(2/ QUALITY AND RELEVANCE OF RESEARCH AND RELATED ACTIVITIES AT THE GORGAS MEMORIAL LABORATORY V V " V W A TECHNICAL MEMORANDUMW‘Z?” / Office of Technology Assessment Congressional Board of the 98th Congress MORRIS K. UDALL, Arizona, Chairman TED STEVENS, Alaska, Vice Chairman Senate ORRIN G. HATCH Utah CHARLES McC. MATHIAS, IR. Maryland EDWARD M. KENNEDY Massachusetts ERNEST F. HOLLINGS South Carolina CLAIBORNE PELL House GEORGE E. BROWN, JR. California JOHN D. DINGELL Michigan LARRY WINN, JR. Kansas CLARENCE E. MILLER Ohio COOPER EVANS Rhode Island Iowa JOHN H. GIBBONS (Non voting) Advisory Council CHARLES N. KIMBALL, Chairman JAMES C. FLETCHER RACHEL McCULLOCH Midwest Research Institute University of Pittsburgh University of Wisconsin EARL BEISTLINE S. DAVID FREEMAN WILLIAM J. PERRY University of Alaska Tennessee Valley Authority Hambrecht & Quist CHARLES A. BOWSHER GILBERT GUDE DAVID S. POTTER General Accounting Office Congressional Research Service General Motors Corp. CLAIRE T. DEDRICK CARL N. HODGES LEWIS THOMAS California Land Commission University of Arizona Memorial Sloan-Kettering Cancer Center Director JOHN H. GIBBONS This Is an OTA Technlcal Memorandum that has neither been reviewed nor approved by the Technology Assessment Board. QUALITY AND RELEVANCE OF RESEARCH AND RELATED ACTIVITIES AT THE GORGAS MEMORIAL LABORATORY A TECHNICAL MEMORANDUM AUGUST 1983 Technical Memoranda are issued by OTA on specific subjects analyzed in recent OTA reports or on projects presently in process at OTA. They are issued at the request of Members of Congress who are engaged in committee legislative actions which are expected to be resolved before OTA completes its assessment. x . ' ' couanss OF THE UNITED suns ' ‘ F 00c. 01 Technology Assessment ‘5: Washington, D. C. 20510 Recommended Citation: Quality and Relevance of Research and Related Activities at the Gorgas Memorial Laboratory—A Technical Memorandum (Washington, DC: U.S. Congress, Office of Tech- nology Assessment, OTA—TM-H-18, August 1983). Library of Congress Catalog Card Number 83-600577 For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC. 20402 /\ Foreword Pa C936” . -1 F1 .5‘ The Gorgas Memorial Institute of Tropical and Preventive Medicine, Inc. (GMI and its operating arm, the Gorgas Memorial Laboratory (GML) have been conducting tropical research, training, and public health activities for more than half a century. Questions about GMI's continued existence were raised this spring when the National Institutes of Health requested no funds for the core support for GML. Gorgas' existence is at stake because the core support appropriation by the United States represents about three-quarters of GMI’s total budget. K The Senate Committee on Appropriations and its Subcommittee on Labor, Health and Human Services, and Education requested that the Office of Technology Assess- ment (OTA) examine the quality and relevance of research and related activities of GML. Such information is needed in order to adequately judge whether the core support should be terminated. The subcommittee also requested that the General Accounting Office undertake a concurrent evaluation of four areas: the peer review process at GMI/GML, the extent of other federally funded tropical medicine research activities, efforts by Gorgas to broaden its financial base of support, and the possible impacts on US. regional rela- tionships if funding was terminated. This technical memorandum presents the results of OTA's examination. It reviews the quality and relevance of activities at GML, based on Gorgas’ publishing record, an OTA-commissioned survey of GML’s scientific reputation, a critical review of re- cent articles and current manuscripts, a comparison of GML’s areas of effort with health problems in tropical America and with scientific opportunity, and a review of past scien— tific evaluations of GML. OTA finds that GML's research and related activities are generally of high quality and relevance to the region and the United States. The United States receives excellent benefit for its contribution to GMI/GML. If Gorgas were to close down, the United States would most likely have to develop a capability to undertake many of the current activities of GML. OTA finds that there would be both health-related and international relations repercussions if the United States were to withdraw its support for GML. Although GMI could be improved in several significant respects, GML is producing important work of high quality and represents an excellent investment of health funds. This memorandum benefited from the consultation and review of a large number of persons in the Federal Government, universities, international health organizations, and private industry. Key OTA staff involved in the analysis and writing were Hellen Gelband, Clyde I. Behney, Steven S. Bjorge, and John S. Willems. 54.. 754 gm JOHN H. GIBBONS Director OTA Staff—Quality and Relevance of Research at Gorgas Memorial Laboratory H. David Banta, Assistant Director, OTA Health and Life Sciences Division Clyde J. Behney, Health Program Manager and Study Co-Director Hellen Gelband, Study Co-Director Steven S. Bjorge, Analyst John S. Willems, Research Assistant Virginia Cwalina, Administrative Assistant Jennifer Nelson, Secretary Mary Walls, Secretary Gwenn Sewell, Research Assistant Contractors Michael B. Macdonald The Johns Hopkins University Richard K. Riegelman The George Washington University OTA Publishing Staff John C. Holmes, Publishing Officer John Bergling Kathie 5. Boss Debra M. Datcher Joe Henson Glenda Lawing Linda A. Leahy Cheryl Manning iv Contents Page CHAPTER 1: INTRODUCTION AND BACKGROUND ................................ 3 Introduction ....................................................................... 3 Organization of the Technical Memorandum ........................................ 6 Summary of Findings and Conclusions ................................................ 6 Background ....................................................................... 9 The Tropics and Tropical Diseases ................................................. 9 The Value of Laboratories Located in the Tropics .................................... 10 CHAPTER 2: GORGAS MEMORIAL INSTITUTE AND LABORATORY ................. 15 Organization ...................................................................... 18 Activities of GML .................................................................. 21 CHAPTER 3: QUALITY OF RESEARCH AT THE GORGAS MEMORIAL LABORATORY. 27 Introduction ....................................................................... 27 Site Visits by the Fogarty International Center ............................... . .......... 27 Review of Research Programs ...................................................... 28 Arbovirus Program ............................................................... 29 Environmental Assessment Program ................................................ 29 Diarrhea] Diseases Program ....................................................... 29 Sexually Transmitted Diseases ..................................................... 30 Cancer Registry/ Cancer of the Cervix .............................................. 30 Training ........................................................................ 30 Publications ..................................................................... 30 Peer Review at the Gorgas Memorial Laboratory ....................................... 34 Grants and Contracts ............................................................... 34 Quality of Research at GML as Seen by Experts ..................................... 35 Summary ....................................................................... 36 CHAPTER 4: RELEVANCE OF RESEARCH AT GORGAS MEMORIAL LABORATORY TO HEALTH PROBLEMS IN TROPICAL AMERICA .............................. 39 Tropical Diseases: Description and Status ............................................. 40 Acute Respiratory Infections ....................................................... 40 Diarrhea] and Enteric Diseases ..................................................... 40 Malnutrition ..................................................................... 41 Malaria ........................................................................... 42 Chagas’ Disease .................................................................. 43 Leishmaniasis .................................................................... 44 Anthropod-Borne Viral Diseases ................................................... 45 Filariasis ........................................................................ 46 Schistosomiasis .................................................................. 47 Leprosy ......................................................................... 47 Tuberculosis ..................................................................... 47 Cancers ......................................................................... 48 Relevance of Research at Gorgas ..................................................... 48 Summary ......................................................................... 51 CHAPTER 5: FINDINGS AND CONCLUSIONS ....................................... 55 Findings ........................................................................... 55 Conclusions ....................................................................... 56 vi Contents—Continued Appendixes A. Acknowledgments; Pan American Health Organization Liaison Group; OTA Health Program Advisory Committee ........................................ B. Tropical Disease Research Activities ............................................... C. Bibliography of Publications by the Gorgas Memorial Laboratory Staff ................ D. Summary of the Telephone Survey on Gorgas Memorial Laboratory .................. E. Glossary of Acronyms and Terms ................................................. References ......................................................................... Tables Table No. 1. The Gorgas Memorial Laboratory's Major Accomplishments From 1970 to the Present . . 2. Major Accomplishments of the Gorgas Memorial Laboratory, 1929-69 ................ Page 61 64 67 77 81 89 Page 7 8 3. A: Sources of Financial Support for the Gorgas Institute and Laboratory Fiscal Years 1975-82 15 B: Sources of Financial Support for the Gorgas Institute and Laboratory Fiscal Years 1975-82 16 4. Gorgas Memorial Institute of Tropical and Preventive Medicine, Incorporated: Operating Budgets Fiscal Years 1982 and 1983 ..................................... . Gorgas Memorial Institute of Tropical and Preventive Medicine, Incorporated: Projection Fiscal Year 1984 ...................................................... . Gorgas Memorial Laboratory Information on Scientific Staff as of July 1983 ........... . Recent Activities of Gorgas Memorial Laboratory ................................... . Total Publications of the Gorgas Memorial Laboratory, 1975-83 ...................... . Gorgas Memorial Laboratory: Publication Location for Articles Written by Staff; 1980 to July 1983 ............................................... 10. Articles and Manuscripts Reviewed for the Office of Technology Assessment by Richard K. Riegelman, M.D., Ph. D ............................................ 11. Gorgas Memorial Laboratory: Grants and Contracts as of July 1983 .................. U'I \OQVO‘. Figures Figure No. 1. Gorgas Memorial Institute Organization ............................................ 2. Gorgas Memorial Institute-Proposed Organization Chart .............................. 17 18 20 22 31 31 32 35 Page 19 20 Chapter1 Introduction and Background Chapter 1 Introduction and Background The Gorgas Memorial Laboratory (GML) is a research institution concerned with tropical medicine and public health. It undertakes both ap- plied and basic research, and performs laboratory, clinical, and field research activities. GML was established in 1928 in commemoration of the work of Gen. William Gorgas in in controlling yellow fever. The Laboratory is located in Panama City, Republic of Panama. It is the research arm of the Gorgas Memorial Institute of Tropical and Pre— ventive Medicine, Inc. (GMI), a (U.S.) domestic, nonprofit corporation headquartered in Washing- ton, D.C. INTRODUCTION GML is a specific subject of evaluation because of questions concerning its fiscal year 1984 ap- propriation. GMI is authorized by act of Congress (Public Law 70-350, as amended) to receive a year- ly appropriation, not to exceed $2 million, from the U.S Government. The original fiscal year 1984 budget request from the Fogarty International Center (FIC)—the unit of the National Institutes of Health (NIH) given responsibility for admin- istering the Gorgas budget request—included a budget request for Gorgas. A subsequent revision by NIH, of the NIH budget, led NIH/FIC to re- quest no funds at all for core support of GMI. Because this core support of close to $2 million is an extremely large percentage of the total GML budget (see ch. 2), this action effectively meant that GML would have to close down. In order to evaluate whether this action was justified on the basis of the quality of Gorgas' research and on its success in identifying needs and conducting research relevant to health con- cerns of Panama and tropical America" (especially Central America and the Caribbean), the re— questing subcommittee and committee asked both ‘The term tropical America here refers to the southern part of North America, all of Central America and the Caribbean, and tropical South America. This technical memorandum presents the results of a review of the quality and relevance of re- search and related activities of GML. The evalua- tion was conducted at the request of the Senate Committee on Appropriations and, especially, its Subcommittee on Labor, Health and Human Services, and Education. It is part of a broader OTA assessment of the status of biomedical re- search and related technology for tropical medi- cine, also requested by the committee and sub- committee. the General Accounting Office (GAO) and the Office of Technology Assessment (OTA) to pro- vide relevant information. The related effort by GAO examines four topics: 1. the process of peer review used by GML before initiating research projects and after their completion, 2. efforts to broaden the financial base of GML, 3. other federally funded tropical medicine research activities, and 4. the possible impact of GML’s closing on U.S.