d a - p d a t p Ž . w Žnenrdupont , or thermo sequenase amersham .life science, inc., cleveland, oh, usa . the samples w Žwere electrophoresed on a sequagel- national di- .agnostics, atlanta, ga, usa or on glycerol-tolerant Žgels amersham life science, inc., cleveland, oh, .usa . the sequence variants were confirmed by pcr- based restriction endonuclease assays. the gender of all samples was confirmed by y-chromosome specific Ž .pcr research genetics, huntsville, al, usa . for genomic pcrs, primers were designed based on pub- Žlished sequences genbank accession number d ; .hammani et al., . primer sequences and pcr conditions are available from the corresponding au- thor upon request. . results and discussion to investigate the possibility that aneurysms are caused by defects in the genes for timp or timp , the sequences of the coding regions of timp and timp were determined in unrelated individuals Ž had aaa, one had aaa and ia, four had ia, and .two were clinically unaffected . all except one of the aneurysm patients had a family history for the disease. the type iii procollagen cdna sequences in Žall of these individuals were normal kuivaniemi et .al., ; tromp et al., . the sequence analyses carried out here provided Ž nt of timp cdna sequences all nt of .coding sequences from each individual. two se- quence variations were found. aaa patient jimm Žhad crt nt proline codon at amino acid position . changes from ccc to cct . all the other individuals had c at nt . another sequence change Žwas found at nt , also reported by others tilson et .al., . six individuals had c at this site, had t and two individuals were heterozygous crt. the se- quence change converted the phenylalanine codon ttc at amino acid position to ttt. Žfor timp , we analyzed -nt all nt of cod- .ing sequences , and two sequence variations were identified. aaa patient jimm had crt at nt . another difference, g to a transition, occurred at nt Ž in three patients jimm , jimm and .jimm , all of whom were heterozygous for this change. both variations occurred at the third posi- tions of codons and did not change the amino acids. the frequencies of these variations were de- termined among control alleles and alleles Žfrom aaa patients of the patients used for dna sequencing and additional unrelated aaa .patients . the timp gene includes four exons Ž .genbank accession number: d , and the vari- ants are in the second and third exons. since timp is on the x chromosome, we report the allele fre- Ž .quencies separately in males and females table . ( )x. wang et al. r matrix biology ] table frequencies of the polymorphisms in timp and timp genes a b clocation chr. controls unrelated aaa patients d d fallele frequency allele frequency p-value e em f het. m f het. Ž . Ž . Ž . Ž .timp nt x c: . . . . . m: . Ž . Ž . Ž . Ž .t: . . . . f: . Ž . Ž . Ž . Ž .timp nt x c: . . . . . . m: . Ž . Ž . Ž . Ž .t: . . . . f: . Ž . Ž . Ž . Ž .timp nt c: . . . . . . m: . Ž . Ž . Ž . Ž .t: . . . . f: . Ž . Ž . Ž . Ž .timp nt g: . . . . . . m: . Ž . Ž . Ž . Ž .a: . . . . f: . a chromosomal localization of the gene. b Ž .twenty-nine controls were males and were females all were from the us . c Ž . Žsixty-four aaa patients were males us, belgian, canadian, swedish, british and finnish and were females us, .canadian, finnish and one italian . d numbers in parentheses indicate number of alleles observed. m, males; f, females. e observed heterozygosity. for timp , calculated using female alleles only. f comparison of allele frequencies between control and aaa groups using fischer’s exact test. no significant differences in the frequencies of the nt polymorphism were found between controls and aaa patients. the frequencies between the two fe- Žmale groups were, however, significantly different p .s . for the nt polymorphism. Žthe timp gene contains five exons hammani et .al., , and the sequence variants are in exons and . the timp sequence variants were polymor- phisms with minor allele frequencies of . and Ž . . for the nt and nt , respectively table , with no significant differences between the controls and the aaa group with nt polymorphism. the frequencies of nt polymorphism were different between the control and aaa groups in males. in further analyses with additional us control individ- uals, and by dividing the groups according to ethnic origin, the frequencies remained significantly differ- Ž .ent in males table . among the us males, the difference between controls and aaa patients was Ž .even more significant table . in summary, no mutations were found in the timp and timp genes in aneurysm patients. the differ- ences in allele frequencies of nt timp polymor- phism between the control and aaa groups are inter- esting preliminary findings that need further follow-up with larger groups and carefully selected control groups for each ethnic group. it is possible that a mutation in the timp or timp gene contributes to table comparison of the allele frequencies for timp nt polymorphism a bethinicity controls unrelated aaa patients c c c c dm f m f p-value Ž . Ž . Ž . Ž .us g: . . . . m: . Ž . Ž . Ž . Ž .a: . . . . f: . m q f: . eŽ . Ž .others g: . . m: . eŽ . Ž .a: . . f: . Ž . Ž . Ž . Ž .total g: . . . . m: . Ž . Ž . Ž . Ž .a: . . . . f: . m q f: . a eighty-two us american control individuals, females and males. b for details, see table . c numbers in parentheses indicate number of alleles observed. m, males, f, females. d comparison of allele frequencies between control and aaa groups using fisher’s exact test. e comparison across populations may not be valid due to allele frequency differences; however, it is evident that adding the non-us patients to the total does not inflate the p-values; rather, it is conservative. ( )x. wang et al. r matrix biology ] the disease process in patients with aneurysms. such mutations could be either mutations in the promoter sequence or large-scale rearrangements in the genome, not easily detected by direct sequencing of rt-pcr products. the polymorphisms will also be useful for genetic analyses in other diseases. for example timp is a candidate gene for autosomal-dominant retinitis pig- Ž .mentosa bardien et al., , and altered activities Žhave been reported in tumor tissues bramhall et al., . . acknowledgements this work was supported by grants from the natio- Ž .nal institutes of health hl and the american heart association, michigan affiliate, and by funds from the wayne state university school of medicine. references bardien, s., ebenezer, n., greenberg, j., et al., . an eighth locus for autosomal dominant retinitis pigmentosa is linked to chromosome q. hum. mol. genet. , ] . bramhall, s.r., neoptolemos, j.p., stamp, g.w., lemoine, n.r., . imbalance of expression of matrix metalloproteinases Ž .mmps and tissue inhibitors of the matrix metalloproteinases Ž .timps in human pancreatic carcinoma. j. pathol. , ] . docherty, a.j.p., lyons, a., smith, b.j., wright, e.m., stephens, p.e., harris, t.j.r., . sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating ac- Ž .tivity. nature london , ] . hammani, k., blakis, a., morsette, d., et al., . structure and characterization of the human tissue inhibitor of metallopro- teinases- gene. j. biol. chem. , ] . kuivaniemi, h., prokop, d.j., wu, y., et al., . exclusion of Ž .mutations in the gene for type iii collagen col a as a common cause of intracranial aneurysms or cervical artery dis- sections by sequence analysis of the coding sequences of type iii collagen from unrelated patients. neurology , ] . olson, t.m., hirohata, s., ye, j., leco, k., seldin, m.f., apte, s.s., . cloning of the tissue inhibitor of metalloproteinase- gene Ž .timp and localization of the timp and timp genes to human chromosomes p and mouse chromosome , respec- tively. genomics , ] . ronkainen, a., hernesniemi, j., puranen, m., et al., . familial intracranial aneurysms. lancet , ] . stetler-stevenson, w.g., brown, p.d., onisto, m., levy, a.t., li- otta, l.a., . tissue inhibitor of metalloproteinases- Ž .timp mrna expression in tumor cell lines and human tumor tissues. j. biol. chem. , ] . tamarina, n.a., mcmillan, w.d., shively, v.p., pearce, w.h., . expression of matrix metalloproteinases and their inhibitors in aneurysms and normal aorta. surgery , ] . tilson, m.d., reilly, j.m., brophy, c.m., webster, e.l., barnett, t.r., . expression and sequence of the gene for tissue inhibitor of metalloproteinases in patients with abdominal aortic aneurysms. j. vasc. surg. , ] . tromp, g., wu, y., prockop, d.j., et al., . sequencing of cdna from unrelated patients reveals that mutations in the triple- helical domain of type iii procollagen are an infrequent cause of aortic aneurysms. j. clin. invest. , ] . verloes, a., sakalihasan, n., limet, r., koulischer, l., . ge- netic aspects of abdominal aortic aneurysms. ann. n.y. acad. sci. , ] . estimate of the relative risk of succinylcholine for triggering malignant hyperthermia | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /ane. b e f e b corpus id: estimate of the relative risk of succinylcholine for triggering malignant hyperthermia @article{dexter estimateot, title={estimate of the relative risk of succinylcholine for triggering malignant hyperthermia}, author={f. dexter and r. epstein and r. wachtel and h. rosenberg}, journal={anesthesia & analgesia}, year={ }, volume={ }, pages={ – } } 	f. dexter, r. epstein, + author h. rosenberg 	published 	medicine 	anesthesia & analgesia background:facilities with volatile anesthetic agents stock dantrolene for the treatment of malignant hyperthermia (mh). the availability of dantrolene at these facilities satisfies cost-utility norms even for sites with as few as anesthetic per workday, based on the overall incidence of mh per anesthetic. we considered the stocking of dantrolene at facilities with succinylcholine alone (i.e., where volatile anesthetics are not available), by using registry data and estimates of the frequency… expand view on wolters kluwer ncbi.nlm.nih.gov save to library create alert cite launch research feed share this paper citationsbackground citations view all topics from this paper 	succinylcholine 	dantrolene 	malignant hyperpyrexia due to anesthesia 	fever 	estimated 	registries 	operating room 	cns disorder 	anesthetics 	anesthesiology 	scientific publication 	assay of volatiles citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by 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published cases 	k. p. strazis, a. fox 	medicine 	anesthesia and analgesia 	 	 save alert research feed incidence of malignant hyperthermia reactions in , patients undergoing muscle biopsy. 	a. carr, j. lerman, m. cunliffe, m. mcleod, b. britt 	medicine 	canadian journal of anaesthesia = journal canadien d'anesthesie 	 	 save alert research feed special article: creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities. 	m. g. larach, s. j. dirksen, + authors c. b. watson 	medicine 	anesthesia and analgesia 	 	 save alert research feed succinylcholine use in adult anesthesia - a multinational questionnaire survey. 	n. karanović, m. carev, + authors zoran dogas 	medicine 	collegium antropologicum 	 	 save alert research feed clinical presentation, treatment, and complications of malignant hyperthermia in north america from to 	m. g. larach, g. gronert, g. allen, b. brandom, e. lehman 	medicine 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involved in procuring a printer, but new print competition did bring substantial changes to the relationship among the printer, the government, and readers. broader civic discourse spurred by commercial competition helped to develop new revolution- ary ideals, including the concept of a constitutional protection for a free press, which ultimately was expressed in the first amendment. roger p. mellen is an assistant professor in the department of journalism and mass communications at new mexico state uni- versity. this article will be appearing in an ed- ited form as a chapter in the origins of a free press in prerevolutionary virginia: creating a culture of political dissent, which will be published soon by the edwin mellen press. thomas jefferson has long been credited with bringing a printer to virginia in , introducing print competition to a colony that until then had only one printing press, which was controlled by the royal government. “until the begin- ning of our revolutionary dispute, we had but one press,” he said, “and that having the whole business of the government, and no competitor for public favor, nothing disagreeable to the governor could be got into it. we procured [william] rind to come from maryland to publish a free paper.” thus, just as parliament’s hated stamp act threatened the printers’ very livelihood, a new printer was encouraged to open a second shop in williamsburg, bringing competition to that field and a second newspaper to virginia for the first time. this was an important watershed for the culture and the government of the colony because it signified a shift in the power structure: control of public messages began to relocate from the royal government to the consumer marketplace. this was a transformation that had a major impact on civic discourse in the colony. despite such significance, the reasons behind such a change and the relevance of it have often been misunderstood. it has widely been accepted that jefferson was responsible for bringing such print competition to virginia and direct “patriot” influence was behind a freer and more open press. this jefferson connection has been repeated continually by histori- ans as has early print historian isaiah thomas’ contention that jef- ferson confirmed this in a letter written to him. this article shows that both these assertions are apparently erroneous and attempts to reach a better understanding of why these claims were originally made, how they were constantly repeated, and the larger signifi- cance of the motivations behind and relevance of such a change. print competition came later to virginia than it did to the northern and mid-atlantic colonies. in virginia, this altered the relationships among printers, the government, and the readers. this study finds that as the role of print expanded and evolved, it had substantial long-term influence on civic discourse, culture, and the radicalization of politics. each of the two printers responded to market pressure and the realities of new competition, both be- coming less an official mouthpiece and more a voice of dissent, which enabled the transition from a deferential society to one that openly questioned the government. as the importance of an open- thomas jefferson and the origins of newspaper competition in pre-revolutionary virginia journalism history : (fall ) and critical press became more evident to residents, the practice of civic discourse became visible in the public prints. this research will discuss these changes and how they influenced the press in the important colony of virginia on the verge of the revolution. thomas was intimately involved in the world of print and printers in the early revolutionary period in america and has left later historians with important details as well as misconceptions. he was the first writer to seriously look at the history of printing in the united states, and he also was an early printer and the founder of the american antiquarian society. in , he published the history of printing in america, which contained considerable re- search plus his intimate knowledge of the early days of printing in the colonies and the republic. as susan macall allen not- ed in her dissertation on the stamp act and colonial printers, thomas’ eye- witness account provided invaluable de- tails regarding american printing, and, “its accuracy has been trusted by schol- ars, and it is often cited as the authorita- tive source.” she also wrote his work “has occasional errors of fact that subsequent scholars have pointed out.” his chapters on virginia and maryland were much shorter than his entry on massachusetts, which was not only where he lived and worked but was where printing in brit- ish america originated. he observed, “as there was but one newspaper published in virginia in ; and but one press in the province, which was judged to have an undue bias from the officers of gov- ernment, a number of gentlemen who were desirous of having a free and unin- fluenced gazette” encouraged a second printer, william rind, to come to wil- liamsburg. he added that a letter to him from jefferson confirmed this because he said he was involved in procuring rind. other historians have repeated these claims endlessly. arthur schlesinger, the elder, noted in that the stamp act was a burden largely for those who were most capable of stir- ring up resistance because they were the most vocal and influential members of society—clergy, lawyers, merchants, and printers. ev- ery newspaper had to carry a minimum of a halfpenny duty with a two-shilling tax for each advertisement. worse still, the stamp act required importing expensive paper instead of using locally pro- duced material. thus, newspapers were changed by this new tax, he suggested, from merely transmitters of information to opinion makers. he quoted from david ramsay’s book, the history of the american revolution, which said printers, who generally favored liberty but were more interested in profits, universally opposed the tax: “a stamp duty, which openly invaded the first, and threatened a great diminution of the last, provoked their united zealous op- position.” while schlesinger repeated thomas’ claims, he also sug- gested the new, second printer in virginia was not influenced by the governor, and in the years ahead, both newspapers supported the patriot cause. in , historian stephen botein concluded printers were more businessmen, or “‘meer’ mechanics,” than revolutionaries, and he wrote the stamp act profoundly changed their business. printers’ normal, cautious tendencies to stay out of controversies were overridden by their financial interest. the standard viewpoint had been that a free press meant presenting both sides while staying out of extreme disputes that might have alienated any customer. this new tax not only threatened their livelihood but political writing be- came a hot seller. most printers, he suggested, abandoned neutrality and chose sides, the majority opting for the patriots’ position. with printing limited to one government-sanctioned press, there could be no real press freedom. as book historian hugh amory noted in , printing was reflective of the power struc- ture of the colony within which it existed. in puritan new eng- land, about which he was writing, printing was initially licensed and sanctioned, serving rather than chal- lenging the power structure. it was the same when the press first came to virgin- ia. by the s, the pressures of trade and merchandising altered the function of a press from merely a duplicator of of- ficial governmental and religious works to one of commercial output. with a second press and consumer pressure, the character of printing and the idea of a “free press” was transformed because a wider range of content freed print to function as a medium for the “diffusion of useful knowledge.” t.h. breen theo- rized in that a rising marketplace and a consumer revolution was an im- portant preface to political change, and newspapers, as part of this increased consumption, helped expand civic dis- course. as historian jack greene wrote in his exploration of the shifting of power in the southern colonies, govern- ment support for a printer was crucial in such colonies as virginia before a strong, commercial economy developed. he sug- gested the royal governor had a great deal of control over what was printed prior to , and he repeated the claim that jefferson was involved in changing that situation. more focused on virginia and its printers, laurie godfrey wrote in that the two virginia newspapers had an “authori- tarian” stance throughout this period, not shifting to a more “liber- tarian” revolutionary ideology until three to six months before the revolution. she concluded this ideological shift in the press hap- pened later in virginia than in the middle and northern colonies, suggesting this was because of the colony’s extremely close trade and ideological ties to england and a social structure in which the plantation gentry were considered the natural rulers. her analysis utilized fred s. siebert, theodore peterson, and wilbur schramm’s four theories of the press and downplayed some obvious shifts in the presses’ viewpoints in the s. however, she did get correct many of the important details that had eluded more prominent historians, and she observed that the character of the press in vir- ginia changed after the mid-eighteenth century. from the beginning, the government in colonial virginia tightly controlled the press, and there was no real freedom of expression. from governor william berkeley’s warning to his superiors, the commissioners of trade and plantations in london, about a troublesome press in , to governor thomas culpeper’s expulsion of a printing press for being unlicensed in “in , historian stephen botein concluded printers were more businessmen, or “‘meer’ mechanics,” than revolutionaries, and he wrote the stamp act profoundly changed their business. printers’ normal, cautious tendencies to stay out of controversies were overridden by their financial interest.” journalism history : (fall ) , to the eventual welcoming by the royal government of a press in , government income and control were the key in- fluences. thus, the press in colonial virginia began as a royally sanctioned and controlled institution, which was paid for and li- censed by the government in power. as both amory and richard d. brown noted, knowledge was power, and in the early colonial period, information was in the hands of governmental and ecclesi- astic authorities. not until a second printer existed, and commer- cial competition began, could there be a free press. the first printer, william parks, began his newspaper publish- ing with an overt recognition of the limits of press freedom and announced a need to defer to those in power. the first issue of the virginia gazette in had an explanation of this in the “printer’s introduction;” by the liberty of the press, we are not to understand any licentious freedom, to revile our governors and magistrates; to traduce the establish’d laws and religion of our country; or any attempts to weaken and subvert by opprobrious writings that sacred respect and veneration which ought always to be maintain’d for authority, and persons in authority such deference was necessary for a printer in early virginia. without any large urban community or a strong commercial econ- omy, all of the southern colonial printers before counted on a government salary as part of their support, but it was not always clear who in the government controlled the printer. the house of burgesses in virginia voted on the printer’s salary, but it also had to be approved by the royal governor and his council. greene suggested that despite the lower house’s control of money, the gov- ernor was generally able to exert the most censorship, at least until the s. however, former governor alexander spotswood wrote printer parks in , complaining that it was the burgesses who maintained a tight control over the content of printed matter. he prefaced what eventually made it into print: “if his worship will permit you to publish in your news paper, this answer.” this was a reference to john randolph, speaker of the house of burgesses and treasurer for the colony, with whom spotswood was having an open dispute over the spending of public money dating back to his administration. as greene observed, the assembly struggled against the royal governor’s authority, and control of the press was an important part of that power structure. this control over the content of the newspaper by the gov- ernor again became apparent in , when a virginia resident turned to the newspaper in the neighboring colony of maryland to complain, “the press in this colony [virginia], either through particular inclination, or some other cogent bias, in the proprietor of it [william hunter, parks’ successor], is, in many instances, shut against us.” the virginia governor had accused the burgesses of neglecting the safety of the colony by not taking any action against french aggression. to counter that accusation publicly, the bur- gesses had to turn to the maryland gazette in annapolis. in con- trast, the few issues of the virginia gazette of that period still ex- tant show only mutual respect and deference between the burgesses and the governor. the williamsburg press appears to have been largely under the control of the governor at this point. as botein suggested, the colonial printer could little afford to offend power- ful individuals or groups with what he printed and often avoided controversy altogether. few issues of the newspaper published by hunter’s successor, joseph royle, still exist, but those that do were mostly filled with literary essays, news from europe, and debates over social practices. for example, a recently recovered rare issue from began with a letter declaring that oaths were sworn all too often without con- sidering the responsibility of making such a promise. two essays took a large portion of column space; one describing a conversa- tion between a master and his dog while the other was a farmer’s dream that led him to gold. both appear to have been an attempt to instill strong moral values in readers. several short items talked about new crops being raised in south carolina, clashes with the indians and the french in other colonies, and scientific advances to measure longitude. finally, future president george washington ran an advertisement in an attempt to find the owner of two run- away horses discovered on his plantation. little in this or other extant issues demonstrated a willingness by the printer to tackle controversial issues. accusations of control by the burgesses, rather than the gov- ernor, again surfaced in one dispute. the controversy over pay for the official church of england ministers in the mid- s brought accusations of censorship by the virginia printer. reverend john camm was forced to turn to the maryland press to print a pam- phlet in answer to comments by two burgesses that had been print- ed in virginia. apparently, printer royle was afraid of offending burgesses who were satirized in camm’s response: [i]f it should displease, would be taken as ill by this assembly, as if pointed directly at them; i am far from saying it would give them offence, nay, i think otherwise; however as there is a possibility in the case, it will be most prudent in me not to risk forfeiting their good-will upon such an issue, as i cannot but own myself a dependent upon the house of burgesses, and the public in general. i therefore return you your pamphlet. royle appeared to be more timid than overtly controlled. while camm argued that he should be able to use the press to tell his side of a story that had already been printed, he recognized thomas jefferson journalism history : (fall ) the printer’s editorial right: “i acknowledge as much prudence as you please, in the rule by which your press is conducted.” this view of the press demonstrated a theory of the press that it was not so overtly controlled by the government but instead the pri- vate printer had some discretion, which he needed to exercise with care. offending either the governor or the burgesses could threaten his government-printing contract, an important part of a printer’s income, which had to be approved by all branches of the colonial government. in , david rawson suggested that for a brief time, the virginia gazette opened its pages to increased local controversy, eventually leading to a reassertion of control by the governor just prior to the stamp act. printer hunter was ill and spent consider- able time out of the colony between and , apparently leaving his assistant, john stretch, in charge of his print shop, the newspaper, and the post office. according to a local resident who wrote hunter upon his return, the newspaper had a slightly more lively, local debate in that interim period, only to become more boring after hunter’s return. “tim pastime” sent a thirty-six page letter to the printer, addressing him as “demipostmaster, printer and linnen draper” (the latter appears to be a bit of cockney rhyming slang, perhaps insulting the newspaper business, as in “linen draper/newspaper”). the pseudonymous author suggested that because stretch, “that flower of beauty, and cream of all proportion, has left this colony . . . your publications are but sometimes little entertaining and, at every other time extremely dull” (from the context, the seemingly positive description of stretch was sarcasm). while presumably not printed in its entirety in the gazette, the letter recommended hanging it on a peg in the printing office where visitors could read it, suggesting that had been done before with other letters. this offers an interesting image of the printing office as a busy center of discourse and information beyond what printed material and post office business would offer. local residents stopped by, read letters not yet printed, and discussed the latest news. according to rawson, stretch was in charge of the newspaper for more than three years, and it offered more lively political debate under his stewardship. he suggested this resulted in governmental pressure on hunter and forced the reassertion of gubernatorial control over the newspaper. this is largely conjectural because there are few ex- tant copies of the virginia gazette from this time period to confirm the content biases suggested by this single letter. it was such control by the royal governors, however, that con-stantly frustrated more radical virginians and eventually led to action. in october , the maryland gazette printed a letter written anonymously to the virginia printer but never published in his paper. it accused williamsburg printer royle of deceiving read- ers and yielding to royal pressures. the annapolis newspaper pub- lished the letter with an added note by the author saying virginia did not have a free press “as the only one we have here, is totally engrossed for the vile purpose of ministerial craft: i must . . . apply to you . . . [b]old and honest assertor of the cause of liberty.” this insinuated not just gubernatorial control of the williamsburg newspaper but implicit bias in favor of corrupt ministers in eng- land. the more radical political element in virginia turned increas- ingly to the maryland press for distribution of its ideas, and this partly fulfilled its goals since the maryland paper had a substantial number of readers in northern virginia. in a virginia ga- zette, a “man of principle” wrote that while royle was the only vir- ginia printer, between and the press “was not renowned for its freedom,” and he alleged the governor was allowed to read the newspaper before it was circulated and actually censored it: if a counselor or a burgess was only squinted at in any thing sent to the press before this period, it was wither too low or too-------but if a governour was------ o horrible!—has it not been said that mr. royle owned a private license, and that a paper was constantly carried to a certain house in palace street [the governor’s palace] to be inspected before it could be seen by the publick? the author of this piece claimed royle acted as though he was dependent upon a license to print, and the governor was checking everything before it could be published. this view was of a press tightly controlled by the royal governor and described a press that was not suited to the needs of political allies (later referred to as the “patriots”) attempting to oppose official british colonial taxation policies. such a tightly controlled government press was a chal- lenge to the evolving concept of civic discourse and a free press. writers were constantly forced to turn to presses elsewhere to print anything critical of the british government or the local governor, and readers also had to look elsewhere for broader discourse. such censorship of the local press also, of course, could have been the result of several other reasons: the printer might have been more timid than others, his personal loyalties may have been closer to the british ministry, and it was always easier to print matter critical of one government in another jurisdiction, where the local gov- ernment was not the focus. whatever the reasons, local patriots found the printer too conservative to allow them to express their dissenting opinions. while it was often inferred that royal governor francis fau- quier kept tight control over the output of the press, he was popu- lar. a young jefferson, often a guest at the governor’s dinner table, later referred to him as “the ablest man who ever filled the chair of government in williamsburg.” fauquier followed an unpopular governor, robert dinwiddie, and was quick to form partnerships with leaders in the house of burgesses. in contrast to his prede- cessor, he had strong alliances with local leaders, including power- ful house speaker and colony treasurer john robinson. the colo- nists appreciated that fauquier sometimes did not obey instructions from his superiors in london and considered him amiable, just, and “moderate in power.” it is clear from the correspondence of fauquier to his supervisors at the board of trade that he closely monitored what was printed in the newspapers, often including copies of the virginia gazette and occasionally the maryland ga- zette in his letters to london. in a letter, fauquier noted the stamp act forced the shutting down of the virginia newspaper, and new print competition was on the way: from the first of november we have been without any newspaper till very lately. the late printer to the colony is dead, and as the press was then thought to be too complaisant to me, some of the hot bur- gesses invited a printer from maryland, upon which the foreman to the late printer, who is also a candidate for the place, has taken up the news paper again in order to make interest with the burgesses. the governor also noted that a second, competitive newspa- per was about to begin and would be in addition to the original virginia gazette, which was being published by alexander purdie, the foreman for the late royle. he suggested that it was the work of some of the more radical burgesses, who were unhappy with the old press because it was too willing to please the royal authority in the colony. as colonial opposition to british taxation policies journalism history : (fall ) gained ground, virginia readers who were not content with the local printer hoped that a new, competitive newspaper would allow for a more critical civic discourse. historians have generally agreed who was involved in this somewhat rebellious move to bring in an opposition printer. thomas claimed that jefferson wrote him: “until the beginning of our revolutionary dispute, we had but one press, and that having the whole business of the government, and no competitor for public favor, nothing disagreeable to the governor could be got into it. we procured rind to come from maryland to publish a free paper.” this claim of jefferson’s involvement has been repeated in many books, including those by schle- singer, philip davidson, sidney kobre, greene, and an anthology edited by ber- nard bailyn. numerous other works also have included the assertion that the former president wrote about this spe- cifically in a letter to thomas. in her dissertation, godfrey said it was extremely unlikely that jefferson was that deeply involved. she noted that at the age of twenty-two, he was likely to be merely a bystander in procuring a printer, and the widely repeated claim actually came from a letter that he wrote to someone else. she did not speculate about why he included himself by using the term “we” and why thomas might have claimed jefferson wrote that in a letter to him, nor did she recognize the significance of print competition on the ideological bent of the newspapers. because it was a minor point not central to her larger work, the argument was not completely researched and developed, and few have noticed her point. a deeper examination of the evidence confirms her doubts of the claim that jefferson was directly involved and that he wrote directly to thomas about it. this raises questions about memory and historical research, and it also helps explain the origins of print competition in the colony. when the provenance of the jefferson claim was cited, it was either directly from thomas’ influential history of printing in america or a secondary or tertiary source that took it from there. thomas wrote “a number of gentlemen who were desirous of having a free and uninfluenced gazette, gave an invitation to rind,” and he foot- noted it: “this fact is corroborated by the following extract of a letter to the author from thomas jefferson, late president of the united states, dated july, .” what godfrey and other researchers failed to note is that only in the second edition of his book did thomas claim jefferson wrote directly to him. the first edition merely noted jefferson wrote this in a letter, and the recipient was unidentified: “this fact is corrobo- rated by the following extract of a letter from thomas jefferson, esq. late president of the united states, dated july .” later editions of history of printing in america claim jefferson wrote the letter specifically to thomas, but the letter does not exist in either thomas’ extensive papers nor in jefferson’s papers, despite the fact that the former president kept copies of virtually all of his corre- spondence in this period. jefferson did write those words about the press being overly influenced by the governor and the procure- ment of rind, with only minor discrepancies of capitalization and abbreviation, to william w. hening the year before thomas’ book was first published. it is also known that hening wrote to thomas about another matter within a year of jefferson’s letter. in a copy of the first edition of history of printing in america that thomas notated for a revised second edition, he wrote “to the author,” in- dicating the former president’s letter was to him, and that is how it ended up in the subsequent edition of the book. it seems prob- able that either thomas stretched the truth to make the point that a former president of the united states corresponded with him, or that time and old age had distorted his memory (he was at least sixty-one years old and possibly as old as eighty-three, when he made that notation). what is remarkable is that this claim, rea- sonably easy to double-check, has been passed on by other historians for more than years. furthermore, the suggestion that jefferson was a key player in the recruit- ment of the new printer does not stand up. as godfrey noted, jefferson was only twenty-two years old and not yet a mem- ber of the house of burgesses. before rind would have left his lucrative part- nership in annapolis, it would have been necessary to offer him either cash or a promise of becoming the official printer of the colony, which would guarantee him an income. according to jefferson’s autobiographical draft, he was a mere law student and not yet a practicing lawyer in . however, he apparently later had some type of relationship with rind’s competitor, printer purdie. while he was writing the declaration of independence at the continental congress in philadelphia in , a friend wrote to him that purdie promised to pack up jef- ferson’s books to be shipped to him. thus, it appears that when jefferson wrote “we procured rind,” he simply meant to include himself among his political associates in williamsburg, who were later identified as patriots, including some who were senior to him and in a better position to do the actual procuring. it is reasonable to conclude that some of the “hot burgesses” to whom the governor referred, and very possibly the lee family specifically, had a greater involvement than jefferson in recruiting a new printer. when rind moved to williamsburg, he lived in and worked out of a brick house on duke of gloucester street that be- longed to philip ludwell iii, the uncle of the lee brothers: thomas ludwell, richard henry, francis lightfoot, william, and arthur. richard henry lee and arthur lee contributed many essays to rind’s newspapers, and in , william lee inherited “the man- sion” in which rind lived. edmund randolph, who was a young contemporary in , described a new group of burgesses at the time of the stamp act, who likely were the governor’s “hot burgess- es.” he suggested that the new “upper counties,” farther from the old power base of the james river, were supplying burgesses who no longer displayed the traditional “fortune, rank, and perhaps fashion,” and he mentioned specifically patrick henry, john flem- ing, and george johnston. later randolph lauded the oratory and patriotism of richard henry lee, whom godfrey included in the group. these men supported henry’s resolves against the stamp act and later became leading virginia supporters of the american revolution. the eventual selection of rind as the official “public printer” of the virginia colony was a disputed one. in november , “the suggestion that jefferson was a key player in the recruitment of the new printer does not stand up. as laurie godfrey noted, jefferson was only twenty-two years old and not yet a member of the house of burgesses.” journalism history : (fall ) four printers, or groups of printers, petitioned the burgesses for the appointment. purdie and john dixon were the successors to the former public printer, the deceased royle, and were a likely lead- ing candidate. however, their combined petition received only ten votes in the house of burgesses, while robert miller had seventeen votes, william stark got nineteen votes, and rind had a majority with fifty-three votes. the governor and his council later agreed, despite the fact that the royle/purdie and dixon press had a his- tory of subservience, and rind was paid £ a year for his official printing. it is clear that someone with a great deal of influence in the government—which jefferson did not yet have—lobbied hard to get rind this appointment. rind’s arrival and election as official printer meant there was now competition for local printing in virginia, and that had an immense impact on the printed material available in the colony. two printing houses now operated in williamsburg. rind imme- diately undercut his rivals’ newspaper sales price, from shillings for a yearly subscription to shillings, pence. the new paper was originally called, rind’s virginia gazette, but soon the printer removed his name from the title, leaving the colony with two news- papers with the exact same name. the first issue of rind’s paper boldly stated his intent to run “a well conducted news-paper,” which he noted was essential just then, “especially at a crisis, which makes a quick circulation of intelligence peculiarly interesting to all the american colonies.” the only extant copy of this issue has an interesting editorial insertion penned in, apparently by the original owner, noting this was the first well conducted news- paper to be printed in the colony: “and the first that has ever been established in this province.” while the writer is unknown, the comment demonstrates the hope of virginia residents of to have a better-run newspaper that would be freer to publish criti- cism of the government. rind claimed his newspaper would be, “open to all parties, but influenced by none.” the original virginia gazette was quick to join the competitive fray, matching the new competitor’s moves and gaining for itself a reputation as a “free press.” now published by purdie, who was soon joined by dixon, they quickly matched the lower price and announced a new, open press policy before rind’s newspaper even came out: “[m]y press shall be as free as any gentleman can wish or desire; that is, as free as any publick press upon the continent.” a few months later, two writers arguing opposing sides of an issue agreed on one thing: the press run by purdie and dixon was now well run. such freedom of the press “is [a] matter of rejoicing,” and “you, sir, have behaved yourself as the director of a press ought to do.” however, these writers’ praise was for both presses. a notice in purdie’s paper acknowledged that only with real competition, only with at least two newspapers, could a free flow of information be sustained. with the loss of the government subsidy, purdie was in danger of being forced out of business, and he pleaded with the “friends of liberty” to help keep his newspaper and print shop in business: “[w]e have reason to believe it the almost universal desire that there should be two presses maintained, for the security of freedom to one or both.” they requested their readers to con- tinue their subscriptions with the original virginia gazette. it was believed that only with two presses, only with competition, could the press be free. for a short period of time, rind included a claim that his was the official newspaper, demonstrating that this was a confus- ing transition period for the press. the masthead of his version of the virginia gazette, beginning early in , included the claim, “published by authority,” which was just months after his appoint- ment as the “public printer.” this phrase had often been used in english papers since the days of licensing to indicate an offi- cial government imprint, and it was on the masthead of the first regularly published british-american newspaper, john campbell’s boston news-letter in , but it had never before been used in virginia. in a letter published in the other virginia gazette, “a man of principle” wrote questioning the “authority” claim: “several of your readers are very solicitous to know what authority you have for publishing a paper now, more than formerly. some, i suppose of the most intelligent, allege that because you have had the good fortune (for certainly you cannot ascribe it to anything else) to be chosen publick printer, that gives you an exclusive privilege.” the author pointed out that anyone who wished could publish a newspaper and call it the virginia gazette. this demonstrated the confusion of the period as printers shifted from functioning as official government printers to public businesses. while rind still had a lucrative government contract, the profit center had shifted to where satisfying the public was one key to financial success, and by july, he had dropped from his masthead the claim that he pub- lished by authority. thus, the newspaper in virginia had moved from a quasi-governmental source to one where public opinion and marketplace competition was paramount. the stamp act controversy offered a contrast between the earlier restricted press with the competitive press exercis-ing greater freedom. when the british tax enraged the colonists, royle failed to print the stamp act resolves, which was passed just down the street by the virginia house of burgesses al- though other newspapers across the colonies published this heated reaction to parliament. instead, his paper called on the assembly to help enforce the tax and warned of “the consequences if you should suffer a confirmed disobedience of this act of parliament to take place.” this was quite different from reports published in the neighboring colony of maryland and also in sharp contrast to what was printed in both versions of the virginia gazette in the next year. the original virginia gazette, now published by purdie, contained an item that referred to the stamp act as a flagrant viola- tion of the british constitution and called the idea of virtual rep- resentation in parliament a “despicable subterfuge.” competitor rind’s newspaper ran two letters from the radical boston gazette, “letters from a farmer” and “the monitor’s letters,” which was a virginia-based attack on the stamp act. the latter admonished britain for attempting to enslave the american colonists, suggest- ing “that though we are a weak people, yet the principles of liberty fully infused into us, will render it impossible to enslave us.” the content in the pages of the two gazettes reflected a sub- stantial change. with considerable coverage of the stamp act crisis and later taxation issues, neither newspaper displayed the former tendency to buckle under royal pressure. the two gazettes ran more articles critical of the colonial government, parliament, and the british ministry, including stories that would not have been printed a few years earlier. each paper also covered the scandal fol- lowing the may death of the powerful virginia treasurer and speaker of the house of burgesses, john robinson, who it was dis- covered had illegally loaned , pounds of public money. one planter complained that “very large sums of the public money have been misapplied” and recommended that in the future, the offices of treasurer and house speaker be held by separate individuals. he noted that his participation in this civic debate “would not have been in my power without the benefit of a free press.” journalism history : (fall ) a related incident displayed the new power to criticize the elites in the public prints. both newspapers published letters ques- tioning the actions of several of the colony’s chief justices following the public killing of robert routlidge by colonel john chiswell in june . according to a detailed newspaper description, an angered but sober chiswell stabbed his unarmed and drunk friend through the heart with his sword. both gazettes eventually ran articles not just about the slaying but about the subsequent actions of the accused killer, including the fact that three of the highest judges in virginia had released him from jail. an anonymous letter noted the original court refused to release the accused murderer on bail and remarked that chiswell was a well-connected member of the colony’s elite (in fact, probably one of those to whom robinson had lent public money). this article questioned the legality of the judges’ release of the accused: “[b]efore he was delivered to the keeper of the publick prison, the judges of the general court, out of sessions, took him [chiswell] from the sheriff who conveyed him from cum- berland, and admitted him to bail, with- out seeing the record of his examination in the county or examining any of the witnesses against him.” another letter writer, who called himself “dikelphilos,” suggested that because of his social stand- ing, “the murderer was treated with in- dulgence and partiality inconsistent with our constitution, and destructive of our security and privileges.” the fact that both newspapers made public the details of this controversy, and included critical comments regarding the actions of the colony’s elite, was something that would not have happened a few decades earlier. thus, by , new commercial competition had led to less gov-ernment control and a freer fo- rum for civic discourse in both virginia newspapers. no longer was there only one press in virginia, and no longer could the governor control the press. power was shift- ing from the governor to the burgesses, and newer, more radical burgesses were gaining in influence. politics in virginia was frac- tionalizing, and soon that was reflected in the media of the time. after a second press began printing in the colony, leading politi- cal elites, the parliament, and the british ministry were subject to criticism on the pages of the virginia newspapers. as carl briden- baugh wrote in his essay about violence in virginia, purdie “completely revised the former policy of the newspaper” and from then on, the residents of virginia were “served up . . . what they had never before experienced, the sensations and sensationalism of a free press.” he suggested that the new freedom of the press brought excesses and sensationalism, but the newspapers also now put the feet of the wealthy to the fire. an anonymous writer wrote of the changed newspapers in mock-biblical fashion: “party shall menace party, and dunce shall enflame dunce, and the gazettes of purdie and of rind shall contain wonders . . . and much paper [will] be wasted, and words shall lose their meaning.” obviously, not everyone was happy with the political controversies now being openly publicized in the newspapers nor with the less sophisticated tone of the letter writers. both newspapers appeared to be directing their content to the same, somewhat middling-to-elite audience with the same political bias. one contributor noted that what was now being printed in the two papers no longer had the high standards of the past. “dikel- phios” requested that potential authors should examine carefully their abilities, and “they would not usher into the world sentiments which are neither useful nor entertaining.” this apparently was an expression of dissatisfaction with the contributions to both papers from those further down the social scale. there was no longer an obvious elite bias to the papers’ content; there were no more latin verses, fewer classical references, and more common pseudonyms, such as “a farmer,” or “tit for tat.” sales and satisfied custom- ers had become more important to the printer than pleasing the governor. as botein wrote, the business phi- losophy of the printers had to change with the times, and it was now political material with a patriot slant that was the best seller. newspaper circulation in the colonies also had increased, and political writings became popular. both print- ers featured a patriot viewpoint in their papers with no noticeable difference in the bias or content, including the adver- tisements. as godfrey concluded, “rind and purdie . . . provided the same voice for the community.” one might add that the readers of the two newspapers also appeared to be the same, geographically and economically. what she did not rec- ognize was that this was not only because of royle’s death or the direct influence of a new political force. it was also because of the new commercial pressures, requir- ing both printers to respond to the needs of the customers. thus, the myth of jefferson corre- sponding with thomas, confirming that he invited rind to bring his printing press to virginia, offers a patent example of question- able memory, misinterpretation, and a weak historical method. human recall is not as precise as is sometimes presumed, and lan- guage is often ambiguous. thomas falsely claimed the former presi- dent wrote to him regarding the virginia printer. however, this did not crop up until later in thomas’ life and only then in his note for the second edition of his book. old age may well have begun to cloud his memory, or it may have been a case of false bragga- docio that a former president had corresponded with him. jeffer- son’s actual statement, written in a letter to hening rather than to thomas, was misinterpreted by thomas and following generations of historians. “we procured rind” did not mean that jefferson was a leading actor as countless historians have inferred from the line. as a twenty-two-year-old student, he did not have the means to arrange rind’s election to the public printer post. he noted in his own autobiographical draft that at an incident during that same time (the passing of the stamp act resolves in williamsburg) he was merely a young observer: “i was yet a student of law in wmsbg. i attended the debate however at the door of the lobby of “by , new commercial competition had led to less government control and a freer forum for civic discourse in both virginia newspapers. no longer was there only one press in virginia, and no longer could the governor control the press. power was shifting from the governor to the burgesses, and newer, more radical burgesses were gaining in influence.” journalism history : (fall ) the h. of burgesses.” it is more likely “we” either meant “we, the people of virginia,” or was a reference to the group of more radical politicians in the colony who later supported the patriot cause. it was a group with whom jefferson was to eventually take a leader- ship role. for nearly years, authors have repeated thomas’ story— even elaborated on it—apparently without confirming its verac- ity. davidson, in his important work, propaganda and the american revolution: - , cited no source for his statement that “thomas jefferson, dissatisfied with the old gazette, now ed- ited by alexander purdie and john dixon, brought william rind from maryland, and the second virginia gazette was begun.” kobre, a venerable journalism historian, also was certain of jefferson’s involvement: william rind’s third [sic] virginia ga- zette indicated the change in the social forces, for thomas jefferson backed rind because he believed the virginia gazette, which was then being published by alexander purdie and john dixon, was too closely tied to england. he considered that it was not representing the colonial cause with any strong determination and belief. he secured william rind from annapolis and rind’s virginia gazette began in williamsburg in may, . since kobre cited no source, it is un- clear how he determined jefferson’s rea- soning in such unlikely detail. influential historian schlesinger cited thomas in a article—“thomas jefferson and his friends persuaded william rind . . . to settle in williamsburg”—but the jeffer- son connection was not repeated in his book on the subject of colonial newspa- pers and the revolution in . more recently, other prominent historians con- tinued the error. greene cited briden- baugh when he wrote of the jefferson connection, and an article by robert weir in bailyn’s and john hench’s book on the press and the american revolution noted that the new printer “had come to williamsburg at the invi- tation of thomas jefferson and some other leading men.” while such prominent historians apparently did not see the weakness in thomas’ attribution, godfrey’s dissertation raised serious questions about jefferson’s involvement. however, it was not a major focus of her work, she apparently did not publish her findings, and she never developed the reason for the errors. this story of how one person’s flawed personal memory be-came part of the historical record holds warnings for histo-rians. too often they take the work of others at face value, without verification, because it is nearly impossible to double-check everything. they constantly build their work on the foundations of prior historians without often enough digging to verify facts, and thus errors large and small often multiply. as alfred young ob- served in , personal memory shifts over time, and historical memory can be far from perfect. going beyond questions of memory and accuracy, the situa- tion in virginia reveals much more about the evolution of print— and of press freedom. the character of the newspapers in the col- ony changed as competition came to williamsburg. from being a single newspaper that several times was accused of censorship in favor of the british ministry, depriving the virginia citizens “of that great support of freedom, the liberty of the press,” the com- peting gazettes now openly published controversy. a year later, in , another reader proclaimed “the press, one of the princi- pal handmaids of liberty, is become a free channel of conveyance whereby men may communicate their sentiments on every subject that may contribute to the good of their country.” another letter directly questioned the official actions of the colony’s supreme judges in their han- dling of the routlidge murder: “i ask, whether this act of the three judges of the general court be legal.” the causes of this radical transfor- mation of the press were more complex than simply jefferson or other patriots importing a new printer to publish a newspaper with more radical sentiments. new competitive pressures that accom- panied an emerging consumer economy brought a change in power and domina- tion. government control dramatically lessened, and marketplace pressures be- came paramount, which were necessary precursors to both a second printer and a more open press. as amory wrote, a single sanctioned printer could not run a truly free press: “the first step toward that distant nineteenth-century goal [of a free press] was often the advent of a second press.” as breen theorized, such marketplace choices began to erode co- lonial power structures, and a new “con- sumer public sphere” developed. news- papers were an essential driver, supplying substance and expanding this new dis- course: “everywhere americans reached out to each other through the channel of print.” as botein noted, colonial print- ers were forced to abandon their cautious approach, attempting to please all sides, as the stamp act threat- ened their livelihood. just as in the other colonies, virginia printers began to take a stand against british policies. thus, the virginia press became freer, more open to a wider range of opinions, including those critical of powerful members of government. quotations from john wilke’s radical newspaper, the north briton, appeared in rind’s gazette. dissent was printed openly, even harsh words written by those farther down the social scale aimed at the once-untouchable elites. for example, “an en- emy to hypocrisy” began his letter to the newspaper with a disclaimer of his abilities, yet he went on with a thinly disguised attack on colonel richard henry lee, calling him a rogue. the new competition in the newspaper and overall printing business in williamsburg assured a broader public of more outlets for wider viewpoints. the new printer did not provide the only open press, however. the older press, now run by royle’s successors, proved just as open to the faction that eventually became the patriots, run- ning stories about the sons of liberty and attacking the stamp “this story of how one person’s flawed personal memory became part of the historical record holds warnings for historians. too often they take the work of others at face value, without verification, because it is nearly impossible to double-check everything. they constantly build their work on the foundations of prior historians without often enough digging to verify facts, and thus errors large and small often multiply.” journalism history : (fall ) act as illegal. governmental pressure no longer reigned supreme. civic discourse in the colony of virginia had broadened and be- come more radical. such new discourse and the economic competition that spurred it have implications worthy of further development by to- day’s historians. the new press freedom and the public recognition of the importance of such broader civic discourse led to the flow- ering of an important new concept in pre-revolutionary virginia; the newly declared independent state’s declaration of rights in contained the first constitutional protection for a free press. article twelve declared, “that the freedom of the press is one of the greatest bulwarks of liberty and can never be restrained but by despotic governments.” this idea emerged directly from the public recognition that such open discussion was essential to a republican government, and such discourse was impossible when a powerful and potentially corrupt government could control the press. just days before this first free press clause was written, “civis” was lob- bying in the virginia gazette for recognition of the importance of a free press, stating, “liberty of the press is the palladium of our liberties,” and while free “speech is a natural right . . . printing is a more extensive and improved kind of speech.” the new civic discourse spurred the recognition of the im- portance of a free press, leading directly to the free press clause in virginia’s declaration of rights, and that—both directly and indirectly—inspired the free press clause in the first amendment to the united states constitution. other states followed virginia’s example and guaranteed a free press in their own constitutions, and when james madison wrote his draft of the bill of rights in , he worked from virginia’s example. the founders of this nation realized that only through a competitive, unfettered, and potentially annoying free press could a powerful government be balanced in the public interest, and they attempted to guarantee a free press by stating unequivocally, “congress shall make no law . . . abridging the freedom of speech, or of the press.” notes quoted by isaiah thomas, the history of printing in america, with a biog- raphy of printers, nd ed. ( ; reprint, new york: weathervane books, ), . susan macall allen, “the impact of the stamp act of on colonial american printers: threat or bonanza?” (ph.d. diss., university of california, los angeles, ), - , . thomas, printing in america, . see arthur schlesinger, prelude to independence: the newspaper war on brit- ain, - (westport, conn.: greenwood press, ), - ; and david ramsey, the history of the american revolution, vol. (philadelphia: r. aitken & son, ), - . thomas was quoted in schlesinger, “the colonial newspapers and the stamp act,” new england quarterly (march ): . see stephen botein, “‘meer mechanics’ and an open press: the business and political strategies of colonial american printers,” in perspectives in american his- tory, vol. (cambridge: cambridge university press, ), - ; and stephen botein, “printers and the american revolution” in bernard bailyn and john b. hench, eds., the press and the american revolution (worcester, mass.: american antiquarian society, ), - . hugh amory, “printing and bookselling in new england, - ,” in hugh amory and david hall, the colonial book in the atlantic world (cambridge: cambridge university press, ), - . t.h. breen, marketplace of revolution: how consumer politics shaped ameri- can independence (new york: oxford university press, ), xvi, , . jack greene, the quest for power: the lower houses of assembly in the south- ern royal colonies, - (chapel hill: university of north carolina press, ), - . laurie e. godfrey, “the printers of the williamsburg virginia gazettes, - : social controls and press theory” (ph.d. diss., regent university, ), especially iv. godfrey, on - , noted that jefferson was unlikely to be in- volved in the procurement of the new printer and raised a question about the claim that the jefferson quotation came from a letter to isaiah thomas. berkeley’s oft-quoted, “but i thank god, there are no free schools nor print- ing, and i hope we shall not have these for hundred years, for learning has brought disobedience, and heresy, and sects into the world, and printing has divulged them, and libels against the best government. god keep us from both!” appeared in wil- liam hening, the statutes at large; being a collection of all the laws of virginia, from the first session of the legislature in the year ( - .; facsimile reprint, char- lottesville: university press of virginia, ), vol. , iv-vi. william nuthead and his printing press were not allowed in jamestown. see douglas c. mcmurtrie, a history of printing in the united states; the story of the introduction of the press and of its history and influence during the pioneer period in each state of the union (new york: r.r. bowker co., ), ; and douglas c. mcmurtrie, the beginnings of printing in virginia (lexington, va.: printed in the journalism laboratory of wash- ington and lee university, ), - . william parks was invited by the lower house to move his printing office from annapolis to williamsburg, and he was paid a government salary. see john pendleton kennedy, ed., journals of the house of bur- gesses, june , , vol. (richmond: colonial press, e. waddey co., - ), - . in , printer joseph royle received a stipend of £ per year, which was voted on by the house of burgesses but also approved by the governor and his council. it was given “for printing the journal of the house of burgesses, printing the laws of each session, and sending as many copies to the county court clerks as there are justices in the commission in each respective county, and one another, which is to be half-bound, for the use of the court, and ten to the clerk of the court of husting of the borough of norfolk, printing inspectors notes and book, proclamations, and other publick advertisements.” this was increased to £ in . the printer also received additional contracts for printing other things, such as paper money and compilations of the laws. see kennedy, journals of the house of burgesses, jan. , , vol. , ; and nov. , , vol. , . see amory, “printing and bookselling in new england, - ,” - ; and richard d. brown, knowledge is power: the diffusion of information in early america, - (new york: oxford university press, ). virginia gazette, aug. , . although this first issue is no longer extant, the “printer’s introduction” from the first issue was quoted in william maxwell, ed., the virginia historical register, and literary companion ( ): - . see alexander spotswood to william parks, , washburn autograph collection, vol. , p. , massachusetts historical society, boston; virginia ga- zette, dec. , ; and greene, the quest for power, - . spotswood and others were referred to here and in contemporary writings as “governor,” when, in fact, they were lieutenant governors acting as governor. maryland gazette, oct. , . the dispute aired here was entangled with the “pistole fee,” which was imposed by governor robert dinwiddie on land sales. the burgesses opposed this arbitrary tax because it was imposed without their consent. see jack greene, “landon carter and the pistole fee dispute,” william and mary quarterly (january ): - . greene identified the author of the newspaper letter as burgess landon carter. at the death of printer william parks in , he was succeeded by william hunter, who was replaced in by joseph royle. the virginia gazette on nov. , , had governor dinwiddie praising the burgesses for approving the supplies, without any indication of the controversy. in , printer joseph royle received a stipend of £ per year, which was voted on by the house of burgesses but also approved by the governor and his council. this was increased to £ in . according to kennedy’s journals of the house of burgesses (jan. , , vol. , , and nov. , , vol. , ), he was paid “for printing the journal of the house of burgesses, printing the laws of each session, and sending as many copies to the county court clerks as there are justices in the commission in each respective county, and one another, which is to be half-bound, for the use of the court, and ten to the clerk of the court of husting of the borough of norfolk, printing inspectors notes and book, proclama- tions, and other publick advertisements.” he also received additional contracts for printing other items, such as paper money and compilations of the laws. botein, “‘meer mechanics’ and an open press,” - . virginia gazette, july , . royle to camm, aug. , , quoted in john camm, single and distinct journalism history : (fall ) view of the act, vulgarly entitled, the two penny act . . . (annapolis, md.; green, ), appendix, - . this dispute, also referred to as the parson’s cause, pitted the burgesses against ministers who contested an act that in essence lowered their pay. ibid., appendix. “tim pastime” to william hunter, ca. , special collections, ms. .d , john d. rockefeller, jr. library, colonial williamsburg foundation, williamsburg, va. emma l. powers, in the department of historical research at the colonial williamsburg foundation, provided a transcript and some annotations of refer- ences within this letter, which was discovered in the s. see david a. rawson, “‘guardians of their own liberty’: a contextual history of print culture in vir- ginia society, to ” (ph.d. diss., college of william and mary, ), - . an advertisement from “deputy postmaster” john stretch in the virginia gazette, april , , suggested that he was editing the newspaper but also leav- ing the colony that summer. a supplement to the maryland gazette, of last week, oct. , . advertisements from fairfax and alexandria in northern virginia often ap- peared in the newspaper from annapolis, and with transportation by water being faster than by land in the eighteenth century, parts of the southern colony were served faster by the northern printer. there were notices for home sales in alexan- dria, and george washington and george william fairfax solicited for a builder for a new church in fairfax county’s truro parish in the maryland gazette. for exam- ple, in the gazette, see house sale advertisements for alexandria on feb. , feb. , and oct. in ; a church builder advertisement on may , ; and a may , , advertisement from william rind, who was now printing in williams- burg, for a revised edition of the laws of virginia at a price of shillings. see also the introduction in edith moore sprouse, along the potomac river: extracts from the maryland gazette, - (westminster, md.: willow bend books, ). virginia gazette, aug. , . this was written after royle’s death and after alexander purdie and john dixon took over the business. there were numerous contemporary references to the governor’s control, including one letter to the newspaper in which the author claimed the virginia gazette was hand-carried to the governor to be inspected before it was distributed. see “man of principle,” virginia gazette, aug. , , which was printed by purdie and dixon. even the governor admitted the press was “thought to be too complaisant to me.” see francis fauquier to the board of trade, williamsburg, april , , handwritten transcription, great britain pro co , container v. : - [ - ], library of congress, washington, d.c. thomas jefferson to l.h. girardin, jan. , , jefferson papers, li- brary of congress, at http://memory.loc.gov/cgi-bin/ampage?collid=mtj &filen ame=mtj page .db&recnum= &itemlink=/ammem/mtjhtml/mtjser . html&linktext= &tempfile=./temp/~ammem_w j &filecode=mtj&next_ filecode=mtj&prev_filecode=mtj&itemnum= &ndocs= (accessed on dec. , ). jefferson also is quoted in dumas malone, jefferson, the virginian: jefferson and his time, vol. (boston: little, brown, ), . see also greene, “landon carter and the pistole fee dispute,” - , which discussed dinwiddie angering the burgesses by his unilateral actions. george reese, ed., the official papers of francis fauquier, lieutenant gov- ernor of virginia, - , vol. (charlottesville: university press of virginia, - ), xxxviii-xliv. he was instructed several times to separate the offices of speaker of the house of burgesses and colony treasurer, but he avoided doing so. he also sided with the burgesses in the parson’s cause, earning him a rebuke by the board of trade. see ibid., xlii-xliv; fauquier obituaries in the virginia gazette, march , ; and a quotation in the virginia gazette, march , . the paper was published by purdie and dixon. francis fauquier to the board of trade, williamsburg, april , , handwritten transcription, great britain pro co , container v. : - [ - ], library of congress. thomas jefferson, quoted by thomas, the history of printing in america, with a biography of printers, . schlesinger, “colonial newspapers and the stamp act,” , cited thomas as his source. philip davidson, propaganda and the american revolution, - (chapel hill: university of north carolina press, ), , did not credit any source for this. also see kobre, the development of the colonial newspaper ( ; reprint, gloucester, mass.: peter smith, ), ; greene, the quest for power, - ; and robert m. weir, “the role of the newspaper press in the southern colonies on the eve of the revolution,” in bailyn and hench, the press and the american revolution, . see, for example, “old virginia editors,” william and mary college quar- terly historical magazine (july ): - ; lyon gardiner tyler, ed., encyclopedia of virginia biography, vol. (new york: lewis historical publishing, ), - ; mcmurtrie, the beginnings of printing in virginia, - ; calhoun winton, “eigh- teenth century southern book trade,” in the colonial book in the atlantic world, ; and martha joanne king, “making an impression: women printers in the southern colonies in the revolutionary era” (ph.d. diss., college of william and mary, ), . godfrey, “the printers of the williamsburg virginia gazettes, to ,” - , noted the quotation was in a letter from jefferson to william w. hening. thomas, the history of printing in america, with a biography of printers, . isaiah thomas, the history of printing in america, with a biography of print- ers, vol. (worcester, mass.: isaiah thomas, ), . email, j. jefferson looney to roger mellen, feb. , . thomas jefferson to william w. hening, july , , thomas jefferson papers, series , general correspondence, - , library of congress. it also was published in j. jefferson looney, ed., the papers of thomas jefferson: retirement series, vol. (princeton, n.j.: princeton university press, ), - . godfrey also pointed to this letter as the source. see “the printers of the williamsburg vir- ginia gazettes, - ,” . emails, thomas g. knoles to roger mellen, dec. , , noted thomas left a handwritten note in an annotated copy of his first edition, stating that hen- ing had written to him on july , , about a fact regarding earlier virginia printing. see thomas, the history of printing in america, with a biography of print- ers, annotated st. ed., in the isaiah thomas papers, box , american antiquarian society, worcester, mass. thomas was not able to publish the second edition of his book before his death. a committee served as editors, following thomas’ notes for changes, and they included the footnote which cited a letter from jefferson to thomas as the source. that decision was based on thomas’ notes. godfrey, “the printers of the williamsburg virginia gazettes, - ,” - , also noted that the popular quotation could not be found in correspon- dence to thomas but was in a letter to hening. she apparently did not explore how this discrepancy got into thomas’ book. ibid., . her argument was simply that he was young and still a law student, and thus could not have been directly involved, but she did not contrast those facts with the financial and political requirements behind bringing a new printer to the colony. rind’s name last appeared on the maryland gazette on oct. , . by the next issue a week later, the name of his former partner, jonas green, appeared alone. while rind’s first virginia newspaper did not appear until may, , , the stamp act interrupted publication of many newspapers. it was likely that whatever negotiations brought rind to williamsburg were completed by october . under the new calendar, jefferson was born on april , , but the actual date was april , , under the old calendar, which was discontinued while he was a boy. see malone, jefferson, the virginian, ; thomas jefferson, “au- tobiography draft fragment, january through july , ,” from paul leicester ford, ed., the works of thomas jefferson in twelve volumes, federal edition, at http:// memory.loc.gov/cgi-bin/query/r?ammem/mtj:@field(docid+@lit(tj ))> (accessed on march , ). william fleming to thomas jefferson, june , , in julian boyd, ed., the papers of thomas jefferson: volume , - (princeton, n.j.; princeton university press, ), . edmund randolph, history of virginia, ed. arthur h. shaffer (charlottes- ville: university press of virginia, ), - , ; and godfrey, “the printers of the williamsburg virginia gazettes, - ,” - . kennedy, journals of the house of burgesses, nov. , , vol. , , , . purdie began publishing the virginia gazette under his name but soon joined with dixon in a partnership. it is not clear from the records who robert miller or william stark were or what happened to them after they lost the vote, but only two print shops re- mained. “gazette” was the name normally used for the official newspaper, and rind may have dropped his name from the masthead because official business tradition- journalism history : (fall ) ally went to the virginia gazette. see godfrey, “the printers of the williamsburg virginia gazettes, - ,” . rind’s virginia gazette, may , . the original is at the new york historical society. see clarence brigham, history and bibliography of american newspapers, - , vol. (worcester, mass.; american antiquarian society, ), - . virginia gazette, march , , . the paper was printed by purdie. “philanthropos,” and “a man of principle,” virginia gazette, aug. , . the paper was printed by purdie and dixon. virginia gazette, nov. , . the paper was printed by purdie and dixon. the virginia gazette that rind published at the end of december did not include this claim. the first extant issue of the next year, on feb. , , included the phrase “published by authority” in the masthead on the top of page one. david a. copeland, the idea of a free press: the enlightenment and its un- ruly legacy (evanston, ill.: northwestern university press, ), , - . virginia gazette, feb. , . the paper was printed by purdie and dix- on. the virginia gazette on july , , which was printed by rind, no lon- ger ran this claim. the march issue did, but there are no extant issues between the two dates. edmund morgan and helen morgan, the stamp act crisis: prologue to revolution ( : revision, chapel hill: university of north carolina press, ), . virginia gazette, oct. , . the annapolis newspaper, published the day before, featured many of the same stories but with a different slant. it also included a story of local opposition to the stamp act rather than warnings about what would happen if it was disobeyed. see second supplement to the maryland gazette, oct. , . from the gentleman’s magazine, quoted in the virginia gazette, april , . copeland, the idea of a free press, , refers to this newspaper as the most radical of this time. the first of the “farmer’s letters” began in the virginia gazette on dec. , . “the monitor’s letters,” credited to arthur lee, ran in the vir- ginia gazette from feb. to april , . see schlesinger, prelude to indepen- dence, ; and quotation from monitor ii, virginia gazette, march , . the paper was printed by rind. rind’s virginia gazette, aug. , . virginia gazette, july , . the paper was printed by purdie and dix- on. see virginia gazette, june , . the paper was printed by purdie and dixon. j.a. leo lemay, “robert bolling and the bailment of colonel chiswell.” early american literature ( ): - , identified the pseudonymous author as robert bolling. see also jack greene, “‘virtus et libertas’: political culture, social change, and the origins of the american revolution in virginia, - ,” in jeffrey j. crow and larry e. tise, eds., the southern experience in the american revolution (chapel hill: university of north carolina press, ), - ; and carl bridenbaugh, “violence and virtue in virginia, ,” early americans (new york: oxford university press, ), - . virginia gazette, aug. , . the paper was printed by purdie and dixon. greene, the quest for power, - , , . bridenbaugh, “violence and virtue in virginia, ,” . ibid., - . virginia gazette, aug. , . the paper was printed by rind. it also is quoted in bridenbaugh, “violence and virtue in virginia, ,” . virginia gazette, nov. , . the paper was printed by purdie and dix- on. see “a farmer,” virginia gazette, dec. , ; and virginia gazette, july , . the first article was printed by rind, and the second was printed by purdie and dixon. botein, “‘‘meer mechanics’ and an open press,” - . there are no spe- cific circulation figures available for the virginia gazette. godfrey, “the printers of the williamsburg virginia gazettes, - ,” . see thomas, the history of printing in america, with a biography of printers, annotated st. ed.; and thomas, the history of printing in america, with a biogra- phy of printers, nd ed., . thomas jefferson to william w. hening, july , , thomas jefferson papers, series , general correspondence, - , library of congress. jefferson, “autobiography draft fragment, january through july , .” davidson, propaganda and the american revolution, - , . kobre, the development of the colonial newspaper, . see schlesinger, “the colonial newspapers and the stamp act,” ; and schlesinger, prelude to independence, . see greene, the quest for power, ; carl bridenbaugh, myths and reali- ties; societies of the colonial south (baton rouge; louisiana state university press, ), - ; and weir, “the role of the newspaper press in the southern colo- nies on the eve of the revolution,” . godfrey, “the printers of the williamsburg virginia gazettes, - ,” - . alfred young, the shoemaker and the tea party: memory and the american revolution (boston: beacon press, ), - , . “a virginian,” “to the printer of the virginia gazette,” a supplement to the maryland gazette of last week, oct. , . “philanthropos,” virginia gazette, aug. , . the paper was printed by purdie and dixon. virginia gazette, june , . the paper was printed by purdie and dixon. amory, “printing and bookselling in new england, - ,” . breen, marketplace of revolution, , - . botein, “‘meer mechanics’ and an open press,” . botein notes that the few who supported a tory position were soon forced to moderate their positions or flee because a “free press” came to mean the freedom to support only the patriot position. the north-briton, issue , quoted in the virginia gazette, may , . the paper was printed by rind. virginia gazette, july , . the paper was printed by rind. see virginia gazette, june , ; and the gentleman’s magazine quota- tion in the virginia gazette, april , . the paper was printed by purdie and dixon. while george mason is recognized as the author of the virginia declaration of rights, the actual author of the free press clause is not clear. see irving brant, james madison, vol. (indianapolis: bobbs-merrill, - ), ; and robert a. rutland, the papers of george mason: - , vol. (chapel hill: university of north carolina press, ), - . virginia gazette, may , . the paper was printed by dixon and hunter. for madison’s draft, see his proposed “amendments to the constitution,” in “remarks to congress,” june , , in gordon lloyd and margie lloyd, eds., the essential bill of rights: original arguments and fundamental documents (lanham, md.: university press of america, ), - . see also leonard levy, essays on the making of the constitution, nd ed. (new york: oxford university press, ), - ; and stephen a. smith, “the origins of the free speech clause,” free speech yearbook ( ): - . for further development of the freedom of the press connection, see roger mellen, “liberty of the press: the emergence of the constitutional doctrine in colonial virginia” (paper delivered at the annual convention of the association for education in journalism and mass communication, washington, d.c., aug. , ). crpc- - -nco-ver -cosgrove_ p .. case report open access a rare case of acinar cell cystadenoma in a -year-old adolescent: a case report natalie cosgrove, joan dipalma, douglas katz, and thomas kowalski ,* abstract background: acinar cell cystadenoma is a rare pancreatic cyst that has been described in several case reports. this lesion may be incidental or asymptomatic, occurs predominately in females, and has a mean age of onset in the fourth decade. case presentation: a previously healthy -year-old male presented with abdominal pain. he was found to have a pancreatic cystic lesion on ultrasound and cross-sectional imaging. his diagnosis remained uncertain de- spite additional analysis, including endoscopic ultrasound with fine-needle aspiration. the patient underwent successful laparoscopic excision for definitive diagnosis and management with an unremarkable postoperative course. he was diagnosed with a multilocular acinar cell cystadenoma. conclusion: acinar cell cystadenoma is a rare pancreatic cyst whose true malignant potential is unknown. although there are no formal recommendations for post-operative monitoring and the true risk of recurrence is unknown, we recommended every other year magnetic resonance imaging/magnetic resonance cholangiopancreatography for postresection surveillance for this patient due to the theoretical risk of recurrence with malignant transformation. key words: acinar cell cystadenoma; pancreas; pancreatic cyst background incidental pancreatic cystic lesions are becoming increasingly common with more widespread use of cross- sectional imaging. pancreatic acinar cell cystadenocarci- noma and acinar cell cystadenoma (aca) account for < % of these lesions. acinar cell cystadenoma is a rare pancreatic cyst that has been described in several case re- ports. – aca typically arise from a background of normal pancreatic parenchyma and may be focal or diffuse in dis- tribution. aca may be unilocular or multilocular, with larger locules harboring internal septations. unilocular aca are predominately lined by well-differentiated acinar epithelium without atypia and scattered ductal cells, whereas patches of ductal epithelium within a background of acinar epithelium are more typical of multilocular aca. acinar cell cystadenoma occurs predominantly in fe- males ( – % female), with the age of diagnosis ranging from to years old and mean age of onset in the fourth decade. , , cysts may be incidental or symptomatic. when symptomatic, the most common presentation is pain. we describe a case of this rare cystic lesion occurring in a healthy adolescent male presenting with abdominal pain. case report a previously healthy -year-old male presented to an emergency room with – days of diarrhea and ab- dominal pain in november . abdominal x-ray dem- onstrated dilated loops of bowel consistent with gastroenteritis. his serum aspartate transaminase was slightly elevated at u/l (uln ); however, his division of gastroenterology and hepatology, department of internal medicine, thomas jefferson university hospital, philadelphia, pennsylvania. division of pediatric gastroenterology, department of pediatrics, nemours dupont, philadelphia, pennsylvania. division of pediatric general surgery, department of surgery, nemours dupont, wilmington, delaware. *address correspondence to: thomas kowalski, md, division of gastroenterology and hepatology, department of internal medicine, thomas jefferson university hospital, s th street, suite , philadelphia, pa , e-mail: thomas.kowalski@jefferson.edu ª natalie cosgrove et al. ; published by mary ann liebert, inc. this open access article is distributed under the terms of the creative commons license (http://creativecommons.org/licenses/by/ . ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. case reports in pancreatic cancer volume . , doi: . /crpc. . .nco case reports in pancreatic cancer remaining hepatic function panel, complete blood count, lipase, and amylase were normal. an abdominal ultra- sound suggested a cystic structure medial to the left kid- ney with thickened internal septations. despite repeating the abdominal ultrasound in multiple planes, it remained unclear whether the structure represented a distended fluid-filled loop of colon or a unique cystic lesion. subse- quent computerized axial tomography (fig. ) revealed a multiseptated cystic structure in the pancreatic tail mea- suring . · · cm with peripheral hyperdensities com- patible with extrapancreatic calcifications. several of the cystic components demonstrated thickened walls with mild enhancement. the pancreatic parenchyma and pancreatic duct appeared normal. no other pancreatic le- sions were identified. multiple mildly dilated fluid-filled loops of large and small bowel with air-fluid levels com- patible with gastroenteritis were also noted, which were felt to be the likely etiology of his symptoms. the patient’s symptoms resolved shortly following his emergency room visit, with normalization of his stools and resolution of his abdominal pain. after care- ful review of his images, his pancreatic lesion was felt to represent a cystic pancreatic mass and less likely a pseudocyst or a solid pseudopapillary tumor with cystic components. he was referred for an endoscopic ultra- sound (eus) to further characterize his lesion. an eus (fig. ) performed in december noted a . · . cm thick-walled pancreatic tail lesion with a hypoechoic center and several adjacent anechoic lesions, the largest of which was . · . cm. the pan- creas otherwise appeared normal. fine needle aspira- tion of the largest anechoic lesion was performed using a g expect� bsci needle. one milliliter of pink tinged nonviscous fluid was aspirated. cyst fluid analysis revealed carcinoembryonic antigen . ng/ml and amylase u/l. aspirate cytology was nondiag- nostic with rare small groups of mildly atypical epithe- lial cells, benign acinar cells, ductal cells, and fragments of fibrous tissue and debris. redpath pathfindertg� integrated diagnosis was also indeterminate, due to lack of polymerase chain reaction amplifiability from low dna quantity and poor dna quality. the patient felt generally well and remained active in several sports, but continued to have episodes of recurrent abdominal pain. repeat contrast-enhanced abdominal fig. . endoscopic ultrasound image of a . · . cm anechoic lesion adjacent to the pancreatic tail. fig. . computer tomographic scan of abdomen. multiseptated cystic structure in the pancreatic tail ( . · · cm). fig. . high-powered magnification of cysts lined by a single epithelial layer of cuboidal to columnar epithelium with focal acini. cosgrove et al.; case reports in pancreatic cancer , . http://online.liebertpub.com/doi/ . /crpc. . .nco computed tomography in july demonstrated a persis- tent pancreatic cystic lesion measuring . · . · . cm, with prior imaging not available for comparison at that time. although a definitive diagnosis had not been estab- lished, due to his recurrent pain and persistent lesion, the patient underwent laparoscopic excision in july . the patient tolerated the procedure well. the lesion was easily dissected from the pancreas. macroscopically, it was noted to have four cystic components, ranging in size from . · . · . to . · . · cm. each cyst con- tained a white smooth wall filled with white cloudy watery fluid. microscopically, the cysts were lined by a single layer of cuboidal to columnar epithelium with focal acini, with one cyst demonstrating internal concretions (fig. ). no cytological atypia or mitoses were present. these features were consistent with a multilocular acinar cell cystadenoma. discussion we have described a case of a young adolescent male with a multilocular acinar cell cystadenoma who underwent suc- cessful cyst excision. to our knowledge, he is the second youngest patient to have been reported with this lesion. in addition, although nearly all previously reported cases of aca resulted in extensive pancreatic resections, including pancreaticoduodenectomy, lateral pancreatec- tomy, and total pancreatectomy, we have described a case with successful cyst excision without pancreas resec- tion. postoperatively, we have recommended every other year magnetic resonance imaging/magnetic resonance cholangiopancreatography surveillance for this patient. whether or not this is warranted or beneficial, especially given this patient’s young age at diagnosis, is unclear. it has been proposed that aca originate from nonneo- plastic acinar dilatation that expand into and incorporate ducts and ductules, eventually forming large cystic lesions as secretions accumulate. ductal-to-acinar metaplasia has also been a theoretical explanation. more recently, however, pancreatic acinar cell cystadenoma has been described as an adenoma. although it has been sug- gested that this lesion is a precursor to acinar cell cysta- denocarcinoma, the true malignant potential of this lesion remains unclear. to our knowledge, no case re- port or case series has reported evidence of malignant transformation of aca with up to . -year follow-up, regardless of whether or not the lesion was completely resected. , although aca lack atypia and mitotic activity that seems to favor a nonneoplastic lesion, the discovery of multiple chromosomal gains on compara- tive genomic hybridization that contain a few cancer- associated genes and genomic instability suggests the le- sion is preneoplastic. in addition, a case of aca with low-grade dysplasia was recently reported. we know from previous studies that aca are likely to grow over time. in a case series of patients, of whom underwent sequential imaging, all four cysts showed in- terval enlargement over time with a mean increase of . cm for more than . years. no postoperative recur- rences have been reported. until the course of aca is better established, however, we believe these lesions should be aggressively monitored, with strong consider- ation for surgical resection to reduce the theoretical risk of malignant transformation. given the rarity of these cysts, future studies to support this will likely be limited. author disclosure statement no competing financial interests exist. references . zamboni g, terris b, scarpa a, et al. acinar cell cystadenoma of the pan- creas: a new entity? am j surg pathol. ; : – . . singhi ad, norwood s, liu tc, et al. acinar cell cystadenoma of the pan- creas: a benign neoplasm or non-neoplastic ballooning of acinar and ductal epithelium? am j surg pathol. ; : – . . khor ts, badizadegan k, ferrone c, et al. acinar cystadenoma of the pan- creas: a clinicopathologic study of cases including multilocular lesions with mural nodules. am j surg pathol. ; : – . . wolf am, shirley la, winter jm, et al. acinar cell cystadenoma of the pancreas: report of three cases and literature review. j gastrointest surg. ; : – . . mcevoy mp, rich b, klimstra d, et al. acinar cell cystadenoma of the pan- creas in a -year-old boy. j pediatr surg. ; :e –e . cite this article as: cosgrove n, dipalma j, katz d, kowalski t ( ) a rare case of acinar cell cystadenoma in a -year-old adolescent: a case report, case reports in pancreatic cancer : , – , doi: . / crpc. . .nco. abbreviations used aca ¼ acinar cell cystadenoma eus ¼ endoscopic ultrasound publish in journal of pancreatic cancer - immediate, unrestricted online access - rigorous peer review - compliance with open access mandates - authors retain copyright - highly indexed - targeted email marketing liebertpub.com/crpc cosgrove et al.; case reports in pancreatic cancer , . http://online.liebertpub.com/doi/ . /crpc. . .nco http://www.liebertpub.com/crpc#utm_campaign=crpc&utm_medium=article&utm_source=advert correction to: neurocritical care survey: physician compensation, unit staffing and structure neurocrit care ( ) : – https://doi.org/ . /s - - - co r r e c t i o n correction to: neurocritical care survey: physician compensation, unit staffing and structure syed omar shah * , julius gene s. latorre and neurocritical care society survey working group members © springer science+business media, llc, part of springer nature and neurocritical care society c orrection to: neurocrit care ( ) : – https ://doi.org/ . /s - - -z the original article had a typo in table  , the “n” for males and females should be switched. the corrected table is shown below: *correspondence: syed.o.shah@jefferson.edu department of neurological surgery, vickie and jack farber institute for neuroscience, thomas jefferson university, walnut street, rd floor, philadelphia, pa , usa full list of author information is available at the end of the article the original article can be found online at https ://doi.org/ . /s - - -z. http://orcid.org/ - - - https://doi.org/ . /s - - -z https://doi.org/ . /s - - -z http://crossmark.crossref.org/dialog/?doi= . /s - - - &domain=pdf https://doi.org/ . /s - - -z https://doi.org/ . /s - - -z author details department of neurological surgery, vickie and jack farber institute for neuroscience, thomas jefferson university, walnut street, rd floor, philadelphia, pa , usa. upstate medical university, syracuse, ny, usa. table median incomes variable variable value n median income gender males $ , –$ , females $ , –$ , age – $ , or less – $ , –$ , – $ , –$ , – $ , –$ , or older $ , –$ , practice location northeast $ , –$ , midwest $ , –$ , south $ , –$ , west $ , –$ , practice setting academic/university faculty $ , –$ , government $ , or less hospital-based group $ , –$ , multispecialty group $ , –$ , private practice $ , –$ , type of compensation productivity only (rvu based) $ , –$ , salary only $ , –$ , salary plus bonus $ , –$ , salary plus productivity $ , –$ , salary plus productivity and bonus $ , –$ , share of total practice income $ , –$ , other $ , –$ , publisher’s note springer nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. published online: august 	correction to: neurocritical care survey: physician compensation, unit staffing and structure 	correction to: neurocrit care ( ) : – https​:doi.org . s ​ - - ​-z 	published online: august wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" 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, a mitochondria in cell life and death -pos board b a step forwardin understanding the mechanismof vdac voltage-gating oscar teijido hermida , shay rappaport , rachna ujwal , jeff abramson , vicente m. aguilella , sergey m. bezrukov , tatiana k. rostovtseva . nichd, national institutes of health (nih), bethesda, md, usa, david geffen school of medicine, ucla, los angeles, ca, usa, universitat jaume i, castello de la plana, spain. the voltage-dependent anion channel (vdac) governs the exchange of ions and metabolites between the mitochondria and the rest of the cell. in its open state vdac exhibits high conductance and selectivity for anions that facilitates the passage of adp, atp, and other metabolites. at increased voltages (> mv) vdac switches to lower conducting states, termed as ‘‘closed’’ states. closed states are cation-selective and impermeable for atp. the voltage-induced transition from the open to closed states is referred to as voltage-gating. although it is well established that vdac voltage-gating in- volves large structural rearrangements, the precise molecular mechanism of this process is still under debate. we investigated vdac voltage-gating by sys- tematically titrating vdac charge residues and by using thermodynamic and kinetic approaches to study opening and closing of the channel. all the models proposed so far agree that n-terminal region plays a key role in vdac voltage- gating. according to the original idea, the n-terminal region is a part of a mo- bile voltage sensor domain, which slides in and out of the channel lumen in re- sponse to the applied voltage. the alternative models consider independent movement of the n-terminal region upon gating. in order to test the role of vdac n-terminal region in voltage-gating, we engineered a double cys mu- tant of murine vdac that cross-links the a-helix to the b-strand of the pore wall. the cross-linked vdac reconstituted into planar lipid membranes exhibited typical voltage gating, which suggests that the n-terminal a-helix is located inside the pore of vdac in the open state and remains associated with the pore wall during voltage gating. our findings support a model where b-bar- rel is not rigid but undergoes a conformational change that leads to a partial constriction upon transition to the closed states. -pos board b novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding kely l. sheldon , coert j. zuurbier , sergey m. bezrukov , tatiana k. rostovtseva . the natl. institutes of health, bethesda, md, usa, university of amsterdam, amsterdam, netherlands. the voltage dependent anion channel (vdac) is involved in regulation of me- tabolite flux across the mitochondrial outer membrane (mom). hexokinse ii (hk ) is known to bind the mom where it phosphorylates glucose into glucose- -phosphate (g p). high expression of hxk is a common phenotype of many cancers, where its concentration can be times of that in noncan- cerous cells, and is implicated in the warburg effect. it is believed that vdac serves as a hxk binding site in the mom. the amino acid n-ter- minal sequence of hxk is responsible for mitochondrial binding and, when conjugated to tat (tat-hk ), binds to mitochondria with higher affinity than native hxk , causing hxk detachment. we have previously found that dimeric tubulin reversibly binds and partially blocks vdac inhibiting me- tabolite flux across the mom. now we show that this binding can be attenuated by tat-hxk peptide as well as by full length hxk . we have found that tat-hxk and recombinant full length hxk inhibit tubulin blockage of vdac reconstituted into planar lipid bilayers without altering characteristic channel properties such as single channel conductance and selectivity. binding of hxk to vdac is verified by the generation of high-frequency excess cur- rent noise without channel closure. hxk bound to vdac prevents subse- quent tubulin binding, but only when added before tubulin, and inhibits tubulin-induced vdac blockage in a dose dependent manner. moreover, g p, which is known to cause hxk detachment from the mom, fully re- verses the inhibition of tubulin-vdac binding. this suggests that hxk de- tachment from vdac (and hence the mom) is caused by a hxk conformational change upon g p binding. thus we propose a novel mecha- nism of mitochondrial respiration control in cancer cells through the competi- tion between hxk and tubulin for vdac binding. -pos board b reprogramming of mitochondrial ca d handling in micu -deficient hela cells tünde golenár , györgy csordás , erin l. seifert , cynthia moffat , fabiana perocchi , yasemin sancak , david weaver , vamsi k. mootha , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. recent studies have revealed mcu as the pore forming domain and micu as a critical ca þ-sensitive regulator of the mitochondrial ca þ uniporter. how- ever, the exact role of micu in ca þ transport remains to be addressed. our previous studies showed that prolonged down-regulation of micu in hela cells (shmicu ) promotes mitochondrial ca þ uptake at low [ca þ ], which unexpectedly, fails to effectively increase matrix [ca þ ]. to determine the source of discrepancy between the mitochondrial ca þ uptake and the ma- trix [ca þ] phenotypes, first we simultaneously monitored ruthenium red- sensitive clearance of added ca þ from the cytoplasm and the corresponding matrix [ca þ] response in permeabilized shmicu cells. under conditions of similar cytoplasmic ca þ clearance, shmicu cells showed a smaller matrix [ca þ ] increase than the control, indicating enhanced buffering of ca þ in the matrix. enhanced ca þ binding in the matrix likely reflects alkalinization and enhanced phosphate transport. to test if upregulation of ca þ buffering is di- rectly linked to micu depletion, we also assessed mitochondrial ca þ han- dling after hr silencing of micu (simicu ). in simicu cells both mitochondrial ca þ uptake and the matrix [ca þ ] rise were effectively stimu- lated at low ca þ levels. thus, upregulation of matrix ca þ buffering seems to be a component of an adaptive response to sensitization of mitochondrial ca þ uptake in shmicu . the adaptive response is likely to be important to attenuate some micu -depletion induced cellular impairments that we found to manifest as attenuated mitochondrial atp production and cell proliferation. -pos board b micu -dependent threshold and cooperativity of mitochondrial ca d uptake in the liver györgy csordás , erin l. seifert , tünde golenár , cynthia moffat , sergio de la fuente perez , david weaver , roman bogorad , victor koteliansky , vamsi k. mootha , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, koch institute for integrative cancer research, mit, cambridge, ma, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. recent studies have revealed mcu as the pore forming domain and micu as a critical ca þ-sensitive regulator of the mitochondrial ca þ uniporter. how- ever, the mechanism of the complex ca þ dependence of the uniporter activity remains elusive. our previous studies showed that prolonged down-regulation of micu in hela cells causes lower threshold and decreased cooperativity of mitochondrial ca þ uptake. to study the functional significance of the effects of micu we used hepatocytes harvested from the liver of mice exposed to in vivo silencing ( weeks). silencing of micu or mcu resulted in > % decrease in their respective mrna levels. silencing of micu caused a left- ward-shifted dose response and decreased cooperativity of mitochondrial ca þ uptake in both permeabilized and intact hepatocytes. by contrast, silenc- ing of mcu resulted in slower ca þ uptake in the entire range of ca þ concen- trations without change in threshold. mitochondrial respiration and cellular atp content were unaffected in media containing both glycolytic and mito- chondrial fuels in either micu or mcu-deficient hepatocytes. however, si- lencing of micu caused an augmented loss of atp when the cells were confined to oxidative metabolism and an enhanced sensitivity to mitochondrial ca þ overload and permeabilization. during stimulation with vasopressin, a ca þ mobilizing hormone, both micu and mcu-deficient cells displayed an attenuated mitochondrial matrix [ca þ ] increase and stimulation of respira- tion. collectively, these results show that keeping the gate of mcu closed by micu at low [ca þ] is required to maintain healthy mitochondria, and micu -mediated control of mcu (cooperativity?) is required to support the propagation of short-lasting calcium spikes and oscillations to the mitochondria and the ensuing physiological stimulation of oxidative metabolism. -pos board b targeting mcl- and bak as a therapeutic tool to selectively induce apoptosis in hepaptocellualr carcinoma nima niknejad, soumya sinha roy, eric knudsen, györgy hajnóczky. thomas jefferson university, philadelphia, pa, usa. in this study we seek to identify novel drug targets to induce apoptosis in he- patocellular carcinoma (hcc) cells thus providing opportunities to develop novel treatments to improve the prognosis of liver cancer patients. several ap- optotic pathways are mediated through cleavage of bid (a bh domain-only, pro-apoptotic protein) to produce truncated bid (tbid). tbid induces apoptosis through induction of outer mitochondrial membrane (omm) permeabilization by activation of pro-apoptotic bak that resides in the omm or cytoplasmic bax. due to its localization, bak can mediate the early phase of the response to tbid. we have recently demonstrated that omm targeting of bak and the sensitivity to tbid-induced omm permeabilization is dependent on the expression of a wednesday, february , voltage-dependent anion channel isoform (vdac ). here, we show that hcc induced by carcinogenic compounds, aflatoxin or den is highly sensi- tized to tbid-induced omm permeabilization and cyto c release when com- pared to normal liver. expression levels of vdac and bak were also higher in hcc than in control liver. the role of the vdac -bak pathway in the differential tbid sensitivity was validated by overexpression of vdac in primary hepatocytes. in hcc cells, elevation of bak was also associated with an increased level of mcl- , an inhibitor of bak. furthermore, both constitutive and drug-induced genetic deletion of mcl- in mouse embryonic fibroblasts caused sensitization to tbid-induced omm permeabilization in the absence of a change in bcl-xl or bax . based on these results, we are evaluating the possibility of selective killing of hcc cells by the combination of a bak activator and an mcl- inhibitor. -pos board b which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c release? shamim naghdi , peter varnai , soumya sinha roy , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadlephia, pa, usa, semmelweis university, budapest, hungary. vdac proteins represent a main component of the outer mitochondrial membrane (omm). the vdac family is composed of isoforms with more than percent similarity. although their primary role was known to be in ion and metabolite transport between mitochondria and cytosol, it has been dis- covered that vdacs are also involved in apoptotic pathways. we have recently found that specifically the vdac isoform is needed for tbid-induced cyto- chrome c release, due to its role in supporting bak insertion to the omm (roy et al. . embo rep. : - ). to determine the domain(s) of vdac which supports bak insertion, vdac and vdac amino acid composition compared and the unique attributes of vdac sequencewereconsideredformutationalanalysis.totestfunctionalsig- nificance of the changes in vdac or vdac , vdac -/- mef cells that are resistant to tbid, were transfected with the mutants and insertion of bak to the omm and cytochrome c release were monitored in permeabilized cells by immunoblotting. previously, we showed that the vdac -specific n terminal tail and cysteins are dispensable for tbid-induced omm permeabilization. to approach the remaining differences four chimeras were prepared: vdac ( - )vdac ( - ), vdac ( - )vdac ( - )vdac ( - ), vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ). these studies revealed that tbid dependent omm permeabilization is only sup- ported by vdac ( - )vdac ( - ) and vdac ( - )vdac ( - ), indicating that the first two third of vdac is required and sufficient for bak targeting to the omm and tbid induced cytochrome c release. -pos board b outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion david weaver , xingguo liu , veronica eisner , peter varnai , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary. cells and tissues deficient in mitochondrial fusion have been shown to have defects linked to the exchange of inner membrane (imm) and matrix compo- nents, particularly mitochondrial dna. outer membrane (omm) constituents originate in the cytoplasm, thus the role of intermitochondrial transfer of omm components by fusion remained unexplored. here we show that fibro- blasts lacking the gtpases responsible for omm fusion, mfn / , have a more heterogeneous distribution of omm proteins than wild-type cells, and in partic- ular that heterogeneity of pro-apoptotic bak leads to dysregulation of bid- dependent apoptotic signaling. homogeneous distribution of bak is partially rescued by introduction of mfn into mfn / -/- cells. furthermore, fusions be- tween mitochondria lacking and containing bak result in hybrids sensitive to bid. proteins with different modes of omm association display varying degrees of heterogeneity in mfn / /- cells and different kinetics of transfer during fusion in fusion-competent cells. efficient coupling of omm to imm fusion depends on the presence of both mfn isoforms and is antagonized by the mitochondrial fission protein, drp . thus, omm function depends on mitochondrial fusion and is a locus of dysfunction in conditions of fusion deficiency. -pos board b mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat veronica eisner , guy lenaers , gyorgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, inserm u- , institut des neurosciences de montpellier, montpellier, france. mitochondria are highly mobile and dynamic organelles in many cell types. however, in the muscle, mitochondria are crammed into the narrow space among the myofilaments. until now, it remained unclear if mitochondrial fusion occurs in and supports the contractile activity of skeletal muscle (sm). here we applied mitochondria matrix-targeted dsred and photoactiv- able gfp to study mitochondrial fusion in rat fdb sm fibers. in vivo electro- porated fibers were imaged by confocal microscopy. when we tagged the mitochondria in ~ % of cell area with twophoton photoactivation of gfp, rapid spreading of fluorescence showed subsets of interconnected mitochondria, mostly in longitudinal direction. matrix fusion occurred with a rate of . and . events/min in adult fibers and skeletal myotubes, respectively. expres- sion of autosomal dominant optical atrophy-causing mutants of the fusion protein opa or ethanol exposure caused suppression of fusion, which is fol- lowed by mitochondrial dysfunction and late onset myopathies. when chal- lenged by repetitive tetanic stimulation, ethanol exposed cells displayed intracellular ca þ dysregulation, appearing as a fatigue pattern. ethanol also induced a decrease in mfn protein levels, without significantly altering mfn , opa or deltapsi. depletion of mfn alone was sufficient to suppress mi- tochondrial fusion in fdb fibers. fusion inhibition was apparent before any cell dysfunction, suggesting that suppression of fusion is not secondary to other problems in the cells. to directly test the role of mfn in ca þ regulation, ryr -transfected control and mfn ko mefs were stimulated with caffeine. mfn ko cells showed oscillatory ca þ transients that decayed faster than that in the control. thus, fusion dynamically connects skeletal muscle mito- chondria and serves as a target mechanism of both mutations and environmen- tal cues to cause impaired excitation-contraction coupling. -pos board b bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action katarina stroffekova, lucia balogová, mária maslaňáková, lenka dzurová, pavol mi�skovský mi�skovský. safarik university, kosice, slovakia. apoptosis is a key process in the development and maintenance of tissue homeostasis. this process of controlled cell death is tightly regulated by a balance between cell survival and damage signals. we focused our attention towards the intrinsic mitochondrial apoptotic pathway, where bcl- family of proteins plays the major role. we were particularly interested in two pro- apoptotic players bak and bax. here we investigated their role in apoptosis triggered by photodynamic action. we show the localization of bax and bak in u- mg human glioma cells incubated with photosensitizer hypericin (hyp) before and after photodynamic action. apoptotic stimulus by hyp photodynamic action caused bax translocation into mitochondria. however our results suggest that under these condi- tions there are two populations of mito- chondria: one which contains bax and bak simultaneously, and is almost exclu- sively localized near the plasma mem- brane; the other which contains bax only and is distributed throughout the cell. the different protein content and spatial distri- bution of these two populations suggest that they can play different roles in re- sponse to apoptotic stimuli. -pos board b stimulation of bax mitochondrial localization by bcl-xl thibaud renault , oscar teijido , gisele velours , yogesh tengarai ganesan , florent missire , nadine camougrand , bruno antonsson , laurent dejean , stephen manon . ibgc-cnrs, bordeaux, france, nyu college of dentistry, new york, ny, usa, merck-serono sa, geneva research center, geneva, switzerland, california state university of fresno, fresno, ca, usa. cytochrome c release, the commitment step of apoptosis, is regulated at the mitochondria through protein-protein interactions between the bcl- family proteins. an imbalance of this interaction network due to the up-regulation of the proto-oncogenes bcl- and/or bcl-xl lead to a resistance to apoptosis and is associated with tumor formation. bcl-xl overexpression act at the level of the mitochondrial outer membrane (mom) by inhibiting bax-mediated apoptosis; more particularly mac formation and cytochrome c release. how- ever, the molecular mechanisms through which bcl-xl affect earlier steps of bax-mediated apoptosis are not fully understood. surprisingly, we found that mitochondrial bax redistribution and change of conformation were not inhibited but rather spontaneously increased in response of bcl-xl overexpres- sion. in order to further investigate the molecular mechanisms involved in this 	a step forward in understanding the mechanism of vdac voltage-gating 	novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding 	reprogramming of mitochondrial ca + handling in micu -deficient hela cells 	micu -dependent threshold and cooperativity of mitochondrial ca + uptake in the liver 	targeting mcl- and bak as a therapeutic tool to selectively induce apoptosis in hepaptocellualr carcinoma 	which domain of vdac is necessary for bak insertion to the outer mitochondrial membrane and tbid - induced cytochrome c re ... 	outer mitochondrial membrane protein distribution and function depend on mitochondrial fusion 	mitochondrial fusion dynamics in skeletal muscle of healthy and diseased rat 	bcl- proapoptotic proteins distribution in u- mg glioma cells before and after hypericin photodynamic action 	stimulation of bax mitochondrial localization by bcl-xl mitochondrial nm -h /ndpk-d is multifunctional: intermembrane cardiolipin transfer linked to apoptosis a monday, february , activates a novel, calcium-independent, pkca-dependent signaling pathway, which results in mitochondrial depolarization. as a result, mitochondrial dys- function is likely to be a key contributor to the pathophysiology of gas embo- lism injury. further, this connection between the endothelial surface layer and endothelial mitochondria may also play an important role in vascular homeo- stasis and disease. -plat calcium-induced ros generation during ischemia triggers mptp- dependent cell death during reperfusion lea k. seidlmayer, vanessa v. juettner, lothar a. blatter, elena n. dedkova. rush university medical center, chicago, il, usa. impairment of mitochondrial function is a central event of ischemia- reperfusion (i/r) injury leading to tissue damage and cell death. we studied the relationship between mitochondrial ca þ overload, reactive oxygen species (ros) generation, opening of the mitochondrial permeability transition pore (mptp) and cell death in rabbit ventricular myocytes exposed to simulated i/r. changes in mitochondrial ca þ ([ca þ]m) were measured with x-rhod- , ros generation with mito-sox red, mptp opening as mitochondrial calcein red release, and cell death as lactate dehydrogenase release. i/r was induced by exposing cells to glucose-free tyrode solution containing mm -deoxyglu- cose and mm nacn, ph . , followed by superfusion with standard tyrode solution. no cell death was observed after min of ischemia despite a signif- icant increase in [ca þ]m, ros and mptp opening, however cell death in- creased significantly after min of reperfusion. the ca þ uniporter blocker ru partially prevented [ca þ ]m increase and completely abolished ros generation and cell death when applied during i/r, however application of ru only during reperfusion did not protect from cell death. scavenging ros with superoxide dismutase mimetic mntbap or antioxidant trolox pre- vented reperfusion-induced cell death. blocking mptp during ischemia by cyclosporine a or depletion of mitochondrial inorganic polyphosphate did not provide protection against cell death during reperfusion, but instead led to increased mitochondrial ros accumulation. however, inhibiting mptp opening during reperfusion with cyclosporine a attenuated cell death. we con- clude that mptp-dependent cell death during reperfusion is mediated by ca þ- dependent ros generation during ischemia. moreover, our data suggest that mptp opening during ischemia could serve as ros escape pathway from mitochondria and thereby attenuate mitochondrial ros accumulation and ros-mediated cell damage during subsequent reperfusion. -plat dynamic measurement of ca d -induced changes in organelle-specific redox microdomains david m. booth , balázs enyedi , miklós geiszt , péter várnai , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary. multiple interactions between ca þ -signalling and reactive oxygen species (ros) production are thought to exist and be of both physiological and patho- physiological relevance. however, until recently, the study of ros in the con- text of ca þ-signalling has been hampered by ros probes limited in both specificity and targeting. to measure ros in discrete subcellular domains, we compared the genetically-encoded ratiometric h o sensor hyper with the redox de-sensitized derivative sypher to control for non-specific changes. these probes, targeted to the er lumen, er membrane (cytosolic face), cyto- sol, mitochondrial matrix and outer membrane (omm) and the ip -receptor, are positioned to assess redox changes at a local level. in resting conditions, the er lumen showed > -fold increased hyper ratio compared to the outside of the er membrane, bulk cytosol and mitochondrial matrix and omm. in the er lumen, ip -linked ca þ -mobilization induced a prounounced, downward shift in hyper ratio, whereas little or no change was detected in other compart- ments. in permeabilized cells, mitochondrial ca þ-overload was accompanied by substantial increase in h o detected in the matrix and at the omm. these data demonstrate that redox environments within individual cellular compart- ments constitute a complex and dynamic interrelationship with the concentra- tion of free ca þ . the er lumen is highly oxidized and exhibits profound decreases in h o concommitant with ca þ -release. interestingly, these changes are not transmitted to the outer leaflet of the er membrane or to other compartments. mitochondria resist redox changes under moderate stimulation, however, during mitochondrial ca þ-overload and collapsed membrane poten- tial, strong h o generation is detectible in the matrix and at the mitochondrial surface. the ros generated and detected at locations immediately apposed to ca þ -transport proteins, such as the ip -receptor, may modify their function at a local level and contribute to the feed-forward cycle of ca þ -dysregulation and subsequent cell death. -plat er-mitochondrial ultrastructure in the liver of normal and ethnaol-fed rats gyorgy csordas , david mankus , antony anil noronha , jan hoek , carmen mannella , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, wadsworth center, albany, ny, usa. chronic alcohol consumption causes severe pathology in liver, associated with altered metabolism and reduced atp production. liver mitochondria isolated from alcohol-fed animals show decreased capacity for electron transport and atp synthesis, impaired calcium handling, and increased ros. in parallel, the endoplasmic reticulum (er) also shows increased ros and a stress re- sponse. the close correlation between defects in mitochondria and er is matched by recent evidence of the functional integration of cellular responses (including calcium signaling) involving these organelles. to evaluate the ultra- structural basis of alcohol-induced changes, we performed transmission elec- tron microscopy and electron tomography studies of rat liver. hepatocytes showed a large number of mostly round mitochondrial cross sections, which oc- cupied ~ % of the cytoplasmic area. the cell cytoplasm in chronic ethanol- fed ( months) condition exhibited reduced particle density, indicative of cell swelling, and contained large lipid vesicles. the mitochondria were generally intact but showed narrower intermembrane spacings within cristae and at the organelle periphery, consistent with low-scale matrix swelling. in both control and ethanol-fed conditions, mitochondria were typically surrounded by exten- sive er, with cisternae sometimes sandwiched between neighboring mitochon- dria. in one case, er was prominent at a site of mitochondrial fusion/fission. as previously reported, regions of close er-mitochondrial association ( - nm) contained numerous ‘‘tethers’’ between outer mitochondrial membranes (omm) and adjacent er. while individual tethers were discernible, dense granular material (including ribosomes) within omm-er interfaces interfered with accurate quantitation of tethers. however, membrane spacings could be readily measured. it was found that the mitochondrial surface in close associ- ation with er was significantly reduced in the chronic ethanol-fed condition as compared to control ( . % vs. %). this might be expected to cause reduced calcium signaling between er and mitochondria in liver after chronic alcohol ingestion. -plat mitochondrial nm -h /ndpk-d is multifunctional: intermembrane cardiolipin transfer linked to apoptosis uwe schlattner , malgorzata tokarska-schlattner , sacnicte ramirez , yulia y. tyurina , andrew a. amoscato , zhentai huang , jianfei jiang , mathieu boissan , raquel f. epand , dariush mohammadsanyi , judith klein-seetharaman , richard m. epand , marie-lise lacombe , valerian e. kagan . joseph fourier university and inserm, grenoble, france, university of pittsburgh, pittsburgh, pa, usa, inserm, umpc université paris and hôpital tenon, paris, france, mcmaster university, hamilton, on, canada, inserm and umpc université paris , paris, france. nm -h /ndpk-d forms symmetrical homohexameric complexes in the mitochondrial intermembrane space. the well established function of the en- zyme is phosphotransfer activity as a nucleoside diphosphate kinase (ndpk), using mitochondrial atp to regenerate nucleoside triphosphates. nm -h is further known to strongly bind in vitro to anionic phospholipids, mainly cardi- olipin, and in vivo to inner mitochondrial membranes. we show here that such protein/lipid complexes inhibit ndpk activity but are necessary for nm -h to function in selective intermembrane lipid transfer. nm -h -deficient hela cells expressing either wild-type nm -h or a membrane-binding deficient mutant were analyzed by membrane fractionation and lc-esi-ms. data revealed that wild-type nm -h increased cardiolipin content in the outer mitochondrial membrane as compared to mutant enzyme. this correlated with higher susceptibility of wild-type enzyme expressing cells to rotenone-induced apoptosis as seen by increased annexin v binding, elevated caspase / activity and stimulated release of cytochrome c into the cytosol. molecular modeling of nm -h binding with cardiolipin reveals potential intermembrane transfer mechanisms. we propose that nm -h acts as a lipid-dependent mitochondrial switch with dual function, allowing either for phosphotransfer or for cardiolipin transfer, with a role in apoptotic signaling. 	calcium-induced ros generation during ischemia triggers mptp-dependent cell death during reperfusion 	dynamic measurement of ca +-induced changes in organelle-specific redox microdomains 	er-mitochondrial ultrastructure in the liver of normal and ethnaol-fed rats 	mitochondrial nm -h /ndpk-d is multifunctional: intermembrane cardiolipin transfer linked to apoptosis letter to the editor volume • number • v a l u e i n h e a l t h © ispor - / /$ . / – blackwell science, ltdoxford, ukvhevalue in health - isporjanuary/february letter to the editorletter to the editorletter to the editor letter to the editor to the editor—as part of the ispor education steering committee, the ispor fellowship task force was formed in the spring of . the task force’s mission is to define the fundamentals of a core curriculum for pharmacoeconomic and out- comes research (pe/or) fellowships, as well as to foster knowledge of these programs among students of various scientific and professional backgrounds. as a result, in the task force began a research study to provide insight into the characteristics and components of the pe/or fellowship programs. the results of this study have recently been described in two articles published in the american journal of pharmaceutical education [ , ]. a brief description of the main research findings is presented. pe/or fellowship programs have been in exist- ence in the united states for more than a decade. with the increasing number of programs, however, it has become difficult to quantify the exact number of programs offered, and little is known about how these programs are structured [ ]. the objectives of the study conducted by the ispor fellowship task force were: ) to describe the organizational structures and educational compo- nents of pe/or fellowship programs within the united states and ) to determine the extent to which these programs adhere to the ameri- can college of clinical pharmacy (accp) pe fel- lowships guidelines. from november through december , the task force conducted a cross-sectional, web- based survey via the ispor web site. the survey population consisted of fellows as well as precep- tors involved in a pe/or fellowship, who were identified by collecting information through differ- ent sources including the accp and ispor direc- tories for these programs. the task force developed a set of three questionnaires, which were adminis- tered, respectively, to current fellows enrolled in a fellowship, to fellows who had finished a fellow- ship, and to preceptors currently involved in a fel- lowship. of the individuals completing the survey, current fellows, former fellows, and preceptors met the inclusion criteria. according to fellows and preceptors’ responses, the results of the study revealed that pe/or fellow- ships have numerous similarities in terms of their general characteristics, as well as their organiza- tional and educational aspects [ , ]. therefore, a common profile for these programs can be described as shown in table . with a program years in length, sponsored by the pharmaceutical industry, and conducted predominantly in academic and pharmaceutical industry sites, pe/or fellow- ships reportedly provide trainees with adequate resources to carry out scientific research [ ]. in addition, programs offer applicants exposure to a variety of types of research design and analysis to enhance their knowledge about pe/or. according to preceptors’ opinions, current pe/ or fellowships appear to adhere to the accp guidelines [ ]. in particular, preceptors reported that programs show significant compli- ance with the main aspects of the guidelines, which define both the structure and the process of fellowships. few preceptors, however, indi- cated that their programs currently offer trainees hands-on research activities at the level suggested by these guidelines. in conclusion, as an initiative of the ipsor fellowship task force, this is the first study to describe the current state of pe/or fellowship programs in the united states. the results of these investigations provide substantial insight to institutions and organizations wishing to develop new or refine existing pe/or fellowship pro- grams.—vittorio maio, pharmd, ms, office of health policy, clinical outcomes, thomas jeffer- son university. table common profile of a us-based pharmacoeco- nomic/outcomes research fellowship program based on fel- lows and preceptors’ responses* organizational features . two-year program. . sponsored by pharmaceutical industry. . conducted primarily in academic and pharmaceutical industry sites. . available facilities, including medical library, computer center, medical database . average fellow’s salary: us$ , – us$ , (year ). educational features . skills taught, including economic analysis and methodologies, as well as research design and methods. . software applications, including sas and access. . exposure to pe/or design and analysis. . research skills, including the conceptualization, operationalization, data management, and application of research projects. *adapted from maio et al. [ , ]. core metadata, citation and similar papers at core.ac.uk provided by elsevier - publisher connector https://core.ac.uk/display/ ?utm_source=pdf&utm_medium=banner&utm_campaign=pdf-decoration-v letter to the editor references maio v, lofland jh, nash db. pharmacoeconomic fellowships. preceptors’ views regarding adherence to the american college of clinical pharmacy guide- lines. am j pharm educ ; :article . maio v, lofland jh, doan qc, et al. organiza- tional structure and educational components of pharmacoeconomic fellowship programs: a fellows’ perspective. am j pharm educ ; :article . maio v, girts tk, lofland jh, nash db. pharmacoeconomic fellowships: the need for out- comes measures. pharmacoeconomics ; : – . shieldsquare captcha we apologize for the inconvenience... ...but your activity and behavior on this site made us think that you are a bot. note: a number of things could be going on here. 	if you are attempting to access this site using an anonymous private/proxy network, please disable that and try accessing site again. 	due to previously detected malicious behavior which originated from the network you're using, please request unblock to site. please solve this captcha to request unblock to the website 	 		you reached this page when trying to access 		https://iopscience.iop.org/article/ . / /pdf from 		 . . . on 		april , : : utc 	 sr-mitochondrial ultrastructure in the heart of normal and ethanol-fed rats tuesday, february , a agent colchicine that is known to increase free tubulin, mitochondrial potential, as measured by tetramethylrhodamine methyester (tmrm) uptake, decreased. inhibition of pka activity with h increased mitochondrial potential and, fur- thermore, reversed mitochondrial depolarization induced by colchicine. to fur- ther explore a role vdac-tubulin interaction in cell proliferation and survival, we studied the effect of erastin, the selective anti-tumour agent involved in the ras-raf-mek signalling pathway, on vdac blockage by tubulin. we found that erastin reverses tubulin blockage of vdac isolated from hepg cells, pro- moting the unblocked state of the channel. our findings suggest a novel func- tional link between serine/threonine kinase signalling pathways, mitochondrial respiration, and highly dynamic microtubule network which is characteristic of carcinogenesis and cell proliferation. -plat the isoform specific n terminus of vdac is dispensable for tbid induced cytochrome c release shamim naghdi , peter varnai , laszlo hunyady , gyorgy hajnoczky . thomas jefferson university, department of pathology anatomy and cell biology, philadelphia, pa, usa, semmelweis university, faculty of medicine, department of physiology, budapest, hungary. vdac proteins represent a main component of the outer mitochondrial mem- brane (omm). the vdac family is composed of isoforms with more than percent similarity. although their primary role was known to be in ion and me- tabolite transport between mitochnodria and cytosol, it has been discovered that vdacs are involved in apoptotic pathways. we have recently found that spe- cifically the vdac isoform is needed for tbid-induced cytochrome c release, due to its role in supporting bak insertion to the omm (roy et al. . embo rep. : - ). sequence analysis of the mammalian vdac isoforms shows a unique n terminal end in vdac , which is likely to be exposed to the cyto- plasm. to test the functional significance of this n terminus, the first amino acids were removed from vdac or were added to vdac . vdac -/- mef cells that are resistant to tbid, were rescued with these constructs and cyto- chrome c release was monitored in permeabilized cells by single cell imaging and immunoblotting. these studies revealed that cytochrome c release upon tbid application is effectively supported by both full length vdac and the vdac n-terminal deletion mutant. furthermore, vdac extended by the n terminus of vdac failed to restore cytochrome c release in vdac -/- mefs. thus the n terminus of vdac seems to be dispensible for tbid- induced omm permeabilization. currently, we are designing different muta- tions which target some addititional unique sequences in vdac to find the specific domain that is essential for tbid induced cytochrome c release. -plat patch-clamp analysis of mitochondrial ca d uniporter in different tissues francesca fieni, yuriy kirichok. ucsf, san francisco, ca, usa. the mitochondrial ca þ uptake has been recognized as a central player in cel- lular pathophysiology for decades. pathways of ca þ transport across the inner mitochondrial membrane (imm) were investigated indirectly with biochemical techniques and most recently by applying the patch clamp technique to mito- plasts isolated from mammalian systems. patch-clamp recording of the imm have proved to provide an unambiguous picture of mitochondrial ca þ uptake under strictly controlled conditions. in this study, we evaluated and compared the biophysical properties of mito- chondrial ca þ uptake in different mouse tissues. freshly isolated mitoplasts from mouse heart, skeletal muscle, liver, kidney, spleen and brown adipose tis- sue were patch clamped in the whole-mitoplast configuration. voltage step and ramp protocols covering the whole range of physiological potentials were ap- plied to elicit the inwardly rectifying ca þcurrent sensitive to rur known as mcu. the distribution of mcu current densities between tissues was as fol- lows: spleen > brown adipose tissue z skeletal muscle > kidney > liver >> heart. interestingly, mcu current density in heart was about times smaller than in skeletal muscle. our results support the view of a differential tissue activity of mcu, which can be explained by either a different distribution of mcu channel and/or by a different expression of its regulatory subunits confer- ing various modes of physiological regulation. further on, in order to investigate the putative direct contribution of uncou- pling protein isoform and (ucp / ) to the uniporter, we investigated mcu properties in wild type (wt) mouse tissues where these two proteins have been found to have a major role and compared its properties in the corre- spondent tissues of ucp and ucp ko mice. we found no significant differ- ences in calcium currents of any of the wt tissues studied compared to their ucp / ko counterparts. -plat sr-mitochondrial ultrastructure in the heart of normal and ethanol-fed rats gyorgy csordas , david mankus , tanvir shaikh , xing meng , jan hoek , carmen mannella , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, wadsworth center, albany, ny, usa. chronic alcoholism causes various forms of stress in the heart, and this is often accompanied by mitochondrial dysfunction. a putative source of mitochondrial dysfunction is sr-mitochondrial stress and the ensuing mitochondrial ca þ overload. to test this possibility, first we isolated mitochondria from chronic ethanol-fed ( months) and paired control rats, and documented ethanol- dependent sensitization to ca þ and ros-induced permeabilization. to evalu- ate the ultrastructural basis of the mitochondrial impairments, we performed transmission electron microscopy (tem) and electron tomography studies of left ventricular muscle. the overall ultrastructure of the myocytes became less organized in the ethanol-fed condition. also, a considerable fraction of the mitochondria lost the highly ordered structure of the cristae and showed an increase in the cross-sectional area. however, the size of the sr- mitochondrial associations and the gap-width at the interface was unchanged. evaluation of the sr-mitochondrial tethers by electron tomography indicates that they occur in clusters and display heterogeneity in length, as previously re- ported for er-mitochondrial tethers in normal rat liver (csordas et al, , j cell biol, : ). overall tether length distribution appears to be unaltered by alcohol ingestion. analyses of effects of alcohol ingestion on tether membrane-surface density and structural classes (linear, v, y and more com- plex shapes) is in progress, as is d analysis of ser and mitochondrial inner- and outer-membrane topologies. (supported by nih grant rc aa .) -plat bcl-xl increases bax mitochondrial localization and activation in non- apoptotic cells laurent m. dejean , thibaud t. renault , oscar teijido , gisele velours , yogesh tengarai ganesan , nadine camougrand , bruno antonsson , stephen manon . california state university of fresno, fresno, ca, usa, cnrs, institut de biochimie et de génétique cellulaires, bordeaux, france, nih, nichd, bethesda, md, usa, memorial sloan kettering cancer center, new york, ny, usa, merck serrono s.a., geneva research center, geneva, switzerland. we report that, in non-apoptotic pro-lymphocyte cells, bcl-xl induced an in- crease of the mitochondrial localization of bax up to the level found in apopto- tic cells. furthermore bcl-xl stimulated both the active conformation of bax and increased the total amount of bax inserted in the outer mitochondrial mem- brane. in order to further investigate the molecular mechanisms involved in this effect, different bax and bcl-xl mutants were co-expressed in yeast. we found that wild-type bcl-xl increased the mitochondrial localization of both wild- type bax and of an active mutant bax-s d, while mutant bcl-xl-g a did not have this effect. further, wild-type bcl-xl protected bax-s d against proteolytic degradation. finally, we found that a c-terminally truncated mutant of bcl-xl, that lost its capacity to inhibit bax-induced release of cyto- chrome c, still increased the mitochondrial localization of wild-type bax, thus promoting the release of cytochrome c. these data suggest that bcl-xl, by act- ing as a modulator of mitochondrial bax localization, may play an active role along the pathway leading to bax activation. -plat the physiological response of intact ex vivo mitochondria upon apopto- tic stress: insight into the regulation of apoptosis at a mitochondrial level martin n. lidman , marcus wallgren , olivier keech , yong-zhi guo , tor ny , gerhard gröbner . chemistry department, umeå university, umeå, sweden, umeå plant science center, umeå, sweden, medical chemistry and biophysics, umeå university, umeå, sweden. apoptosis - programmed cell death - is vital for multicellular organisms to dis- pose of redundant, damaged or infected cells. this mechanism becomes dys- functional in cancer where tumor cells survive drug-induced death signals. reversely, upregulated apoptosis can induce premature neuronal cell death in amyloidogenic diseases such as alzheimer’s disease (ad) or amyotrophic lateral sclerosis (als). mitochondrion, the power plant of the cell, contains an arsenal of proteins which regulate programmed cell death. there, the pro- and anti-apoptotic bcl- proteins meet at the mitochondrial membrane to decide the fate of a cell. how the molecular activities of the anti-apoptotic 	the isoform specific n terminus of vdac is dispensable for tbid induced cytochrome c release 	patch-clamp analysis of mitochondrial ca + uniporter in different tissues 	sr-mitochondrial ultrastructure in the heart of normal and ethanol-fed rats 	bcl-xl increases bax mitochondrial localization and activation in non-apoptotic cells 	the physiological response of intact ex vivo mitochondria upon apoptotic stress: insight into the regulation of apoptosis a ... [pdf] complex interplay of kinetic factors governs the synergistic properties of hiv- entry inhibitors | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /jbc.m . corpus id: complex interplay of kinetic factors governs the synergistic properties of hiv- entry inhibitors @article{ahn complexio, title={complex interplay of kinetic factors governs the synergistic properties of hiv- entry inhibitors}, author={k. ahn and m. root}, journal={the journal of biological chemistry}, year={ }, volume={ }, pages={ - } } 	k. ahn, m. root 	published 	medicine, biology 	the journal of biological chemistry the homotrimeric hiv- envelope glycoprotein (env) undergoes receptor-triggered structural changes that mediate viral entry through membrane fusion. this process is inhibited by chemokine receptor antagonists (coras) that block env–receptor interactions and by fusion inhibitors (fis) that disrupt env conformational transitions. synergy between coras and fis has been attributed to a cora-dependent decrease in the rate of viral membrane fusion that extends the lifetime of the intermediate state… expand view on asbmb jbc.org save to library create alert cite launch research feed share this paper citationshighly influential citations background citations methods citations view all figures, tables, and topics from this paper 	 figure 	 table 	 figure 	 figure 	 figure 	 figure 	 figure 	 figure 	 figure view all figures & tables 	chemokine receptor 	enfuvirtide 	membrane fusion 	ervw- gene 	antiviral agents 	fusion inhibitor 	receptor binding 	viral membrane 	hiv infections 	kinetics 	affinity 	cora (plant) paper mentions news article hiv drugs: why do some act synergistically and others not? technology networks october news article here's why hiv drugs don't synergize medindia october news article when hiv drugs dont cooperate infection control today october news article when hiv drugs don't cooperate eurekalert! october citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency structural and thermodynamic analysis of hiv- fusion inhibition using small gp mimetic proteins. 	s. jurado, mario cano-muñoz, + authors f. conejero-lara 	chemistry 	 	 save alert research feed identification of a glycan cluster in gp essential for irreversible hiv- lytic inactivation by a lectin-based recombinantly engineered protein conjugate. 	bibek r parajuli, k. acharya, + authors i. chaiken 	chemistry, medicine 	the biochemical journal 	 	 save alert research feed how entry inhibitors synergize to fight hiv 	g. melikyan 	biology, medicine 	the journal of biological chemistry 	 	 	highly influenced 	pdf 	view excerpts, cites background save alert research feed molecular mechanism of hiv- resistance to sifuvirtide, a clinical trial–approved membrane fusion inhibitor 	d. yu, x. ding, + authors y. he 	chemistry, medicine 	the journal of biological chemistry 	 	 	pdf 	view excerpt, cites background save alert research feed potent inhibition of hiv replication in primary human cells by novel synthetic polyketides inspired by aureothin 	alexander herrmann, m. roesner, + authors r. brack-werner 	biology, medicine 	scientific reports 	 	 	pdf save alert research feed comparison of null models for combination drug therapy reveals hand model as biochemically most plausible 	mark sinzger, j. vanhoefer, c. loos, j. hasenauer 	computer science, biology 	 	pdf 	view excerpts, cites background save alert research feed comparison of null models for combination drug therapy reveals hand model as biochemically most plausible 	mark sinzger, j. vanhoefer, c. loos, j. hasenauer 	computer science, medicine 	scientific reports 	 	 	pdf 	view excerpts, cites methods save alert research feed the herbert tabor young investigator awards: meet the awardees! 	l. gierasch, g. demartino 	sociology, medicine 	the journal of biological chemistry 	 	 	pdf 	view excerpt, cites background save alert research feed references showing - of references sort byrelevance most influenced papers recency asymmetric deactivation of hiv- gp following fusion inhibitor binding 	kristen m kahle, h. steger, m. root 	chemistry, medicine 	plos pathogens 	 	 	pdf 	view excerpts, references background and methods save alert research feed kinetic dependence to hiv- entry inhibition* 	h. steger, m. root 	chemistry, medicine 	journal of biological chemistry 	 	 	pdf 	view excerpts, references methods and background save alert research feed sensitivity of hiv- to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics 	j. reeves, s. gallo, + authors r. doms 	biology, medicine 	proceedings of the national academy of sciences of the united states of america 	 	 	pdf save alert research feed receptor activation of hiv- env leads to asymmetric exposure of the gp trimer 	mukta d. khasnis, konstantine halkidis, a. bhardwaj, m. root 	chemistry, medicine 	plos pathogens 	 	 	pdf 	view excerpts, references background and methods save alert research feed kinetic factors control efficiencies of cell entry, efficacies of entry inhibitors, and mechanisms of adaptation of human immunodeficiency virus 	e. platt, james p. durnin, d. kabat 	biology, medicine 	journal of virology 	 	 	pdf 	view excerpt, references results save alert research feed targeting therapeutics to an exposed and conserved binding element of the hiv- fusion protein 	m. root, d. hamer 	biology, medicine 	proceedings of the national academy of sciences of the united states of america 	 	 	pdf 	view excerpt save alert research feed early steps of hiv- fusion define the sensitivity to inhibitory peptides that block -helix bundle formation 	kosuke miyauchi, m. kozlov, g. melikyan 	biology, medicine 	plos pathogens 	 	 	pdf 	view excerpt, references results save alert research feed env-glycoprotein heterogeneity as a source of apparent synergy and enhanced cooperativity in inhibition of hiv- infection by neutralizing antibodies and entry inhibitors. 	t. ketas, s. holuigue, k. matthews, j. moore, p. j. klasse 	biology, medicine 	virology 	 	 	 	view excerpt, references background save alert research feed is there a future for antiviral fusion inhibitors? 	b. berkhout, d. eggink, r. sanders 	biology, medicine 	current opinion in virology 	 	 save alert research feed hiv- gp as a target for viral entry inhibition. 	m. root, h. steger 	biology, medicine 	current pharmaceutical design 	 	 	view excerpts, references background save alert research feed ... ... related papers 	abstract 	figures, tables, and topics 	paper mentions 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue lessons in empowerment: transparency editorial poultry science : – doi: . /ps. - lessons in empowerment: transparency colin g. scanes , editor-in-chief a previous editorial addressed the importance of honesty (scanes, ). this editorial discusses the is- sues of transparency. in my opinion, transparency is one of the requirements for engendering trust, and trust is critical to so much of what we do. a culture of transparency is essential for research. the results section of a paper is arguably the most im- portant section. we expect that the results presented fairly summarize the data obtained. it is clearly wrong to selectively present data to be included. this is fal- sification of results and this is scientific misconduct. the corollary is that we should not bury data that does not fit with our well-established position or working hypothesis. alter the results or there is statistical sig- nificance. again, this is falsification of results and sci- entific misconduct. i encourage authors to place their raw data into the journal’s data repository (as a data supplement) linked electronically to the paper. a culture of transparency is also important for a journal. there needs to be clarity of expectations. for instance, what statistics are appropriate to report? an area where transparency is not used is with review of manuscripts. i firmly believe in the peer-review process: reviewers need keep confidential the manuscripts they review, and papers are frequently reviewed “blind”; that is, not identifying the authors or the institution where the research was conducted. i say “frequently” because an experienced reviewer can often discern the labora- tory where the work was done. a culture of transparency is critically important for teaching. students need to understand the expectations of the instructor. what metrics will be used? what materials will be covered and at what level? how will the textbook be used? most importantly, when will ex- aminations and tests occur? i would argue for a culture of transparency in a uni- versity, a company, a government laboratory, and in so- ciety as a whole. thomas jefferson stated that, “when- ever the people are well-informed, they can be trusted with their own government.” i would suggest that this be paraphrased to “when people are well-informed, they trust their own government.” references scanes , c. g. . lessons in empowerment: honesty is essential for trust. poult. sci. : . university of delaware center for health profession studies david barlow, phd director, university center for health professions studies; director, college of arts & sciences medical/dental scholars program; faculty, university of delaware historical foundation origin the office of the provost created a taskforce in the spring of to examine the status of “premedical education at the university of delaware” existing at that time. membership on the taskforce was highly diverse with representatives from thomas jefferson university, christiana care hospital services, the college of arts & sciences, the college of health sciences, the office of admissions, and premedical/health profession students. dr. david barlow from the college of health sciences was designated chair. the taskforce was charged to review and evaluate current premedical studies practices, with the goal of making recommendations for changes perceived essential for enhancing the success of all students in gaining admission into medical schools and other health profession programs. the first major recommendation endorsed unanimously by the taskforce was to create a “center for premedical and health profession studies.” the focus of this center would be to help students across all colleges who wanted to pursue careers in the health professions. the provost’s taskforce viewed the center as the best approach for advising pre-health profession students in a comprehensive manner. locations a three-year agreement was created in the summer of to locate and host the new center for premedical and health profession studies (cphps) within the facilities of the career services center. reporting to the office of the provost, the center was formally announced with a university-wide opening ceremony in january of . the center’s goal was to benefit students in all colleges, and the success of the center would depend on university-wide support. the cross-college initiative is reflective of a new emerging approach to healthcare which is inter- professional and across disciplines. initial funding for the center came in part from a unidel grant received in . the name of the center was shortened to the center for health profession studies (chps) in . following an almost two-year temporary location in hullihen hall, the center was formally relocated and re-dedicated at its permanent location in e pearson hall in october of (see figure ). figure . pearson hall initial staffing initial staffing included the assignment of a center director (david barlow) and an administrative assistant (laura pawlowski). the demand for staffing increased dramatically and, starting in , expanded to include a program manager, two partial workload faculty health professions advisors (hpa), a miscellaneous wage hpa/hpec assistant, a graduate assistant hpa, and a number of undergraduate assistants/peer mentors. the additional staffing served to address a rapid increase in the demand for advisement services, the growing popularity of numerous co-curricular programs, and the increased sponsored activities that the center provides students. mission statement and goals the center for health profession studies supports and encourages students from all majors who are pursuing careers in the health professions. the center remains focused on student outcomes – helping students achieve success in careers that they have chosen: medicine, dentistry, optometry, podiatry, physician assistant, advanced practice registered nurse, pharmacy, physical/occupational therapy and other health profession programs. the center provides advisement and referral services to a growing community of pre-health profession students in all colleges in their academic and extracurricular preparation to improve success of acceptance into healthcare profession programs. over students utilized the resources and services of the center in alone. three main goals of the center are to: • help students make informed decisions about their choice of a future healthcare profession. • promote academic excellence by providing accurate and up-to-date guidelines for completing pre-health profession curricular requirements, for thoroughly understanding all admission requirements, and for using all available resources of the center. • support active student engagement within the healthcare community, primarily through clinical work, voluntary service, and translational research. services/program activities of the center in addition to group meetings, special programs, field trips, and sponsored monthly guest lecturers, students may seek individual assistance from the center. students can schedule an appointment via email, online, or phone to meet with one of the health professions advisors. additionally, center administrative staff members are available for walk-in students to meet briefly, one-on-one, to discuss their academic goals or concerns. no appointments are necessary and students are seen on a first-come, first-served basis. walk-in hours are provided during the fall and spring semesters. a few phone appointments are set aside each week. standardized test preparation resources kaplan/nextstep/uworld/examkrackers and other standardized test preparation programs are frequently supported often with financial incentives/discounts to aid pre-health profession students in their preparation for mcat/dat/gre examinations. pre-health profession’s living learning community since the center has created and sponsored a highly successful first-year pre-health professions living learning community for freshmen students interested in pre-health professions. students accepted into the program have the opportunity to live in close proximity with over other freshmen, mentored by two upperclassman peer mentors and one graduate assistant, all who have similar career interests and are taking similar courses. the students have access to extra support from faculty and staff of the center to pursue career and graduate school interests. in addition, they have access to professionals knowledgeable about standardized tests (e.g., mcat), graduate school applications, academic, and co-curricular requirements. programs and events in the residence hall include exciting speakers from the healthcare industry, extracurricular enrichment, health-related volunteer experiences, and social events. since the initiation of this living learning community, the program has produced a remarkable % retention rate over the past five years. medical internships abroad programs students have the opportunity to participate in exciting health profession medical internship opportunities abroad sponsored by the center during special sessions. since , over students have performed medical internships traveling to seven different countries including spain, portugal, italy, greece, hungary, china, and turkey in partnership with the university institute of global studies and a program called atlantis. in all the programs, students shadow doctors, interact with health profession students from other cultures, and gain an understanding of international healthcare systems. in june of , students participated in st. george’s university “summer leadership academy” in the west indies experiencing introductions to their medical, veterinary, and public health professional programs of study on the island of granada in the west indies. all of these study abroad experiences hosted and guided by ud faculty help students distinguish themselves as outstanding applicants for medical school and other health-related professional schools. premedical post-baccalaureate certificate program this unique program, limited to post-baccalaureate students, is designed for those qualified individuals who have previously completed a bachelor's degree in a non-science related field but who now want to fulfill the requirements for admission to medical, dental, or other health profession schools. accepted students work closely with the center to develop a structured individualized program of study that addresses the academic and co-curricular requirements to be considered for admission to medical, dental, or other health profession schools. since , over % of these post baccalaureate students completing this program achieving a certificate of academic excellence have successfully matriculated into medical/physician assistant programs of study. designed to support “career changers”, this program is affiliated with the philadelphia college of osteopathic medicine which is a part of a cohort agreement with the ud post baccalaureate program. collaborations the center has established affiliations/agreements with area hospitals and healthcare organizations to provide ud students with unique learning experiences. some of these include the delaware institute for medical education and research (dimer) and the delaware health science alliance (dhsa). in addition, the center has agreements with christiana care health system and st. francis hospital of wilmington. these latter affiliations support approximately premedical studies students each year performing over hours each of shadowing medical preceptors in a variety of different healthcare settings. in the past this also included shadowing opportunities for students in the delaware division of forensic science. through the medical scholars program, the center has formal affiliations with the sidney kimmel medical college at thomas jefferson university, the philadelphia college of osteopathic medicine, and the rowan university school of osteopathic medicine. the center sponsors frequent field trips to these institutions as well as to other institutions such as the pennsylvania state university hershey college of medicine, cooper medical school of rowan university, and the geisinger commonwealth school of medicine. in addition, students in the past have visited the virtual education simulation training center at christiana care health system. medical scholars program (msp) established in , the medical scholars program is a unique early admissions premedical + academic program in the center sponsored by the college of arts and sciences at the university of delaware and by the sidney kimmel medical college of thomas jefferson university. as a dual major, eight-year academic program, in / the ud msp expanded to affiliate with the philadelphia college of osteopathic medicine and the rowan school of osteopathic medicine. it is designed for students who are certain that they want to become physicians and who desire a program that blends the scientific and cultural aspects of the medical humanities. the msp is accomplished by providing highly qualified students with a balanced education in liberal arts, science, and professional studies. the program includes the traditional courses in the life/physical sciences as well as a specialization in areas related to medicine dealing with bioethics, administration and public policy, translational research, or nutrition and health. small group discussions, problem-based instruction, and discipline specific practicum experiences in clinical/ institutional settings, all experienced with strong mentoring, are special aspects of this program. to become a part of this early conditional acceptance programs, students in the second semester of their freshman year attend an orientation meeting to declare an interest in the program. students are required to attend monthly medical scholar program (msp) meetings, accumulate volunteer/shadowing hours, obtain letters of recommendation, and achieve academic excellence. during the spring semester of the sophomore year, students from this group complete an application to the program, and as qualified rising juniors, are recommended by the university of delaware for interviews at one of the prestigious medical school cohorts. following a successful interview, students are granted provisional acceptance to medical school. students then declare a second major, bachelor of arts in liberal studies, completing the core science medical school requirements, combined with studies in the arts, humanities, and social sciences. seniors in the msp must continue to demonstrate a high level of academic performance and achieve a minimum score on the mcat prior to medical school matriculation. since , a total of students have obtained baccalaureate degrees in the medical scholars program resulting in a medical school matriculation rate of % in post-graduate year one (pgy ) (see figure ). in pgy the success rate rises to a remarkable % over this same period. dimer eligible in-state students accounted for slightly more than % of these former ud msp graduates. in the past years a total of medical practica/internships were performed by these same students involving at minimum , hours of shadowing healthcare professionals regionally and internationally. note that the major percentage of these shadowing hours were supported by christianacare and other local area medical facilities such as st. francis hospital in wilmington. the msp is operated through the center for health profession studies under the direction of david a. barlow, phd, since . figure . recent ud msp graduates now in medical schools center future goals the center for health profession studies strives to expand services to students and alumni not only to the university, but also to our neighboring state institutions who are considering careers in the various health professions. available to students across all majors and colleges, the center will continue to enable a growing population of students who are interested in the highly competitive health profession careers to make conscious and thoughtful decisions about their future paths. increased guidance and resources are provided along the “pre-health profession” pathways, from curricular planning, to securing clinical and research opportunities, to preparation for required standardized tests, to participation in health-related internships/in- service activities, and finally to the successful completion of the application process for medical, dental, veterinary and other health profession graduate schools. for more information about the center, please visit: center for health profession studies, university of delaware e pearson hall academy street newark, delaware https://sites.udel.edu/healthpro summary list of center sponsored programs medical/dental scholars program (college of arts & sciences) premedical post baccalaureate certificate program (pmpb) pre-health professions living learning community medical internships abroad/domestically medical practica capstone courses arsc arsc hosp soci regional medical/dental school field trips medical school affiliations sydney kimmel medical college (thomas jefferson university) philadelphia college of osteopathic medicine rowan school of osteopathic medicine st. george’s university (medicine/veterinary medicine) area hospital affiliations christiana care health services st. francis hospital (wilmington) standardized test preparation programs writing personal essays mock interview training admissions applications/process (amcas, aacomas, otcas, ptcas, caspa) exam preparation affiliations (mcat, gre, dat, etc.) kaplan nextstep uworld examkrackers magoosh baron health professions advisement services medicine dentistry optometry podiatry physician assistant advanced nurse practitioner pharmacy occupational/physical therapy anesthetist assistant veterinary medicine chiropractic prepmed/medical devices post baccalaureate certificate program registered student organization sponsorships pre-soma pre-dental society phi delta epsilon making doctors minority association of pre-health students occupational therapy club annual spring “health professions fair” professional affiliations north east association of advisors for the health care professions (neaahp) national association of advisors for the health professions (naahp) 	university of delaware center for health profession studies 	historical foundation 	origin 	locations 	initial staffing 	mission statement and goals 	services/program activities of the center 	standardized test preparation resources 	pre-health profession’s living learning community 	medical internships abroad programs 	premedical post-baccalaureate certificate program 	collaborations 	medical scholars program (msp) 	center future goals access constraints and binding energetics of a potassium channel inactivation gate sunday, february , a -pos board b access constraints and binding energetics of a potassium channel inactivation gate gaurav venkataraman, deepa srikumar, miguel holmgren. nih, bethesda, md, usa. voltage-activated potassium (kv) channels open an intracellular gate in re- sponse to changes in transmembrane voltage, allowing k þ to permeate at rates near diffusion. in some kv channels, permeation can be interrupted by the n-terminus of the protein acting as a blocking particle, binding at the intracel- lular cavity of the channel and physically obstructing the permeation pathway. despite being tetramers, kv channels require only one bound n-terminus to inactivate. in nature, inactivation is targeted by rna editing, which converts an isoleucine of the intracellular cavity into a valine. the functional conse- quence is a large increase in unbinding kinetics. how does each ‘‘wall’’ of the cavity contribute to the increase in unbinding kinetics of a single bound n-terminus? to address this question we made con- catenated shaker heterotetramers consisting of only one free n-terminus and a single isoleucine to valine mutation at position (i v), mimicking the rna editing site in humans and rodents. surprisingly, the rate of unbinding was the same for individual i v mutations in each wall; each corresponded to a decrease in binding energy of about . rt. in fact, the binding energy de- creased linearly as a function of the number of i v mutated subunits. these results suggest that despite being tethered to a particular subunit, the single in- activation particle has sufficient freedom to interact with position of each subunit with roughly equal probability. where does this freedom come from? it is expected that the inactivation gates enter the cavity through lateral ‘windows’, similarly to k þ . can our single tethered inactivation gate enter through each of the four windows of the protein? we will address this question by making individual cysteine mutations at each window and testing the inac- tivation gate’s binding kinetics after chemical modification. -pos board b gating interactions between the cytoplasmic t domain and pore of a kv channel brian urbani, manuel covarrubias. jefferson medical college of thomas jefferson university, philadelphia, pa, usa. whereas the gating roles of the voltage-sensing and pore domains of kv channels have been extensively investigated, much less is known about the mechanisms governing the regulation of gating by the cytoplasmic t domain. previous work from this lab strongly suggests that the kv . t domain un- dergoes conformational changes directly linked to gating (j. gen. physiol., : - , ); however, the structural basis of the communication between the activation gate and the t domain has remained elusive. to tackle this problem, we applied cysteine scanning mutagenesis, voltage- clamp electrophysiology, double mutant cycle analysis (dmca) and oxidizing reagents to probe specific interactions between the cytoplasmic t domain l helix, the s -s linker and s tail. the energetic impact of the mutations on activation gating is apparently small. by comparison, the energetic impact of the mutations on inactivation gating was significantly greater. dmca of k c(l )þa c(s ) revealed a significant interaction energy ( kcal/ mol), which suggests an interaction between k in the l helix and a in s . supporting this possibility, the currents induced by k c(l )þ a c(s ) are inhibited (~ % of control) by an oxidizing agent (tbuho ), whereas the single mutants are not; and the effect is reversed by the reducing agent dtt. these results indicate the formation of a disulfide bond between the interacting side chains, which is consistent with physical interaction between k (l ) and a (s ). overall, we conclude that regulation of inactivation gating by the t domain involves a physical interaction between the t l helix and the distal segment of s . supported by nih grant r ns (mc). -pos board b is the activation gate closed in kv channel closed-state inactivation? jeffrey d. fineberg, manuel covarrubias. thomas jefferson university, philadelphia, pa, usa. kv .x channel complexes including auxiliary subunits such as dpp -s and kchip undergo preferential closed-state inactivation (csi; baehring and covarrubias, , j physiol, . : - ; fineberg et al., , j gen physiol, in press). however, the molecular basis of csi in kv .x channels remains poorly understood. a key unanswered question of this problem is whether the channel’s activation is actually closed, as csi implies. we have previously proposed that csi results when the activated channel fails to open or simply prefers to close. this hypothesis specifically suggests that the intra- cellular activation gate may adopt a stable closed conformation, even under depolarized conditions that would initially favor the activated ‘‘up’’ state of the voltage sensors. to test this hypothesis, we are exploiting the trapping paradigm previously investigated by holmgren et al. to test the state of the intracellular activation gate ( , j gen physiol, : - ). essentially, if the activation gate closes behind a quaternary ammonium (qa) blocker inside the pore, the blocker cannot exit the pore; effectively, it is trapped. we are expressing the ternary kv . /i c channels (this mutation favors trap- ping) including dpp -s and kchip in xenopus oocytes. then, in the inside- out patch-clamp configuration, we are using a computer-controlled perfusion system to deliver the qa derivative decyltrimethylammonium bromide (c ) to the bath and probe the ability of the channel’s activation gate to trap c in the closed, open and inactivated states. preliminary results show that the trapping paradigm may yield an answer to the central question of this study. if the activation gate is indeed closed during csi, c trapping will only occur when the drug is applied to the conducting channel, but no trapping of c will be observed in the closed and inactivated states. supported by nih grant r ns (mc). -pos board b water at the potassium channel gate: quantum calculations show an oscillation in water structure alisher m. kariev, michael e. green. city college of the city university of ny, new york, ny, usa. quantum calculations on the open gate and the immediately surrounding re- gion of the kv . voltage gated potassium channel show that water adopts two conformations there, one when the ion is present, and another with no ion present. an energy minimum at the gate with no ion allows an ion to enter from the solution; from the gate it repels an ion in the channel pore cavity into the selectivity filter (essentially the ‘‘knock-on’’ mechanism). the pore cavity minimum can then be occupied by the ion moving from the gate minimum, leaving it available for anion from bulk, so the cycle continues. the arrange- ment of water, and the ion hydration, defines the gate energy minimum, and this in turn depends on the highly conserved prolines, especially p ( a pdb numbering), in the pvpv sequence in the gate. absent an energy minimum at the gate an ion entering from solution would be repelled back into solution by the ion in the cavity. furthermore, the ion remains hydrated by water molecules, at least more than in bulk, as it passes through the gate, based on optimizations with the ion at three different positions: ) at the gate position nearest p ) å above ) å below, this position. the open gate maintains very nearly the same protein atom positions throughout. additional calculations will be required to determine the exact interaction en- ergy with an ion in the cavity, and the amount of water that is present in the cavity. optimizations of the system configuration were done at hf/ - gsp level, with atoms ( with the ion). energy was determined using both b lyp/ - g* and bvp / - g*, but the system was too large for free en- ergy determination. -pos board b water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computational mutations, and the role of a histidine in gating alisher m. kariev, michael e. green. city college of the city university of ny, new york, ny, usa. conservation of the pvpv sequence at the potassium channel gate has not been well understood. quantum computations (optimization at hf/ - gsp level) of the gate of the kv . channel that are presented here show that the proline-proline distances (ring atoms) are preserved as the ion moves through the gate. this calculation is supplemented by mutating one of the prolines to valine (p v, a pdb numbering for all residues in this abstract) in the computation, producing a pvvv sequence. water structure changed dramati- cally, as the protein backbone moved inward nearly å, effectively closing the channel; the proline ring n-n distance between diagonally opposite pro- lines dropped from . å (distance from optimization: x-ray distance = . å) to . å, too small to allow passage of a hydrated k þ . this suggests that the prolines play a key structural role, modulating both protein and water structure. furthermore, protonation of h may close the channel. protonation of this histidine shows it moving toward the gate by about å, which should close the gate electrostatically, while deprotonation opens the gate. protonation was calculated with two added protons, the other being accepted by e of the t intracellular moiety. when deprotonated, the histidine does not move as much as å from the x-ray position in the optimization, and is linked to e ; this accounts for the known importance of the t segment in gating. e , also of t , could accept a third proton. there is a salt bridge structure including these residues similar to the one occupying a key position in the pro- ton pathway in the hv channel. 	access constraints and binding energetics of a potassium channel inactivation gate 	gating interactions between the cytoplasmic t domain and pore of a kv channel 	is the activation gate closed in kv channel closed-state inactivation? 	water at the potassium channel gate: quantum calculations show an oscillation in water structure 	water structure at the potassium channel gate: the importance of the prolines in the pvpv sequence, as shown by computation ... wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" 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chlorophyte algal ancestor to an apicomplexan ancestor ( ). waller et al. ( ) oppose this interpretation based on a phylogeny implying close affilia- tion of apicomplexan cox a and cox b genes with ciliate cox homologues; a -bp in- sertion that separates the corresponding do- mains in ciliate mitochondrial cox genes; and low hydrophobicity values for ciliate mitochondrial coxii and apicomplexan coxiia and coxiib subunits. they suggest that mitochondrial cox genes were split and transferred to the nuclei of the apicomplexan and chlorophyte ancestors during indepen- dent events. we find their phylogenetic argument uncon- vincing because, as they admit, statistical sup- port for the position of the ciliate sequences is lacking. affiliation of ciliates and apicomplex- ans previously noted in mitochondrial sequence phylogenies should also be interpreted with caution because both lineages are rapidly evolv- ing and may be artifactually grouped due to long-branch attraction ( ). furthermore, the ad- dition of ciliate cox sequences to our previous phylogenetic analysis ( ), does not show a re- lationship between ciliates and apicomplexans (fig. , a and b). nevertheless, we are pleased that in agreement with our findings in ( ), waller et al. ( ) confirm the common branch for apicomplexan and chlorophyte coxiia and coxiib sequences—an otherwise unex- pected affiliation. the presence of an insertion in the mito- chondrial cox genes of ciliates does not nec- essarily imply kinship with apicomplexan frag- mented cox a and cox b genes. the cox gene is susceptible to insertions between regions that encode the hydrophobic and hydrophilic do- mains of coxii. insertions of variable lengths have been described in cox genes of unrelated organisms ( ), including brown marine algae (nc_ , nc_ ), microflagellates (nc_ ), and bacteria (nc_ ). localization of insertions in cox is most likely constrained by the difficulty of inserting in the gene without disrupting the structure of the coxii protein ( ). ciliates also exhibit an in- sertion in cox and a fragmented mitochondrial nad ( ). these rearrangements most likely occurred after the divergence of ciliates from apicomplexans and dinoflagellates ( ), since no sequence remnants of insertions are present in cox in apicomplexans ( ) or dinoflagellates ( ). the cox and cox insertions were most likely absent in the alveolate ancestor and were acquired by ciliates independently. therefore, the proposed vertical inheritance of cox a and cox b genes in apicomplexans is not directly supported by the presence of insertions in ciliate cox . the hydrophobicity analysis presented by waller et al. ( ) provides no evidence for a common origin of ciliate coxii and apicom- plexan coxiia and coxiib sequences. we agree that hydrophobicity is one of the rate- limiting steps in functional gene transfer from the mitochondrion to the nucleus ( , – ). it is therefore not surprising that apicomplexan coxiia and coxiib subunits exhibit di- minished hydrophobicity. nevertheless, the low mean hydrophobicity values of ciliate mitochondrial coxii sequences merely indi- cate that, from the hydrophobicity point of view, the corresponding genes are ready to migrate—not that they migrated in the distant past. ciliate mitochondrial dna (mtdna) contains more than the standard set of genes encoded by mtdna in other eukaryotes ( ) and therefore does not seem to show an in- creased rate of gene migration. the hydro- fig. . phylogenetic analysis of coxii. (a) maximum likelihood (ml) tree. coxiia and coxiib (excluding mts and extensions) were fused in silico as a single polypeptide and aligned with orthodox mitochondrial coxii sequences ( ). (b) phylogram showing branch lengths estimated with ml implementing the data, model, and parameters used to perform the ml search. coxii sequences for tetrahymena pyriformis (nc_ ), t. thermophila (nc_ ), and paramecium aurelia (nc_ ) were obtained from genbank. (c) multiple protein sequence alignment of the n-terminal regions of coxiib sequences. shown are the n-terminal extensions of nuclear cox b genes from chlorophytes and apicomplexans (blue), the conserved residues in these domains (yellow), the conserved residues found only in chlorophytes and ampicomplexans (black back- ground), the corresponding region of the -residue insertion in ciliate mitochondrial coxii (gray), and the conserved residues between ciliates and apicomplexans (bold). droso (drosophila mela- nogaster), homo (homo sapiens), arabi (arabidopsis thaliana), mesos (mesostigam viride), theil (theileria parva), plasm (plasmodium yoelli), toxop (toxoplasma gondii), chlam (chalmydomonas reinhardtii), polyt (polytomella sp.), tther (tetrahymena termophila), tpyri (tetrahymena pyriformis), and param (paramecium aurelia). technical comment www.sciencemag.org science vol july b o n a p ril , h ttp ://scie n ce .scie n ce m a g .o rg / d o w n lo a d e d fro m http://science.sciencemag.org/ phobicity of contemporary ciliate coxii is unlikely to bear on either the location of its gene or apicomplexan coxiia and coxiib phylogeny. in addition, the hydrophobicity analysis does not argue against the proposal that the original apicomplexan mitochondrial cox gene was eliminated after functional acquisition of chlorophyte cox a and cox b sequences ( ). coxiib has a unique n-terminal exten- sion that most likely arose since the splitting of the original mitochondrial cox gene of the chlorophyte ancestor ( ). protein sequencing has confirmed the presence of this extension in mature chlorophyte coxiib ( ). all chlo- rophyte and apicomplexan sequences share n-terminal extensions of coxiib containing the conserved pxxxpxxy motif not present in the canonical coxii. these extensions seem homologous and suggest a common origin for chlamydomonad and apicomplexan coxiia and coxiib sequences. the proposal of waller et al. ( ) would imply that this domain conservation is due to convergent evolution, which we consider unlikely. the correspond- ing borders of the ciliate coxii insertions and the apicomplexan coxiib extensions reveal no similarities (fig. c). we originally described rare characteris- tics that are shared solely between apicom- plexans and certain chlorophyte algae ( ), namely, the presence of nucleus-encoded split cox a and cox b genes and a conserved domain present in a region of coxiib that is not derived from orthodox coxii. functional fragmentation of a mitochondrial gene followed by functional integration in the nucleus is an extremely rare event, unlikely to happen several times. the current evidence suggests that this phenomenon was confined to the ancestor of chlorophyte algae. our analyses support a close relationship between apicomplexan and chlorophyte cox a and cox b sequenc- es specific to the mitochondrion, whereas analysis of apicoplast genome organization has suggested a red algal origin of the organelle ( ). clearly, there is still con- flicting evidence for green versus red algal ancestry in the apicomplexans ( ). what- ever the outcome of this debate, the pres- ence of nucleus-encoded, fragmented cox a and cox b genes of green origin in apicom- plexans must be considered whenever the evolutionary story of these parasites is re- constructed. soledad funes instituto de fisiologı́a celular universidad nacional autónoma de méxico (unam) d.f., mexico edgar davidson department of biochemistry and molecular pharmacology thomas jefferson university philadelphia, pa , usa adrián reyes-prieto instituto de fisiologı́a celular, unam susana magallón instituto de biologı́a, unam pascal herion instituto de investigaciones biomédicas, unam michael p. king department of biochemistry and molecular pharmacology thomas jefferson university diego gonzález-halphen instituto de fisiologı́a celular, unam e-mail: dhalphen@ifc.unam.mx references and notes . s. funes et al., science , ( ). . r. f. waller, p. j. keeling, g. g. van dooren, g. i. mcfadden, science , ( ); www.sciencemag. org/cgi/content/full/ / / a. . g. burger et al., j. mol. biol. , ( ). . m. p. oudot-le secq et al., j. mol. evol. , ( ). . x. pérez-martı́nez et al., j. biol. chem. , ( ). . n. m. fast et al., j. eukaryot microbiol. , ( ). . j. e. feagin, int. j. parasitol. , ( ). . s. lin et al., j. mol. biol. , ( ). . x. pérez-martı́nez et al., j. biol. chem. , ( ). . s. funes et al., j. biol. chem. , ( ). . d. o. daley et al., proc. natl. acad. sci. u.s.a. , ( ). . b. stoebe, k. v. kowallik, trends genet. , ( ). . j. d. palmer, j. phycol. , ( ). . sequences were aligned using clustalx ( ), with subsequent manual refinements. the corresponding aligned nucleotide sequences were used in the anal- ysis. agrobacterium was specified as outgroup. the model that best fits the data (gtr�i� �) and its parameters (base frequency: . , . , . , . ; rate matrix: . , . , . , . , . , . ; proportion of invariable sites: . ; shape of gamma distribution: . ) were identified with modeltest ( ) and implemented in heuristic searches with tbr branch swapping, to obtain a ml tree (score of –ln l � . ). branch support was obtained from ml bootstrap replicates con- ducted under the same model and parameters as the ml search. analyses were performed using paup* . b for macintosh and unix ( ). . j. d. thompson et al., nucleic acids res. , ( ). . d. posada, k. a. crandall, bioinformatics , ( ). . d. l. swofford, paup* . : phylogenetic analysis us- ing parsimony (*and other methods) (sinauer asso- ciates, sunderland, ma, ). march ; accepted may t e c h n i c a l c o m m e n t july vol science www.sciencemag.org b o n a p ril , h ttp ://scie n ce .scie n ce m a g .o rg / d o w n lo a d e d fro m http://science.sciencemag.org/ response to comment on "a green algal apicoplast ancestor" gonzález-halphen soledad funes, edgar davidson, adrián reyes-prieto, susana magallón, pascal herion, michael p. king and diego doi: . /science. 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http://www.sciencemag.org/help/reprints-and-permissions http://www.sciencemag.org/about/terms-service http://science.sciencemag.org/ historical perspectives of the american association for thoracic surgery: john h. gibbon, jr ( - ) presidential perspectives historical perspectives of the american association for thoracic surgery: john h. gibbon, jr ( - ) thomas p. theruvath, md, phd, and john s. ikonomidis, md, phd birth and upbringing john heysham gibbon, jr, st president of the american association for thoracic surgery (aats), was born on september , , as the first son to marjorie glendolyn young gibbon and john heysham gibbon, at their home at south th street, in philadelphia, pa. philadelphia was home to generations of gibbons. the first american gibbon had emigrated in from wiltshire, england. john h. gibbon, jr, came from a long line of physicians, starting back in england, where his great-great-great grand- father had been a london physician. furthermore, previ- ous generations of gibbons were graduates of jefferson medical college. his father was a respected surgeon and co-chairman of the department of surgery at jefferson and had held many honorable positions, including the pres- idency of the american surgical association. although his father was his counselor in later years, his mother was more influential during his childhood. marjorie gibbon came from the west and was the daughter of a distinguished career officer. she taught him the value of books, and they both indulged in reading during any spare time. she devel- oped his curiosity in literature, philosophy, and poetry, which would be a major interest for the rest of his life. john h. gibbon, jr, or jack, as he was called, had an older sister, marjorie, and was the older brother to sam and rob- ert. as a determined and competitive child, he became an excellent athlete, including tennis, and horse rider, which was fostered on the family’s -acre farm. figure . professor john heysham gibbon, jr. education and surgical training john gibbon, jr, entered princeton college just before his th birthday and matriculated at jefferson medical college in at age . regrets of not following his longing to pursue literature and poetry studies marked the initial years. at one point, he had decided to quit medical school so he could continue his literature studies. however, after consul- ting with his father, whose ideas and proposals he valued, he decided to continue medical school. he described the initial from the division of cardiothoracic surgery, medical university of south carolina, charlotte, sc. disclosures: authors have nothing to disclose with regard to commercial support. received for publication oct , ; accepted for publication nov , ; available ahead of print dec , . address for reprints: john s. ikonomidis, md, phd, division of cardiothoracic sur- gery, medical university of south carolina, courtenay dr, suite , charleston, sc (e-mail: ikonomij@musc.edu). j thorac cardiovasc surg ; : - - /$ . copyright � by the american association for thoracic surgery http://dx.doi.org/ . /j.jtcvs. . . the journal of thoracic and ca years of medical school as ‘‘boring with needless memori- zation.’’ nevertheless, he was a fast and dedicated learner, mastering the final clinical years, and finished medical school in . without any doubt, this was the correct de- cision, as the global medical community would witness years later. after finishing medical school at jefferson, he continued with a -year internship at the pennsylvania hospital. his interest in general thoracic surgery led him to contact dr edward delos churchill ( th aats president), who was one of the significant figures in the early development of surgery for lung cancer. he had an active laboratory and later became chief of general surgical services at massachu- setts general hospital. gibbon pursued a research fellow- ship position in dr churchill’s laboratory and in rdiovascular surgery c volume , number delta: _given name delta: _surname mailto:ikonomij@musc.edu http://dx.doi.org/ . /j.jtcvs. . . figure . dr gibbon’s first version of the heart–lung machine (ibm i). this machine was used up to in experimental canine models. presidential perspectives theruvath and ikonomidis started to perform feline experiments to investigate the me- chanical influences of the pericardium on cardiac function and the physiologic changes of an increasing pulmonary ar- tery pressure such as occurs in pulmonary embolism. , together with mary hopkinson, dr churchill’s research assistant, and later dr gibbon’s wife, they published very efficiently in highly ranked journals such as the journal of clinical investigation and annals of surgery. - surgical career after an internship and clinical fellowships at the penn- sylvania hospital, dr gibbon became a faculty member as a surgeon in and later an assistant professor of sur- gery at the university of pennsylvania in . during world war ii, john gibbon, jr, volunteered for duty and was in the united states army from to . he served as major and lieutenant colonel on the surgical ser- vice for the nd evacuation hospital in the south pacific and later at mayo general hospital. in , he returned to his alma mater at the jefferson medical college, where he quickly ascended to the rank of full professor and in became the samuel d. gross professor of surgery and chairman of the department of surgery (figure ). he remained the head of the department and also a consultant surgeon at the pennsylvania hospital and veterans affairs hospital in philadelphia until his retirement in . curriculum vitae highlights although dr gibbon will always be known as the inven- tor of the cardiopulmonary bypass machine, he also made several other clinical contributions. he served on the edito- rial board of annals of surgery from to and was its chairman from to . he authored the textbook surgery of the chest, which is in its th edition and has set the standard as a reference in the field of cardiothoracic surgery. he was a member of the examination committee of the american board of surgery from to and served as its chairman from to . he was president of the american surgical association in , the aats for to , the society of vascular surgery for to , and the society of clinical surgery for to and was elected to the national academy of sciences in . among his numerous awards was the albert lasker clinical research award, which he received in , often referred to as the american nobel prize. , , accomplishments and contributions to the field of cardiothoracic surgery dr gibbon’s pursuit of advancing medicine was fueled by the well-described event in boston in october of , when a young woman, after an uneventful cholecystectomy, developed severe onset of chest discomfort and difficulties breathing, consistent with acute pulmonary embolism. she was moved to the operating room for constant close the journal of thoracic and cardiovascular surg observation. it was dr gibbon who was given the responsi- bility to assess her clinically and to document her pulse, res- piratory rate, and blood pressure every minutes starting at pm that day. he was ordered to inform dr churchill immediately when her vital signs would deteriorate so that an emergent embolectomy could be performed. dr gibbon reported that at am the next day, she had become apneic and was without a measurable blood pressure. dr churchill opened her chest, incised the pulmonary artery, removed the blood clot, and placed a side-biting clamp on the pulmonary artery, all within less than minutes. this patient, however, died, just as had most of the patients for whom dr friedrich trendelenburg had described this tech- nique in leipzig, germany, years earlier. for dr gibbon, it was this event that sparked the idea of a cardiopulmonary bypass machine, which would, years later, advance and revolutionize the entire field of cardiothoracic surgery. he described his thoughts as follows: during that long night, watching helplessly the pa- tient struggle for life as her blood became darker and her veins more distended, the idea naturally occurred to me that if it were possible to remove some of the blue blood from the patient’s swollen veins, put oxygen into that blood and allow carbon di- oxide to escape from it, and then inject continuously the now-red blood back into the patient’s arteries, we might have saved her life. we would have bypassed the obstructing embolus and performed part of the work of the patient’s heart and lungs outside the body. during the next decades, he continued his search for a heart–lung substitute, tireless and with utmost persever- ance. a fruitful collaboration with ibm corporation al- lowed him to develop and assemble a first model of a bypass machine, which was successfully used in canine ex- periments (figure ). an upgrade of his cardiopulmonary bypass machine allowed increased blood flow, allowing its use in humans (figure ). on may , , at the ery c march figure . dr gibbon and his wife mary (‘‘maly’’) gibbon with the newer version of the heart–lung machine (ibm ii). this was the second and more refined model that dr gibbon used on his first patients. figure . may , : the bavolek operation. drs gibbon (left) and frank allbritten (right) performing the first successful open heart surgery to close an atrial septal defect in cecilia bavolek. figure . dr gibbon during his retirement at his family homestead in . theruvath and ikonomidis presidential perspectives pennsylvania hospital, the first successful use of dr gibbon’s heart–lung bypass machine was used on an -year-old woman, named cecilia bavolek. she had been diagnosed with an atrial septal defect, which had been undiagnosed until then, given the insufficient diag- nostic modalities of the previous era. although her parents had been told of some congenital heart disease, she had re- mained asymptomatic until she necessitated admission for severe fatigue and hemoptysis. dr gibbon operated with dr frank allbritten (who had invented the left ventricular apex vent) and of his residents using his heart–lung ma- chine. , by way of a clamshell incision, the defect was repaired primarily. the heart and lung functions were bridged with cannulation of the left subclavian artery and bicaval venous cannulation for minutes (figure ). ceci- lia bavolek had an uneventful recovery and was discharged home on postoperative day . , dr gibbon’s creative imagination, which was sparked in from the inability to help a dying patient, and his dedi- cation and perseverance in designing an efficient heart and lung substitute, led to the landmark operation in . although other national and international centers were ex- perimenting in an effort to assemble a heart–lung machine for clinical use in the late s and s, it was john the journal of thoracic and ca gibbon’s work as a physician and scientist in its ultimate definition that led to the first successful and safe conduct of open cardiac surgery. however, both of his subsequent patients whom he operated on a few months later using his heart–lung bypass machine died during the procedure. deeply disappointed by these failures to rescue these pa- tients, he chose to let additional clinical use of his machine be performed by others in the field. it is hardly surprising that he has been called the ‘‘father of extracorporeal circu- lation.’’ to honor dr gibbon at thomas jefferson univer- sity in philadelphia, his alma mater, one of the university hospital buildings has been renamed the ‘‘gibbon building.’’ summary of aats presidential address the presidential address of dr john h. gibbon, jr, ‘‘the road ahead for thoracic surgery,’’ presented at the st rdiovascular surgery c volume , number presidential perspectives theruvath and ikonomidis annual meeting of the aats, in philadelphia, april to , , was influenced by his extremely successful physi- cian and scientist career in an era when significant contribu- tions to cardiothoracic surgery had climaxed and revolutionized the field. he started by explaining how the field of thoracic surgery had slowly matured from an embryonic state in , when the aats was founded, to a youthful state in , and that it still had not attained maturity. he gave examples of the advancements in thoracic, cardiac, and pediatric cardiac surgery, including his own contribution of using his cardio- pulmonary bypass machine to perform safe open heart sur- gery. he delineated how these early advancements were only possible because of concomitant advancements and developments in other fields of medicine, such as the devel- opment of heparin, antibiotics, and a better understanding of cardiopulmonary physiology. dr gibbon stated that ‘‘much remains to be done,’’ specifically, increasing the safety of thoracic operations and understanding the physi- ology of cardiac ischemia and hypothermia-induced slow- ing of metabolic demand. the proposed transition of thoracic surgery from its youth in the s to manhood is what dr gibbon presented in the second part of his pres- idential address. he documented that in an era of funding abundance in which the department of health, education, and welfare had increased their spending fourfold from to and with well-equipped laboratories, the essential require- ment was well-trained physician-investigators. he then asked the question of whether enough young medical stu- dents and physicians have been properly educated in the methods of scientific education and have engaged in research. dr gibbon emphasized that a good researcher needs qualities such as honesty, integrity, passion, patience, persistence, and attention to detail and must be incorrupt- ible. he noted that many with these qualities might have no interest in research, but instead in teaching, and should not be institutionally forced into conducting experimental investigations. as such, he proposed that every academic institution should have positions designed solely for teach- ing and others solely to conduct research. he then stated that, during surgical education, at least year should be spent in a laboratory, where the young sur- geon in training will, at a minimum, become a critical reader of surgical published studies. after the formal surgical edu- cation, ‘‘the embryo surgeon’’ should pursue a second period of research, preferably at a different institution, to give young clinicians and investigators greater experience and the basics of conducting bench research. he empha- sized the significance of a good mentor, teacher, and inves- tigator. he finished his presidential address by providing the journal of thoracic and cardiovascular surg common errors in conducting research and the notion that fewer, but more concentrated, endeavors of the society toward properly motivated and qualified investigators will result in more significant contributions. personal life dr john h. gibbon, jr, met his wife mary hopkinson, or maly as she was known to most, at the age of . mary was the daughter of charles hopkinson, one of america’s great- est portraitists. they met as he started his research fellow- ship in february , in boston, where maly was working as dr edward d. churchill’s laboratory assistant at the massachusetts general hospital. they married on march , , and had children, mary, john, alice, and marjorie. gibbon retired from his chairmanship in and from then on indulged in poetry, painting, and sports, spending most of his time at the farm (figure ). a devastating heart attack took his life on the tennis court on february , , at the age of . figures to have been provided courtesy of the archives and special collections, thomas jefferson university, philadelphia, pa. the authors would like to thank f. michael angelo, ma, uni- versity archivist, thomas jefferson university, for his assistance in providing the images. references . shumacker hb. a dream of the heart. santa barbara: fithian press; . . gibbon jh, churchill ed. the mechanical influence of the pericardium upon cardiac function. j clin invest. ; : - . . gibbon jh, hopkinson m, churchill ed. changes in the circulation produced by gradual occlusion of the pulmonary artery. j clin invest. ; : - . . gibbon jh, churchill ed. the physiology of massive pulmonary embolism: an experimental study of the changes produced by obstruction to the flow of blood through the pulmonary artery and its lobar branches. ann surg. ; : - . . shumacker hb. john heysham gibbon, jr.: september , –february , . biogr mem natl acad sci. ; : - . . gibbon jh. surgery of the chest. philadelphia: wb saunders; . . bing r. john h. gibbon, jr. cardiopulmonary bypass—triumph of perseverance and character. clin cardiol. ; : - . . cohn lh. fifty years of open-heart surgery. circulation. ; : - . . gibbon jh jr. the development of the heart–lung apparatus. rev surg. ; : - . . miller bj, gibbon jh jr, greco vf, smith ba, cohn ch, allbritten ff jr. the production and repair of interatrial septal defects under direct vision with the assistance of an extracorporeal pump-oxygenator circuit. j thorac surg. ; : - ; discussion - . . miller bj, gibbon jh jr, greco vf, cohn ch, allbritten ff jr. the use of a vent for the left ventricle as a means of avoiding air embolism to the sys- temic circulation during open cardiotomy with the maintenance of the cardiorespiratory function of animals by a pump oxygenator. surg forum. ; : - . . hedlund kd. a tribute to frank f. allbritten, jr.: origin of the left ventricular vent during the early years of open-heart surgery with the gibbon heart–lung machine. tex heart inst j. ; : - . . gibbon jh jr. application of a mechanical heart and lung apparatus to cardiac surgery. minn med. ; : - . . gibbon jh jr. the road ahead for thoracic surgery. j thorac cardiovasc surg. ; : - . ery c march http://refhub.elsevier.com/s - ( ) - /sref http://refhub.elsevier.com/s - ( ) - /sref http://refhub.elsevier.com/s - ( ) 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http://refhub.elsevier.com/s - ( ) - /sref http://refhub.elsevier.com/s - ( ) - /sref http://refhub.elsevier.com/s - ( ) - /sref http://refhub.elsevier.com/s - ( ) - /sref http://refhub.elsevier.com/s - ( ) - /sref http://refhub.elsevier.com/s - ( ) - /sref 	historical perspectives of the american association for thoracic surgery: john h. gibbon, jr ( - ) 	birth and upbringing 	education and surgical training 	surgical career 	curriculum vitae highlights 	accomplishments and contributions to the field of cardiothoracic surgery 	summary of aats presidential address 	personal life 	references micu -dependent threshold and cooperativity of mitochondrial ca + uptake in the liver wednesday, february , a mitochondria in cell life and death -pos board b a step forwardin understanding the mechanismof vdac voltage-gating oscar teijido hermida , shay rappaport , rachna ujwal , jeff abramson , vicente m. aguilella , sergey m. bezrukov , tatiana k. rostovtseva . nichd, national institutes of health (nih), bethesda, md, usa, david geffen school of medicine, ucla, los angeles, ca, usa, universitat jaume i, castello de la plana, spain. the voltage-dependent anion channel (vdac) governs the exchange of ions and metabolites between the mitochondria and the rest of the cell. in its open state vdac exhibits high conductance and selectivity for anions that facilitates the passage of adp, atp, and other metabolites. at increased voltages (> mv) vdac switches to lower conducting states, termed as ‘‘closed’’ states. closed states are cation-selective and impermeable for atp. the voltage-induced transition from the open to closed states is referred to as voltage-gating. although it is well established that vdac voltage-gating in- volves large structural rearrangements, the precise molecular mechanism of this process is still under debate. we investigated vdac voltage-gating by sys- tematically titrating vdac charge residues and by using thermodynamic and kinetic approaches to study opening and closing of the channel. all the models proposed so far agree that n-terminal region plays a key role in vdac voltage- gating. according to the original idea, the n-terminal region is a part of a mo- bile voltage sensor domain, which slides in and out of the channel lumen in re- sponse to the applied voltage. the alternative models consider independent movement of the n-terminal region upon gating. in order to test the role of vdac n-terminal region in voltage-gating, we engineered a double cys mu- tant of murine vdac that cross-links the a-helix to the b-strand of the pore wall. the cross-linked vdac reconstituted into planar lipid membranes exhibited typical voltage gating, which suggests that the n-terminal a-helix is located inside the pore of vdac in the open state and remains associated with the pore wall during voltage gating. our findings support a model where b-bar- rel is not rigid but undergoes a conformational change that leads to a partial constriction upon transition to the closed states. -pos board b novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding kely l. sheldon , coert j. zuurbier , sergey m. bezrukov , tatiana k. rostovtseva . the natl. institutes of health, bethesda, md, usa, university of amsterdam, amsterdam, netherlands. the voltage dependent anion channel (vdac) is involved in regulation of me- tabolite flux across the mitochondrial outer membrane (mom). hexokinse ii (hk ) is known to bind the mom where it phosphorylates glucose into glucose- -phosphate (g p). high expression of hxk is a common phenotype of many cancers, where its concentration can be times of that in noncan- cerous cells, and is implicated in the warburg effect. it is believed that vdac serves as a hxk binding site in the mom. the amino acid n-ter- minal sequence of hxk is responsible for mitochondrial binding and, when conjugated to tat (tat-hk ), binds to mitochondria with higher affinity than native hxk , causing hxk detachment. we have previously found that dimeric tubulin reversibly binds and partially blocks vdac inhibiting me- tabolite flux across the mom. now we show that this binding can be attenuated by tat-hxk peptide as well as by full length hxk . we have found that tat-hxk and recombinant full length hxk inhibit tubulin blockage of vdac reconstituted into planar lipid bilayers without altering characteristic channel properties such as single channel conductance and selectivity. binding of hxk to vdac is verified by the generation of high-frequency excess cur- rent noise without channel closure. hxk bound to vdac prevents subse- quent tubulin binding, but only when added before tubulin, and inhibits tubulin-induced vdac blockage in a dose dependent manner. moreover, g p, which is known to cause hxk detachment from the mom, fully re- verses the inhibition of tubulin-vdac binding. this suggests that hxk de- tachment from vdac (and hence the mom) is caused by a hxk conformational change upon g p binding. thus we propose a novel mecha- nism of mitochondrial respiration control in cancer cells through the competi- tion between hxk and tubulin for vdac binding. -pos board b reprogramming of mitochondrial ca d handling in micu -deficient hela cells tünde golenár , györgy csordás , erin l. seifert , cynthia moffat , fabiana perocchi , yasemin sancak , david weaver , vamsi k. mootha , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. recent studies have revealed mcu as the pore forming domain and micu as a critical ca þ-sensitive regulator of the mitochondrial ca þ uniporter. how- ever, the exact role of micu in ca þ transport remains to be addressed. our previous studies showed that prolonged down-regulation of micu in hela cells (shmicu ) promotes mitochondrial ca þ uptake at low [ca þ ], which unexpectedly, fails to effectively increase matrix [ca þ ]. to determine the source of discrepancy between the mitochondrial ca þ uptake and the ma- trix [ca þ] phenotypes, first we simultaneously monitored ruthenium red- sensitive clearance of added ca þ from the cytoplasm and the corresponding matrix [ca þ] response in permeabilized shmicu cells. under conditions of similar cytoplasmic ca þ clearance, shmicu cells showed a smaller matrix [ca þ ] increase than the control, indicating enhanced buffering of ca þ in the matrix. enhanced ca þ binding in the matrix likely reflects alkalinization and enhanced phosphate transport. to test if upregulation of ca þ buffering is di- rectly linked to micu depletion, we also assessed mitochondrial ca þ han- dling after hr silencing of micu (simicu ). in simicu cells both mitochondrial ca þ uptake and the matrix [ca þ ] rise were effectively stimu- lated at low ca þ levels. thus, upregulation of matrix ca þ buffering seems to be a component of an adaptive response to sensitization of mitochondrial ca þ uptake in shmicu . the adaptive response is likely to be important to attenuate some micu -depletion induced cellular impairments that we found to manifest as attenuated mitochondrial atp production and cell proliferation. -pos board b micu -dependent threshold and cooperativity of mitochondrial ca d uptake in the liver györgy csordás , erin l. seifert , tünde golenár , cynthia moffat , sergio de la fuente perez , david weaver , roman bogorad , victor koteliansky , vamsi k. mootha , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, koch institute for integrative cancer research, mit, cambridge, ma, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. recent studies have revealed mcu as the pore forming domain and micu as a critical ca þ-sensitive regulator of the mitochondrial ca þ uniporter. how- ever, the mechanism of the complex ca þ dependence of the uniporter activity remains elusive. our previous studies showed that prolonged down-regulation of micu in hela cells causes lower threshold and decreased cooperativity of mitochondrial ca þ uptake. to study the functional significance of the effects of micu we used hepatocytes harvested from the liver of mice exposed to in vivo silencing ( weeks). silencing of micu or mcu resulted in > % decrease in their respective mrna levels. silencing of micu caused a left- ward-shifted dose response and decreased cooperativity of mitochondrial ca þ uptake in both permeabilized and intact hepatocytes. by contrast, silenc- ing of mcu resulted in slower ca þ uptake in the entire range of ca þ concen- trations without change in threshold. mitochondrial respiration and cellular atp content were unaffected in media containing both glycolytic and mito- chondrial fuels in either micu or mcu-deficient hepatocytes. however, si- lencing of micu caused an augmented loss of atp when the cells were confined to oxidative metabolism and an enhanced sensitivity to mitochondrial ca þ overload and permeabilization. during stimulation with vasopressin, a ca þ mobilizing hormone, both micu and mcu-deficient cells displayed an attenuated mitochondrial matrix [ca þ ] increase and stimulation of respira- tion. collectively, these results show that keeping the gate of mcu closed by micu at low [ca þ] is required to maintain healthy mitochondria, and micu -mediated control of mcu (cooperativity?) is required to support the propagation of short-lasting calcium spikes and oscillations to the mitochondria and the ensuing physiological stimulation of oxidative metabolism. -pos board b targeting mcl- and bak as a therapeutic tool to selectively induce apoptosis in hepaptocellualr carcinoma nima niknejad, soumya sinha roy, eric knudsen, györgy hajnóczky. thomas jefferson university, philadelphia, pa, usa. in this study we seek to identify novel drug targets to induce apoptosis in he- patocellular carcinoma (hcc) cells thus providing opportunities to develop novel treatments to improve the prognosis of liver cancer patients. several ap- optotic pathways are mediated through cleavage of bid (a bh domain-only, pro-apoptotic protein) to produce truncated bid (tbid). tbid induces apoptosis through induction of outer mitochondrial membrane (omm) permeabilization by activation of pro-apoptotic bak that resides in the omm or cytoplasmic bax. due to its localization, bak can mediate the early phase of the response to tbid. we have recently demonstrated that omm targeting of bak and the sensitivity to tbid-induced omm permeabilization is dependent on the expression of 	a step forward in understanding the mechanism of vdac voltage-gating 	novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding 	reprogramming of mitochondrial ca + handling in micu -deficient hela cells 	micu -dependent threshold and cooperativity of mitochondrial ca + uptake in the liver 	targeting mcl- and bak as a therapeutic tool to selectively induce apoptosis in hepaptocellualr carcinoma corrections corrections diabetes mellitus and outcome after primary coronary angioplasty for acute myocardial infarction: lessons from the gusto-iib angioplasty substudy. j am coll cardiol ; : – . there is an error in figure on page . the horizontal axis should have read as follows: time to death (days). the corrected figure appears below. detection of myocardial ischemia using additional left posterior and right precordial leads during exercise electrocardiography. abstract—cardiac function and heart failure, session – . j am coll cardiol ; : a. this abstract was presented at the th annual scientific session of the american college of cardiology, anaheim, california. the first author of this abstract was incorrectly listed as “vijendra swamp.” the first author’s correct name is “vijendra swarup.” in addi- tion, the first sentence in the conclusions should have read as follows: the addition of right precordial and left posterior leads to the standard lead ecg significantly improves the sensitivity of the exercise ecg for the diagnosis of myocardial ischemia. we regret these printing errors. the corrected abstract appears below: - detection of myocardial ischemia using additional left posterior and right precordial leads during exercise electrocardiography vijendra swarup, neal skop, joel s. raichlen, thomas jefferson university, philadelphia, pennsylvania, usa background: although stress electrocardiography (ecg) is less expensive than imaging stress studies, it is relatively insensitive for detecting myocardial ischemia. we examined the value of adding two right sided (rv , rv ) and two left posterior (v , v ) leads ( lead ecg) to improve the sensitivity of exercise ecg for detecting myocardial ischemia. methods: we prospectively studied patients ( men and women) with a mean age of who were undergoing nuclear exercise stress testing. % were hypertensive, % diabetic, % hypercholesterolemic, % smoked and % had a family history of premature coronary artery disease (cad); % had known cad (prior infarction or revascularization). results: patients exercised . minutes achieving an average heart rate of bpm with . % achieving their target heart rate. ischemia was present in patients ( . %) as evidenced by at least one reversible perfusion defect. there was evidence of myocardial ischemia on the standard lead ecg in patients ( . %). an additional patients met criteria for ischemia on the lead ecg. the lead ecg increased the sensitivity of the lead ecg from . % to . % (p , . ) with no reduction in specificity ( . % versus . %). the lead ecg improved the sensitivity for detecting ischemia in women for . % to . %, in patients with known cad from . % to . % and in patients who did not achieve their target heart from . % to . %. conclusion: the addition of right precordial and left posterior leads to the standard lead ecg significantly improves the sensitivity of the exercise ecg for the diagnosis of myocardial ischemia. figure . kaplan-meier curves depicting the estimated survival for diabetic and nondiabetic patients within months of follow-up after (re)mi. (re)mi reinfarction. journal of the american college of cardiology vol. , no. , © by the american college of cardiology issn - / /$ . published by elsevier science inc. - _ .. i american association for cancer research. doi: . / - .can- - references . girnita a, girnita l, del prete f, bartolazzi a, larsson o, axelson m. cyclolignans as inhibitors of the insulin-like growth factor- receptor and malignant cell growth. cancer res ; : – . . cortese f, bhattacharyya b, wolff j. podophyllotoxin as a probe for the colchicine binding site of tubulin. j biol chem ; : – . . gupta rs. podophyllotoxin-resistant mutants of chinese hamster ovary cells: cross- resistance studies with various microtubule inhibitors and podophyllotoxin analogues. cancer res ; : – . . loike jd, brewer cf, sternlicht h, gensler wj, horwitz sb. structure-activity study of the inhibition of microtubule assembly in vitro by podophyllotoxin and its congeners. cancer res ; : – . . strömberg t, ekman s, girnita l, et al. igf- receptor tyrosine kinase inhibition by the cyclolignan ppp induces g -m-phase accumulation and apoptosis in multiple myeloma cells. blood ; : – . picropodophyllotoxin or podophyllotoxin does not induce cell death via insulin-like growth factor-i receptor to the editor: the cyclolignan picropodophyllotoxin (ppp) was recently launched as an anticancer drug specifically targeting insulin-like growth factor-i receptor (igf-ir; ref. ). ppp is an epimer of podophyllotoxin (ppt), an established inhibitor of microtubule assembly used to treat genital warts. ppt binds to the colchicine binding site of tubulin ( ). ppt-resistant cells are cross-resistant to colchicine, colcemid, and vinblastine ( ). ppp is - to -fold less potent than ppt in inhibition of microtubule assembly ( ) and the gi of ppp is � -fold that of ppt (� versus � nmol/l). this would be expected if growth inhibition by ppp is due to microtubule inhibition (discussed in ref. ). also consistent with this notion is that ppt-resistant cells are resistant to ppp ( ). despite the documented microtubule effects, an association between igf-ir expression and sensitivity to ppt/ppp was reported ( ). eleven cell types expressing igf-ir were found sensitive to ppp, and three cell types lacking igf-ir expression were resistant in vitro and/or in vivo ( ). the in vitro gi for cell types lacking igf-ir expression (r� cells, hepg cells) was > amol/l for both drugs ( ). s. linder and m. c. shoshan reexamined ppt/ppp effects on igf- ir–deficient r� cells, which were reported resistant to amol/l ppt/ppp ( ). r� cells ( from dr. renato baserga, kimmel cancer center, thomas jefferson university, philadelphia, pa) and mouse embryo fibroblasts (mefs) were exposed to . amol/l ppt or ppp ( from dr. girnita, department of oncology-pathology, karolinska institute, stockholm, sweden), a concentration used to inhibit igf-ir ( ). both cell types were equally sensitive; ppp reduced viability of r � cells to . f . % of control and of mefs to . f . % of control, whereas ppt reduced viability to . f . % and . f . % of control, respectively [ -( , -dimethylthiazol- -yl)- , -diphenyltetra- zolium bromide assay; h]. four independent experiments yielded similar results. both drugs induced sub-g debris in r� cells, indi- cative of cell death (ppt, % of total counts; ppp, %; controls, %). ppp induces g -m arrest ( ). this effect is not dependent on igf-ir: ppp ( . amol/l, h) induced g -m arrest in igf- r–deficient cells ( . % in g -m; . % in untreated cells). r. s. gupta reexamined ppt/ppp effects on hepg cells, which were reported resistant to > amol/l ppt/ppp ( ). hepg cells were sensitive to ppt and ppp; the ic was nmol/l for ppt and . amol/l for ppp. ppt treatment of cancer is limited by severe side effects. although igf-ir is an attractive cancer therapy target, our data showing that ppt and ppp induce loss of viability and cell death in igf-ir–deficient cells contest their potential as igf-ir–specific anticancer drugs. stig linder maria c. shoshan cancer center karolinska, department of oncology-pathology, karolinska institute, stockholm, sweden radhey s. gupta department of biochemistry and biomedical sciences, mcmaster university, hamilton, ontario, canada www.aacrjournals.org cancer res ; : ( ). march , letters to the editor research. on april , . © american association for cancercancerres.aacrjournals.org downloaded from http://cancerres.aacrjournals.org/ ; : . cancer res stig linder, maria c. shoshan and radhey s. gupta cell death via insulin-like growth factor-i receptor picropodophyllotoxin or podophyllotoxin does not induce updated version http://cancerres.aacrjournals.org/content/ / / . access the most recent version of this article at: cited articles http://cancerres.aacrjournals.org/content/ / / . .full#ref-list- this article cites articles, of which you can access for free at: citing articles http://cancerres.aacrjournals.org/content/ / / . .full#related-urls this article has been cited by highwire-hosted articles. access the articles at: e-mail alerts related to this article or journal.sign up to receive free email-alerts subscriptions reprints and .pubs@aacr.orgdepartment at to order reprints of this article or to subscribe to the journal, contact the aacr publications permissions rightslink site. (ccc) click on "request permissions" which will take you to the copyright clearance center's .http://cancerres.aacrjournals.org/content/ / / . to request permission to re-use all or part of this article, use this link research. on april , . © american association for cancercancerres.aacrjournals.org downloaded from http://cancerres.aacrjournals.org/content/ / / . http://cancerres.aacrjournals.org/content/ / / . .full#ref-list- http://cancerres.aacrjournals.org/content/ / / . .full#related-urls http://cancerres.aacrjournals.org/cgi/alerts mailto:pubs@aacr.org http://cancerres.aacrjournals.org/content/ / / . http://cancerres.aacrjournals.org/ jnccn .. commentary the home is the new cancer center nathan r. handley, md, mba; justin e. bekelman, md; and adam f. binder, md as oncologists in the era of coronavirus disease (covid- ), we are taskedwith caring for patients who are at high risk for adverse effects from the novel coronavirus (sars-cov- ). patients with cancer face fear and anxiety related to their immunocompromised status, and early data suggest patients with cancer may be more susceptible to infection with sars-cov- . during this pandemic, a new vu- lnerability has arisen: how can patients receive life-sustaining treatment for cancer if they cannot get to the clinic or if the system is overwhelmed by patients with covid- ? how can patients stay in what may be the safest place for them—the home—while still receiving high-quality care? covid- provides an opportunity to recognize and improve on shortcomings in our cancer care delivery system: interacting with the health system puts already tenuous patients at risk for nosocomial infection, high-quality cancer care requires a high level of coordination that is challenging to achieve, and accessing care can be difficult or impossible for some individuals. moving components of cancer care into the home can facilitate high-touch care, minimize risk by reducing unnecessary exposures to the health system, and improve access to treatment. cancer care at home can augment or replace current models for clinic visits, chemotherapy, and acute care, deleveraging healthcare facilities as primary sites of care while ensuring safety for patients and providers, and improving patient-centeredness of care. al- though important during a pandemic, cancer care at home can also have a lasting impact when healthcare returns to “normal operations.” this commentary de- scribes home-based approaches for clinic visits, chemotherapy, and acute care; examines concerns stakeholders have raised about implementation of these approaches; and evaluates needs for the sustainability of cancer care at home after resolution of the pandemic. clinic visits the transition from in-person clinic visits to telemedicine-based virtual visits has been rapid and dramatic since the pandemic began. at jefferson health, jeffconnect, a telemedicine platform for virtual visits, has seen a -fold increase in use. this modality is appropriate for patients presenting for routine follow-up care or receiving oral chemotherapy, and can be readily adapted for patients receiving infusional treatments. similarly, we have found that supportive care services—including peer support groups, patient-facing educational courses, and palliative care appointments—readily lend themselves to the virtual format. hollander and sites recently outlined concerns regarding telemedicine: it’s too difficult, it’s too transactional, the physical examination is inadequate, it’s ineffective, and it’s not financially viable. as the uptake of telehealth during the pandemic has soared, clinicians and patients are now recognizing the many positive attributes of telehealth and its clinical effectiveness. although some of the mo- mentum telemedicine has experienced during covid- is due to temporary waivers that facilitate reimbursement, telemedicine has now been thrust into the mainstream, and the gains will inevitably pave the way for broader uptake in the future. chemotherapy patients are encouraged to shelter in place to minimize exposures to sars-cov- . for patients who require infusional chemotherapy, however, some interaction with the health system is inevitable. yet receiving treatment within a hospital or an infusion jnccn.org | volume issue | october nathan r. handley, md, mba nathan r. handley, md, mba, is assistant professor in the department of medical oncology at thomas jefferson university. he is a board certified oncologist special- izing in genitourinary malignancies. his research interests involve the development and implementation of strategies to improve cancer care delivery. doi: . /jnccn. . the ideas and viewpoints expressed in this commentary are those of the author and do not necessarily represent any policy, position, or program of nccn. http://www.jnccn.org https://doi.org/ . /jnccn. . center carries nosocomial risk: in the infusion suite, dozens of potentially immuno- compromised patients are collocated with a variety of healthcare providers who may be vectors for sars-cov- . for these patients, home-based chemotherapy, administered by a trained team, can be considered. chemotherapy at home remains uncommon in the united states, although models for its use exist globally. in these models, home-based chemotherapy has been safe, was preferred by patients, and could be administered at lower cost. the christie nhs foundation trust, the largest single-site cancer center in europe, recently described “christie at home,” a model of home-based anticancer therapy designed to reduce pressure on clinics and improve the patient experience. in this model, a trained nurse can deliver sub- cutaneous or intramuscular treatments or or intravenous treatments per day, with real-time documentation completed via g-enabled laptops. christie at home delivered , in-home treatments between and ; in , % of surveyed patients receiving care at home rated their care as excellent and indicated a preference for home-based care over other sites. in some cases, a physical care team may not be required for administration of therapy, which may further streamline treatment. for instance, at jefferson health, our specialty pharmacy can deliver certain injectable agents, such as leuprolide, to the patient’s home for self- administration. concerns surround home-based chemotherapy as well. these concerns include fear that it is not safe, that logistics are insurmountable, that it cannot be reimbursed, and that patients do not want it. successful models, both domestically and abroad, address these concerns. for example, penn medicine is now scaling a home-infusion demonstration program called “cancer care at home” (cc@h). this program provides different cancer drugs, which are typically provided in outpatient cancer settings, to patients with lymphoma or breast, prostate, lung, or head and neck cancer for home administration. patients discuss cc@h with their provider, who then prescribes home treatment in the electronic medical record. after insurance au- thorization and discussion of out-of-pocket costs by penn home infusion therapy, a courier delivers the treatment to the patient’s home (up to days in advance); the treatment is then administered in the home by a nurse. acute care in the era of covid- , minimizing unplanned and potentially preventable acute care use for patients with cancer is particularly important. these encounters, in- cluding emergency department (ed) visits, acute hospitalizations, and -day rehospitalizations, use limited resources and put patients, staff, and providers at increased risk for infection. however, the desire to prevent unnecessary acute care use by patients with cancer is not unique to the pandemic. many of these patients can be managed in the home setting via hospital-at- home models. although these programs are currently uncommon in the united states, they do exist and are increasing in number. for example, huntsman cancer institute currently operates huntsman at home (h@h), which provides acute care services for oncology patients who live within miles of the institute. this program was born out of a need to address full bed occupancy and after-hours ed visits. both of these problems are highly pertinent during a pandemic. h@h reports reduced hospitalizations, ed visits, and total costs among patients who participate in the program. concerns about safety, feasibility, patient-centeredness, and reimbursement exist for cancer hospital-at-home programs as well. despite these concerns, how- ever, hospital-at-home models exist and are expanding. reimbursement may be the biggest barrier, but payment models are developing. for example, in , the physician-focused payment model technical advisory committee recommended a bundled payment for home-based acute care (consisting of acute hospital-level care © jnccn—journal of the national comprehensive cancer network | volume issue | october commentary handley et al justin e. bekelman, md justin e. bekelman, md, is director of the penn center for cancer care innovation at the abramson cancer center, professor in the departments of radiation oncology and medical ethics and health policy at the perelman school of medicine, faculty in the center for health incentives and behavioral economics, and senior fellow at the penn center for precision medicine and the leonard davis institute for health economics, all at the university of pennsylvania. dr. bekelman leads research programs to improve the length and quality of life for patients with cancer. his research focuses on healthcare delivery, payment reform, and cancer care transformation, integrating methods from the fields of innovation, epidemiology, clinical trials, behavioral and health economics, and public policy. http://www.jnccn.org and days of transition services) to be implemented as an alternative payment model. similar payment models exist in collaborations between health systems and private payers. cancer care at home is not a replacement for all care. much of cancer care should not transition to the home, and identifying which treatments, and for which patients, can be safely and effectively delivered at home is crucial. cancer care at home may not be appropriate for every eligible patient and will not be appropriate for every treatment. shared decision-making between clinicians, patients, and family members can help tailor care to the needs of the individual patient. ultimately, however, reserving facilities for those who truly need facility-level care will best serve all stakeholders. conclusions covid- has illuminated the need for reform of the cancer care delivery system. by moving components of care to the home, the current system could effectively engage patients and improve access to care while reducing unnecessary and risky exposure to the healthcare system. furthermore, increased time at home would align with a new proposed patient-determined quality indicator for cancer care: days at home in the last months of life. challenges remain if cancer care at home, which has the potential to be of critical importance during the pandemic, is to become a standard option for cancer care delivery after the pandemic. to be sustainable, virtual visits, chemotherapy, and acute care at home require reallocation of resources, development of infrastructure, and durable payment reform. covid- can be a catalyst for such change. we should leverage this momentum to transform care for our patients. disclosures: dr. bekelman has disclosed that he has received honoraria from optum and cvs health. dr. bekelman and dr. binder have disclosed that they have no financial interests, arrangement affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. correspondence: nathan r. handley, md, mba, department of medical oncology, thomas jefferson university, walnut street, suite , philadelphia, pa . email: nathan.handley@jefferson.edu references . wang d, hu b, hu c, et al. clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china. jama ; : – . . yu j, ouyang w, chua mlk, et al. sars-cov- transmission in patients with cancer at a tertiary care hospital in wuhan, china. jama oncol ; : . . hollander je, sites fd. the transition from reimagining to recreating health care is now. accessed june , . available at: https://catalyst.nejm.org/doi/full/ . /cat. . . handley nr, bekelman je. the oncology hospital at home. j clin oncol ; : – . . burns v, misra v, paton n. systemic anti-cancer therapy delivery in the home: a service model. br j nurs ; :s – . . laughlin ai, begley m, delaney t, et al. accelerating the delivery of cancer care at home during the covid- pandemic. accessed july , . available at: https://catalyst.nejm.org/doi/full/ . / cat. . . mooney k, titchener k, haaland b, et al. the oncology hospital at home: health care utilization outcomes from the huntsman at home trial [published online may , ]. j clin oncol, doi: . / jco. . . _suppl. https://ascopubs.org/doi/abs/ . /jco. . . _suppl. . physican-focused payment model technical advisory committee. report to the secretary of health and human services. accessed july , . available at: https://aspe.hhs.gov/system/files/pdf/ /mtsinaihahreportsecretary.pdf . murali n, messina t. no place like home: bringing inpatient care to the patient [published online august , ]. njem catalyst, doi: . /cat. . . /cat. . . andersen sk, croxford r, earle cc, et al. days at home in the last months of life: a patient-determined quality indicator for cancer care. j oncol pract ; :e – . jnccn.org | volume issue | october commentarythe home is the new cancer center adam f. binder, md adam f. binder, md, is assistant professor in the department of medical oncology and quality officer in the division of hematologic malignancies at thomas jefferson university. he is a board certified hematologist specializing in multiple myeloma. his interests include quality improvement and cancer care delivery research. mailto:nathan.handley@jefferson.edu https://catalyst.nejm.org/doi/full/ . /cat. . https://catalyst.nejm.org/doi/full/ . /cat. . https://catalyst.nejm.org/doi/full/ . /cat. . https://ascopubs.org/doi/abs/ . /jco. . . _suppl. https://aspe.hhs.gov/system/files/pdf/ /mtsinaihahreportsecretary.pdf https://aspe.hhs.gov/system/files/pdf/ /mtsinaihahreportsecretary.pdf http://www.jnccn.org er-mitochondrial ultrastructure in the liver of normal and ethnaol-fed rats a monday, february , activates a novel, calcium-independent, pkca-dependent signaling pathway, which results in mitochondrial depolarization. as a result, mitochondrial dys- function is likely to be a key contributor to the pathophysiology of gas embo- lism injury. further, this connection between the endothelial surface layer and endothelial mitochondria may also play an important role in vascular homeo- stasis and disease. -plat calcium-induced ros generation during ischemia triggers mptp- dependent cell death during reperfusion lea k. seidlmayer, vanessa v. juettner, lothar a. blatter, elena n. dedkova. rush university medical center, chicago, il, usa. impairment of mitochondrial function is a central event of ischemia- reperfusion (i/r) injury leading to tissue damage and cell death. we studied the relationship between mitochondrial ca þ overload, reactive oxygen species (ros) generation, opening of the mitochondrial permeability transition pore (mptp) and cell death in rabbit ventricular myocytes exposed to simulated i/r. changes in mitochondrial ca þ ([ca þ]m) were measured with x-rhod- , ros generation with mito-sox red, mptp opening as mitochondrial calcein red release, and cell death as lactate dehydrogenase release. i/r was induced by exposing cells to glucose-free tyrode solution containing mm -deoxyglu- cose and mm nacn, ph . , followed by superfusion with standard tyrode solution. no cell death was observed after min of ischemia despite a signif- icant increase in [ca þ]m, ros and mptp opening, however cell death in- creased significantly after min of reperfusion. the ca þ uniporter blocker ru partially prevented [ca þ ]m increase and completely abolished ros generation and cell death when applied during i/r, however application of ru only during reperfusion did not protect from cell death. scavenging ros with superoxide dismutase mimetic mntbap or antioxidant trolox pre- vented reperfusion-induced cell death. blocking mptp during ischemia by cyclosporine a or depletion of mitochondrial inorganic polyphosphate did not provide protection against cell death during reperfusion, but instead led to increased mitochondrial ros accumulation. however, inhibiting mptp opening during reperfusion with cyclosporine a attenuated cell death. we con- clude that mptp-dependent cell death during reperfusion is mediated by ca þ- dependent ros generation during ischemia. moreover, our data suggest that mptp opening during ischemia could serve as ros escape pathway from mitochondria and thereby attenuate mitochondrial ros accumulation and ros-mediated cell damage during subsequent reperfusion. -plat dynamic measurement of ca d -induced changes in organelle-specific redox microdomains david m. booth , balázs enyedi , miklós geiszt , péter várnai , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, semmelweis university, budapest, hungary. multiple interactions between ca þ -signalling and reactive oxygen species (ros) production are thought to exist and be of both physiological and patho- physiological relevance. however, until recently, the study of ros in the con- text of ca þ-signalling has been hampered by ros probes limited in both specificity and targeting. to measure ros in discrete subcellular domains, we compared the genetically-encoded ratiometric h o sensor hyper with the redox de-sensitized derivative sypher to control for non-specific changes. these probes, targeted to the er lumen, er membrane (cytosolic face), cyto- sol, mitochondrial matrix and outer membrane (omm) and the ip -receptor, are positioned to assess redox changes at a local level. in resting conditions, the er lumen showed > -fold increased hyper ratio compared to the outside of the er membrane, bulk cytosol and mitochondrial matrix and omm. in the er lumen, ip -linked ca þ -mobilization induced a prounounced, downward shift in hyper ratio, whereas little or no change was detected in other compart- ments. in permeabilized cells, mitochondrial ca þ-overload was accompanied by substantial increase in h o detected in the matrix and at the omm. these data demonstrate that redox environments within individual cellular compart- ments constitute a complex and dynamic interrelationship with the concentra- tion of free ca þ . the er lumen is highly oxidized and exhibits profound decreases in h o concommitant with ca þ -release. interestingly, these changes are not transmitted to the outer leaflet of the er membrane or to other compartments. mitochondria resist redox changes under moderate stimulation, however, during mitochondrial ca þ-overload and collapsed membrane poten- tial, strong h o generation is detectible in the matrix and at the mitochondrial surface. the ros generated and detected at locations immediately apposed to ca þ -transport proteins, such as the ip -receptor, may modify their function at a local level and contribute to the feed-forward cycle of ca þ -dysregulation and subsequent cell death. -plat er-mitochondrial ultrastructure in the liver of normal and ethnaol-fed rats gyorgy csordas , david mankus , antony anil noronha , jan hoek , carmen mannella , gyorgy hajnoczky . thomas jefferson university, philadelphia, pa, usa, wadsworth center, albany, ny, usa. chronic alcohol consumption causes severe pathology in liver, associated with altered metabolism and reduced atp production. liver mitochondria isolated from alcohol-fed animals show decreased capacity for electron transport and atp synthesis, impaired calcium handling, and increased ros. in parallel, the endoplasmic reticulum (er) also shows increased ros and a stress re- sponse. the close correlation between defects in mitochondria and er is matched by recent evidence of the functional integration of cellular responses (including calcium signaling) involving these organelles. to evaluate the ultra- structural basis of alcohol-induced changes, we performed transmission elec- tron microscopy and electron tomography studies of rat liver. hepatocytes showed a large number of mostly round mitochondrial cross sections, which oc- cupied ~ % of the cytoplasmic area. the cell cytoplasm in chronic ethanol- fed ( months) condition exhibited reduced particle density, indicative of cell swelling, and contained large lipid vesicles. the mitochondria were generally intact but showed narrower intermembrane spacings within cristae and at the organelle periphery, consistent with low-scale matrix swelling. in both control and ethanol-fed conditions, mitochondria were typically surrounded by exten- sive er, with cisternae sometimes sandwiched between neighboring mitochon- dria. in one case, er was prominent at a site of mitochondrial fusion/fission. as previously reported, regions of close er-mitochondrial association ( - nm) contained numerous ‘‘tethers’’ between outer mitochondrial membranes (omm) and adjacent er. while individual tethers were discernible, dense granular material (including ribosomes) within omm-er interfaces interfered with accurate quantitation of tethers. however, membrane spacings could be readily measured. it was found that the mitochondrial surface in close associ- ation with er was significantly reduced in the chronic ethanol-fed condition as compared to control ( . % vs. %). this might be expected to cause reduced calcium signaling between er and mitochondria in liver after chronic alcohol ingestion. -plat mitochondrial nm -h /ndpk-d is multifunctional: intermembrane cardiolipin transfer linked to apoptosis uwe schlattner , malgorzata tokarska-schlattner , sacnicte ramirez , yulia y. tyurina , andrew a. amoscato , zhentai huang , jianfei jiang , mathieu boissan , raquel f. epand , dariush mohammadsanyi , judith klein-seetharaman , richard m. epand , marie-lise lacombe , valerian e. kagan . joseph fourier university and inserm, grenoble, france, university of pittsburgh, pittsburgh, pa, usa, inserm, umpc université paris and hôpital tenon, paris, france, mcmaster university, hamilton, on, canada, inserm and umpc université paris , paris, france. nm -h /ndpk-d forms symmetrical homohexameric complexes in the mitochondrial intermembrane space. the well established function of the en- zyme is phosphotransfer activity as a nucleoside diphosphate kinase (ndpk), using mitochondrial atp to regenerate nucleoside triphosphates. nm -h is further known to strongly bind in vitro to anionic phospholipids, mainly cardi- olipin, and in vivo to inner mitochondrial membranes. we show here that such protein/lipid complexes inhibit ndpk activity but are necessary for nm -h to function in selective intermembrane lipid transfer. nm -h -deficient hela cells expressing either wild-type nm -h or a membrane-binding deficient mutant were analyzed by membrane fractionation and lc-esi-ms. data revealed that wild-type nm -h increased cardiolipin content in the outer mitochondrial membrane as compared to mutant enzyme. this correlated with higher susceptibility of wild-type enzyme expressing cells to rotenone-induced apoptosis as seen by increased annexin v binding, elevated caspase / activity and stimulated release of cytochrome c into the cytosol. molecular modeling of nm -h binding with cardiolipin reveals potential intermembrane transfer mechanisms. we propose that nm -h acts as a lipid-dependent mitochondrial switch with dual function, allowing either for phosphotransfer or for cardiolipin transfer, with a role in apoptotic signaling. 	calcium-induced ros generation during ischemia triggers mptp-dependent cell death during reperfusion 	dynamic measurement of ca +-induced changes in organelle-specific redox microdomains 	er-mitochondrial ultrastructure in the liver of normal and ethnaol-fed rats 	mitochondrial nm -h /ndpk-d is multifunctional: intermembrane cardiolipin transfer linked to apoptosis ama journal of ethics, november ama journal of ethics® november , volume , number : e - art of medicine representing communication, compassion, and competence in the era of ai antonio yaghy, md, jerry a. shields, md and carol l. shields, md abstract artificial intelligence (ai) is now integrated into a variety of fields, including medicine. ai applications raise numerous ethical questions, particularly about quality of care and patient- clinician relationships. this article accompanies digital photo- paintings that address these ideas narratively and visually, with special emphasis on communication, compassion, and competence. three c’s excellence is widely regarded as an attribute of good health care quality, often defined in terms of communication, compassion, and competence. restricted time is an obstacle to acquiring and mastering these c’s if health care delivery systems focus too narrowly on volume and ignore patients’ and clinicians’ needs for compassion. ai power artificial intelligence (ai) is currently being adopted in many sectors, including health care. the power of ai technologies is evident in innovations in processing huge amounts of data, deep-learning algorithms, and expansion of machine learning capacity to learn in less time than it takes a human being. ai applications in health care include faster and often more accurate diagnosis through image recognition, pathology detection, and diagnostic assessment. quality care and patient-clinician relationships ethical questions have been raised about ai’s capacity to undermine or extinguish compassion and human connection in health care. if properly implemented in caregiving, however, ai could nurture excellence and motivate organizational cultures in which the c’s could be practiced and cultivated with rigor, diligence, and care. for example, while an ai application is executing tasks, clinicians might be able to spend time communicating with patients, expressing compassion, and delivering care with competence and satisfaction. , incorporating ai-based decision aids could also boost clinicians’ confidence in care management decisions. www.amajournalofethics.org representing the c’s visually the first image invites a viewer to consider communication and compassion as features of everyday patient-clinician encounters. these skills are displayed on screens suggestive of ai in the form of a digitized symbol of traditional professional caregiving—a stethoscope—and in the form of a digitized pair of holding hands, a traditional symbol of solidarity and care. figure . communication and compassion media digital photo-painting. in the foreground of the image, the woman—perhaps a patient or a clinician— might regard this larger-than-life stethoscope as a means of emphasizing listening as a key to good communication in any relationship. the blue upper surface of the stethoscope’s bell and diaphragm suggests how listening can be healing in the same way that water quenches thirst. ama journal of ethics, november a second image portrays competence in forms: experience, represented as gained in surgical practice; and knowledge, represented in books. figure . competence: experience and knowledge media digital photo-painting. www.amajournalofethics.org in the foreground of this image, a man regards a larger-than-life surgery in progress. this surgeon’s upper eyelids and nose bridge suggest years of accumulated experience and knowledge put into the service of patients. at the right of the image, a book’s blue spine suggests this time that, as water quenches a clinician’s thirst for knowledge, it flows later to patients during clinical encounters. references . allen-duck a, robinson jc, stewart mw. healthcare quality: a concept analysis. nurs forum. ; ( ): - . . snyderman r, gyatso t the th dalai lama. compassion and health care: a discussion with the dalai lama. acad med. ; ( ): - . . mintz y, brodie r. introduction to artificial intelligence in medicine. minim invasive ther allied technol. ; ( ): - . . tran bx, vu gt, ha gh, et al. global evolution of research in artificial intelligence in health and medicine: a bibliometric study. j clin med. ; ( ): . antonio yaghy, md is a research intern at the ocular oncology service at wills eye hospital in philadelphia, pennsylvania, and is interested in ophthalmology. jerry a. shields, md is director emeritus of the ocular oncology service at wills eye hospital and a professor of ophthalmology at thomas jefferson university in philadelphia, pennsylvania. the first president of the international society of ocular oncology, he has published more than medical articles and textbook chapters and has authored or co-authored major textbooks related to ocular tumors. carol l. shields, md is the director of the ocular oncology service at wills eye hospital, a professor of ophthalmology at thomas jefferson university in philadelphia, pennsylvania, where she is also a consultant at children’s hospital of philadelphia. she has published more than articles and book chapters on eye cancer and has co-authored textbooks on ocular tumors. she serves on the editorial board of several ophthalmic journals and was the first woman to be elected president of the international society of ocular oncology. ama journal of ethics, november citation ama j ethics. ; ( ):e - . doi . /amajethics. . . conflict of interest disclosure the author(s) had no conflicts of interest to disclose. the viewpoints expressed in this article are those of the author(s) and do not necessarily reflect the views and policies of the ama. copyright american medical association. all rights reserved. issn - clinical trials in metastatic uveal melanoma: current status review article ocul oncol pathol ; : – clinical trials in metastatic uveal melanoma: current status tamara a. sussman a pauline funchain a arun singh b a department of hematology/oncology, taussig cancer institute, cleveland clinic foundation, cleveland, oh, usa; b department of ophthalmic oncology, cole eye institute, cleveland clinic foundation, cleveland, oh, usa received: march , accepted: may , published online: september , arun singh department of ophthalmic oncology, cole eye institute cleveland clinic foundation euclid avenue, cleveland, oh (usa) singha @ ccf.org © s. karger ag, baselkarger@karger.com www.karger.com/oop doi: . / keywords uveal melanoma · metastasis · oncology · clinical trials · liver-directed therapy abstract background: uveal melanoma is a rare subtype of melano- ma. prognosis and survival rates for patients with metastatic uveal melanoma remain poor. no current fda-approved standard of care therapy is available for patients with meta- static uveal melanoma. thus, clinical trials are essential for the development of new therapies and to provide patients hope for improved survival and outcomes. summary: in this article, we review clinical trials identified on the database https://clinicaltrials.gov that are open and enrolling patients with metastatic uveal melanoma as of november , . this search produced active trials involving liver-directed therapy, cns-directed therapy, and systemic therapy with immunotherapy, targeted therapy, or oncolytic virus thera- py. here, we discuss liver and cns-directed therapy as well as systemic targeted therapy and oncolytic virus therapy. im- munotherapy clinical trials are discussed in a companion re- view article by dr. marlana orloff. key messages: various novel therapeutic targets and immunomodulatory ap- proaches are on the horizon for patients with metastatic uveal melanoma and may yield incremental therapeutic benefit. selecting a clinical trial must be individualized and made jointly with the patient and his/her oncologist. © s. karger ag, basel introduction uveal melanoma is the most common intraocular tu- mor in adults. the overall incidence of uveal melanoma has remained stable from to , with about pa- tients per million affected, which comprises % of all mel- anomas [ , ]. for all stages, the -year overall survival (os) remains about . % [ ]. while about % of patients present with metastatic disease, up to % develop meta- static disease with subsequently worse prognosis [ ]. of patients who develop metastatic disease, liver is the most common site ( %) [ ]. historically, median os for met- astatic uveal melanoma ranges from to months, with a -year os of % [ , ]. however, more recent data from clinical trial patients suggests a median progression- free survival (pfs) and os of . months and . months, and -year os of % [ ]. prognosis and survival rates for metastatic uveal melanoma remain poor, and there is cur- rently no fda approved therapy in the metastatic setting. clinical trials are essential for the development of new therapies and to provide patients hope for improved sur- vival and outcomes. methods we conducted a search for active clinical trials available world- wide for metastatic uveal melanoma on november , , through the clinical trial database available at https://clinicaltrials. gov. clinicaltrials.gov is run by the national library of medicine sussman/funchain/singhocul oncol pathol ; : – doi: . / at the national institutes of health, and is the largest clinical trials registry, currently holding registrations from over , trials from countries. our search produced available trials for uveal melanoma (fig.  ), with a significant proportion ( %, n = ) of trials not accruing patients due to status of completed, ter- minated, withdrawn, suspended, active – not recruiting, or un- known status. once removed, currently recruiting trials re- mained. of these trials, were excluded: nontherapeutic trials, localized eye therapy trials, and trials for neoadjuvant or adju- vant therapy for resectable disease. a final trials were identified for treatment of metastatic uveal melanoma; including trials uti- lizing liver-directed therapy, trial with cns-directed therapy, and trials with systemic immunotherapy or targeted therapy used in combination or as single agent. trials including immuno- logical checkpoint inhibitors with liver-directed therapies are cat- egorized as liver-directed therapy trials. similarly, a trial including an immunological checkpoint inhibitor in combination with cns- directed therapy is categorized as cns-directed therapy trial. all clinical trials for metastatic uveal melanoma discussed in this re- view are summarized in table . clinical trials for patients with metastatic uveal melanoma systemic therapy clinical trials no current standard of care therapy exists for meta- static uveal melanoma. response rates with checkpoint inhibitor therapy with single agent anti-ctla (ipilim- umab) or anti-pd (nivolumab) or combination anti- ctla /anti-pd inhibition have been disappointing, as of november , clinical trials identified for uveal melanoma clinicaltrials.gov trials excluded on basis of trial status: completed terminated withdrawn suspended active, not recruiting not yet recruiting (questionnaire) enrolling by invitation (observational) unknown* clinical trials in uveal melanoma with status of recruiting trials excluded on basis of description, objective or outcome: new imaging technique biomarker analysis localized eye therapy clinical trials in high risk or stage iii-iv uveal melanoma trials excluded on basis of treatment type: adjuvant neoadjuvant clinical trials in metastatic or unresectable uveal melanoma: systemic therapy immunotherapy targeted therapy oncolytic virus therapy liver directed therapy cns directed therapy *study has passed its completion date and status has not been verified in more than years fig. . flow diagram of clinical trials for uveal melanoma. clinical trials in metastatic uveal melanoma ocul oncol pathol ; : – doi: . / with response rates of . % with single agent, and – % with combination therapy [ – ]. pfs and os with immu- notherapy are . months and . months, respectively. similarly, pfs and os with targeted (kinase) therapy are . months and . months [ ]. currently, clinical tri- als with systemic therapy are available, specifically trials with immunological checkpoint inhibitors, trials with targeted therapy, and trials with oncolytic virus therapy. the trials with systemic immunotherapy are discussed separately in the companion review article by marlana orloff, md. the remaining systemic therapy trials will be discussed in this review. trials with agents targeting spe- table . clinical trials in metastatic uveal melanoma nct number trial status phase locations nct intermittent selumetinib for uveal melanoma recruiting i columbia university medical center; memorial sloan kettering cancer center; md anderson cancer center nct ide in patients with solid tumors harboring gnaq/ mutations or prkc fusions recruiting i/ii columbia university medical center; thomas jefferson university; sarah cannon research institute/tenessee oncology; md anderson cancer center; westmead hospital (sydney, australia) nct niraparib in bap and other dna damage response deficient neoplasms recruiting ii university of florida nct nivolumab in combination with talazoparib in melanoma and mutations in brca or brca-ness genes active, not yet recruiting ii cleveland clinic nct plx in advanced malignancies recruiting i/ii honor health (arizona); sylvester comprehensive cancer center/university of miami miller school of medicine; columbia university; south texas accelerated research therapeutics; virginia cancer specialist nct radiation and gene therapy before nivolumab for metastatic non-small cell carcinoma and uveal melanoma recruiting ii houston methodist hospital nct modified virus vsv-ifnbetatyrp in treating patients with stage iii-iv melanoma recruiting i mayo clinic in florida; mayo clinic in rochester nct yttrium , ipilimumab, & nivolumab for uveal melanoma with liver metastases recruiting i/ii california pacific medical center; university of chicago; thomas jefferson university nct ipilimumab and nivolumab with immunoembolization in treating participants with metastatic uveal melanoma in the liver recruiting ii thomas jefferson university nct the scandinavian randomized controlled trial of isolated hepatic perfusion for uveal melanoma liver metastases recruiting iii sahlgrenska university hospital (sweden) nct a study to assess pv- chemoablation of cancer of the liver recruiting i sharp memorial hospital (san diego, california); florida hospital tampa; st. luke’s university health network (bethlehem, pennsylvania); vanderbilt university medical center; md anderson cancer center nct percutaneous hepatic perfusion in patients with hepatic-dominant ocular melanoma (focus) recruiting iii stanford university; moffit cancer center; emory university; university of chicago; university of maryland cancer center; atlantic melanoma center at morristonwn medical center (nj); roswell park cancer institute; duke university medical center; ohio state university; st. luke’s university hospital cancer center; thomas jefferson university; university of tennesee; md anderson cancer center; sites in austria, belgium, france, germany, italy, spain, switzerland, uk nct intravenous and intrathecal nivolumab in treating patients with leptomeningeal disease recruiting i md anderson cancer center sussman/funchain/singhocul oncol pathol ; : – doi: . / cific pathways alone or in combination with immuno- logical checkpoint inhibitors are categorized as targeted therapy clinical trials. similarly, trials with oncolytic viral therapies alone or in combination with immunological checkpoint inhibitors are categorized as oncolytic virus therapy trials. details of the targeted therapy and onco- lytic virus therapy trials are presented in table . targeted therapy clinical trials the current landscape of systemic therapy for cutane- ous melanoma is largely driven by immunotherapy. al- though effective in treating patients with cutaneous mel- anoma, response rates have been disappointing in uveal melanoma. different approaches, including targeted should also be explored in this field. four clinical trials are currently available utilizing targeted therapy. a phase trial of intermittent dosing of the mitogen-activated pro- tein kinase kinase (mek) enzyme inhibitor, selumetinib, in metastatic uveal melanoma patients who have not re- ceived prior mek inhibitor therapy (nct ), tar- gets the mitogen-activated protein kinase (mapk) path- way, regardless of tumor mutational status. oncogenic mutations in gnaq or gna are observed in more than % of primary uveal melanomas and activate signaling pathways primarily including the mapk pathway, which leads to cell proliferation and survival [ , ]. a prior randomized phase trial compared selumetinib to che- motherapy in metastatic uveal melanoma patients and found a modest benefit in pfs ( . vs. weeks) and in objective response rate ( vs. %) for those treated with selumetinib [ ]. however, treatment-related ad- verse events were observed in % of patients treated with selumetinib. with this trial, an intermittent dosing sched- ule may achieve a better toxicity profile and response rate if higher doses of selumetinib can be achieved. mutations in gnaq or gna also activate the pro- tein kinase c pathway, which also leads to cell prolifera- tion and survival and thus serves as another target for cancer-directed therapy. a current phase / basket trial is available to metastatic uveal melanoma patients and other solid tumors, which uses the drug ide in pa- tients harboring gnaq/ mutations or protein kinase c fusions (nct ). a recent phase study of ide in patients with metastatic uveal melanoma dem- onstrated encouraging clinical activity with / patients achieving a partial response and / with stable disease [ ]. the toxicity profile was tolerable, with % of pa- tients developing grade – adverse events, namely hypo- tension. while two dosing strategies were employed in this trial (once daily dosing and twice daily dosing), twice daily dosing was better tolerated and potentially exhibited longer duration of response. all patients (n = ) in the daily dosing regimen discontinued treatment due to pro- gressive disease, whereas patients in the twice-daily dos- ing regimen (n = ) remained on treatment for greater than months. of these patients, maintained a par- tial response and had stable disease [ ]. for this reason, the study design for ide includes a dose escalation phase for twice daily dosing to determine the recom- mended phase dose in patients with metastatic uveal melanoma, cutaneous melanoma, colorectal cancer, and other solid tumors. another target for clinical trials is double stranded dna damage repair genes. germline and somatic muta- tions in the double-stranded dna damage repair gene bap have been found in patients with uveal melanoma. parp / enzymes are responsible for repairing single- stranded dna breaks. inhibition by a parp inhibitor, along with a deficient dna damage repair gene, ultimate- ly leads to truncation of dna replication, transcription, and cell death, also known as synthetic lethality [ ]. sev- eral trials in other tumor types, specifically breast, ovari- an, and prostate cancers that target the brca / genes have successfully shown improved response rates and pfs with parp inhibitor therapy [ – ]. a current clin- ical trial is evaluating niraparib in bap and other dna damage response deficient neoplasms in metastatic uveal melanoma, mesothelioma, and renal cell carcinoma (nct ). similarly, another phase trial that is active, but not yet recruiting patients, is using the combi- nation of talazoparib (parp inhibitor) and nivolumab (anti-pd- immunotherapy) in metastatic uveal or cuta- neous melanoma patients that harbor a mutation in a dna damage repair gene (nct ). the dna damage repair genes included in this study are brca / and brcaness genes, which are specifically responsible for homologous recombination repair of dna. in cuta- neous melanoma, the combination of parp and pd- inhibition has shown to increase the immunogenicity of tumor cells by promoting t cell and natural killer cell in- filtration, and increasing tumor expression of pd-l in vitro and in vivo [ – ]. lastly, a phase / trial evaluates plx in advanced malignancies (nct ). plx is an inhibitor of bromodomain-containing protein (brd ), a bet family member, an epigenetic regulator that is known to exert key roles involved in chromatin remodeling and transcriptional regulation. brd is significantly upregu- lated in melanoma tissue; treatment with brd or bet inhibitors have shown to impair melanoma cell prolifera- clinical trials in metastatic uveal melanoma ocul oncol pathol ; : – doi: . / tion and tumor growth in vitro and in vivo [ ]. simi- larly, brd inhibition demonstrated cytotoxic activity in uveal melanoma cell lines and mouse xenograft models carrying gnaq/ mutations [ ]. oncolytic virus therapy clinical trials oncolytic viruses are also an alternate approach in treating metastatic uveal melanoma patients. oncolytic virus therapy has been utilized in cutaneous melanoma with the development of talimogene laher- parepvec (tvec), approved by the fda in october . tvec is currently being studied in combination to ex- pand its use and synergize with other interventions, in- cluding immune checkpoint inhibitor therapy. however, oncolytic virus therapy has not yet been introduced in the field of uveal melanoma. currently, two clinical trials are available for intratumoral injection of oncolytic virus therapy. one is a phase trial for anti-pd- naïve patients to receive gene therapy with intralesional injection of ad- enovirus-mediated expression of herpes simplex virus thymidine kinase (adv/hsv-tk) with valacyclovir and stereotactic body radiation therapy followed by nivolum- ab administration on day (nct ). this thera- peutic combination builds on the concept of “suicide gene therapy,” where a therapeutic gene-encoding en- zyme (adv/hsv-tk) is capable of transforming a non- toxic prodrug (valacyclovir) into a cell toxin that enhanc- es the cytotoxic effect within cancer cells and protects the healthy cells [ ]. another clinical trial using a modified virus is a phase study of vsv-ifnbetatyrp in pa- tients with metastatic uveal or cutaneous melanoma (nct ). the vesicular stomatitis virus (vsv) is altered to include two extra genes: human interferon beta (hifn-β), which may protect normal healthy cells from becoming infected with the virus, and tyrp , which is expressed mainly in melanocytes and melanoma tumor cells. tyrp can trigger a strong immune response to kill the melanoma tumor cells. vsv has been shown to have a rapid replication rate within the tumor and to be cyto- toxic in melanoma xenograft models. targeting tyrp antigen has been shown to increase cd t cells and il- in vitro and in vivo, resulting in increased immune cell infiltration into the tumor microenvironment [ – ]. liver-directed therapy clinical trials as up to % of patients with metastatic uveal mela- noma develop metastatic disease to the liver, recent stud- ies have suggested statistically significant improved pro- gression-free survival (pfs) and os with liver-directed therapy when compared to systemic therapy (median pfs . vs. . months; mos . vs. . months) [ ]. how- ever, when controlling for key patient characteristics, the os benefit for liver-directed therapies is no longer seen. five studies are currently available for metastatic uveal melanoma patients with significant liver disease burden and limited extrahepatic disease, which include: a phase / study of combination immunotherapy with ipilim- umab/nivolumab with sirspheres yttrium- internal hepatic radiation (nct ); combination ipilim- umab/nivolumab with immunoembolization (phase ) to liver metastases (nct ); phase isolated hepat- ic perfusion study where high concentration chemother- apy is perfused through the liver with minimal systemic exposure (nct ); a phase study of intralesion- al injection of pv- ( % rose bengal disodium), which has an expansion cohort of patients that can receive im- mune checkpoint inhibitor therapy (nct ); and a phase study of percutaneous hepatic perfusion with melphalan (nct ). this study (also known as the focus trial) delivers melphalan mg/kg using the delcath hepatic delivery system via percutaneous cath- eterization of the femoral artery to access the hepatic ar- tery to infuse the chemotherapeutic agent, and in the in- ferior caval vein to aspirate the chemosaturated blood re- turning through the hepatic veins, which is perfused through an extracorporeal filtration system, and then re- turned to systemic circulation. patients can receive up to six treatments at -week intervals. in another phase tri- al, percutaneous hepatic perfusion of melphalan was compared with best alternative care in patients with melanoma liver metastases. eighty-three patients in this study had uveal melanoma. hepatic pfs was significant- ly prolonged with melphalan infusion (median . vs. . months); however, no difference was observed in os (median . vs. . months) [ ]. cns-directed therapy clinical trial while uveal melanoma does not typically metastasize to the central nervous system, several case reports and case series have demonstrated leptomeningeal involve- ment [ , ]. data from metastatic cutaneous melanoma patients with leptomeningeal disease has shown a median os of only . months [ ]. limited treatment options are available for cutaneous and uveal melanoma patients with leptomeningeal disease with limited evidence of long-term clinical benefit from them [ ]. a current phase clinical trial available for uveal melanoma pa- tients with leptomeningeal disease involves the adminis- tration of intrathecal nivolumab with intravenous nivolumab beginning in cycle (nct ). sussman/funchain/singhocul oncol pathol ; : – doi: . / conclusions the current landscape of clinical trials available for treatment of metastatic uveal melanoma is comprised of active trials that encompass a range of modalities, in- cluding immunotherapy, targeted therapy, oncolytic vi- rus therapy, as well as liver-directed therapy, and cns- directed therapy. while informative, our review of avail- able clinical trials has limitations. while our search criteria were broad in order to encompass all clinical trials available for metastatic uveal melanoma, trials were large- ly limited to “recruiting” status. therefore, trials that opened or started recruiting after the search date of no- vember , , were not included in this review. as uve- al melanoma is a rare disease, we would expect a few trials may have opened after the search was performed. as no current standard of care therapy exists for metastatic uve- al melanoma, clinical trials are essential for developing new therapies and offering patients hope for improved outcomes. various novel therapeutic targets and immu- nomodulatory approaches are on the horizon and may yield incremental therapeutic benefit. selecting an appro- priate clinical trial can be overwhelming and should be made with a patient’s oncologist. oncologists and their clinical trial team can discuss with patients the details of a trial, eligibility criteria, and expected toxicity. addition- ally, oncologists can compare available clinical trials to standard of care therapy in the context of a patient’s co- morbidities, location, and burden of metastatic disease. conflict of interest statement tamara sussman has no conflicts of interest to declare. pauline funchain receives consultant fees from eisai and research funding from pfizer. arun singh receives consulting fees from eckert and zeigler, and isoaid; advisory board meeting with immunocore; and stock options with aura. funding sources no funding was received for the preparation of the manuscript. author contributions t.a.s. collected data, performed search, and wrote manuscript. a.s. designed concept and revised manuscript. p.f. revised manu- script. all authors approve the final version of the manuscript. references aronow me, topham ak, singh ad. uveal melanoma: -year update on incidence, treatment, and survival (seer - ) [internet]. ocul oncol pathol. apr; ( ): – . 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[cited nov ] available from: http://www.ncbi. nlm.nih.gov/pubmed/ hughes ms, zager j, faries m, richard alex- ander h, royal re, wood b, et al. results of a randomized controlled multicenter phase iii trial of percutaneous hepatic perfusion compared with best available care for pa- tients with melanoma liver metastases. ann surg oncol. apr; ( ): – . fedorenko iv, evernden b, kenchappa rs, sahebjam s, ryzhova e, puskas j, et al. a rare case of leptomeningeal carcinomatosis in a patient with uveal melanoma: case report and review of literature. melanoma res. oct; ( ): – . glitza ic, reddy st, patel sp. leptomenin- geal disease in uveal melanoma: a case series. j neurooncol sep; ( ): – . davies ma, liu p, mcintyre s, kim kb, papa- dopoulos n, hwu wj, et al. prognostic factors for survival in melanoma patients with brain metastases. cancer. apr; ( ): – . groves md. leptomeningeal disease. neuro- surg clin n am. jan; ( ): – . https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref https://www.karger.com/article/fulltext/ ?ref= #ref 	tabellentitel wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); 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// // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ microsoft word - -cr- a- - - -r f d.docx case report | jogcr. ; ( ): - volume , winter journal of obstetrics, gynecology and cancer research 	journal of obstetrics, gynecology and cancer research | issn: - analysis of ultrasonographic misdiagnosis of cephalothoracopagus janiceps conjoined twins: a case report mehnoosh torkzaban , nesa rajabpoor nikoo , ateeh kalateh , mahboobeh shirazi * . department of radiology, thomas jefferson university hospital, philadelphia, pa, united states . shohada hospital, qom, iran . department of obstetrics and gynecology, north khorasan university of medical sciences, bojnurd, iran . maternal, fetal and neonatal research center, tehran university of medical sciences, tehran, iran introduction conjoined twining (ct) is a rare complication of monozygotic twinning. the frequency of ct is approximately : , gestation, while the true incidence is around . : , live births ( , ). the incidence is three times higher among female than male twines ( ) . in humans, monozygotic monoamniotic twins develop when an implanted blastocyst splits at about – days after fertilization. failure to undergo a complete spillage of the embryonic disc at or later than days results in conjoined twin development (fissure theory) ( , , ). the etiology of ct is obscure and none of race, consanguinity, hereditary, birth order, maternal age, acute and chronic diseases during pregnancy, or maternal exposure has revealed any association with ct ( , ). conjoined twinning has been reported in twine and triplet pregnancies following assisted reproductive techniques such as in- vitro fertilization and intracytoplasmic sperm injection ( , ). conjoined twins are classified according to the most prominent site of attachment, plus “pagus”, a term that means “fixed” in greek ( ). cephalothoracopagus is the rarest subtype of cts and occurs once in every sets of conjoined twins or once in every three million births ( , ) ; it refers to twins with fused head and thorax but separate pelves and limbs. if the single fused head has two faces each looking in opposite directions, the twins are referred to as cephalothoracopagus janiceps twins ( , ). the term janiceps has its origin in janus, the two‐faced roman god. when the two faces are asymmetrical and only one normal face can be seen alongside with a second incomplete face (single naris, cyclopic eyes, synotic ears, a proboscis, or two small eyes in a single palpebral fissure), it is called cephalothoracopagus article info abstract . /jogcr. . . background & objective: conjoined twins (cts) are rare complications of monozygotic twinning. cephalothoracopagus is the rarest subtype of cts and occurs once in every sets of conjoined twins or once in every three million births. here we present such a case and analyze the possible reasons for ultrasonographic misdiagnosis and recommend solutions to avoid it. case report: in this article, we have reported a case of cephalothoracopagus janiceps twining. the ultrasonographic diagnosis was missed at and weeks scans. increased thickness of nuchal translucency and absent nasal bone was observed alongside with suspected gastroschisis. the patient was referred for further evaluation at - weeks of pregnancy. unexpectedly, two alive fetuses were reported fused in the head, thorax, and abdomen. because of the poor prognosis, counseling was provided for parents and elective medical pregnancy termination was carried out. we have analyzed the possible reasons for ultrasonographic misdiagnosis. conclusion: without applying a standardized scanning of the entire uterus both in a longitudinal and transverse approach in early pregnancy, cephalothoracopagus twining may be misdiagnosed with a singleton pregnancy. a high level of concerns may raise for conjoined cephalothoracopagus twinning in case of finding a single fetal pole with an irregular body outline and a disproportionally large head in the presence of two separate fetal hearts in early pregnancy. two fused heads with two brains and two sets of lower and upper extremities do confirm the diagnosis. keywords: cephalothoracopagus janiceps, conjoined twins, ultrasonographic misdiagnosis received: / / ; accepted: / / ; published online: aug ; use your device to scan and read the article online corresponding information: mahboobeh shirazi, maternal, fetal and neonatal research center, tehran university of medical sciences, tehran, iran . email: mahboobehshirazi @gmail.com copyright © , this is an original open-access article distributed under the terms of the creative commons attribution-noncommercial . international license which permits copy and redistribution of the material just in noncommercial usages with proper citation. ultrasonographic misdiagnosis of conjoined twins volume , winter journal of obstetrics, gynecology and cancer research janiceps monosymmetros ( ). here we present such a case. case report a -year-old g p pregnant woman, who had conceived spontaneously and had an unremarkable medical history with no history of drug, alcohol or cigarette smoking, underwent her early pregnancy ultrasound. the scan revealed one fetal pole, one yolk sac, and a normal fetal heart rate (fhr). the crown- rump length (crl) was mm equal to weeks days of pregnancy. she was scanned next time for aneuploidy screening ultrasound at weeks, days of the last menstrual period (lmp). the gestational age (ga) based on the crl was equal to weeks, day of pregnancy. the thickness of the nuchal translucency (nt) was reported as mm. the radiologist had reported possible technical errors in nt measurement and inability in nasal bone (nb) visualizing due to unfavorable fetal position. a hyperechoic herniated mass was also visualized at the level of the anterior abdominal wall and gastroschisis was suspected. the patient was referred to a tertiary health center, (yas hospital, tehran, iran), for further evaluation. the next ultrasound exam was performed at - weeks of pregnancy. unexpectedly, two alive fetuses were reported fused in head, thorax, and abdomen. the ultrasound diagnosis of cephalothoracopagus cts was made. because of the poor prognosis, counseling was provided for parents and elective medical pregnancy termination by misoprostol was carried out. the expelled twines were fused at the cranium, thorax, and abdomen to the umbilicus. twines had a shared placenta and umbilical cord. the faces were dissimilar and on opposite sides of the head, degrees to the separate spines. there was one normal face with two eyes, one complete nose, and one mouth, and one set of low-set ears (figure a), and the opposing face had incomplete facial features as one cyclopic eye and irregular fused naris and mouth orifices (figure b). the arms and legs of each of the twins were of similar length and development and followed the orientation of the spine (figure c). the twines’ sex was not obvious but more likely were females. figure . a. normal face with two eyes, one complete nose and one mouth, and one set of low set ears; b. incomplete facial features as one cyclopic eye and irregular fused nares and mouth orifice; c. the arms and legs of each of the twins were of similar length and development and followed the orientation of the spine figure . a. longitudinal section of twins, mimicking singleton pregnancy at weeks days of pregnancy; b. fused brains at - weeks of pregnancy; c. two separate beating heart at - weeks of pregnancy; d. longitudinal section of twins at - weeks of pregnancy. mehnoosh torkzaban & et al. volume , winter journal of obstetrics, gynecology and cancer research discussion the worldwide use of the ultrasound in prenatal screening for down syndrome provides the diagnosis of conjoined twinning in early pregnancy. since all cts are monochorionic monoamniotic, when only one yolk sac is seen alongside two embryos in very early pregnancy, the index of suspicion should be raised. two of first-trimester sonographic indications for possible conjoined twinning are: -bifid appearance of a sole fetal pole in the first trimester seen before weeks of gestation, and - visualization of two hearts or two stomachs ( ). from weeks of gestation, fetal activity increases progressively, which facilitates the differential diagnosis between conjoined and non- conjoined monoamniotic twins ( ) . the first trimester ( - w+ days) ultrasound is the best method for early diagnosis of cts ( ) . the earliest prenatal diagnosis of cephalothoracopagus twins was reported by lam et al. ( ). the diagnosis was made by vaginal ultrasound examination at weeks' gestation from the findings of a single fetal pole with an irregular body outline, a disproportionally large head, and two separate cardiac pulsations and was confirmed after rescanning at weeks ( ). while early diagnosis of conjoined twins is feasible, it is not always easy in cephalothoracopagus twinning due to extensive conjoining; a single fused head and thorax, and limited fetal movement as was seen in our case. due to the monoamniocity of the conjoined twins, a single yolk sac alongside a single crl and normal fetal heart were observed at - weeks of gestation in our case; mimicking a singleton pregnancy and substantial missing of the second fetal heart (figure a). when the second ultrasound scan was performed at weeks days of lmp in our case for nt measurement, the operator reported a fetus with normal fetal heart, increased nt, non-visualized nb, and herniated mass at the ventral abdominal wall, but yet to notice the second fetal heart and fused brains. following the detection of the aforementioned anomalies, a thorough evaluation of the fetal thorax and cranium via scanning the entire uterus both in a longitudinal and transverse approach could be helpful in revealing two separate hearts, fused brains, and duplicated extremities, leading to the accurate diagnosis of cts. increased nt, cystic hygroma, and abdominal wall defects are the most common findings in conjoined twins ( ). currently, certain congenital fetal anomalies are diagnosed even before the twentieth week of gestation with the use of high-resolution ultrasound equipment, but without following a standardized approach to fetal ultrasound and in case of lack of suspicion to any abnormal condition, misdiagnosis may happen ( , ). the final ultrasound scan was performed at - weeks of ga in our reported case. the diagnosis of cephalothoracopagus cts was made by finding one shared placenta and umbilical cord, two fused brains without separating bony skull, two deformed spinal columns, one common thoracic cage with two separate beating hearts and one stomach, two separate sets of lower and upper extremities, and two separate pelvises. one of the twins had cystic hygroma in the posterior neck. the estimated ga based on both twines’ approximate crl was weeks days (figures b, c and d). the next step after diagnosis of conjoined twinning is a prognostic assessment to propose timely medical termination of pregnancy in case of non-viability and prevent complicated surgical delivery. in cephalothoracopagus cts, due to the fusion of the heads and abnormal arrangement of the superior central nervous system, no attempt at surgical separation should be considered and the prognosis is very poor ( ) . we arranged a medical pregnancy termination accordingly. the recurrence risk for conjoined twins appears to be negligible ( ). conclusion in cephalothoracopagus twining a single yolk sac alongside a single crl and normal fetal heart at - weeks of gestation may mimic a singleton pregnancy and lead to missing the second fetal heart and fused brains without applying a standardized scanning of the entire uterus both in a longitudinal and transverse approach. a high level of concerns may raise for conjoined cephalothoracopagus twinning in case of finding a single fetal pole with an irregular body outline and a disproportionally large head in the presence of two separate fetal hearts in early pregnancy. two fused heads with two brains and two sets of lower and upper extremities do confirm the diagnosis. acknowledgments the authors would like to thank all those who helped them writing this paper. conflict of interest authors declared no conflict of interests. references . pajkrt e, jauniaux e. first‐trimester diagnosis of conjoined twins. prenatal diagnosis: published in affiliation with the international society for prenatal diagnosis. sep; ( ): - . 