-Panamanian relations. That report is scheduled for completion in August 1983. The OTA effort devotes some attention to the first of those four topics, but is primarily ad- dressed to issues of: 1. the quality of GML's applied biomedical research projects, epidemiological activities, maintenance of research animal populations, and other research-related activities such as training; and 2. the relevance of GML’s research and other activities to the health needs and problems of Panama, other tropical American coun- tries, the U.S. interests, and to tropical medicine in general. The Amerlcas 2158.5 >3» 33:3 h. 830%. v . m... avoiuuw RNQQN u E a a a Q 4”,: , w. w 3.3“. 3 .. n are . .3535 8 £3 ‘3... .2, 8,5 .3 8:32.... . . .1. 0 pk N O Q U-L£NN~Q . . .2 . k \ ~3N‘9Hs ~N a . #6 V . . 8.65m . m f1). .aaimbqn. “M3933 2£...8 é Hr . _ m . . a a , W f . . 1395 v. mu mg Pa uw‘ .. . . em3w5..§v. 5. 8. . 2.3: 81 . .uEutuk uh: E. . . ,<;< . 32“.:qu wot: no? , m . cxumEN u 35.3.2, . 3 “WW fiohom 3‘ . cmcisqrw .1 95:3. h 3 £9... . 99> 3.33 00:50 .. 9‘0 \0 \V .1 G... \U . . oz 3.. e§$§m§m Organization of the Technical Memorandum The remainder of this chapter contains a sum— mary of the findings and conclusions of the technical memorandum and background informa- tion on the Tropics, tropical diseases, and the role of research laboratories located in the Tropics. Chapter 2 presents descriptive material on Gorgas, its structure, and past and current research activ- ities. Chapter 3 examines evidence on the quali- ty of GML’s research, public health, and train- ing activities. The fourth chapter presents descriptions and brief data on the status of the diseases and health problems of critical importance to tropical Amer- ica and of research related to them. Gorgas’s ac- tivities are then discussed in the context of these diseases and conditions. The final chapter presents the findings and conclusions. Appendix A presents the acknowledgments, lists the members of the Liaison Group formed by the Pan American Health Organization to pro- vide advice to OTA on this project, and lists the OTA Health Program Advisory Committee. Ap- pendix B is a brief presentation of other current research activities in tropical health. Appendix C is a bibliography of publications since 1975 by GML staff. Appendix D is a summary of the OTA survey of experts' opinions concerning Gorgas and its research quality and relevance. Appendix E contains a list of acronyms and a glossary of terms. SUMMARY OF FINDINGS AND CONCLUSIONS OTA examined the quality and relevance of tropical medicine research and related activities at GML. The evaluation of the quality of an in— stitution such as Gorgas cannot take place with- out explicit recognition of certain premises: 0 There is an inherent value in supporting tropical research laboratories in tropical countries. Field conditions present opportu- nities that cannot be duplicated by organiza- tions such as NIH. 0 Evaluations of the quality of research are in- evitably, and properly, made partly on the basis of fairly objective criteria such as publications record and partly on the basis of subjective judgments by qualified individ- uals. 0 The criteria used to judge quality, although similar in type, need to be modified and weighted differently for research performed in well-equipped, state-of-the-art laboratories than for field research laboratories. 0 Relevance is directly dependent on the type and location of institution, and it should be examined from each of the appropriate view- points (e.g., host country, region, United States, general advancement of knowledge). With these premises in mind, OTA examined the quality of Gorgas’ research against a range of objective and subjective criteria. There was very impressive agreement among the results of: 1) the past scientific evaluations of GML, 2) the critical evaluation of the research design and presenta- tion of articles and manuscripts, 3) the survey of expert scientific opinion on Gorgas’ quality, 4) in- terviews with Panamanian health officials and professionals, 5) the examination of GML staff's publications record, and 6) an examination of GML's record of competing for grants and con- tracts. All evidence gathered by OTA led to the finding that the overall scientific quality of GML is high, especially when considered in the context of GML’s status as a research laboratory located in the Tropics. Quality was, naturally, not uniformly even. OTA also found that the large majority of GML’s research is highly or adequately relevant to health concerns and problems of Panama, the tropical American region, US. interests, and the advancement of scientific knowledge and the field of tropical medicine in general. (Table 1 lists significant accomplishments of GML in the past decade; table 2 shows significant activities dur- ing the previous period of GML's history.) The evidence for this finding lies, for the first two, in the match between tropical health problems and GML research directed at them, and from strongly Table 1.—The Gorgas Memorial Laboratory’s Major Accomplishments From 1970 to the Present 0 Continued yellow fever surveillance and monitoring of vectors 0 St. Louis encephalitis and Venezuelan equine encephalitis vectors and reservoirs o Insect genetic studies using isozyme markers - Transovarial transmission of yellow fever virus in mosquitoes - Use of Aotus monkey model for testing of therapeutics 0 Several new viral isolates in area 0 Screening of antimalarial drugs and identification of promising therapeutic antimalarial compounds 0 WHO regional center for bloodmeal analysis 0 Improved identification of insect vectors: sandflies, triatomines, blackflies, etc. 0 Development of cancer registry in the Republic of Panama 0 Discovery of high incidence of cervical and penile cancer in Herrera Province (Republic of Panama) - Studies of sexually transmitted diseases in the Republic of Panama (the first such studies in Latin America) 0 Rapid identification of viral agent in recent epidemics of conjunctivitis and encephalitis in the Republic of Panama - Discovery of high HTLV antibodies in the Republic of Panama 0 Environmental impact assessment of Tabasara Hydroelectric project SOURCE: Gorgas Memorial Laboratory, Office of the Director, August, 1983. expressed opinions and examples by various Pan- amanian officials and professionals. The importance of GML to Panama cannot be judged solely on the basis of Panama’s monetary contribution. Panama is going through a difficult economic period. Even so, the Ministry of Health has arranged a loan to keep GML in operation for the remainder of fiscal year 1983. The value of the land, buildings, and tax-favored status have never been adequately assessed. And to put the often criticized direct financial contribution of $10,000 from Panama in perspective, the research budget of the Panamanian medical school is re- portedly only $20,000. As one official of the US. Department of State expresses it: Each year, the United States sends a message to Panama and the region by funding GML and supporting activities related to the health of US. and Panamanian citizens alike (51). Activities related to the recent Panama Canal Treaty process provide a specific example of the importance of GML to Panama. As part of the treaty, a Joint Committee on the Environment was established. Panama turned to GML, as the only institution in Panama with the necessary skills and experience, for assistance in relation to environ— mental protection and human and animal health, and additionally named Dr. Pedro Galindo, for- merly of GML, as the senior Panamanian on the Committee. Relevance to U.S. health interests can be found in the surveillance activities, the training activities, and the various research activities undertaken under contract to the US. military. There are about 20,000 US. Government employees and de- pendents in Panama; and many thousands more in nearby countries. The work of GML is direct- ly relevant to the health of these people. Gorgas’s contributions in the areas of malaria, yellow fever, and leishmaniasis illustrate its relevance to the general advancement of knowl- edge (see also, tables 1 and 2). Based on the above evidence, OTA finds that with some exceptions that occur almost entirely within the core-funded activities, the research con- ducted at Gorgas is relevant to the various par- ties at interest. Conclusions: OTA concludes that the benefits of supporting GML justify, on scientific and other grounds, the relatively small amount of funds re- quired. Quality and relevance are high. With- drawing core support from Gorgas would prob- ably not even save the amount of the appropria- tion, since other Federal agencies may need to either conduct or support research now carried out at GML. Gorgas is not ideal; improvements could cer- tainly be made. Some of the shortcomings stem from its uncertain funding. The prospect of unstable funding and perhaps closure may have kept individual scientists from joining GML or becoming visiting scientists there and may reduce the desire of U.S. universities to collaborate with GML on research projects. Another example of the effect of uncertain funding has been the decision by the US. Navy to hold off on the next scheduled training class, because the course would extend a few weeks into fiscal year 1984. It is extraordinarily difficult to Table 2.—Major Accomplishments of the Gorgas Memorial Laboratory, 1929-69 l. Protozoa! Diseases of Man and Lower Animals: Malaria: 1933 and subsequently: First long-range, large-scale field tests of the antimalarial drugs, Atebrine, chloro- quine, and paludrine under controlled conditions in the New World Tropics. 1954: First long-range field tests of DDT house-spraying to control malaria. 1960: Field demonstration of the effectiveness of weekly doses of pyrimethamine-primaquine drugs com- bined with the eradication of Plasmodium falciparum malaria from a tropical area. 1966: Demonstration that certain common human malaria parasites could be grown in certain species of Panamanian monkeys and could be transferred to man and other monkeys by blood inoculation and by bites of mosquitoes. American Trypanosomiasis: 1931: First report of Chagas' disease in Panama and discovery of the vectors. 1959: First report of Trypanosoma range/i from man and wild vertebrates in Panama and demonstration of the development of the human strain in the salivary glands of Rhodnius pal/escens. 1965: Demonstration that the Panamanian strain of T. range/i differs from the South and Central American strains in its behavior of development in the insect vector. Leishmaniasis: 1965: Incrimination of seven wild vertebrates as reservoir hosts of human leishmaniasis. 1966: Demonstration that Ieishhmania infection may com- monly occur in the apparently normal skin of some feral animals without producing lesions. 1945-68: Recognition of over 70 species of Phlebotomus in Panama, of which 4 or 5 have been found infected with leishmania. Animal Trypanosomiasis: 1932: Discovery of the vampire bat transmission of equine trypanosomiasis. 1932: Discovery of bovine trypanosomiasis in Panama. Intestinal Protozoa: 1944: First finding of Isopora hominis in Panama. II. Helminthic Diseases of Man and Lower Animals: 1934-35: First comprehensive survey of the worm parasites of equines in Panama. 1966: Finding a new human disease entity caused by Echinococcus oligarthrus, a little known cestode parasite of pumas and other large felines; descrip- tion of the first known human case that terminated fatally; and demonstration of the life cycle of the parasite. III. Rickettsial Diseases: 1946: First report of Q Fever in Panama. 1947: First report of murine typhus in Panama. 1951: First recognition of Rocky Mountain Spotted Fever in Panama. IV. Virus Diseases: 1949: First demonstration of the mosquito vectors of yellow fever in Panama and Central America and the inauguration of comprehensive studies on vector ecology and transmission capabilities. 1957: First recovery of St. Louis encephalitis virus and recognition of human cases in Panama. 1958: First isolation of llheus virus in Central America. 1960: First isolation of Changuinola virus from man. 1961: Discovery of four new arboviruses: Madrid, Ossa, Patios, and Zegla. 1963: First isolation of Wyeomyia subgroup of arboviruses from man. 1964: Recognition of the first human case of llheus encephalitis. 1965: Finding of crab-hole mosquitoes (Deinocerites) as hosts for St. Louis encephalitis virus. 1968: First isolation of Vesicular Stomatitis virus (Indiana) from man in Panama and detection of virus transmis- sion by the use of sentinel monkeys. V. Medical Entomology: 1929: First elucidation of the human botfly, Dermatobia hominis, in man. 1935: First establishment of a laboratory colony of anopheles albimanus, the main vector of malaria in Central America. 1944: First tests of DDT to control phlebotomine sandflies. 1945: First experimental trials of DDT for the control of Simulium spp., the vectors of Onchocerca volvu/us, the blinding filariid parasite of man. 1945: First experiments with DDT for the control of Culicoides sandflies. 1945: First observations in Panama on the habits and life histories of chigger mites (Trombiculidae), potential vectors of disease. 1966: First comprehensive survey of the ticks and biting insects of Panama. VI. Miscellaneous Projects: 1930-54: Comprehensive survey of the poisonous snakes of Panama and the incidence of snake bites. SOURCE: Willard H. Wright. 40 Years of Tropical Medicine Research (Washington, DC: Reese Press, 1970). plan and carry out research related to tropical dis— eases without multiyear budgeting and some as- surance of multiyear funding. Gorgas itself could improve its standing and its relevance by: 0 being more aggressive in its publishing, 0 by making better use of its Advisory Scien- tific Board (see ch. 5 for examples of possi- bilities), 0 by more actively seeking out associations and collaborations with a range of universities, groups from other countries, and internation- al organizations, 0 by making strategic plans to move more fully into the developing areas of modern science (e.g., work with monoclonal antibodies and other immunological diagnostics, and bio- technology approaches to vaccine-related research and development), and 0 by making more of an effort to run vigorous visiting scientist and fellowship programs. OTA concludes that the only benefit to the United States of defunding Gorgas would be sav- ings of perhaps significantly less than $2 million a year. The negative consequences would include loss of one of the few, high-quality, broadly rele- vant, tropical research institutions located in a tropical country. The standing of the United States in tropical America would inevitably suffer. BACKGROUND The Tropics and Tropical Diseases The Tropics can be roughly considered to in- clude Central America, much of South America, the South Pacific, southern Asia, and most of sub- Saharan Africa. Tropical nations are usually characterized by poverty, substandard drinking water and sanitation, hot and humid climates, poor health services, low levels of education, and in some cases swampy or jungle areas. Annual per capita income is often extremely low (as low as or even less than $100). Ir; tropical America, the average per capita gross domestic product was $1,500 in 1980. However, the variation is wide, ranging from nearly $9,000 in the Bahamas and $2,685 in Barbados (both figures may be decep- tive) to $267 in Haiti and $568 in Bolivia (75). Of the world's approximately 41/2 billion peo- ple, about three-quarters live in less developed countries, most of which are tropical. Of the ap- proximately 600 million population (1980 figures) of the Western Hemisphere, about 60 percent live in Latin America, most of which is tropical. Health status is generally poor, with high rates of infant mortality (primarily due to malnutrition, lack of prenatal care, and diarrhea] and respira- tory infections), widespread infection with debil- Ironically, GML is in danger of extinction at the very time that U.S. interest in Latin America is high, and at a time when tropical medicine has never been more relevant to U.S. interests. In summary, OTA concludes that the positive consequences of U.S. core support of Gorgas greatly outweigh the amount of funds involved. Defunding now, followed by an appreciation of the loss later and a subsequent attempt to reinstate such a research capability, may result in much larger required investments, an inability to recreate successful conditions for quality research, or both.* 'In fact, it may be impossible to recreate GML or a similar in- stitution in the current political climate in Latin America (51). itating disease, and high mortality and morbidi- ty rates from all diseases except certain chronic ones associated with a higher standard of living (such as some cancers). Any definition of “tropical disease" is arbitrary. In its strictest sense, perhaps, a tropical disease is one found—for reasons of physical environment and climate or the presence of specific disease vectors—entirely or predominantly in tropical re— gions. However, a more realistic, and more useful, definition includes those diseases or conditions— such as acute respiratory infection, tuberculosis, malnutrition, or cholera—that occur or could oc- cur in many regions, but which are considerably more prevalent in tropical areas because of the social and economic conditions that characterize many tropical countries. In countries with very low per capita gross domestic products, inade- quate or unsafe water supplies and sanitation, low levels of health care services, high levels of il- literacy, and similar conditions, certain diseases are able to flourish beyond the extent that would be predicted simply on the basis of climate. The OTA assessment, including this technical memorandum, will consider ”classic" tropical dis- 10 eases such as malaria that fit the narrower defini- tion, but it will more generally be guided by the broader definition. Thus, a more appropriate phrase to describe the subject of the assessment and the context in which Gorgas will be evaluated is “medicine and health in the tropics." The direct economic and social impacts of widespread disease are obvious, but the most substantial economic impacts may be indirect ones, affecting a country’s human resources and productivity. For example, a country whose pop- ulation has an extremely high prevalence of debilitating disease loses labor resources, and pro- ductivity inevitably suffers. In addition to the humanistic concern with the health and quality of life of people in tropical countries, and in addition to the stake that all developed countries have in the economic health and development of developing countries, there is a smaller, yet definite benefit that can accrue to the United States through support of tropical disease research and technology development. Tropical countries are no longer—if they ever really were—“exotic" far off lands seen only by adventurers. A great many people now travel to and live in tropical countries, as tourists, in the diplomatic or military service, or as employees of U.S. or multinational companies. The number of such people is most likely increasing.* ”The tropics are coming closer and bringing their dis- eases with them” (69). In addition, advances in tropical disease re- search can represent valuable knowledge in gen- eral medical science, particularly in the areas of infectious disease control, general preventive med- icine, and environmental health. The Value of Laboratories Located in the Tropics Laboratories and field stations located in the Tropics have played a vital role in tropical dis- ease research during this century. There is a cer- tain point at which research taking place in tem- ‘The increasing number of refugees in recent years serves as a dramatic example of an additional reason for regarding attention to tropical medicine as an important priority for the United States. perate countries, even though aimed at eventually eliminating or controlling tropical diseases, can go no further, regardless of the quality of re- searchers or institutions. Initially, information about the occurrence (incidence, prevalence, case- fatality rates), natural history, and transmission of diseases is necessary for the rational design of strategies to deal with diseases, and this can only be collected in the field. Finally, the fruits of research—e.g., drugs and vaccines, vector con- trol programs—must be tested where the diseases occur: in tropical regions. These are the very minimum involvements for institutions in the Tropics. There is absolutely no substitute for field con- ditions in tropical countries. This point has been made to OTA time and again by tropical health experts in academia, Government research orga- nizations, and the US. military. Apart from research, training in tropical medicine can only reasonably take place in the Tropics. Training needs and expertise have tradi- tionally been concentrated largely in the military. Additionally, professionals with training in trop- ical medicine are in demand by foreign govern- ments, academic institutions, and voluntary agen- cies (107). In addition to benefits to the US. population from knowledge of the control of tropical diseases, the existing tropical field laboratories benefit the countries in which they are located. The coun- try’s health science professionals who are involved in the projects or receiving training raise the level of sophistication of biomedical research in these countries. The disease problems studied are of ob— vious importance to the populations in these coun- tries, and any progress in treatment or control will benefit them. An additional benefit can be a less— ening of the ”brain drain" that occurs in many, especially developing, countries. When a good quality research institution exists in a country, its professionals have a place and the opportunity to work and develop without emigrating and thus not depriving the country of their skills. The US. Government supports a relatively small number of laboratories in tropical areas (see app. B). The Department of Defense operates eight medical research laboratories in the Tropics. 11 In Latin America, the Centers for Disease Con- trol (CDC) operates the Medical Entomology Re— search and Training Unit in Guatemala. CDC pre- viously ran a field station in El Salvador, which has been closed. The United States also supports tropical health research through contributions to international development agencies and through bilateral aid. Establishing new field laboratories is a difficult and time—consuming task. Building good relations with the host country and becoming a produc- tive unit may take years. The decision to eliminate an existing laboratory should consider that point. Thus, any evaluation of GML must not only consider the quality and relevance of its research, but also its role as a research, training, and public health unit actually located in the Tropics. Chapter2 Gorgas Memorial Institute and Laboratory Photo credits: Gorgas Memorial Laboratory Front entrance to the Gorgas Memorial Laboratory, in Panama City, Republic of Panama (bottom photo). Photo at top shows the Laboratory complex in Panama City. At the extreme left is the side of the administrative offices; the lower connecting structure houses the Library; to the right rear are the research laboratories. The complex also contains animal buildings and an insect facility (insectory) Chapter 2 Gorgas Memorial Institute and Laboratory The Gorgas Memorial Institute of Tropical and Preventive Medicine, Incorporated (GMI), a pri- vate, nonprofit organization, was incorporated in Delaware and registered in the Republic of Panama in 1921 as a memorial to Major General William Crawford Gorgas (47). The Gorgas Memorial Laboratory (GML), GMI’s research arm and primary function, was established in 1928 in the Republic of Panama, with resources made available by the Govern— ments of the United States and Panama and by several national and international agencies. The establishment of GML was made possible by an act of Congress (Public Law 70-350), which authorized a permanent annual contribution for the facility, provided that a site and building were made available from other sources, and by action of the National Assembly of the Republic of Pan- ama, which granted land and a building on the condition that the property be used for a research laboratory (47). The contribution made annually by the U.S. Government to GMI, which constitutes the core support for the maintenance and operation of GML, is administered by the Fogarty International Center (PIC) of the National Institutes of Health (NIH). Public Law 70-350, as amended, authorizes Congress to provide up to $2 million for GMI. In fiscal year 1983 GMI received $1.8 million through FIC, an increase from the fiscal year 1982 allotment of $1.692 million. Although GMI asked for $1.9 million in core support for GML in fiscal year 1984, the latest fiscal year 1984 NIH budget request targets no funds for GMI (47,115). GML also receives grants and contracts sup- porting specific research projects from a variety of United States, Panamanian, and international organizations. In fiscal year 1982, total U.S. con- tributions including research grants from the U.S. Army, Navy, NIH, and the Agency for Inter- national Development totaled approximately $2,225,200, or 96.9 percent of all direct financial support for GMI/GML (see tables 3A and 3B). Panamanian support for GML, which largely comes in the indirect form of property grants and a tax-favored status, is more difficult to tabulate. In 1930, the appraised value of the land donated by the Republic of Panama was $126,750. Esti- mates of the current value of the land and facilities have gone as high as $20 million by one senior Panamanian official, but no exact figure is avail- able. In 1979, FIC estimated the value of the ”in- Table 3A.—Sources of Financial Support tor the Gorgas Institute and Laboratory Fiscal Years 1975-82 (dollars In thousands) 1975-82 1975 1976 1977 1978 1979 1980 1981 1982 total US Appropriation .................. 3 707.5 31,360 31,400.0 31,400.0 31,700.0 31,700.0 31,800.0 31,692.0 $11,759.0 National Institutes of Health ........ 929.1 174.8 228.1 248.4 333.3 255.9 305.1 219.2 2,693.1 Health and Human Service (HEW). . . . — — — -— 4.4 4.7 0.9 — 10.0 U.S. Army ......................... 223.4 203.5 111.7 130.2 145.2 187.5 257.8 228.6 1,488.0 . 35.0 33.8 25.0 25.0 30.0 35.0 35.0 35.0 235.8 AID .............................. 120.0 5.5 — — 8.1 23.3 45.2 — 202.1 Subtotal Federal support ......... 32,0150 31,777.6 31,764.8 31,803.6 32,221.0 32,205.5 32,444.0 32,174.9 $16,406.3 Other U.S. support ................. 3 7.3 3 4.3 3 2.7 — 3 58.3 3 89.5 3 58.6 3 50.3 3 271.1 Total U.S. support ................ 32,022.3 31,781.9 31,767.6 31,803.6 32279.2 32,295.0 32,502.6 32,225.2 $16,677.5 Government of Panama ............. — 3 59.3 3 17.2 3 37.1 3 1.0 3 308.4 $251.0 $22.5 $696.5 WHO/PAHO ....................... 3 7.7 4.4 16.0 36.9 118.2 57.0 47.8 49.0 336.9 World Bank ....................... — — — 6.9 — — — — 6.8 Wellcome Laboratories ............. — — — (a) 1.0 — — — 1.0 Total non-U.S. Support ............ 3 7.7 3 63.7 3 33.2 3 80.8 3 120.2 3 365.4 3 298.8 3 71.5 3 1,041.3 Total support .................. 