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geopend met acrobat en adobe reader . en hoger.) /nor <feff b e e c c e e c e f f d f b d e f d e f f b b b f b c e d f b d e e b e e e f c c f e c c e e> /pol <feff e f f a e f b d e f a a e a f e f b f f b a a b f b e f b d e d f c e f f d f f e e f a d e> /ptb <feff c a f e e f f d f d e f f d f e d d f c c e f f d e f f f d f f d f f f f e f f f e> /rum <feff c a e f d e f e c f e f d e c f f c f e f e c c f e> /rus <feff f e b c d d b d e a b f e d f e a c d e f c c a c b c d e f e e f b f b e a e a d d e e e f d e e b e e e d d b d e a c d b c e d e e a b c f e c e c e f f e e b f e d e> /sky <feff f e e f e e e e f b d e f f c b f e e a c f e b c e fa c d e f e e f b d e d f e e e f f f d f f f e e f ed e> /slv <feff e f a a e a f b d e f f c b f e a d e a a b b f f e f b e a f e b e a e f b d e a d f f d f a f e f e e e f a d e> /suo <feff b e e e e e b c b e c f c e e e e e e b e c d c f f e f f d f b d e a e c f d f b d e f e f c c a f e a c c a d d c c e> /sve <feff e e e e 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/addpageinfo false /addregmarks false /convertcolors /converttocmyk /destinationprofilename () /destinationprofileselector /documentcmyk /downsample bitimages true /flattenerpreset << /presetselector /mediumresolution >> /formelements false /generatestructure false /includebookmarks false /includehyperlinks false /includeinteractive false /includelayers false /includeprofiles false /multimediahandling /useobjectsettings /namespace [ (adobe) (creativesuite) ( . ) ] /pdfxoutputintentprofileselector /documentcmyk /preserveediting true /untaggedcmykhandling /leaveuntagged /untaggedrgbhandling /usedocumentprofile /usedocumentbleed false >> ] >> setdistillerparams << /hwresolution [ ] /pagesize [ . . ] >> setpagedevice c:\documents and settings\buckland\my documents\wpd\pap \democratic.wpd buckland. democratic theory in library information science. jasist : . letter to the editor of the journal of the american society for information science and technology. published in vol. , no ( ), page . published version may differ slightly. democratic theory in library information science abstract: a recent article by joseph buschman regrets that democratic theory is an unfinished idea. the argument appears to assume an essential relationship between library information science (lis) and democratic theory. libraries services are important for undemocratic purposes also, and like other sociotechnical systems partake on the cultural context in which they are deployed. sir: in his article “democratic theory in library information science: toward an emendation” (august , jasist [ ], pp. - ), joseph buschman notes that thomas jefferson in and james madison in stressed the importance of newspapers and popular information for a liberal democratic government (p. ). he regrets that in library information science (lis) “democratic theory is an unfinished, truncated idea remaining at its jeffersonian/madisonian beginnings” (p. ), cites a wide range of authors as evidence of a chronic collective failure to develop “democratic theory” in lis, and concludes with a forceful demand that “lis must ask itself the question where it stands in this configuration and in relation to democracy” (p. ). buschman appears to assume (if i have understood the complex language of the article correctly) that there is an essential (meaning inherent) mutual relationship between democratic theory and lis. i suggest that there is an different and simpler explanation. when library systems and resources (or any other technologies) are deployed a socio- technical system is created. the “socio” component is shaped by the cultural context in which the technology is deployed, so library service would be democratic only accidentally through the happenstance of deployment within a democratic situation. it is widely accepted that accessible public libraries with liberal collection development practices are important for the health of democratic political systems. but so is oil. more to the point, effective library services are also important for non-democratic political regimes. lenin and his wife, n. k. krupskaya, herself a librarian, thought so. mussolini’s minister of education was enthusiastic about the role of public libraries in evolving a new fascist culture, and the nazis had a vigorous and well-known interest in collection development. part of the problem in philosophical writings about libraries has been a failure (reflected in danton’s famous article of ) to distinguish between philosophical analysis (rigorous critical thought) and a philosophy (a set of motivating beliefs, concepts and values). the latter always pervades library service and it is not necessarily democratic. different political regimes have different social agendas, so lis will be differently deployed. lenin wrote: “but we must build our own library–a library of a different kind, more in keeping with our socialist way of life.” (quoted in simsova ( , ). there are, i submit, two reasons for the lack of democratic theories of lis. first, the assumption that lis is essentially democratic has been explicitly refuted in at least one introductory lis textbook (e.g. buckland , - ). second, the general lack of developed buckland. democratic theory in library information science. jasist : . democratic theories of lis (as distinct from the democratic uses of lis) in the lis literature, as documented by buschman, implies that personified lis has indeed revealed where it stands: the evidence indicates that writers have found it to be an unproductive line of inquiry. abandoning the notion of a democratic theory of lis would not end the possibilities for fruitful inquiry. there is ample scope for more work on the democratic uses of lis--and if this is what buschman meant, i agree with him. there is also, as i have suggested elsewhere (buckland, , - ), scope for examining whether library and other information and communication services are inherently subversive because they tend to lead to new ideas, but subversion is not always democratic in tendency. references buckland. m. k. ( ). library services in theory and context. nd ed. oxford: pergamon press. available online at http://sunsite.berkeley.edu/literature/library/services/ buckland, m. k. ( ). five grand challenges for library research. library trends. , - . special issue on “research questions for the twenty-first century” edited by mary jo lynch. http://www.sims.berkeley.edu/~buckland/trends .pdf danton, j. p. ( ). plea for a philosophy of librarianship. library quarterly, , - . reprinted in b. mccrimmon (ed.), american library philosophy: an anthology (pp. - ). hamden, ct: shoe string press. simsova, s. (ed.). ( ). lenin, kruskaia and libraries. london: clive bingley. michael k. buckland school of information, university of california, berkeley, ca - wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ t h e american archivist october, published quarterly by the society of american archivists d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j prq by c arnegie m ellon u niversity user on a pril the society of american archivists officers w a l d o gifford leland, fresident p h i l i p coolidge brooks, secretary h e r b e r t a. kellar, vice fresident j u l i a n parks boyd, treasurer council members robert digges w i m b e r l y connor margaret cross norton w i l l i a m d. m c c a i n morris l. radoff lawrence counselman wroth the american archivist editorial board christopher bush coleman edna louise jacobsen l u t h e r harris evans h e r b e r t ingram priestley theodore calvin pease, managing editor t h e university of illinois, sfonsor the american archivist is published quarterly in the months of january, april, july, and october by the society of american archivists at ahnaip street, menasha, wisconsin. subscription price five dollars per year. entered as second-class matter february , , at the post office at menasha, wisconsin, under the act of march , . all contributions should be addressed to the editor, lincoln hall, urbana, illinois. sub- scriptions and communications should be sent to ahnaip street, menasha, wisconsin, or the secretary, box , washington, d.c. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j prq by c arnegie m ellon u niversity user on a pril t h e american archivist october, volume iv number published quarterly by t h e society o f a m e r i c a n archivists d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j prq by c arnegie m ellon u niversity user on a pril contents baldassare bonifacio and his essay de archivis lester k. born the papers of thomas jefferson . . h e l e n duprey bullock a ten year experiment in archival practices r u t h k. nuermberger some problems of state archival administration c. c. crittenden the archives of new york edward f. rowse extension service records in alabama . . . charles s. davis reviews of books john m. gaus and leon o. wolcott, public administration and the united states department of agriculture theodore r. schellenberg lloyd a. brown, notes on the care and cataloguing of old maps elizabeth t. platt j. b. speer, functional file classification david c. duniway preliminary inventory of the war industries board records c. c. crittenden margaret ells, compiler, a calendar of the white collec- tion of manuscripts in the public archives of nova scotia; and, historical records survey, calendar of the stevens family papers grace l e e n u t e heinrich otto meisner, der archivar carl ludwig lokke margaret c. norton, "archives and libraries, a compari- son drawn" william j. van schreeven shorter notices news notes iii d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .j prq by c arnegie m ellon u niversity user on a pril the american archivist volume xii january to october, published quarterly by the society of american archivists d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .c ru by c arnegie m ellon u niversity user on a pril contents of volume xii number i , january, the archivist as a public servant-christopher crittenden research for the archivist of today and tomorrow ..harry f. lewis have you seen? archives in the library of congress john andreassen the archives of small business thomas d. clark from the microphotographer's mail daniel f. noll records of the american school of classical studies at athens oscar broneer hawaii territorial archives in the war maude jones the society of american archivists proceedings reports of committees the archivist's book shelf guides to the use of american government publications - jerome k. wilcox reviews of books news notes number , april, the interest of j. franklin jameson in the national ar- chives: - fred shelley the papers of thomas jefferson: progress and procedures in the enterprise of princeton..lyman h. butterfield d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .c ru by c arnegie m ellon u niversity user on a pril the twelfth annual meeting of the society of american archivists william j. van schreeven archival activity in american universities and colleges.... john melville jennings have you seen? the conservation of medieval seals in the swedish rik- sarkiv. [translated by margareth jorgensen.] gustav fleetwood the archivist's book shelf general reference books roland c. mcconnell reviews of books news notes number , july, the president's page christopher crittenden modern records management emmett j. leahy the archival program of wisconsin clifford l. lord have you seen? the archival program of pennsylvania henry howard eddy technical topics the microphotography of current court records daniel f. noll the scholar's interest in personnel records almon r. wright the archivist's book shelf air conditioning as a means of preserving books and records..francis keally and henry c. meyer, iii cartographic record filing in the national archives j. fred winkler reviews of books news notes d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .c ru by c arnegie m ellon u niversity user on a pril number , october, fdr visits the national archives r. d. w. connor what the genealogist expects of an archival agency or historical society milton rubincam the national archives at a turn in the road oliver w. holmes a plan of organization for a university archives henry j. browne letter to the editor a note on the authentication of documents herman kahn the president's page christopher crittenden the processing procedures of the manuscript department of duke university mattie russell and edward g. roberts writings on archives and manuscripts, july -june reviews of books news notes d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .c ru by c arnegie m ellon u niversity user on a pril volume xii january number the archivist published quarterly by the society of american archivists d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .c ru by c arnegie m ellon u niversity user on a pril the society of american archivists officers christopher crittenden, lester j. cappon, president secretary herbert a. kellar, h e l e n l. chatfield, vice-president treasurer council members dorothy k. taylor oliver w. holmes howard h. peckham ernst posner karl l. trever t h e american archivist editorial board leon de valinger, j r . karl l. trever william d. overman grace lee n u t e margaret c. norton, managing editor richard g. wood, reviews editor mary c. lethbridge, news notes editor carl l. lokke, committee on archival research gust skordas vernon d. tate technical committee william j. barrow william d. overman, advertising the american archivist is published quarterly in the months of january, april, july and october by the society of american archivists, margaret c. norton, editor, archives department, illinois state library, springfield, illinois. subscription price five dollars per year. entered as second-class matter at the post office at cedar rapids, iowa, under the act of march , . all contributions should be addressed to the editor, archives department, illinois state library, springfield, illinois. subscriptions and communications should be sent to the secretary, box , williamsburg, virginia. materials for book reviews and news notes should be addressed to the review and news notes editors, the national archives, washington , d. c. technical questions, notes on technique or equipment should be addressed to the technical committee, maryland hall of records, annapolis, maryland. communications regarding advertising should be addressed to william d. overman, e. catawba avenue, akron , ohio. address all change of address communications to lester j. cappon, secretary, p.o. box , williamsburg, virginia. printed at the torch press, d st., s.e., cedar rapids, iowa. d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .c ru by c arnegie m ellon u niversity user on a pril the american archivist volume xii january, number contents the archivist as a public servant..christopher crittenden research for the archivist of today and tomorrow harry f. lewis have you seen? archives in the library of congress john andreassen the archives of small business thomas d. clark from the microphotographer's mail daniel f. noll records of the american school of classical studies at athens oscar broneer hawaii territorial archives in the war maude jones society of american archivists proceedings reports of committees the archivist's book shelf guides to the use of american government publications jerome k. wilcox reviews of books: annual report on historical collections university of virginia li- brary. sixteenth and seventeenth for the years - i * roger t h o m a s pursuits of war. the people of ckarlottesville and albemarle county, virginia, in the second world war, by gertrude dana perlier and others, edited by w . edwin hemphill w i l l i a m d. hoyt, j r . selected papers of robert c. binkley, edited by max h. fisch morris l. radoff united states department of commerce, united states library of con- gress, state censuses, an annotated bibliography of censuses of population taken after the year ijqo by states and territories of the united states, prepared by henry j. dubester forrest r. holdcamper archeion: [periodical of science devoted to archival matters} xvii genevieve e. bator meddelanden fran svenska riksarkivet for aren - matilda h. eliason pasado, presente y futuro de los archivos historicos, by rolando dorcas berro gaston litton news notes d ow nloaded from http://m eridian.allenpress.com /doi/pdf/ . /aarc. . .c ru by c arnegie m ellon u niversity user on a pril \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m j . m a r b u r y a n d w h e n a n o f f i c e v e s t s saikrishna bangalore prakash* introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . r i. a strategy of removal and reappointment . . . . . . . . . . . . . r ii. five theories of when an appointment vests . . . . . . . . . . r a. by the advice and consent of the senate . . . . . . . . . . . . . . . . . r b. after the senate consents, but before commissioning . . . . . . r c. commissioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . r d. delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . r e. acceptance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . r iii. the making of appointments under the constitution . r a. the discretionary theory of appointment . . . . . . . . . . . . . . . . . r b. the discretionary theory applied to other provisions . . . . . . r c. restrictions on the rule of appointer discretion . . . . . . . . . . . r d. the functions of commissions . . . . . . . . . . . . . . . . . . . . . . . . . . r e. congress, the senate, and the vesting of appointments . . . . . r f. reconsidering the theories of appointment . . . . . . . . . . . . . . . . r iv. the marbury appointment revisited . . . . . . . . . . . . . . . . . . . . r conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . r appendix a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . r  saikrishna bangalore prakash. individuals and nonprofit institutions may reproduce and distribute copies of this article in any format at or below cost, for educational purposes, so long as each copy identifies the author, provides a citation to the notre dame law review, and includes this provision in the copyright notice. * james monroe distinguished professor of law, horace w. goldsmith research professor, university of virginia school of law. thanks to scott baker, kevin collins, deborah dinner, aziz huq, john inazu, kurt lash, david law, tom ginsburg, ronald levine, greg magarian, david strauss, suja thomas, laura weinreb, ted white, and participants in the chicago law school works-in-progress workshop, the washington university faculty workshop, and the university of illinois constitutional colloquium for comments. thanks also to john harrison for helpful conversations. finally, thanks to the reference librarians at the university of virginia for research support, to andrew bentz, simon cataldo, rachel kincaid, alexander krueger-wyman, w. andrew lanius, seth meyer, and archith ramkumar for research assistance and comments, and to the virginia law school for summer research support. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : abstract scholars have ignored the most important question in one of the most famous constitutional law cases, obscuring the machinations that spawned the dispute. this article sheds light on the events that precipitated marbury v. madison and also explains when an appointment vests. thomas jefferson famously refused to deliver a commission to william j. marbury, causing the latter to seek a writ of mandamus from the supreme court. the received wisdom supposes that jefferson’s refusal rested on the grounds that marbury had not been appointed a justice of the peace precisely because he never had received a commission. in fact, jefferson’s delivery argument was a post-hoc rationalization, having nothing to do with his actions in march of . john adams’s midnight appointments incensed jefferson, leading the new president to treat all of the justice of the peace appointments as nullities. to jefferson, the failure to deliver commissions to some of those appointees mattered not a whit. what seems to have been far more significant is his sense that the justices of the peace served at his pleasure. acting on this belief, he simultaneously removed them all and recess- appointed most of them, save for more than a dozen, including william j. marbury. this article also addresses whether william j. marbury and the other midnight appoin- tees who never received their commissions were nonetheless appointed, considering five theories of when an appointment vests: when the senate consents; after consent but before commissioning; when commissioning occurs; with the delivery of a commission; and with acceptance of the office. in the course of considering these theories, the article discloses the surprising fact that thomas jefferson, as secretary of state, endorsed the second theory, namely that appointments vest before the act of commissioning. moreo- ver, well before marbury v. madison, the adams administration likewise concluded that appointments could vest prior to any commission being issued or delivered. despite this convergence, the article contends that none of the five theories is correct because each reads the constitution as enshrining a single answer regarding when an appoint- ment vests. there is no single answer. rather an appointment vests whenever the president determines that it shall. the constitution grants power to the president to appoint, never precisely specifying when or how an appointment vests. by not specify- ing when or how appointment is made, the constitution leaves it to the president to decide the manner in which he appoints. this conclusion derives from a general prin- ciple of constitutional law: when the constitution grants power to an entity but does not specify the precise means by which it will be exercised, the grantee may decide the means of exercising it. introduction scholars have dissected marbury v. madison ad nauseum. they have trained their energies on the broader battle between the republicans and federalists, what mistakes chief justice john marshall made in his opinion, whether leaving the jurisdictional issue for last was deviously brilliant, and whether he concocted judicial review. the books and articles on marbury are almost innumerable. among the best are alexander bickel, the least dangerous branch ( ); robert lowry clinton, mar- bury v. madison and judicial review ( ); donald o. dewey, marshall versus jeffer- \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y missing from these works is any sustained analysis of the question fore- most in the minds of william marbury and john marshall: had john adams appointed marbury prior to leaving office? if he had, jefferson and secre- tary of state madison arguably violated marbury’s rights by denying him a commission, for one of the president’s article ii duties is to “commission all officers of the united states.” or at least that is the prism through which the plaintiffs saw the dispute. after all, they sought copies of their commis- sion, documents that confirmed their previous appointments. certainly that son ( ); charles f. hobson, the great chief justice: john marshall and the rule of law – ( ); leonard w. levy, original intent and the framers’ consti- tution – ( ); sylvia snowiss, judicial review and the law of the constitution ( ); dean alfange jr., marbury v. madison and original understanding of judicial review: in defense of traditional wisdom, sup. ct. rev. , – ( ); william w. van alstyne, a critical guide to marbury v. madison, duke l.j. ; akhil reed amar, mar- bury, section , and the original jurisdiction of the supreme court, u. chi. l. rev. ( ); david f. forte, marbury’s travail: federalist politics and william marbury’s appointment as justice of the peace, cath. u. l. rev. ( ); michael j. klarman, how great were the “great” marshall court decisions?, va. l. rev. , – ( ); michael w. mcconnell, the story of marbury v. madison: making defeat look like victory, in constitu- tional law stories (michael dorf ed., ); james m. o’fallon, marbury, stan. l. rev. ( ); jack n. rakove, the origins of judicial review: a plea for new contexts, stan. l. rev. ( ); alan f. westin, introduction to charles a. beard, the supreme court and the constitution (prentice-hall ) ( ). for a discussion of marbury within the sweep of american legal history, see g. edward white, law in american history: from the colonial years to the civil war – ( ). when scholars have considered the appointment question, they usually say no more than that marshall’s claims about when an appointment vests were not obviously right. see, e.g., van alystne, supra note , at (noting that marshall’s conclusion has been “substan- tially modified” by the supreme court); michael stokes paulsen, marbury’s wrongness, const. comment. , , ( ) (arguing that marshall was wrong in holding that marbury’s appointment had vested). in fairness, both examine numerous legal issues raised by the opinion, making it impossible to examine any one in depth. perhaps because scholars have ignored the question of when an appointment vests, courts that discuss the issue invariably treat marbury as dispositive, despite the fact that its discussion is clearly dicta. these tendencies were not lost on jefferson. see letter from thomas jefferson to william johnson (june , ), in the works of thomas jeffer- son n.i (paul l. ford ed., ). courts often cite marbury for the proposition that there must be a time when an appointment is complete, a statement that no one can dispute and one that does not specify when or how an appointment is made complete. see, e.g., nat’l treasury emps. union v. reagan, f. d , (d.c. cir. ) (“for more than one hundred and seventy-five years, the rule as to when an appointment takes place has been clear: ‘when the last act to be done by the [appointing authority] was per- formed . . . .’ ” (quoting marbury v. madison, u.s. ( cranch) , ( )) (altera- tion in original)); speed v. united states, fed. cl. , ( ) (“a federal employee is appointed to a position ‘when the last act to be done by the [appointing authority] [i]s performed.’ ” (quoting nat’l treasury emps. union, f. d at ) (alteration in original)). u.s. const. art. ii, § . see mcconnell, supra note , at (noting that the plaintiffs’ sought a writ of man- damus to compel madison to handover copies of their commissions). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : is the way the chief justice must have seen the case. why else discuss this issue before ultimately deciding that the court lacked jurisdiction? in partic- ular, why would the chief justice go on at great length, insisting that the commission was evidence that adams had already appointed marbury; that if the commission was the appointment, the president’s signature vested the office; that if the signature was insufficient, that sealing the commission made the officer; and that if delivery was required, delivery to the secretary of state was sufficient? jefferson surely understood the question’s import, for marshall had branded the president a scofflaw. marshall’s claims “stuck in jefferson’s craw for the rest of his life.” when an appointment vests matters. for the appointee, it marks the point when she may function in office and draw a salary. it is especially important when the office has a durable tenure, such as good behavior ten- ure. the question of when an appointment vests matters to the president, too. even as to officers serving at pleasure, removal can be risky. the list of chief executives condemned, impeached, or challenged in court for removals includes george washington, andrew jackson, andrew johnson, frank- lin roosevelt, and george w. bush. finally, when an office vests matters to the public because it marks when a private citizen can act as an official— prosecute, create rules, or adjudicate cases. when an appointment vests also matters because it is part of a broader question of when events of constitutional significance occur. for instance, when does a pardon vest? does it vest when the president signs the pardon, upon notification, upon delivery, or some other time? or consider an officer’s removal. is the officer ousted when the president decides as much, when the public is advised, or when the officer receives notice? the answer g. edward white’s discussion best captures the contemporary significance of the appointment question. see white, supra note , at . louis h. pollak, marbury v. madison: what did john marshall decide and why?, proc. am. phil. soc’y , n. ( ). u.s. const. art. iii, § (federal judges hold office during “good behaviour”). for an explication of this tenure, see saikrishna prakash & steven d. smith, how to remove a federal judge, yale l.j. ( ). see james monroe, a view of the conduct of the executive in conduct of the foreign affairs of the united states, connected with the mission to the french republic, during the years – (kessinger publ’g, llc ) ( ) (criticizing washington for removing him from office of minister plenipotentiary to france). the senate censured andrew jackson for his removal of the treasury secretary. see robert v. remini, andrew jackson and the bank war – ( ). see generally michael les benedict, the impeachment and trial of andrew john- son ( ) (discussing andrew johnson’s impeachment); david o. stewart, impeached: the trial of president andrew johnson and the fight for lincoln’s legacy ( ) (same). see, e.g., humphrey’s ex’r v. united states, u.s. , – ( ) (upholding a challenge to roosevelt’s removal of a commissioner of the federal trade commission). see adam zagorin, why were these u.s. attorneys fired?, time (mar. , ), http:// content.time.com/time/nation/article/ , , , .html (discussing the allegedly political firings of eight federal prosecutors and ensuing public outcry). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y to when an appointment vests might shed light on these related issues of constitutional timing. the failure of scholars to consider the appointment question also has left the true story of william marbury’s appointment buried. first, a glimpse of the untold story: upon assuming office in , president jefferson said he would treat all of the midnight justice of the peace appointments as if they were nullities. this stance meant that jefferson cared little about whether the appointees had received commissions. underscoring his view that the midnight appointments were to be treated as nullities, jefferson appointed some of these appointees to the identical office, an action clearly signifying that they were not otherwise in office except by virtue of his appointment. only in , years later, did he harp on the failure to deliver certain commissions. given his apparent failure to espouse the delivery theory in , jefferson’s belated claim that john adams had not appointed marbury because the latter had received no commission was a post hoc justification. somewhat ironically, our hyperfocus on the marbury opinion, with its empha- sis on the plaintiffs’ demands for commissions, has left hidden the story of jefferson’s nullification strategy and his initial view that the commissions and the appointments were beside the point. if jefferson lacked a delivery theory of appointment in , what justi- fied his treating all of the midnight appointments as nullities, as if they had never been made? while he was never crystal clear, it nonetheless seems reasonably certain that president jefferson acted on the belief that he could remove the justices of the peace. he noted that most of the midnight appointees served at his pleasure. as to these non-article iii appointees, jefferson believed that he should treat them as nullities because he thought it utterly outrageous that adams had appointed them during the twenty-first hour of the last day of his presidency. somewhat ironically, the means by which he removed all the justices of the peace was a global commission, one that recess-appointed some of the non-article iii midnight appointees. the implication was that all justices of the peace had been terminated, with only some given new (and shorter) terms of office. the dearth of scholarly inquiry also has left concealed a good deal of historical evidence on an issue chief justice marshall struggled with in mar- bury: the question of when an appointment vests. prior to marbury, it was common to consider an appointment complete even when no commission see infra text accompanying notes – . see infra text accompanying note . see infra text accompanying notes – . see infra text accompanying notes . see infra text accompanying notes . see circular letter from thomas jefferson to midnight appointees (mar. , ), in the papers of thomas jefferson – (barbara r. oberg & j. jefferson looney eds., ). see infra text accompanying notes . see infra text accompanying notes . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : had been issued. commissions were hardly irrelevant; they were good and perhaps conclusive evidence of appointment. but appointments could and did vest independent of the signing, sealing, or delivery of commissions. evidence for this proposition comes from the practices of jefferson’s predecessors. both george washington and john adams appointed to office without first issuing a commission. moreover, in , adams and his cabi- net concluded that the president had appointed officers to a court martial even though no one had signed, sealed, or delivered commissions. persuasive evidence favoring some aspects of marshall’s opinion in mar- bury also comes from an improbable source: thomas jefferson. as secretary of state, jefferson opined to george washington that appointment had to precede commissioning, meaning that commission delivery was unnecessary for an appointment to vest. moreover, the first secretary of state issued commissions to individuals already appointed to office. later, as president, jefferson signed commissions that purported to appoint via the commission itself and not upon delivery. he even sent letters to individuals notifying them that he had appointed them even before they had their commission in hand. prior to the court issuing marbury, he recess-appointed some of the justices of the peace that john adams previously had appointed using lan- guage indicating that their appointment had preceded delivery of the global commission. finally, around the time he first criticized marbury, he issued commissions that purported to appoint via the signing of the commissions, without regard to delivery. this mass of evidence indicates that in and thereafter, jefferson was wrong to insist that commission delivery was crucial for an appointment to vest. to the contrary, early practice proves that john marshall was right that neither delivery of a commission nor acceptance of office was absolutely necessary to appoint to office. yet the great chief justice was mistaken too. he wrongly insisted that delivery of a commission to the appointee and acceptance of the office were irrelevant because in both cases the president had already made the appoint- ment. the better view is that because the constitution does not specify when or how an appointment vests, it leaves these matters to the appointer to see infra text accompanying notes – . see thomas jefferson, opinion on the powers of the senate respecting diplomatic appointments (apr. , ), in the papers of thomas jefferson, supra note , at . see infra text accompanying notes – . see commission to the office of secretary of state (mar. , ), in the papers of james madison (robert j. brugger et al. eds., ). see letter from thomas jefferson to william c. claiborne (july , ), in the papers of thomas jefferson, supra note , at . see charles s. bundy, a history of the office of the justice of the peace of the district of columbia, records of the columbia historical soc’y , ( ). see elliott coues, history of the expedition under the command of lewis and clark, at lxxiii (courier dover publications ) ( ) (commission providing that it appointed william clark). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y decide. this discretionary theory posits that the constitution cedes flexibility to appointers, permitting them to vest offices in a number of ways. this conclusion derives from a general principle of constitutional law: when the constitution grants power to an entity but does not specify how and when the power must be exercised, the entity empowered may decide how and when to exercise that power. for instance, congress may decide whether to use english, spanish, or both, when it makes laws, for the consti- tution never specifies a particular language for federal statutes. the federal courts may decide whether to issue oral or written opinions because the con- stitution does not require one or the other. and the president may decide how to convey his veto objections to congress, whether in person or via mes- senger, because the constitution never fixes that detail. because the constitution is best read as never dictating how or when an appointment vests, the president may decide those details with respect to his appointments. he might choose to have appointments automatically vest upon the senate’s consent. he might elect to have an appointment vest as soon as a commission is signed, sealed, or delivered. or the president might make appointments vest only upon acceptance of the office. hence, mar- shall and jefferson were mistaken because each definitively rejected some methods when, in fact, the constitution leaves it to the appointer to decide how and when her appointments will vest. to be clear, the claim is not that whenever the constitution grants a power to a branch (e.g., commerce power or the authority as commander in chief), that branch is empowered to determine, authoritatively, the scope of its power. though each branch must judge for itself what powers the consti- tution cedes, it hardly follows that those judgments are conclusive or impervi- ous to review in the other branches. marbury v. madison proves as much. instead, the claim is that when the constitution does not specify how a branch must exercise one of its powers, it implicitly delegates to that branch the ability to determine the means of exercising that power. part i tells the story of marbury’s appointment, why it incensed jeffer- son, and what he did about it. jefferson was outraged because a lame duck had foisted partisans on him. as a balm to his anger, jefferson treated adams’s midnight appointments as nullities, without regard to whether com- missions were delivered, on the theory that all of the non-article iii appoin- tees served at his pleasure. in essence, jefferson removed the midnight appointees. only later, years after marbury was issued, did jefferson claim that delivery of a commission was essential to appointing. part ii considers five theories of appointment bandied about in the late eighteenth and early nineteenth centuries. some thought that the senate’s consent automatically made an appointment, with no further presidential action necessary. others believed that an appointment vested after the sen- this article’s claims do not rest on a functional argument about how best to allo- cate interpretive responsibility for resolving supposed constitutional ambiguities. rather, as noted in the text, i argue that the constitution is best read as delegating the mechanics and timing of appointments to those who appoint. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : ate’s consent and before the issuance of a commission. a third school claimed that the commission made the appointment, suggesting that signing the commission vested the office. another group, consisting of jefferson’s partisans, claimed that without commission delivery, no appointment had been made. finally, in marbury, marshall considered whether acceptance of an office completed the appointment. part iii argues that, subject to limitations, the president may decide when an appointment vests. because the constitution does not specify when an appointment is made, it leaves the details to the appointer. when the president appoints, he not only can choose from among the possibilities dis- cussed in part ii, he also can adopt other triggers, such as deciding that appointments vest upon a certain date or upon the retirement of existing officers. the point is that the constitution does not adopt a one-size-fits-all approach to the vesting of offices. using this framework, part iii addresses similar questions, such as when a pardon vests. finally it considers con- straints on the president’s power to decide when an appointment vests and whether congress may regulate the means of appointing. part iv reconsiders whether, in light of the discretionary theory, john adams appointed william marbury. it turns out that there is powerful (albeit indirect) evidence on this point. i. a strategy of removal and reappointment some of this story is familiar, while the rest is unknown or misunder- stood. it begins not with the infamous judiciary act of , but with the (mostly) forgotten organic act of and its creation of officers for the district of columbia. our focus is on the organic act’s grant of authority to the president to appoint as many justices of the peace as he deemed necessary. each justice would have a five-year term. john adams signed the act on february , , ten days after the house had elected thomas jefferson and a week before the latter’s inaugura- tion on march th. adams waited until march nd to nominate forty-two justices. the next day, the last day of the lame duck session, the federalist senate confirmed them. that same day, adams signed all of the commis- judiciary act of , ch. , stat. (repealed ). act of feb. , , ch. , stat. . justices of the peace had judicial, legislative, and executive powers and were the “primary political force in the community.” forte, supra note , at . they arrested, arraigned, and generally preserved a community’s peace and morals. id.; see also the law-dictionary: explaining the rise, progress, and present state of the british law (thomas edlyne tomlins ed., ) (entry for justice of the peace) (describing power to conserve peace, apprehend criminals, and try them). act of feb. , , ch. , § , stat. , . id. journal of the executive proceedings of the senate of the united states of america ( ). id. at . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y sions and forwarded them to john marshall, secretary of state, so that the latter could affix the seal of the united states. after sealing the commis- sions, john marshall asked his brother, james, to deliver them. but some went undelivered, supposedly because there were too many. john marshall might have had someone deliver them the next day, as he remained secre- tary of state a day into the jefferson presidency. but john marshall did nothing to see them delivered. much later, jefferson claimed that upon entering the state department for the first time, he came across the commissions and ordered that they remain unsent. some have suggested that he ordered them burnt, with one contemporary account claiming that they were discarded along with the office’s refuse. the midnight appointments rankled jefferson. he believed that the lame duck ought to have appointed no one. writing to abigail adams in , he said that the only actions that her husband had taken that “ever gave [him] a moment’s personal displeasure” were his “last appointments to office.” jefferson complained that those appointments “laid me under the embarrassment of acting through men whose views were to defeat mine, or to encounter the odium of putting others in their places.” at his inaugural address, jefferson bit his tongue, perhaps because he was unaware of what transpired the night before. “we are all republicans: we see james f. simon, what kind of nation?: thomas jefferson, john marshall, and the epic struggle to create a united states – ( ). id. at . id. john marshall’s letter to his brother suggests that james marshall was not entirely to blame for the non-delivery. john marshall explained: i did not send out the commissions because i apprehended such as were for a fixd [sic] time to be completed when signd [sic] and seald [sic] & such as depended on the will of the president might at any time be revokd [sic] . . . . i should however have sent out the commissions . . . .” letter from john marshall to james m. marshall (mar. , ), in the papers of john marshall (charles f. hobson et al. eds., ). here, john marshall speaks as if the failing was his. it also seems as if john marshall decided that commissions did not need to be delivered, suggesting that the difficulty in delivering them was not so consequential, at least in his mind. see r. kent newmyer, john marshall and the heroic age of the supreme court ( ). id. see letter from thomas jefferson to william johnson, supra note , at n. (say- r ing that he “forbade the[ ] delivery” of commissions found in the state department). see leonard w. levy, seasoned judgments: the american constitution, rights, and history ( ). extract of a letter from a member of congress to his friend in this city, am. citizen & gen. advertiser (dec. , ) [hereinafter letter from a member of congress]. letter from thomas jefferson to abigail adams (june , ), in the adams- jefferson letters , (lester j. cappon ed., ). id. id. at . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : are all federalists,” he said. the amicable tone hinted that he would retain many federalists in office. john marshall, who administered the oath, said the address was “well judged and conciliatory.” yet the reality was that the new president faced intense pressure to replace the “monarchists” (federalists) with suitable republicans. how far to go was the only question. as jefferson noted, no one thought that all holdovers should remain, no one supposed that all should be ousted, and no one agreed how many ought to be dismissed. what was clear is that if he ousted a sizable figure, federalists would cry that he had dismissed dutiful officials to slake a thirst for the spoils of victory. jefferson sought to minimize the number of apparent removals in order to lessen the expected “odium.” one clever method was to treat the mid- night appointees as a sui generis category, one where the concept of removal might seem irrelevant. jefferson adopted this strategy. at some point in his early days in office, jefferson drafted a letter to be sent to midnight appoin- tees. he observed that president adams “not long before his retirement . . . made several appointments to civil offices holden during the will of the presi- dent.” he further stated that the “present president deems it proper that those appointments should be a subject of reconsideration & further enquiry.” because he desired people who would execute his views, he declared: “you will therefore be pleased to consider the appointment you thomas jefferson, inaugural address (mar. , ), in the papers of thomas jefferson, supra note , at . letter from john marshall to charles pinckney (mar. , ), in richard j. hooker, john marshall on the judiciary, the republicans, and jefferson, march , , am. hist. rev. , – ( ). see carl russel fish, civil service and patronage – ( ) (describing the pressure). one contemporary editorial complained that if there were not more removals of federalists, “for what, in the name of god, have we [republicans] been contending?” note, in the papers of thomas jefferson, supra note , at , . see letter from thomas jefferson to william branch giles (mar. , ), in the papers of thomas jefferson, supra note , at . see pollak, supra note , at – . letter from thomas jefferson to pierpont edwards (july , ), in the papers of thomas jefferson, supra note , at . carl prince describes the tactics that jefferson used to minimize the appearance of removals. carl e. prince, the passing of the aristocracy: jefferson’s removal of the federalists, – , j. am. hist. , – ( ) (describing jefferson’s schemes as including failing to announce some removals, coercing resignations from some officeholders, and disestablishing offices). circular letter from thomas jefferson to midnight appointees, supra note , at – . jefferson evidently believed that the justices of the peace were removable even as he took pains to claim that he was not removing them. for a discussion of the president’s power to remove, see saikrishna prakash, removal and tenure in office, va. l. rev. , – ( ). for a discussion of the congres- sional decision that read the constitution as conferring a removal power, see saikrishna prakash, new light on the decision of , cornell l. rev. , – ( ). circular letter from thomas jefferson to midnight appointees, supra note , at . the editors of the jefferson papers surmise that the letter was sent, but cannot deter- mine the actual addressees. id. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y have received as if never made, of which this early notice is given to prevent any derangement which that appointment might produce.” if such letters were delivered, one doubts that they pleased the recipients. we do know that jefferson had his staff determine which commissions the previous administration delivered and which remained undelivered. we also know that on march , , less than two weeks after taking office, jefferson recess-appointed thirty justices of the peace for the district of columbia. twenty-four of these had been on adams’s list of appointees, with six new men. that meant that eighteen men that john adams had sought to appoint as justices of the peace were omitted from jefferson’s recess appointee list. judging by lists that the jefferson administration compiled, everyone who had received a justice of the peace commission signed by adams also received a new recess appointment. on the one hand, perhaps this was a coincidence. after all, only a half dozen fit into the category. jefferson may have decided that he should appoint these individuals without regard to whether they had a commission from adams. on the other hand, perhaps this pattern suggests that jefferson believed that those who received their commissions had been appointed. maybe he understood the litigation risk of denying them their jobs, and so he decided to appoint them himself. yet if jefferson supposed that those who received their commissions were securely in office, he should not have granted new recess appointments to those who had received their commissions. after all, if he believed that commission delivery vested the appointments, those who had received com- missions from adams did not need new ones, especially ones that purported to reduce their term to the end of the next session of the senate. relatedly, there would have been no need to re-nominate them a year later, as jefferson did. again, at the time of jefferson’s nomination of these justices of the id.; see also nathan schachner, thomas jefferson, a biography – ( ) (detailing jefferson’s approach to dealing with the midnight appointees). but as late as march , , jefferson boasted that he would ignore the appointments and not even notify the appointees that he considered their appointments nullities. see letter from thomas jefferson to benjamin rush (mar. , ), in the papers of thomas jeffer- son, supra note , at – . see thomas jefferson, to the senate: interim appointments, i. tables of justices of the peace for the district of columbia [before mar. , ] (jan. , ), in the papers of thomas jefferson, supra note , at [hereinafter tables of justices of the peace] (table listing commissions, delivered and undelivered). thomas jefferson, to the senate: interim appointments, ii. memorandum on jus- tices of the peace for the district of columbia [on or before mar. , ] (jan. , ), in the papers of thomas jefferson, supra note , at [hereinafter memorandum on justices of the peace]. id. compare tables of justices of the peace, supra note , with memorandum on jus- tices of the peace, supra note . see tables of justices of the peace, supra note ; see also letter from thomas jeffer- son to the senate (jan. , ), in the papers of thomas jefferson, supra note , at – . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : peace in , they already had appointments with about four years left in office, at least under the theory that delivery of the commissions had made the appointment complete. in his message to the senate, which gave notice of his recess appointments and advanced a reconstituted slate of justices, jef- ferson ignored all the legal questions. he tersely noted that john adams had nominated many of the same people in and that adams had nomi- nated too many justices of the peace. he cagily said nothing about whether adams had successfully appointed any of those individuals as justices of the peace. why did jefferson recess-appoint those who had received their commis- sions? he had resolved to treat all the midnight appointments as nullities. in a half dozen or so letters written to republicans and federalists, jefferson laid out his views: “[a]ll appointments to civil offices during pleasure, made after the event of the election,” jefferson wrote, “ . . . are considered as nulli- ties. i do not view the persons appointed as even candidates for the office, but make others without noticing or notifying them.” this last comment contained more than a bit of bluster because, as noted, jefferson appointed the majority of adams’s midnight justices. in other letters, he emphasized the travesty’s timing: “[a]ppointments” that adams made as late as “ . aclock of the night at . aclock of which he was to go out of office,” were an “outrage on decency,” making it appropriate to treat them as “nullities.” letter from thomas jefferson to the senate, supra note . id. at . he treated other last-minute appointments slightly differently, but no less cagily. in his private notes, jefferson had identified some of his new appointments as replacements for “midnight appointment[s]”. see list of appointments and removals (ca. mar. , –may , ), in the papers of thomas jefferson, supra note , at (comment- ing on the replacement of thomas duncan, hugh barclay, etc). this conceded that these men had been appointed and that he was removing and replacing them. indeed, in some of his notes, he claimed that some of the midnight appointees were being removed “on the principle of giving some participation in office to republicans.” list of appointments and removals (after may , ), in the papers of thomas jefferson, supra note , at – (listing “edwd st. loe livermore” as so removed). in his notes from a cabinet meeting early in his administration, jefferson similarly mentioned that he was removing livermore and that barclay, a “new appt” was being replaced. notes on a cabinet meeting (mar. , ), in the papers of thomas jefferson, supra note , at . but in his senate message listing his appointments and removals, jefferson conspicuously said that these individuals had been nominated, “but not appointed.” see letter from thomas jefferson to the senate, supra note , at – (listing about twenty officials as nomi- nated but not appointed, including duncan, barclay, and livermore). it seems clear that jefferson sought to obscure these removals by publicly asserting that adams had never appointed the gentlemen even as he privately acknowledged that adams had appointed them. letter from thomas jefferson to william branch giles, supra note , at – (emphasis added). letter from thomas jefferson to benjamin rush, supra note , at . letter from thomas jefferson to henry knox (mar. , ), in the papers of thomas jefferson, supra note , at . id. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y the only appointments he would acknowledge were those to judicial office, as those officers were “irremoveable [sic].” seeking to show his reasonable- ness, jefferson sometimes claimed, “[m]r[.] a[dams]’s best friends ha[d] agreed” that treating the appointments as nullities was “right.” whether allies of adams approved of jefferson’s tactic is unknown. even if some federalists accepted the approach, others complained. in late march of , a squib in the philadelphia gazette accused jefferson of a “direct departure” from his inaugural speech: “he has had the imprudence to stop the commissions of several justices of the peace appointed by mr. adams . . . and to substitute some of the most ignorant and ill-qualified men in their stead.” because the justices had five-year terms, the paper confi- dently predicted that the president “will be obliged to give up the commis- sions which have been thus illegally detained.” the author seemed unaware that most of the justices had been recess- appointed. perhaps because this complaint was grounded on jefferson’s withhold- ing of certain commissions, his defenders largely ignored the president’s tac- tic. in april, the national intelligencer argued that neither signing nor sealing a commission made an appointment. like all “sealed” documents, delivery was essential to effectiveness. because the commissions had not been delivered, the president had not violated the constitution or done any- thing improper. levi lincoln, the attorney general, forwarded the defense to jefferson, admitting that he had yet to opine on jefferson’s actions. lincoln complained that because few had paid any attention to jefferson’s actual actions, he had “not heard or seen a syllable on the sub- ject.” there seems no trace of any lincoln opinion on the nullification stratagem. things stayed quiet until the winter. in december of , william mar- bury and three others wrote to james madison informing him that they id. letter from thomas jefferson to william branch giles, supra note , at . philadelphia gazette, mar. , , at . id. one exception was the national intelligencer, which argued that the president had shown restraint in reappointing so many of the adams’s justices of the peace. see nat’l intelligencer, & wash. advertiser, mar. , , at . nat’l intelligencer, & wash. advertiser, apr. , , at . letter from levi lincoln to thomas jefferson (apr. , ), in the papers of thomas jefferson, supra note , at – . id. at . the other petitioners were william harper, robert townsend hooe, and dennis ramsay. see marbury v. madison, u.s. ( cranch) , – ( ). because marbury is the most famous petitioner, a brief sketch is in order. marbury was a banker, investor, and a federalist appointee in the maryland and federal governments. jefferson probably did not appoint marbury because the latter was a hated financier and had tried to swing maryland’s electors to john adams. see forte, supra note , at . for a more complete portrait of marbury, see generally id. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : would ask the supreme court to order the delivery of their commissions. the very next day, marbury and his associates filed suit. interestingly, a member of the first congress had predicted that some- one might file such a suit. representative william smith of south carolina had hoped that the first congress would say nothing about removal in , leaving it to a president to remove someone and have it tested in courts: it will be time enough to determine the question when the president shall remove an officer . . . . i conceive it can properly be brought before [the courts]; the officer will have a right to a mandamus to be restored to his office, and the judges would determine whether the president exercised a constitutional authority or not. smith was responding to james madison (and others), who sought a con- gressional pronouncement indicating that the president had a power to remove. though james madison prevailed in the fight, securing legislation signaling that the president enjoyed a constitutional power to remove, smith was right that one might file such a suit. but it was lodged against james madison, as secretary of state, and not the president. the supreme court seemed to agree with representative smith that it could adjudicate the constitutional question, and quickly issued a rule directing madison to explain why the court should not order the delivery of the commissions. some speculate that petitioners sought a writ of manda- mus fully aware that the court would conclude that it lacked jurisdiction, but also knowing that it would first declare that adams had appointed the petitioners. because congress barred the court from sitting in , marbury v. madison was not heard until . charles lee, the attorney general under adams, argued for the plaintiffs that the appointments had vested once the commissions had been signed and sealed, and that the president lacked authority to remove the justices of the peace. while some members of the jefferson administration participated in the case, they did so as witnesses only, and did not defend the president. this made for a curious mix of respect and defiance on the part of the administration. the attorney gen- letter from william marbury to james madison, secretary of state (dec. , ), in the papers of james madison, supra note , at – . see richard e. ellis, the jeffersonian crisis ( ). annals of cong. ( ) (joseph gales ed., ). see marbury, u.s. ( cranch) at . see susan low bloch, the marbury mystery: why did william marbury sue in the supreme court?, const. comment. , – ( ) (suggesting that marshall and the marbury plaintiffs may have orchestrated the suit in the supreme court). see judiciary act of , ch. , § , stat. ; see also cliff sloan & david mckean, the great decision: jefferson, adams, marshall, and the battle for the supreme court ( ) (noting that congress had barred court from sitting in ). marbury, u.s. ( cranch) at – . id. at – . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y eral, levi lincoln, participated as a witness. james madison, the defendant, flouted the court’s order to show cause. john marshall’s opinion never definitively said when adams had appointed marbury and the others. instead, it declared that appointments might vest when sealed, when signed, or even earlier. whatever the case, it was uncontested that the commissions had been signed and sealed. to show that the appointments necessarily had vested, marshall rejected the notion that delivery to, or acceptance by, the appointee might vest the office, con- cluding that the appointment had to be complete prior to either event. further, marshall concluded that the president could not remove justices of the peace, basing his judgment upon a rather disputable implication of the five-year term of office found in the statute. much of what marshall said in marbury could be ignored because the portion discussing the merits was dicta. and, in fact, both marbury and madison ignored it, each in his own way. after the case, marbury never got his commission nor attempted to assume his office, despite the fact that his attorney had argued that marbury already was in office. madison seems never to have commented on the opinion, much less complied with its rea- soning. given that the justices likely knew that jefferson would ignore the first two parts of the marbury opinion and the fact that the court opined in the wake of the repeal of the judiciary act of , the opinion should “be id. see mcconnell, supra note , at (claiming that failing to respond to the court’s rule dramatically signaled that the executive denied any claim that the court could enter- tain a mandamus action against a cabinet officer). marbury, u.s. ( cranch) at . id. at . marshall concluded that because the justices of the peace had statutory five-year terms, they did not serve at pleasure, but rather had a right to hold office “independent of the [e]xecutive.” id. this was consistent with his conclusion in . see supra note . he never discussed the possibility that the justices of the peace had fixed terms, subject to presidential removal. cf. judiciary act of , ch. , § , stat. , (establishing four-year terms for marshals and making clear that they served at the president’s pleasure). the advantage of this reading of the statute is that it gives meaning to the fixed term (no one could stay in office beyond five years without a renewed appointment) without raising the constitutional question of whether congress could limit the removal power that was thought to reside in the president. for jefferson’s view that the justices served at pleasure, see supra text accompanying notes – . in , jefferson took the view that the state justices of the peace served during good behavior, unlike colonial justices of the peace. see letter from thomas jefferson to unknown (dec. , ), in the papers of thomas jefferson, supra note , at . the virginia constitution never expressly granted such tenure to justices of the peace and i have been unable to determine whether the legislature had conveyed it via statute. much later, the court rejected marshall’s claim that the president lacked authority to remove the justices of the peace. see myers v. united states, u.s. , – ( ). see gregory e. maggs & peter j. smith, constitutional law: a contemporary approach ( d ed. ). see sloan & mckean, supra note , at – . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : understood as the product of a defeated and demoralized court,” one strain- ing for power and relevance. in the immediate wake of the case, jefferson apparently wrote nothing of it. over decades, he was more voluble. in letters to friends, he insisted that marshall was wrong to say that the justices of the peace who had not received commissions had been appointed. everyone knew, jefferson said repeatedly and insistently, that delivery was necessary to vest the office. whatever the merits of this belated legal argument, the actual grounds for jefferson’s decision not to recognize the appointments had nothing to do with the non-delivery of some commissions. recall that jefferson’s actions reflected an intense desire to treat the “indecent” midnight appoint- ments as nullities. whether jefferson forgot the actual events is unknown. perhaps looking back on the events years later led jefferson to adopt the arguments found in the national intelligencer, that delivery is necessary for an appointment to vest. this may have been for no other reason than that mar- bury was only about individuals who did not receive their commissions; it did not address the status of those who had received them but nonetheless had their supposed appointments nullified. jefferson’s nullification strategy, and the reaction to it, warrants further scrutiny, primarily because both have long been obscure and misunderstood. one might suppose that jefferson treated the vast bulk of midnight appoint- ments as nullities because he thought they had never been consummated. perhaps he thought something had arrested their completion, like non-deliv- ery of commissions. yet there is no theory of appointment that could have sanctioned his course in . recall that he recess-appointed justices of the peace, including those who had received a commission, meaning that he treated delivery as irrelevant. we are drawn to the question of whether he differentiated those who received commissions and those who did not because jefferson, in and mcconnell, supra note , at . see letter from thomas jefferson to george hay (june , ), in the works of thomas jefferson, supra note , at n.i; letter from thomas jefferson to judge r spencer roane (sept. , ), in id. at , ; letter from thomas jefferson to william johnson, in id. at n. . jefferson seemed less interested in the mandamus question. in his letter to dis- trict attorney hay, jefferson denied that a court could order the executive to deliver a commission. see letter from thomas jefferson to george hay, supra, note , at n.i. in , his attorney general opined that executive officers could not be mandamused with respect to “acts purely ministerial and executive in nature.” letter from the attorney general to the president of the united states (july , ), in am. l.j. , (john e. hall ed., ). this was not a belated response to marbury. rather caesar rodney’s opinion came on the heels of a circuit court opinion that had issued a writ of mandamus against a port collector. see id. at . the rodney opinion emphasized that the statute in question granted discretion to the collector and to the president, perhaps indicating that a mandamus might be appropriate where there was no discretion. if that was rodney’s posi- tion, it did not deviate much from marshall’s opinion in marbury, for the latter also distin- guished acts of discretion from acts compelled by law. see letter from thomas jefferson to benjamin rush, supra note , at – . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y thereafter, emphasized that distinction and because it was the focus of mar- bury. but this focus is misplaced, at least if we wish to discern jefferson’s justification for his treatment of the midnight appointees. it seems reasona- bly clear that jefferson’s original justification had little to do with commis- sions, delivery, or when an appointment vests, and instead turned on whether the justices of the peace held tenure at the president’s pleasure. jefferson likely supposed that adams had appointed the justices but thought that he could remove them from office and had in fact done so via the omnibus recess appointment commission. first, jefferson seemed to admit, repeatedly, that the justices of the peace were in office. indeed, his draft letter to the midnight appoin- tees instructed that “the appointment . . . received” was to be treated as if it never had been made. he also referred to “appointments” two other times in that draft and in other letters that actually were mailed. second, in that same letter meant for the midnight appointees, he noted that they had been appointed “during the will of the president.” when read in conjunction with the rest of the letter, this passage suggests that he was implicitly removing them. why else mention that they held ten- ure at the pleasure of the president? a jeffersonian letter about remov- ing justices of the peace helps reinforce that inference. “lawyers know that either estates or offices held during will are determinable by the slightest acts implying only, without positively expressing, a change of will. hence the issu- ing [sic] a new commission of the peace determined the offices of those named in the former [commission].” that is exactly what president jeffer- son had done in . whether or not he had sent the letter to the adams’ appointees, he had issued a new omnibus justice-of-the-peace commission. the letter went on to state that those who were to continue in office had to be mentioned in the new commission. this was precisely the tack president jefferson took. he recess-appointed only some of the existing justices of the peace, thereby removing all those who left unmentioned. so why did jefferson repeatedly discuss treating the midnight appoint- ments as “nullities”? by treating them as “nullities,” jefferson avoided having to admit that he had removed the justices of the peace. as he explained to henry knox, a colleague of jefferson’s from the washington administration, “in the class of removals . . . i do not rank the new appointments which [m]r[.] a[dams] crouded [sic] in with whip & spur from the th of dec.” circular letter from thomas jefferson to midnight appointees, supra note , at . id. letter from thomas jefferson to unknown, supra note , at . id. omnibus commission to justices of the peace (march , ), in bundy, supra note , at . letter from thomas jefferson to henry knox, supra note , at ; see letter from thomas jefferson to william findley (mar. , ), in the papers of thomas jeffer- son, supra note , at – (noting that he had to remove some officials and then declaring that he would consider the midnight appointments as “nullities”). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : consistent with this stance, in his own list of removals, he left out the justices of the peace. likewise, in his catalog of appointments and removals sent to the senate in january of , he did not list any of the justices as removed. reflecting the success of his scheme, newspapers did not list them either. jefferson’s obfuscation was a success, in the sense that his treatment of the midnight appointees was not seen as an omnibus removal coupled with partial reappointment. but he paid a price for that approach because many erroneously supposed that he had somehow either blocked the appointments (prevented their consummation) or had (improperly) denied commissions for those lawfully in office. this affected the legal arguments. commenta- tors focused on when an appointment vested, saying nothing about removal. the plaintiffs said surprisingly little about removal, with chief justice mar- shall saying even less. logically, however, the removal question was no less important than whether marbury and the others had been appointed, for if jefferson had removed them from office, they no longer had a right to a commission. jefferson himself was not immune to the tactic’s lingering effects. when jefferson belatedly commented on marbury in , he said nothing about removal, focusing on delivery alone. he thereby ignored what seemed the actual justification for his actions in and also disregarded a potent and complete defense of his actions. so what seemed to be a wholesale removal of the non-article iii midnight appointees followed by a partial reappoint- ment has gone down in history as a fight about when offices vest. ii. five theories of when an appointment vests if i am right about jefferson’s original theory of the midnight appoint- ments, removal should be no less important in any discussion of whether jefferson’s actions were legal. although i believe jefferson’s implicit view about removal was correct—that the justices of the peace held five-year terms terminable at the president’s pleasure—the rest of this paper concerns the plaintiffs’ primary focus, namely when an appointment vests. was marshall correct that an appointment vested prior to delivery of a commission? or was jefferson on the mark when he claimed in that delivery of a com- mission was necessary for an appointment to vest? four constitutional provisions frame the dispute. first, the appoint- ments clause provides that the president “shall nominate, and by and with the advice and consent of the senate, . . . appoint” all officers of the united see list of appointments and removals (ca. may ), in the papers of thomas jefferson, supra note , at – ; list of appointments and removals (after may , ), supra note , at – . see letter from thomas jefferson to the senate, supra note , at – (listing various officers removed, noting recess appointments of justices of the peace, and not list- ing any of them as removed). see, e.g., u.s. oracle, & portsmouth advertiser, oct. , , at . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y states. second, congress may vest the appointment of inferior officers with the president, the department heads, or the courts. third, the presi- dent may appoint during the recess of the senate, with the tenure of such an appointment expiring at the end of the next senate session. fourth, the president must commission all officers of the united states. using text, structure, and early practice as yardsticks, this part considers five answers to the question, “when does an appointment vest?” those answers are: ( ) when the senate consents; ( ) after the senate consents, but prior to commissioning; ( ) when a commission is signed or sealed; ( ) when a commission is delivered to the appointee; and ( ) when an individual accepts an offer of appointment. this part focuses on the appointment of senate-confirmed individuals, with little discussion of recess appointments and unilateral appointments to inferior offices. a. by the advice and consent of the senate some might suppose that the constitution creates a default rule of auto- matic appointment. under this theory, while nomination rests solely with the president, an appointment results automatically from the joint action of the president and the senate. in particular, the president’s “action” of keep- ing the nomination before the senate (i.e., not withdrawing the nomina- tion), combined with the senate’s consent, results in an appointment to office. just as the house and senate, acting together, pass bills, perhaps the president and the senate, acting together, appoint officers. this rule is sub- ject to the exceptions found in the constitution, namely the president’s abil- ity to appoint during a senate’s recess, and congress’s ability to vest unilateral appointment authority over inferior officers. to make this automatic appointment theory concrete, consider a scena- rio: the president nominates a person to serve as an article iii judge. the senate considers the nominee and advises and consents to her appointment. as soon as the senate supplies its advice and consent, the appointment is complete because under the automatic appointment theory the constitution provides that the appointment vests when the senate consents. while the president must still commission the new judge (because the constitution requires as much), the appointment is already made. had john marshall endorsed the automatic appointment theory, his argument that william marbury had been appointed would have been short and sweet. he might have said that president john adams nominated and the senate consented, thereby appointing marbury and the others. yet mar- shall never made the assertion, much less discussed this possibility. had he u.s. const. art. ii, § , cl. . id. u.s. const. art. ii, § , cl. . id. id. u.s. const. art. ii, § , cl. . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : wished to do so, he might have cited portions of the federalist. when “pub- lius” spoke of the appointment power as confided “jointly” in the senate and president, perhaps he endorsed the automatic appointment theory. some of jefferson’s critics pressed the theory, insisting that the justices of the peace were appointed on march , when the senate consented. as one put it, “the concurrence of the president and the senate in naming to office, complete the act of appointment.” the detractor added that the president had to commission those whom “he finds on the records of the senate to have been appointed.” while jefferson’s critics spoke in the context of a partisan row, others made similar claims at a time when they had no stake in the justice of the peace controversy. in , a court martial sentenced richard hunt to death. hunt complained that the proceedings were invalid because, among other things, members of the court had never received their commis- sions and hence were unable to conduct a court martial. president john adams sought the advice of members of his cabinet. the treasury secretary, oliver wolcott, claimed that the concurrent act of the senate and the presi- dent constituted an appointment. timothy pickering, who as secretary of state was charged with affixing the seal to civil commissions, agreed that appointments automatically vested when the senate consented. so at least two members of the adams cabinet believed that the senate’s consent com- pleted the appointment, with no further act necessary on the president’s part. and while there was no consensus as to the precise moment of appoint- ment, there was agreement in the cabinet that the court martial judges had been appointed even though they lacked commissions and even though none were prepared. though the episode occurred less than two years before jefferson’s actions in the spring of , no member of the adams the federalist no. , at (alexander hamilton) (garry wills ed., ). no. xvi, addressed to the president of the united states, courier of n.h., dec. , , at ; see also executive dismissal of a judge, republican, mar. , , at (stating that “appointment [is complete], by the joint act of the president and the senate”). no. xvi, addressed to the president of the united states, supra note , at . see letter from james mchenry to alexander hamilton (july , ), in the papers of alexander hamilton (harold c. syrett ed., ). letter from john adams to james mchenry, secretary of war (june , ), in the works of john adams (charles francis adams ed., ). see letter from oliver wolcott, secretary of the treasury, to james mchenry, secre- tary of war (july , ), papers of the war department: – , available at http:// wardepartmentpapers.org/docimage.php?id= &doccolid= . see letter from timothy pickering, secretary of state, to james mchenry, secretary of war (july , ), papers of the war department: – , available at http://war departmentpapers.org/docimage.php?id= &doccolid= . see letter from timothy pickering, secretary of state, to james mchenry, secretary of war, supra note ; letter from benjamin stoddert, secretary of the navy, to james mchenry, secretary of war (july , ), papers of the war department: – , available at http://wardepartmentpapers.org/docimage.php?id= &doccolid= ; letter from oliver wolcott, secretary of the treasury, to james mchenry, secretary of war, supra note . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y administration seems to have brought it to light during the marbury contro- versy. indeed, no one seems to have discussed the episode at all either dur- ing – or in modern times. evidence for the automatic appointment theory also comes from an improbable source: the presidency of james madison. less than a decade after marshall admonished president jefferson and secretary of state madison, president madison wrote a letter that seemed to endorse the auto- matic appointment theory. after noting that he had nominated william eus- tis to serve as secretary of war, madison observed that the “senate have compleated [sic] the appointment.” though a commission accompanied the letter to eustis, madison’s language suggests that he believed the senate’s consent made the appointment. the automatic appointment theory rests on a plausible reading of the constitution. after all, the text speaks of the president appointing “by . . . the . . . consent of the senate.” this language could be read to indicate that while the president appoints, he does so via the senate’s consent. the president might withdraw a nomination pending before the senate. but once the senate consents to a nomination left before it, the appointment is made, or so the automatic appointment theory supposes. yet the theory suffers from some insuperable difficulties. the full clause speaks of appointing “by and with the advice and consent of the sen- ate,” a phrase that suggests that the senate merely consents to the appoint- ment and advises the president to consummate it. had there been a desire to make the office vest upon the senate’s consent, other text could have accomplished that purpose, something like: “the president shall nominate to office, with the senate’s consent completing the appointment.” moreover, “advice and consent” comes from english enactment clauses. the crown would make law “by and with the advice and consent” of the two chambers. a law was not made merely because both chambers passed it. rather, the crown retained a right to veto bills presented to it. if “advice and consent” permitted the crown’s rejection of bills, it would be odd to repeat the phrasing in the constitution and expect it to operate differently with respect to appointments. finally we have evidence from practice to suggest that the automatic appointment theory is mistaken. the treaty clause, which has similar phras- ing (“[h]e shall have power, by and with the advice and consent of the sen- ate, to make treaties” ), is read as authorizing the president to make or ratify treaties only with the senate’s advice and consent, not as indicating that the treaty is made by virtue of the senate’s consent. early senates would letter from james madison to william eustis (mar. , ), in the papers of james madison, supra note , at . u.s. const. art. ii, § , cl. . id. (emphasis added). william blackstone, commentaries on the laws of england ( ). id. at – . u.s. const. art. ii, § , cl. . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : “consent” to the treaty and “advise the president of the united states to ratify the same.” similarly, early senates would “advise and consent to the appointment,” a locution suggesting that the senate consented to an appointment to be made in the future by the president. that is to say, the senate seemed to acknowledge that while its consent was a precondition, the consent did not complete the appointment. b. after the senate consents, but before commissioning in marbury, the chief justice claimed, as an initial matter, that appointing was distinct from commissioning. besides noting that the acts were discussed in different sections of article ii, marshall observed that the constitution seemingly required the president to commission all officers, including those appointed by department heads and the courts. marshall believed that because the president had to commission officers appointed by others, that proved that the acts of appointing and commissioning were nec- essarily separate. it was a clever argument, yet one somewhat blunted by his admission that, whatever the constitution might seem to require, in practice presidents only commissioned their appointees. perhaps marshall was aware that others had made similar claims about the distinctiveness of appointing and commissioning. in , an author crit- ical of jefferson’s treatment of another supposed appointee of john adams reluctantly admitted that “some [separate] act of appointment is necessary on the president’s part,” even after senate consent. believing that john adams had appointed the judge in question, the critic asked, “[i]s not the order to the secretary of state to make out and deliver a commission, such an act of appointment?” another critic claimed that because the constitu- tion said that the president must commission “all the officers,” it implied that all those receiving commissions must already be officers—in other words, have been appointed prior to commissioning. this theory supposes that the president appoints via an act distinct from senate consent and presidential commissioning. it is focused on the sequence of events (nomination, senate consent, appointment, commission- ing) and does not specify what the president must do to appoint. consider this scenario: the president nominates an individual to serve as treasury secretary and the senate consents. under this theory, the nominee e.g., journal of the executive proceedings of the senate of the united states of america, supra note , at . e.g., id. at . admittedly, had the senate provided that it “consented” to the appointment and “advised the president to appoint,” the point would be clearer still. see marbury v. madison, u.s. ( cranch) , – ( ). id. at . id. (admitting that the commissions clause “may never have been applied to officers appointed” by others). executive dismissal of a judge, supra note , at . id. no. xvi, addressed to the president of the united states, supra note , at . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y is not yet treasury secretary. furthermore, the president can issue no com- mission until the appointment has been made because appointment must precede commissioning. if the president orders someone to assume an office, that order signals that the appointment has been made, for the presi- dent would not issue such an order without first appointing the person. like- wise, if the president notifies the senate of an appointment, that announcement signals that the appointment is complete. looking to early practice, some of president george washington’s let- ters discussed appointment as occurring after senate consent but before sign- ing any commission. in one he wrote, “i do hereby appoint you [the recipient]” to the command of a revenue cutter, and that a commission would follow upon acceptance of the office. in another missive, washing- ton informed someone of his appointment, with a commission issuing only much later. believing that rapid appointments were necessary, alexander hamilton once claimed that washington could appoint without delay, with “antedated” commissions issued later. ironically, thomas jefferson knew that it was possible to appoint without signing or delivering a commission. as washington’s secretary of state, jef- ferson issued the antedated commissions that hamilton had recommended, meaning jefferson should have known that washington had already appointed those people to office. more tellingly, the first secretary of state had opined on this very issue. in the course of telling washington that only the president (and not the senate) could decide a diplomat’s destination (e.g., england) and grade (e.g., ambassador), jefferson declared that the constitution established a “natural order” of nomination, appointment, and commission. “[a]ppointment does not comprehend the neighboring acts of nomination, or commission,” he insisted. jefferson’s actions as president also indicated that appointments could vest prior to commissioning. in a july letter to the governor of the mississippi territory, jefferson told him that he had “appointed” a consul at new orleans. the commission was not issued until days later, meaning that the appointment occurred prior to commissioning or any delivery. but letter from george washington to william cooke (apr. , ), in the papers of george washington (dorothy twohig et al. eds., ). letter from george washington to benjamin lincoln (aug. , ), in the papers of george washington (w.w. abbot et al. eds., ) (“i . . . have appointed you.”); george washington, proclamation to the southern indians (aug. , ), in id. at (“i have . . . appointed and constituted, and i do appoint and constitute by these presents . . . benjamin lincoln.”). letter from alexander hamilton to george washington (july , ), in the papers of george washington (philander d. chase et al. eds., ); see also letter from tobias lear to thomas jefferson (oct. , ), in id. at – (requesting backdated commissions for those already appointed). thomas jefferson, opinion on the powers of the senate respecting diplomatic appointments, supra note , at . id. letter from thomas jefferson to william c. claiborne, supra note , at . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : there is an even earlier episode of president jefferson partially confirming what secretary of state jefferson said and did. within days of his decision to withhold (and presumably dispose of) those justice of the peace commissions that remained in the department of state in the wake of his inauguration, jefferson issued an omnibus commission to the justices of the peace that he had recess-appointed. the relevant portion of the commission reads as fol- lows: “i have appointed you jointly and severally” justices of the peace. the past tense suggested that jefferson had appointed them prior to the sign- ing or delivery of the commission. whereas jefferson would insist later that delivery was necessary to appoint, in the wake of treating the midnight appointments as nullities he seemed to appoint some of those same justices prior to commissioning them, much less delivering a commission. c. commissioning recall that chief justice marshall speculated that signing or sealing the commission might make the appointment. others had voiced similar views, even prior to that case. before ultimately concluding that a commission was mere evidence of an appointment, john adams speculated in june of “whether the signature of the commission is not the act of appointment.” if so, that meant that adams had not appointed those judges who had sen- tenced richard hunt to death because, as discussed earlier, no commissions had been made out. this commission theory posits that the satisfaction of the president’s duty to commission simultaneously completes the appointment. there is plenty of evidence that presidents appointed via commissions. in a diary entry, washington wrote that he had appointed two diplomats via “sign[ing]” their commissions. likewise, the commissions he granted to the first supreme court justices read, “i . . . do appoint him,” a present tense locution that insinuated the commissions appointed. occasionally, commissions would read, “[i] hereby appoint” individuals to an office, clearly indicating that the commission was the instrument of the appointment. letter from robert smith to thomas jefferson (july , ), in the papers of thomas jefferson, supra note , at – (editors’ note) (noting that clark’s commis- sion was dated july , ). omnibus commission to justices of the peace, supra note , at . id. letter from john adams to james mchenry (june , ), in the works of john adams, supra note , at . see supra text accompanying notes – . george washington, tuesday, april , , in the diaries of george washing- ton (donald jackson & dorothy twohig eds., ). documentary history of the supreme court of the united states, – , at , , (maeva marcus & james r. perry eds., ) (commissions for john jay, james wilson, and thomas johnson). george washington, commission (jan. , ), in the papers of george washington, supra note , at (appointing thomas johnson, daniel carroll, and david stuart). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y judging by the extant commissions, it seems that the dominant locution was “i do appoint” an individual to office, suggesting that the predominant means of appointment was via commission. jefferson should have known that commissions could serve as a means of appointing. with respect to the washingtonian commissions for the supreme court justices, ones that used the “i do appoint” language, a statute required jefferson to affix the seal of the united states to them. moreover, on his second day of office, president jefferson issued a com- mission to james madison which read, “i have nominated, and . . . do appoint him secretary of state.” if this language is to be believed, jefferson appointed madison via the commission itself, not waiting until delivery to madison. this was not some anomaly, for president jefferson (and secretary of state madison) issued many such commissions. in , around the same time he claimed that delivery of a commission was essential to appoint to office, jefferson issued a commission that read, “i do by these presents appoint” william clark as brigadier general of the louisiana militia. jef- ferson ought to have read the commissions prior to affixing the seal to them as secretary of state and prior to signing them as president. had he done so, he would have seen that commissions sometimes served as instruments of appointment. if commissioning completed the appointment, was it the signature, the affixing of the seal, or some other part of the commissioning process that ensured completion? for good reason, john marshall, in marbury, struggled to supply an answer. the constitution does not detail what the president must do to “commission” an officer. presumably, he must issue a written document with an individual named, provide that the individual has been, is, or will be given a particular office, and sign that document. perhaps the president also must take measures to ensure that the commission is regarded as an official document. early washington commissions indicated that he had affixed the seal of the united states, as federal law required. even if the statute had said nothing, however, something like a sealing requirement may have arisen from the constitution itself, for such steps help validate the commission in a way that a signature, by itself, might not. the president’s signature might have been hard to forge; similarly, a seal was perhaps diffi- cult to replicate. put a signature and a seal together and the authentication might seem airtight. act of sept. , , ch. , § , stat. , – (creating the state department). commission to the office of secretary of state, supra note , at . see letter from thomas jefferson to george hay, supra note , at n.i. coues, supra note , at lxxiii. see act of sept. , , ch. , stat. . the statute imposed the duty upon the secretary of state. washington performed that duty in several circumstances while the office was vacant. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : d. delivery the delivery theory rests upon common law concepts applicable to deeds and related instruments and contends that without commission deliv- ery, the president has not filled the office or made an officer. the delivery theory has two rather different guises. in marbury, marshall supposed that the president had to complete the entire act of appointment without the aid of others, the theory being that the constitution granted the appointment power to the president alone. as marshall put it, “appointment is the sole act of the president” because under the constitution the appointment is “to be made by the president per- sonally.” based on this belief, he ruled out delivery to the appointee because the president never personally delivered commissions. instead, he focused on delivery to the secretary of state: “if then the act of livery be necessary to give validity to the commission, it has been delivered when exe- cuted and given to the secretary” to the appointee. that is to say, if deliv- ery mattered, delivery to the secretary of state made the appointment. jefferson and his defenders had a different delivery theory in mind, one where delivery to the putative appointee was crucial. in , jefferson wrote that for a “commission, a deed, a bond, delivery is essential to give validity. until . . . the commission is delivered out of the hands of the executive & his agents, it [the office] is not his [the potential appointee’s] deed. [the presi- dent] may withhold or cancel it at pleasure . . . .” the point would stick with jefferson, for in he continued to insist “if there is any principle of law never yet contradicted, it is that delivery is one of the essentials to the validity of a deed.” even if signed and sealed, “as long as it remains in the hands of the party himself, it is in fieri [pending] only, it is not a deed, and can be made so only by its delivery.” though marbury and his fellow applicants rejected jefferson’s version of the delivery theory, the fact that they sought commissions and had never tried to assume office without them one might characterize the delivery theory as a subset of the commission theory if one believed that the president does not actually commission anyone until and unless the potential officer receives the commission. under this theory, signing and sealing a com- mission does not actually satisfy the commission duty of the constitution. there is much to be said for this understanding of the duty to commission because it is hard to see how anyone benefits from a constitutional obligation to sign and seal a document that is never actually given to the officer. see infra text accompanying notes – . for our purposes, it does not matter whether one characterizes the delivery theory as a separate appointment theory or merely as a subset of the commission theory discussed in supra section ii.c. marbury v. madison, u.s. ( cranch) , – ( ). id. at ; see also id. (describing appointment as “the mere act of the president”). id. at . id. id. see letter from thomas jefferson to george hay, supra note , at n.i. letter from thomas jefferson to william johnson, supra note , at n.i. id.; see also letter from thomas jefferson to judge spencer roane, supra note , at , . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y lent it some plausibility. one might suppose that they wanted commissions to remove all doubts that they had been appointed. but insecurity about their status may have arisen because they lacked commissions, an uncertainty that suggested the importance of delivery. with the jeffersonian delivery theory in mind, consider the hypothetical: the president nominates, the senate consents, and the president signs and seals the commission for a potential federal marshal. there still is no appointment. even after the president directs delivery and the commission is in transit, the appointment is not made until receipt by the would-be mar- shal. if the commission is lost and never found, the office is not vested. another commission must be made out and actually delivered. in contrast to the sequence suggested by secretary of state jefferson in an early opinion to washington (nomination, appointment, commissioning), president jeffer- son’s delivery theory contemplates a different sequence: nomination, commissioning, and then appointment (via delivery of the commission to the appointee). the jeffersonian delivery theory had some evidence to commend it. first, the statute requiring the secretary of state to affix the seal suggested that even after a commission was made, an appointment was not complete. the law (which marshall quoted in marbury) provided that the secretary had to “affix the said seal to all civil commissions, to officers of the united states, to be appointed by the president.” the provision, passed during the first session of the first congress, could be read to suggest that appointment fol- lowed commissioning because the statute discussed individuals “to be appointed” after the seal was affixed to the commission. second, the constitution’s text had similar hints, or so one of jefferson’s defenders argued. in april of , within weeks of jefferson’s decision to treat the adams appointments as nullities, a good republican rose to jeffer- son’s defense with respect to the charge of “illegally withholding the commis- sions.” the partisan focused on the recess appointments clause: the president “shall have power to fill up all vacancies that may happen during the recess of the senate, by granting commissions which shall expire at the end of their next session.” jefferson’s defender argued that this language showed that recess appointments—filling up vacancies during the senate’s of course some officers might be unable to produce a previously delivered commis- sion because it was lost or destroyed. so delivery alone would not necessarily remove all doubts about whether a person was an officer. one could imagine a “possession” theory where appointment and continuation in office was tied to possession of a commission. in the course of rejecting the delivery theory, marshall ridiculed the idea that delivery to the person might matter, for then “fraud, fire, or theft, might deprive an individual of his office.” marbury, u.s. ( cranch), at . but the jeffersonian delivery theory did not turn on continued possession; it turned on delivery alone. thomas jefferson, opinion on the powers of the senate respecting diplomatic appointments, supra note , at . act of sept. , , ch. , § , stat. , . the nat’l intelligencer, & wash. advertiser, apr. , , at a . u.s. const. art. ii, § , cl. . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : recess—were to be made by the act of “granting commissions.” what was true for recess appointments was true for appointments more generally, or so the defender insisted. a grant of a commission, the author claimed, meant delivery; anything short of delivery could not constitute “granting commis- sions.” while a commission was in the executive’s hand, he could “stop short” and choose neither to grant it nor make the appointment. such a system of appointing made sense, said the writer, for information about a candidate’s “[k]navery, partiality, or innocent mistake” might come to light after signing and sealing the commission, but prior to delivery. despite the fact that the attorney general sent this defense to jefferson, no one in his administration made it at the time or thereafter. in , john marshall endorsed the delivery theory as applied to par- dons. writing for the court, marshall claimed in united states v. wilson that a pardon became effective only upon delivery. “a pardon is a deed, to the validity of which delivery is essential . . . .” marshall never commented on this apparent inconsistency with marbury. perhaps marshall thought pardons and appointments were rather different, with only the former requiring deliv- ery to the beneficiary. or maybe he did not pause to consider what his claim about pardons suggested about his earlier, more famous opinion about appointments. whatever the case may be, there is little evidence that many thought that delivery of a commission was essential to make an appointment. certainly jefferson’s predecessors did not believe as much. as noted, washington claimed to have appointed individuals prior to the making of any commis- sion. he also asserted that he had appointed via the commission itself, prior to any delivery. likewise, in the wake of the richard hunt court martial, all members of the adams cabinet concluded that an appointment could be made without issuing a commission, meaning that delivery could hardly be requisite. president adams had come to the same conclusion, claiming that a commission was evidence of the appointment and not the appointment itself. the nat’l intelligencer, & wash advertiser, apr. , , at a (emphasis omitted). id. id. letter from levi lincoln to thomas jefferson (apr. , ), supra note , at . united states v. wilson, u.s. ( pet.) , ( ). letter from george washington to thomas jefferson (oct. , ), in the papers of george washington (w.w. abbot et al. eds., ). commission (jan. , ), in the papers of george washington, supra note , at . see supra text accompanying note . letter from john adams to j. mchenry (july , ), in the works of john adams, supra note , at . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y there is also little evidence that president jefferson thought that deliv- ery was essential to an appointment. as noted, jefferson spoke of individ- uals being appointed prior to any commission being made out, much less delivered. his commissions also discussed appointments as having been made by the commission and not by its delivery. in adopting these conclu- sions, perhaps president jefferson drew on his experience as secretary of state. maybe he also recalled what transpired in late . though washing- ton appointed jefferson on september , , jefferson received his com- mission in late november, upon his return from france. in sum, jefferson’s claim that delivery to the putative appointee was essential is belied by his actions as secretary of state and president. e. acceptance jefferson never argued that acceptance of the office was necessary to appoint. marshall raised the issue sua sponte out of a sense that he should canvas all the arguments, especially since madison had ignored the court’s order to explain why a writ of mandamus should not issue. the acceptance theory posits that someone cannot be appointed to office against her will, meaning that the president (and other appointers) the editors of the thomas jefferson papers discuss an interesting episode during the washington administration that might suggest that both washington and jefferson thought commission delivery was necessary to appoint. after the senate consented to the appointment of joseph anderson as a territorial judge, allegations of revolutionary war improprieties arose against him. washington forwarded these allegations to jefferson and requested his opinion on the matter. jefferson concluded that the evidence favored anderson and washington agreed, with a commission issued to anderson. see generally the judicial appointment of joseph anderson, editorial note, in the papers of thomas jeffer- son, supra note , at – (narrating the contentious appointment of joseph inslee anderson to civil office). this episode might suggest that neither washington nor jeffer- son thought the appointment was complete until the delivery of anderson’s commission. yet there is little to support this inference. the actions of washington and jefferson can be read as supporting the delivery theory only if a commission had been signed and sealed at the time of their discussion. after all, if a commission had not been signed or sealed, that fact (and not the absence of delivery) could explain why neither washington nor jefferson believed the appointment was complete at the time washington asked for jeffer- son’s opinion. there is nothing in the records indicating that anderson’s commission had been signed or sealed prior to the discussion between washington and jefferson. moreo- ver, because in other cases both washington and jefferson repeatedly acted as if delivery was not necessary to make an appointment, it makes little sense to think that either thought that anything turned on delivery. see supra text accompanying notes – . see supra text accompanying note – . see elmer plishke, u.s. department of state ( ); letter from george wash- ington to thomas jefferson (nov. , ), in the papers of george washington, supra note , at (noting that commission had been sent to virginia). marbury v. madison, u.s. ( cranch) , ( ). marshall said the court had to consult its own “imagination” in an “anxious[ ]” quest for principles that might suggest the court’s view of when an appointment vests was mistaken. id. at . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : cannot unilaterally appoint to office. so even after the president nominates, the senate consents, and a commission is made out and delivered, the poten- tial officer may still refuse the office and prevent her appointment. moreo- ver, the acceptance theory does not require any commission, focusing instead on acceptance of the office. consider the following: the president nomi- nates, and after securing the senate’s consent, offers the office of supreme court justice to a lawyer. whether or not a commission has been made out or delivered is irrelevant to whether the president has appointed the lawyer. offer and acceptance, though insufficient to satisfy the president’s commis- sion obligation, does make an appointment. there is much to be said for this theory. after all, theories that do not turn on acceptance contemplate that people are appointed even if they reject the office and never carry out any official functions. in such cases, compet- ing theories that do not require acceptance envision an appointment fol- lowed by a quick resignation, when most people might conclude that the person never really was in office and hence was never appointed. nevertheless marshall rejected the acceptance theory. he claimed that because the appointment power rested with the president, he had to be able to exercise it unilaterally, without regard to acceptance by a putative officer. he also noted when a person appointed “refuses to accept that office, the successor is nominated in the place” of the person declining the office, implying that the person refusing the office had occupied it none- theless. he also claimed that the salary of the officer “commences from his appointment, not from” any delivery of the commission or acceptance of the office. marshall was generally correct about early practice. as the chief justice claimed, people concluded that the president had appointed even when the persons so appointed declined the office. moreover, subsequent individu- als were nominated to fill the vacancy occasioned by the resignation that was implicit in the declination. consider robert harrison’s refusal to serve on the supreme court. in his letter to washington explaining his decision, harrison acknowledged his appointment and the honor it bestowed upon him, meaning that harrison understood that washington had appointed him without his consent. similarly, washington subsequently told the senate that among those who had been “appointed” during the last session were some who had “declined serving.” in his list of new nominations, washington recorded robert id. at . id. id. id. letter from robert harrison to george washington (oct. , ), in documen- tary history of the supreme court of the united states, – , supra note , at . letter from george washington to the senate of the united states of america (feb. , ), in the papers of george washington (dorothy twohig et al. eds., ). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y harrison as resigning from the court and james iredell as his new nomi- nee. and in washington’s letter to iredell, he noted that the office had become vacant via resignation of the “gentlemen appointed.” yet despite these practices, acceptance had to matter in certain cases. imagine that a federal statute prohibits a judge from occupying two judicial posts. further, suppose the president purports to appoint a current district judge to a circuit court. does the appointment automatically divest the indi- vidual of their district judgeship, even against their will? it cannot do so. if it could, a devious president could temporarily “promote” a disfavored judge via a recess appointment to a higher court (thereby divesting him of his cur- rent office) and then decline to send his name to the senate for the perma- nent position. or consider a more realistic scenario. suppose the president appoints a sitting senator to the supreme court during the senate’s recess. the consti- tution forbids sitting members of congress from simultaneously serving as officers of the united states. if the president can appoint the senator to the supreme court without the latter’s consent, the president has effectively forced the senator’s resignation from the senate. finally, there are state constitutional prohibitions on dual office hold- ing. almost all states bar at least some of their officers from serving in the federal government. if the president can force a federal appointment on a state official, the federal office would automatically divest the individual of her state post. essentially, the president would have power to oust a governor or state assembly speaker by granting a minor federal appointment during a senate recess. the point is that in certain situations, it makes little sense to suppose that the president can involuntarily divest someone of their current office or station by appointing them to a new office. if that is so, then perhaps accept- ance is sometimes necessary for an appointment to vest. there is evidence that members of the jefferson administration thought that acceptance was sometimes crucial. at the end of his administration, john adams had tried to appoint ray greene to the rhode island district court. one problem was that greene’s commission was made out as if he had been appointed to the circuit court. yet the senate had never consented to such an appointment. but an even greater difficulty was that the district court judgeship was occupied at the time of the attempted appointment. prior to leaving office, adams had tried to appoint the existing district judge, benjamin bourne, to the circuit court. yet bourne did not accept the pro- id. letter from george washington to james iredell (feb. , ), in documen- tary history of the supreme court of the united states, – , supra note , at . for a discussion and summary of the many state-level incompatibility rules that bar dual state and federal office-holding, see steven g. calabresi & joan l. larsen, one person, one office: separation of powers or separation of personnel?, cornell l. rev. , – ( ). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : motion until march of . based on these facts, levi lincoln declared that there was “no vacancy” in the district court when adams had attempted to appoint ray greene. by deciding that bourne had remained a district judge until march rd, lincoln concluded that no article iii judge could be divested of his office merely by a supposed appointment to another office. iii. the making of appointments under the constitution as we have seen, early commentators were quite divided. some argued that an office vests upon the senate’s consent. others claimed that appoint- ments were made after senate consent but before the issuance of a commis- sion. a third cohort asserted that to commission someone was to appoint them. still others contended that delivery made the appointment. and some, like thomas jefferson, endorsed different views over time. early practice was similarly divergent. some officers were appointed without any commission being made. others, jefferson included, were appointed after a commission had been made out but before receiving it. in other cases, the president claimed to appoint via a commission. and in one case, acceptance was deemed crucial. the dissonant voices and varied practices may lead some to conclude that the constitution says anything about the matter. perhaps those search- ing for a right answer are asking too much of a constitution written in gen- eral terms and incapable of answering all disputed questions. while this conclusion has its merits, it fails to consider another possibil- ity. perhaps each theory is right insofar as each provides a possible way of appointing officers. perhaps each is wrong insofar as each purports to offer an exclusive means of appointing. maybe the constitution permits variation in appointment methods, ceding appointers significant discretion in how and when they appoint. this part offers a discretionary theory of appointment, a theory that accounts for the variations in early practice. this discretionary theory posits that the constitution never enshrines a single method by which appoint- ments become valid. instead, the appointer has flexibility in deciding the means and methods of appointment. the part also considers application of the discretionary theory to other constitutional powers where the means and methods of their exercise are not obvious, such as pardons, orders to executive officers, and exercises of the judicial power. it also addresses constitutional restrictions on the general rule of appointer discretion. next, it turns to a discussion of commissioning in greater depth and the role that commissions can serve as evidence of the appointment. then it considers whether congress may dictate, via statute, how and when an appointment vests. finally, it reconsiders the appointment methods discussed in part ii in light of the discretionary theory and argues that none of them should be viewed as the exclusive means of appointing. see letter from levi lincoln to thomas jefferson (apr. , ), in the papers of thomas jefferson, supra note , at . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y a. the discretionary theory of appointment the early use of multiple means of appointing officers suggests a possi- bility left unmentioned in the constitution’s early years. because the consti- tution never dictates how or when an appointment is made, an appointment vests however and whenever the appointer decides that it should vest. this is the best answer because it makes sense of practice and the constitution’s text and structure. the textual and structural case for the discretionary theory is simple. article ii grants the president the power to appoint, but it does not decree when or how such appointments are to be made. nor does it elsewhere declare that someone else must dictate, in the first instance, how or when an appointment vests. the natural supposition is that the person empowered may decide such matters, for the power is given without any indication that others may specify these details. the conclusion follows from principles related to incidental authority under agency law. we the people are the principals. the actors created by the constitution are our agents. we the people have delegated, over time, certain powers to those agents. we have placed procedural (e.g., bicamera- lism, presentment, senate consent) and substantive (e.g., the bill of rights) constraints on the exercise of these powers. beyond such constraints, our agents may decide how and when to exercise the powers delegated to them so long as they continue to act in the best interests of their principals, because such authority is incidental to the express grant. there is an “ines- capable proposition that it is not necessary . . . to spell out every detail in granting express authority” to an agent. this principle applies just as forcefully to the constitution. because the constitution contemplates various appointers, and because the appointer, under the discretionary theory, may decide how and when her appointments will vest, each appointer may choose her own method of appointment. when the president is the appointer, she may decide when her appointments shall vest. when appointing a secretary, the president can decide that the appointment vests when the senate consents. or she may decide the offices vest with the delivery of a commission. if she wishes to recess-appoint someone, the president might choose to have the appoint- ment vest if, and only if, the appointee accepts the office. others who may appoint inferior officers (department heads and courts) pursuant to statutory grants also may choose the manner and timing of their appointments. similarly, because each chamber may select its own officers, each may decide what, if anything, must be done as a formal matter after the chambers vote on those officers. in this way, the constitu- william a. gregory, the law of agency and partnership § (d), at ( ); see restatement (third) of agency § . ( ) (discussing how agents have incidental and necessary powers to pursue a principal’s objectives). u.s. const. art. ii, § . u.s. const. art. i, §§ – . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : tion contemplates multiple appointers, each of whom may choose to appoint in multiple ways. b. the discretionary theory applied to other provisions this discretionary theory of appointment derives from a general and underappreciated rule of constitutional law: when the constitution grants power and does not specify the means of exercising it, the recipient of that power generally may decide the means by which to exercise it. as noted ear- lier, this discretion is an implied feature of the power granted. an agent given power to do x, without more, may choose the mechanism by which to exercise that power to do x, consistent with the constraints, express and implied, the principal has placed on the agent. because the discretionary theory is a general principle of constitutional law, it applies to other powers. consider something as simple as language. the constitution never specifies the language to be used in laws and treaties. whether congress uses english or some other language in its bills is left to its discretion, for the constitution never specifies the language to be used in bills and laws. indeed, congress might choose to pass bilingual bills, contain- ing text in english and french. none of this should seem strange because the use of multiple languages has long been a staple of federal treaties, many of which are written in more than one language. the point is that while both laws and treaties must be in writing, the constitution never specifies the language of those texts, leaving that decision to the institution empowered to craft the text. or consider the return of a vetoed bill. whether the president returns a bill personally, via a messenger, or via e-mail to the originating chamber is for him to decide, because while the constitution specifies “return” within ten days as a precondition to the exercise of the veto power, it never dictates the methods. in a related context regarding the signing of bills into law, the office of legal counsel has opined that others may sign bills as agents for the president, meaning that the power to sign includes the option of signing the bill oneself or delegating that specific task to a subordinate. early treaties were often in both english and another language. see, e.g., treaty of alliance, u.s.-fr., feb. , , stat. (french); treaty of amity and commerce, u.s.- neth., oct. , , stat. (dutch); a treaty of amity and commerce, u.s.-prussia, july, aug. & sept. , stat. (french); treaty of friendship, limits, and navigation, u.s.-spain, oct. , , stat. (spanish). u.s. const. art. i, § , cl. . the office of legal counsel in the department of justice recently opined that the president could return bills electronically to congress. see opinion on whether bills may be presented by congress and returned by the president by electronic means, op. o.l.c. ( ), available at www.justice.gov/olc/ /bills-electronic-means.pdf. see opinion on whether the president may sign a bill by directing that his signa- ture be affixed to it, op. o.l.c. ( ), available at www.justice.gov/olc/ / opinion_ .pdf. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y this choice is the president’s to make because the constitution never speci- fies a precise mechanism of signing. the same flexibility is implicit in the treaty clause. the president must seek the senate’s advice and consent prior to ratifying a treaty. to get that advice and consent, the president might appear in person, ready to field questions as they arise. or he might messenger the treaty and direct his aides to respond to senatorial queries. though practice for over years deci- sively favors the latter option, the constitution dictates neither one. indeed, the first president personally went to the senate for its advice on a number of treaty matters, a practice that lapsed not because it was unconstitutional or improper, but because washington and certain members of the senate found it less than ideal. finally, think of the judicial power. because the constitution does not dictate how courts will exercise their judicial power, the courts may decide whether and how to issue opinions that accompany judgments. for example, the courts may decide whether to issue oral or written opinions. likewise, courts can decide whether there will be a majority opinion or merely seriatim opinions. courts may even decide that certain cases or matters do not need an opinion, meaning that they may exercise judicial power with a judg- ment unaccompanied by any explanatory opinion. as hinted at above, some constitutional interpreters recognize that a constitutional grant of power implicitly comes with certain discretion in the manner the power will be exercised. the office of legal counsel seems eager to recognize the discretion inherent in the verbs “present[ ],” “return,” and “sign,” all found in article i, section , probably because such flexibility empowers the president. it is right to find such flexibility. but other times this discretion has been lost on the interpreter. it seems to have been lost on the marshall court not once, but twice. besides mar- bury, the discretion as to means implicit in grants of power was also lost to the court in united states v. wilson. as noted earlier, the court decided that a pardon vests upon delivery because, the court said, pardons are a species of deed, and deeds require delivery to be valid or effective. hence, in wilson marshall established a single point in time when a pardon vested and thereby ruled out other means of pardoning. yet what is to prevent a pardon from see joseph hayden, the senate and treaties, – , at – ( ) (discuss- ing early senate practices and rules that discussed these possibilities). id. at – . until the th century, the supreme court did not issue written opinions, leaving justices to give reasons for their opinions from the bench. see william d. popkin, the evolution of the judicial opinion – ( ). prior to the marshall era, the supreme court typically used seriatim opinions follow- ing the english practice. see george lee haskins & herbert a. johnson, history of the supreme court of the united states – ( ). see supra note and accompanying text. see united states v. wilson, u.s. ( pet.) , ( ). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : vesting when the president signs it or at some other time of his choosing? more generally, what reason is there to suppose that pardons must even be written? the constitution says nothing suggesting that a pardon must be reduced to writing, much less that it must be delivered. indeed, attorneys general have long endorsed the idea of an implied or constructive pardon. in , the question of when a pardon vests resurfaced. two days before christmas, george w. bush signed and sealed a “master warrant” that purported to pardon isaac robert toussie, a convicted felon. within a day, the president learnt that toussie’s father had contributed to the repub- lican party. on christmas eve, bush “revoked” the pardon. the department of justice apparently concluded that the pardon had not vested because no pardon had been delivered to toussie. some com- mentators, citing wilson, agreed. despite the sense that president bush had “revoked” the pardon, there was no revocation as much as there was a decision not to complete the process of granting a pardon. after all, under wilson, no pardon was final until delivery and acceptance. one commenta- tor suggested that there had been a long practice of presidents revoking com- pleted pardons. others disagreed, noting that president bush had a signed a document that declared that the president “hereby grant[s] full and unconditional par- marshall seemed moved by the fact that a court could not take judicial notice of a private pardon unless it was brought to its attention. see id. while that may be true, it hardly matters for when the pardon vests. it surely does not show that delivery is necessary for the pardon to vest. opinions of the attorneys general endorsed the concept of implicit or constructive pardons, relying upon english jurists. see effect of a promotion on a suspended, passed midshipman, op. att’y gen. , ( ); court martial—pardon, op. att’y gen. , ( ). the general idea is that if an offender is ordered to do something inconsistent with his or her potential prosecution or conviction, etc., the official so ordering has pardoned the offender, albeit implicitly or constructively. hence if the president ordered a federal warden to release an inmate who still had time left on his sentence, the order should be understood, at the very least, as a remission of that inmate’s remaining sentence. more generally, one might suppose that if the president publicly declares in a speech that he “hereby pardons” various offenders for their offenses, that would be a pardon. again, nothing in the constitution specifies that pardons must be reduced to writing. see jeffrey crouch, the toussie pardon, “unpardon,” and the abdication of responsibility in clemency cases, congress & presidency , ( ). see david stout & eric lichtblau, pardon lasts just one day for man in fraud case, n.y. times, dec. , , at a . see id. at a . see, e.g., george lardner jr., a test of the power to unpardon, wash. post, jan. , , at a . see p.s. ruckman, jr., can a president revoke a pardon he has granted?, pardon power (dec. , ), http://www.pardonpower.com/ / /can-president-revoke- pardon-he-has.html. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y dons to the following named persons,” including toussie. furthermore, the administration had called to convey news of the pardon. these com- mentators argued that the pardon had been delivered orally and had been accepted (by either toussie or his attorney). for all these reasons, some believed that the pardon had vested and could not be revoked. others noted that neither delivery nor acceptance was necessary, pointing out that presi- dents previously had issued pardons benefitting the dead, a context where delivery and acceptance is generally impossible. under the discretionary theory, toussie’s case was somewhat easy. the constitution does not specify when a pardon vests, leaving it to the president to decide. president bush could have made a pardon vest prior to delivery, with delivery, upon acceptance, or after certain conditions were satisfied (say a public apology and restitution). the language of the master warrant sig- naled that bush unconditionally pardoned toussie via the warrant itself because it stated that it constituted a pardon. that the department of justice never prepared or delivered an individualized pardon to toussie was irrele- vant. while toussie might have preferred a pardon in this form, the master warrant was a wholly adequate pardon. does a constitutional actor have complete discretion as to the exercise of her constitutional powers? no. an agent given power to do x must comply with the constraints, express and implied, the principal has imposed on the agent. because some limits are implied, a mere reading of the grant of power may convey an inaccurate sense of the agent’s authority. for instance, though the federal courts have judicial power to decide cases, they cannot decide cases by reference to which party is wealthier or has a more congenial political ideology. those bases cannot be relevant in a system where justice is supposed to be blind to party attributes. nor could a federal judge decree that a trial by combat would decide a case. by the late eighteenth century that method of resolving judicial disputes generally was forbidden to anglo-american jurists. accordingly, any claim about the proper means of exercising some power must be based not only the constitution’s text but also on a contextu- ally-sensitive understanding of the extant practices. had the constitution been enacted in the fourteenth century, perhaps article iii judges could decide cases by reference to who survived a trial by combat. the text and history of the appointment power leads me to conclude that the president enjoys tremendous discretion in the manner and timing of appointment because there are very few express constraints and seemingly few implied constraints. with respect to the type of opinions that courts issue (majority vs. seriatim) and with respect to when pardons vest, i am similarly confident that the relevant actors had discretion. brian c. kalt, once pardoned, always pardoned, wash. post, jan. , , at a ; see also harlan j. protass, signed, sealed, delivered, but not yours, chi. trib., jan. , , at c . kalt, supra note , at a ; protass, supra note , at c . see protass, supra note , at c . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : in sum, when the constitution grants powers without specifying the mechanisms for their exercise, the institution empowered generally may decide the means of implementing the power. this discretion extends to the form the exercise of power will take and when the power will be exercised. at the same time such discretion is subject to express and implied con- straints, meaning that the institution does not necessarily have absolute dis- cretion as to the means of that power’s exercise. c. restrictions on the rule of appointer discretion as noted, sometimes the constitution constrains the manner in which a power may be exercised. to present a bill to the president, the house and senate must first pass a bill with the same text. to make a treaty, the president must first receive the senate’s consent. courts must have a justi- ciable case or controversy prior to exercising the judicial power. the general rule of appointer discretion is subject to its own set of con- straints. first, while the senate is in session, the president cannot appoint individuals to non-inferior offices unless he first secures senate consent. for such offices, there is a required sequence because under the appoint- ments clause, the senate’s consent is clearly an ex ante constraint on appointments and not an ex post means of ousting people from office. second, the president generally cannot appoint unless there is a preex- isting office created by congress. the appointments clause refers to offices “established by law,” a phrase that suggests that though the president appoints, only congress may create the offices via laws. indeed, that has been our practice from the constitution’s inception. the only exception to this rule is a curious one: the president has long created foreign diplomatic postings, such as the ambassador to france, without the assistance of con- gress. even for such offices, the senate must provide its advice and con- sent prior to appointment, at least while it is in session. a third constraint on appointment discretion is implied. as suggested earlier, certain people cannot be appointed without their acceptance of the office. in particular, it seems clear that no member of congress can be appointed to an executive or judicial office without her consent. the incom- patibility clause signals that no attempted unilateral appointment of a sitting u.s. const. art. i, § , cl. . u.s. const. art. ii, § . id. recently professor matthew stephenson has argued that senate consent can be implied and need not be express. see generally matthew c. stephenson, can the president appoint principal executive officers without a senate confirmation vote?, yale l.j. ( ). u.s. const. art. ii, § . saikrishna b. prakash & michael d. ramsey, the executive power over foreign affairs, yale l.j. , ( ). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y member of congress to an executive or judicial office can succeed. if a president could so appoint a legislator to a federal office, it would only be so because the presidential appointment automatically divested the legislator of her congressional post. but if an appointment could accomplish that, the president would have the power to oust any federal legislator by unilaterally appointing them during the senate’s recess. surely the constitution grants no such power to the president, via the appointments clause or otherwise. if the president wishes to appoint a senator to serve as secretary of state, the senator must resign from the senate prior to the appointment vesting. of course a senator would only resign if she desired the appointment in the first place, meaning that the president cannot appoint federal legislators to fed- eral office without their express or implied acceptance of the office. perhaps the appointment of sitting judges to an executive office is sub- ject to a similar constraint. if one supposes that a federal judge cannot simul- taneously occupy an executive office based on a sense that there is an implied incompatibility bar that forbids appointment to multiple branches, then the president cannot force an executive appointment on a federal judge. for instance, a circuit court judge cannot be appointed to be a district attorney without her consent. any attempt would fail because of the implied incom- patibility rule and because the president clearly lacks the power to unilater- ally oust a federal judge, even via an exercise of his appointment power. because the president lacks the power to oust a federal judge, she can appoint a federal judge to an executive office only after the judge resigns from her judicial office (at least under the theory that there is an implied incompatibility bar). as noted, a resignation signals consent to the new appointment, making it clear that an appointment of a federal judge to an executive office only may occur via her acceptance of the new office. in sum, the president lacks a power to unilaterally appoint any member of the house or senate to an office of the united states. and it may be that the president cannot force an executive appointment on a federal judge. either sort of appointment arguably requires consent to the new appoint- ment, meaning that the president may not confer unwanted executive offices on federal legislators and federal judges. some might suppose that there is a fourth constraint on an appointer’s discretion. in particular, one might imagine that the power to appoint only can be exercised in the present, meaning that the president cannot use the appointment power to dictate that an appointment will vest in the future. for instance, if the president wanted an appointment to vest on january , perhaps he must take action on january , rather than attempting to provide, in advance, that an appointment automatically will vest on the first of the u.s. const. art. i, § , cl. (“[n]o person holding any office under the united states, shall be a member of either house during his continuance in office.”). typically the case for an implied prohibition on office holding across the judicial and executive departments rests on the supposedly longstanding practices of the branches. for discussions of this view, see calabresi & larsen, supra note , at – . my esteemed colleague, john harrison, brought this possibility to my attention. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : year. likewise, maybe the president cannot appoint conditional upon the occurrence of an event, such as the senate’s consent. under this reading of the appointments clause, the power to “appoint” is the power to grant an office in the present; it does not encompass authority to dictate that an appointment will or may vest at some point in the future. to flesh out the contours of these supposed restrictions, consider the organic act. it allowed the president to appoint as many justices of the peace as he thought necessary. rather than acting only at the points in time when he deemed it necessary to appoint new justices of the peace, the presi- dent might want to decree that new appointments automatically vest if cer- tain population thresholds are met. for instance, the president might provide, via executive order, that when a particular threshold had been exceeded, a named person would be a new justice of the peace. yet if the appointing power is a power to vest an office only in the present, the president could not appoint someone to office over time. he would have to take action to appoint as and when he wished to fill an office. perhaps it makes sense to read the power to appoint as something that only may be exercised in the here and now and not over time. reading the appointment power in this way has a salutary effect, because it prevents the current president from deciding personnel matters beyond his term. if the president could use his appointment power to appoint conditionally upon some event far into the future, a sitting president could extend his sway beyond his term in office. for instance, the president would be able to decide, with the senate’s consent, the next occupant of a supreme court seat currently occupied. indeed, a president might even be able to decide the successor to the successor, in much the same way the act of settlement deter- mined succession for the english crown. despite some reasons to read the appointment power narrowly, the bet- ter view is that the president can use that power to decide that appointments will vest in the future. to begin with, there are other powers of government that clearly have effect in the future, suggesting that there would be nothing untoward with understanding the appointment power as permitting condi- tional appointments. when congress exercises its lawmaking powers, it cre- ates laws, some of which only take effect in the future, typically upon a certain date. hence the legislative power encompasses the ability to make rules that do not take effect immediately. the president has similar powers. using the pardon power, the presi- dent can issue conditional pardons that only take effect if individuals take particular actions, such as admitting guilt, laying down arms, paying a fine, etc. this means that the pardon power includes authority to extend for- giveness in the future, upon the satisfaction of conditions. act of feb. , , ch. , stat. ( ). act of settlement, , & w. & m. , c. (eng.). see generally harold j. krent, conditioning the president’s conditional pardon power, cal. l. rev. ( ) (discussing the benefits of allowing the president to make par- dons conditional on future conduct or events). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y consider the ratification of treaties. under the constitution, the presi- dent can make treaties, provided the senate consents. according to the terms of typical treaties, a treaty is made once the parties ratify it. suppose the united states has, via the president, ratified a treaty before the other party or parties have ratified it. subsequently, the other parties ratify it. must the president ratify again in order to exercise his power to make treaties? in other words, is the power to make treaties a power to make treaties in the here and now and not a power to make treaties conditional on another nation’s ratification? if the treaty power were read as only the power to make treaties in the here and now, the president could only ratify a treaty previ- ously ratified by the other party or parties. this has never been our practice. the treaty power has been read for two hundred years as including the power to make treaties conditioned upon the subsequent ratification of the treaty by other nations. presidents have often ratified first, with the treaty automatically going into effect if the other party ratifies. in such cases, no further presidential action is necessary. finally, consider conditional nominations. one of the best sources of candidates for office is the pool of existing officers. a lieutenant may be made a captain and a captain a major. an assistant deputy treasury secretary may be made a deputy secretary, and a deputy treasury secretary. presi- dents could choose to nominate each person in the chain separately, waiting for an actual promotion to make room for another vacancy. so the president might nominate a captain to be a major and only nominate a new captain after the previous captain vacates his former office. alternatively, the president could nominate to the captain and major offices, with the nomination to the captain’s office conditional on the cur- rent captain’s promotion to major. this is exactly the tack that george wash- ington took. the first president sometimes simultaneously nominated a for office x and b for office y, where a currently occupied office y. although washington’s nomination of b to office y was conditional, it was a nomina- tion nonetheless. he never had to re-nominate b once office x actually became vacant due to the actual promotion of a. the appointment power, like the pardon, treaty, and nomination pow- ers, is best read to include the ability to make appointments conditional upon some event. hence, the president may decide that an appointment vests with the senate’s consent, upon some date certain, or when an office currently occupied becomes vacant. when the president makes a condi- u.s. const. art. ii, § , cl. . see treaty of amity, commerce, and navigation (jay treaty), u.s.-gr. brit., nov. , , stat. (discussing wherein president ratified and england ratified only later). the documentary history of the first federal congress of the united states of america (linda grant de pauw et al. eds., ) (nominating john sitgreaves to be a judge and william hill to be an attorney “in place of john sitgreaves, if his nomina- tion as judge meets your concurrence”); id. at (confirming ziegler, doyle, and sedam, with doyle succeeding ziegler and sedam succeeding doyle, thereby indicating that wash- ington conditionally nominated doyle and sedam). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : tional appointment, he exercises his appointment power over time, with the appointment actually vesting when the conditions are met. but even if presidents can only appoint in the present and cannot make conditional appointments, perhaps presidents could work around this restric- tion by issuing standing orders to appoint. in other words, even if the appointment power, by itself, is not up to the task, maybe that power coupled with the president’s authority to direct the executive branch is sufficient. if the president declares on january that an appointment will vest on march and that he should be deemed to have made the appointment on that date in the future, he need not restate his desire to appoint an individual in order for the appointment to vest. on march , his subordinates can take whatever measures are useful or necessary, including issuing the commission and allowing the individual to assume office, on the understanding that the appointment has vested pursuant the president’s standing order. this system of standing orders to appoint may seem odd to some. yet presidents certainly exercise other powers via standing orders having effects in the present and in the future. consider military orders. the president could issue an order only good for one event, much like a ticket that is only good for the day sold. or he can issue standing orders that have effect in the future. either way, he is acting as commander in chief. likewise, as chief executive of his branch, the president can create standing rules for the con- duct of executive officers without having to reissue them every day. the executive orders related to cost-benefit analysis are of this sort, creating dura- ble rules that executive officers must follow until they are countermanded. if the president can issue standing orders that his subordinates, civil and mili- tary, must obey, those standing orders can pertain to the steps that officers must take to ensure that an appointment shall vest upon some event or occurrence in the future. there remains the concern that a president might appoint to office well after he leaves office, thereby extending his powers beyond his term. this should not long trouble us. presidents routinely take actions that have effects beyond their terms in office, such as issuing pardons, appointing individuals who remain in office after the president’s term, and issuing standing direc- tives to executive officers via executive orders. in the case of executive orders, they continue in force unless the new executive rescinds or modifies them. their continuing force causes no alarm precisely because the new chief executive may modify them at will. as long as an appointment has not vested, the successor president may alter or eliminate the conditional appointment. so while an incumbent might try to make a series of appointments that will vest after he leaves the presidency, the successor president always may nullify the conditional see, e.g., exec. order no. , fed. reg. (jan. , ); exec. order no. , , fed. reg. , (sept. , ). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y appointments, in the same way that a sitting president may nullify or modify an executive order issued by a predecessor. in sum, the better view is that the president can decide that an appoint- ment will vest in the future. whether the appointment power is exercised via a conditional appointment or by a standing appointment order is of no con- sequence. if the president can do either, he can make appointments vest immediately upon the senate’s consent, on a date certain, upon acceptance, or when the current occupant vacates the office. d. the functions of commissions the constitution obliges the president to commission officers. in marbury, marshall claimed that transmission of the commission to the appointee was not required by the constitution or by law. if the commis- sions clause never requires delivery of a commission to an appointee, it does no more than establish a record-keeping requirement, one satisfied by a ledger with a list of appointees. the great chief justice was certainly mistaken, likely blinded by a desire to insist that delivery to the appointee was irrelevant. to begin with, early federal commissions were addressed to people outside the executive branch. some were addressed to the individual appointed, making it odd to sup- pose that the addressee never had a right to something directed to him. most were addressed to the world. they typically began with the presi- dent’s name and title and then said, “to all who shall see these presents, greeting.” after this introduction came the specification of the office and for example, president obama’s first executive order rescinded president george w. bush’s executive order, which had given former presidents robust authority to claim executive privilege. exec. order no. , , fed. reg. (jan. , ). i do not believe that the president may exercise his appointment power to prevent a successor from nullifying or modifying his conditional appointments, just as i do not believe that a president may issue a non-rescindable executive order. as long as the appointment is not made, the president may arrest and terminate the pending appoint- ment. cf. krent, supra note , at (claiming that presidents cannot bind their successors). u.s. const. art. ii, § (explaining that the president “shall commission all the officers of the united states”). marbury v. madison, u.s. ( cranch) , ( ) (“the transmission of a commission [to the appointee], is a practice directed by convenience, but not by law.”). see washington’s commission from congress (june , ), in this glorious struggle (edward g. lengel ed., ) (“to george washington, esquire[:] we repos- ing especial trust and confidence in your patriotism, conduct and fidelity do by these presents constitute and appoint to be general and commander in chief of the army.”). for an earlier example of such a commission, see commission to william lewis, in the papers of thomas jefferson, supra note , at . see appointment of david rittenhouse (mar. , ), available at https://www. gilderlehrman.org/collections/ d fd b- e a- ba- - ; see also commis- sions on file with author (commissions of william nelson, oliver wolcott, john brooks). see appointment of david rittenhouse, supra note ; see also commissions on file with author, supra note . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : individual. the commissions typically closed with, “in testimony whereof i [the president] have caused these letters to be made patent and the seal of the united states to be hereunto affixed.” again, it seems strange to address a commission to the world, to speak of the president’s “[t]estimony”, and to make the letters “patent,” if there was no duty to deliver the com- mission to an officer who might produce it whenever his authority was in doubt. a commission that does no more than gather dust alongside other commissions in the state department files hardly testifies to anything. little wonder that many spoke of commissions as evidence of an appointment. as secretary of state, jefferson had said that commissions were “public evidence” of an appointment. president john adams doubted that commissions were the “exclusive evidence of appointments,” thereby con- firming that they were a species of evidence. some of his advisors said the same, with one secretary claiming, “it is desirable that in all cases where officers enter upon duty, they should have it in their power by producing their commissions to show that clearest and best evidence of authority.” written evidence of an appointment is always better than oral testimony. something signed and sealed was likewise better than informal papers or letters. whereas today, officers keep their commissions as mementoes of their service, some were asked to return theirs and others returned them volun- tarily. george washington requested that john marshall send back his commission after the latter declined to serve as a district attorney. pre- sumably returns were necessary to ensure that no one believed that the appointed individual remained in office after a declination or resignation. see appointment of david rittenhouse, supra note . “letters patent” were government documents open to the world, meant to be a matter of public record, and usually addressed to mankind. they were in contradistinction to “letters close” which were for the “closed up and sealed” and for a particular person. see richard burn, a new law dictionary ( ). thomas jefferson, opinion on the powers of the senate respecting diplomatic appointments, supra note , at – . letter from john adams to j. mchenry, supra note , at . letter from benjamin stoddert, secretary of the navy, to james mchenry, supra note . see letter from tobias lear to matthew clarkson (march , ), in the papers of george washington, supra note , at . see letter from alexander hamilton to george washington (july , ), in the papers of george washington (theodore j. crackel ed., ) (noting return of commission); see also letter from robert denny to george washington (dec. , ), in id. at (voluntarily returning commission). the editors of the thomas jefferson papers believe that most military officers did not return their commissions at the close of the revolutionary war. see george washington’s resignation as commander-in-chief, editorial note, the papers of thomas jefferson, supra note , at , . whether that prac- tice of officers keeping their commissions continued under the constitution is unknown. see letter from george washington to john marshall (nov. , ), in the papers of george washington, supra note , at , n. (asking for return of com- mission because “some other person must be appointed”). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y other times, the return was symbolic, meant to show respect to the appointer. george washington’s famous resignation as commander in chief occurred via his public return of his commission to congress. in a ceremony fraught with symbolism, washington ended his emotional farewell address to congress by declaring that he was returning his commission, whereupon he pulled it out from his bosom and handed it to the president of the continental congress. when we think of a commission serving as evidence of an appointment, the modern equivalent might be the badge used by police officers. the badge reveals that someone is a law enforcement officer, whether they wear a uniform or not. and the return of the badge similarly signals that the officer has resigned or been ousted from office. commissions also might serve as the means of an appointment. a commission might declare that it does “hereby appoint” the named individu- als to a particular office or that the appointer “do[es] constitute” some person an officer. in such cases, the commission had a dual role, serving not only as evidence of an appointment, but also an instrument of appointment. sometimes commissions were used to establish the metes and bounds of the office, in much the same way that a deed for land might describe the parcel conveyed. the english crown typically issued rather detailed commis- sions to its colonial governors, documents that authorized, constrained, and obliged in various ways. such commissions, containing numerous sections and running for pages, were longer than many statutes. similarly, when the continental congress appointed george washing- ton as commander in chief, his commission served as a means of conveying power and issuing rudimentary instructions. it gave washington “full power and authority to act as [he] shall think for the good and welfare of the ser- vice.” it further required all soldiers to obey washington and enjoined him to exercise the soldiers and maintain strict discipline. because congress creates offices via its laws, commissions under the constitution typically do little more than mention the office conveyed. that see george washington’s resignation as commander-in-chief, supra note , at – . see thomas sheridan, a general dictionary of the english language ( ) (defining commission as “[t]he act of entrusting any thing; a trust, a warrant by which any trust is held; a warrant by which a military officer is constituted”). sheridan defined “to commission” as “[t]o empower, to appoint.” id. although commissioning could be used as a synonym for appointing, that clearly was not the only usage, as evidenced by early american practices. george washington, commission, supra note , at – (appointing thomas johnson, daniel carroll, and david stuart). commission as lieutenant colonel (oct. , ), in the papers of alexander hamilton, supra note , at (appointing alexander hamilton). r see evarts boutell greene, the provincial governor in the english colonies of north america, at app. a ( ) (reprinting detailed commissions for several colonial governors). see washington’s commission from congress, supra note , at . id. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : is to say, because the president lacks constitutional authority to create offices, he has no occasion to specify the features of an office in the commissions he issues. but one can imagine scenarios where the president might use a com- mission to limit discretion or issue general instructions to an executive officer. for instance, the president might use a commission to direct a cabi- net secretary to take particular considerations into account in promulgating new regulations. indeed, commissions might be a rather useful means of giving particularized instructions to a specific officer. finally, commissions also might be issued prior to appointment, effec- tively constituting an offer for office. the jefferson administration con- cluded that the circuit court commission sent to district judge benjamin bourne was not evidence of an appointment. rather, it was an implicit offer of an office that bourne belatedly accepted weeks later. more generally, the president might send a commission and explicitly declare that the office vested only when the individual accepted it. such a sequence would effec- tively subvert the “natural order” that secretary of state jefferson discerned in the constitution. in sum, commissions can serve many roles. typically, they serve as evi- dence of an appointment. but they may serve other functions as well, includ- ing a means of appointing, a method of delimiting an office, or as an offer of appointment. the precise functions a commission play turns upon the con- text and its content. e. congress, the senate, and the vesting of appointments because appointers have discretion as to when their appointments vest and because the constitution permits multiple appointers, there is the poten- tial for uncertainty as to when someone became an officer. to ameliorate such confusion, appointers should establish bright lines for when their appointments vest. a clear, simple rule, set out in advance, has much to com- mend it. hence, the president might declare via an executive order that none of his appointments are complete without the delivery of a commission. other appointers might borrow the best practices of others, avoiding the need to reinvent the wheel. for instance, rather than coming up with its own rules, a court of law might wish to borrow whatever appointing rules the pres- ident implements. of course federal appointers might choose to promulgate no such rules, leading to confusion about when its appointments vest. faced with uncer- tainty about when offices vest, congress might wish to enact a statute dictat- ing a specific process. congress might declare that appointments only vest with the signing of a commission. or congress might specify that appoint- ments vest upon publication in the federal register. see supra text accompanying note . thomas jefferson, opinion on the powers of the senate respecting diplomatic appointments, supra note , at – . \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y the difficult question is whether congress may dictate when appoint- ments vest. congress enjoys the power to enact necessary and proper laws for carrying into execution the powers of the federal government, including the appointment power. some might suppose that the necessary and proper clause includes authority to specify how and when appointment powers will be carried into execution. yet there are sound reasons for doubting that congress has power to tell the other branches how to exercise their powers, even when such congres- sional regulation might be beneficial. the necessary and proper clause clearly enables congress to help implement presidential and judicial powers, say by creating institutions that help the president and courts better exercise their respective powers. but the clause, properly understood, does not empower congress to direct how other branches exercise their respective powers. if it did, congress might forbid presidential pardons for murderers and specify the content of the first amendment to the courts. it seems rather unlikely that the sweeping clause sweeps so far. and if it does not permit such laws, the clause likewise should not be read to authorize statu- tory rules for when an appointment vests. even if this reading of the necessary and proper clause is mistaken— i.e., one concludes that congress may specify how and when an appointment vests—that conclusion would not detract from the claim that the constitu- tion itself cedes discretion to appointers about how and when to make appointments. one might well suppose that while the constitution adopts a default rule of appointer discretion, congress nevertheless may dictate, via legislation, the methods and timing of appointments. given its check on appointments, there is the separate and interesting question of whether the senate (acting alone) may decide when an appoint- see u.s. const. art. i, § , cl. . see saikrishna prakash, regulating presidential powers, cornell l. rev. ( ) (reviewing harold j. krent, presidential powers ( )) (arguing that congress lacks a generic power to regulate exercise of presidential powers). the court has yet to say whether congress can either prescribe the means of appointment or establish conditions precedent to an appointment. in le baron, the court held that congress could require that an individual take certain actions “before he shall enter on the possession of the office.” united states v. le baron, u.s. ( how.) , ( ). but le baron also declared that the appointment was complete after the commis- sion was signed and sealed. id. the two statements can be squared if one supposes that one can be appointed to office without necessarily being able to function in it. in other words, the court might have supposed that while the president appoints, congress can prevent appointees from functioning in office. an early twentieth-century case, glavey v. united states, suggested that the appointment might not be complete until a required oath was taken, thereby hinting that the president could not unilaterally appoint at least as to such offices. u.s. , ( ) (declar- ing that an appointment was “complete, at least, when [an individual] took the required oath and transmitted evidence of that fact to the secretary”). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : ment will vest. although the senate has apparently never tried to dictate when an appointment will vest, the senate’s advice and consent resolution might be a vehicle for constraining when an appointment vests. there is precedent for advice and consent resolutions constraining exec- utive power. occasionally the senate consents to the making of a treaty only if certain changes are made. such conditional consent does not permit the president to ratify the treaty without the changes demanded by the senate, because the senate has not consented to the original treaty. given that the senate may advise the president to alter a treaty he has negotiated, even in significant ways, one might suppose that the senate like- wise could advise when an appointment will vest. the senate might declare that it “advises and consents to the appointment of [a nominee] on april .” or the senate might advise and consent to an “appointment to be made via commission.” if the senate has such power, it might have as much discretion as the president in deciding when an appointment vests. i do not endorse the notion that the senate can impose such constraints on the president via its advice and consent resolution. indeed, there are important differences between conditional consent in the treaty context and the sort of conditional consent discussed above. in the treaty context, the conditional consent goes to the substance of the treaty and not, to my knowl- edge, to the timing and method of the president’s ratification. in the appointment hypothetical discussed above, the conditional consent affects the timing and method of the appointment. these differences may lead some to reject the idea that the senate may set constraints on the conferral of offices. moreover, it is important to note that while any such advice and consent resolutions could constrain the president’s power to appoint, they would not compel anything. as noted, the president does not have to appoint someone merely because the senate consented to the appointment. if the president did not like the procedural constraints placed on his appointment power, he could decide not to appoint the person at all. in any event, regardless of whether the constitution permits the senate to constrain when or how an appointment vests, such senatorial power does not detract from the main thrust of the discretionary theory. the principal claim here is that the president has discretion to decide the timing and means of his appointments. that claim’s validity does not turn on whether the senate may, through its advice and consent role, impose conditions on how the president exercises his discretion. of course, the senate influences when an appointment will vest, because until the senate consents to an appointment, the president cannot appoint (at least while the sen- ate is in session). in most cases, such a tack would seem akin to throwing out the baby with the bathwater. if the ultimate goal is appointing someone to office and not to mount a defense of the discretion that the constitution implicitly confers upon appointers, the president likely will swallow and accept whatever minor constraints the senate might impose. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y f. reconsidering the theories of appointment even as the constitution does not enshrine the automatic appointment theory, neither does it bar the president from declaring that an appointment vests upon the senate’s consent. the president might wish people to assume their offices immediately without the need for him to take any appointive action subsequent to the senate’s consent. the downside of such a default rule is that senate debate might generate new information about the nomi- nee, facts that might lead the president to abort the appointment. the risk of damaging revelations is not so high if the senate confirms and the person occupies an office from which the president can remove at pleasure; in that case the president can simply remove his misbegotten appointee. but in the case of federal judges, the president might wish to refrain from having appointments automatically vest upon senate concurrence. alternatively, with a high enough confirmation threshold, the president might decide, rather sensibly, that there is no reason to revisit the nominee’s fitness for office. for instance, a president might provide that a judgeship automatically vests when the senate consents to it with a certain supermajority, say eighty percent. absent that threshold, he will decide whether to appoint after the senate consents. similarly, though the constitution does not dictate that appointments vest upon either commission delivery or office acceptance, nothing prevents the president from conditioning the appointment on such events. the best reason for conditioning appointment on commission delivery is if the presi- dent wants someone to refrain from taking official action until she has physi- cal proof of appointment. yet in modern times, those who doubt an appointee’s authority have ample means of verifying an appointment. besides the internet, there are books that list officers. while commissions remain evidence of an appointment, they certainly are not the only means of judging whether someone is a federal officer. likewise, the president has no need to make appointments vest with acceptance. for some individuals, such as federal legislators (and perhaps federal judges), the constitution itself requires something like acceptance prior to the grant of an office. for others, the president almost always will gauge willingness to serve well in advance of appointing. this was not always possible in eras with slower means of communicating. even though conditioning an appointment on commission delivery or office acceptance likely confers little benefit in the modern age, other condi- tional appointments might be somewhat useful. with the senate’s advice and consent, the president might create conditional backup appointments that would automatically vest should the current occupant leave office via removal, resignation, or death. having backup appointments would not save time; it would merely shift the use of time forward. but it would help ensure see, e.g., committee on oversight and government reform, th congress, the plum book ( ); leadership directories, the federal yellow book ( ). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : a quick transition (and avoid disruption and delay) once an office became vacant. what of the claim that appointment must occur via commissioning? that a commission can be a means of appointing hardly means that the con- stitution establishes commissioning as the sole means. as we have seen, presi- dents often appointed prior to signing any commission, probably because they were eager for appointees to assume office. finally, the claim that appointment must be a wholly separate act from senate consent and presidential commissioning reads too much into the constitution. admittedly, presidents occasionally acted in a manner consis- tent with this theory. yet it is also clear from early practice that the president need not separate appointment from these other acts. in sum, constitutional text, structure, and early practice do not establish a single constitutionally required means of appointing. to the contrary, they suggest that the constitution grants the appointer considerable flexibility. presidents appointed by various means not because they acted upon mis- taken readings of the constitution. rather, presidents appointed in different ways because the constitution granted them discretion regarding how and when they made appointments. iv. the marbury appointment revisited what does the discretionary theory suggest about william marbury? was he appointed on march , , or is there some reason to suppose that john adams never appointed marbury, as jefferson later claimed? the arguments developed here suggest that the plaintiffs ought to have deposed their patron, john adams, and obtained his testimony about when he vested the appointment. of course, adams would have said that the appointment vested before jefferson took office, without any need for deliv- ery of commissions. one exceedingly important piece of evidence to corrob- orate any such claim would be william marbury’s commission, signed by adams, and signed and sealed by john marshall. if we had the commission, we could read it and see what adams purported to do. if in the commission adams had claimed to have already appointed marbury—“i have appointed you to the office of the justice of the peace”—the commission likely would be conclusive evidence of a prior appointment. if the commission purported to appoint—“i hereby appoint you”—it would have served as the instrument of appointment. if the commission provided that the appointment would vest upon delivery—“when you receive this, you are appointed”—that informa- tion would settle the matter in favor of the delivery argument, at least with respect to these appointments. congress has ameliorated some of these difficulties by allowing existing officers to serve in an “acting” capacity until a new officer is properly appointed. see, e.g., u.s.c. § ( ) (permitting other officers to assume the duties of a vacant office for a period of time). see supra section ii.b. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y unfortunately, we lack william marbury’s commission or a copy of it. it, along with the other undelivered commissions, likely was destroyed. because we lack the best evidence, we can never be certain whether john adams appointed william marbury on march . yet we do have a strong sense of what marbury’s commission likely said. that evidence makes it almost certain that adams had appointed william marbury. appendix a reproduces a march , commission for george gilpin, one of the midnight justices of the peace. the commission signed by john adams and sealed by john marshall provided that “i have nominated and by and with the advice and consent of the senate do appoint him a justice of the peace for the count of alexandria in the district of columbia.” given the language used (“i . . . do appoint”), adams appointed gilpin on march rd. adams signed more than forty justice of the peace commissions on that day. a template likely was used, meaning that the commissions would have been identical, save for the appointee’s name and the county of the district of columbia. hence it is quite likely that marbury’s commission mir- rored gilpin’s. that is to say, adams likely signed a commission for marbury that purported to “appoint” on march , . when one considers the situation, it is hard to reach any other conclu- sion. march was the last day of the adams presidency. adams clearly was trying to foist officers on the new president and to reward federalists. undoubtedly, adams would have attempted to complete the appointments on his last day. the language of the gilpin commission indicates that adams believed he had appointed gilpin, marbury, and the other justices of the peace. given adams’s early experience with the commission-less officers on the court martial, the outgoing president knew that he did not need to sign, seal, or send anything to make an appointment. why would he make last- minute appointments that required the assistance of others when he could make them unilaterally? adams was never called to the stand in marbury; had he been summoned, he might have recalled the hunt court martial episode and told the court that he had appointed the justices of the peace before signing or even seeing the commissions, meaning that they were but evi- dence of appointments already made. had marbury actually received his commission, he would have had the best evidence of his appointment. instead he had to gather testimony of the clerks in the department of state and get them to admit that they had seen a signed and sealed commission for him. but as marshall indicated in his opin- ion and as marbury’s lawyer claimed, marbury did not need the commission see letter from a member of congress, supra note ; letter from thomas jefferson to abigail adams, supra note , at . see infra app. a. it was common to create a template with blanks and then send to the printer who would then print multiple copies. see contingent expenses of the department of state, – , in the papers of thomas jefferson, supra note , at , , – , , (listing expenses for various blank commissions bought in bulk). \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : to function. adams had appointed marbury, whether or not the latter had a commission to prove it. oddly enough, marbury’s commission would not have helped him assume office. recall that in , jefferson never claimed that the appoint- ments were not made. rather, he said that he would treat them as nullities— as if they were never made—because they were “indecent,” having been made after the defeat of john adams. as noted earlier, his actions are best understood as an implicit removal of those justices of the peace. the most the delivery of marbury’s commission might have accomplished is that jeffer- son might have recess-appointed marbury, as he did for other midnight appointees who received their commissions. of course, by the time they filed suit, neither marbury nor his fellow plaintiffs had any thought of assuming office. they had waited a year to press their claim and apparently had never tried to assume office, the definition of sleeping on their rights. moreover, their attorney suggested that his clients were uninterested in office. they were fighting for the “principle,” said charles lee. knowing this made it easier for marshall to declare that jef- ferson had violated the constitution and a statute, for the court was all but assured that the plaintiffs would do nothing with the court’s opinion other than relish its expected criticisms of jefferson and madison. though the court concluded that the petitioners had a right to their commissions, its ruling had no effect on jefferson. he ignored the supreme court’s dicta on when an appointment vests in much the same way he had ignored the appointments of john adams. both were treated as if they were nullities. conclusion john marshall’s opinion in marbury canvassed several (though not all) possible appointment methods, each of which was, and is, plausible. their plausibility should have raised the possibility that each was a suitable means of vesting offices and that there was no constitutionally prescribed means of appointing. instead, marshall struggled to find a single right answer that the constitution never supplies. the discretionary theory makes sense of previous practice and mar- shall’s failure to disprove any of the theories he mooted. the constitution provides that the president may appoint to office after certain conditions are satisfied, such as the senate’s advice and consent. but it does not specify when or how the appointment must be made. when the constitution grants a power but does not specify the means of its exercise, the grantee may decide the means of its exercise. the best reading of the constitution is that because it never specifies when or how an office vests, it conveys discretion to the president to determine those modalities. marbury v. madison, u.s. ( cranch) , – ( ). id. \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : ] t h e a p p o i n t m e n t a n d r e m o v a l o f w i l l i a m m a r b u r y appendix a john adams, president of the united states of america to all who shall see these presents—greeting: know ye, that reposing especial trust and confidence in the integrity, ability, diligence, and discretion of george gilpin, esquire, i have nominated and by and with the advice and consent of the senate do appoint him a justice of the peace for the county of alexandria, in the district of columbia, and do authorize and empower him to execute and fulfil the duties of that office according to law; and to have and to hold the said office with all the powers, privileges, and emoluments to the same of right appertaining unto him the said george gilpin for the term of five years from the day of the date hereof. in testimony whereof i have caused these letters to be patent and the seal of the united states to be hereunto affixed. given under my hand at the city of washington the third day of march in the year of our lord one thousand eight hundred and one, and of the independence of the united states of america the twenty fifth. john adams (signature) by the president john marshall (signature) acting as secretary of state \\jciprod \productn\n\ndl\ - \ndl .txt unknown seq: -nov- : n o t r e d a m e l a w r e v i e w [vol. : researchers knock down gene to stop hiv in its tracks researchers knock down gene to stop hiv in its tracks last month, san francisco officials granted a city proclamation to gero hütter for his discovery that a bone marrow transplant could, it seems, cure a person of hiv. the german hematologist’s findings raised hopes for a new therapeutic treatment, but the shortage of tissue-matched donors has prompted some researchers to apply the lessons learned to new techniques. the hiv-resistant bone marrow donor in hütter’s study carried a rare mutation in the gene encoding c-c chemokine receptor type , or ccr , a surface protein essential for helping hiv attach and infect healthy cells (n. engl. j. med. , – , ). the absence of this molecular portal makes infection nearly impossible. however, individuals with the ccr mutation are rare, and their bone marrow is not always a good match for all recipients. to emulate the protection of this mutation, several research teams are devising ways to downregulate the expression of ccr so that hiv does not recognize and invade sensitive cells in susceptible individuals. one line of attack involves rna interference. last month, for example, irvin chen and his colleagues at the university of california–los angeles school of medicine reported that short hairpin rna could successfully knock down ccr expression in human induced pluripotent stem cells (hum. gene ther. doi: . /hum. . , ). chen, backed by a $ million grant from the california institute for regenerative medicine (cirm), has now partnered with the tuscon, arizona–based biotech startup calimmune to develop therapies based on the approach. another strategy takes advantage of a newly developed technology based on zinc finger nucleases. with this approach, pioneered by sangamo biosciences of richmond, california, engineered enzymes make precise cuts in the genome to disrupt gene function. in , carl june’s team at the university of pennsylvania in philadelphia used zinc finger nucleases to disrupt ccr expression in human t cells, which they injected into hiv-infected mice. the gene therapy lowered viral loads and increased t cell counts in the mice (nat. biotech. , – , ). sangamo, in collaboration with june, has since started extracting mature t cells from hiv-positive individuals, knocking down expression of the ccr gene with zinc fingers, and then re-infusing the cells back into the blood. preliminary results from their first patient indicate that the modified cells are tolerated and persist at stable levels. mighty marrow the t cell approach, however, offers only a treatment—not a cure. so other researchers are focusing instead on altering bone marrow stem cells to provide an everlasting resistance to hiv. last year, cirm funded a team led by john zaia at the city of hope in duarte, california, in collaboration with sangamo, to start pursuing preclinical research applying the same gene therapy tactic in bone marrow. jerome zack of the university of california- los angeles aids institute notes that bone marrow stem cell therapy has the advantage of potentially lasting a lifetime, unlike gene therapy aimed at t cells, which must be repeated over and over again after the mature immune cells die out. what’s more, says zack, who is not involved in these studies, bone marrow transplants should help achieve higher cell counts. “we do not lack ways to attack hiv,” says david strayer, a virologist at thomas jefferson university in philadelphia. “we lack ways to deliver genes adequately.” a potential obstacle to ccr -based gene therapy is that the protein is not the only receptor recognized by the virus—some viral strains bind the cxcr chemokine receptor instead. so june and his colleagues are also developing zinc finger nucleases that target cxcr . however, some scientists have increased concerns about this approach’s safety, because the receptor may have an important role in healthy cells to attract white blood cells to sites of inflammation or injury. “the problem is that [cxcr ] may be more important to the cell for its normal functions than ccr ,” says ramesh akkina, who studies hiv gene therapy at colorado state university in fort collins. what’s more, even strains that normally rely on ccr can evolve to use cxcr instead. instead of focusing solely on these receptors, zaia also recently completed a phase trial of an hiv gene therapy technique involving three genes—two that interfere with viral replication and one that blocks ccr . reporting last month, zaia’s team showed that patients with aids-related lymphoma expressed the modified genes in their blood and showed no signs of short-term toxicity (sci. trans. med. , ra ). gene therapy against hiv “is now within the realm of feasibility,” says zaia. “now we can design larger studies and figure out ways to improve it.” janelle weaver, san francisco n e w s nature medicine volume | number | july canadian beacon each year, around a million americans purchase cheap medicines from online canadian pharmacies to help make ends meet. according to the canadian international pharmacy association (cipa), which surveyed its member pharmacies for the best sellers to us consumers in , most people who turn to internet drugstores north of the border are buying everyday prescriptions to treat common chronic conditions, such as heart disease, diabetes and arthritis. “this is the mainstay of our business,” says tim smith, cipa’s general manager. “the bulk of our patients are people who are living on fixed income; they’re concerned about the high cost of drugs, and they have concerns about their ongoing medical conditions.” here, in no particular order, are the top selling drugs: plavix (anticoagulant) advair (treats asthma) flomax (muscle relaxant) asacol (anti-inflammatory, irritable bowel disease) nexium (antacid) synthroid (thyroid problems) celebrex (anti-inflammatory, arthritis) dilantin (anticonvulsant) zetia, lipitor, crestor (cholesterol lowering) premarin (female hormone replacement therapy) actos, januvia, prandin (control blood sugar) © n a tu re a m e ri c a , i n c . a ll r ig h ts r e s e rv e d . reprogramming of mitochondrial ca + handling in micu -deficient hela cells wednesday, february , a core metadata, citation and similar papers at core.ac.uk provided by elsevier - publisher connector mitochondria in cell life and death -pos board b a step forwardin understanding the mechanismof vdac voltage-gating oscar teijido hermida , shay rappaport , rachna ujwal , jeff abramson , vicente m. aguilella , sergey m. bezrukov , tatiana k. rostovtseva . nichd, national institutes of health (nih), bethesda, md, usa, david geffen school of medicine, ucla, los angeles, ca, usa, universitat jaume i, castello de la plana, spain. the voltage-dependent anion channel (vdac) governs the exchange of ions and metabolites between the mitochondria and the rest of the cell. in its open state vdac exhibits high conductance and selectivity for anions that facilitates the passage of adp, atp, and other metabolites. at increased voltages (> mv) vdac switches to lower conducting states, termed as ‘‘closed’’ states. closed states are cation-selective and impermeable for atp. the voltage-induced transition from the open to closed states is referred to as voltage-gating. although it is well established that vdac voltage-gating in- volves large structural rearrangements, the precise molecular mechanism of this process is still under debate. we investigated vdac voltage-gating by sys- tematically titrating vdac charge residues and by using thermodynamic and kinetic approaches to study opening and closing of the channel. all the models proposed so far agree that n-terminal region plays a key role in vdac voltage- gating. according to the original idea, the n-terminal region is a part of a mo- bile voltage sensor domain, which slides in and out of the channel lumen in re- sponse to the applied voltage. the alternative models consider independent movement of the n-terminal region upon gating. in order to test the role of vdac n-terminal region in voltage-gating, we engineered a double cys mu- tant of murine vdac that cross-links the a-helix to the b-strand of the pore wall. the cross-linked vdac reconstituted into planar lipid membranes exhibited typical voltage gating, which suggests that the n-terminal a-helix is located inside the pore of vdac in the open state and remains associated with the pore wall during voltage gating. our findings support a model where b-bar- rel is not rigid but undergoes a conformational change that leads to a partial constriction upon transition to the closed states. -pos board b novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding kely l. sheldon , coert j. zuurbier , sergey m. bezrukov , tatiana k. rostovtseva . the natl. institutes of health, bethesda, md, usa, university of amsterdam, amsterdam, netherlands. the voltage dependent anion channel (vdac) is involved in regulation of me- tabolite flux across the mitochondrial outer membrane (mom). hexokinse ii (hk ) is known to bind the mom where it phosphorylates glucose into glucose- -phosphate (g p). high expression of hxk is a common phenotype of many cancers, where its concentration can be times of that in noncan- cerous cells, and is implicated in the warburg effect. it is believed that vdac serves as a hxk binding site in the mom. the amino acid n-ter- minal sequence of hxk is responsible for mitochondrial binding and, when conjugated to tat (tat-hk ), binds to mitochondria with higher affinity than native hxk , causing hxk detachment. we have previously found that dimeric tubulin reversibly binds and partially blocks vdac inhibiting me- tabolite flux across the mom. now we show that this binding can be attenuated by tat-hxk peptide as well as by full length hxk . we have found that tat-hxk and recombinant full length hxk inhibit tubulin blockage of vdac reconstituted into planar lipid bilayers without altering characteristic channel properties such as single channel conductance and selectivity. binding of hxk to vdac is verified by the generation of high-frequency excess cur- rent noise without channel closure. hxk bound to vdac prevents subse- quent tubulin binding, but only when added before tubulin, and inhibits tubulin-induced vdac blockage in a dose dependent manner. moreover, g p, which is known to cause hxk detachment from the mom, fully re- verses the inhibition of tubulin-vdac binding. this suggests that hxk de- tachment from vdac (and hence the mom) is caused by a hxk conformational change upon g p binding. thus we propose a novel mecha- nism of mitochondrial respiration control in cancer cells through the competi- tion between hxk and tubulin for vdac binding. -pos board b reprogramming of mitochondrial ca d handling in micu -deficient hela cells tünde golenár , györgy csordás , erin l. seifert , cynthia moffat , fabiana perocchi , yasemin sancak , david weaver , vamsi k. mootha , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. recent studies have revealed mcu as the pore forming domain and micu as a critical ca þ-sensitive regulator of the mitochondrial ca þ uniporter. how- ever, the exact role of micu in ca þ transport remains to be addressed. our previous studies showed that prolonged down-regulation of micu in hela cells (shmicu ) promotes mitochondrial ca þ uptake at low [ca þ ], which unexpectedly, fails to effectively increase matrix [ca þ ]. to determine the source of discrepancy between the mitochondrial ca þ uptake and the ma- trix [ca þ] phenotypes, first we simultaneously monitored ruthenium red- sensitive clearance of added ca þ from the cytoplasm and the corresponding matrix [ca þ] response in permeabilized shmicu cells. under conditions of similar cytoplasmic ca þ clearance, shmicu cells showed a smaller matrix [ca þ ] increase than the control, indicating enhanced buffering of ca þ in the matrix. enhanced ca þ binding in the matrix likely reflects alkalinization and enhanced phosphate transport. to test if upregulation of ca þ buffering is di- rectly linked to micu depletion, we also assessed mitochondrial ca þ han- dling after hr silencing of micu (simicu ). in simicu cells both mitochondrial ca þ uptake and the matrix [ca þ ] rise were effectively stimu- lated at low ca þ levels. thus, upregulation of matrix ca þ buffering seems to be a component of an adaptive response to sensitization of mitochondrial ca þ uptake in shmicu . the adaptive response is likely to be important to attenuate some micu -depletion induced cellular impairments that we found to manifest as attenuated mitochondrial atp production and cell proliferation. -pos board b micu -dependent threshold and cooperativity of mitochondrial ca d uptake in the liver györgy csordás , erin l. seifert , tünde golenár , cynthia moffat , sergio de la fuente perez , david weaver , roman bogorad , victor koteliansky , vamsi k. mootha , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, koch institute for integrative cancer research, mit, cambridge, ma, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. recent studies have revealed mcu as the pore forming domain and micu as a critical ca þ-sensitive regulator of the mitochondrial ca þ uniporter. how- ever, the mechanism of the complex ca þ dependence of the uniporter activity remains elusive. our previous studies showed that prolonged down-regulation of micu in hela cells causes lower threshold and decreased cooperativity of mitochondrial ca þ uptake. to study the functional significance of the effects of micu we used hepatocytes harvested from the liver of mice exposed to in vivo silencing ( weeks). silencing of micu or mcu resulted in > % decrease in their respective mrna levels. silencing of micu caused a left- ward-shifted dose response and decreased cooperativity of mitochondrial ca þ uptake in both permeabilized and intact hepatocytes. by contrast, silenc- ing of mcu resulted in slower ca þ uptake in the entire range of ca þ concen- trations without change in threshold. mitochondrial respiration and cellular atp content were unaffected in media containing both glycolytic and mito- chondrial fuels in either micu or mcu-deficient hepatocytes. however, si- lencing of micu caused an augmented loss of atp when the cells were confined to oxidative metabolism and an enhanced sensitivity to mitochondrial ca þ overload and permeabilization. during stimulation with vasopressin, a ca þ mobilizing hormone, both micu and mcu-deficient cells displayed an attenuated mitochondrial matrix [ca þ ] increase and stimulation of respira- tion. collectively, these results show that keeping the gate of mcu closed by micu at low [ca þ] is required to maintain healthy mitochondria, and micu -mediated control of mcu (cooperativity?) is required to support the propagation of short-lasting calcium spikes and oscillations to the mitochondria and the ensuing physiological stimulation of oxidative metabolism. -pos board b targeting mcl- and bak as a therapeutic tool to selectively induce apoptosis in hepaptocellualr carcinoma nima niknejad, soumya sinha roy, eric knudsen, györgy hajnóczky. thomas jefferson university, philadelphia, pa, usa. in this study we seek to identify novel drug targets to induce apoptosis in he- patocellular carcinoma (hcc) cells thus providing opportunities to develop novel treatments to improve the prognosis of liver cancer patients. several ap- optotic pathways are mediated through cleavage of bid (a bh domain-only, pro-apoptotic protein) to produce truncated bid (tbid). tbid induces apoptosis through induction of outer mitochondrial membrane (omm) permeabilization by activation of pro-apoptotic bak that resides in the omm or cytoplasmic bax. due to its localization, bak can mediate the early phase of the response to tbid. we have recently demonstrated that omm targeting of bak and the sensitivity to tbid-induced omm permeabilization is dependent on the expression of https://core.ac.uk/display/ ?utm_source=pdf&utm_medium=banner&utm_campaign=pdf-decoration-v 	a step forward in understanding the mechanism of vdac voltage-gating 	novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding 	reprogramming of mitochondrial ca + handling in micu -deficient hela cells 	micu -dependent threshold and cooperativity of mitochondrial ca + uptake in the liver 	targeting mcl- and bak as a therapeutic tool to selectively induce apoptosis in hepaptocellualr carcinoma volatile general anesthetic interactions with a bacterial sodium channel a sunday, february , stabilized by surrounding hydrophobic residues. we propose that mutations of the asparagines affect activation-inactivation of the channels and drug action through destabilizing the open state. diversity of h-bonding partners explains different effects of mutations of individual asparagines on the channel activa- tion, inactivation, and drug sensitivity. supported by nserc grant to bsz, the ras program ‘‘molecular and cell biology’’ to dbt, and cihr award to ib. -pos board b binding of isoflurane to a bacterial voltage-gated sodium channel: structure and accessibility of distinct interaction sites srinivasa g. raju , vincenzo carnevale , david n. lebard , annika f. barber , michael l. klein . temple university, philadelphia, pa, usa, yeshiva university, new york, ny, usa, thomas jefferson university, philadelphia, pa, usa. the most likely targets for volatile anesthetics (va) are ion channels. the mechanism of volatile anesthetic action is not completely understood. identify- ing the molecular pathway for drug binding is crucial to understand the effect of va on voltage gated sodium channels. we use molecular dynamics simula- tions to identify the binding sites for a hydrophobic general anesthetic isoflur- ane, on voltage gated bacterial sodium channel nachbac. apart from the voltage sensing domain (s -s ), linker and the pore domain (s -s ), bacterial sodium channels also have fenestrations, which provide a hydrophobic tunnel through the lipid-embedded portion of the channel to the central cavity, where the known local anesthetic site is located. unbiased ‘‘flooding’’ simulations were performed on the activated open confirmation of nachbac. we per- formed a cluster analysis to identify all the possible binding sites of isoflurane. the three most important ones among them are: a region near the selectivity filter, called the extracellular site, a region near the s -s linker, called the linker site, and a region within the cavity, called the cavity site. the most important observation is that isoflurane enters the central cavity through the fenestrations. free energy perturbation method was employed to calculate the binding affinities of isoflurane for each of these sites. we also studied the interactions between isoflurane and the amino acids in these three binding sites. -pos board b a key gating charge interaction required for slow inactivation of the navab bacterial sodium channel tamer m. gamal el-din, todd scheuer, william a. catterall. university of washington, seattle, wa, usa. bacterial voltage-gated sodium (nav) channels are considered an ideal model for structure-function studies. the elucidation of the crystal structure of the bacterial channel navab (payandeh et al., nature , - , ) opened an avenue to understand electrical signaling in excitable cells at the structural level. navab expressed in hi insect cells as for structural studies has unusually negative voltage-dependent activation (va ~ mv). navab also has three phases of inactivation, a biphasic early inactivation process (t ~ ms, t ~ . s, at � mv) followed by an unusually strong and use-dependent slow-inactivation process. to search for the molecular basis for negative activation and slow inactivation of navab, we mutated the outer- most gating charge partner in the s segment, asn , to lys. this mutation shifted the activation curve ~ mv toward more positive potentials. surpris- ingly, it also completely abolished use-dependent slow inactivation. we showed previously that the equivalent residue in nachbac (asp ) interacts with the r gating charge in the s segment during activation using the disul- fide locking method (decaen et al, pnas ( ) - ). to test whether this interaction between r and n was critical for slow inactivation, we mutated navab r to cys. the resulting mutant navab_r c also had positively shifted channel activation (þ mv) and no use-dependent slow inactivation. the fact that these reciprocal mutations have the same functional effects suggests that interaction between r in the s segment and n in the s segment is an important link that stabilizes the activated state of the voltage sensor and triggers the slow inactivation process. -pos board b computational study of the prokaryotic sodium channel karen m. callahan, benoit roux. university of chicago, chicago, il, usa. ion-selective voltage-gated ion channels allow ions of a specific element or set of elements to pass, but exclude other ions. recently, the crystal structure of navab was published (payandeh et al ( ) nature , ), giving an un- ambiguous picture of the structure of the sodium channel selectivity filter (sf) of the prokaryote arcobacter butzleri. the filter is much wider than that of the narrow, carbonyl-lined potassium channels, allowing ions to penetrate with minimal dehydration, multiple pathways, and even to pass each other. previous computational studies have attempted to explain sodium selectivity, and claimed consensus (corry and thomas ( ) jacs , , furini and domene ( ) plos , e ). experimental ion selectivity determina- tion from pore-only constructs of a sodium channel with the same sf sequence shows stronger ion selectivity from reversal potential than from the ratio of the fluxes of sodium and potassium (shaya et al ( ) pnas , ), but selectivity, na þ/kþ, was still less than five. simulations based upon the closed-pore crystal structure could not determine selectivity directly from con- duction. to investigate this issue, we first calculated multi-ion potentials of mean force in the selectivity filter of pore-domain-only navab with an ex- tended equilibration period, and a replica-exchange molecular dynamics scheme, which allows for improved sampling. we then explored the non- equilibrium conduction of sodium and potassium in the presence of an applied electric field through a model navab pore truncated to mimic the conformation of the open pore. we also present multi-ion pmf calculations to illustrate similarities and differences between this model and the intact pore. when taken together, these two methods provide complementary views of ion selectivity and conduction based upon the conformation of the navab crystal structure of payandeh et al ( ). -pos board b volatile general anesthetic interactions with a bacterial sodium channel annika f. barber , srinivas g. raju , david lebard , vincenzo carnevale , michael l. klein , manuel covarrubias . thomas jefferson university, philadelphia, pa, usa, temple university, philadelphia, pa, usa. general anesthesia results from complex interactions involving ion channels in the brain. voltage-gated ion channels are modulated by halogenated inhaled general anesthetics, however the drug-channel interactions are generally believed to be non-specific making it difficult to investigate the molecular mechanisms of anesthetic action. we find, however, that the bacterial sodium channel nachbac exhibits differential regulation by different general anes- thetics, suggesting that there may be specific interactions. molecular dynamics (md) simulations have identified several possible binding sites for isoflurane in the nachbac channel structure. here, we have characterized the affinity, occu- pancy and hydrogen bonding for these sites and identified key interactions. in addition, experimental evidence suggests that both isoflurane and sevoflurane have dual actions on nachbac, possibly involving action at two different sites. consistent with pore block, sevoflurane accelerates the decay of the current ( % faster at . mm sevoflurane) but, at the same time, increases the peak current ( % increase with . mm sevoflurane), which argues against the blocking mechanism. we hypothesize that an additional mechanism involving a distinct site is necessary to explain the latter effect. we are currently employ- ing md simulation and structural modeling combined with mutagenesis and electrophysiology to test this two-site hypothesis and investigate the molecular mechanisms of these opposing effects. supported by ninds f ns (afb) and nigms p gm (mlk). -pos board b polymodal, high affinity actions of m-conotoxins on a bacterial voltage- gated sodium channel rocio k. finol-urdaneta , robert glavica , jeff r. mcarthur , robert j. french . university of calgary, calgary, ab, canada, rmit, melbourne, australia. m-conotoxins (mctxs) are potent blockers of eukaryotic sodium channels, and individual members of the mctx family are highly specific for particular nav isoforms. we have begun to explore mctx interactions with nachbac, a pro- karyotic nav channel closely related to navab, whose crystal structure was re- cently determined (payandeh et al, , nature : ). our data reveal actions on both ion conduction and gating, consistent with polymodal actions on the pore domain. under voltage clamp, whole-cell currents from nachbac expressed in tsa- cells were reduced, up to nearly complete block, by concentrations in the pm to mm range, for wildtype toxins and derivatives of mctx piiia and kiiia. for wildtype piiia, dose-response data ( . - , nm) yielded the following: ic = . nm; maximal fraction of current blocked = . ; hill coefficient = . . chen & chung ( , biophys. j. : ) predicted an ic of . nm for piiia when the navab channel is occupied by sodium ions. even at very low [piiia] ( pm), the unblocked currents showed increasing rates of inactivation as the peptides were washed in, suggesting a gating mod- ulation, that was not tightly associated with pore block. for mctx piiia ( . nm), or kiiia ( nm), inactivation accelerated by ~ -fold. substitution of key basic residues (piiia-r a and kiiia-k a) reduced blocking potency and decreased the speeding of inactivation to less than -fold. given the remarkably high selectivity and affinity that mctxs show for certain eukaryotic nav channels with highly asymmetric pores, it may seem surprising that they bind to symmetric bacterial nav channels with such high affinity. 	