32,0300 31,8456 31,8008 31,8845 32,3995 32,660.4 32,801.4 32,296.? $17,718] 8Less than $50. 15 16 Table aB.—Sources of Financial Support for the Gorgas Institute and Laboratory Fiscal Years 1975-82 (as of percent) 1975-82 1975 1976 1977 1978 1979 1980 1981 1982 average U.S Appropriation .................. 34.9 73.7 77.7 74.3 70.8 63.9 64.3 73.7 66.4 National Institutes of Health ........ 45.8 9.5 12.7 13.2 13.9 9.6 10.9 10.0 16.7 Health and Human Service (HEW) . . . . —- — — — 0.2 0.2 (a) — 0.1 U.S. Army ......................... 11.0 11.0 6.2 6.9 6.1 7.0 9.2 10.0 8.4 US. Navy ......................... 1.7 1.8 1.4 1.3 1.3 1.3 1.2 2.0 1.4 AID .............................. 5.9 0.3 —— — 0.3 0.9 1.6 — 1.1 Subtotal Federal support ......... 99.3 96.3 98.0 95.7 92.6 82.9 87.2 94.7 92.6 Other US. support ................. 0.4 0.2 0.2 — 2.4 3.4 2.1 2.2 1.5 Total US. support ................ 99.6 96.5 98.2 95.7 95.0 86.3 89.3 96.9 94.1 Government of Panama ............. — 3.2 1.0 2.0 (a) 11.6 9.0 1.0 3.9 WHO/PAHO ....................... 0.4 0.2 0.9 2.0 4.9 2.1 1.7 2.1 1.9 World Bank ....................... — — — 0.4 — —- — — (a) Wellcome Laboratories ............. — — — (a) (a) — — — (a) Total non-U.S. Support ............ 0.4 3.5 1.8 4.3 5.0 13.7 10.7 3.1 5.9 Total support .................. 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 aLess than 0.05 support. SOURCE: Gorgas Memorial Institute, 1983. direct services” provided each year by the Pana- manian Government to be $175,000. GMI is required by law to make an annual re- port to Congress on the activities and expenditures of the laboratory. The US. General Accounting Office (GAO) audited all GMI/GML financial statements until 1980 (47). GML is currently engaged in an effort to cut costs and broaden its financial base of support. This issue is being addressed in the related GAO study, and will not be covered in this technical memorandum. Plans call for the the closure of Building 265, which cost an estimated $279,102 to maintain in fiscal year 1982 (see table 4); however, modifications to accommodate the re- location of the virology program formerly housed in the building are estimated at a one-time cost of $250,000 (table 5 shows this figure, as well as other projected costs for fiscal year 1984). The Laboratory has just finished terminating the employment of some 29 of GML’s employees and staff. The closing of the entire bacteriology department eliminated three Panamanian scien- tists with 10 to 22 years tenure at GML (121). GMI sought relief from the Panamanian Minister of Health and Minister of Labor from penalty charges attributable to early termination of Pan- amanian employees (47), but waivers were not granted. GMI has established a Development Committee to explore fund-raising possibilities in the private sector. Because of the completion of a number of commissioned projects, revenues from research grants and contracts dropped from $995,641 in fiscal year 1981 to $594,224 in fiscal year 1982. As a result of this decline, the propor- tion of total funding represented by US. core sup- port rose from 64.3 percent of all revenues in fiscal year 1981 to 73.7 percent in fiscal year 1982. Of the $1,884,824 spent by GMI/GML over the 12-month period ending July 1983 after the reduction-in-force, over half ($928,101) went towards salary costs. Utility charges, including those for Building 265, came to $413,257. Ad- ministrative costs accounted for $130,732, and another $163,258 was spent to maintain the GMI office in Washington, DC. The “direct” nonsalary research dollars amount for the laboratory was $209,476 (121). At its headquarters in Washington. DC, GMI is governed by a 47—member Board of Directors, which includes officials of the Governments of the United States and Panama, representatives of na- tional and international agencies active in areas of common interest, and US. and Latin American scientists and professionals. The board meets an- nually to determine the policies of the organiza- 17 Table 4.—Gorgas Memorial Institute of Tropical and Preventive Medicine, Incorporated: Operating Budgets Fiscal Years 1982 and 1983 Fiscal year 1982 Fiscal year 1983 Budgeted Actual W. (1/20/82) unaudited Old New Revenue: Contribution by the United States ................................... $1,692,000 $1,692,000 $1,800,000 $1,800,000 Research grants and contracts ..................................... 609,407 594,224 346,209 346,209 Other ............................................................ 2,500 10,442 10,000 10,000 Subtotal ....................................................... 2,303,907 2,296,666 2,156,209 2,156,209 Additional revenue required ........................................ 386,888 —— 390,930 524,011 L Total revenue required ........................................... 2,690,795 2,296,666 2,547,139 2,680,220 ; Expenditures: Core— lnfectious Disease Program Virology ....................................................... 275,390 340,752 383,547 374,146 Bacteriology ................................................... 105,765 110,826 114,741 183,052 Parasitology .................................................... 78,515 85,053 79,565 73,920 Immunology .................................................... 21,430 21,585 35,364 48,166 Clinical ........................................................ 71,297 81,809 60,366 67,688 Total ........................................................ 552,397 640,025 673,583 746,972 Ecology & Epidemiology Program Ecology ....................................................... 110,216 95,840 105,155 106,586 Vertebrate Zoology ............................................ 42,474 39,831 41,039 41,039 Entomology .................................................. 17,000 15,801 18,029 18,029 Epidemiology 494 6,664 9,331 9,331 Vector Biology 143,839 158,478 139,477 139,477 Total 314,023 316,614 313,031 314,462 Primatology & Laboratory Animals Program Animal Models ................................................. 46,254 47,350 57,754 53,954 Animal Colony .................................................. 73,546 81,969 85,977 88,427 Total ........................................................ 119,800 129,319 143,731 142,381 Education & Technical Support Program Educational Programs ........................................... 5,425 4,346 6,139 5,639 Library .............. . ......................................... 57,991 56,829 62,451 71,056 Total ........................................................ 63,416 61,175 68,590 76,695 Data Processing .................................................. 43,712 36,777 39,551 45,738 Administration Washington, DC. ............................................... 161,256 146,242 163,258 163,258 Panama ....................................................... 326,647 256,095 313,609 330,765 Total ........................................................ 487,903 402,337 476,867 494,023 Maintenance Panama ....................................................... 232,992 269,449 277,804 290,539 Building 265 .................................................... 309,693 279,102 290,583 321,011 Total ........................................................ 542,685 548,551 568,387 611,550 Seniority Premium .............................................. 25,000 21,028 15,000 * Total core expenditures .............................................. 2,148,936 2,155,826 2,298,740 2,431,821 Direct grant and contract expenditures ................................. 541,859 445,089 248,399 248,399 Total expenditures .............................................. 2,690,795 2,600,915 2,547,139 2,680,220 Excess revenue over/(under) expenditures ..................................................... $ -0- $ (304,249) $ -0- $ ~0- SOURCE: Gorges Memorial Institute, 1983. tion, review the managerial and fiscal operation, approve budgets, and elect officers, Board mem- bers, and advisors. Between meetings, the Board’s functions are delegated to the 9-member Executive Committee, which meets monthly under the chair- manship of the President of GMI, Dr. Leon Jacobs, a Scientist Emeritus of NIH. The 24-mem— ber Advisory Scientific Board, consisting of scien- tists in various disciplines, is to advise on the development and review of scientific programs Table 5.—Gorgas Memorial Institute of Tropical and Preventive Medicine, Incorporated: Projection Fiscal Year 1984 Revenue: Contribution by the United States ......... $1,899,000 Research grants and contracts ............ 300,000 Other .................................. 10,000 Subtotal ............................. 2,209,000 Additional revenue required .............. 18,000 Total revenue required ................. 2,227,000 Expenditures: Core— Epidemiology ........................... 180,509 Microbiology ........................... 276,237 Tropical Ecology ........................ 326,553 Applied Pharmacology ................... 165,699 Administrative Services & Training— Panama .............................. 913,553a Administration—Washington, D.C .......... 177,000 Total core expenditures ................ 2,039,551 Direct grant and contract expenditures ..... 187,449 Total expenditures .................... 2,227,000 Excess revenue over/(under) expenditures . . . . $ -0- aIncludes $250,000 for anticipated facilities renovation. SOURCE: Gorgas Memorial Institute, 1983. ORGANIZATION The organization of research activities of GML is currently undergoing change. Previously (and still officially) GML was divided among four sci- entific programs (see fig. 1). The Infectious Diseases Program was divided into Virology, Bac- teriology, Parasitology, Immunology, and Clin- ical sections. The Ecology and Epidemiology Pro- gram was responsible for Vertebrate Zoology, Entomology, Epidemiology, and Vector Biology. Animal Models, Primate Biology, and Animal Colony research were under the Primatology and Laboratory Program. Education and Technical Support programs handled the Library, Photo- Laboratory, and Educational sections. In additon, GML maintained administrative and data process- ing sections. Tentative plans for departmental reorganiza- tion have been drawn up, but will not be imple- mented until GML's financial situation is more secure (121). The new organization will include divisions for epidemiology, laboratory sciences (e.g., immunology, parasitology, serum bank), environmental biosciences (e.g., vector bionom- ics, ecology), Clinical therapeutics (e.g., animal and, if plans are fulfilled, to serve as an editorial review board for GML staff’s scientific manu- scripts.* The officers, members, and advisors serve without compensation (47). In 1972, the Middle American Research Unit, which had been in existence since about 1960 in the Canal Zone as an offsite laboratory of the Na- tional Institute of Allergy and Infectious Diseases (NIAID), was merged with GML. At the end of fiscal year 1975, NIAID concluded its support for the work formerly done by this unit with a re- sulting loss of senior personnel and financial sup- port for GML (110).” 'See the GAO report for a review of the activities of the Advisory Scientific Board. "Because of a deteriorating political situation, the Centers for Disease Control was forced to close its own Central American Research Center located in El Salvador in 1981 and relocate to a smaller research and training unit in Guatemala (53). models, clinical investigation), and support serv- ices (library, administration, etc.). Figure 2 il- lustrates the proposed organization. The interdisciplinary scientific staff of six Americans, nine Panamanians, and one Peruvian includes entomologists, arbovirologists, parasit- ologists, and other specialists (see table 6). One US. Navy medical officer and one Navy Ph. D. parasitologist are currently on GML’s scientific staff. The director of GML, Raymond H. Wat- ten, M.D., previously the commanding officer at the Navy’s Medical Research Unit in Cairo, over— sees a total of 94 staff members and employees (121). GML is strategically located for studies of dis- ease transmission and movement in tropical America. Panama is a crossroad of transporta- tion in the region and GML itself is in close prox- imity to the field. GML also benefits from an available supply of Aotus monkeys, a simian valuable for the study of human malaria (110). The US. Fish and Wildlife Service classifies the Aotus as an animal which could become en- dangered by international trade. 19 Figure 1.—Gorgas Memorial Institute Organization (currently olticial. but In process of being changed) Data Processing Biostatician (Reeves) infectious Disease Program V roiogy: Reeves“ (Hayes, Oro, Justines. Dutary. Peralta, Qulroz) Bacteriology: Kourany', (Vasquez) Parasitology: Sousa' (Bawden) immunology: (Johnson"), (Saenz) > Clinical: Saenz' (Wignali) Gorgas Memorial insitute Gorgas Memorial Laboratory Director Raymond H. Watten Advisor: Pedro Galindo Assistant Director Rolando E. Saenz Ecology and Epidemiology Primatology & Laboratory Program Programs Animal Models: Ecology: Rossan‘ 736:68 (1) (Christensen), e ersen) (Escajadillo) Vertebrate Zoology: Primate Biology: Mendez' Escaladillo‘ Entomology: (Reeves) (1) (Christensen) Animal Colony: Escajadillo' Epidemiology: (Reeves) (Saenz) Vector Biology: Christensen‘ Petersen SOURCE: Gorgas Memorial Institute, July 1982. Administration Administrator Alvaro E. Paredes’ Finance-De La Lastra' Personnel-(Parades) Maintenance-Nelson' Supplles-(Paredes) Education & Technical Support Programs Education: Wignall“ (Bawden) Library: De Las Casas' Photo-Laboratory: (Bawden) Figure 2.—Gorgas Memorial institute-Proposed Organization Chart SOURCE: Gorgas Memorial Laboratory, 1983. Table 6.