binding of isoflurane to a bacterial voltage-gated sodium channel: structure and accessibility of distinct interaction sites 	a key gating charge interaction required for slow inactivation of the navab bacterial sodium channel 	computational study of the prokaryotic sodium channel 	volatile general anesthetic interactions with a bacterial sodium channel 	polymodal, high affinity actions of μ-conotoxins on a bacterial voltage-gated sodium channel institute news acknowledgment. we appreciate the technical assistance of mark barnes, guillermo ramirez, and deborah steely. references . badaruddin, m , and d.w. meyer. . green-manure legume effects on soil nitrogen, grain yield and nitrogen nutri- tion of wheat. crop sci. : - . . crozier, c.r. . tracing nitrogen movement in north carolina pied- mont corn production systems using n pool size analysis and n tracing. ph.d. dissertation. dept. of soil science, north carolina state univ., raleigh. . doyle, a.d., k.j. moore, and d.f. her- ridge. . the narrow leafed lupine (lupinus angustifolius) as a nitrogen fix- ing rotation crop for cereals production, iii. residual effects of lupines on sub- sequent cereal crops. australian j. agric. res. : - . . harris, g.h., and o.b. hesterman. . quantifying the nitrogen contri- institute news henry a wallace honored with festivities at birthplace henry a. wallace was recognized last october in iowa with a dinner in honor of the extended family of henry a. and ilo browne wallace, the dedication of his birth- place, and an all-day country life folk festi- val. the dinner program, which was hosted by pioneer hi-bred international and iowa state university, gave tribute to the "wal- lace family legacy," which continues today with his daughter, wallace institute honor- ary president jean wallace douglas, and his sons, robert b. wallace, and h.b. wallace. the tribute particularly praised henry a. wallace, who represented "'good farm- ing, clear thinking, and right living,' and planted the seeds that grew such iowa state programs as agronomy and applied statistics into international powers." wallace's birthplace in greenfield, iowa, was dedicated as the henry a. wallace country life center, and celebrated with a country life festival which featured theater, puppetry, music, poetry, and the works of iowa artists. bution from alfalfa to soil and two suc- ceeding crops using nitrogen- . agron- omy j. : - . . king, l.d., and m. buchanan. . reduced chemical input cropping sys- tems in the southeastern united states. i. effect of rotations, green manure crops and nitrogen fertilizer on crop yields. amer. j. alternative agric. : - . . lachat instruments. a. quikchem method no. - - - -a. nitrate + nitrite. lachat instruments, milwaukee, wisconsin. . lachat instruments. b. quikchem method no. - - - -b. ammonia in soils. lachat instruments, milwau- kee, wisconsin. . ladd, j.n., and m. amato. . the fate of nitrogen from legume and fertil- izer sources in soils successively cropped with wheat under field conditions. soil biology and biochemistry : - . . ladd, j.n., j.m. oades, and m. amato. . distribution and recovery of ni- trogen from legume residues decompos- the birthplace dedication address was given by former iowa senator john c. cul- ver who said that wallace "would have en- joyed this scene. much of what he held dear is represented here today. the joy and satis- faction of rural life. the honor and duty of family. the importance of cooperative ef- fort, the beauty of nature, the value of con- servation. these were essential elements of henry wallace, the private man and the public figure....we know he believed the land and the people who tend it are the foundation upon which all civilization rests. like thomas jefferson, he believed the farmer was performing god's work." culver described wallace as a man who "lived in cities large and small; travelled the world and knew its leaders; edited an influ- ential farm journal and a famous magazine; blazed new trails in economics, statistics, and plant genetics; founded a great business, served in the cabinet, became vice presi- dent of the united states and ran for the presidency—but his guiding principle was grounded here, in the soil of adair county." wallace's birthplace, according to culver, is "an unusually fitting memorial to his life ing in soils sown to wheat in the field. soil biology and biochemistry : - . . perkin-elmer. . instruction manual - . norwal, connecticut. . reeves, t. g., a. ellington, and h.d. brooke. . effect of lupine-wheat rotations on soil fertility, crop disease, and crop yields. australian j. experi- mental animal husbandry : - . . sas institute. . sas user's guide: statistics. cary, north carolina. . strong, wm, j. harbison, r.g.h. niel- sen, b.d. hall, and e.k. best. . ni- trogen availability on a darling downs soil following cereal, oilseed and grain legume crops. . effects of residual soil nitrogen and fertilizer nitrogen on sub- sequent wheat crops. australian j. ex- perimental agric. : - . . zentner, r.p, e.d. spratt, h. reisdorf, and c.a. campbell. . effect of crop rotations and n & p fertilizer on yields of spring wheat grown on a black cher- nozemic clay. canadian j. plant sci. : - . and work. here on this farm, and in this modest farmhouse, we can see expressed the values that informed his life: the great drama of sowing and reaping; the satisfaction of hard work; our responsibility to the land and to our fellow man; the dignity of common people, the beauty of nature, the glory of god. 'and, of course, family. the great impor- tance of family to the wallaces, and the peerless contribution the wallace family made to american life and agriculture are symbolized by this site." wallace's heart and soul never left the land of his birth, culver said. "his was a lifetime of unprecedented service to the cause of agricul- ture and scientific work that revolutionized world food production to the benefit of all mankind. the efforts made to preserve land were among his proudest accomplishments." culver ended his address by quoting wallace himself, who said, "the improved quality and increased abundance of life is a progressive matter and has to do not only with human life but with all plants and animals as well...the highest joy of life is complete dedication to something outside yourself." continued on page volume , number , https://doi.org/ . /s downloaded from https://www.cambridge.org/core. carnegie mellon university, on apr at : : , subject to the cambridge core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/ . /s https://www.cambridge.org/core https://www.cambridge.org/core/terms a step forward in understanding the mechanism of vdac voltage-gating wednesday, february , a mitochondria in cell life and death -pos board b a step forwardin understanding the mechanismof vdac voltage-gating oscar teijido hermida , shay rappaport , rachna ujwal , jeff abramson , vicente m. aguilella , sergey m. bezrukov , tatiana k. rostovtseva . nichd, national institutes of health (nih), bethesda, md, usa, david geffen school of medicine, ucla, los angeles, ca, usa, universitat jaume i, castello de la plana, spain. the voltage-dependent anion channel (vdac) governs the exchange of ions and metabolites between the mitochondria and the rest of the cell. in its open state vdac exhibits high conductance and selectivity for anions that facilitates the passage of adp, atp, and other metabolites. at increased voltages (> mv) vdac switches to lower conducting states, termed as ‘‘closed’’ states. closed states are cation-selective and impermeable for atp. the voltage-induced transition from the open to closed states is referred to as voltage-gating. although it is well established that vdac voltage-gating in- volves large structural rearrangements, the precise molecular mechanism of this process is still under debate. we investigated vdac voltage-gating by sys- tematically titrating vdac charge residues and by using thermodynamic and kinetic approaches to study opening and closing of the channel. all the models proposed so far agree that n-terminal region plays a key role in vdac voltage- gating. according to the original idea, the n-terminal region is a part of a mo- bile voltage sensor domain, which slides in and out of the channel lumen in re- sponse to the applied voltage. the alternative models consider independent movement of the n-terminal region upon gating. in order to test the role of vdac n-terminal region in voltage-gating, we engineered a double cys mu- tant of murine vdac that cross-links the a-helix to the b-strand of the pore wall. the cross-linked vdac reconstituted into planar lipid membranes exhibited typical voltage gating, which suggests that the n-terminal a-helix is located inside the pore of vdac in the open state and remains associated with the pore wall during voltage gating. our findings support a model where b-bar- rel is not rigid but undergoes a conformational change that leads to a partial constriction upon transition to the closed states. -pos board b novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding kely l. sheldon , coert j. zuurbier , sergey m. bezrukov , tatiana k. rostovtseva . the natl. institutes of health, bethesda, md, usa, university of amsterdam, amsterdam, netherlands. the voltage dependent anion channel (vdac) is involved in regulation of me- tabolite flux across the mitochondrial outer membrane (mom). hexokinse ii (hk ) is known to bind the mom where it phosphorylates glucose into glucose- -phosphate (g p). high expression of hxk is a common phenotype of many cancers, where its concentration can be times of that in noncan- cerous cells, and is implicated in the warburg effect. it is believed that vdac serves as a hxk binding site in the mom. the amino acid n-ter- minal sequence of hxk is responsible for mitochondrial binding and, when conjugated to tat (tat-hk ), binds to mitochondria with higher affinity than native hxk , causing hxk detachment. we have previously found that dimeric tubulin reversibly binds and partially blocks vdac inhibiting me- tabolite flux across the mom. now we show that this binding can be attenuated by tat-hxk peptide as well as by full length hxk . we have found that tat-hxk and recombinant full length hxk inhibit tubulin blockage of vdac reconstituted into planar lipid bilayers without altering characteristic channel properties such as single channel conductance and selectivity. binding of hxk to vdac is verified by the generation of high-frequency excess cur- rent noise without channel closure. hxk bound to vdac prevents subse- quent tubulin binding, but only when added before tubulin, and inhibits tubulin-induced vdac blockage in a dose dependent manner. moreover, g p, which is known to cause hxk detachment from the mom, fully re- verses the inhibition of tubulin-vdac binding. this suggests that hxk de- tachment from vdac (and hence the mom) is caused by a hxk conformational change upon g p binding. thus we propose a novel mecha- nism of mitochondrial respiration control in cancer cells through the competi- tion between hxk and tubulin for vdac binding. -pos board b reprogramming of mitochondrial ca d handling in micu -deficient hela cells tünde golenár , györgy csordás , erin l. seifert , cynthia moffat , fabiana perocchi , yasemin sancak , david weaver , vamsi k. mootha , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. recent studies have revealed mcu as the pore forming domain and micu as a critical ca þ-sensitive regulator of the mitochondrial ca þ uniporter. how- ever, the exact role of micu in ca þ transport remains to be addressed. our previous studies showed that prolonged down-regulation of micu in hela cells (shmicu ) promotes mitochondrial ca þ uptake at low [ca þ ], which unexpectedly, fails to effectively increase matrix [ca þ ]. to determine the source of discrepancy between the mitochondrial ca þ uptake and the ma- trix [ca þ] phenotypes, first we simultaneously monitored ruthenium red- sensitive clearance of added ca þ from the cytoplasm and the corresponding matrix [ca þ] response in permeabilized shmicu cells. under conditions of similar cytoplasmic ca þ clearance, shmicu cells showed a smaller matrix [ca þ ] increase than the control, indicating enhanced buffering of ca þ in the matrix. enhanced ca þ binding in the matrix likely reflects alkalinization and enhanced phosphate transport. to test if upregulation of ca þ buffering is di- rectly linked to micu depletion, we also assessed mitochondrial ca þ han- dling after hr silencing of micu (simicu ). in simicu cells both mitochondrial ca þ uptake and the matrix [ca þ ] rise were effectively stimu- lated at low ca þ levels. thus, upregulation of matrix ca þ buffering seems to be a component of an adaptive response to sensitization of mitochondrial ca þ uptake in shmicu . the adaptive response is likely to be important to attenuate some micu -depletion induced cellular impairments that we found to manifest as attenuated mitochondrial atp production and cell proliferation. -pos board b micu -dependent threshold and cooperativity of mitochondrial ca d uptake in the liver györgy csordás , erin l. seifert , tünde golenár , cynthia moffat , sergio de la fuente perez , david weaver , roman bogorad , victor koteliansky , vamsi k. mootha , györgy hajnóczky . thomas jefferson university, philadelphia, pa, usa, koch institute for integrative cancer research, mit, cambridge, ma, usa, harvard medical school and massachusetts general hospital, boston, ma, usa. recent studies have revealed mcu as the pore forming domain and micu as a critical ca þ-sensitive regulator of the mitochondrial ca þ uniporter. how- ever, the mechanism of the complex ca þ dependence of the uniporter activity remains elusive. our previous studies showed that prolonged down-regulation of micu in hela cells causes lower threshold and decreased cooperativity of mitochondrial ca þ uptake. to study the functional significance of the effects of micu we used hepatocytes harvested from the liver of mice exposed to in vivo silencing ( weeks). silencing of micu or mcu resulted in > % decrease in their respective mrna levels. silencing of micu caused a left- ward-shifted dose response and decreased cooperativity of mitochondrial ca þ uptake in both permeabilized and intact hepatocytes. by contrast, silenc- ing of mcu resulted in slower ca þ uptake in the entire range of ca þ concen- trations without change in threshold. mitochondrial respiration and cellular atp content were unaffected in media containing both glycolytic and mito- chondrial fuels in either micu or mcu-deficient hepatocytes. however, si- lencing of micu caused an augmented loss of atp when the cells were confined to oxidative metabolism and an enhanced sensitivity to mitochondrial ca þ overload and permeabilization. during stimulation with vasopressin, a ca þ mobilizing hormone, both micu and mcu-deficient cells displayed an attenuated mitochondrial matrix [ca þ ] increase and stimulation of respira- tion. collectively, these results show that keeping the gate of mcu closed by micu at low [ca þ] is required to maintain healthy mitochondria, and micu -mediated control of mcu (cooperativity?) is required to support the propagation of short-lasting calcium spikes and oscillations to the mitochondria and the ensuing physiological stimulation of oxidative metabolism. -pos board b targeting mcl- and bak as a therapeutic tool to selectively induce apoptosis in hepaptocellualr carcinoma nima niknejad, soumya sinha roy, eric knudsen, györgy hajnóczky. thomas jefferson university, philadelphia, pa, usa. in this study we seek to identify novel drug targets to induce apoptosis in he- patocellular carcinoma (hcc) cells thus providing opportunities to develop novel treatments to improve the prognosis of liver cancer patients. several ap- optotic pathways are mediated through cleavage of bid (a bh domain-only, pro-apoptotic protein) to produce truncated bid (tbid). tbid induces apoptosis through induction of outer mitochondrial membrane (omm) permeabilization by activation of pro-apoptotic bak that resides in the omm or cytoplasmic bax. due to its localization, bak can mediate the early phase of the response to tbid. we have recently demonstrated that omm targeting of bak and the sensitivity to tbid-induced omm permeabilization is dependent on the expression of 	a step forward in understanding the mechanism of vdac voltage-gating 	novel mechanism of mitochondrial respiration control through competition between hexokinase- and tubulin for vdac binding 	reprogramming of mitochondrial ca + handling in micu -deficient hela cells 	micu -dependent threshold and cooperativity of mitochondrial ca + uptake in the liver 	targeting mcl- and bak as a therapeutic tool to selectively induce apoptosis in hepaptocellualr carcinoma rop volume issue back matter t h e r e v i e w o f p o l i t i c s volume xi editor: waldemar gurian managing editors: thomas t. mcavoy, frank o'malley editorial consultants: m. a. fitzsimons, f. a. hermens advisory editors francis j. boland, charles c. miltner, willis d. nutting, yves r. simon, leo r. ward t h e review c politics, without neglecting the analysis of institutions and techniques, is primarily interested in the philosophical and historical approach to political realities issued each january, april, july, and october. opinions expressed in the articles printed in t h e review of politics are those of the authors alone and are not necessarily opinions held by the editors. the subscription price of t h e review of politics is $ . per year in the u. s. and canada, foreign, $ . . single copies, $ . . entered as second-class matter. april , , at the postoffice at notre dame, indiana, under the act of march , . published by the university of notre dame notre dame, indiana h tt p s: // w w w .c am b ri d g e. o rg /c o re /t er m s. h tt p s: // d o i.o rg / . /s d o w n lo ad ed f ro m h tt p s: // w w w .c am b ri d g e. o rg /c o re . c ar n eg ie m el lo n u n iv er si ty , o n a p r a t : : , s u b je ct t o t h e c am b ri d g e c o re t er m s o f u se , a va ila b le a t https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core contents index of articles page abell, aaron i., origins of catholic social reform in the united states: ideological aspects barghoorn, frederick c , russian radicals and the west european revolutions of black, cyril e., constitutional trends in eastern europe, - bromage, mary o , prisoner into politician heady, ferrel, the reports of the hoover commission kcrtesz, stephen church and state in hungary kertesz, stephen, the plight of satellite diplomacy kheraskov, ivan, a leninist before lenin: ernest coeurderoy ( - ) knorr, klaus, problems of a western european union kohn, hans, father jahn's nationalism leonhardt, hans, he nuremberg trial: a legal analysis maritain, jacques, on the aleantng of contemporary atheism mcclosky, herbeit, state sovereignty: alexander h. stephen's defense munzer, egbert, solovyev and the meaning of history murray, john c , the political thought of joseph de maistre nef, john u., the economic road to war neumann, robert g., u. s, foreign policy and the soviet satellites pieper, josef, on the christian idea of man rossiter, clinton l., constitutional dictatorship in the atomic age rossiter, clinton l., the political philosophy of f. d. roosevelt voegelin, eric, the philosophy of existence: plato's gorgias wall, bernard, 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(hermens) h tt p s: // w w w .c am b ri d g e. o rg /c o re /t er m s. h tt p s: // d o i.o rg / . /s d o w n lo ad ed f ro m h tt p s: // w w w .c am b ri d g e. o rg /c o re . c ar n eg ie m el lo n u n iv er si ty , o n a p r a t : : , s u b je ct t o t h e c am b ri d g e c o re t er m s o f u se , a va ila b le a t https://www.cambridge.org/core/terms https://doi.org/ . /s https://www.cambridge.org/core crpc- - -ver -chai_ p .. case report open access taking the lead: a case report of a leiomyoma causing duodeno-duodenal intussusception and review of literature louis f. chai, philip m. batista, and harish lavu ,* abstract background: duodenal masses are rare entities and symptomatic presentation generally is due to abdominal pain or the presence of gastrointestinal bleeding. a number of published case reports in the literature have de- tailed various neoplasms that have caused an intussusception isolated to the duodenum. this is a particularly unusual phenomenon due to the location and fixation of this portion of the proximal small bowel to the retro- peritoneum. we present here a case of duodeno-duodenal intussusception secondary to a leiomyoma. case: a -year-old caucasian male presented with intermittent bloody stools and syncope over a -month pe- riod secondary to a duodenal leiomyoma causing intussusception, which was treated through a pancreaticoduo- denectomy. conclusion: intussusception of the duodenum is an uncommon entity and the diagnosis of a leiomyoma should be considered in the setting of a potential mass in the small intestine. key words: leiomyoma; duodeno-duodenal intussusception; gastrointestinal bleed introduction etiologies for gastrointestinal (gi) bleeding commonly include bleeding ulcers, arterial venous malformations, diverticular disease, hemorrhoids, and anal fissures, whereas uncommon causes include meckel’s diverticu- lum and intussusception. typically, conventional diag- nostic modalities such as physical examination, endoscopy, and radiological imaging yield a cause, although occa- sionally surgical intervention is required to obtain a di- agnosis. here, we report the first case of a patient with gi bleeding secondary to duodeno-duodenal intussus- ception caused by a leiomyoma. case a -year-old male presented to the thomas jefferson university hospital in august with a syncopal epi- sode, fatigue, abdominal pain, and dyspnea on exertion. a review of the patient’s records revealed two previous hospitalizations to an outside institution over the prior months for melena and near syncope. a computed tomography (ct) with enterography performed at the outside hospital in november revealed a cm intraluminal mass-like density. an esophagogastroduo- denoscopy (egd) with endoscopic ultrasound was per- formed at that time, which revealed an extrinsic thickened fold of the second portion of the duodenum (d ), con- cerning for a duodenal duplication cyst. fine-needle aspi- ration of the suspected mass revealed normal villous morphology. at the patient’s second presentation to the outside hospital in july , a second egd evalua- tion revealed a bleeding ulcer in the stomach and a repeat ct showed that the duodenal mass had increased to cm. rutgers-robert wood johnson medical school, piscataway, new jersey. department of surgery, jefferson pancreas, biliary, and related cancer center, thomas jefferson university hospital, philadelphia, pennsylvania. *address correspondence to: harish lavu, md, department of surgery, jefferson pancreas, biliary, and related cancer center, thomas jefferson university hospital, walnut street, philadelphia, pa , e-mail: harish.lavu@jefferson.edu ª louis f. chai et al. ; published by mary ann liebert, inc. this open access article is distributed under the terms of the creative commons license (http://creativecommons.org/licenses/by/ . ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. case reports in pancreatic cancer volume . , doi: . /crpc. . case reports in pancreatic cancer at the time of transfer to our institution, the patient reported a recent episode of melena without gross blood. he was found to have a hemoglobin of . g/dl and received two units of packed red blood cells. a ct scan to evaluate the abdominal mass revealed focal dilation and thickening of the third portion of the duodenum (d ) with intussusception of d into d (fig. ). there was also mild intrahepatic biliary di- latation and common bile duct dilatation to . cm, likely resulting from intussusception of the ampulla of vater and the distal common bile duct. egd was performed again, revealing a submucosal lesion along the lateral aspect of d , causing % narrowing of the lumen and erythematous mucosa overlying the lesion. colonoscopy showed nonbleeding diverticula and a nonbleeding, benign sessile polyp. capsule endoscopy was nonrevealing. due to the concern for a malignant mass involving the ampullary complex, a pylorus-preserving pancrea- ticoduodenectomy was performed. the specimen was removed and gross pathology revealed a · · . -cm duodenal submucosal leiomyoma (fig. ). the mass stained positive for actin and desmin and negative for dog- , s , sd , and alk- (fig. ). negative mar- gins were obtained and none of the harvested lymph nodes were involved with disease. the patient recovered well from surgery, with no further episodes of melena or syncope. discussion intussusception is a condition that is more common in children and rarely seen in the adult population. the condition results from the full-thickness invagination of a proximal portion of the bowel into the distal por- tion. presenting symptoms are classically described with the triad of abdominal pain, a palpable abdominal mass, and bloody stools, but all three are clinically found in less than % of the population with intussus- ception. more commonly, patients present with non- specific symptoms including intermittent abdominal pain, nausea, vomiting, and anemia. given the wide fig. . (a, b) axial and coronal ct scan slices showing invagination of proximal portion of duodenum into distal (white arrows). ct, computed tomography. fig. . gross pathology specimen with dissection of duodenum revealing a submucosal leiomyoma (white arrow) measuring · · . cm. chai, et al.; case reports in pancreatic cancer , . http://online.liebertpub.com/doi/ . /crpc. . range of diseases with this constellation of symptoms, physicians must have a strong clinical suspicion to make the diagnosis. work-up may include hemoglobin levels, fecal occult blood tests, cross-sectional imaging (ct or mri), and endoscopy (egd, colonoscopy, cap- sule endoscopy, or push endoscopy). definitive diagno- sis may require operative intervention with surgical exploration of the abdomen. the most common location for intussusception is the ileocolic junction, followed by ileoileal and colocolic. intussusception of the proximal small bowel, especially with the intussusceptum and intussuscipiens isolated to the duodenum, is a rare condition with only reported cases in the literature occurring in total patients (table ). , , – typically, the anatomic posi- tion of the duodenum in the retroperitoneal space and its fixed attachments in this region serve to prevent it from being susceptible to intussusception. however, this condition can occur due to a lead point such as a mass ( % of adults cases) or secondary to con- genital malrotation of the bowel, where the duodenum is more mobile, allowing the intussuception to occur. the most common etiologies for such lead points in- clude both benign and malignant tumors, lipomas, brunner’s gland hamartomatous polyps, or adeno- mas. although leiomyomas have been known to cause intussusception in other parts of the intestine, our patient represents the first reported case to our knowledge of duodeno-duodenal intussusception sec- ondary to leiomyoma. neoplasms of the small bowel as a whole are exceed- ingly rare, comprising only – % of all gi neoplasms, with only – % of these being malignant. – the more frequently encountered malignant small bowel tumors are adenocarcinomas, lymphomas, and neuro- endocrine tumors. rarely seen are gi stromal tumors, leiomyosarcomas, and leiomyomas. although leiomyo- mas are the most common benign lesions of the small intestine, they are a small proportion of total small in- testine neoplasms. at one institution over a -year span, fewer than nine leiomyomas were diagnosed fig. . h&e stain of pathological specimen. analysis revealed mitotic figures less than per high-powered field. specimen stained positive for actin and desmin, negative for dog- , s , cd , and alk- . h&e, hematoxylin and eosin. table . english literature review highlighted reports of total patients with confirmed duodeno-duodenal intussusception study patient age (years) presenting symptom(s) lead point causing intussusception vinnicombe and grundy abdominal pain, jaundice villous adenoma o’connor et al. abdominal pain, anorexia, vomiting duplication cyst mishra et al. abdominal pain and distention, fever, vomiting none gupta et al. — — adenoma — — adenoma limi et al. abdominal discomfort, melena, diarrhea brunner’s gland adenoma abeysekera et al. abdominal pain, melena brunner’s gland adenoma singla et al. abdominal discomfort, fatigue, generalized weakness brunner’s gland adenoma blanchet et al. abdominal pain, nausea, vomiting lipoma ko et al. abdominal pain, melena duplication cyst watanabe et al. abdominal pain tubulovillous adenoma naik et al. abdominal pain, vomiting tubulovillous adenoma larsen et al. abdominal pain, nausea, vomiting duodenal membrane sinhal et al. abdominal pain and distention, vomiting tubulovillous adenoma shakhnovich et al. vomiting duplication cyst gardner-thorpe et al. abdominal pain, lethargy, pruritus villous adenoma pradhan et al. — — adenocarcinoma — — villous adenoma — — tubulovillous adenoma —, indicates nonreported data. chai, et al.; case reports in pancreatic cancer , . http://online.liebertpub.com/doi/ . /crpc. . per year, whereas a second report examining smooth muscle tumors of the small intestine found that only % were truly leiomyomas. , leiomyomas are found most often in the jejunum followed by the ileum and lastly the duodenum. they are characteristically well-defined solitary masses and may appear gray or white. within the small intestine, they can be found intraluminal, extraluminal, or intra- mural. diagnosis may be difficult despite modern im- aging modalities and endoscopy, as was demonstrated in this patient. he suffered from symptoms for nearly months before the diagnosis was confirmed through surgical exploration. in the setting of intermittent gi bleed and abdominal pain with no easily identifiable source, it is important to consider the diagnosis of small bowel intussusception in an adult due to a neoplasm. conclusion this case report is that of gi bleeding due to a rare duodeno-duodenal intussusception secondary to a small bowel leiomyoma. we emphasize the importance of a keen awareness for this diagnosis and thorough work-up. in this scenario, surgical intervention may prove to be both diagnostic and therapeutic as demon- strated here. acknowledgment no funding was needed for the writing of this case re- port or review of literature. author disclosure statement no competing financial interests exist. references . naik bm, arjun n, kudari a. a case of duodeno-duodenal intussusception. j med dent sci. ; : – . . gupta v, doley rp, bharathy kgs, et al. adult intussusception in northern india. int j surg. ; : – . . chen xd, yu yy, yang l, et al. duodenal intussusception due to a giant neuroendocrine carcinoma in a patient with peutz-jeghers syndrome: case report and systematic review. eur j gastroenterol hepatol. ; : – . . mishra sk, mohapatra kc, panda g, et al. pseudocyst of pancreas sec- ondary to duodeno-duodenal intussusception: rare presentation of rare disease. int j innov res adv stud. ; : – . . gardner-thorpe j, hardwick rh, carroll nr, et al. adult duodenal intus- susception associated with congenital malrotation. world j gastroen- terol. ; : – . . watanabe f, noda h, okamura j, et al. acute pancreatitis secondary to duodenoduodenal intussusception in duodenal adenoma. case rep gastroenterol. ; : – . . vinnicombe s, grundy a. case report: obstructive jaundice secondary to an intussusception duodenal villous adenoma. clin radiol. ; : – . . o’connor pa, mcgrath fp, lane be. duodenal intussusception secondary to internal duodenal duplication. clin radiol. ; : – . . limi l, liew nc, badrul rh, et al. duodenal intussusception of brunner’s gland adenoma mimicking a pancreatic tumor. med j malaysia. ; : – . . abeysekera wym, de silva wdd, pragatheswaran p, et al. brunneroma presenting with radiologic features of duodeno-duodenal intussuscep- tion. sri lanka j surg. ; : – . . singla r, bharti p, jain r, et al. giant brunner gland adenoma manifesting as iron deficiency anaemia and intussusception. natl med j india. ; : – . . blanchett mc, arnal e, paparel p, et al. obstructive duodenal lipoma successfully treated by endoscopic polypectomy. gastrointest endosc. ; : – . . ko sy, ko sh, ha s, et al. a case of a duodenal duplication cyst presenting as melena. world j gastroenterol. ; : – . . larsen po, ellebaek mb, pless t, et al. acute pancreatitis secondary to duodeno-duodenal intussusception caused by a duodenal membrane, in a patient with intestinal malrotation. int j surg case rep. ; : – . . sinhal m, kang m, narayana s, et al. duodenoduodenal intussusception. j gastrointest surg. ; : – . . shakhnovich v, colombo j, desai aa, et al. rare presentation of pancre- atitis secondary to intussusception of duodenal duplication cyst, a pedi- atric case report. j ped surg case reports. ; : – . . pradhan d, kaur n, nagi b. duodenoduodenal intussusception: report of three challenging cases with literature review. j can res ther. ; : . . ko sf, lee ty, ng sh, et al. small bowel intussusception in symptomatic pediatric patients: experiences with surgically proven cases. world j surg. ; : – . . serour f, dona g, birkenfeld s, et al. primary neoplasms of the small bowel. j surg oncol. ; : – . . chaaya a, heller sj. introduction to small bowel tumors. tech gastroint endosc. ; : – . . blanchard dk, budde jm, hatch gf, et al. tumors of the small intestine. world j. surg. ; : – . . xynopoulos d, mihas aa, paraskevas e, et al. small bowel tumors. ann gastroenterol. ; : – . cite this article as: chai lf, batista pm, lavu h ( ) taking the lead: a case report of a leiomyoma causing duodeno-duodenal intussusception and review of literature, case reports in pancreatic cancer : , – , doi: . /crpc. . . abbreviations used ct ¼ computed tomography egd ¼ esophagogastroduodenoscopy gi ¼ gastrointestinal h&e ¼ hematoxylin and eosin mri ¼ magnetic resonance imaging publish in journal of pancreatic cancer - immediate, unrestricted online access - rigorous peer review - compliance with open access mandates - authors retain copyright - highly indexed - targeted email marketing liebertpub.com/crpc chai, et al.; case reports in pancreatic cancer , . http://online.liebertpub.com/doi/ . /crpc. . http://www.liebertpub.com/crpc#utm_campaign=crpc&utm_medium=article&utm_source=advert filling in gaps in the historical record: accuracy, authenticity, and closure in ann rinaldi’s wolf by the ears filling in gaps in the historical record: accuracy, authenticity, and closure in ann rinaldi’s wolf by the ears brian dillon children's literature, volume , , pp. - (article) published by johns hopkins university press doi: for additional information about this article [ access provided at apr : gmt from carnegie mellon university ] https://doi.org/ . /chl. . https://muse.jhu.edu/article/ https://doi.org/ . /chl. . https://muse.jhu.edu/article/ children’s literature , hollins university © . filling in gaps in the historical record: accuracy, authenticity, and closure in ann rinaldi’s wolf by the ears brian dillon in wolf by the ears, ann rinaldi creates a voice for the only daughter (who survived) of thomas jefferson and sally hemings, harriet hemings, an intriguing figure who has no voice in the historical record. rinaldi depicts harriet on the cusp of maturity in her final years at monticello, from december to august . more than half a century after the events covered in this novel, her younger brother madison mentions her in an ohio newspaper article, and various notations about her are marked in jefferson’s farm book. but no journal entries, memoir, or piece of correspondence written by harriet have emerged. faced with an absent voice—as well as any visual representation of harriet—rin- aldi needed to situate a believable character within the context of a monticello community, about which an abundance of evidence exists, and in relation to the third president, about whom competing claims have been fiercely argued. the opening paragraph of rinaldi’s “au- thor’s note” identifies the key source for her publication: fawn brodie’s thomas jefferson: an intimate history, first published in and responded to with dismay by numerous established jefferson scholars. brodie constructed a provocative circumstantial case about the intimate relationship between jefferson and his slave—and deceased wife’s half-sister—sally hemings, as well as their offspring. decades later, in , dna evidence corroborated brodie’s investigative work and ef- fectively silenced historians who had doubted that jefferson could lead such a double life. rinaldi’s gamble in relying upon brodie proved prescient. though our understanding of jefferson’s personal actions has advanced considerably since , wolf by the ears continues to function as a complex, meaningful novel in itself and as a springboard to classroom examinations of the role of slavery. yet, without blaming brodie, there are passages in rinaldi’s novel that prove to be problematic when the historical evidence is exam- ined. with the hindsight of over twenty years since wolf by the ears was published, readers may judge how faithful rinaldi’s novel is to the historic record. carrie hintz and eric tribunella define terms key for such a judgment: brian dillon accuracy depends upon the correspondence between recorded history and fictional representation, whereas authenticity indi- cates how a literary work fills in the gaps of the historical record and whether the imaginative components of the work are plau- sible. while accuracy is a matter of how faithful the work is to what is thought to be true, authenticity is a matter of whether the fictional additions or imaginings are within the realm of likeli- hood or possibility. ( ) this definition sounds circular: the reader affirms that characters and situations are authentic if the reader finds them plausible, and in a work of historical fiction, the reader will find plausible those characters and situations that adhere to the reader’s knowledge of the history of the same or similar people and situations as presented in the fictional work. such circular logic may be unavoidable. catherine butler and hallie o’donovan acknowledge the difficulty in determining whether a fictional work achieves authenticity: historical fiction is haunted by the demand for, and the impos- sibility of, authenticity in its representations of the past. the concept of authenticity covers a lot of semantic territory, en- compassing not only the criterion of factual accuracy—that is, of telling it like it is (or was)—but also the questions of who is doing the telling, and how and why. any modern representation of the experiences of those who lived in the past must necessarily be a ventriloquistic performance, given in terms designed to be understood by a modern audience. ( ) determining authenticity requires a more subjective interpretive re- sponse than the effort to determine accuracy. this essay examines the novel’s authenticity: the difficulty in judging the authenticity of wolf by the ears is compounded by the presentation of historic individuals. harriet, narrating between the ages of eighteen and twenty-one, is circumspect, reflective, intent on processing the abundance of advice thrust on her. for the novel to seem authentic, from the very first scene the reader must accept as plausible that har- riet has been tutored sufficiently to compose such a narrative and that jefferson would encourage such private reflections. the histori- cal record remains silent about such crucial possibilities. butler and o’donovan stress “the questions of who is doing the telling, and how and why.” rinaldi chose to depict jefferson and the monticello com- munity through the eyes of a house slave who enjoys privileges alien filling in gaps in the historical record to the slaves who work in the fields, for example, under the sway of a brutal overseer. harriet admits she has never been away from monti- cello except for brief visits “to a neighboring plantation” ( ). the lengthy entries in her private journal highlight the comparative luxury of a slave who seems unaware that other slaves are victims of rapes and beatings and forcibly separated from their own families, while she is granted many months to contemplate the choice—over which she has much control—to leave her family. rinaldi remains true to the testi- mony provided decades later by madison hemings: “my brothers, sister harriet and myself, were used alike. we were permitted to stay about the ‘great house,’ and only required to do such light work as going on errands. harriet learned to spin and to weave in a little factory on the home plantation. we were free from the dread of having to be slaves all our lives long, and were measurably happy. we were always permit- ted to be with our mother, who was well used” (qtd. in gordon-reed, thomas jefferson and sally hemings ). presumably, rinaldi considered the soft focus on slavery that harriet provides a legitimate trade-off for the insights harriet has access to about jefferson and other historically prominent members of jefferson’s extended white family. ideally, when examined in a classroom setting, rinaldi’s novel would be considered in the context of other documents, including madison’s concise recol- lections in his memoir. evaluating authenticity relies upon gap-filling strategies that a reader must devise. because no written testimony by harriet is extant, because jefferson chose silence rather than any acknowledgement of his hemings children, rinaldi’s reader must explain why his speech and her response to him seem plausible, why her personal and moral con- fusion strikes an authentic note. wolf by the ears achieves a convincing degree of cultural authenticity: harriet’s life at monticello falls within the boundaries of the historical record. furthermore, her internal life, her identity formation, achieves a convincing degree of psychological authenticity. this point is especially crucial as the novel engages with this personal dimension of authenticity: whether harriet can remain authentic to herself if she leaves monticello and passes as white. this essay also examines the accuracy of rinaldi’s novel based upon historical documents available to her, as well as evidence from the past two decades since wolf by the ears was published. four historical inaccuracies are identified that bolster harriet’s view of jefferson as a morally centered man whose current political powerlessness provokes her pity: references to her older brother tom, to jefferson’s mentor brian dillon george wythe, to the composition of the declaration of independence, and to the missouri compromise. it would be unrealistic to expect that most readers, especially ya readers, would be capable of identifying the inaccuracies or why they matter. consequently, the novel needs to be approached with guarded skepticism. a reader informed with more historical evidence than the novel provides may question whether jef- ferson deserves harriet’s pity-provoking depiction of him: this essay provides such evidence and expands the ability of rinaldi’s readers to evaluate jefferson’s conduct and its consequences. it is insufficient, though, to assess accuracy simply by noting paral- lels or deviations from the historical record in the novel. the issue of accuracy must be linked to “who is doing the telling, and how and why.” harriet perceives jefferson with a mixture of awe, the godlike former president whose knowledge of the world exceeds that of anyone she knows; pity, over his inability to change cultural norms regarding the treatment of slaves; and exasperation, in regard to his silence on the issue most crucial to her personally—her own paternity. of these three, the affective response that most risks distorting what is known about jefferson is pity. the closure to the novel confirms a sense of jefferson as pitiful and pushes the injustice of slavery out of sight. this essay will consider an alternative ending that rinaldi chose not to construct, one that challenges the implicit emphasis on pity and sentimentality and that is historically based. rinaldi succeeds in avoiding historical anachronism: she does not impose contemporary cultural norms on a society roughly years in the past. she leaves much interpretive room for the reader to determine whether jefferson deserves to be judged harshly. jefferson effectively succeeded in controlling the narrative of his pri- vate life until the end of the twentieth century. wolf by the ears disrupts the narrative jefferson wanted told. “historical novels,” kim wilson states, “holding the peculiar position of being both fiction and fact simultaneously, are effective vehicles to promote values and attitudes pertinent to the formation and perpetuation of a national identity” ( ). despite the four historical inaccuracies that this essay will ex- amine later, and despite harriet’s relatively privileged slave status, the novel’s authenticity implicitly challenges the white supremacist political power structure of the early nineteenth century. despite harriet’s pity- ing perspective, the novel subverts efforts to engage in hero worship of the complex former president and slave owner. filling in gaps in the historical record rinaldi’s reliance upon a young adult narrator and some initial historical points before discussing these four historical inaccuracies and why they mat- ter, this section examines rinaldi’s choice of harriet rather than sally as narrator and indicates that harriet operates as a pawn or by-product within the larger plot of the jefferson-sally hemings relationship. also, certain episodes in the novel that prove to be partially accurate must be analyzed to provide a context for understanding the four inaccuracies. without using the terminology of this essay—accuracy and authen- ticity—rinaldi’s preliminary note to her novel positions herself on the defensive, offers disclaimers: she did not intend to “put down” jefferson, but to depict him as accurately as she could based upon his own writ- ing (x–xi). yet the novel’s display of jefferson’s passivity and duplicity challenges the heroic-ideal conception of him. rinaldi’s preliminary note to her novel also self-consciously explains why she composed her narrative by relying upon harriet’s point of view. of course, as a twentieth-century white woman she does not claim to “know what it felt like to be a slave,” but she understands the concept of alienation based upon her lack of knowledge of her own mother who died when she was born (xi). the author’s response to the historical fact of harriet’s departure from monticello on her own, leaving her family behind, perhaps forever, is “how terrible!” (x), and her novel then justifies why harriet’s decision to leave monticello does not fit the stereotypical flight from slavery to freedom that would be celebrated. but the preliminary note does not explain why rinaldi chose an unusually privileged slave to tell her story, a choice which may upset readers expecting a narra- tive of the dehumanizing realities of slavery. nor does it reflect on her depiction of sally hemings, whose decision to stay with jefferson and whose motivations for urging harriet to leave monticello perplex har- riet. while some readers may consider this relationship romanticized by rinaldi, historical evidence published after wolf by the ears implicitly supports rinaldi’s view. with all the available written documents by—and about—jefferson and absolutely none by sally hemings, not even one letter from her hand, it was inevitable that following the dna studies new evaluations of jefferson’s character would circulate, while sally hemings would remain a mystery to be speculated about. her son madison in his memoirs explains the situation sally dealt with while in france as the servant to jefferson’s daughter maria: brian dillon [d]uring that time my mother became mr. jefferson’s concubine, and when he was called back home she was enceinte [pregnant] by him. he desired to bring my mother back to virginia with him but she demurred. she was just beginning to understand the french language well, and in france she was free, while if she returned to virginia she would be re-enslaved. so she refused to return with him. to induce her to do so he promised her extraor- dinary privileges, and made a solemn pledge that her children should be freed at the age of twenty-one years. in consequence of his promise, on which she implicitly relied, she returned with him to virginia. (qtd. in gordon-reed, thomas jefferson and sally hemings ) annette gordon-reed, who of all historians has been most successful in reconstructing the lives of sally, her siblings, and her children, evaluates sally’s decision, which she made while in her mid-teens and presumably with the guidance of her older brother james who was living in paris at the same time, in training as a chef. (the father of sally and her five siblings, john wayles, was also the father of jefferson’s wife martha, who died prior to jefferson’s sojourn in paris.) having spent her previous years at monticello, sally would have noted the favoritism accorded to hemings females: she “watched every female go to the fields at harvest time, except her sisters, mother, and whatever white females were at the plantation. she learned from all this that, in jefferson’s eyes, she was a female to be protected from certain things, when most women of her same legal status received no protection at all” (the hemingses of monticello ). gordon-reed also speculates on what james and another older brother robert may have thought of her arrangement with jefferson. as the adult children of the same white father, they may have “simply viewed their sister’s connection to jefferson as a predicat- able [sic] event in life as they knew it. . . . and if they had any degree of trust in his [jefferson’s] word—that he was going to stick by his bargain with their sister—she was already better off than their mother who had not obtained freedom for any of her children” (the hemingses of monticello ). gordon-reed speculates further that the jefferson- hemings relationship was monogamous, lasted nearly four decades, and was mutually satisfying. salamishah tillet notes the uniqueness of this interpretation: “ironically, gordon-reed’s historical romance not only challenges those jefferson scholars who have vigorously denied the possibility that jefferson might have coerced hemings, but it is also a radical departure from canonical black feminist scholarship on filling in gaps in the historical record enslaved women, consent, and rape” ( ). such scholarship “suggests that enslaved african american women could not willingly engage in sexual encounters with white men without coercion” ( ). in one extended discussion of rinaldi’s novel, emily honey acknowl- edges the constraints placed upon a young adult author in treating this historic topic: [b]ecause she was writing for a younger audience, [rinaldi] could not be nearly as explicit about sexual matters, or about the power dynamic that would have been involved in any relationship they might have had, topics that might have been too weighty for adolescent readers. it might have seemed better to create a narrative from harriet’s perspective, one that would still deal with the conflicts of her race, parentage, and position as a slave, but would be removed enough from sally and jefferson to avoid confronting the issues head on. therefore, harriet becomes the narrator and the focus, and her relationship with jefferson of primary importance—once again leaving sally rather in the background, overshadowed by the white man who controlled her world. (honey ) in rinaldi’s novel, sally does tell harriet that she negotiated with jefferson while she was a teen in france: she acquired her children’s freedom before they were born, presumably a pre-intimacy promise extracted from jefferson ( , ). in a passage that dovetails with the romantic speculations gordon-reed promotes, rinaldi’s version of sally even asserts, on the day before harriet is to leave monticello forever, that she loved jefferson: “‘that’s why i came back from paris too. no sense lying. didn’t say it was right. just saying i loved him.’ it was the first time she had ever spoken of herself and the master to me” ( ). this is all harriet learns from her mother about the degree and duration of her mother’s intimacy with jefferson. as honey claims, for harriet—and many ya readers—to be more specific would be too “weighty.” yet harriet inquires in her own way on the topic of intimacy between sally hemings and jefferson: harriet’s dialogues with jefferson frame the novel—the first in december and the last in august when she departs from monticello—and thus have prominence of place. rinaldi lowers jefferson’s pedestal by highlighting his indirect manner when speaking to harriet, which veers into dishonesty by his omissions. in the first dialogue, in which harriet carries in a tray of tea while brian dillon jefferson sits writing his autobiography in his “sanctum sanctorum,” the private rooms where he works and sleeps, previously a forbidden zone to harriet, sally is present when harriet asks: “will you put my mama in” your autobiography ( , )? jefferson deflects her questions; he concentrates instead on praising her accomplishments, gifting her with a leather journal (in which she writes the narrative that is this nov- el), and offering advice about writing. this brief exchange highlights one of harriet’s primary concerns: will her mother acknowledge the relationship directly, and will jefferson acknowledge it even indirectly? what harriet does not learn is that the -year-old jefferson ceased composing his autobiography after “sixty-odd pages”: he only included his experiences up until , when he was about to leave paris. brodie proposes one reason why he abandoned his autobiography at this early point in his complex political and personal life: to shield “the most pressing secret of his life” ( ), the beginning of his relationship with sally hemings. jefferson gently instructs harriet: “write down what you see, what is important to you, whether it be the sound of a bird, the snow on the blue ridge, or the taste of your mama’s salmagundi. . . . write down what you feel, harriet. it eases the heart. you will discover that in your own good time” ( ). he could not anticipate either the depth of insight evident in her narratives or her interrogation of his personal choices. jefferson apparently presumed that harriet inherited his own aversion to private revelations. but rinaldi demonstrates a range of influences upon this -year-old woman that trumps the “master’s” habitual denial of self-disclosure. members of both her immediate and extended family instruct her regarding her present identity and whether she should alter that identity by departing from monticello and pass- ing for white. other slaves and a white architect who visits jefferson’s estate to use his library also contribute direct advice to harriet. the interest others take in harriet’s future suggests she is a most fortunate young adult. she’s no holden caulfield, crudely dismissing the guid- ance well-intentioned adults offer; instead, harriet weighs the merits of what she is told, however emotionally unsettling the advice may be. writing in this journal allows harriet her first sustained attempt at self- reflection, a task both assisted and thwarted by the variety of advice from others she must process. the novel’s central plot, in general terms, is one of self-realization, but it unfolds in a hyper-specific, extraordinary historical circumstance. with rare exceptions, the individuals in this novel who move through the main house and over the grounds of monticello are known to filling in gaps in the historical record history, though what we know (or think we know) remains in dispute nearly years later. rinaldi shapes her story with a crowded cast, by necessity: harriet and her three brothers—beverly, madison, and eston; martha randolph, jefferson’s only living child from his marriage, her husband thomas mann randolph, and their sprawling family (eleven children who lived to adulthood, three born after harriet’s birth); other house slaves (such as jefferson’s “body man,” burwell colbert); as well as, of course, harriet’s mother and jefferson; and a variety of visitors, including dignitaries and extended family members. rinaldi does err in claiming that harriet lives on the third floor of the main building ( , – , ). jefferson’s daughter martha and her chil- dren, as well as guests, resided under the same roof as jefferson. for the hemings children to do so would have been an announcement to visitors of sally’s children’s privileged status. in the year that harriet was born, , construction began on the “dependencies connecting the south pavilion with the mansion, . . . joined rooms, which included the kitchen, smokehouse, dairy, and slave quarters” for house slaves (mclaughlin ), and this would be where harriet and her brothers resided. rinaldi’s error does not detract from the overall quality of her novel, as harriet’s movements through the more public rooms of the house tend to be precisely circumscribed. the opening scene does emphasize, appropriately enough, harriet’s trepidation in entering jefferson’s private quarters, at his invitation and accompanied by her mother. further selective attention to rinaldi’s treatment of the historical record must be noted here, if only to test the novel’s accuracy. for example, harriet presents her ancestry, tracing her roots back to her maternal great-grandmother, and she notes that jefferson’s father-in- law (and sally’s father) bequeathed him slaves, including sally and her mother elizabeth ( – ). she recounts the anecdote from of jefferson watching through a telescope as british troops approached monticello, and then escaping on horseback, calm when others may have panicked ( – ). with the first example, which sweeps over many decades, and the second, which provides a close-up of one man’s con- duct at one particular moment, rinaldi moves her narrative forward on firm ground. also, in regard to accuracy, mention of the scornful press reports of the jefferson-sally hemings relationship, which emerged even after harriet’s birth, occurs three times. the novel’s authenticity, rinaldi’s craftsmanship in filling in gaps plausibly, requires more interpretive labor. the reporter responsible brian dillon (or the irresponsible reporter, depending upon one’s view of presiden- tial privacy), james callender, is not named by harriet. she focuses on jefferson’s silence in response to the published reports. when harriet enters his “sanctum sanctorum” without his permission in order to examine her “passing” wardrobe, she is discovered by jefferson, who urges her to ignore the evidence: he was asking me not to leave. he was asking me to forget that my mama was sewing a wardrobe for my departure. . . . and he was asking me to bide by his rule, which dismissed, by silence, anything unpleasant in the household. he wanted me to pretend my mother’s efforts never took place. the way he responded over the years, with silence and pretense, to the savage rumors in the press about himself and sally hemings. ( ) one month following this unplanned meeting, harriet approaches jefferson as he gazes out from the portico of the entrance hall of the main house. since they last spoke, harriet was assaulted by charles bankhead, husband of jefferson’s granddaughter, anne randolph, and took to her sickbed for a number of days. in this encounter, jef- ferson shows some concern for harriet but feigns ignorance of the drunken attack that occurred under his roof: “he cannot bring himself to speak of it, i thought, so he is acting like he acted years ago when they accused him, in the press, of taking my mother for a mistress. he never spoke of it. and his accusers went away” ( ). again, rinaldi is appropriately accurate: jefferson made no public comment in response to callender; evidence exists of bankhead’s brutality. furthermore, harriet’s awareness of the pretense that jefferson maintains and that her mother colludes with creates additional internal tension in an au- thentic way as she moves towards her decision to start a new life away from the only home she has ever known. bankhead’s assault on harriet should be labeled partially accurate: no historical evidence corroborates the specific episode in rinaldi’s novel. but historical evidence supports the possibility that such an event may have occurred. rinaldi adapts the historical evidence pro- vided by brodie: one night burwell prevented the drunken bankhead from obtaining more brandy, shouting erupted, and thomas mann randolph arrived and knocked bankhead to the floor (brodie ). no historian identifies harriet as the object of an attack. the novel situates harriet alone initially when confronting bankhead, and his violent actions against her thwarted first by thruston (a gardener, a filling in gaps in the historical record character not in the historical record), followed by the arrival of burwell and randolph. perhaps rinaldi also relied upon the scholar dumas malone who claimed that jefferson freed harriet to protect her virtue at monticello. gordon-reed, who never comments on rinaldi’s work, dismisses malone’s claim: “there is no record of a precipitating event— a rape or attempted rape of harriet hemings, for example—that might have increased the sense of urgency to have her leave monticello. there is no indication that there was a persistent but unwanted suitor with whom harriet had to contend” (thomas jefferson and sally hemings ). rinaldi authentically depicts harriet awakening to a profound comprehension of her vulnerability. the belatedness of her compre- hension—harriet is nineteen at this point—reminds readers of her sheltered status. this scene certainly increases “the sense of urgency” that compels harriet to accept the advice to leave, and thus propels the plot. rinaldi also strikes a culturally authentic note, however unintentional this may be: if harriet risks a sexual assault within the main house, how much more vulnerable must be the slave women at monticello—or on other plantations—who are never privileged enough to enter the master’s house? harriet does not ponder whether other female slaves at monticello or neighboring plantations would consider her assault an exceptional occurrence or a regular threat they are forced to live with, and it would be inauthentic for her to inquire about such acts typically conducted in secret, considering how sheltered she has been. rinaldi deserves some credit for providing at least a partial view of this serious issue. conflicting influences: thomas mann randolph and martha randolph again, before examining the four historical inaccuracies, the accuracy and authenticity in the characterizations of jefferson’s daughter martha randolph and her husband thomas mann randolph must be consid- ered, especially in regard to what their characterizations reveal about harriet and jefferson. the depiction of this married couple, who never appear together in the novel, adheres to the historical records known about them. while thomas mann randolph’s generosity and martha randolph’s bitterness may both be exaggerated to serve rinaldi’s plot strategy, their depictions do not violate the criteria for accuracy. rinaldi sets up harriet to transform over the two and a half year period her narrative covers, to develop a complex, thoughtful recognition of her immediate life choices. both randolphs provoke her transformation. brian dillon in particular, thomas mann randolph is presented as a countervoice to jefferson in his empathetic encouragement of harriet. jefferson’s son-in-law makes a number of crucial appearances in harriet’s final years at monticello. rinaldi depicts martha and their children residing at monticello (having moved there years before the narrative begins), while he visits occasionally, and in the years during which harriet keeps her journal he serves as governor of virginia. rinaldi’s favorable depic- tion of him is the most radical departure from the conventional views of any particular historical individual featured in this novel. the first time harriet mentions him, she attributes his alleged loneli- ness to being married to martha, and she asserts that “everybody” knows “he’s crazier than a loon” ( ). gossip about randolph referred, to some degree, to his mental instability. (rinaldi even depicts randolph declaring, “i feel like the proverbial silly bird who cannot feel at ease among the swans,” a self-conscious assessment randolph did utter, in a different context, of course [ ; ellis ].) sally hemings springs to his defense: folks may label him “crazy,” but at the time of this mother- daughter dialogue in , jefferson’s son-in-law is “about to propose to the legislature that all virginia’s slaves be freed and deported,” a much bolder effort on behalf of slaves than anything jefferson attempted, sally says ( ). “thomas mann randolph, the person they all say is crazy. well, if he’s crazy, that man, then i’m the queen of france” ( ). in their first dialogue, randolph dismisses harriet’s restatement of her mother’s claim about the state’s emancipation legislation. it will not pass, he accurately affirms ( ). though blocked in his efforts to reduce the number of slaves in the state, to distinguish his politi- cal record from jefferson’s passive acquiescence to the status quo, he focuses on harriet’s potential freedom. the issue of determining authenticity necessarily becomes more elaborate when the reader must disentangle various historically based characters’ motives. sally seems intent on counteracting what she per- ceives to be her daughter’s inflated view of jefferson. sally had prepped randolph to speak to harriet about her choice to leave monticello. this implies not only sally’s elevated view of randolph, but also a concern that her own persuasive powers may be inadequate. furthermore, sally does not request that jefferson or martha randolph propose to harriet that she make plans to leave, and perhaps she has not even discussed harriet’s leaving with martha randolph. randolph speaks to harriet of jefferson creating a “velvet trap” for himself at monticello, a metaphor suggesting current comforts are a filling in gaps in the historical record temporary illusion and will be paid for eventually with painful conse- quences. he questions whether harriet would be willing to escape the trap by leaving monticello. he tells harriet that if she stays, marries, and bears children they will be slaves: “‘worse than you. by then your master will be dead. and who’s to care about whether your children are slaves or not. or if they’re sold or not.’ well, the man had me there, just like a fox caught in a leg trap” ( ). harriet reveals that previously she never considered the potential status of her children. that’s a remarkable admission for a -year-old who has lived her entire life on a slave plantation. it suggests that her mother and older brother neglected to alert her to, arguably, her most pressing personal responsibility. her lack of foresight emphasizes how contentedly she has dwelt in the present, as well as how unwilling her mother has been to discuss the choices she made when she was younger than harriet. is it authentic, “within the realm of likelihood or possibility,” to use hintz and tribunella’s criteria, that sally would not have discussed with har- riet the consequences of her sexual choices or that harriet would not have imagined them on her own? that seems doubtful. but in terms of narrative strategy, a degree of authenticity may be sacrificed in order for harriet to achieve meaningful insights that readers may presume a -year-old living as a (relatively privileged) slave would have acquired at a younger age. the next time harriet and the governor talk, one month later, a sense of urgency compels randolph to insist that harriet prepare to leave. he knows that harriet has been assaulted by his son-in-law and, unlike jefferson, openly acknowledges and even condemns bankhead’s conduct. randolph’s attitude strikes an authentic note, even if no docu- mentation exists about his direct influence on harriet. he regrets not killing bankhead after he stabbed his son, thomas jefferson randolph, and then delivers the fiercest, most graphic condemnation of slavery in the entire narrative: bankhead represents everything that is so despicable about this system we live under. and i see you as a victim, along with my anne. for the same system that nurtures slavery, nurtures and tolerates all the evil impulses in men. it tolerates their laziness. and violence. it looks the other way when they turn from their wives to the women in the quarters and produce children like you and your brothers, who are left to find their way in such confu- sion, belonging neither to the nigra nor the white community, yet being part of both. ( – ) brian dillon this is a cry of helplessness, by both a governor and a father, when confronting a cultural norm, and his empathy for harriet is evident as he creates a parallel between his own daughter and harriet. the reader must presume that harriet does not personally know any slave who could articulate such antagonism, a circumstance that contributes to the soft focus in which her narrative views slavery. randolph’s speech counteracts jefferson’s silence: it would be hypocritical, certainly not authentic to what is known of jefferson, for him to state such a condem- nation. randolph acts upon his moral concern: he will advise jefferson about harriet’s decision, negotiate for his wife, martha, to tutor harriet, and reveal in private to a white bachelor who has visited monticello and voiced his admiration to him of harriet that a betrothal to harriet would provide cover for her, and perhaps the good deed could lead to marriage, which would require that harriet pass. effectively, randolph becomes harriet’s plot director and the behind-the-scenes hero of the novel, while jefferson remains an observer. thomas mann randolph addresses harriet like a young adult who will be capable of adapting to her move away from monticello. martha randolph attempts to belittle harriet. rinaldi’s unflattering depiction of martha may prompt readers to wonder whether martha was so sour on the hemingses and so duplicitous in her treatment of harriet. she senses that her husband plotted to allow harriet to leave, and she describes his legislative proposal: all this nonsense about introducing legislation to give virginia’s slaves their freedom. freedom to do what, i ask? and how? why, all the nigra servants on this place, with the exception of your mother, have to be led by the hand to eat, or they’d starve. that’s how much sense they have. you think it’s easy out in the world? you think all you have to do is smile and curtsy and you’ll have your supper? ( ) her racist-coated assessment is challenged by the evidence of the network of slave laborers who maintained the property and produced revenue from the nailery and elsewhere (stanton – ). her intensely pessimistic outlook plays off against the realistic, even existential, out- look her husband expresses to harriet. when thomas mann randolph develops his “velvet trap” metaphor, harriet notes that jefferson is kind to her. he responds, “kind, eh? well, kindness is not freedom. and security is not freedom. freedom is often lonely. nobody takes care of you. you take care of yourself. you think for yourself. you do filling in gaps in the historical record dim-witted things, and you are sorry for them. you pay for them. but there is no feeling in the world like freedom” ( ). madison does not indicate in his memoirs how martha interacted with him or sally and harriet. cynthia kierner’s recent biography of martha implicitly challenges the harsh depiction that rinaldi offers. while kierner’s conclusions deserve to be weighed against rinaldi’s depiction, her biographical study will not lead a reader to conclude that martha’s role in wolf by the ears is historically inaccurate. at the time in which harriet writes her narrative, martha’s mother and all her siblings from her parents’ marriage have been deceased for over years. (her mother died when she was just ten.) such a circumstance allows us to understand why the father-daughter bond would be so tight. her life story, kierner asserts, “counters the rhetoric of southern patriarchy to the extent that she herself had significant authority and influence— along with myriad responsibilities and obligations—throughout her adult life,” and it can be interpreted “as a case study of what could hap- pen when patriarchy malfunctioned because men [both her father and husband] were unable or unwilling to fulfill their prescribed domestic roles,” especially in fending off debt ( ). in rinaldi’s novel, martha complains to harriet, “there are alto- gether too many hemings on this place to suit me.” she refers to herself as jefferson’s “only surviving child” ( ). nearly two years later and just a few months prior to harriet’s departure, martha tells harriet that her father is peter carr, jefferson’s nephew, a man, she claims, her father indulged: “it was no way to repay my father for his kindnesses, mixing with the servant women and producing children in so irresponsible a fashion. but then, peter carr never was responsible. i suppose that’s why my father feels obligated to help sally hemings’ children” ( ). the oral tradition supports not the claim itself, of course, but the ac- curacy of martha promoting such a claim: her eldest son, thomas jef- ferson randolph, told a nineteenth-century biographer of carr’s role and attributed his information to his own mother. martha defended her father’s reputation with the ugly tactic of smearing sally (as well as her cousin carr). even prior to the scientific findings of the dna research, martha’s claim was demolished as a convenient fiction. it seems preposterous that martha would not know of her father’s long- term intimacy with sally hemings: that would require an excessive amount of willful ignorance. she also presumes that her allegations will not be challenged: “i know your mama hasn’t told you. and she never will” ( – ). brian dillon when thomas mann randolph talks to harriet, he presumes she has been coddled at monticello, allowed to live in a safe, cocooned world where few demands are made upon her. martha randolph adopts a similar stance. but note the differences: he wants her to perceive herself as an agent of her adult years, to make choices that assert her own independence. he pushes her out for her own good. he wants harriet to recognize how confined she is at monticello; martha, in her complaining mode, wants her to see that she is privileged. martha scorns her half-sister and essentially demands she express thanks for all she has been given. and she lies to her about her parentage: can we be sure she does not believe her own lie? thomas mann randolph presumes harriet is capable of imminent maturation; martha does not. he presses harriet to change her status; she urges harriet to accept her status as a powerless individual who should be grateful for her comfortable existence. he wants harriet to adopt a new identity who wields as much freedom of choice as her gender allows in the s; she seeks to impress upon harriet her sense of alienation from both the white randolphs and the mulberry row slaves. harriet responds to the contradictory concerns this couple raises with an authentic intent to figure out who deserves her trust. based upon her own instinctual feelings and later by the corroboration her brother beverly provides from the farm book regarding the absence from monticello of peter carr at the time of the hemings children’s conception, harriet clings to her belief that jefferson is her father. she also will not relinquish her view of jefferson as a man deserving pity. why she does not will be examined in conjunction with rinaldi’s four historical inaccuracies. harriet’s in-between status and her absent brother tom harriet’s reflections on the frequent references to her absent oldest brother, tom, the first of the four historical inaccuracies, highlight the unique in-between status she occupies at monticello. this first inaccuracy deserves to be considered in light of this context. harriet moves between the mulberry row values expressed by thruston (the gardener) and mammy ursula (who tells folktales and dispenses advice regarding potions and superstitions), and the white culture’s values, expressed by jefferson, martha and thomas mann randolph, and thad sandridge. this in-between status complicates in interesting ways both harriet’s efforts to assert her own identity and a reader’s efforts to prove filling in gaps in the historical record her character achieves authenticity. weimin mo and wenju shen begin with the distinction between facts and values when discussing accuracy and authenticity yet acknowledge the conceptual vagueness with these terms. more specifically, they note that cultures “affect each other. they constantly absorb each other’s values, attitudes, and beliefs; sometimes they actively clash. therefore, cultural values are not stagnant. when an author’s version of a culture can be accommodated inside the range of values acceptable within that social group, a measure of authentic- ity has been achieved” ( ). harriet receives conflicting advice from members of both monticello communities and must determine which values to accept and which to reject. in one dialogue, jefferson, a master of indirection, suggests to har- riet that she may be romantically interested in thruston. rinaldi con- structs this dialogue that accurately depicts jefferson’s attitude towards slaves intermarrying but within the conflicted context of obligations made to sally to free her children. operating with much cunning, jefferson attempts to plant a seed that would serve his current and long-term purposes: marriage with thruston would keep harriet on his premises until he dies. their offspring would add to jefferson’s capital and help offset his debt. he would be appalled if harriet had thought he wanted her to stay due to her monetary value as a breeder of slaves (overseen, perhaps, by his daughter martha). in fact, harriet does not indicate that such a thought enters her mind, though she should be labeled realistic rather than cynical if it did. lucia stanton notes, “like other slave owners, jefferson recognized the value of family stability in the slave quarters and tried to discourage abroad [off-plantation] mar- riages” ( ). as he wrote in to one of his property’s overseers, “there is nothing i desire so much as that all the young people in the estate should intermarry with one another and stay at home. they are worth a great deal more in that case than when they have husbands and wives abroad” (qtd. in stanton ). also, potential offspring from a harriet-thruston marriage would divert attention, jefferson may be thinking, from his genetic responsibility. when harriet introduced thruston in her narrative she noted, “he is light skinned, but darker than i am. i’m practically white. and i’m tall. and i have reddish hair. and some freckles. which ought to give a body an idea of the trouble i’m in right off” ( ). thruston’s role highlights harriet’s in-between status. she scolds him for speaking “like a field darkie who didn’t know any better” ( ), a remark that acknowledges her awareness of most slaves’ illiteracy brian dillon and limitations and thruston’s choice to align himself with those at monticello incapable of advancement as long as slavery persists. at this early point in her narrative, harriet still seems content with her current status. thruston, angry because of his recognition of the limitations on his potential choices, pushes back against “miss high and mighty,” as he labels harriet in this scene: “why should i talk like white peoples? . . . ain’t never gonna get me anything. doan wanna talk like white folk, anyway. ain’t nuthin’ ‘bout them i admire” ( ). she offers no response. this exchange segues into her encounter with thomas mann randolph as she serves him breakfast. he scolds her in a manner that echoes harriet’s confrontation with thruston: “talk to me. . . . don’t give me that stupid darkie routine” ( ). randolph’s effort to draw harriet out provokes her identity confusion, disrupts her contentment. and who is to blame for her extraordinary reticence with monticello’s white residents? who has sheltered her? though tutored academically ( ), harriet moves in a twilight world, immersed neither in the slave community nor the white world of jefferson’s extended family. later, thruston concedes that he wants to marry harriet but that she should seek her freedom. harriet fears the unpredictability of her life if she leaves monticello and enters a white community yet knows that she does not want to marry thruston. the perspective that harriet takes of the mulberry row slaves is dis- torted by her lack of regular contact with those who live there as well as her love for jefferson and pitying attitude towards him. while this perspective fails to conform to the historical record, to achieve accuracy, it does achieve authenticity considering the limitations that stem from harriet’s in-between status and defines her identity. in a later episode, harriet silently criticizes the limited goals of two girls from mulberry row who are nearly her age—her peers and yet not her peers—who flirt with the well-muscled field hand jupiter: “how stupid! where would it all lead? where would it get them? one of them will marry jupiter and have baby after baby down in the slave cabins” ( ). one of harriet’s internal conflicts centers on her recognition that her opportunities far exceed the mulberry row residents’: neither these two young women nor jupiter would be keeping a journal or tutored in french. harriet is tutored by mr. oglesby, and once her plans for leaving begin to form, by martha, with a curriculum that jefferson oversees (which includes limits on reading fiction [ ]). again, though, as sally’s child, har- riet proves to be an exception: “unlike many slaveholders, jefferson did not try to prevent his slaves from learning to read (although there filling in gaps in the historical record is evidence he frowned on the second stage of the learning process, writing), but he apparently took no active part in providing them with an education” (stanton ). yet the white community’s values have up until recently been considered out of her reach. in their dialogue that takes place days after harriet has been as- saulted by bankhead, after jefferson succeeds in proving to himself that harriet is discreet (she does not burst out crying or accuse jefferson of failing to control his own in-law and guest), he raises the issue of her leaving monticello. as evident in all five of his dialogues with harriet, as well as the one heated exchange she overhears between jefferson and beverly regarding her older brother’s desire to attend the newly formed university of virginia, jefferson exhibits contrary sensibilities: self-absorbed and emotionally guarded, yet intent on establishing a meaningful personal link. he admits that the influence of sally and thomas mann randolph prompted his willingness to allow harriet to leave: so, then, it is best that you go. i realize i was unfair to you at our last meeting, harriet. i tried to impose my will upon you for my own selfish reasons. yes, of course, i want you to stay, as i want beverly to stay and as i wanted tom to stay. but i must be a realist. there is nothing for you here. you are young and of a fine countenance and well bred. you must take your place in the world. ( ) presumably, jefferson trusts that she will understand that his “own selfish reasons” refers to a degree of emotional neediness, however incapable he may be of overtly expressing such needs to her. the reference to tom challenges the historical record. rinaldi tries to have it both ways: in the family tree listed at the front of the book under the name thomas hemings it says, “(possibly).” rinaldi seems to fashion “tom hemings” out of speculations in brodie’s biography, which acknowledged that references in jefferson’s farm book to vari- ous individuals named tom proved confusing rather than conclusive ( – n ). yet as the absent oldest sibling of harriet who left monti- cello when harriet was ten and passed as white, he is referred to in wolf by the ears as a real individual, not only by jefferson and harriet, but also mammy ursula and other slaves quartered on mulberry row, sally, and thomas mann randolph. madison’s memoir names only beverly, harriet, and eston as his siblings. callender reports gossip about a son named tom, but no credible historian confirms his existence. the brian dillon novel’s references to absent tom do not undermine in any genuine way the authenticity of harriet’s internal conflict. they are gratuitous. the manner of his leaving serves as a counterexample to jefferson’s wishes for harriet’s departure: “when you go, harriet, i would like it to be done right. no running off into the night like tom. promise me you will not run off” ( ). harriet will dutifully accept this advice. alert readers should recognize that such an example is unnecessary for rinaldi’s narrative purpose: harriet’s efforts to please jefferson are on display in every one of their scenes together. jefferson’s wistful recol- lections about tom do conjure a sentimental view of the slave-holding ex-president, though, that the historical record fails to support, and thus this first of the novel’s four inaccuracies deserves our attention. negative stereotypes of slaves are promoted by characters whom the reader is discouraged from agreeing with (such as martha randolph), and harriet confronts in a meaningful way her in-between status as neither wholly slave nor wholly free. yet at times the sidelong view of slavery that harriet provides from her comparatively privileged position as a house slave veils the documented evidence of the daily working conditions and inferior accommodations for the slaves of monticello, thereby sentimentalizing their existence. in an early entry in her journal, she gushes: “i love him, i know i do. and to show how much, i write down here and now another truth. the nigra servants on this place are well treated. and well clothed and fed. mama says the master, like his father, peter jefferson, has never used a whip on one of his servants. and no one goes cold or hungry” ( – ). though harriet does work occasionally in the weaver’s cottage on mulberry row, she avoids the nailery or the fields where many of the monticello slaves were employed and subject to punishments. stanton asserts that whipping of slaves at monticello occurred at “levels well below those of many of his neighbors. the whip was, however, by no means eliminated. from the s jefferson employed on the monticello plantation over twenty overseers with diverse temperaments and management styles. some were cruel, even by the standards of the day” ( ). such cruelties are removed from harriet’s line of vision. rinaldi’s choice of narrator— a domestic servant granted privileges unavailable to the other slaves jefferson owns—significantly softens what may very well be the high school reader’s first literary introduction to slavery in the south in the early s. the division in jefferson’s mind between the hemings children and the mulberry row slaves lurks behind his admission that “there filling in gaps in the historical record is nothing for you here.” no one disputes that sally’s children were relatively privileged, never sent to work in the fields or in the nailery, for example. his praise of her “fine countenance” and breeding, weirdly ironic because he does not acknowledge his role in her breeding, con- flicts with his previously published arguments of african americans’ racial inferiority. query xiv from notes on the state of virginia is often cited as an early expression (written in – ). in a question and answer format, jefferson ponders why emancipation of the slaves within the state will not occur: why not retain and incorporate the blacks into the state, and thus save the expence of supplying, by importation of white settlers, the vacancies they will leave? deep rooted prejudices entertained by the whites; ten thousand recollections, by the blacks, of the injuries they have sustained; new provocations; the real distinc- tions which nature has made; and many other circumstances, will divide us into parties, and produce convulsions which will probably never end but in the exterminations of the one or the other race. ( – ) jefferson then labels skin color in the category of “physical and moral” objections: “is it not the foundation of a greater or less share of beauty in the two races? . . . they are more ardent after their female: but love seems with them to be more an eager desire, than a tender delicate mixture of sentiment and sensation. their griefs are transient” ( ). he compares african americans unfavorably with native americans: “never yet could i find that a black had uttered a thought above the level of plain narration” ( ). such remarks, though written decades before harriet’s birth, provide some context for understanding his praise of her. rinaldi’s novel implies, at least, he was capable of making an exception to his theory in regard to both his sentimental worries about absent tom and his view of harriet: this may be pure fantasy on the novelist’s part. rinaldi’s depiction defies what we do know of jefferson’s attitude toward slavery in his post-presidential years. to note one example, in a letter from , jefferson tried to discourage a wealthy neighbor, edward coles, from carrying out his plan to move his slaves to illinois, where coles intended to free them and give them land: while jefferson recognizes that “the hour of emancipation is advancing,” he advocates that slave owners like coles “reconcile yourself to your country and its unfortunate condition,” and that while such proposals are worthy of brian dillon discussion, the time is not right to enact them. in this same letter he also asserts a point that directly echoes his sentiments regarding the inferiority of african americans from his notes: “their amalgamation with the other color