—Gorgae Memorial Laboratory Iniormatlon on Sclentlllc Stall as of July 1983 Watten, Raymond H., MD. (U.S.) Director Seenz, Rolando E., MD. (Panamanian) Assistant Director Adamee, Abdlel J., Ph. D. (Panamanian) Ecologist-Entomologist Christensen, Howard A., Ph. D. (U.S.) Entomologist Dutary, Bedsy c., Ph. D. (Panamanian) Arbovirologist Escajadillo, Alfonso, D.V.M. (Peruvian) Medical Veterinarian Justines, Gustavo, Ph. D. (Panamanian) Vlrologlst Kourany, Miguel, M.P.H., Ph. D. (Panamanian) Bacteriologlat Mendez, Eustorglo, Ph. D. (Panamanian) Vertebrate Ecologist Oro, Gladys, M.S. (Panamanian) Microbiologlst Peralia, Pauline, Ph. D. (U.S.) Virologlst Petersen, John L., Ph. D. (U.S.) Insect Genetlcist Reeves, William C., MD. (U.S.) Medical Virologlst Rossan, Richard N., Ph. D. (U.S.) Parasitologist-Primatologlst Sousa, Octavio E., Ph. D. (Panamanian) Parasitologist Vasquez, Manuel A., MD. (Panamanian) Physician-Microbiologist SOURCE: Office of the Director. Gorgas Memorial Laboratory, July 1963. 21 ACTIVITIES OF GML The activities at GML can be characterized as basic and applied biomedical research, public health and medical services, and training. Projects use the laboratory, the clinic, and the field as bases. Neither the types of-activities nor the areas where they are carried out are entirely categorical or mutually exclusive. The border between basic and applied research, for instance, is not a clean line. Basic biomedical research, as used in this paper, refers to work that seeks to advance the state of knowledge about the vital processes that underlie the normal functioning of organisms and their malfunctioning in disease. Applied biomed- ical research draws upon basic information to develop means of prevention, treatment, and cure of disease (4). At the two ends of the research spectrum, the distinction is clear. Observing and characterizing the physical and metabolic behavior of a malarial parasite is basic research. Using the information gained in that way to design an intervention, e.g., a vaccine or drug therapy, is applied research. Further down the line, e.g., testing the drug or vaccine in nonhuman primates, a major line of research at Gorgas, the work falls farther toward the applied end of the spectrum. A clinical trial of the intervention in humans is a final step before research turns to practice. Even during a clinical trial, however, observations can be made that would fit the definition of basic research, in fur- thering the basic knowledge of normal and ab- normal human functioning. Marking the check- point between basic and applied research in the process described is all but impossible, and to spend a great deal of time attempting to do so is unproductive. Many projects at GML have both research and service components. About 1,000 patients per year are treated in the clinic, providing an impor- tant service to the community. Observations of those patients are an important source for learn- ing about the natural history and treatment of dis- eases, many of which cannot be adequately stud- ied elsewhere. GML began as a traditional tropical medicine research institute concentrating on studies of malaria, trypanosomiasis, and leishmaniasis. In recent years, attention has been increasingly directed to arboviruses and their vectors (110). Currently, GML also is involved in research proj- ects concerning sexually transmitted diseases, specific cancers, and ecological studies (see table 7 for a more detailed listing of areas of activity). In the past, GML has been called on to serve as a reference center for the region (76). GMI also offers ”Medicine in the Tropics," a 6-week tropical medicine training program offered primarily to physicians from the U.S. Navy, intended to pre- pare the medical officers for operational assign- ments in tropical areas. GML also hosts predoc- toral and postdoctoral students and scientists. In 1981, students came from Venezuela, Costa Rica, Panama, and the United States; in 1982, from Kenya, Hungary, Argentina, Brazil, Cuba, Pan- ama, and the United States. In the past 12 months, GML lists these training figures (121): 30 Students, Medicine in the Tropics (6-week course) 25 Visiting scientists 1 Postdoctoral student 2 Predoctoral students 3 Bachelor—level students 6 Trainees and graduate students GML has working relationships with the Med- ical Entomology Research and Training Unit in Guatemala, the Centers for Disease Control, NIH, Louisiana State University (LSU), Johns Hopkins University, and other academic and scientific in- stitutions. Most of these arrangements are “infor- mal,” but GML has a Memorandum of Agreement with LSU, Yale University, Johns Hopkins, and the University of Panama (121). 22 Table 7.—Recent Activities of Gorgas Memorial Laboratory Area of activity Active/recent Funding Animal colonies ....................................................... A Core Care and maintenance of experimental animals Applied pharmacology: Malaria drug testing (Aofus studies) (also under Malaria) .................. A U.S. Army contract Rabies, clinical trial to identify best minimal ‘ dose of human diploid vaccine ...................................... R Core, with MOH Arboviruses (various): Arbovirus survey in Tabasara River Basin ............................... R Contract Various projects relating to characterization of arboviruses and investigating outbreaks Aseptic meningitis ..................................................... R Core Blackflies: Vector competence of S. quadriviffatum for O. volvulus ................... R Core, with Johns Blackfly control in Fortuna Hydroelectric project Hopkins University Species bionics; intervention at breeding sites Blood meal analysis: Feeding habits of known and potential vectors .......................... A Core and WHO TDR Campylobacter: Survey of this important cause of diarrhea in Panama .................... R Core Cancer: Human T-cell leukemia virus ........................................... A Core and NCI grant Cervical and penile cancer in Herrera Province ........................... A Core Association with HTLV; and with herpes simplex Cervical cancer and Herpes simplex .................................... A Core, with McMaster Cell culture lines: University Culturing of Sloth kidney cells ......................................... A Core Culturing of haemogogus equinus cells Chagas’ disease: Study of risk of infection and human manifestations of Chagas' disease transmitted by R. pallescens (Central Panama) and T. dimidiata (Western Panama) .................................................. A WHO TDR grant (partial) Biological and lsozyme characterization of T. cruzi and T. range/i strains ........................................ A Core Clinical diagnosis and treatment (approximately 1,000 cases per year) ........ A Core, with MOH Data Processing: National Cancer Registry (Panama) ..................................... A Core, plus miscellaneous Cervical cancer project National serologic survey Bayano Lake clinical surveillance project Malaria chemotherapy project STD Project Environmental Impact Assessement: Tabasara Hydroelectric Project ........................................ R Contract Fortuna River ........................................................ R Contract Influenza and clinical diagnostic virology services and surveillance ............................................. A Core, with MOH Leishmaniasis: Identification of vector special; identification of reservoir (porcupine) ....... A Core and WHO TDR grant lsozyme electrophoresis diagnosis of strain and species of Leishmania ‘ and identification of leishmaniasis vectors ............................ A Core and WHO TDR grant Library: Reference service and collection available to staff and outside researchers ................................................ A Core and grant from Malaria: Panama In Vitro cultivation of infectious agent .................................. R AID grant Antimalarial Drug Testing in Aotus monkey .............................. A U.S. Army contract Phlebotomus fever: Serologic surveys of U.S. troops and Panamanians for Chagres and Punta Toro Fevers .................................................. R Core Comparison of Punto Toro and Rift Valley Fevers ........................ R Core Identification of amplifying host vertebrates ............................. R Core Retinochorolditis due to Toxoplasmosis .................................. R Core Serum Bank Reference Collection ........................................ A Core 23 Table 7.—Recent Activities of Gorgas Memorial Laboratory—Continued Area of activity Active/recent Funding Sexually transmitted diseases (STDs): Gonorrhea—survey of prostitutes on prevalence and penicillin resistance ................................................ Epidemiology of STDs In Panama (prevalence; maternal STD and effect on pregnancy outcomes) .................................. Shigellosis: Core Core, with MOH Study of drug resistance in shigella isolates ............................. Core St. Louis encephalitis (SLE): Study of how virus is maintained in the tropics .......................... NIH grant Studies with olivaceous cormorant ..................................... NIH grant Susceptibility to infection of Panamanian vector with three geographic isolates of SLE virus ............................................... NIH grant Virulence testing and RNA fingerprinting of Panamanian SLE virus isolates ...................................................... NIH grant Training: Medicine and health in the Tropics ..................................... US. Navy Triatoma Colony maintained for xenodiagnosis ............................ Core Trypanosomiasis ....................................................... Core and WHO grant Venezuelan equine encephalitis (VEE): 111)) > >>ZU > >>> 10 SD 3320 I) > :0 Search for epizootic virions from enzootic strains ........................ Core Vertebrate zoology Survey of Mammalian Fauna of Panama ................................. Core Long-term survey of rodents (zoogeography) ............................. Core Studies of Ectoparasites .............................................. Core Yellow fever: Monitoring of animal reservoirs ........................................ Core Monitoring of epizootics in Spider monkeys Monitoring of variations in vectors’ ability to transmit virus ................ Core Genetic studies of jungle vectors ...................................... NIH grant Longevity and age structure of Sylvan Yellow fever vectors ................ NIH grant KEY: AID-US. Agency for International Development; MOH—Panamanian Ministry of Health; NCI—Natlonal Cancer institute; NIH—Natlonal Institutes of Health; TDR— Special Programme for Research and Training in Tropical Diseases (WHO); WHO—World Health Organization. SOURCE: Office of Technology Assessment, 1983. Information provided by Gorgas Memorial Laboratory; WHO; and Gorgas Memorial Laboratory fiscal year 1981 and 1982 reports, Chapter3 Quality of Research at the Gorgas Memorial Laboratory Chapter 3 Quality of Research at the Gorgas Memorial Laboratory INTRODUCTION The Gorgas Memorial Laboratory (GML) en- gages in a wide range of public health, research, and training activities. Gorgas scientists work in the laboratory, in the field, and in the medical clinic. GML performs applied and basic research, and provides public health services in those set— tings. (See ch. 2 for a description of current activities.) This chapter examines the quality of research, training, and public health activities at GML. Ideally, assessing the quality of the work at GML would be accomplished by a review of each proj- ect in each program. A multidisciplinary team of scientists would visit GML, speak with investi- gators, review research protocols, procedures, and publications, and evaluate the physical plant. An overall rating would then be made, pointing out strong and weak points. Such a thorough review would serve as the basis for recommending changes in current programs, and to point out areas with future potential. OTA was unable to take such an approach. Another avenue for assessing the quality of GML activities, and one that was suggested to the Office of Technology Assessment (OTA) by a number of people, is to compare GML activities and its record of productivity with that of a similar institution. The logical choices for such a comparison might be, e.g., Institute of Nutri- tion of the Caribbean and Panama, International Laboratory of Research on Animal Diseases, the Department of Defense (DOD) medical research units, or the Centers for Disease Control’s former field station in El Salvador. Even these institu- tions, however, are very different from GML in their administrative structures and their research agendas. While it was possible with the time avail- able and information at hand to make gross com- parisons of GML and DOD budgets, it was not possible to make adequate comparisons of the quality of scientific activities. For its review, OTA relied on: 1. the record of past scientific review of GML's programs; 2. a review of recent publications by GML researchers, including an in-depth analysis of a selection of active manuscripts and published articles; 3. an assessment of peer review at GML; 4. a review of recent grants and contracts held by GML; and 5. the results of a telephone survey, commis- sioned by OTA, of experts familiar with GML. OTA is aware that this type of assessment is not definitive. It relies heavily on circumstantial evidence about quality (e.g., number of publica— tions), some unsubstantiated opinions about qual- ity (e.g., comments from the telephone survey), and the opinions of site visitors in previous years. As discussed above, other, more detailed methods of assessment are possible which would both give a better reading of the state of GML activities and serve as a guide for future directions. Such an assessment could be valuable to GML as well as its funding agencies, and might be considered as a GML priority for the near future. SITE VISITS BY THE FOGARTY INTERNATIONAL CENTER The Fogarty International Center (FIC) at the National Institutes of Health (NIH) has conducted two site visits to GML, one in 1976 (110) and the other in 1980 (111). In 1978, a review of all pro- grams was carried out by a