produces a degradation to which no lover of his country, no lover of excellence in the human character can innocently consent” (letter to edward coles ). andrew burstein comments, “jefferson’s pseudoscience rightly diminishes him in the eyes of history for one inescapable reason: he did not grow over time” ( ). rin- aldi’s depiction of jefferson in this scene with harriet conflicts with the language of this letter. she also ignored brodie’s analysis of this letter, in particular the quoted sentence regarding “amalgamation” (misce- genation). brodie states that jefferson’s “octoroon children had been subjected by virginia society to the same degradation as the blackest african, and he had been pilloried for siring them. amalgamation for jefferson truly did not raise the black; it only degraded the white” ( ). of course, it is highly unlikely that ya readers would find any in- consistency here: harriet indicates no awareness of jefferson’s notes. presumably, she would not intend to please him if she was aware of his pseudoscientific racial theory, and knowledge of his theory would undermine her sentimental response to slavery. therefore, while it is plausible that harriet knows nothing of this publication from nearly years earlier or his current thoughts as expressed in his correspon- dence, this literary criteria of authenticity is earned at the sacrifice of exposing jefferson’s hypocrisy. his command that harriet must take her “place in the world” sounds sententious, even paternalistic, and the irony, of course, is that taking her place requires disguising her identity. he wields language with impressive authority, yet so many of his statements open up rabbit holes down which he refuses to go. harriet’s intense admiration for jefferson blocks her from challenging as suspect any of his stated intentions for her. this contributes to her portrait of jefferson as a figure deserving pity. jefferson’s confusing claims about george wythe and his self-promoting recollections about the declaration harriet’s inability at crucial points in her narrative to decipher when jefferson speaks in deceptive ways to manipulate her and others may very well be authentic: she does admit how sheltered her life has been. this inability is most evident in the extended scene that highlights beverly’s creative intellect and his frustration with jefferson, a scene filling in gaps in the historical record in which the novel’s second and third historical inaccuracies emerge. working from written accounts of the previous generation’s fascination with the pioneering work of hot air balloons, beverly has constructed one of his own, fueled not by straw or sticks but a burning claret-soaked sponge. he intends to impress jefferson in an effort to convince him that he should be allowed to enroll at the newly established university of virginia. beverly and jefferson confer about this on a hilltop near mulberry row. hiding behind a washhouse, harriet listens in to their exchange. though this narrative strategy of overhearing crucial infor- mation may be somewhat clumsy, the scene effectively pits a defensive jefferson against a frustrated beverly. jefferson acknowledges that beverly’s intellect warrants his admis- sion to a university program, but he lacks the power to institute such race mixing even on a campus he founded. jefferson argues by anal- ogy: he summarizes the case of the white man who murdered george wythe and a young man living with wythe, michael brown. in addition to being jefferson’s most influential teacher at the college of william and mary, wythe also served in the continental congress, and remained a lifelong friend. jefferson explains to beverly that wythe, twice widowed, developed a relationship with his mulatto housekeeper, lydia broadnax, and that she bore him a son (michael brown), whom wythe educated. in his will, wythe left the housekeeper his home and other property, and for brown half of his bank account. the other half was left to his white grandnephew who poisoned wythe, broadnax, and brown in an effort to inherit it all. the will (written while jefferson was president) entrusted jefferson to be in charge of brown. rinaldi apparently relies upon brodie to create this scene. the his- torical evidence does not support the claim that wythe and broadnax produced a son, nor that wythe was intimate with broadnax, whom wythe had freed and who continued to care for him as a paid servant. brodie states, “jefferson must have surmised, with many others in vir- ginia once the details of the will were circulated, that lydia broadnax was almost certainly wythe’s concubine and michael brown his son. that the president believed that wythe had waited in writing his will till he was certain he could count on jefferson’s support for his son seems likely” ( ). in rinaldi’s scene, jefferson speaks in a lawyerly manner to beverly regarding the exact nature of the relationship: “it was common knowledge that the boy was wythe’s illegitimate son” by his mulatto housekeeper, lydia broadnax ( ). bruce chadwick challenges this claim: the “copious population records . . . kept at the brian dillon time” never listed broadnax as a mother; “wythe had a long history of tutoring both black and white teenagers, and michael was just one more” ( n ). philip morgan notes: “of the fourteen witnesses who testified to wythe’s poisoning, not one mentioned that lydia broad- nax was his mistress or that michael brown was his son. no newspaper reported any such gossip” ( ). rinaldi blends some historically accurate claims with brodie’s specu- lations in this scene. broadnax, jefferson explains to beverly, survived: but because, under virginia law, no nigra can testify against a white, [this grandnephew] was acquitted. leading men in richmond rushed to defend him. the indictment against him was quashed without a trial. and a murderer was allowed to go free because my dear friend and mentor, a signer of the declara- tion of independence, did not try to hide the fact that he had a mulatto mistress and could not disown his son. now do you understand? ( ) the implication is that fourteen years later, the political culture in vir- ginia has not progressed, and jefferson is powerless to provoke change. jefferson’s support for beverly will not extend beyond monticello: he will neither help nor hinder him in the outside world. jefferson may fear that beverly’s presence at the university will expose beverly’s ances- try and provoke newspaper writers to resurrect stories of his intimacy with sally hemings. he will not allow any attention to be drawn to his role as the father of a mixed-race child, as he may have felt such atten- tion affected wythe’s posthumous reputation. while rinaldi is correct in depicting jefferson as asserting that state laws prohibited testimony from a black person against a white person, it bears noting that wythe and jefferson had formally approved this law when they reviewed the state statutes decades earlier (chadwick – ). jefferson’s pleading insistence that he cannot push against the weight of virginia’s white supremacist conventions contributes to the novel’s pattern of viewing him with pity, as a man with a steady moral compass whose willingness to guide others in the right direction is ignored. when rinaldi’s dra- matic dialogue—which embeds both this second inaccuracy regarding wythe and the third, to be considered below—is set against the histori- cal record, the reader’s pity may dissolve. jefferson’s effort to convince beverly of his powerlessness leads him to refer to his early draft of the declaration, the novel’s third historical inaccuracy, which he claimed called for the abolition of slavery: “but filling in gaps in the historical record there were those who would have seceded from the yet unformed union if my phrases about doing away with slavery were not struck from the document” ( ). jefferson’s claim accurately reflects his excised por- tions of his draft of the historic document, in which he blamed “the christian king of great britain” for the “horrors of the slave trade.” but jefferson only favored banning the importation of more slaves from africa, not the ownership of slaves, and in , he owned about slaves (mccullough ). he did write the astonishing phrase “all men are created equal,” but his own life proved he did not accept this either literally or legally. seeking from beverly understanding and forgiveness for his passivity, jefferson disingenuously simplifies the argument he crafted years earlier, and thus his remarks constitute a historical inaccuracy. yet his posture as a morally astute statesman powerless to affect change is authentic regarding the consistency in jefferson’s thinking about slavery from his early years in politics to his retirement at monticello. it is impossible to determine whether rinaldi knows that jefferson veers sideways from honesty here or that she presumes her reader will view jefferson with suspicion. ellis peels away jefferson’s layers of obfuscation to uncover his support of the south’s status quo: jefferson knew . . . that many established slaveowners in the tidewater region favored an end of imports because their own plantations were already well stocked and new arrivals only re- duced the value of their own slave populations. ending the trade in virginia, in short, was not at all synonymous with ending slavery. with regard to slavery itself, jefferson’s formulation made great polemic sense but historical and intellectual nonsense. it absolved slaveowners like himself from any responsibility of complicity in the establishment of an institution that was clearly at odds with the values on which the newly independent america was based. ( ) in rinaldi’s account, jefferson trusts that beverly lacks the knowledge to challenge him. in reporting this dialogue, harriet lacks the knowledge to treat jefferson’s claim with any skepticism. but a reader informed about the composition of the declaration and alert to jefferson’s in- tentions should challenge his self-serving and dishonest appeals in this exchange with beverly. near the end of his second term as president (in ), a ban was issued against the further importation of africans to serve as slaves. as historian alan taylor writes, “but the new law manifested no brian dillon commitment to antislavery within the nation and no bar to the booming interstate trade in slaves. indeed, by eliminating foreign competition, virginians could sell more slaves to the lower south. the sellers also expected to sleep more securely as the domestic slave trade diffused their surplus slaves at higher prices to the south and west. by banning the import slave trade while expanding the interstate slave trade, the virginians hoped to render slavery safer and more profitable” ( ). from his composition of the notes to the end of his second presidential term and all the way to his retirement at monticello, jefferson remained consistent in regard to slavery. open-ended closure in the novel and the historical record rinaldi’s choice of closure must be set against the historical record before proceeding to the novel’s fourth historical inaccuracy regard- ing the missouri compromise. beverly is not won over by jefferson; he refuses to commiserate with jefferson’s excuse-making. in his final dialogue with harriet, late at night, with beverly on horseback set to run away from monticello, he claims he does not know where he will go. (gordon-reed notes, “there is no record of an event that led to [beverly’s] departure” [thomas jefferson and sally hemings ].) he shares his breakthrough insight gleaned from the pages of jefferson’s farm book: “i check it every chance i get. . . . to see. how he marks us down. . . . on bread lists. on blanket lists. we’re on those lists, you and me. and mad and eston. with all his other slaves” ( – ). while harriet will soon leave in a state of sentimental ambivalence, beverly leaves full of righteous anger. “when he dies, people will see those lists. they’ll see we were slaves. a hundred years from now that’s all people will see of us, all they’ll know” ( ). rinaldi’s novel responds to beverly’s despair by animating the lives of what could have remained only names in the farm book. the novel comes full circle, from har- riet’s concern regarding whether jefferson will discuss her mother in his autobiography to beverly’s evidence that their mother and her children exist on paper only as budget items. the farm book establishes that beverly left monticello either in or and harriet in (brodie – ). rinaldi closes her story after harriet details her first night away from monticello. gordon-reed speculates that beverly may have eased harriet’s transition to wash- ington’s white culture (thomas jefferson and sally hemings ). rinaldi presents harriet’s departure as the ultimate leave-taking of her family: filling in gaps in the historical record both she and beverly presumed their parting was final, and there is no suggestion of a reunion at some unspecified time. the reader travels with harriet only miles from monticello to the first stop on her way to washington. this is the only break in the narrative from the spatial limitations of monticello. a white chambermaid and her daughter tend to her in her room above a tavern. though on this first night there is no challenge to her passing, her inadequate preparation for entering the world outside monticello, her lifetime of being sheltered, is evident in her response to the chambermaid: “it came to me, watching the woman, that she was of a poorer class than i had known any white woman to be. . . . i never considered that there were white folk in the world worse off than i” ( – ). working from madison’s memoir and the profun- dity of silence required by beverly and harriet who chose to abandon their black past and their bond with the third president, gordon-reed asserts that beverly and harriet “left monticello as white people, with no learning curve for how to present themselves as caucasians. they married white people who may not have known they were of african origin or had ever been enslaved” (the hemingses of monticello ). of course, if gordon-reed’s speculation were true, then harriet did not marry someone like thad sandridge, and her life did not follow the direction in which her narrative seemed to be headed. yet rinaldi’s open-ended conclusion certainly sounds authentic. lacking historical evidence that harriet’s older brother facilitated her move, rinaldi creates this scenario: thomas mann randolph plots a meeting between harriet and thad sandridge, a harvard-educated northerner, an architect appalled by slavery and physically attracted to harriet. somewhat late in her narrative, harriet reminds her reader that though she fended off thruston’s appeals and suffered from a thwarted violent attack by a sexual predator, her romantic experiences are limited and make her vulnerable. upon first meeting thad she decides she’s in love with him ( ). he demonstrates restraint and indicates his awareness of their power differential: “i’ll force you into no decision concerning me. i have the advantage of having known you for some time now. you do not know me. i would have you taste free- dom first. with no conditions attached to it. i do not wish to be a new master. i wish to be your friend” ( ). the romance plot is implied yet deferred. thad, calmer in his ardors, indicates he favors a leisurely pace to whatever mutual feelings may develop. harriet’s admission that she thinks she has fallen in love at first sight indicates she could benefit by restraining her emotions. he asks harriet to call him by his first name brian dillon and just once to call her master “mister jefferson.” harriet acts upon this advice. the novel closes with harriet’s description of jefferson’s response to the only time she referred to him this way: “his gaze held mine for a moment and there, in those blue depths, i saw the shock and confusion, yes, even the hurt. his head went back a little, with my words, as if i had struck him” ( ), and then he shed tears. success for harriet is achieved by evoking from jefferson a genuine emotional response to her departure, though readers should question how long she will feel satisfaction over such a slight victory. rinaldi gives this scene prominence of place. but alert readers may presume that while such an ending makes sense structurally, harriet’s overbearing emphasis on a tear (“tears! for me!” [ ]) may indicate only that her movement into adulthood has barely begun. harriet’s parting words to jefferson indicate her eagerness to take directions from thad. drop- ping the title “master” in favor of “mister jefferson” seems to serve as a transgression that only thad, harriet, and jefferson will know. it marks a shift away from subservience, but harriet’s intentions are not thought through. does she imply that if he must persist in remaining silent about her paternity she will address him as no more than her landlord? if so, his tear signifies his emotional pain. or is it her way of indicating she will play along with his desire for history to be uninformed of his double life, that she implies she will maintain their secret? if so, then his tear signifies his satisfaction that harriet has acquired, in his misted eyes, an adult-like acceptance of southern social conventions. werner sollors’ neither black nor white yet both identifies concerns specific to the issue of closure in fiction like wolf by the ears: “it is not surprising that interracial literature has displayed a good amount of self-consciousness and some ambivalence about where and how the plot lines could be brought to a conclusion” ( ). sollors distinguishes “two recurring patterns of closure”: the one that rinaldi’s novel follows is “the wish for ‘a world elsewhere,’ whether or not it is realized,” with harriet changing her name, securing a place to live and employment, with thad’s help, and the likelihood of “a happy interracial marriage” (sollors ). (sollors does not discuss wolf by the ears.) rinaldi deserves credit for undermining the potential for readers to view the ending as absolutely optimistic. both thomas mann randolph and martha randolph attempt to check her glowing assumption of what “freedom” might consist of. she is reminded (accurately, by sally) of the cautionary tale of her mother’s brother james: trained as a chef in france while living there with jefferson, he was given his freedom by jefferson, and filling in gaps in the historical record within a few years took his own life (rinaldi ; gordon-reed, the hemingses of monticello – ). harriet moves from a protected estate where she was familiar with everyone she encountered to an urban area where she knows only one man (and with a knowledge colored by unfamiliar intense emotions). she moves from a site where her identity both protected her and provoked uncertainty for her to a site where she will assume a false identity. in her introduction to paradoxes of au- thenticity, julia straub defines the term in a way that applies especially to rinaldi’s chosen closure, as well as the alternative closure this essay proposes: “authenticity is not a key to happiness, a state of mind pow- erful enough to iron out the ruptures in identity and life experience that afflict modern individuals. it can also denote conflict and needs to be seen as a term of crisis” ( ). the anxiety harriet expresses over leaving her family and the only home she has ever known for good certainly constitutes a “rupture” and a “crisis.” beverly rebukes her for choosing to pass: “what’s festering inside me is that my only sister is passing into the white world and turning her back on her people” ( ). harriet’s response reveals how genuinely guilt ridden her decision makes her: “there’s days i know i’m nigra, and what’s mine is in those cabins down there. days when i know it so much that i hate myself for wanting to leave, let alone pass!” ( ) families divided between those who did and did not pass: harriet’s anxieties anticipate this new reality. whites who abide by the legal and ethical code that stipulates that harriet’s one-eighth bloodline defines her and denies her the freedom entitled to whites would perceive har- riet’s action as a form of deception. beverly’s argument is that she is being dishonest towards the one-eighth blackness that should define her identity. implicitly, beverly argues that the martha randolphs of the culture should determine how and where harriet should live. he presumes that harriet will enter a privileged status and that by doing so she somehow harms those (such as the mulberry row residents) whose status is oppressed. but as this essay has demonstrated, harriet has never been totally absorbed by either the black or white culture at monticello. she is uncomfortable in the presence of whites, as her early remarks about serving thomas mann randolph indicate. she is perturbed that thruston insists on “talking like a field darkie who didn’t know any better” ( ), and she both respects and remains skeptical about the folk stories and spells that mammy ursula taught her. she moves uneasily between two worlds, belonging in neither. if we under- stand the ambivalence involved in harriet’s choice, her decision to pass brian dillon highlights a dimension that kathleen pfeiffer finds in other works of interracial literature: it “offers a problematic but potentially legitimate expression of american individualism, one that resists segregation’s one-drop logic and thereby undermines american’s consciously con- structed ideology of racial difference” ( ). in her final conversation with her mother, harriet is told that bev- erly passed. this complicates the reader’s efforts to understand har- riet’s often angry older brother. the historical record about beverly is as insubstantial as it is about harriet. consequently, the reader is on unstable ground when judging the accuracy of rinaldi’s closure. rinaldi’s decision to depict beverly as critical of harriet’s decision to pass serves a meaningful purpose in her psychological development: she reaches her decision through intense internal struggle, without her older brother’s full support. readers who move from rinaldi’s conclusion to madison’s memoir learn that beverly and harriet did pass, though madison provides no indication that his two older siblings ever contacted one another again or if he ever saw them again after they left monticello when he was a teenager. madison’s statements about harriet create a lacuna that rinaldi fleshes out in an authentic way with thad sandridge’s role: “harriet married a white man in good standing in washington city, whose name i could give, but will not, for prudential reasons” (qtd. in gordon-reed, thomas jefferson and sally hemings ). madison’s reminiscences indicate his knowledge of harriet’s life post-monticello is limited, that the color barrier he chose not to cross separated him from harriet (and beverly) for over half a century. she raised a family of children, and so far as i know they were never suspected of being tainted with african blood in the com- munity where she lived or lives. i have not heard from her for ten years, and do not know whether she is dead or alive. she thought it to her interest, on going to washington, to assume the role of a white woman, and by her dress and conduct as such i am not aware that her identity as harriet hemings of monticello has ever been discovered. (qtd. in gordon-reed, thomas jefferson and sally hemings ) gordon-reed parses the tone of this account, detecting madison’s anger towards harriet, his assumption that she was selfish, either in passing or in failing to maintain communication with her siblings, or both. the reference to harriet’s children not being “tainted with african filling in gaps in the historical record blood” may be madison’s sarcasm and resentment toward her decision to pass (thomas jefferson and sally hemings ). rinaldi again remains true to the testimony madison provides in the one scene harriet shares with her younger brothers as they discuss her leaving. harriet’s state- ments express a sweetness that she knows to be superficial: “‘because of who we are, no matter where we go, we’ll always be together in our hearts.’ . . . they agreed with me, but i knew in my bones they were saying it just to make me happy. and i became more desolate than ever” ( – ). madison then forecasts—accurately, according to the historical madison’s memoir—that he will stay with their mother after they leave monticello. the “world elsewhere” that harriet chooses to enter provokes nightmares for her as she anticipates her new life ( ); readers may admire her bold spirit in making her move and passing despite her legitimate fears. thruston’s role typifies rinaldi’s ability to dramatize crucial features the historical record substantiates. he refers accurately to jefferson’s debts that may be relieved to some degree by selling his slaves. in a dialogue with harriet, thruston accurately forecasts that jefferson’s slaves risk being sold off and separated upon his death: he is alert to jefferson’s significant financial debts and his old age, which compounds the urgency of his cautionary advice. jefferson already sold sally’s sister thenia to james monroe decades earlier and, thruston asserts, all of the rest of his slaves are at risk: “mister bacon [edmund bacon, jef- ferson’s overseer] says the place’d be sold to pay the master’s debts. a bidder will come. . . . put us on the block. for sale. ‘what’ll i get for this fine nigra gal? she has quality.’ they’ll sell us all. and a white man would pay a good price for a piece of property like you” ( , ). while thruston intended his speculative scene to terrify harriet into fleeing monticello, to step into her freedom as soon as possible, he exagger- ated the threat to her personally. harriet and her older brother beverly were allowed to leave when they were twenty-one. five of jefferson’s slaves, including harriet’s two younger brothers, were not sold: his will stipulated they be granted their freedom (stanton n). jon kukla’s mr. jefferson’s women contrasts the treatment following upon jefferson’s death accorded to some members of the hemings family with the more than other slaves who called monticello home: “with his daughter’s help, jefferson finally rescued sally hemings and all their surviving children from slavery. against some formidable obstacles—through thoughtful actions that implied respect, gratitude, and some measure of affection—their story ended in a way that suggests that promises had been made and were kept” ( ). brian dillon the residents of mulberry row, like thruston, that is, the field hands, the nailmakers, the “superannuated” women (to use jeffer- son’s term from his farm book, which he applied to those slaves who could mind the children; harriet puzzles over this term that implies jefferson’s view of the material value of certain slaves [ ]), and oth- ers whom we may presume never entered the main house where the hemings children were welcomed, were sold in january . families were divided. thomas jefferson randolph, the president’s grandson, served as executor: he “compared the wretched scene of the dispersal sale at monticello to ‘a captured village in ancient times when all were sold as slaves’” (kukla ). though harriet’s narrative—rinaldi’s novel—ends with her departure from monticello in , the reader may imagine the sale four and a half years later of thruston, jupiter, both girls whom harriet observed flirting with jupiter, and any of their offspring. but a reader must be aware of the historical record, must have knowledge that exceeds what harriet comprehends, in order to claim her sentimental view of slavery is counteracted by the grim reality of monticello slaves on the auction block that the novel merely anticipates but does not depict. sollors acknowledges “the structural ambivalence in plot lines that are brought to forced closure at a price: each resolution rests on the denial of another possibility that is being eliminated by the choice made” ( ). rinaldi chose not to close with a more definitive tragic ending: for example, she could have added an epilogue in which har- riet returns, perhaps under some form of disguise, on the january day in when the slaves at monticello were put on the auction block. she could observe the “superannuated” mammy ursula, thruston, and others purchased by new owners: their lack of choice over their futures combined with harriet’s impotence at the sale would close the story on a deeply tragic—and authentic—note. harriet’s qualified achievement of independence would be viewed in its rightful context against the lack of any choice for her former fellow slaves. such an ending would be accurate to the historical circumstances and reinforce the rupture in harriet’s choice to leave. rinaldi’s allusion to the missouri compromise and the personal consequences of jefferson’s grim foresight in one exchange between harriet and her mother, sally discusses jefferson’s despair following upon the debates in congress over the filling in gaps in the historical record missouri compromise in : this sets up the novel’s fourth historical inaccuracy. jefferson senses that the national union achieved by allow- ing slavery to be maintained (as discussed above on his writing of the declaration) will eventually collapse. sally explains: “he fears for the union. . . . he talks about an imaginary line they are drawing across the country, with certain states slave and others free. he says a hideous evil is dividing america. he says the line will never be erased. some southern states threatened to leave the union if missouri wasn’t admit- ted as a slave state. he says it fills him with terror” ( ). rinaldi allows sally to speak lines that echo jefferson’s letter to senator-elect (of the new state of maine) john holmes: “this momentous question, like a fire bell in the night, awakened and filled me with terror. i consid- ered it at once as the knell of the union” (letter ). terror is the appropriate anticipatory emotion for the civil war, “which destroyed slavery, the political primacy of the south and the doctrine that the states were sovereign agents in the federal compact” (ellis ). but what sally does not explain, and what harriet does not know, is that jefferson feared restrictions imposed by northerners on southerners’ expansion of slavery. he favored the interstate sale of slaves, without any restrictions from the north, and he feared the potential for a slave revolt in virginia (taylor ). “the diffusion over a greater surface would make [slaves] individually happier, and proportionally facilitate the accomplishment of their emancipation, by dividing the burthen on a greater number of coadjutors,” his letter to holmes stated ( ). sally’s account, as in the three previous examples of historic inaccura- cies in this novel (in regard to tom hemings, george wythe, and the composition of the declaration), allows the reader to pity jefferson for his moral stand while powerless to affect change. on a more personal level, the civil war prompted jefferson’s grandsons to fight against one another. martha’s son george wythe randolph, who plays a silent, cameo role as a three-year-old sitting on his mother’s lap while she interrogates harriet ( ), served in the military for the confederacy, including a stint as jefferson davis’ secre- tary of war (crawford ). two of eston hemings’ sons served in the union army, beverly jefferson and john wayles jefferson, who rose to the rank of colonel in the wisconsin infantry (stanton – ). two of madison hemings’ sons crossed the color line and served in white units in ohio regiments. “they would have known that had they joined one of the available ohio black regiments, they would have been denied equal pay and equal access to advancement. . . . the hemings brothers brian dillon had identified themselves as ‘colored’ in their prewar lives. thus every day spent with a thousand white soldiers must have been full of tension as well as the dread of discovery and its disagreeable consequences” (stanton ). in his memoirs, madison reports that his son thomas eston hemings died in the notorious andersonville prison. we do not know what any of the hemings grandchildren thought of jefferson. however arrogant it may seem to assess moral responsi- bility from a position of roughly two hundred years, an examination of jefferson’s role in the maintenance of slavery and the personal and national consequences of his actions—and inactions—undermines any naive sense of patriotic pride in the decisions of the declaration author and third president. while harriet’s view of jefferson as deserving pity is authentic, considering her lack of knowledge of his various writings and his proximity to her, it is not a response that jefferson deserves. by exploring the hemings family’s life while at monticello, with rinaldi’s novel as a springboard, as well as the years after jefferson’s death, a more richly informed response to the consequences of slavery, histori- cally and for one young woman, will result. notes i thank amanda cockrell and the children’s literature anonymous readers for their patience and meaningful insights on drafts of this essay. newell bringhurst’s “a popular but controversial biography” provides a useful overview of the response to brodie’s book. see <http://www.pbs.org/wgbh/pages/ frontline/shows/jefferson/cron/ brodie.html>. six years before brodie’s biography, winthrop jordan noted that jefferson’s farm book indicated he was present at monticello nine months prior to the birth of each of sally hemings’s children, though overall he was absent from monticello for nearly two-thirds of the period when sally hemings conceived. jordan acknowledges that the evidence available to him prevents any claims of certainty regarding the extent of jefferson’s relationship with sally hemings. “the question of jefferson’s miscegenation,” jordan asserts, “is of limited interest and useful- ness even if it could be satisfactorily answered” ( ). though brodie refers respectfully to jordan in the opening paragraph of her acknowledgements, she strongly disagrees with his view of “jefferson’s miscegenation.” jon meacham provides thorough documentation on this matter ( – ). joseph ellis, a skeptic as late as regarding the relationship (see american sphinx – ), asserted in , “if history is an argument without end, skeptics and agnostics will still have a role to play in the debate. but the new scholarly consensus is that jefferson and hemings were sexual partners” ( ). the publication of paula byrne’s belle and the release in the same year of the same-titled movie emphasizes the current interest in a true story of a light-skinned daughter of an african slave woman raised in the household of her politically powerful guardian. dido belle, whose father is a british naval captain, is raised by her great-uncle, the earl of mansfield, and comes of age at the same time that the earl, who serves as england’s lord chief justice, must render a verdict in the zong appeal, the case in which a british slave-trading firm sought insurance company compensation for the human filling in gaps in the historical record “cargo” who had been tossed overboard on the middle passage in . granted, notable differences between the circumstances of belle and harriet hemings exist: to note one crucial fact, belle’s guardian wielded substantial political power, whereas jefferson’s authority to continue or correct america’s treatment of slaves effectively ended a full decade prior to the events rinaldi—through harriet—narrates. byrne frequently does remind her readers, though, that reasonable speculations must be relied upon when historical evidence is thin or nonexistent, as in this admission: “we simply don’t know whether dido belle was conceived by force, by mutual consensual passion, or as a ‘duty’ that might bring material benefits to her powerless mother” ( ). rinaldi might admit the same regarding sally’s children. byrne acknowledges that the “only way of glimps- ing [dido belle’s] life is through the lives of others” ( ). this parallels rinaldi’s task in creating an authentic version of harriet hemings, who engages in many dialogues with others who attempt to influence her. the movie belle takes considerable liberties with the available historical evidence and may be played off against byrne’s book: time sequences are compressed, and belle’s romantic life unfolds along with the debate about the zong decision. this essay examines harriet’s in-between status. curiously, the movie indicates that belle fluctuated in an uncomfortable in-between status in the mansfield household, allowed neither to dine with the family nor eat in the kitchen with the ser- vants, for example. yet as a further reminder of the instability of all “texts,” whether a novel, a movie, or a historical document, byrne asserts that proof is lacking that belle “was normally excluded from family meals” ( ). madison’s memoirs, which were first published in an ohio newspaper in , run for just four pages and are included as an appendix in brodie’s biography, the selected writings of thomas jefferson, and gordon-reed’s thomas jefferson and sally hemings. some caution should be used, though, if his brief text were brought into a classroom: madison refers to harriet’s life post-monticello, and many readers would prefer not to know what he says until after finishing the novel. in , jefferson returned to monticello from washington in order to be with his fatally ill daughter maria, the daughter sally hemings had escorted to france to visit jefferson in . “it is quite telling that he turned to hemings during one of the most heartbreaking periods of his life, when he was a veritable portrait of emotional devasta- tion. madison hemings’s conception in the harrowing six weeks jefferson was at home to attend to his daughter shows that this extremely sensitive man sought the comfort of the familiar with the person who understood better than anyone besides his daughter martha what maria had meant to him” (gordon-reed, the hemingses of monticello ). for example, in an early scene harriet intends to exit the house by walking past the underground kitchen, which would seem to place her as emerging from the servants’ rooms under the south terrace, in contradiction to the later references to her third floor room ( ). sally, in the kitchen, sees harriet and tells her to serve a tray of food to thomas mann randolph in the dining room. together, mother and daughter move “through the underground corridor” and then harriet alone ascends “the stairway to the hall outside the dining room” ( , ). (the website www.monticello.org provides a virtual tour of the house and enables viewers to track many of harriet’s movements.) harriet conducts five dialogues with jefferson, and for four of these the location is specified: two in his sanctum sanctorum, one overlooking the east balcony, and one by the carriage as she leaves monticello. (another exchange is brief, with the location of their meeting not specified.) rinaldi’s depiction of people’s circulation in and around the great house may seem contrived at times. typically, though, the author stipulates why harriet enters a specific location, such as when sally directs her to move from the kitchen up to the entrance hall overlooking the east balcony to speak with jefferson ( ) or to serve food to thomas mann randolph, or when randolph directs her to serve tea to thad sandridge ( – ): these set-up meetings are presented as highly unusual, as are harriet’s exchanges with jefferson in his sanctum sanctorum. brian dillon on harriet’s ancestry, see gordon-reed, the hemingses of monticello and stanton, “those who labor for my happiness.” on slaves bequeathed to jefferson upon his marriage, see gordon-reed, the hemingses of monticello and ellis . the telescope incident is recalled in meacham – . rinaldi relied, of course, on brodie and earlier authors. on callender, see ellis – , gordon-reed, thomas jefferson and sally hemings, and meacham – . on bankhead, see stanton , gordon-reed, the hemingses of monticello – , and kierner – . though pursuing this topic may be too “weighty” (to again use honey’s term) for ya readers, the following information certainly is useful. according to lucia stanton, “the extreme imbalance of power in a slave society made the whole idea of consent, when it concerned a female slave and a free white man, especially if he owned her, an absurdity. nevertheless, it is apparent that interracial sex in virginia and elsewhere in the south took every form from the most cruel exploitation to the most enduring affection” ( ). alan taylor notes, “no law punished masters who raped slave women or kept them as concubines. neighbors did little more than gossip so long as a master kept a low profile and did not marry a slave partner: a model of discretion set by jefferson” ( ). see brodie and ellis – . though acknowledging the “anxiety and rage that afflicted him in middle age,” cynthia kierner adopts a more empathetic view: she notes his debts, both inherited and created during his marriage to martha; his lack of a dowry for some of his younger daughters, which inhibited their marriage prospects; the viciousness of his son-in-law bankhead; and the difficult position he maintained as the son-in-law of jefferson while residing at monticello ( ). barbara chase-riboud’s best-selling novel sally hemings piles up the references to thomas mann randolph as a drunken fool accruing severe financial debts. curiously, rinaldi does not refer to this novel in her bibliography. as randolph should have been aware before he began the first of his three one-year terms of office, the authority of virginia’s governor “had been clearly and deliberately limited by the framers of the constitution of ” (gaines ). thus his proposal may have been evident even to randolph as more provocative than practical. by modern standards, it certainly could not be labeled progressive: fearing violent slave rebellions, “he suggested that ‘a fair proportion’ of slave youths in the different parts of virginia be manumitted every year. to accelerate the process, he recommended further that ‘a double proportion of females’ over males be released annually.” he wanted “those manumitted under his program [to] be sent to the island of santo domingo, which was ‘sufficiently near to admit of emigration at little cost,’ and where a self-governing com- munity of liberated negroes was already in existence” (gaines ). see brodie, – and gordon-reed, thomas jefferson and sally hemings . see gordon-reed, thomas jefferson and sally hemings – . gordon-reed offers these valuable insights that apply not only to harriet but to her mother, her aunts, her grandmother, and her great-grandmother: “throughout their time at monticello, none of the hemings women married men from ‘down the moun- tain’ who worked in the fields. they were either in long-term liaisons with high-status white males or white workers at the plantation, or they married household servants from other plantations who were also mixed race or, in the case of critta hemings [sally’s older sister], a free black man. one could say that these women had no choice regard- ing the white men, even the men who did not own them. it is also possible, of course, that given a choice they would have preferred white mates. that might be a disturbing thought from a modern perspective, with our knowledge of slavery and views about the value of solidarity in the face of oppression. this possibility, however, must not be discounted outright, especially in light of the behavior of some of the hemings children and grandchildren” (gordon-reed, the hemingses of monticello ). madison’s memoirs assert that sally was impregnated by jefferson while in france, that she delivered the child after they returned to virginia, and that the child died soon filling in gaps in the historical record thereafter. also, gordon-reed asserts that her analysis “tended to support madison hemings’s version of his family story: sh had a child in , but that child did not live. there are no records of a child named thomas linked to sh in tj’s farm book, even in the years before sh and tj’s relationship was exposed to the public.” she also exam- ined the records of vaccinations against small pox that jefferson maintained: “jefferson vaccinated his children beverley and harriet in , and madison and eston in . all four are listed as children of sally hemings. there is no hemings child named tom on the list, as he certainly would have been had he existed. again, these vaccinations began well before callender ever wrote about a child named tom at monticello.” see gordon-reed, the hemingses of monticello – n. tom is referred to on pp. – , , , – , , , , and . an instructor intent on challenging rinaldi’s depiction of jefferson in this exchange that refers to tom, or other scenes, could turn to any of the jefferson documents already noted (from his letters and notes) in order to position jefferson’s own writing against this fictional version. this would allow young readers, especially, to assess rinaldi’s accuracy and to begin to recognize the slipperiness of historical “truth.” see meacham – , n. gordon-reed refers to a balloon flight in petersburg, virginia, in perhaps that might be attributed to beverly. jefferson’s own interest in balloon flights extends over decades and is well documented. “by today’s standards ballooning may seem a trivial activity, a thing of sport. during jefferson’s era it was considered a scientific venture with travel and even military implications. it would be intriguing if he passed his interest in aerial transportation on to beverly and madison hemings, all the more so if beverly undertook to become a balloonist” (thomas jefferson and sally hemings ). the circumstances of the trial of wythe’s grandnephew are more complicated than jefferson’s “lesson” to beverly indicates. the forensic reports by three of richmond’s leading doctors who performed an autopsy of wythe proved to be incompetent: they did not establish that he had been poisoned (chadwick – ). “they did not perform any of the standard tests to discover arsenic and even ignored the simple -year-old taste test that would have at least alerted them to a poison of some kind. the autopsies that should have conclusively proved that arsenic was responsible for the deaths of michael brown and george wythe were, in short, colossal forensics failures” (chadwick ). also, virginia’s governor at the time shared privileged information with the defense counsel, which also weakened the prosecution’s case (chadwick ). when beverly left in , there is no evidence “that jefferson tried to bring him back” (gordon-reed, thomas jefferson and sally hemings ). had wythe died and michael brown lived, jefferson would have faced a circumstance that may have contrasted with how he treated his four hemings’s children: “how would jefferson have carried out wythe’s final request about his involvement with michael brown? would he really have brought the african american boy to monticello or to the president’s house to continue his studies, or would he have used the money from wythe’s estate to hire tutors for him? brown at monticello would indeed have been an interesting and problematic sight” (gordon-reed, the hemingses at monticello ). delegates to the continental congress “eliminated entirely jefferson’s long pas- sage on the slave trade. in the notes he kept of congress’s proceedings, jefferson said that change was made ‘in complaisance to south carolina & georgia,’ which had never tried to restrain the slave trade and, indeed, wanted it to continue, with the consent of ‘northern brethren’ who had few slaves but were sensitive on the issue because they had been ‘pretty considerable carriers of them to others.’ maybe so, but the very acknowledg- ment that colonists had been in the past or were at present willing participants in the slave trade undermined the assertion that ‘the christian king of great britain’ was alone responsible for that outrage on humanity” (maier ). brian dillon the farm book has been examined in ways that jefferson could not possibly have anticipated: “it is, in fact, highly unlikely that it ever occurred to jefferson that his record of the lives of his slaves would become the subject of scholarly interest, even a passion among some—that his slaves’ lives would be chronicled and followed in minute detail, the interest in them often unmoored from any interest in him. . . . in jefferson’s monumentally patriarchal and self-absorbed view, one shared by his fellow slave-owning planters, this was oh, the responsibilities i have! here is what i have done and have yet to do for all ‘my family’” (gordon-reed, the hemingses of monticello ). among a variety of outcomes that resulted when some member(s) of a family chose to pass, stanton identifies the following: “important life passages like births, marriages, and deaths became painful reminders of family division, and only those remaining in the black community came to family reunions” ( ). though she appears in only three brief episodes when harriet seeks her at her mulberry row cabin, mammy ursula’s role deserves attention. this “superannuated” woman avoids the race-segregated sunday baptist services where the white minister tells the slaves to obey their masters: this hints at her positive mentoring role ( ). she lived at monticello even before jefferson and his wife first moved there ( ). she not only validates harriet’s decision to leave but seems to support her decision to pass, as though she may live vicariously through harriet: “i’se part of this place. but you ain’t. you, chile, is part of somethin’ else. somethin’ new. out there. go. however you wants. for all of us” (emphasis added, ). eston lived as a black man near madison in ohio until he moved his family to wisconsin, passed for white, and changed his name to e.h. jefferson. in his memoirs, madison said, “eston married a colored woman in virginia, and moved from there to ohio, and lived in chillicothe [ohio] several years. in the fall of he removed to wisconsin, where he died a year or two afterwards. he left three children” (qtd. in gordon-reed, thomas jefferson and sally hemings ). note all the information that is missing, including the vagueness—and inaccuracy—of the death date: eston died in . there is no follow-up regarding what eston and his family did after they left ohio, no awareness that eston’s sons ran madison, wisconsin’s oldest hotel or that they served in the military during the civil war (stanton – ). the implication seems to be that communication between madison and his brother and his brother’s children ceased after eston left ohio and passed. many biographers address the linked issue of jefferson’s expensive tastes and sub- stantial debts. jack mclaughlin comments, “in spite of his exacting eye for the details of income and expenditure, he seldom stepped back to observe his economic landscape. because he notched each financial tree, he thought he knew the forest; until it was too late, he had little idea of his net worth.” though he received an annual salary of $ , while serving as president, it apparently was not evident to him “that he was living well beyond his income during his eight years in the presidency, and that a day of reckoning must come” ( ). gordon-reed offers this practical opinion that applies to the conse- quences experienced by both martha randolph and her children and sally’s children: “parents are expected to attend to the well-being of their children; it is, in fact, seen as their highest duty. jefferson’s handling, or, more accurately, not handling, of his finances in the final two decades of his life conflicted with that duty. why wouldn’t jefferson’s actions on this score count as examples of insufficient regard for his family?” (thomas jefferson and sally hemings ). curiously, the title of john chester miller’s book, which rinaldi “borrows,” is a metaphor derived from this same letter jefferson wrote in in regard to the mis- souri controversy (and both miller and rinaldi include a brief passage from the letter in their epigraphs). he believed slavery would only end if the slaves were expatriated. “but as it is, we have the wolf by the ears, and we can neither hold him, nor safely let him go. justice is in one scale, and self-preservation in the other.” he closes his letter with a filling in gaps in the historical record remarkable emotional mixture of self-congratulation, sorrow, and blame: “i regret that i am now to die in the belief, that the useless sacrifice of themselves by the generation of , to acquire self-government and happiness to their country, is to be thrown away by the unwise and unworthy passions of their sons, and that my only consolation is to be, that i live not to weep over it. if they would but dispassionately weigh the blessings they will throw away, against an abstract principle more likely to be effected by union than by scission, they would pause before they would perpetuate this act of suicide on them- selves, and of treason against the hopes of the world” (letter to john holmes ). is it too extravagant a point to claim he foresees the violent division within his own country and among his own descendants? works cited brodie, fawn. thomas jefferson: an intimate history. new york: bantam, . print. burstein, andrew. jefferson’s secrets: death and desire at monticello. new york: basic, . print. butler, catherine and hallie o’donovan. reading history in children’s books. new york: palgrave macmillan, . print. byrne, paula. belle: the slave daughter and the lord chief justice. new york: harper, . print. chadwick, bruce. “i am murdered”: george wythe, thomas jefferson, and the killing that shocked a new nation. hoboken: wiley, . print. chase-riboud, 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( ): – . print. jefferson, thomas. letter to john holmes. [ april ]. the selected writings of thomas jefferson. ed. wayne franklin. new york: norton, , – . print. ———. letter to edward coles. [ aug. ]. the selected writings of thomas jefferson. ed. wayne franklin. new york: norton, , – . print. ———. notes on the state of virginia. the selected writings of thomas jefferson. ed. wayne franklin. new york: norton, . – . print. jordan, winthrop. white over black: american attitudes toward the negro, – . chapel hill: u of north carolina p, . print. kierner, cynthia. martha jefferson randolph, daughter of monticello: her life and times. chapel hill: u of north carolina p, . print. kukla, jon. mr. jefferson’s women. new york: knopf, . print. maier, pauline. american scripture: making the declaration of independence. new york: knopf, . print. brian dillon mccullough, david. john adams. . new york: simon and schuster, . print. mclaughlin, jack. jefferson and monticello: the biography of a builder. new york: holt, . print. meacham, jon. thomas jefferson: the art of power. new york: random house, . print. miller, john chester. the wolf by the ears: thomas jefferson and slavery. . charlottesville: u of virginia p, . print. mo, weimin and shen, wenju. “accuracy is not enough: the role of cultural values in the authenticity of picture books.” stories matter: the complexity of cultural authen- ticity in children’s literature. ed. dana fox and kathy short. urbana: ncte, . – . print. morgan, philip. “interracial sex in the chesapeake and the british atlantic world, c. – .” sally hemings and thomas jefferson: history, memory, and civic culture. ed. jan ellen lewis and peter onuf. charlottesville: u of virginia p, . – . print. pfeiffer, kathleen. race passing and american individualism. amherst: u of massachusetts p, . print. rinaldi, ann. wolf by the ears. new york: scholastic, . print. sollors, werner. neither black nor white yet both: thematic explorations of interracial literature. new york: oxford up, . print. stanton, lucia. “those who labor for my happiness”: slavery at thomas jefferson’s monticello. charlottesville: u of virginia p, . print. straub, julia. “introduction: the paradoxes of authenticity.” paradoxes of authenticity. ed. julia straub. london: transaction, . print. taylor, alan. the internal enemy: slavery and war in virginia, – . new york: norton, . print. tillet, salamishah. sites of slavery: citizenship and racial democracy in the post-civil rights imagination. durham: duke up, . print. wilson, kim. “‘are they telling us the truth?’ constructing national character in the scholastic press historical journal series.” children’s literature association quarterly . ( ): – . print. mennonites, amish, and the american civil war (review) mennonites, amish, and the american civil war (review) sean a. scott ohio history, volume , , pp. - (review) published by the kent state university press doi: for additional information about this article [ this content has been declared free to read by the pubisher during the covid- pandemic. ] https://doi.org/ . /ohh. . https://muse.jhu.edu/article/ https://doi.org/ . /ohh. . https://muse.jhu.edu/article/ bo ok reviews of these men joined harrod and bowman on the unsuccessful ohio foray, and subsequently “capt. wm. harrod, with others, went up the ohio to red stone in the two keel boats &c. and took along several bones & tusks got at the big bone lick.” what became of these specimens remains unknown, but this was an important early effort at “mining” the deposits at big bone. similarly, neither jillson nor hedeen mentions thomas rodney’s well-doc- umented stop there on october , , less than a week after meriwether lewis’s collecting visit for thomas jefferson. rodney not only took measure- ments of several of the remaining fossil bones but speculated (incorrectly) that no animals larger than bison ever existed there, larger bones being “only fossil concretions.” rodney himself collected a mastodon tooth and a tusk fragment, but these were lost when his boat sank at natchez. curiously, hedeen merely reproduces without explanation a photograph of three paleo-indian points “collected” at big bone lick. elsewhere, he has written that these were discovered in the lowest level of the big bone de- posits during william clark’s excavations for thomas jefferson and are “now likely” housed at the cincinnati museum center. the significance of associated paleo-indian artifacts and megafauna at big bone lick should certainly be acknowledged but so too should the considerable debate exist- ing about the precise provenance and pedigree of these artifacts. such strictures aside, this book provides ample context for the present big bone lick state park museum and should remain a standard resource for many years. ja m e s l . m u r p h y the ohio state university mennonites, amish, and the american civil war. by james o. lehman and steven m. nolt. (baltimore: johns hopkins university press, . xiv, pp. cloth $ . , isbn - - - .) when war engulfed virginia in the summer of , mennonite christian good was conscripted into the state militia. after good experienced battle and failed to discharge his rifle, his perturbed captain asked him why he . henry hill, “bowman’s campaign— ,” ohio archaeological and historical publica- tions ( ): . . simon gratz, “thomas rodney,” pennsylvania magazine of history and biography . ( ): ‒ . . stanley hedeen, natural history of the cincinnati region. cincinnati museum center scientific contributions no. (cincinnati: the center, ), . in the same publication, these artifacts are captioned only as “most likely [discovered] during william clark’s expedition” (plate ). ohio history had refused to shoot at union soldiers in clear view. the committed pacifist reportedly responded, “they’re people; we don’t shoot people” ( ). while most protestants north and south wholeheartedly supported their governments and sent scores of soldiers to fight in the civil war, members of anabaptist sects struggled to balance the conflicting duties of citizen- ship in both an earthly state and a heavenly kingdom. as religious outsiders who traced their origins to the radical fringe of the protestant reformation, many mennonites and amish had settled in america to avoid compulsory military service in europe. more significant than challenging their civic loyalty and threatening their commitment to the principles of pacifism, the civil war forced them to engage the political and cultural mainstream and adapt to the contingencies of war in order to protect their distinctive and countercultural religious beliefs. in a compelling narrative, lehman and nolt effectively recount the unique circumstances of american anabaptists in three geographic regions. in vir- ginia’s shenandoah valley, conscripted pacifists could secure an exemption from military service by paying a $ commutation fee or furnishing a substitute. although a few mennonites fought for the confederacy, many more attempted to flee north and avoid supporting the rebellion. during the autumn of , the union’s hard war policy resulted in the destruction of several mennonite farms, and these southern conscientious objectors suf- fered at the hands of rebels who confiscated their crops and livestock and federals who destroyed what remained. pennsylvania mennonites, in contrast, benefited from political ties to radical republican senator thaddeus stevens, who helped his constituents secure military exemptions from the state militia without paying a commu- tation fee. most pennsylvania pacifists realized that political participation was essential to the preservation of their religious privileges. for several reasons, midwestern mennonites and amish lacked the po- litical connections of their pennsylvania brethren. many pacifists drafted in ohio and indiana paid a $ commutation fee or hired substitutes to avoid service. several ohio anabaptists supported the democratic party, and townships with large pacifist populations in holmes and wayne counties produced large majorities for clement vallandigham in the gubernato- rial contest. however, by the campaigns of , many midwestern menno- nites had adopted the apolitical stance espoused by john funk, who began publishing the herald of truth in elkhart, indiana, and asserted in its pages that a consistent application of pacifist principles prevented a conscientious objector from voting, seeking public office, or purchasing a substitute. most mennonites and amish, the authors conclude, remained true to their spiritual convictions despite the turbulent conditions of civil war. by highlighting the struggles of these religious outsiders who strived to keep bo ok reviews the church distinct from the world, lehman and nolt have produced an insightful study that further elucidates the centrality of religion for a proper understanding of the civil war. s e a n a . s c o t t ouachita baptist university politician extraordinaire: the tempestuous life and times of martin l. davey. by frank p. vazzano. (kent, ohio: kent state university press, . xiv, pp. cloth $ . , isbn - - - - .) with his biography of martin davey, frank vazzano sets out to tell the “good story” of a “very, very interesting man” (x). he accomplishes this goal admi- rably as an “unabashed story teller” and as an historian. certainly, no one knows davey better than the author who has written three articles about davey’s terms as governor, all of which appeared in ohio history. an effective biography not only examines the subject’s life but also the nature of place and time and the meaning of change. as the title indicates, vazzano understands this well. vazzano is especially successful in describing davey’s life and times during his formative years and early career during the late nineteenth and the early twentieth centuries. born of an immigrant father obsessed with the apparently quixotic quest for scientific tree care and raised in poverty in small town kent, ohio, davey grew to manhood as a gifted salesman and businessman, community booster, and brilliant politician. vaz- zano captures the transformation of davey during changing times as he turns his father’s vision into a successful business with customers across much of the nation and helps “boost” kent from a nineteenth-century village with dirt streets to a modern community with all the amenities of public services. vazzano successfully captures the emergence of modern america and the nature of local politics. barely out of his teens, davey is traveling to cleveland to sell his father’s book, the tree doctor, and then new york to promote the davey tree expert company. he boldly cultivates captains of industry, wins the tree care of the capitol grounds, and uses advertising to creatively expand the reach of the business. at the same time, vazzano aptly shows davey mastering local politics: the network of friendships and personal alliances, the use of patronage to reward friends and define politi- cal power, the necessity of strong organization, and the efficacy of public speaking. he was elected mayor of kent, served well, and, as countless poli- ticians before and after him, used that base to win higher office. although one of ohio’s most successful politicians in the twentieth cen- tury who served multiple terms as mayor, in congress, and as governor of ohio, davey remains elusive as a political leader. vazzano documents davey’s brilliance and limitations as a politician; his organizational skills, his tireless wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ the rna-binding protein hur contributes to neuroinflammation by promoting c-c chemokine receptor (ccr ) expression on th cells | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . /jbc.m . corpus id: the rna-binding protein hur contributes to neuroinflammation by promoting c-c chemokine receptor (ccr ) expression on th cells @article{chen therp, title={the rna-binding protein hur contributes to neuroinflammation by promoting c-c chemokine receptor (ccr ) expression on th cells}, author={j. chen and j. martindale and c. cramer and m. gorospe and u. atasoy and p. d. drew and s. yu}, journal={the journal of biological chemistry}, year={ }, volume={ }, pages={ - } } 	j. chen, j. martindale, + authors s. yu 	published 	biology, medicine 	the journal of biological chemistry in both multiple sclerosis and experimental autoimmune encephalomyelitis (eae), the c-c chemokine receptor (ccr ) is critical for pathogenic t helper (th ) cell migration to the central nervous system (cns). whereas many cytokines and their receptors are potently regulated via post-transcriptional mechanisms in response to various stimuli, how ccr expression is post-transcriptionally regulated in th cells is unknown. here, using rna-binding protein hur conditional knock-out (ko) and… expand view on asbmb doi.org save to library create alert cite launch research feed share this paper citationsbackground citations methods citations results citations view all figures, tables, and topics from this paper 	 figure 	 table 	 figure 	 table 	 figure 	 table 	 figure 	 figure 	 figure view all figures & tables 	th cells 	gene expression 	experimental autoimmune encephalomyelitis 	chemokine receptor 	ccr protein, human 	elavl wt allele 	promotion (action) 	multiple sclerosis 	chemokine ccl 	parathyroid hormone receptor 	il ra wt allele 	cns disorder citations citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by relevance sort by most influenced papers sort by citation count sort by recency interaction of rna-binding protein hur and mir- i regulates gm-csf expression 	j. chen, william adamiak, ganlei huang, u. atasoy, a. rostami, shiguang yu 	chemistry, medicine 	scientific reports 	 	 	pdf save alert research feed rna-binding protein hur promotes th cell differentiation and can be targeted to reduce autoimmune neuroinflammation 	j. chen, j. martindale, + authors shiguang yu 	biology, medicine 	the journal of immunology 	 	 	 	view excerpts, cites methods, background and results save alert research feed the retinoic acid receptor drives neuroinflammation and fine tunes the homeostasis of interleukin- -producing t cells 	rasmus agerholm, john rizk, darshana kadekar, annie borch, s. hadrup, vasileios bekiaris 	chemistry, biology 	 	pdf 	view excerpt, cites background save alert research feed hur controls apoptosis and activation response without effects on cytokine ’ utrs 	fedor v. karginov 	biology, medicine 	rna biology 	 	 save alert research feed understanding and targeting the disease‐related rna binding protein human antigen r (hur) 	christopher w. schultz, r. preet, teena dhir, d. dixon, j. brody 	biology, medicine 	wiley interdisciplinary reviews. rna 	 	 	view excerpt, cites background save alert research feed unraveling a new player in multiple sclerosis pathogenesis: the rna-binding protein hur. 	cristiana pistono, m. c. monti, + authors a. pascale 	medicine 	multiple sclerosis and related disorders 	 	 save alert research feed regulation of mrna stability by rbps and noncoding rnas contributing to the pathogenicity of th cells. 	y. zhang, zhiyuan wei, + authors y. tian 	biology, medicine 	rna biology 	 save alert research feed posttranscriptional regulation of mmp‐ by hur contributes to il‐ β‐induced pterygium fibroblast migration and invasion 	yu-hong cui, qingyang feng, + authors hong-wei pan 	chemistry, medicine 	journal of cellular physiology 	 	view excerpt, cites background save alert research feed post‐transcriptional control of immune responses and its potential application 	masanori yoshinaga, o. takeuchi 	biology, medicine 	clinical & translational immunology 	 	 	 	view excerpts, cites background save alert research feed exploring the factors underlying remyelination arrest by studying the post-transcriptional regulatory mechanisms of cystatin f gene. 	j. li, w. durose, + authors k. ikenaka 	biology, medicine 	journal of neurochemistry 	 save alert research feed ... ... references showing - of references sort byrelevance most influenced papers recency posttranscriptional gene regulation of il- by the rna-binding protein hur is required for initiation of experimental autoimmune encephalomyelitis 	j. chen, jason a. cascio, + authors u. atasoy 	biology, medicine 	the journal of immunology 	 	 	highly influential 	pdf 	view excerpts, references background, results and methods save alert research feed conditional knockout of the rna-binding protein hur in cd + t cells reveals a gene dosage effect on cytokine production 	m. m. gubin, patsharaporn techasintana, + authors u. atasoy 	biology, medicine 	molecular medicine 	 	 	pdf 	view excerpt, references methods save alert research feed coordinate regulation of gata- and th cytokine gene expression by the rna-binding protein hur 	c. stellato, m. m. gubin, + authors u. atasoy 	biology, medicine 	the journal of immunology 	 	 	pdf 	view excerpt, references methods save alert research feed up-regulation of macrophage inflammatory protein- α/ccl and cc chemokine receptor in psoriasis 	b. homey, m. dieu-nosjean, + authors a. zlotnik 	biology, medicine 	the journal of immunology 	 	 	pdf 	view excerpt, references background save alert research feed ccr regulates the migration of inflammatory and regulatory t cells 	t. yamazaki, x. yang, + authors c. dong 	biology, medicine 	the journal of immunology 	 	 	highly influential 	pdf 	view excerpts, references background and methods save alert research feed epigenetic modification of the human ccr gene is associated with stable ccr expression in t cells. 	s. steinfelder, s. floess, + authors a. hamann 	biology, medicine 	blood 	 	 	pdf 	view excerpts, references background save alert research feed preferential recruitment of ccr -expressing th cells to inflamed joints via ccl in rheumatoid arthritis and its animal model 	k. hirota, h. yoshitomi, + authors s. sakaguchi 	biology, medicine 	the journal of experimental medicine 	 	 	highly influential 	pdf 	view excerpts, references background save alert research feed elav protein hua (hur) can redistribute between nucleus and cytoplasm and is upregulated during serum stimulation and t cell activation. 	u. atasoy, j. watson, d. patel, j. keene 	biology, medicine 	journal of cell science 	 	 	pdf 	view excerpts, references methods and results save alert research feed the orphan nuclear receptor rorγt directs the differentiation program of proinflammatory il- + t helper cells 	i. ivanov, b. mckenzie, + authors d. littman 	biology 	cell 	 	 , 	 	view excerpt, references background save alert research feed transcriptional control of human antigen r by bone morphogenetic protein* 	s. jeyaraj, m. singh, d. ayupova, s. govindaraju, b. lee 	biology, medicine 	the journal of biological chemistry 	 	 	pdf 	view excerpt, references background save alert research feed ... ... related papers 	abstract 	figures, tables, and topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue türk kütüphaneciliği , ( ), - editörden ______________ editorial geleceğin kütüphaneleri türk kütüphaneciler demeği tarafından üç ayda bir yayımlanan türk kütüphaneciliği dergisinin editörü olarak, - ağustos tarihleri arasında yapılacak olan . ifla konsey ve genel konferansına katılmak üzere dünyanın dört bir yanından güzel kentimiz İstanbul’a gelen seçkin meslek­ taşlarımıza hoş geldiniz demekten büyük onur duyuyorum. ifla genel merkezi ve onun profes­ yonel kurulu, ifla’ ulusal düzenleme komitesi ile birlikte, bu yıl da olağanüstü bir program hazırladılar. İstanbul’da bulun­ dukları süre içinde herkesin (ister mesleki ve sosyal etkinlikler, ister gezi turları olsun) izlemeye değer birşeyler bulacağını umut ediyoruz. ifla konferansının teması, “geleceğin kütüphaneleri,” çok uygun seçilmiş. Çünkü kütüphane ve bilgi hizmetlerinin sağ­ lanmasında daha önce örneği görülmemiş gelişmeler ve değişiklikler yaşıyoruz. bugünlerde “bilgi çağı,” “bilgi toplumu,” “sanayi ötesi toplum” gibi terimleri sık sık duyuyor ve kullanıyoruz. Çoğu kimse bilginin karar vermedeki rolünü teslim etmektedir. “bilgi” giderek artan biçimde bir ürün olarak değerlendirilmektedir. bir toplumun ne kadar bilgi “tüketirse” ekono­ mik yönden o denli gelişeceğine inanıldı­ ğından, herkesin istekli birer “bilgi tüketicisi” olması beklenmektedir. dahası, bilgi gsmh’nin geliştirilmesi için enerji kadar önemli ve değerli görülmektedir. Örneğin, yüzyılımızda tarımsal üretimde libraries of the future as the editor of the türk kütüphaneciliği, a quarterly journal published by the turkish librarians association, i am honored to welcome our distinguished colleagues from all over the world to the beautiful city of istanbul to take part in the st ifla council and general conference from - august . once again, the ifla hq and its professional board, along with the ifla’ national organizing committee, put together an outstanding program this year. we hope that everyone would find something worthwhile to pursue (be it professional and social activities or sightseeing tours, to name but a few) while staying in istanbul. the theme of the st ifla conference, “libraries of the future,’’ was chosen aptly as we have been experiencing unpre­ cedented developments and changes in the provision of library and information services. nowadays we often hear and use such terms as “information age,” “information society," and “post-industrial society” in our daily life. most people recognize the role of information in decision-making as “information” is increasingly treated as a commodity. everybody is expected to become an avid “information consumer” as it is believed that the more information a society “consumes,” the more developed it becomes economically. furthermore, information is seen as valuable and important a resource yaşar tonta meydana gelen artışın fiziksel kaynakların ar tışına değil, büyük oranda yeni bilgi kullanımına bağlı olduğu bilinmektedir. ekonomik kalkınma ile bilgi erişim olanaklarının varlığı arasındaki ilişkiyi fark eden ülkeler kütüphane ve bilgi merkezlerini gelişmiş teknoloji ürünleriyle donatmak için bilgi teknolojisi alanında önemli yatırımlar yaptılar. bu ülkeler çok değişik format- lardaki bilgi kaynaklarının seçimi, düzen­ lenmesi ve bu bilgilere erişim için kütüphaneci ve bilgi profesyonellerinin uzmanlığına gereksinimi olduklarının da farkına vardılar. diyelim ki on yıl önce “gopher” ve “web” gibi internet hizmetleri aracılığıyla saat kullanıma açık tutulan dijital kütüphanelerimizin olacağını kim tahmin ederdi? türk kütüphanecilerinin evlerindeki koltuklarından bile kalkmadan louvre müzesinin koridorlarında dolaşıp oradaki sanat yapıtlarını inceleyeceklerini kim tahmin ederdi? bir gün “bilgi otoyolu”na çıkıldığında, birkaç örnek vermek gerekirse, kütüphane ve bilgi mer­ kezlerindeki, sinema ve tv arşivlerindeki, coğrafık bilgi sistemlerindeki, eğit'm, sağlık ve adalet konusundaki veri taban karındaki her tür bilgiye (metin, grafik, ses ve hareketli görüntüler içeren çoklu ortam) erişebileceğimizi kim tahmin ederdi? sanırım çok az kişi.. ekonomik kalkınma ile bir ülkedeki bilgi teknolojisi araçlarının varlığı arasında nasıl bir ilişki varsa, bilgiye özgürce erişim ile demokrasi arasında da bir ilişki olduğu gözlenmektedir. bu ilişkiyi çok önceleri fark eden thomas jefferson, bilgiyi “demok­ rasinin değer birimi” olarak nitelendirmiştir. bu yaklaşımı benimseyen ve demokrasilerin ancak bilgili vatandaşlar tarafından geliştirilip güçlendirilebileceğini fark eden ülkeler bilgi edinme özgürlüğünün önündeki tüm engelleri kaldırmakta ve kütüpha­ nelerini ve bilgi merkezlerini büyük ölçüde desteklemektedirler. as energy for the development of the gnp. for instance, it is known that the increase in the agricultural productivity within the last century is primarily due to the use of new information, not because of increase in the physical resources. countries that have noticed the relation­ ship between the economic development and the availability of information access and retrieval capabilities have invested heavily in information technology to equip their library and information centers with fairly developed technological products. they also realized that they needed the expertise of library and information professionals to cope with the selection, organization and retrieval of information sources available in a multitude of format. who would have thought, say, ten years ago that we would have digital libraries that are open to public hours a day through the internet services such as gopher and the world-wide web? who would have thought that turkish librarians would stroll through the corridors of the. louvre museum virtually and explore some of the artwork there without even leaving their seats at home? who would have thought that one day, once on the “information superhighway,” one could get access to all sorts of information (textual, graphical, multimedia including sound and live pictures) that are available through libraries and information centers, cinema and tv archives, geographic information systems, education, health and justice databases, to name just a few? very few> people would, i reckon. just as there is a relationship between the level of the economic development and the availability of information technology tools in a given country, there appears to be a strong relationship between democrat­ ization and the freedom of access to information. thomas jefferson, who noticed this relationship long ago described in- editörden / editorial ancak, bilgiye erişimle demokrasi ve ekonomik kalkınma ile bilgi teknolojisi kolaylıklarının varlığı arasındaki bu olumlu ilişkilere karşın, insan, yine de, kendi aramızda barışı sağlama ve koruma konusunda katedeceğimiz uzun bir yol olduğunu düşünmekten kendini alamıyor. bir yandan, başka ülkelerdeki çevrimiçi ve dijital kütüphanelere ve bilgi kaynaklarına hemen hemen hiçbir engelle karşılaşmadan anında erişim sağlamak ve bu erişimi sürekli kılmak bizim için çok önem taşıyabiliyor. Öte yandan, bu çevrimiçi bilgilerin ana kaynağı ve bilgi ile kültürün fiziksel yapıtları olan kütüphane, arşiv ve müzelerin tahrip edilmesine karşı daha az duyarlı olabili­ yoruz. kütüphaneler, arşivler ve müzeler geçmişte her zaman demokrasinin kaleleri olmuş ve bundan bütün uluslar eşit biçimde yararlanmışlardır. ancak demok­ rasinin kaleleri bosna-hersek’te uygar dünyanın gözleri önünde yerle bir edil­ meye ve yakılmaya devam edilmektedir. buna izin vermemeliyiz. İstanbul’da ileriye bakıp geleceğin kütüphaneleri hak­ kında düşünürken, şimdiki ve geçmişteki kütüphanelere de bakalım. profesör riedlmayer’in dediği gibi: “kütüphane ve arşivlerin yakılması, doğrunun ortada bir yerlerde olduğunun farzedildiği iki taraflı bir siyasi anlaşmazlıkta taraflardan birinin görüşlerini ifade etmesi şeklinde değerlendirilemez.” bu hain eylemleri kınıyor ve tüm meslektaşlarımızı çok geç olmadan bu tür eylemlere karşı çıkmaya çağırıyoruz. değilse, uzun vadede bundan hepimiz zarar göreceğiz. andrâs riedlmayer, “erasing the past: the destruction of libraries and archives in bosnia- herzegovina,” middle east studies association bulletin ( ): - , july . riedlmayer’in maka­ lesinin türkçe çevirisini bu sayıda bulabilirsiniz. türk kütüphaneciliği*nin ifla’ formation as the “monetary value of democracy." countries which have adopted this approach and noticed that democracies can only be developed and strengthened through informed citizens, abolish all barriers before the freedom of information and support their libraries and information centers to a great extent. one cannot help but think, however, that, despite the positive inter­ relationships between the freedom of access to information and democracy, and between the economic development and the availabiliy of information retrieval facilities, it appears that we have a long way to go in protecting and preserving the peace among ourselves. on the one hand, it may be tremendously important for us to get access to the online and digital libraries and information sources of other countries within a fraction of a second with virtually no boundaries, and keep it that way. yet, on the other hand, we may be less sensitive against the destruction of physical artefacts of information and culture such as libraries, museums, and archives which are the main sources of most online and digital information in the first place. library and information centers, archives, and museums have always been the bastions of democracy in the past and all the nations have benefitted equally from that. yet the bastions of democracy continue to be burned and leveled to the ground in bosnia-herzegovina before the very eyes of the civil world. we must not allow this to happen. while looking ahead and contemplating about the libraries of the future here in istanbul, let’s look also at the libraries of the present and the past. as professor riedlmayer puts it: “the burning of libraries and archives cannot be construed as a mere expression yaşar tonta Özel sayısıyla ilgili olarak da birkaç söz söylemek istiyorum: türk kütüphaneleri ve arşivleri hakkında çeşitli makalelerin yanı sıra her zamanki yazıları da içeren bir özel sayı hazırladık (üniversite, halk ve okul kütüphaneleri, kütüphanecilik eğitimi, yazma ve nadir eser kütüphaneleri, türk arşiv araştırmaları, vd.). Özel sayı yayımlama düşüncemizi destekledikleri ve maddi kaynak sağladıkları için ifla‘ ulusal düzenleme komitesi başkanı ve üyelerine teşekkür etmek isterim. yardımcı editör olarak aramıza katılan meslektaşımız müjgân Şan’a da hoş geldin diyorum. İstanbul’u ziyaretinizden memnun kalmanızı ve verimli bir ifla konferansı geçirmenizi umuyoruz. gelecek yıl pekin’de görüşmek üzere. güle güle! yaşar tonta of one side’s views in a two-sided politi­ cal dispute where right is assumed to re side somewhere in the middle.” we condemn these wicked acts and urge our colleagues to take a stand against such acts before it is loo late. if not, we will all suffer in the long run. i would also like to add a few notes about the ifla’ istanbul special issue of the türk kütüphaneciliği. we have put together a special issue that contains a wide range of articles on turkish libraries and archives as well as our regular features (turkish university, public and school libraries, education for librarianship in turkey, manuscripts and rare books libraries, turkish archival studies, networked information in turkey, etc.). i would like to thank the president and members of the ifla ‘ istanbul national organizing committee for supporting the idea of publishing a special issue and sponsoring it. i would also welcome my colleague ms. müjgân Şan who joined the editorial board as an associate editor. we hope you all enjoy your stay here in istanbul and have a fruitful ifla conference. looking forward to meeting you in beijing, china, next year. güle güle! yaşar tonta andras riedlmayer. "erasing the past: the destruction of libraries and archives in bosnia- herzegovina," middle east studies association bulletin ( ): - , july . the turkish hanslation of riedlmayer’s article can be found elsewhere in this issue. wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ doi: . /j.bpj. . . a monday, february , mechanisms through which upregulation of bcl affects earlier steps of bax- mediated apoptosis are not fully understood. we found that bax insertion into the mom was the earliest apoptotic step inhibited by bcl overexpression. paradoxically, we also found that bax translocation to the mitochondria was not inhibited but rather spontaneously increased in this same genetic context. this increase in mitochondrial associated bax required a physical interaction be- tween bax and bcl . we therefore propose that, at least when upregulated, bcl behaves as a ‘decoy receptor’ which sequestrates bax at the mitochondria but inhibits its insertion into the mom, committing the cell to survive. supported by nyu research challenge funds to ld. -pos compartmentalization of bcl family proteins mediated by organelle lipid membranes rebecca j. boohaker, ge zhang, adina loosley, kathleen nemec, annette r. khaled. university of central florida, orlando, fl, usa. cancer is defined by a pronounced inhibition of cell death. the bcl family of proteins tightly regulates the delicate balance between life and death. one method of regulation is the compartmentalization of antagonistic members. for example, bax, a pro-apoptotic member of this family, acts as the penulti- mate factor in the apoptotic cascade by releasing apoptogenic factors such as cytochrome c from the mitochondrial lumen. the normally cytosolic protein translocates from one internal compartment to another through an elusive mechanism. individual organelles are defined not only by function (mediated by specific membrane bound proteins), but by the unique composition of their phospholipid membranes. in this work, we have evaluated the contribution of organelle lipids to the localization of of bcl proteins. -pos in search of the structure of mac in the mitochondrial outer membrane pablo m. peixoto , christian renken , shefali haldar , carmen mannella , kathleen w. kinnally . new york university college of dentistry, new york, ny, usa, wadsworth center, albany, ny, usa, academy of the holy names, albany, ny, usa. several groups have tried to determine the structure of the channel (mac) formed in mitochondrial outer membranes (om) of apoptotic cells or in syn- thetic membranes by bax and related proteins/peptides, using electron micros- copy (em), atomic force microscopy and x-ray diffraction. here, pore-like structures ~ - nm were handpicked from transmission em images of ura- nyl-acetate-stained oms isolated from control and apoptotic (il -deprived) fl . cells. these ‘‘candidate pores’’ were aligned by correlation procedures, and class averages defined by principal component and k-means analyses. main differences in the class averages were ( ) the presence of one or more dark (stain-filled) pores, and ( ) the nature of white (stain excluding) features around the pores. a class average consisting of a single -nm pore with pro- nounced white rim was rotationally averaged and used as a reference for cross-correlation searches of om images from control and apoptotic cells. searches using this -nm ‘‘donut’’ motif and the same motif doubled in size ( -nm ‘‘donut’’) yielded thousands of ‘‘hits’’ in both control and apoptotic membranes, which were subsequently aligned and classified as before. the pre- dominant stain-filled structures found with both motifs were not circular but elongated (up to ~ x nm), extending away from stain-excluding crescent- shaped features. the radial anisotropy ruled out reference bias and was in- consistent with pores formed by rings of evenly spaced protein subunits. we hypothesize that the different classes of structures detected represent stages in formation of mac as an increasingly large membrane bilayer defect (or ‘‘cleft’’) induced by successive aggregation or clustering of bax/bak molecules. a progressive assembly mechanism for mac has been recently suggested by real-time monitoring of mac conductances in isolated mitochondria by patch clamping (martinez-caballero et al. j biol chem : - ). supported by nih grant gm . -pos effects of mac formation on mitochondrial morphology pablo m. peixoto, shin-young ryu, robert range, kathleen w. kinnally. new york university college of dentistry, new york, ny, usa. accumulating literature associate mitochondrial dynamics with apoptosis, since regulation of either process has reciprocal effects. these processes seem to converge in formation of the mitochondrial apoptosis induced channel, mac, which releases cytochrome c and triggers the degradation phase of apo- ptosis. while bax and bak, core components of mac, were shown to interact with fusion and fission proteins, some studies also suggest proteins from the in- termembrane space could leak to the cytosol and further promote mitochondrial fission during apoptosis. the temporal relationship between apoptosis induc- tion, mac formation and mitochondrial fragmentation was investigated by time lapse microscopy. mac function was induced through staurosporine treat- ment and microinjection of tbid or cytochrome c. mac formation and mito- chondrial dynamics under these conditions were monitored in hela cells (clone ) that stably express low levels of gfp-bax and were transiently transfected with a pdsred- plasmid. gfp-bax relocation to mitochondria only during apoptosis signals mac formation, while pdsred- expression shows mito- chondrial structure as red fluorescence. treatment with staurosporine and microinjection with tbid or cytochrome c induced relocation of bax and col- lapse of the mitochondrial network. the temporal relationship between these two events was further analyzed. interestingly, pretreatment with imac , a spe- cific mac blocker, protected against cell death and prevented mitochondrial fragmentation after tbid injection. our results suggest a link exists between mac formation and collapse of the mitochondrial network during apoptosis. supported by nih grant gm . -pos mechanism of the mitochondrial cytochrome c release wave in bid-induced apoptosis soumya sinha roy, cecilia garcia-perez, erika davies, xuena lin, györgy hajnóczky. thomas jefferson university, philadelphia, pa, usa. bid, a bh -only bcl family protein, plays a central role in apoptosis. bid is cleaved by caspase- and other enzymes forming tbid that induce mitochon- drial outer membrane (omm) permeabilization and cytochrome c (cyto-c) re- lease. however a mystery remains how bid synchronizes the function of a large number of discrete organelles, particularly in mitochondria-rich liver or muscle cells. here we showed that tbid ( . - nm) elicited progressive omm perme- abilization and complete cyto-c release with a dose-dependent lag time and rate in h c cell populations. once started, the omm permeabilization was not pre- vented by tbid washout. in contrast, the dose-response for digitonin-induced omm permeabilization displayed quantal behavior. in single cell imaging studies, permeabilized h c and primary human cardiac cells transfected with cyto-c-gfp showed complete tbid-induced cyto-c-gfp release closely followed by mitochondrial depolarization. the cyto-c-gfp release started at discrete sites and propagated through the mitochondria with a constant velocity and a relatively stable kinetic of release in each organelle. similar tbid-induced cyto-c-gfp release wave was documented in intact h c cells transfected with tbid. the waves were not dependent on ca þ , caspase activation or permeabil- ity transition pore opening. however, treatment with mntmpyp, a ros scav- enger or overexpression of mitochondrial superoxide dismutase suppressed the coordinated cyto-c release and also inhibited tbid-induced cell death. on the other hand, both superoxide and hydrogen peroxide sensitized mitochondria to the tbid-induced permeabilization. thus, tbid engages a ros-dependent inter-mitochondrial signaling mechanism for spatial amplification of the apoptotic signal by mitochondrial waves. -pos role of milton domains in the calcium-dependent regulation of mito- chondrial motility sudipto das, gyorgy hajnoczky. thomas jefferson university, philadelphia, pa, usa. the mammalian grif and oip , and the drosophila milton are kinesin- binding proteins that form a complex with the miro gtpase, an outer mitochon- drial membrane ef-hand protein, to support the movement of mitochondria along the microtubules. our study demonstrates that in h c cells overexpress- ing oip or grif , the basal motility of mitochondria is increased, whereas the sensitivity to calcium-induced movement inhibition is decreased. to dissect the interaction between milton, kinesin and miro, three different milton constructs were tested: milton ( - ), the soluble domain of milton; milton ( - ), lacking the kinesin heavy chain binding site and milton ( - ) that lacks additional ~ amino acid presumably containing part of the miro binding site. immunohistochemistry revealed that the overexpressed milton ( - ) was cytoplasmic, whereas the other two milton constructs showed mitochondrial localization. the basal mitochondrial motility was in- creased by milton ( - ) but was not altered by milton ( - ) or mil- ton ( - ). a plot of mitochondrial motility against slowly rising cytoplasmic [ca þ] induced by thapsigargin ( mm), shows that overexpression of milton ( - ) significantly reduced the calcium sensitivity of mitochondrial motil- ity reminiscent of oip and grif . by contrast, milton ( - ) or milton ( - ) did not have any effect. the thapsigargin-induced cytoplasmic calcium signal was not affected by any of the milton constructs. these data indicate that 	compartmentalization of bcl family proteins mediated by organelle lipid membranes 	in search of the structure of mac in the mitochondrial outer membrane 	effects of mac formation on mitochondrial morphology 	mechanism of the mitochondrial cytochrome c release wave in bid-induced apoptosis 	role of milton domains in the calcium-dependent regulation of mitochondrial motility wp-p m- .ebi.ac.uk params is empty sys_ exception wp-p m- .ebi.ac.uk no params is empty exception params is empty / / - : : if (typeof jquery === "undefined") document.write('[script type="text/javascript" src="/corehtml/pmc/jig/ . . /js/jig.min.js"][/script]'.replace(/\[/g,string.fromcharcode( )).replace(/\]/g,string.fromcharcode( ))); // // // window.name="mainwindow"; .pmc-wm {background:transparent repeat-y top left;background-image:url(/corehtml/pmc/pmcgifs/wm-nobrand.png);background-size: auto, contain} .print-view{display:block} page not available reason: the web page address (url) that you used may be incorrect. message id: (wp-p m- .ebi.ac.uk) time: / / : : if you need further help, please send an email to pmc. include the information from the box above in your message. otherwise, click on one of the following links to continue using pmc: search the complete pmc archive. browse the contents of a specific journal in pmc. find a specific article by its citation (journal, date, volume, first page, author or article title). http://europepmc.org/abstract/med/ molecular medicine reports : , corrigendum doi: . /mmr. . farnesoid x receptor deletion improves cardiac function, structure and remodeling following myocardial infarction in mice jianshu gao, xiaoqiang liu , bingjian wang, haiyan xu, qiang xia, tianfei lu and fang wang mol med rep : - , ; doi: . /mmr. . following the publication of this article, an interested reader drew to our attention that we had incorrectly reported (in the materials and methods section, ‘western blot analysis’, on p. ) that the anti-farnesoid x receptor (fxr) antibody of cell signalling technology, inc., cat. no. # , had been used in this study to probe for fxr. in fact, the antibodies used in the above-mentioned study were a gift from the group of dr xin-liang ma at thomas jefferson university (philadelphia, pa, usa), as referenced in the following article: [pul j, yuan a, shan p, gao e, wang x, wang y, lau wb, koch w, xin-ma xl and he b: cardiomyocyte-expressed farnesoid-x-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury. eur heart j : - , ]. the antibody that was used for the western blotting analysis was raised against the c-terminus of fxr (c- ; cat. no. sc- , santa cruz biotechnology, san diego, ca, usa). we sincerely apologize for this mistake, and thank the reader of our article who drew this matter to our attention. the error made in our incorrect referencing of the antibody did not affect the conclusions reported in this study. furthermore, we regret the inconvenience that this mistake caused. thickness of retinal nerve fiber layer correlates with disease duration in parallel with corticospinal tract dysfunction in untreated multiple sclerosis jrrdjrrd volume , number , pages – journal of rehabilitation research & development thickness of retinal nerve fiber layer correlates with disease duration in parallel with corticospinal tract dysfunction in untreated multiple sclerosis rebecca i. spain, md; – * mitchell maltenfort, phd; robert c. sergott, md; thomas p. leist, md, phd department of neurology, thomas jefferson university, philadelphia, pa; department of neurology, oregon health & science university school of medicine, portland, or; neurology service, portland department of veterans affairs medical center, portland, or; department of neurological surgery, jefferson medical college, thomas jefferson university, philadelphia, pa; neuro-ophthalmology service, wills eye institute, thomas jefferson university, philadelphia, pa; comprehensive multiple sclerosis center, department of neurology, jefferson medical college, thomas jefferson university, philadelphia, pa abstract—optical coherence tomography (oct) is an emerg- ing clinical and research measure of retinal nerve fiber layer (rnfl) loss in multiple sclerosis (ms) and may reflect neuro- degeneration. few studies capture the effect of disease duration on the rnfl in subjects without exposure to disease-modulating therapies. we assessed the relationship of rnfl loss with dis- ease duration in subjects with untreated ms and determined if such loss paralleled corticospinal tract dysfunction in ms. sub- jects underwent oct (n = ) and visual testing (n = ). either they were either examined or they participated in a vali- dated telephone interview so we could determine their expanded disability status scale (edss) scores. both rnfl thickness (spearman rs = – . , p < . ) and edss scores (rs = . , p < . ) correlated with disease duration. rnfl thick- ness correlated with edss scores (rs = – . , p < . ). in conclusion, rnfl loss correlates with disease duration and edss scores in subjects with untreated ms, indicating that oct may capture neurodegeneration. key words: disease duration, disease-modifying therapy, expanded disability status scale, multiple sclerosis, neurode- generation, optic nerve diseases, optical coherence tomogra- phy, rehabilitation, retinal nerve fiber layer, visual acuity. introducton in multiple sclerosis (ms), both inflammatory demye- lination and axonal loss in gray and white matter are observed early, even presymptomatically [ ]. these losses lead to central nervous system (cns) atrophy [ ] and abbreviations: ci = confidence interval, cns = central ner- vous system, dmt = disease-modifying therapy, edss = expanded disability status scale, hcva = high-contrast visual acuity, lcva = low-contrast visual acuity, logmar = logarithm of minimum angle of resolution, mri = magnetic resonance imaging, ms = multiple sclerosis, oct = optical coherence tomography, on = optic neuritis, ou = oculus uter- que (both eyes), rnfl = retinal nerve fiber layer, rnflt = rnfl thickness, rrms = relapsing-remitting ms, va = visual acuity. *address all correspondence to rebecca i. spain, md; department of neurology, oregon health & science uni- versity, sw sam jackson park road, portland, or ; - - ; fax: - - . email: spainr@ohsu.edu doi: . /jrrd. . . mailto:spainr@ohsu.edu jrrd, volume , number , functional disability [ ]. standard outcome measures of relapse rate and magnetic resonance imaging (mri) lesion load neither correlate well with functional decline nor reflect cns neurodegeneration [ – ]. optical coher- ence tomography (oct) is under evaluation as an out- come measure of axonal degeneration for use in clinical trials and practice [ ]. oct is a noninvasive technique that uses infrared laser light to create cross-sectional images of the retina; this technique provides quantitative analysis of the retinal nerve fiber layer (rnfl) thickness (rnflt), macular thickness, and macular volume. the mechanism and reli- ability of oct are well described [ ]. oct detects changes in the rnfl, which contains unmyelinated axons subject to damage in glaucomatous and ischemic optic neuropathies [ ]; more recently, oct has been applied to optic neuritis (on) [ ]. short-term follow-up studies after acute on demonstrate an acute decrement of the peripapillary rnflt that plateaus by to months [ ]. oct also detects changes in the macula after on [ ]. the calculated macular volume includes the inner macular thickness, which contains the retinal ganglion cells presumably affected after on by a dying-back axonopathy, as seen in animal models [ ]. alternatively or additionally, primary neuronal degeneration may affect the retinal ganglion cells. oct has been shown to correlate with functional optic nerve measures such as multifocal visual-evoked potentials [ ] and low-contrast visual acuity (lcva) [ ]. as one of the longer white matter tracts in the cns, the optic nerve is likely to show the effects of both acute inflammation and neurodegeneration early in ms. on is the presenting symptom of ms in to percent of cases and eventually affects up to percent of patients during the illness, causing significant morbidity [ ]. rnflt in subjects with ms without a history of on is lower than in control subjects, indicating subclinical axonal loss [ , ]. thus, oct is an attractive candidate measure for capturing early changes in ms. the corticospinal tract is another long cns white matter tract frequently affected in ms. like the optic nerve, it is subject both to acute inflammation in the form of transverse myelitis and to neurodegeneration as seen by increasing gait dysfunction, mri atrophy [ ], and recently, gray matter demyelination on high-field mri [ ]. the expanded disability status scale (edss) is a standard measure of gait dysfunction and may correlate with other long tract signs, including rnfl loss and cog- nitive dysfunction [ ], although it poorly predicts long- term disability [ ] and its validity in relapsing-remitting ms (rrms) has been recently challenged [ ]. oct may provide a more sensitive research and clinically applicable measure to capture neurodegeneration in ms. most studies using oct have not accounted for the effects of disease-modifying therapies (dmts) on the rnfl, which may be significant if similar to dmt effects in early ms [ ]. we studied oct in subjects with ms of varying disease durations and with no expo- sure to dmts to test the hypothesis that in untreated ms, rnflt loss occurs both over the course of disease and in parallel with corticospinal tract dysfunction reflecting cns neurodegeneration. methods subjects the institutional review board approved all study procedures, and subjects gave their written informed con- sent. we recruited subjects over years of age from the thomas jefferson university comprehensive ms center (philadelphia, pennsylvania) and the neuro-ophthalmology service at wills eye institute (philadelphia, pennsylva- nia) with no exposure to dmt. subjects met revised mcdonald criteria for ms [ ]. we included subjects with clinically isolated syndrome if they fulfilled two or more modified barkhof mri criteria [ ]. we deter- mined disease-duration subject history. we considered neurological symptoms occurring before the diagnosis date to be caused by ms if they were of a typical nature (brainstem, spinal cord, visual, or multisystem), lasted for at least hours, and were unexplained by other neu- rological or systemic conditions. exclusion criteria included any dmt use, including interferon beta preparations, glatiramer acetate, natali- zumab, mitoxantrone, chemotherapeutics, or immuno- suppressants. we did not consider corticosteroid treatment a dmt for the purpose of this study, although the effects of corticosteroids on rnflt after on are largely unknown. of the subjects, had been treated with corti- costeroids before enrollment; only had received corti- costeroid treatment for acute on in the year before enrollment. we delayed enrollment in subjects with acute on for to months to allow the rnfl to stabilize [ ] and for at least month after intravenous corticosteroid treatment. we excluded subjects with comorbid systemic spain et al. retinal nerve thickness in untreated ms diseases that could mimic ms, ocular disease that might affect the oct results, or other abnormal fundoscopic findings unrelated to ms. we also excluded subjects with octs performed at nonparticipating facilities or who were unable to cooperate with testing. the primary end point was to establish a correlation between rnflt and disease duration. secondary end points included establishing correlations between edss scores and disease duration, rnflt and edss scores, and rnflt and both high-contrast visual acuity (hcva) and lcva and determining the effects of on history on these relationships. the study was powered on the pri- mary end point only. we calculated a sample size of subjects to achieve percent power to detect a moderate spearman rank correlation of . with a percent two-sided test. after study initiation, data regarding the normal age-related rnfl decrement of µm/decade over the age of years became available [ ]. we increased rnflt by a factor of µm for every decade over age for each subject, and we recruited additional subjects to allow for a lower correlation coefficient. we did not age adjust macular data because limited data on normative age-related decrements exists [ ]. of the subjects, we screened , enrolled , and then excluded an additional after enrollment, leaving subjects. screen failures were from lack of interest (n = ), dmt use (n = ), uncertainty of ms diagnosis (n = ), on within months of oct (n = ), comorbid sys- temic or ocular disease (n = ), clinically isolated syn- drome failing mri criteria (n = ), and oct from a nonparticipating facility (n = ). reasons for exclusion after enrollment were dmt use (n = ), clinically iso- lated syndrome failing mri criteria (n = ), on within months of oct (n = ), lack of informed consent (n = ), uncertainty of ms diagnosis (n = ), and comorbid ocular disease (n = ). history of optic neuritis prior studies have shown an absolute difference in rnflt based on individual eye on history [ , ]. we obtained on history in our study by subject report. because on history is subject to recall and other biases, we performed multivariate analyses considering the effect of individual eye on history and thinner side rnflt in the manner proposed by sepulcre et al., presuming the thinner side is most affected by inflammation [ ]. retinal imaging oct images were acquired with a stratus oct with (software version . , carl zeiss meditec, inc; dublin, cali- fornia) by trained technicians at the wills eye institute and thomas jefferson university, and dr. sergott reviewed them for quality. we dilated the subjects’ pupils with . percent phenylephrine hydrochloride and . percent tropicamide if a small pupil sized impaired image quality [ ]. we captured three . -mm diameter fast rnfl pro- tocol scans (scan length = . mm) centered on the optic disk for each eye. the stratus oct software calcu- lated mean rnflt values from each ° scan, and we averaged the three means for each eye using microsoft excel (version , microsoft corp; redmond, wash- ington) to reduce the influence of technical error during scan acquisition. the fast macular protocol (scan length = . mm, reliability within ± µm) used the average of six radial lines to compose a macular thickness/volume map. we reviewed additional fast optic disk and fast crosshair images to exclude other ocular pathologies. all images met the signal strength requirements of at least (maximum ) as per manufacturer recommendation. visual testing we measured the hcva of each eye with appropriate refraction using a retro-illuminated early treatment dia- betic retinopathy study chart (precision vision; la salle, illinois) at m, and we recorded m as the loga- rithm of minimum angle of resolution (logmar) acuity. we tested lcva at m and evaluated given data sug- gesting improved sensitivity for optic nerve dysfunction [ ] using a . percent low contrast sloan letter chart (precision vision). we determined the eye with greater visual impairment by logmar value; we considered eyes with equal logmar values equally impaired. corticospinal tract dysfunction dr. spain examined thomas jefferson university subjects (n = ) for their edss scores [ ]. because they were unavailable to be evaluated in the clinic, wills eye institute subjects (n = ) participated in a stan- dardized and validated telephone interview conducted by dr. spain that established their edss scores [ ]. statistical analysis we used spearman rank correlation to assess correla- tions between oct parameters, edss scores, visual jrrd, volume , number , acuity (va), and disease duration. oct parameters from each eye included the average rnflt; the thickness of the temporal, inferior, nasal, and superior quadrants of the rnfl; the total macular volume; and the minimum and average thicknesses of the fovea. we age-adjusted rnflt as described previously. we performed multivari- ate analyses to determine the effects of on history as described previously. we used the tukey test method to limit type error from performing more than one statistical test; individual p-values of . and . limited the overall type rate at . as indicated. we used analysis of variance to compare the mean rnflt for both eyes (ocu- lus uterque [ou]) between cohorts with and without on history. we performed statistical analyses using jmp, ver- sion . (sas institute, inc; cary, north carolina). results table shows subject demographics. wills eye institute subjects (n = ) were more likely to have rrms ( % vs %), on ( % vs %), a higher mean edss score ( . vs . ), and a lower mean rnflt ( . µm vs . µm) than thomas jefferson university subjects (n = ). we found no other systematic differences between recruitment sites. the distribution of subjects by disease duration demonstrated a wide spread, with subjects in the - to -year duration group, in the - to -year group, in the - to -year group, and in the > -year group. the rnflt ou correlated significantly with ms dis- ease duration (spearman rs = – . , p < . ) (figure (a) and table ). other oct parameters, including macular volumes and foveal thicknesses, did not demon- strate superior correlations with disease duration com- pared with the rnflt (table ). the inferior quadrant rnflt had the strongest correlation with disease dura- tion than any other sector, although all were significant (data not shown). while some studies suggest a greater absolute rnflt loss in the temporal sector [ ], others do not [ ]; as yet, little data exist to suggest differing regional rates of rnfl decline. corticospinal tract dysfunction as captured by edss also correlated with disease duration (rs = . , p < . ) (figure (b) and table ). finally, rnflt ou correlated with edss scores (rs = – . , p < . ) (fig- ure (c) and table ). we performed multivariate analyses to determine the effects of individual eye on history and the thinner rnflt on the correlations between rnflt and edss scores with disease duration. while rnflt differed sig- nificantly between eyes with a history of on ( . µm, % confidence interval [ci] . – . µm) compared with no history ( . µm, % ci . – . µm; p < . ) and between thinner ( . µm, % ci . – . µm) and thicker side ( . µm, % ci . – . µm; p < . ), neither had a significant affect on the relationship between rnflt or edss scores and dis- ease duration (table ). of note, of the subjects with known on had been affected bilaterally, thereby decreas- ing a possible on effect. interestingly, the on eye did not always demonstrate a more impaired oct; of sub- jects with monocular on, had a thinner rnflt and had a lesser macular volume in the opposite eye. as a proof of concept, va worsened at a lower rnflt. hcva was shown to correlate with rnflt (rs = – . , p < . , n = ) (table ), as did lcva (rs = – . , p = . ), although we tested fewer subjects using lcva (n = ). both on history and thinner-side rnflt influenced the va results, as shown by multivariate analyses (table ), although none reached significance after we applied the tukey test for multiple analyses. a categorical difference existed between subject cohort-based on history. the mean rnflt ou was sig- nificantly lower in subjects with a history of on ( . µm, % ci . – . µm) compared with in those without ( . µm, % ci . – . µm; p < . ) (figure ). the distinction in baseline rnflt based on subject on table . subject demographics. variable number (%) total ( ) thomas jefferson university ( ) wills eye institute ( ) female ( ) age (yr, mean ± sd) . ± . (range – ) type of ms clinically isolated syndrome ( ) relapsing-remitting ( ) secondary progressive ( ) primary progressive ( ) history of optic neuritis ( ) disease duration (yr, mean ± sd) . ± . disease duration (yr, median) . (range . – . ) edss score (mean ± sd) . ± . edss score (median) . (range . – . ) edss = expanded disability status scale, ms = multiple sclerosis, sd = standard deviation. spain et al. retinal nerve thickness in untreated ms history may have implications for using oct as an out- come measure in populations with ms heterogeneous in on status. discussion few studies have assessed rnfl loss in subjects with ms who had not received dmts. we found that in ms, a greater correlation existed between rnfl loss and desease duration than could be accounted for by age alone, corroborating other recent studies [ , ]. in addi- tion, the functional measure edss also correlated with disease duration, supporting the hypothesis that long white matter tracts (optic nerve and corticospinal tracts) are frequently affected by symptomatic inflammation and insidious neurodegeneration. while rnfl and edss scores correlated with each other, as has been shown in other studies [ , ], com- parison of their relative sensitivities to change over the figure . (a) retinal nerve fiber layer thickness (rnflt) of both eyes correlates with disease duration. (b) expanded disability status scale (edss) scores correlates with disease duration. (c) rnflt of both eyes correlates with edss scores. “+” = subject history of optic neuritis (on), “×” = no subject history of on. jrrd, volume , number , short term cannot be evaluated in this cross-sectional design. furthermore, oct is a continuous physiological measure, while edss is an ordinal functional measure and thus not directly comparable. this study does, how- ever, provide baseline data for a prospective study of rnfl loss in subjects with untreated ms to assess the true rates of loss regarding on history and sensitivity to short-term changes. rates of rnfl loss need to be assessed in conjunction with whole brain or gray matter atrophy measures [ ] and more sensitive measures of cor- ticospinal tract dysfunction than the edss [ – ] so we can gain a comprehensive measure of the neurodegenera- tive component of ms. only then can neuroprotective strategies for preserving vision, gait, cognition, and the other debilitating effects of ms be more confidently tested. we found that peripapillary rnfl measures pro- duced stronger correlations with disease duration than did macular measures of thickness [ ] or volume [ ], which have been found in other studies to be more sensi- tive to the effects of on. further elucidation is required. correlations between rnflt ou and disease dura- tion were relatively modest. exclusion of subjects with clinically isolated syndrome based on mri criteria may have biased the subjects with shorter disease duration toward those with more advanced disease and potentially more rnfl involvement than a true early ms cohort. additionally, some of the subjects with longer disease duration, having chosen not to initiate dmt, may have been biased toward less severe disease and potentially less rnfl loss. the cross-sectional design of the study and heterogeneous subject population regarding ms type and stage of disease may also have influenced the strength of correlations. multivariate analysis using individual eye on his- tory and thinner rnflt side did not affect the relation- ships of rnflt and edss scores to disease duration, although this study was not powered to address these sec- ondary outcomes. this finding may indicate that subclin- ical on and/or ongoing neurodegeneration affect both optic nerves sufficiently to negate the influence of symp- tomatic on. interestingly, oct data contradicted the recalled history of on in one-quarter of subjects with lesser rnflt in the reportedly unaffected eye. a larger prospective study of rnfl loss is necessary to determine the character and tempo of neurodegeneration given on history. at a given time point, using the averaged rnflt ou may prove a more useful global measure of disease burden. the smaller baseline rnflt among subjects with a history of on as found in other trials may require sub- ject stratification by subject history of on rather than individual eye history of on in clinical trials [ ]. table . spearman correlation coefficients (rs) and p-values between optical coherence tomography (oct) parameters and disease duration (in years) and between expanded disability status scale (edss) scores and disease duration. significance set at p < . for multiple comparisons (tukey test). outcome measure disease duration rs p-value oct parameter rnflt ou (µm) – . < . rnflt inferier quadrant ou (µm) – . . total macular volume ou (mm ) – . . fovea minimum thickness ou (µm) . . fovea thickness ou (µm) — — edss . < . ns = not significant, ou = oculus uterque (both eyes), rnflt = retinal nerve fiber layer thickness. table . spearman correlation coefficients (rs) and p-values between retinal nerve fiber layer thickness (rnflt) of both eyes (oculus uterque [ou]), expanded disability status scale (edss) scores, and both high- and low-contrast visual acuities (hcva and lcva, respectively). significance set at p < . . outcome measure rnflt ou (µm) edss edss rs = – . — p < . — hcva rs = – . rs = . p < . p < . lcva rs = – . rs = . p = . p = . spain et al. retinal nerve thickness in untreated ms as proof of concept, we found worse va to correlate with a lower rnflt and a more impaired edss score, with stronger correlations for hcva than lcva likely influenced by the unequal numbers tested (table ). overall, correlations between rnflt and va measures were sensitive to the effects of on and thinner rnflt side, although the study was underpowered to these sec- ondary outcomes. the poorer visual outcomes at lower rnflt underscore the need to measure and preserve reti- nal axons. larger prospective studies that include more sensi- tive measures of corticospinal tract dysfunction than the edss, coupled with advanced neuroimaging techniques and, ideally, histopathological investigations, will help detect differences in the pattern and rate of rnfl loss by disease subtype and on history, pointing to underlying pathological mechanisms of neurodegeneration [ , ]. studies comparing dmt-exposed (including corticoster- oids) and non-dmt-exposed subjects may help detect treatment effect on the rnfl. finally, improvements to the current to µm resolution of the stratus oct will have greater power to differentiate neurodegeneration from normal age-related losses to the rnfl, as well as any potential dmt effects on preserving crucial visual function in ms. conclusions in summary, we found rnflt to correlate with dis- ease duration in parallel with corticospinal tract dysfunc- tion, as measured by the edss in a population with ms untreated by dmts. subjects with on history had a lower baseline rnflt. this study suggests that oct may prove to be a useful instrument for capturing the cns effects of inflammation and neurodegeneration for use in both clinical trials and practice. table . multivariate analyses to determine if factors of individual eye optic neuritis (on) history or thinner retinal nerve fiber layer (rnfl) interacted with correlations between rnfl thickness (rnflt) and disease duration, between expanded disability status scale (edss) scores and disease duration, and between rnflt and both high- and low-contrast visual acuities (hcva and lcva, respectively). significance set at p < . for multiple comparisons (tukey test). parameter mean parameter estimate ± standard error p-value rnflt and disease duration by on history . ± . . rnflt and disease duration by thinner side – . ± . b . edss and disease duration by on history . ± . . edss and disease duration by thinner side – . ± . . rnflt and hcva by on history . ± . . rnflt and hcva by thinner side – . ± . . rnflt and lcva by on history . ± . . rnflt and lcva by thinner side – . ± . . figure . subjects with history of optic neuritis (on) ( ) had significantly lower mean retinal nerve fiber layer thickness (rnflt) in both eyes ( . µm, % confidence interval [ci] . – . µm) than subjects without history of on ( . µm, % ci . – . µm; p < . ). jrrd, volume , number , acknowledgments author contributions: study concept and design: r. c. sergott, t. p. leist. subject recruitment: r. c. sergott, t. p. leist, r. i. spain. collection of data: r. i. spain. statistical analysis and interpretation of data: m. maltenfort. drafting of manuscript: r. i. spain. critical revision of manuscript for important intellectual content: r. i. spain, r. c. sergott, t. p. leist. financial disclosures: the authors have declared that no competing interests exist. funding/support: this material was based on work supported by dr. spain’s fellowship that was funded through educational grants from emd serono, inc (rockland, massachusetts) and pfizer, inc (new york, new york). additional contributions: clinical trial registration was not required for this study. we would like to thank farah johnson and elizabeth affel for their help in obtaining octs. dr. spain is no longer with thomas jefferson university, phila- delphia, pennsylvania. participant follow-up: the authors plan to inform participants of the publication of this study. references . de stefano n, narayanan 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[pmid: ] doi: . / .wnl. . .d submitted for publication november , . accepted in revised form march , . http://www.ncbi.nlm.nih.gov/pubmed/ http://dx.doi.org/ . /j.neuroimage. . . http://www.ncbi.nlm.nih.gov/pubmed/ http://dx.doi.org/ . / .wnl. . .d 	thickness of retinal nerve fiber layer correlates with disease duration in parallel with corticospinal tract dysfunction in untreated multiple sclerosis 	rebecca i. spain, md; - * mitchell maltenfort, phd; robert c. sergott, md; thomas p. leist, md, phd 	 department of neurology, thomas jefferson university, philadelphia, pa; department of neurology, oregon health & science unive... 	introducton 	methods 	subjects 	history of optic neuritis 	retinal imaging 	visual testing 	corticospinal tract dysfunction 	statistical analysis 	results 	table . 	figure . 	discussion 	table . 	table . 	table . 	figure . 	conclusions 	acknowledgments 	references pin determinants of total hospital costs among inpatients with candidemia a abstracts parison purposes, the mortality rate of all inpatients with s. aureus infections was . %. patients with s. aureus csssis were older (mean age years vs. years for the comparison group) and were more likely to have congestive heart failure, diabetes with chronic complications and bacteremia/septicemia. relative to the comparison group, patients with s. aureus csssis had significantly (p < . ) longer mean length of stay ( . vs. . days) and higher average costs per stay ($ , vs. $ , ). after con- trolling for potentially confounding factors, the excess mean costs associated with s. aureus csssis were estimated to be $ , . conclusion: our findings suggest that the clinical and eco- nomic burden of complicated skin and skin structure infections (csssis) due to staphylococcus aureus among hospitalized patients is substantial. pin impact of s. aureus infections on expenditures and length-of-stay in u.s. hospitals noskin g , rubin r , schentag j , kluytmans j , hedblom e , jacobson c , smulders m , gemmen ek , bharmal m northwestern university feinberg school of medicine, chicago, il, usa, georgetown university, washington, dc, usa, university at buffalo school of pharmacy, buffalo, ny, usa, amphia hospital and vumc medical university, amsterdam, rk, the netherlands, m medical, st paul, mn, usa, quintiles, falls church, va, usa, quintiles strategic research & safety, falls church, va, usa objectives: evaluate the incremental impact of s. aureus infection stays on hospital charges and length-of-stay in u.s. hospitals in . methods: the nationwide inpatient sample data were analyzed. hospital discharges were classified as either a s. aureus–related infection stay or a non-s. aureus- related infection stay using a combination of several icd- codes. incremental effect of s. aureus infection on hospital charges and length-of-stay was estimated using multivariate regression models adjusting for hospital fixed effects and patient variables including age, gender, race, payer, diagnosis-related grouping and concomitant conditions including diabetes, dialy- sis and lung disease. results: s. aureus infection was reported as a discharge diagnosis for . % of all hospital inpatients, or , stays, in . s. aureus infection hospital stays were significantly more likely among male, older patients, stays that were paid by medicare, white or non-hispanics and hospital stays among individuals with diabetes, lung disease or dialysis. after adjusting for covariates, the mean incremental impact of s. aureus infection on hospital charges and length-of-stay was $ , ( % confidence interval (ci): $ , –$ , ) and . days ( % ci: . – . ) among all inpatient stays, $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among surgical stays, $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among invasive cardiovascular stays, $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among invasive orthopedic stays and $ , ( % ci: $ , –$ , ) and . days ( % ci: . – . ) among invasive neurosurgical stays. conclusion: s. aureus infections present a considerable economic burden to u.s hospitals. based on the prevalence of s. aureus infection and its incremental impact, the total economic impact of s. aureus among all hospital admissions was estimated at $ . billion in u.s. dollars. pin determinants of total hospital costs among inpatients with candidemia lee sp , bunz t , gagne jj , maio v , goldfarb ni , horn dl , swanson r thomas jefferson univeristy, philadelphia, pa, usa, thomas jefferson university, philadelphia, pa, usa, pfizer inc, new york, ny, usa objectives: to identify factors associated with total hospital costs among patients with candidemia in a large, urban, tertiary care, teaching hospital. methods: this retrospective cohort study examined hospitalizations during calendar years and at thomas jefferson university hospital in philadelphia, pa, using data from various hospital systems. candidemia cases were identified via the microbiological laboratory information system as those patients with at least one confirmed positive blood culture for any candida species at any point during the study period. demographic, economic, and clinical data, includ- ing length-of-stay (los), payer types, total costs, and diagnosis related group (drg) assignments were collected from the hos- pital cost accounting system. pharmacy data (i.e. medications administered and associated costs) were retrieved from the phar- macy electronic information system. a multivariate regression analysis, using the natural logarithm of total hospitalization costs as the dependent variable, was conducted. independent variables included demographic information, relative drg weights, and candida species. results: among , total hospitalizations during the study period, cases were con- firmed positive for candidemia. the mean age of cases was years, % were female, and % were caucasian. the mean los was . days and the average inpatient cost for candidemia cases was $ , (sd = $ , ; median, $ , ). the most common candida species was c. albicans (n = ; %). the most commonly used antifungal treatment was fluconazole (n = , %). age, and relative drg weights (p < . ) were significantly positively correlated with total hospital costs. older patients with higher relative drg weights were associated with the higher total costs. race, gender, and marital status were not associated with total costs. conclusion: relative drg weights, as well as age are associated with total hospital costs among patients with candidemia. candidemia is expensive to treat and results in lengthy hospital stay. early detection and treatment may significantly reduce resource use as well as improve outcomes. pin the economic impact of methicillin resistance in staphylococcus aureus bacteremia in korea park ej , lee ek , chae s korea institute for health and social afffairs, seoul, south korea, sookmyung women’s university, seoul, south korea, korea institute for health and social affairs, seoul, south korea objectives: the objective of this study is to examine the eco- nomic outcome of methicillin resistance in staphylococcus aureus bacteremia in korea, where mrsa is endemic in major- ity of hospitals. methods: we conducted retrospective case- control study of patients admitted to three university-based teaching hospitals in seoul, korea in . cases were defined as patients with methicillin-resistant s. aureus (mrsa) bac- teremia and controls were methicillin- susceptible s. aureus (mssa) bacteremia selected according to a priori matching cri- teria. cases and controls were identified. hospital charges were collected from hospitals’ billing system. results: the median hospital charge after the development of bacteremia was higher for cases with mrsa bacteremia ($ ) than for con- trols with mssa bacteremia ($ ). the median hospital hp the relationship of direct-to-consumer advertising and clinician behavioral intentions abstracts used to apply hospital- and revenue center-specific cost-to-charge ratios to estimate pharmaceutical costs from charges at the discharge level. the diagnosis- related group (drg) methodology was used to case-mix adjust the results. relative value units were derived from the hospital specific cost estimates. after trimming at +/- three standard deviations, cluster analyses methods were applied to the hospitals to allocate each hospital into one of four levels of pharmaceutical service intensity. results: the data set included acute care hospi- tals, representing inpatient pharmacy cost information on more than . million discharges. the time period was federal fiscal year . drg , lung transplant, was the most costly group, while the least costly group was drg , normal newborn. of the hospitals, ( . %) were excluded after trimming on intensity score. the mean relative value score for the remaining hospitals was . , with a range of . to . . the standard deviation was . . conclusions: these results provide empirical evidence from a very large sample of hospitals that the intensity of pharmaceutical interventions in acute care hospitals in the u.s. exhibits considerable variability. a four-fold difference was detected in intensity score between the lowest intensity hospitals and the highest. this drg-adjusted difference was not due to differences in case-mix across hospitals. further research should be done to determine whether patient outcomes are associated with low versus high pharmaceutical service intensity. mi developing a quality appraisal instrument to evaluate the pediatric health economics literature ungar wj , menon d , lee a , stafinski t the hospital for sick children research institute, toronto, on, canada; institute of health economics, edmonton, ab, canada objectives: the pediatric economic database evaluation (pede) project features a database of pediatric economic evaluations published between and . a goal of the pede project is to appraise the quality of pediatric economic evaluations published over this period. the objective of this research was to develop a valid and reliable quality appraisal instrument applica- ble to economic evaluations in the pediatric population. methods: a draft instrument was constructed from published checklists and questionnaires. new questions pertaining to the pediatric population were incorporated. an expert panel reviewed the draft instrument and the proposed scoring scheme for face and content validity. a revised version was pilot-tested by three independent appraisers. after addressing discrepancies in scores, a final version was created and subjected to inter-rater and test-retest reliability assessment. results: the items in the final questionnaire were mapped onto fourteen domains: economic evaluation, comparators, target population, time horizon, perspec- tive, costs and resource use, outcomes, quality of life, analysis, discounting, incremental analysis, sensitivity analysis, conflict of interest, and conclusions. among the items, have response options that are scored from to . inter-rater reliability was . ( % ci . – . ) and test-retest reliability was . ( % ci . – . ). conclusions: the pediatric quality appraisal ques- tionnaire is a comprehensive instrument demonstrating face and content validity and very good reliability for application in the appraisal of pediatric economic evalu- ations. the instrument is currently being used in a quality appraisal of a random sample of publications from the pede database. health policy—consumer advertising issues hp the relationship of direct-to-consumer advertising and clinician behavioral intentions zachry iii wm, jackson tr the university of arizona, tucson, az, usa objective: to examine the relationship between the exposure of a patient to direct-to-consumer advertising (dtca), and the likelihood of clinician behavioral inten- tions to provide information and medications. methods: a randomized mail survey of arizona primary care physicians (n = ) and physician assistants (n = ) was conducted. questionnaires were created with a hypothetical patient scenario varying according to the informational exposure of the patient ( levels: dtca or drug reference book). all other wording in the hypothetical scenarios was controlled. clinicians were randomly assigned one form of the questionnaire. each form solicited responses to questions related to the likelihood of respondent behavioral intentions ( -point scale, = very likely to = very unlikely) when faced with the hypothetical patient scenario. results: the response rate for useable questionnaires was % ( . % physicians and . % physician assis- tants). no overall statistically significant differences were found between the early responders and late responders. also, no statistically significant differences were found between responders and non-responders based on the metropolitan designations of their practice settings. relative to clinicians who received the “drug reference book” patient scenario, clinicians who received the dtca patient scenario were: more likely to become annoyed with a patient for asking for more information about medications (p = . ); less likely to answer the patient’s questions (p = . ) or provide additional written information (p = . ); more likely to attempt to change the subject rather than discuss an advertised abstracts medication (p = . ); more likely to become frustrated (p = . ) and annoyed (p < . ) with the patient for asking to try a medication; and less likely to provide samples (p = . ) or a prescription (p < . ) for a medication. conclusion: clinicians are amenable to patients asking for drug information and medications, but their level of receptiveness is associated with the source from which the patient’s questions originate. hp relationship of direct-to-consumer advertising spending and drug pricing for the top twenty drugs from to : an exploratory study parthan ag, anantharaman rt, shepherd md the university of texas at austin, austin, tx, usa there exists an ongoing debate regarding the effect of direct-to-consumer (dtc) advertising spending on drug prices. the two opposite views are: (a) increase in dtc advertising spending would be added to drug prices (b) dtc advertising would increase competition and thus reduce drug prices. objective: explore the relationship of dtc advertis- ing spending and drug pricing for the top twenty drugs from to . methods: top twenty drugs were selected on the basis of their dtc advertising spending (source: competitive media reporting, ny) for . for analysis, average wholesale price (awp) per unit was used from the blue book awp unit pricing. for each of the top twenty drugs, the following trend graphs were plotted for to : (a) the total dtc advertising spending and per unit price of the drug; (b) the percent changes in the dtc advertis- ing spending and drug price. the percent change in dtc advertising spending and drug price for a year was calculated as percent change from the previous year. results: only sildenafil (viagra) and sibutramine (meridia) showed an increase in the actual drug price with an increase in the dtc advertising spending. however, for these two drugs in year , the percent change in dtc advertising spending decreased and the percent change in drug price increased. no trend was evident from the graphs of the other eighteen drugs. on an average dtc advertising spending for most of the drugs decreased with time while drug prices continued to increase. conclusion: results indicate a very weak relation- ship between dtc advertising spending and drug prices. the increase in drug price in spite of the decrease in the dtc advertising spending contradicts both rationale i.e. dtc advertising spending reduces drug price through competition or increase in drug price is due to increase in dtc advertising spending. hp impact of direct to consumer advertising—the consumer search for information belazi dt , crawford a , pizzi l thomas jefferson university & abbott laboratories, philadelphia, pa, usa; thomas jefferson university, philadelphia, pa, usa objective: the purpose of this study is to identify factors associated with consumers’ seeking various infor- mation sources about medications sought in response to direct to consumer advertising. methods: in the spring and summer of , the fda, division of drug marketing, advertising, and commu- nication conducted a national telephone survey of adults regarding direct-to-consumer (dtc) promotion of prescription drugs and its effects on visits to the doctor. in addition to consumer attitudes, opinions and responses to direct to consumer advertising, the survey also elicited responses regarding consumer utilization of information sources such as reference books, -telelphone number, and health care providers. there were total respon- dents, of whom completed the required questions regarding information sources. chi square analysis was used to assess associations between consumer demographic information and the different types of informational resources that consumers used after exposure of direct to consumer advertising. results: the analysis showed significant associations (p £ . ) between gender, race, education, health status, self-perceived knowledge of health, prescription medication use, and internet use and many of the following information resources: reference books, asking friends/neighbors, -telephone number, primary doctor, pharmacist, specialist, and nurse. across all information sources, female gender, decreased health status, low education, and higher than average medica- tion use were the variables that had the strongest associ- ations. a model was developed depicting the associations between these findings. results pertaining to specific sources will be presented. conclusions: this study evaluated how different consumers seek information from different sources as a result of direct to consumer advertising. this study will assist those interested in identifying and further educat- ing consumers about their health and novel treatments or therapies. hp fda regulatory actions against misleading or unsubstantiated economic and quality-of-life claims: an analysis of warning letters and notices of violation stewart ka, neumann pj harvard school of public health, boston, ma, usa a-type kv channel closed-state inactivation is modulated by the tetramerization domain interacting with auxilary kchip a sunday, february , a receptor x were transfected into cho cells. the cho transfectants were char- acterized by facs and then scaled up for kinexa binding studies. kinexa has been used to measure binding affinity of adnectin-a to the cell surface ex- pressed receptor x to measure the effect of avidity of the multivalent adnectin binding to receptor clusters. as controls for the functional activity of the adnectin-a and the affinity of the monovalent interaction, the same kinexa assay was used, substituting the soluble receptor x extracellular domain for the transfected cho cells. the binding avidity measured by kinexa for cho expressed receptor is pm for both species of receptor x. however, the affinity of adnectin-a for monovalent soluble receptor x was quite different between the species suggesting that avidity due to receptor clustering equilizes the functional avidity at the cell surface. platform: voltage-gated k channels: activation/ inactivation mechanisms -plat a-type kv channel closed-state inactivation is modulated by the tetramerization domain interacting with auxilary kchip a yi-quan tang , fan yang , jingheng zhou , jie zheng , kewei wang . peking university, beijing, china, university of california at davis, davis, ca, usa. a-type kv potassium channels undergo a conformational change towards a non-conductive state at negative membrane potentials, a dynamic process known as closed-state inactivation (csi). csi causes inhibition of channel ac- tivity without prerequisite of channel opening, thus providing a dynamic regu- lation of neuronal excitability, dendritic signal integration and synaptic plasticity. however, the structural determinants underlying kv csi remain largely unknown. we have recently demonstrated that auxiliary kchip a sub- unit contains an n-terminal kv inhibitory domain (kid) that directly interacts with kv . channels to enhance csi. in this study, we utilized the fret two- hybrid mapping and bifc-based screening combined with electrophysiology, and identified the intracellular tetramerization (t ) domain that functions to suppress csi and serves as a receptor for the binding of kid. disrupting kv . t -t interaction by mutating c a within the c h motif of t domain facilitated csi, and ablated the kid-mediated enhancement of csi. furthermore, replacing the characteristic c h motif of kv . t domain with the t domain from kv . without the c h motif or kv . with the c h motif resulted in channels functioning with enhanced or suppressed csi, respectively. taken together, our findings reveal a novel role of the t domain in suppressing kv csi with the c h motif functioning to stabilize the channel activation gate; and kchip a kid directly interacts with the t domain to relieve the stabilization, leading to facilitation of csi and inhibition of channel function. -plat two-in-one: activation and inactivation at the intracellular gate of a kv channel manuel covarrubias , jeffrey d. fineberg . neuroscience, jefferson medical college of thomas jefferson university, philadelphia, pa, usa, physiology and molecular biophysics, jefferson medical college of thomas jefferson university, philadelphia, pa, usa. n-type and p/c-type inactivation are firmly established mechanisms of inac- tivation in voltage-gated kþ (kv channels). however, kv .x channel com- plexes, which undergo fast preferential closed-state inactivation (csi; fineberg et al., , jgp . : - ), appear to use a distinct but un- known inactivation mechanism. previously, we hypothesized that a weak interaction between the voltage sensing domain and the intracellular activa- tion gate underlies csi (bähring & covarrubias, , j physiol : - ). thus, csi is essentially governed by the intracellular activation gate, which fails to open and adopts an inactivated conformation. to directly test this hypothesis, we investigated the heterologously expressed kv . ternary channel complex including accessory subunits kchip and dpp , and ex- ploited the ‘‘trap-door’’ paradigm of the activation gate. the results show that kv . inactivation traps intracellularly applied quaternary ammonium blockers (btbua and tbua) inside the channel’s pore. the trapped blockers can only escape if the channels are opened again by subsequent depolariza- tions. by contrast, inactivation cannot trap tea, whose binding kinetics is faster than that of channel gating. moreover, under identical conditions, a shaker kv channel (shb-t k) known to exhibit fast p/c-type inactivation cannot trap btbua. these findings conclusively suggest that the intracellular activation gate of the kv . ternary channel complex plays a novel dual role, controlling both activation and inactivation. supported in part by nih grant r ns (mc). -plat development and validation studies of universal pharmacophore models for herg channel openers serdar durdagi , , matthew patterson , sergei y. noskov . department of biophysics, bahcesehir university, faculty of medicine, istanbul, turkey, biological sciences, institute for biocomplexity and informatics, university of calgary, calgary, ab, canada. the intra-cavitary drug blockade of herg channel, a common off-target for many drugs, have been extensively studied both experimentally and theoreti- cally. structurally diverse ligands inadvertent blockade of rapid component of delayed rectifying kþ currents are potentially pro-arrhythmic and may lead to drug-induced long qt syndrome-lqts. there are a number of natural strategies for rational drug design; one dubbed the ‘‘passive’’ approach avoids block of herg whereas the ‘‘proactive’’ strategy designs treatments to acti- vate the channel. while ‘‘passive’’ approach has been developed for decades, studies of structural mechanisms of herg channel activation by small mole- cules are truly novel. accordingly, design of the herg openers or current ac- tivators may offer a momentum for modern anti-arrhythmia drug development. significant number of small molecules with capacity for herg activation was identified in mandatory herg screens. to establish possible correlation be- tween activators structure and reactivity, we attempted to construct a universal pharmacophore model for herg channel openers using phase protocol. the biochemical data on kþ channel activators are used in training and test sets. these compounds span a wide range of structurally different chemotypes with ~ ^ -fold variances in binding affinity, which is sufficient for statistically sound model. a developed five sites aahhr (a, hydrogen-bond accepting, h, hydrophobic, r, aromatic) pharmacophore model has showed reasonable high statistical results compared to other constructed models and was selected for steric and electrostatic contour maps analysis. the predictive power of the model was also tested with external test-set (as true unknowns) compounds. pharmacophore model is also combined with previously developed receptor- based homology model of herg k channel and novel activators are generated and screened. the developed ligand-based models may serve as a basis for the synthesis of novel potential therapeutic herg activators. -plat n-terminal regulation of herg kd channel deactivation steven j. thomson, angela hansen, michael c. sanguinetti. nora eccles harrison cardiovascular research and training institute, university of utah, salt lake city, ut, usa. slow deactivation of herg (kv . ) potassium channels maintains ikr dur- ing final repolarization of the cardiac action potential and opposes asynchro- nous early depolarization. inherited point mutations in herg that accelerate deactivation of ikr cause long qt syndrome (lqts), a disorder of ventricular repolarization that increases the risk of lethal cardiac arrhythmia. the intracellular n-terminal domain of herg is known to be essential for slow deactivation. deletion of the entire (~ residues) or just the initial residues of the n-terminus accelerates deactivation -fold. the same effect is achieved by neutralization of the charged residues, arg or arg . how many of the n-termini are required to slow channel deactivation is unknown. herg , like other kv channels, is a homotetramer. by repeatedly linking the c-terminal of one subunit to the n-terminal of the next subunit we constructed concatenated herg tetramers. a variety of homomeric and heteromeric concatenated tetramers were characterized (i.e., wtn/r a:r a( -n); where n = to ). the concatenated channel containing a single r a/r a subunit and wild-type subunits deactivated as fast as the concatenated channel con- taining only r a/r a subunits. the lqts-associated mutation r q, located in the n-terminal of herg was also studied. again, a concatenated tetramer containing a single mutant subunit deactivated as fast as channels with r q mutations in all four subunits. our results show that all n-termini are required to mediate slow deactivation in wild-type herg channels. -plat lipid affinity to the voltage-gated potassium channel kvap elise faure , christine thompson , rikard blunck , . physiology, université de montréal, géprom, montréal, qc, canada, physique, université de montréal, géprom, montréal, qc, canada. voltage-gated potassium channels (kv) are formed by a central conducting pore surrounded by four voltage sensor domains. functional studies have re- vealed that biophysical properties of lipid molecules in the channels environ- ment can have strong effects on the activity of kv channels. here, we investigated the influence of different lipids as well as their affinity to kvap channels. we carried out electrophysiology measurements by fusing vesicles containing purified channels into planar lipid bilayers with varied lipid compo- sitions. we found that kvap properties are mainly determined by the lipid 	a-type kv channel closed-state inactivation is modulated by the tetramerization domain interacting with auxilary kchip a 	two-in-one: activation and inactivation at the intracellular gate of a kv channel 	development and validation studies of universal pharmacophore models for herg channel openers 	n-terminal regulation of herg k+ channel deactivation 	lipid affinity to the voltage-gated potassium channel kvap december , volume , numbe american association for the advancem:ent of science science serves its readers as a forum for the presentation and discussion of important issues related to the advancement of science, including the presentation of minority or conflicting points of view, rather than by publishing only material on which a consensus has been reached. accord- ingly, all articles published in science-including editorials, news and comment, and book reviews -are signed and reflect the individual views of the authors and not official points of view adopted by the aaas or the institutions with which the authors are affiliated. editorial board gustaf . anrhenius richard c. lewontin fred r. eggan alfred . c. ner harry f. harlow frank w. putnam milton harris thomas eisner neal miller amitai etzioni bruce murray emil haury john r. pierc daniel koshland, jr. editorial staff editor philip h.. abelson publisher business manager william bevan hans nussbaum managing editor: robert v. ormes assistant editors: ellen e. murphy, john b. ringle assistant to the editor: nancy teimourian news editor: daniel s. greenberg foreign editor: john walsh news and conlment: luther j. carter, philip m. boffey, constance holden, robert j. bazell, scherraine mack research topics: allen l. hammond book reviews: sylvia eberhart, katherine liv- ingston, ann barkdoll cover editor: grayce finger editorial assistants: joanne belk, isabella bouldin, eleanore butz, corrine harris, olivr heatwole, anne holdsworth, eleanor johnson, marshall kathan, margaret lloyd, daniel rabov- sky, patricia rowe, leah ryan, lois schmitt, barbara sheffer, richard sommer, ya li swigart, alice theile, marie webner membership recruitment: leonard wray; sub- scriptions: betr seemund; addressing: thomas bazan advertsing staff director production manager earl j. scherago bonnie semel advertising sales manager: richard l. charles sales: new york, n.y. : robert s. bugbee, w. st. ( -pe- - ); scotch plains, n.j. : c. richard calms, unami lane ( - ); medfield, mass. : richard m. ezequelle, rolling lane ( - - ); chicago, ill. : herbert l. burklund, room , n. michigan ave. ( -de- - ); beverly hills, calif. : winn nance, n. la cienega blvd. ( - - ) editorial correspondence: massa- chusetts ave., nw, washington, d.c. . phone: - - . cable: advancesci, washington. copies of "instructions for contributors" can be obtained from the editorial office. see also page xv, science, september . advertising correspond- ence: room , w. st., new york, n.y. . phone: -pe- - . ,r sciesnce: . - d educational obsolescence the obsolescence of education in rapidly developing fields of knowl- edge has become about equal in rate to the obsolescence of an auto- mobile. in to years it is due for a complete replacement. conse- quently, our times, to a degree generally quite unrecognized, demand a major reconstitution of the educational process, which must become one of lifelong renewal. perhaps a month out of every year, or months every third year, might be an acceptable new pattern. indeed, instead of cramming the educational years of life into adolescence and early maturity, a more efficient plan might be to interrupt education with work periods after elementary school, high school, and college. in any case, programs of continuing education for all professional people must become mandatory, and the educational effort and expenditures must be expanded by at least a third to permit adequate retraining and reeducation. the obsolescence of education differs only in degree in the several sciences, and even in the humanities. ... i recently heard a distinguished historian, who had been in university administration for only years, say that his field had advanced so much in the interim that it would take him a year of concentrated study just to catch up with its development. in spite of a very general recognition of these hard facts, little is done to alter our pattern of education to cope with them. physicians continue to practice medicine, although years have elapsed since their youthful preparation. dentists do the same. lawyers and engineers live comfort- ably on their antiquated stock in trade. teachers slide steadily downhill through failure to grasp new developments in their own subjects. perhaps worse is the virtually universal ignorance, on the part of educated men and women, of any advancement of knowledge outside their own profes- sional specialties. surely we need a complete and thoroughgoing change in attitude toward "adult education," a careful planning of programs and courses appropriately designed for the intelligent adult who has become out of touch with his new world, and a mandatory, cyclic renewal of training for the professional specialist. the cry of the student throughout the land is for "relevance" in the curriculum. what does he mean? change has become the major feature of human civilization, driven by an increasingly rapid development of enormous powers to modify and oontrol raw nature; and the advance of science is the principal factor in this technological revolution. education must prepare each person to cope with changes that are unpredictable. as heraclitus wisely said, "no man steps into the same river twice." the river flows, and the man ages. all is change. yet the life of an ancient greek was not so different from the life of thomas jefferson as jefferson's life is from ours today. the content of the curriculum should therefore embrace both the timely and the timeless, for top- ical and social relevance and timeless natural law alike deepen our per- spective and assist us to adapt ourselves to altered circumstances. un- fortunately, the timely and the timeless are both often displaced by the trivial, or the significance of the two former is left obscure, so that to the young mind they seem to be trivial. this must not be!-bentley glass, vice president for academic affairs, state university of new york, stony brook adapted from the timely and the timeless (basic books, new york, ). o n a p ril , h ttp ://scie n ce .scie n ce m a g .o rg / d o w n lo a d e d fro m http://science.sciencemag.org/ educational obsolescence bentley glass doi: . /science. . . 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"we need more dia- logue with industry;' says who director general, hiroshi nakajima. the who-unicef report, "state of the world's vaccines and immunization;' lauds recent successful campaigns to deliver vac- cines against diseases-including polio, measles, neonatal tetanus, diphtheria, per- tussis, tuberculosis, hepatitis b, and yellow fever-to the world's children, particularly in developing countries. but the report also warns that, "unless the international com- munity continues to back scientific research and global immunization with adequate resources for new vaccines. . .the great promise of molecular biology and genetic engineering may be squandered:' high on the list of global vaccination campaigns are efforts to eradicate polio-a goal that officials expect to meet by the year . in , for instance, nearly half of all children under five, some million, received supplementary doses of polio vac- cines during special national immunization days. but even here, officials are concerned over budget "shortfalls;' mainly from decreased donor funding, that now have the managers of this campaign scrambling for the $ - million needed for vaccine purchases, personnel, training, research, logistics, establishment of a cold chain to preserve vaccine activity, and development of a global laboratory network. the current full allotment of six childhood vaccines (against polio, diphtheria, pertussis, tetanus, measles, and tuberculosis) now costs less than $ for the vaccines-plus $ for program costs. the hepatitis b vaccine has been a touch- stone for the vaccine cost discussion. nakaji- ma points out that the cost of the recombinant hepatitis b vaccine has been dropping, in part because several countries in the developing world, including china, korea, and cuba, now are manufacturing the prod- uct and making it widely available. however, he adds, unless its price falls below $ per dose, this vaccine remains out of reach for much of the world. "we're not saying all vac- cines should be free;' says carol bellamy, executive director of unicef. "we're hoping for a healthy, competitive market and to cre- ate a varied pricing structure." but thomas bombelles, who specializes in international issues for the pharmaceutical research and manufacturers of america association (phrma, washington, dc), argues that innovation can be expensive. "the development costs for vaccines are not all that much lower than for drugs;' he says. "r&d for vaccines is often on the lower end of the range for pharmaceutical products, but it can child receiving an oral polio vaccine in a hospital in phnom penh, cambodia. be from $ - million, which is still an awful lot of money, and there has to be a rea- sonable return on such development costs:' in any case, he says, "the cost is actually very small:' even though its price is higher than that of older vaccine products, its effectiveness makes it a "fantastic bargain" when health outcomes are considered, he says. other improved recombinant vaccine products are nearing regulatory review. for instance, chiron corporation (emeryville, ca) announced in october that it is seeking regulatory clearance for the marketing of pertugen, a diphtheria, tetanus, and geneti- cally engineered acellular pertussis (dtap) vaccine for infants and children. pertugen is the first recombinant dtap vaccine to detox- ify the pertussis toxin. pricing is not the only impediment to wider vaccine development and usage. bombelles notes that adequate safeguards for intellectual property rights are crucial. strengthening of intellectual property laws in china, he says, made it easier for merck (whitehouse station, nj) to share some of its hepatitis b vaccine know-how with chinese collaborators, enabling them to build up domestic vaccine manufacturing capacity. another issue pivots on health-care pri- orities in developing countries. with more than candidate vaccines "in the pipeline," developing countries "need to make resources available at the national level;' points out ciro de quadros, nakaji- ma's special advisor for the who global program for vaccines and immunization. institutions in such countries need to form "consortia to bring vaccine prices down and make sure these products are widely used." jeffrey l. fox edible plant vaccines the first human clinical trial for an edible, plant-based vaccine could start at the beginning of . a team headed by charles arntzen at the boyce thompson institute for plant research (bti, ithaca, ny) is currently undertaking advanced preclinical research on a vaccine for diar- rhea that consists of raw transgenic pota- toes expressing an escherichia coli enterotoxin lt-b subunit gene. if the work goes as planned, the vaccine could enter clinical trials on volunteers at the balti- more vaccine testing center (baltimore, md) in the new year. the potato vaccine, may, however, be beaten to the market by more palatable or technically accessible alternatives. arntzen's research and the similar work of hilary koprowski's group at thomas jef- ferson university (philadelphia, pa) on plants that produce rabies and human immunodeficiency virus antigens are directed at producing edible vaccines for developing countries. "how would you expect [people in] africa or asia to be vacci- nated except by the oral route?" asks koprowski. plants are "the cheapest and the most accessible production method," he says, and they eliminate both the need for refrig- eration, needles, and trained medical staff, and the risks of pathogen-derived vaccines. the bt! potato vaccine has been shown to stimulate the production of specific an tien- terotoxin igg and lga in mice. the next pre- clinical hurdle for the vaccine is to show that it can protect mice against challenge with the e.coli toxin, or with e.coli itself. even though the potato vaccine will be the first plant-based vaccine in human tri - als, it is still rea lly just a model system. few people enjoy raw potatoes (altho ugh charles arntzen did as a ch ild , he told nature biotechnology). according to arntzen's colleague, hugh mason, the first commercial edible plant vaccine will be in bananas. they are much more palatable, nature biotechnology volume november 	who and unicef find vaccines too costly with surgical bypass, with shorter hospitalizations in symptomatic and asymptomatic patients. further long-term follow-up is required to compare these two treatment modalities for durability to determine the optimal popliteal aneurysm management. multifactorial disease severity score (dss) predicting the success of endovascular intervention of femoropopliteal peripheral arterial disease in-kyong kim, md, natalia egorova, phd, andrew j. meltzer, md, james f. mckinsey, md . columbia university, new york presbyterian hospital system, new york; mount sinai university, new york; and new york presbyterian hospital, new york, ny objective(s): the goal was to create a multifactorial disease severity score (dss) for characterization of femoropopliteal arterial lesions. by having a greater understanding of the effect of patient comorbidities and an in-depth method to characterize an arterial lesion, we may be able to better compare lesions in different studies and predict which therapy is most appropriate for each lesion undergoing an endovascular intervention (evi). methods: we evaluated lesion and patient characteristics in our prospectively maintained lower extremity arterial lesion database from to to create a gradated dss. results: we identified femoropopliteal lesions in patients. statistical analysis by multivariable cox proportional hazards model identi- fied variables that impact patency: seven lesion characteristics (table i) and nine patient characteristics or comorbidities (table ii). factors with the most impact were a chronic total occlusion (dss ), lesion length � mm (dss ), and no runoff vessels and stenosis of % to % (dss ). the following factors were considered baseline, or score of : stenosis � %, lesion length � mm, and three-vessel runoff. by adding these variable scores, a dss was created and used to predict patency of the evi. conclusions: the presence of a chronic total occlusion, lesion length � mm, poor runoff, and the presence of congestive heart failure have the most dramatic effect on patency after evi. a compre- hensive dss allows for the in-depth classification of lesion characteristics and factors that predict success of evi and can allow for comparison of distinct lesions. future comparisons of effectiveness of treatment modal- ities can be possible. table i. significant femoropopliteal lesion characteristics that negatively impact patency after endovascular intervention factor score hr ( % ci) chronic total occlusion . ( . - . ) stenosis %- % . ( . - . lesion length � mm . ( . - . ) vessel runoff . ( . - . ) . ( . - . ) . ( . - . ) lesion calcification . ( . - . ) ci, confidence interval; hr, hazard ratio. table ii. patient characteristics that impact patency after endovascular intervention factor (n � ) score cox coefficient hr ( % ci) chf . . ( . - . ) female sex . . ( . - . ) current smoker . . ( . - . ) former smoker . . ( . - . ) diabetes . . ( . - . ) cad . . ( . - . ) renal . . ( . - . ) age, years - . . ( . - . ) - � � . . ( . - . ) cad, coronary artery disease; chf, congestive heart failure; ci, confi- dence interval; hr, hazard ratio. defining the role of endovascular therapy in critical limb ischemia with tissue loss andrew j. meltzer, md, gisberto evangelisti, md, ashley graham, francesco aiello, md, peter h. connolly, md, harry l. bush, md, john k. karwowski, md, darren b. schneider, md. new york presbyterian hospital, new york, ny objective(s): we compare the utility of endovascular therapy (et) with bypass surgery for critical limb ischemia (cli) with tissue loss and identify risk factors for failure of et. table. hazard ratio (hr/ aor) % ci for hr/ aor p value overall survival dialysis dependence . . – . . angina . . – . . copd . . – . . amputation free survival rutherford . . – . . copd . . – . . limb salvage rutherford . . – �. wound healing at months diabetes . . – . current smoking . . – . patency loss . . – . methods: a retrospective review ( to ) of patients under- going et for tissue loss (rutherford class and ) provided data for multivariate models of overall survival, amputation-free survival (afs), limb salvage, and wound healing. comparisons were made with a bypass surgery cohort matched for tissue loss. results: ninety-four patients underwent et ( % transatlantic intersociety concensus [tasc] c/d; % tibial) for rutherford ( %) or rutherford ( %) cli with tissue loss of the heel ( %), forefoot ( %), toe(s) ( %), calf/ankle ( %), or multiple locations ( %). sustained limb salvage was % � %. overall survival was % � % and afs was % � % at years. predictors of failure by multivariate models are reported in the table. comparison between the rutherford wrsubgroup (n � ) and an rutherford bypass cohort (n � ), suggest equivalent limb salvage, with reduced afs (p � . ) and a trend toward reduced overall survival (p � . ). early would healing was higher after bypass: % vs % at months (p � . ) and % vs % at months (p � . ). conclusions: given the short life expectancy of patients with tissue loss, et permits sustained limb salvage in patients at high risk for bypass (particularly rutherford ). however, wound healing is slow compared with bypass and requires sustained patency. midterm results of limb salvage and stent patency with popliteal artery stenting across the knee joint aleksandra policha, md, neil moudgill, md, lily chang, bs, anu- meha whisenhunt, do, shawn pierce, crnp, luis eraso, md, paul dimuzio, md, atul rao, md, joshua eisenberg, md . department of general surgery and division of vascular and endovascular surgery, thomas jefferson university hospital, philadelphia, pa; thomas jefferson university college of medicine, philadelphia, pa; and division of vascular medicine, thomas jefferson university hospital, philadelphia, pa objective(s): this study evaluated the relationship of stent location on limb salvage and stent patency in patients undergoing popliteal artery stenting. methods: we performed a retrospective review of a prospectively collected database, identifying all patients undergoing popliteal artery stenting between september and february . patients were divided into two groups based on the position of the distal end of the stent in relation to the knee joint. the proximal popliteal stent group included patients receiving a stent ending above the patella (above the flexion point of the knee). the distal popliteal stent group included patients receiving a stent(s) ending below the patella (in the flexion zone). data collected included demographics, indication for surgery, journal of vascular surgery volume , number abstracts er calcium release is tuned by mitochondrial redox nanodomains a wednesday, february , co-expression and co-evolution with mcu. micu has been demonstrated to be a ca þ -sensing protein, which both sets a threshold for low ca þ concentration while it assures cooperative activation during high ca þ rises. mitochondrial ca þ uptake shows tissue specific differences and interestingly, mrna level for micus and mcus also displays tissue specificity. we set out to investigate if the stoichiometry between micu and mcu could account for the previously described differences between heart and liver in mitochondrial ca þ uptake. immunoblotting showed higher expression for all micu , micu and mcu in mouse liver versus heart mitochondria, and a . fold higher micu to mcu ratio in liver. in fluorometric measurements of mitochondrial ca þ uptake, heart mitochondria displayed a decreased threshold and lesser cooperativity compared to liver mitochondria. additionally, nad(p)h elevation was detect- able after exposure to moderate [ca þ ] elevations only in heart mitochondria. overexpression of micu in the heart using aav -micu tail-vein injection significantly increased the micu protein level without any changes of micu or mcu. this increased the micu to mcu ratio in the heart and led to increased thresholding and cooperativity, reproducing the liver-like mito- chondrialca þ uptakephenotype.viceversamicu downregulationintheliver has been shown to lower the threshold and cooperativity of mitochondrial ca þ uptake in hepatocytes. thus, heart and liver mitochondria show different levels of ca þ threshold and cooperative activation of ca þ uptake, which seem to result from differential quantitative relationship between micu and mcu. -pos board b er calcium release is tuned by mitochondrial redox nanodomains david m. booth , balázs enyedi , miklós geiszt , péter várnai , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, department of physiology, semmelweis university, budapest, hungary. spatially and temporally controlled increases of h o emerge as an intracellular signal. we hypothesized that ros and ca þ interact locally, in the restricted vol- ume of the er-mitochondrial interface. these physically tethered structures host enrichments of ion transport proteins such as the ip receptor, which support elevated nanodomains of ca þ during signalling events and are sensitive to h o . we used the genetically encoded h o sensor hyper incorporated into an inducible linker system to probe the redox environment at the er- mitochondrial interface in hepg cells. we found a moderately elevated h o nanodomain which developes into a h o transient following ip receptor- mediated er ca þ release and mitochondrial ca þ uptake. pharmacological in- hibition showed that the transient was dependent upon er ca þ, mitochondrial membrane potential and functional electron transport chain. hyper measure- ments of the mitochondrial intermembrane space revealed significantly elevated h o within this volume. using electron microscopy we found that hepg mito- chondria possess a cohort of dilated cristae, which disappeared following ip - linked ca þ release. paxilline that inhibits mitochondrial bkca channels blocked the cristae reshaping and also abolished the h o transient at the inter- face. furthermore, paxilline caused suppression of the ip -linked calcium signal, whereas interface targeted killer red, a photoactivated h o source, induced sensitization to the ip -linked agonist. we conclude that the intermembrane/ cristae volume of mitochondria represents an oxidized pool fed by the electron transport chain. ca þ -uptake stimulates expansion of the mitochondrial matrix via kþ and concomitant water uptake, squeezing the oxidized volume of the cristae to the interface. here, a transient h o nanodomain sensitizes ip recep- tors to further stimulation. we demonstrate a physiological setting where ca þ release may autoregulate using mitochondrial h o released from the cristae. -pos board b reactive oxygen species (ros) suppress mitochondrial motility valentina debattisti, masao saotome, sudipto das, gyorgy hajnoczky. mitocare center, thomas jefferson university, philadelphia, pa, usa. mitochondrial distribution and transport play pivotal roles for many cellular functions, including cell differentiation, cell division to ensure proper inheri- tance, apoptosis, atp supply at the local sites of demand, ca þ buffering for intracellular ca þ homeostasis. we previously showed that mitochondrial motility (mito-motility) is regulated by the cytosolic ca þ concentration ([ca þ]c), providing the basis for a homeostatic circuit in which the organelles decrease their movements along microtubules to locally buffer high [ca þ ]c and contribute to atp supply. mito- chondria are also a major site for production and scavenging of ros that serve as both a messenger and regulator of calcium signaling and are particularly rele- vant for the control of mitochondrial function. here we tested the hypothesis that ros target mito-motility to control mitochondrial function. h c myoblast cells were transfected with a mitochondrial matrix targeted yfp and then loaded with fura , to monitor the mito-motility simultaneously with [ca þ ]c. h o ( mm) caused a decrease in mito-motility ( %) and an elevation in [ca þ ]c (from to nm) at the same time. when the cells were incu- bated in a ca þ -free medium and were pretreated with thapsigargin to prevent ca þ entry and intracellular ca þ mobilization, respectively, h o continued to inhibit the mito-motility dose-dependently without any changes in [ca þ]c. these results indicate that h o can cause suppression of mito-motility through a ca þ independent mechanism we are currently analyzing. -pos board b miro is dispensable for calcium-mediated inhibition of mitochondrial movement david b. weaver , agnieszka lewandowska , tammy t. nguyen , valentina debattisti , janet m. shaw , gyorgy hajnoczky . mitocare center, dept of pathology, anatomy and cell biology, thomas jefferson university, philadelphia, pa, usa, biochemistry, university of utah school of medicine, salt lake city, ut, usa. miro and are (rhot and ) are two highly similar gtpases that are bound to the surface of mitochondria and possess ef-hand calcium binding motifs. several groups have reported that miro is involved in mitochondrial motility and inheritance, and particularly its calcium regulation, but the roles of the two isoforms have not been established. genetic deletion of miro in mouse is lethal at birth (nguyen et al., ) and fibroblasts (mefs) derived from miro ko em- bryos show abnormal mitochondrial distribution, but the calcium-dependent in- hibition of motility is unaffected and the respiratory and calcium buffering capacities are normal. neuron-specific knockout of miro leads to progressive deficits of upper motor neuron function, however mitochondria in processes of cortical neurons from miro ko and wild-type embryos showed comparable calcium-sensitive motility inhibition. while no significant increase in miro pro- tein was observed in miro ko mefs, these data raise two possibilities: miro and are interchangeable with regard to calcium regulation of mitochondrial motility or miro is the key player in this regard. to finally resolve this question, we are in the process of generating miro ko and miro / ko cell lines. -pos board b mitochondrial fusion dynamics in the heart veronica eisner , ryan cupo , erhe gao , györgy csordás , lan cheng , jessica ibetti , j. kurt chuprun , walter j. koch , györgy hajnóczky . mitocare center, pathology, thomas jefferson university, philadelphia, pa, usa, center for translational medicine, temple university school of medicine, philadelphia, pa, usa, center for translational medicine, thomas jefferson university, philadelphia, pa, usa. heart physiology depends on oxidative metabolism that likely requires dy- namic and permanent reorganization of mitochondria by fusion and fission. to directly evaluate mitochondrial fusion dynamics in cardiomyocytes (cm), mitochondrial matrix-targeted photoactivatable gfp and dsred were intro- duced either in vitro or in vivo by adenovirus and were followed by confocal microscopy. four conditions were analyzed: to h cultured neonatal and in vitro transduced adult cm, and cm from in vivo infected rat hearts. in the latter case, cm were isolated - days after infection and were imaged promptly or - h post harvesting. neonatal cm mitochondria form a highly connected network, whereas both in vitro and in vivo transformed cultured cm displayed only some connectivity. impressively, in vivo transduced adult cm that were imaged promptly after harvesting, unveiled a significantly higher con- nectivity among mitochondria than the - h cultured adult cm. furthermore, fusion events (f.e./ square micrometers/min) were almost absent in cultured in vitro transduced cm, meanwhile in vivo transduced and cultured cm showed . . f.e./min, whereas isolated, freshly-imaged cm displayed . . f.e./min. imaging in perfused whole heart ex vivo, showed consider- able mitochondrial continuity and fusion activity in ventricular cm. to study more directly the role of cm’s contractile activity in mitochondrial fusion, cm were incubated with verapamil ( mm), that blocked spontaneous contrac- tion and partially suppressed the fusion activity of mitochondria. also, mito- chondrial fusion activity appeared to be higher after spontaneous contraction or short term field stimulation in isolated freshly-imaged cm. thus, mitochon- dria are dynamic in both neonatal and adult cm, but under culture conditions, adult cm lose mitochondrial fusion activity. this might be at least in part, because cardiomyocyte contractile activity is altered in culture and contractions likely provide some factors to support mitochondrial fusion activity. -pos board b mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide venkat r. pannala, ranjan k. dash. bioengineering and biotechnology, department of physiology, medical college of wisconsin, wauwatosa, wi, usa. the thioredoxin system plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (h o ). specifically, 	er calcium release is tuned by mitochondrial redox nanodomains 	reactive oxygen species (ros) suppress mitochondrial motility 	miro is dispensable for calcium-mediated inhibition of mitochondrial movement 	mitochondrial fusion dynamics in the heart 	mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide smallpox vaccination: an early start of modern medicine in america | semantic scholar skip to search formskip to main content> semantic scholar's logo search sign increate free account you are currently offline. some features of the site may not work correctly. 	doi: . / . . corpus id: smallpox vaccination: an early start of modern medicine in america @article{liebowitz smallpoxva, title={smallpox vaccination: an early start of modern medicine in america}, author={d. liebowitz}, journal={journal of community hospital internal medicine perspectives}, year={ }, volume={ }, pages={ - } } 	d. liebowitz 	published 	medicine 	journal of community hospital internal medicine perspectives abstract smallpox was eradicated by the world health organization in . before its eradication thedisease had a mortality rate upwards of % and had a significant impact on society. during theamerican revolutionary war, smallpox outbreaks were impeding the american war effort until when george washington carried out a mass inoculation campaign in the continentalarmy that reduced the mortality from smallpox to less than %. inoculation was an early formof vaccination that used live virus… expand view on taylor & francis tandfonline.com save to library create alert cite launch research feed share this paper citations view all topics from this paper 	vaccination 	american revolution 	smallpox viruses 	smallpox vaccine 	mortality vital statistics one citation citation type citation type 	all types 	cites results 	cites methods 	cites background has pdf publication type author more filters more filters filters sort by most influenced papers sort by citation count sort by recency vaccines: a clinical overview and practical guide 	j. domachowske, manika suryadevara 	 save alert research feed references showing - of references sort byrelevance most influenced papers recency edward jenner and the history of smallpox and vaccination 	s. riedel 	medicine 	proceedings 	 	 	pdf 	view excerpts, references background save alert research feed vaccines for preventing smallpox. 	w. metzger, b. mordmüller 	medicine 	the cochrane database of systematic reviews 	 	 	 	view excerpt, references background save alert research feed smallpox in washington's army: strategic implications of the disease during the american revolutionary war 	a. becker 	history 	 	 	pdf save alert research feed the evolution of preventive medicine in the united states army, - 	s. bayne-jones, r. s. anderson 	medicine 	 	 	highly influential 	 	view excerpts, references background save alert research feed pox americana: the great smallpox epidemic of - 	e. rhoades 	medicine 	 	 	pdf 	view excerpt, references background save alert research feed letter from george washington to william shippen jr. national archives founders online; 	feb . [cited nov ] 	 letter from thomas jefferson to benjamin waterhouse. national archives founders online; jul . [cited nov 	<http://founders.archives.gov> 	 smallpox in the th century 	m. c. buer 	history 	 	 save alert research feed smallpox variolation during the revolutionary war. 	j. cantey 	medicine 	the pediatric infectious disease journal 	 	 save alert research feed vaccines for preventing smallpox. cochrane infectious diseses group 	 ... ... related papers 	abstract 	topics 	 citations 	 references 	related papers stay connected with semantic scholar sign up about semantic scholar semantic scholar is a free, ai-powered research tool for scientific literature, based at the allen institute for ai. learn more → resources datasetssupp.aiapiopen corpus organization about usresearchpublishing partnersdata partners   faqcontact proudly built by ai with the help of our collaborators terms of service•privacy policy the allen institute for ai by clicking accept or continuing to use the site, you agree to the terms outlined in our privacy policy, terms of service, and dataset license accept & continue  a third-generation human gucy c-targeted car-t cell for colorectal cancer immunotherapy most of the chpd t cell receptor combinations secreted both pro-inflammatory (ifng, tnfa, il- , gm-csf, il- , and il- ) and anti-inflammatory cytokines (il- ), chpd t cells containing a dap costimulatory domain secreted high levels of proinflammatory cytokines but did not secrete a significant amount of anti-inflammatory cytokines. furthermore, t cells expressing chpd receptors with a dap domain also had the strongest anti-tumor efficacy in vivo. chpd t cells did not survive for longer than days in vivo, however treat- ment with chpd t cells induced long-lived protective host- anti-tumor immune responses in tumor-bearing mice. conclusions therefore, adoptive transfer of chpd t cells could be a novel therapeutic strategy to treat multiple types of cancer and inclusion of the dap costimulatory domain in chimeric antigen receptors may induce a preferential cytokine profile for anti-tumor therapies. ethics approval the study was approved by longwood uni- versity’s iacuc. http://dx.doi.org/ . /jitc- -sitc . bcma-targeting car-t cells expanded in il- have an improved phenotype for therapeutic use compared to those grown in il- or il- /il- anthony battram*, mireia bachiller, Álvaro urbano-ispizua, beatriz martin-antonio. idibaps, barcelona, spain background chimeric antigen receptor-t (car-t) cells that target b cell maturation antigen (bcma-cars) have emerged as a promising treatment for multiple myeloma (mm). despite impressive initial responses to bcma-car therapy in clinical trials, relapse is common, signifying a need to improve the in vivo efficacy and persistence of bcma-cars. the develop- ment of unfavourable differentiation or t cell dysfunction, such as exhaustion and senescence, during the ex vivo expan- sion of the bcma-cars could be limiting their therapeutic potential. for cd -directed cars, reduced dysfunction and differentiation and improved anti-tumour responses were achieved by expanding the cells with il- instead of il- . therefore, in this study, our aim was to determine whether expanding bcma-cars with il- or il- /il- instead of il- alters their levels of exhaustion, senescence, differentia- tion and activity. methods t cells stimulated with anti-cd /anti-cd -coated beads were supplemented with il- , il- , il- + il- or no cytokine and transduced with ari h, a bcma-car with a - bb co-stimulatory domain produced at our institution. expanded bcma-cars were analysed by flow cytometry for markers of t cell dysfunction, or challenged with mm cell line arp- and then tested for cytokine production, cytotoxic ability and activation signals. results bcma-cars cultured in il- or il- /il- expanded similarly to those grown in il- , with comparable car trans- duction efficiencies, cd :cd ratios and proliferation rates. bcma-cars grown in il- had low expression of exhaus- tion marker lag- and high expression of the costimulatory molecule cd , which is important for t cell survival and persistence, when compared to bcma-cars cultured in il- . moreover, bcma-cars grown solely in il- were less dif- ferentiated than those supplemented with il- , and had higher expression of stem cell memory marker cxcr within the naïve population than those expanded with il- . when challenged with mm cell line arp- , il- -grown bcma- cars upregulated activation marker cd , exhibited strong cytotoxicity and robust production of ifng and il- . how- ever, in comparison to bcma-cars expanded in il- or il- /il- , those grown with il- had lower mtorc activity and p mapk phosphorylation when activated by arp- cells, suggesting differential regulation of key pathways for t cell metabolism and senescence, respectively. conclusions to summarise, bcma-cars expanded with il- alone exhibited the most favourable phenotype for therapeutic use compared those grown with il- or il- /il- . future experiments using murine mm models will be critical in understanding the in vivo benefits or drawbacks of culturing bcma-cars in il- compared to il- or il- /il- . ethics approval research involving human material was approved by the ethical committee of clinical research (hos- pital clinic, barcelona). peripheral blood t cells were obtained from healthy donors after informed consent in accordance with the declaration of helsinki. references . roex g, feys t, beguin y, kerre t, poiré x, lewalle p, et al. chimeric antigen receptor-t-cell therapy for b-cell hematological malignancies: an update of the pivotal clinical trial data. pharmaceutics [internet]. ; : – . available from: http://www.ncbi.nlm.nih.gov/pubmed/ . alizadeh d, wong ra, yang x, wang d, pecoraro jr, kuo cf, et al. il enhan- ces car-t cell antitumor activity by reducing mtorc activity and preserving their stem cell memory phenotype. cancer immunol res ; : – . . perez-amill l, suñe g, antoñana-vildosola a, castella m, najjar a, bonet j, et al. preclinical development of a humanized chimeric antigen receptor against b cell maturation antigen for multiple myeloma. haematologica [internet]. ; avail- able from: http://www.ncbi.nlm.nih.gov/pubmed/ http://dx.doi.org/ . /jitc- -sitc . a third-generation human gucy c-targeted car-t cell for colorectal cancer immunotherapy trevor baybutt*, adam snook, scott waldman, jonathan stem, ellen caparosa, alicja zalewski. thomas jefferson university, philadelphia, pa, usa background colorectal cancer (crc) presents a significant public health burden, responsible for the second most cancer- related deaths in the united states, with an increasing inci- dence in young adults observed globally. , while the blockade of immune checkpoints received fda approval as a crc ther- apeutic, only patients with microsatellite instability, accounting for % of sporadic cases, demonstrate partial or complete responses. we present a third-generation chimeric antigen receptor (car)-t cell directed towards the extracellular domain of the mucosal antigen guanylyl cyclase c (gucy c), which is over-expressed in % of crc cases, as a therapeu- tic alternative for late stage disease. here, we demonstrate that human gucy c car-t cells can selectively kill gucy c-expressing colorectal cancer cells in vitro and pro- duce inflammatory cytokines in response to antigenic stimulation. methods peripheral blood mononuclear (pbmcs) cells were isolated from leukoreduction filters obtained from the thomas jefferson university hospital blood donor center (irb # d. ). magnetic activated cell sorting (macs) technol- ogy was used to negatively select pan-t cells (miltenyi biotec), followed by activation and expansion using anti-cd , anti- cd , and anti-cd coated microbeads (miltenyi biotec) and supplemented with il- and il- (biological resources abstracts j immunother cancer ; (suppl ):a –a a o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://jitc.b m j.co m / j im m u n o th e r c a n ce r: first p u b lish e d a s . /jitc- -s it c . o n d e ce m b e r . d o w n lo a d e d fro m http://jitc.bmj.com/ branch preclinical biologics repository – nci). t-cells were transduced with a lentiviral vector encoding the anti-gucy c car. our car utilizes a single chain variable fragment of human origin directed towards the extracellular domain of gucy c, the cd hinge, transmembrane, and intracellular signaling domain (icd), - bb (cd ) icd, and cd z icd. car-t cells were used for experiments between to days after activation in vitro using the xcelligence real time cytotoxicity assay and intracellular cytokine staining. results gucy c-directed car-t cells specifically lysed the gucy c-expressing metastatic crc cell line t , while the control car did not. gucy c-negative crc cells were not killed by either. in addition to cell killing, gucy c-directed car-t cells of both the cd + and cd + co-receptor lineage produced the inflammatory cytokines ifn-g and tnfa in response to gucy c antigen. conclusions we demonstrate that human gucy c-directed car-t cells can selectively target gucy c-expressing cancer cells. we hypothesize that gucy c-directed car-t cells present a viable therapeutic option for metastatic crc. in vivo animal models to examine this potential are currently on- going. acknowledgements this work was supported by the depart- ment of defense congressionally directed medical research programs (w xwh- - - , w xwh- - , and w xwh- - - ) to aes and targeted diagnostic & therapeutics to saw. aes is also supported by a degregorio family foundation award. saw is supported by the national institutes of health (nih) (r ca , r ca , and p ca ), and the department of defense congres- sionally directed medical research program w xwh- - prcrp-ttsa. saw and aes were also supported by a grant from the courtney ann diacont memorial foundation. saw is the samuel m.v. hamilton professor of thomas jefferson university. js, ec, and az were supported by an nih institu- tional award t gm for postdoctoral training in clinical pharmacology. ethics approval this study was approved by the thomas jef- ferson university institutional review board (irb control # d. ) and the institutional animal care and use com- mittee (protocol # ). references . siegel rl, miller kd, jemal a. cancer statistics, . ca cancer j clin ; : – . doi: . /caac. . araghi m, soerjomataram i, bardot a, ferlay j, cabasag cj, morrison ds, et al. changes in colorectal cancer incidence in seven high-income countries: a popula- tion-based study. lancet gastroenterol hepatol ; : – . doi: . / s - ( ) - . overman mj, mcdermott r, leach jl, lonardi s, lenz h-j, morse ma, et al. nivo- lumab in patients with metastatic dna mismatch repair-deficient or microsatellite instability-high colorectal cancer (checkmate ): an open-label, multicentre, phase study. lancet oncol ; : – . doi: . /s - ( ) - http://dx.doi.org/ . /jitc- -sitc . increasing ampk activity in human t cells enhances memory subset formation without sacrificing in vitro expansion erica braverman*, andrea dobbs, darlene monlish, craig byersdorfer. university of pittsburgh, pittsburgh, pa, usa background the ideal adoptive cell therapy consists of mem- ory-like t cells with enhanced oxidative potential. however, current expansion protocols drive t cells towards terminal dif- ferentiation, decreasing the number of t cells fit for the in vivo environment. amp-activated protein kinase (ampk), whose activity increases in memory cells, is a key regulator of mitochondrial biogenesis and oxidative metabolism, making ampk activation an attractive candidate to improve adoptive t cell function. methods to increase ampk activity, ampkg, which controls the phosphorylation status of ampka and therefore activity of the ampk complex, was cloned into a lentiviral plasmid downstream of the elongation factor a (ef a) promoter and upstream of green fluorescent protein (gfp). an empty vector, containing gfp only, served as a negative control. human t cells were transduced and expanded in vitro in the presence of il- . ampk activity was assessed via immunoblot for phos- phorylation of ampka on thr and s on downstream target unc- -like kinase (ulk ). memory-marker expres- sion and mitochondrial density (using mitotracker red) were analyzed by flow cytometry. oxidative metabolism and spare respiratory capacity (src) were determined using the seahorse metabolic analyzer. fold changes of in vitro expansion were calculated by adjusting manual cell counts for gfp positivity and cd +/cd + staining. results ampkg was efficiently transduced and expressed by human t cells, which significantly increased ampk activity (ampka phosphorylation . ± . vs . ± . , p< . , ulk phosphorylation . ± . vs . ± . , p< . ). ampkg-overexpressing t cells augmented expression of memory markers cd l, cd , and ccr , with an increased yield of stem cell memory-like t cells marked by co-expression of cd ra and cd l (figure ). mitochondrial density, src, and maximal oxygen consumption rates were similarly increased in ampkg-transduced cells (fig- ure a,b). further, while enhanced memory cell production is often linked with reduced proliferation, t cells with increased ampk activity maintained and even trended towards increased rates of expansion compared to empty-transduced controls (figure a), with a measurable increase in cd + t cell per- centages by flow cytometry (figure b). abstract figure ampk-transduced t cells increase expression of memory surface markers. human t cells were transduced with ampk-gfp or gfp-only control (empty). memory markers were assessed by flow cytometry on days – of in vitro culture following expansion with il- . plots are representative of separate donors abstracts a j immunother cancer ; (suppl ):a –a o n a p ril , b y g u e st. p ro te cte d b y co p yrig h t. h ttp ://jitc.b m j.co m / j im m u n o th e r c a n ce r: first p u b lish e d a s . /jitc- -s it c . o n d e ce m b e r . d o w n lo a d e d fro m http://jitc.bmj.com/