team with represent- atives from FIC and the Gorgas Memorial Institute 27 28 (GMI) Executive Committee and Advisory Scien- tific Board. These are the only comprehensive pro- gram reviews that have taken place in recent years. A scheduled site visit for 1983 has been postponed due to the uncertainties surrounding GML’s future (57). Before those site visits, com- mittees of GMI's Advisory Scientific Board had conducted reviews of the virology and parasitol- ogy programs in 1973 and 1974, respectively. The FIC site visits were conducted by multidis- ciplinary teams which evaulated the scientific ac- tivities at GML. The charge of the 1980 five- person team was: . . an examination of the scientific programs of the Laboratory as to their quality, adequacy, and relevance in furtherance of the mission of the laboratory, to provide advice and to make recom- mendations as to any alterations in priorities and program or project implementation that seemed indicated, and in the final analysis to arrive at some composite judgment as to the value of the scientific work relative to the investment by the US Government. In addition to reviewing the research programs, the site visit report comments on administrative operations and GML's program in tropical medi- cine training. Both FIC site visit reports were strongly positive about the overall operation of GML, while iden- tifying weaknesses and areas of unused potential. The 1980 report concludes: The core long-range program emphases of the GML on parasitology, arbovirology, and ecologic studies continue to be of scientific importance, relevant to the health concerns of the United States, Panama, and the region, and appropriate to the unique location and facilities offered by GML. The overall quality of research conducted by GML is of high standard, nationally (United States) and internationally. As with any institu- tion undertaking a broad spectrum of projects, there are unevennesses that necessitate periodic review and reevaluation, especially in terms of priority relative to available resources. The Team felt that, in general, this [review and reevaluation] was being done conscientiously and well. It would emphasize, as the previous FIC review did, that GMI actively continue to support the GML Direc- tor in this respect through regular site visits by members of the Executive Committee and/ or the Advisory Scientific Board. The 1980 report noted a strengthening and con- solidation of research activities since the previous (1976) site visit. A major factor facilitating that improvement was the relatively stable funding through the core grant, after several years of “uncertainty and adjustments" associated with GML's absorption of the former NIH Middle America Research Unit (MARU). At this time, ad- justments are continuing, as described in chapter 2. Equilibrium has not yet been reached, and the research programs may be affected to some de- gree, particularly in terms of long-range planning, until the reorganization is complete. Review of Research Programs The FIC team critiqued each program as to its quality and relevance, and developed specific recommendations for each. The findings and recommendations of the 1980 site visit report are summarized below. Parasitic Infections Programs in leishmaniasis, trypanosomiasis, malaria, and toxoplasmosis are critiqued separate- ly. In general, these diseases are considered to be important in Panama. The site visit report, however, pointed out the need for refocusing some of the studies. The report stressed the unique availability of large numbers of patients with leishmaniasis, and the potential for expanding and redirecting efforts in clinical investigations. Ongoing research with a known major animal reservoir of leishmaniasis, the two-toed sloth, is promising, and could also be more carefully focused. GML has conducted research on Chagas’ dis- ease (American trypanosomiasis) for many years. Although GML is in possession of a large pool of clinical data, little has been published. The site visitors suggested that a major contribution to un- derstanding the importance of Chagas’ disease in Panama could result from analysis and publica- tion of clinical observations. GML had made some interesting observations about treatment of Chagas' disease with metronidazole, which the site visit team thought worthy of followup by other laboratories. Studies of vectors and animal reser- voirs, and longitudinal prevalence studies in one population had provided interesting information, but the goals of those projects required reevalua- tion. Malaria The main activities in malaria research are drug testing for the US. Army, in Aotus monkeys. This work is considered important, but the site visitors recommended expanding the scope of ma- laria research to make greater use of the exper- tise and resources at GML. Toxoplasmosis Toxoplasmosis is a major cause of chorioret- initis (inflammation of parts of the eye) in Pana- ma, and as such is important, although, accord- ing to the site visit report ”not of the highest pri- ority." While the site visit team thought contribu- tions could be made toward understanding toxo- plasmosis, “the principal focus of the project as described seems somewhat lacking in relevancy.” Arbovirus Program Yellow fever, Venezuelan equine encephalomy- elitis, and St. Louis encephalitis are the major ar- boviral diseases studied at Gorgas, though GML retains the capability to investigate and evaluate outbreaks of other diseases. Yellow Fever The site visit report deemed the yellow fever surveillance “one of the most important programs of GML." Panama is the key location for early detection of spreading yellow fever from Colom- bia into Central America. Gorgas has developed a proven method for surveillance of wild howler and spider monkeys, the animal reservoirs of yel- low fever. At this time there is no alternative method. The report favored continuation of mon- itoring seasonal variations in known mosquito vectors of yellow fever, and expanded efforts in studying transmission of yellow fever. Venezuelan Equine Encephalomyelitis (VEE) Past efforts in VEE research have produced use- ful information. The site visit report suggests ex— panding in this area. St. Louis Encephalitis (SLE) Comments on the SLE research program indi- cate that they are headed in productive directions and the work should be continued. Environmental Assessment Program Assessments of two major hydroelectric schemes have been carried out under contract to the Panamanian power authority. Although very different in nature from most of the activities tak- ing place at GML, these assessments were con- sidered successful and useful by the site visitors. They concluded: In addition to their technical and social impor- tance, such environmental assessment projects can help provide a model for similar studies in other parts of the developing and developed world. Fur- thermore, they can readily be perceived by the public as dealing with actual concerns of that country’s society. We feel that more than anything else in recent years, these projects in Panama have probably helped improve the im- age of the GML in the eyes of Panamanians. Diarrheal Diseases Program Several projects in diarrhea] diseases were in progress at the time of the site visit. They were of variable quality and relevance, according to the report. For instance, a project demonstrating the efficacy of oral fluid therapy in the treatment of dehydration secondary to acute diarrhea du- plicated research done elsewhere, but the project appeared to be beneficial nonetheless. The report states: Although the merits of the project as original research are relatively low, the project served as an educational effort of considerable importance. A study of travelers’ diarrhea in Panamanian visitors to Mexico was considered of only second- ary importance and not central to the mission of GML. 30 At the time of the site visit, a collaborative ar- rangement with the Johns Hopkins University School of Medicine had produced worthwhile re- sults in studying the incidence of acute diarrhea] disease in the San Blas Islands with respect to the availability of water. However, the Hopkins unit was not refunded beyond 1980 and the research was terminated. Sexually Transmitted Diseases Studies in sexually transmitted diseases (STDs) were carried out in collaboration with the Pana- manian Ministry of Health. They have focused on the epidemiology and etiology of STDs, and have led to further studies bearing on the very high rate of cervical cancer in Panama. The site visit report commented that STD research was of “secondary importance" to the other major pro- grams in parasitology, arbovirology, and envi- ronmental impact studies. Cancer Registry/Cancer of the Cervix GML has worked with the Panamanian nation- al cancer registry in epidemiologic studies of cer- vical cancer. Analysis of registry data indicated that Panama has one of the highest rates of cer- vical cancer in the world, and that geographic clusters in certain provinces have extremely high rates. Though not considered of the highest priori- ty by the site visitors, they rated the work of high quality and recommended that it be continued. Training The site visit team was enthusiastic about the excellence of training provided in the "Medicine in the Tropics” course. To be more consistent with the mission of GML, however, it was suggested that Panamanians be included in the course on a regular basis" and that GML take over the direc- tion of the course entirely, rather than the direc- tor being a U.S. Navy assignee. They concluded: . . it appears that the training capabilities and opportunities offered by GML, including the Lis— ter Hill fellowships of GMI itself, warrant wider notice in the scientific community. ‘According to the Director of GML, only one or two Panamani- ans take the 6—week course each session (121). PubHcafions Research and scientists are often judged on their publication records. The number of publications, the journals in which they are published, and the number of other authors who later cite the papers are some objective, though indirect, indicators of quality. However, there are no fixed standards against which to make a judgment of excellence. Research activities, in general, are aimed toward publishing results, while public health service ac- tivities do not have publication as a primary goal. Even in research, each field of study and type of research varies greatly, and may result in a dif- ferent array of publications. Long-term field sur- veillance studies may result in a major publica- tion only after several years. Clinical observations may be published as case reports after only a sin- gle visit. Environmental assessments are performed un- der contract to development agencies or compa- nies, and may result in few external publications, though they may be quite successful. Surveillance activities are routine until something is found. In Panama, yellow fever outbreaks have occurred every 8 or 9 years, but surveillance must go on continuously. Given the above perspective, OTA examined the GML publication record by looking at the number of publications in recent years and the journals in which they were published, and by evaluating the quality of a sample of recent publications and active manuscripts. Number of Publications and Journals of Publication Over the years of its existence, GML researchers have been authors or coauthors of about 950 published scientific papers, about 200 of them since 1975. (App. C lists publications since 1975.) Though it is impossible to rate the number of publications on a meaningful, objective scale, GML's record is indicative of continuous publish- ing activity. Table 8 shows the number of publi- cations by GML staff by year. Whether more publications should have been expected is a subjective matter. A comparison of GML scien- tists’ publishing record to that of six of the 31 Table 8.—Total Publications of the Gorgas Memorial Laboratory, 1975-83 Year Total articles appearing 1975 ......................... 34 1976 ......................... 18 1977 ......................... 14 1978 ......................... 7 1979 ......................... 16 1980 ......................... 24 1981 ......................... 10 1982 ......................... 17 1983 (to date) ................. 6 SOURCE: Office of Technology Assessment, 1983. Based on data provided by Gorgas Memorial Laboratory. Offlce of the Director, Raymond Watten, July 1983. centers supported by the Rockefeller Foundation’s Great Neglected Diseases program shows GML to be at an acceptable but rather low level. GML scientists should certainly give more atten— tion to publishing the results of their work, and GMI/GML management should be aggressive in urging such activity (the Director of GML and the President of GMI have indicated they share this view). GML researchers publish in a variety of scien- tific journals. Table 9 lists the journals in which papers have appeared since 1980. These are large- ly refereed journals, meaning that papers are scru- tinized in some formal way before acceptance, and generally there is some competition for publica- tion. In most cases, Gorgas investigators were the principal authors (listed first among the authors, and generally taken to mean that the ideas and most of the work can be attributed to that indi- vidual). Publications appear in both English and Spanish language journals. In general, papers of direct relevance to medical practice in tropical America appear in Spanish language publications (e.g., Revista Medica de Panama). Those of more global interest have appeared in journals with more international circulation (e.g., The Ameri- can journal of Tropical Medicine and Hygiene). An example of a subject of interest both locally and internationally is oral rehydration therapy of infantile diarrhea. On the basis of clinical research carried out at GML, a paper was published in 1980 in Revista Medica de Panama (6). The research and resulting publication was of great value to local physicians in demonstrating the value of oral Table 9.—Gorgas Memorial Laboratory: Publication Location for Articles Written by Staff; 1980 to July 1983 Number of Journal or other location: publications American Journal of Tropical Medicine and Hygiene ................. 15 Revista Medica de Panama ............... 13 Revista Medica de la Caja de Seguro Social ...................... Applied and Environmental Microbiology . . . Infection and Immunity .................. American Museum of Novitates ........... Journal of Medical Virology ............... Journal of Medical Entomology ........... Mosquito News ......................... Epidemiological Bulletin ................. Ecological Entomology ................... Bulletin of the WHO ..................... Revista de Biologica Tropical ............. Journal of Pacific Insects ................ Transactions of the Royal Society of Tropical Medicine and Hygiene ......... Entomological and Ecological Studies ..... International Journal for the Study of Animal Problems .............. Journal of Infectious Diseases ............ Journal of the National Cancer Institute . . . . Journal of Wildlife Diseases .............. New England Journal of Medicine ......... Journal of Economic Entomology ......... Revista Medico Cientifica ................ Annals of Internal Medicine ............... Mosquito Systematics ................... PAHO Workshop ........................ BOOKS ................................ Bacterial Infections of Humans Paediatric Cardiology Presentations at Symposia/Conferences . . . . 3 Total articles appearing .................. 64 SOURCE: Office of Technology Assessment, 1983. Data from Office of the Direc- tor, Gorgas Memorial Laboratory, Raymond Watten, July 1983. Ad—Ld—AA—ANNNNQ _A._A ”#444444444 rehydration. Subsequently, the same research served as a basis for the Panamanian arm of a con- trolled study of oral rehydration therapy of chil- dren in the United States and Panama, which was published in the New England Iouma] of Medicine (95). An editorial accompanying the article (12) highlighted the importance of this work, making the point that “Western-trained pediatricians . . . have created major impediments . . . to the promulgation of oral-rehydration treatment . . . Indeed, local herb doctors, quick to recognize the value of oral rehydration, have often been more helpful than their Western-trained colleagues in disseminating the concept of oral rehydration.” The contribution of GML in this case was to fa— cilitate a ”technology transfer” to medical prac- tice in the developed world. 32 Quality of Articles OTA commissioned a review, * summarized here, of five currently active manuscripts and four recently published articles written by Gorgas staff members (the articles and manuscripts are listed in table 10). The articles are not necessarily a rep— resentative sample of the total GML output. They were selected by OTA to cover as diverse a group of topics as possible, subject to the practical con- straint of what was available immediately. The review assessed the process of the research, in- cluding the adequacy of study design, extent of data collection, and methods of presenting the research findings. Presented below is an examina- tion of the overall features which characterize the research reports, and assessment of the methods of presentation of the data. "The review was carried out for OTA by Richard K. Riegelman, M.D., Ph. D., author of Studying a Study; Testing a Test, and a member of OTA’s Health Program Advisory Committee. This sec— tion is based entirely on that review. Table 10.—Articles and Manuscripts Reviewed for the Office of Technology Assessment by Richard K. Riegelman, M.D., Ph. D. Articles 1. Christensen, H., and DeVasquez, A. M., “The Tree-Buttress Biotope: A Pathobiocenose of Leishmania braziliensis,” American Journal of Tropical Medicine and Hygiene 31(2):243-251, 1982. 2.Dietz, E., Galindo, P., and Johnson, K., “Eastern Equine Encephalomyelitis in Panama: The Epidemiology of the 1973 Epizootic,” American Journal of Tropical Medicine and Hygiene 29(1):133-140, 1980. 3 . Dietz, W., Peralta, P., and Johnson, K., “Ten Clinical Cases of Human Infection With Venezuelan Equine Encephalo- myelitis Virus, Subtype I-D," American Journal of Tropical Medicine and Hygiene 29(2):329-334, 1979. 4.Young, M., Baerg, D., and Flossan, H., “Studies With In- duced Malarias in Aotus Monkeys,” Institute Animal Sciences 25(6):1131-1137, 1976. Manuscripts 5.Petersen, J., “Identification of Phlebotomine Sand Flies (Diptera: Psychodidae) by Cellulose Acetate Electrophor- esis" (in press). 6 . Piesman, J., Sherlock, I., and Christensen, H., “Triatomine Density and Host Availability” (in press). 7 .Seymour, 0., Kramer, L., and Peralta, P., ”Experimental St. Louis Encephalitis Virus Infection of Sloths and Cormo- rants” (in press). 8.Seymour, C., Peralta, P., and Montgomery, G., “Serologic Evidence of Natural Togavirus Infections in Panamanian Sloths and Other Vertebrates” (in press). 9.Seymour, C., Peralta, P., and Montgomery, G., “Viruses Isolated From Panamanian Sloths" (in press). SOURCE: Office of Technology Assessment, 1983. Overall Features of the Articles and Manuscripts The articles and manuscripts reviewed reflect a wide spectrum of scientific activities. These ac- tivities include: 0 study of a naturally occurring epidemic with potential for human transmission; 0 development of new animal models for studying human disease; 0 investigations of the mechanisms for trans- mission and reservoirs of disease in their na- tural field environment; 0 laboratory investigations designed to assess the susceptibility of animal hosts as interme- diaries in the transmission of human disease; 0 reporting on a series of human cases of dis- ease collected over more than 15 years; 0 development of a new technique for perform- ing enzymatic studies on disease vectors; 0 field studies of the effect of a human living environment on the transmission of disease; and 0 correlation of biochemical genetic character- istics of disease vectors with the epidemiology of disease. Important features of these investigations in- clude the ability to collect and coordinate data from a variety of sources. The ability of the in- vestigators at GMI to bring together data from a variety of sources is demonstrated in these stud- ies in at least the following ways. 0 correlation of their laboratory investigations with findings from their field research and knowledge of the epidemiology and natural history of disease; 0 cooperation with other laboratories, in- cluding CDC and a number of U.S. univer- sity, public health, and military programs; 0 ability to respond to a naturally occurring epidemic, collecting data requiring coopera- tion with public health control programs, hospitals, and correlation with laboratory in- vestigations; and 0 ability to collect and test large numbers of disease vectors from a variety of natural en- vironments. The majority of the investigations represent un— related studies. Three of the investigations how- 33 ever, include coordinated studies using two- and three-toed sloths found in the Panamanian forests. These three studies reflect the ability of in- vestigators at the laboratory to: 0 collect a large spectrum of species of birds and mammals from a variety of natural en- vironments; 0 track the natural history of disease by plac- ing radio transmitters on selected animals and recapturing them for sequential testing; 0 perform viral isolation and serological testing needed to correlate with the epidemiology and natural history of disease found in the Panamanian forests; 0 relate the field and laboratory findings to human disease potential; and 0 use knowledge gained from earlier studies to improve the design and performance of sub- sequent studies. Presentations of Data Background and Hypotheses.—The authors frequently introduce their presentations by a suc- cinct discussion of their study's purpose and its relationship to existing knowledge. These intro- ductions are well referenced and place the studies in a context which does not require the reader to have a previous detailed knowledge of the field. The study hypotheses are usually clearly stated and their relationship to previous studies are, on the whole, well outlined. Study Methods.—The authors of the field laboratory studies provide detailed discussions of the location of their collections and the methods of preservation and preparation of their materials. The experimental studies provide an adequate de- scription of the study methods, including refer- ences to the specific techniques employed. These presentations appear to fulfill the essential criteria that other investigators are provided adequate in- formation to attempt to reproduce the findings. When judgments as to technique and criteria for positive results are required the authors ap- propriately present the justifications for their choice. When the methods themselves possess lim- itations in their ability to measure the intended phenomena, the authors clearly identify these lim- itations. Results.—The authors present the results of their studies in adequate detail. They consistent— ly present and acknowledge their failures and the limitations of their results as well as presenting their positive findings. This practice should add to the value of these investigations by identify- ing areas for further research, appropriately lim- iting the conclusions, and preventing other inves- tigators from pursuing unproductive approaches. The statistical methods used in the articles re- quire only basic methods. However, the methods used are appropriate and appear to be properly employed. When interpreting the results of their studies the authors usually present a variety of potential explanations for their findings, including the ex- planation they favor. In presenting their results, the authors generally are able to relate their findings to current scien- tific thinking as well as their implications for im- mediate disease prevention or control. The articles often suggest areas for further investigations. Summary In summary, the articles and manuscripts re- viewed reflect a high level of expertise in design- ing and carrying out scientific research. The in- vestigators demonstrate an ability to collect and coordinate data from a variety of sources, pre- sent data in an analytical manner, and build on and contribute to the worldwide scientific litera- ture. The authors are able to take advantage of the unique features of their setting and experi- ments to contribute to knowledge of basic and ap— plied biological science. 34 PEER REVIEW AT THE GORGAS MEMORIAL LABORATORY One of the questions being addressed by the General Accounting Office (GAO) is about the peer review process at GML. Thus, this memoran- dum will not discuss peer review except for some comments on the relationship of peer review to the quality of research. By peer review, OTA is considering basically the process by which deci- sions are made to fund research projects with in- ternal (core grant) money and the process of evaluating internal research. Research funded through grants and contracts is subject to peer review by the funding agencies, e.g., NIH and the World Health Organization (WHO). In those cases, GML is competing with other research organizations for support. In a sense, GML staff are competing with each other for core funds to support their projects that are not under grants or contracts. A peer review system for research proposals, and reviews of ongoing and completed work are mechanisms used to allocate resources according to merit and to assure that research quality is acceptable. It is not uncommon for internal peer review systems to be less rigorous than externally funded systems. For instance, at NIH, researchers on the campus do not submit proposals through the same system that funds extramural research. Research- ers within each institute do go through a formal process for allocation of intramural research funds, but review is basically within the institute itself. Proposals and protocols are not scrutinized by outside experts, but, at specified intervals out- siders do evaluate the work that goes on within institutes. OTA gained some insight into the peer review process at GML through the telephone survey about Gorgas. There was a general lack of agree- ment about whether a peer review process—either GRANTS AND CONTRACTS The record of an institution or a researcher can be measured in the number and dollar value of grants and contracts awarded from external sources. Externally funded projects are more likely to review research proposals, protocols, or re- sults—does in fact exist. It is clear that even if a process has been set up on paper, it does not func- tion effectively on a regular basis. The fact that GML does not seem to have a well-known system for allocating money within the organization is something that requires con- sideration in future plans. A truly internal system, such as NIH uses, may not be the best plan for GML. Institutes in NIH have a large core of in- dividuals with knowledge in a specific field. For instance, all researchers at the National Cancer Institute are knowledgable about some aspect of cancer. There is a large number of people there to provide adequate review of internal research proposals. At GML, investigators are unique in education, training, and research areas. It would probably be difficult and perhaps not so effective to have only GML staff review each other’s proposals and research results, though that is also desirable. The main peer review body could be drawn from the Advisory Scientific Board, which has good scien- tific representation from the relevant disciplines. A model for how such a group might operate is the peer review process of the Plum Island (New York) Animal Disease Center of the U.S. Depart- ment of Agriculture. In that case, there are five non-Govemment consultants who visit once each year (but may be called to visit in the interim if necessary). The consultants are selected by the laboratory director and are responsible directly to that person. The consultants produce a report assessing all programs. The consultants’ expenses for the visit are paid (98). Paying for travel is even more critical for GML, since travel to Panama is relatively expensive. to undergo vigorous peer review than are those funded internally by an institution. (See ”Peer Review at the Gorgas Memorial Laboratory," above.) This is a particularly appropriate measure for researchers in the United States, where there is a relatively large amount of money available for research, though competition is quite keen. Most of the research at GML is funded through the core grant, rather than through competitive grants and contracts. Addressing this, the 1980 Fogarty Site Visit Report states: In these times of financial constraint every- where, the Team does not feel that too many ex— pectations should be held out that project grants and contracts could or even should supplant the necessity for the maintenance of adequate core support. A number of past and current projects have re- ceived grant or contract funding from sources other than the core grant, including the WHO Special Programme for Research and Training in Tropical Diseases (see app. A), the U.S. Army and Navy, NIH, and private foundations. Table 11 lists current, completed, newly approved, and Table 11.—Gorgas Memorial Laboratory: Grants and Contracts as of July 1983 Current grants: U.S. Army Drug Evaluation Contract U.S. Navy Training Project WHO/TDR Triatomine Blood Meal Contract WHO Clinical Trial for Evaluation of Leishmaniasis Therapy WHO lsozyme Lutzomyia—Sand Flies NIH/Yale Arbovirus—Yellow Fever WHO/TDR Chagas’ Disease UNDPIWorId BankNVHO Leishmaniasis in Honduras Completed and or termlnated' grants/contracts: Tabasara Hydroelectric Environmental Impact Study NIH/NCI Cervical Cancer Study NIH/NIAID Epidemiology of St. Louis Encephalitis AID In Vitro Malaria Culture WHO/TDR Control of Simuliids Approved contracts: Panamanian Ministry of Health/lnteramerican Development Bank—Malaria and Leishmaniasis NIH/NCI Epidemiology of Human T-CeII Lymphoma Virus WHO/PAHO Epidemiology of Childhood Respiratory Illnesses in Panama Pendlng grants: Rapid Early Serodiagnosis of Leptospirosis by Detection of Antigen in Body Fluids of Infected Persons Epidemiologic Assessment of Preventable Illness in Honduran Refugee Camps Effects of Two Arbovirus in the Development of Panama Regional Reference Center for Studies on New World Phlebotomine Sand Fly Host Feeding Patterns aUsually because of lack of fundlng. SOURCE: Gorgas MemorIaI Laboratory, Olflce of the Director, July 1983. pending grants and contracts. There are some grants and contracts in every GML program. The fact that GML has competed successfully for research money is evidence that the quality of research is equal to other research projects funded by those agencies at other institutions. Support for new projects by these funding bodies is also dependent on successful past performance, giving some assurance that GML is considered de- pendable. An official at the National Cancer In- stitute (32) was very positive about Gorgas’ ability to carry out a newly approved epidemiologic study involving human T-cell lymphoma virus, based on their past work. He also mentioned that GML is the obvious choice as a coordinating center for a possible future collaborative study of cervical cancer in several countries in the region. Quality of Research at GML as Seen by Experts Several questions in the telephone survey that was commissioned for this technical memoran- dum (see app. D for a more detailed discussion of the survey results) addressed the quality of research and training at GML. In response to a general question, “How would you rate the work of GML?" most of the 23 experts interviewed reacted positively. Some programs were rated ex- cellent, including the work in virology (especial- ly in arboviruses), malaria, medical entomology, trypanosomiasis and leishmaniasis, cancer, STDs, and environmental studies. Other programs, bac- teriology, for instance, were rated lower. A commonly held sentiment was that the quali- ty of work varies from program to program, with many strong points and some weak points, but that such a state of affairs was to be expected in an institution that has been in existence for so long. In some areas the work has become routine, with slow but steady progress. Some work was described as not very original, but, technically good. Presumably this refers to such activities as serotyping of viruses, which is of public health importance, and is done routinely at GML, but is not necessarily innovative. Several people made the point that judgments about quality of research must be tempered by 36 consideration of the conditions under which work is done—field conditions make for a much dif- ferent situation than that encountered at NIH. Particularly in light of working conditions in the Tropics, GML was rated highly. The uncertainty of financial support affects the quality of research, according to a number of ex- perts. Lacking a secure future, it is difficult to at- tract top scientists to work at any institution. In addition, the researchers already there are ham- pered in planning for all but the most immediate research. There was a diversity of opinion about whether the quality of research at GML has changed ap- preciably over the years. Research emphases have changed and the whole field of scientific research has changed so greatly that such a judgment is difficult to make. Of those who did answer, some felt there was no change, others a change for the better (variously since World War II, to within the last 11/2 years). A number noted a general de- cline in research quality over the years, all of those respondents relating the decline to uncertain fund- ing. The experts contacted were asked about the quality of tropical medicine training offered at GML. Most gave it a high rating. The unique set- ting was considered the most important asset in the training programs. The opportunities for clin- ical experience were particularly important for the military. In this regard two respondents referred to a comment of General Douglas MacArthur’s that in the Philippines he needed three divisions to do the work of one, since two would be in the hospital with malaria or dengue. The disease ecology is such in Panama that similar oppor- tunities for learning about tropical diseases do not exist in many other places. One expert mentioned that training in Puerto Rico, for instance, would not be as valuable as that at GML. A few people said that the training had gone downhill during the past few years because of financial constraints. Summary The research carried out at GML over the years has been of generally high quality. OTA’s analy- sis, the survey of expert opinion, the critical review of articles and manuscripts, and past site visits are all in agreement on this general conclu- sion. As is the case in any institution with a long history, there are strengths and weaknesses. Re- search emphases have shifted over the years, and the quality has varied as well. The results of the telephone survey confirm that most of the major programs are strong and of good quality, and that there are fewer weak points. However, mechanisms to assure continued high quality of research are not in evidence. There is a lack of an effective peer review process for allocating money to research projects funded by the core grant. While grants and contracts funded externally have passed through a competitive process designed to assure high quality, internal- ly generated and funded projects do not necessari- ly receive the same degree of scrutiny. Another example of a potential problem area is collabora- tion with other high-quality institutions. GML must become more aggressive in seeking and in strengthening interaction and collaboration with scientists and institutions from other countries (especially the United States). And, as mentioned, GML could make a larger effort to publish study results. OTA finds that GML is carrying out research of high quality, and that the institution enjoys a generally solid reputation in the field of tropical medicine research. The most serious threat to maintaining good research is continuing uncer- tainty about future financial support. Chapter4 ‘ Relevance of Research at Gorgas Memorial Laboratory to Health Problems in Tropical America Chapter 4 Relevance of Research at Gorgas Memorial Laboratory to Health Problems in Tropical America This technical memorandum considers the term tropical diseases to refer both to those classically defined as tropical diseases, such as schistosomi- asis, and to those in a broader definition of the term, such as tuberculosis and malnutrition (see ch. 1). Socioeconomic status (e.g., malnutrition, poverty) defines the Tropics and, to a very large degree, tropical diseases. Otherwise life in ur- banized tropical America presents the same haz- ards to health as life in North America or Europe. The intimate relationship between health status and economic and social progress means that some health problems in tropical America will only succumb to long-term socioeconomic ad- vancement, yet tropical diseases, by their enor- mous impact on health status, simultaneously and seriously affect the economies of tropical coun- tries. The six tropical diseases singled out by the World Health Organization (WHO) for special programmatic research support—malaria, schis- tosomiasis, filariasis, trypanosomiasis, leishma- niasis, and leprosy—together affect between 700 million to 800 million people. The first three each affect more than 200 million people worldwide (5). The resulting amount of human suffering and disability is enormous. This argues for urgent humanitarian action where feasible interventions exist. Significant costs are involved in treating such diseases and in implementing public health programs for their prevention and diagnosis, even though health services are usually underfunded and inadequate in most of the less developed countries. However, the most substantial econom- ic impacts may be the indirect ones affecting a country's human resources and productivity. Health problems in the region of tropical Amer- ica cover a broad range because of the great varia- tions in climate, geography, socioeconomic con- ditions, and culture. Modernization, population growth, and rapid rural-to-urban migration cause many diseases of the developed world to have growing significance in tropical and developing America, especially among affluent, middle-aged, and urbanized persons. For example, heart dis- ease, stroke, diabetes, cancers, and accidental in- juries are all emerging as major causes of mor- bidity and mortality in statistics for the Latin American and Caribbean regions.* Even as diseases of the developed world acquire increasing importance as major causes of mortali- ty in tropical America, the nonfatal diseases caused by parasitic and infectious agents remain a critical drag on developmental progress and the quality of life. Furthermore, in the developing countries, life expectancy at birth is much lower than in the developed world. This is a direct result of high infant and childhood mortality. The ma- jor killers of infants and children are three groups of diseases: diarrhea] and enteric infections (fecal- borne), respiratory infections and measles, and malnutrition. This chapter will first describe some of the ma- jor tropical diseases and conditions of ill-health of tropical America. Following that, the Gorgas Memorial Laboratory's (GML) research and re- lated activities will be discussed in light of the in- formation on regional health problems and re- search needs. Evaluation of research relevance quickly be- comes subjective. Research by its nature is open- ended. If science administrators and researchers could predetermine all lines of productive re- search, they would do so. The reality is often a simpler hope—for good judgment and good luck. *Caution is necessary, however, in interpreting these statistics, because they derive from health care systems that are weighted (because of the training of physicians, the availability of health fa- cilities, the logistical problems of data collection, etc.) towards the diagnosis and recording of acute, traumatic, or degenerative disease presentations in urban areas. 39 40 In evaluating the relevance of research at GML, OTA depended on identified health problems and needs, resulting research questions and opportu- nities, and the relationship of GML's research to those health problems and research needs. TROPICAL DISEASES: DESCRIPTION AND STATUS Acute Respiratory Infections Acute respiratory infections (ARI) are a major cause of mortality in children under 5 and the elderly. The group includes many viral and bac- teria] infections: influenza (myxoviruses, type A, B, C), parainfluenza (paramyxoviruses), measles (paramyxovirus), respiratory syncytial viruses, adenoviruses, rhinoviruses, Streptococcus pneu- monia and other bacteria, chlamydia (congenital), and mycoplasma. Influenza and pneumonia are among the top five causes of death in children under 5 in every country of the Pan American Health Organization (PAHO) region (75). In ad- dition to the serious mortality risk for the very young and the very old, these infections are a tremendous social burden in terms of work pro- ductivity lost and demands on the health care system by all age groups. These infections are aggravated in conditions of malnutrition and substandard living conditions, and in combination with other infectious diseases. A principal epidemiological factor of ARI trans- mission is close, overcrowded associations that promote inhalation of aerosolized pathogens by coughs, sneezes, and personal contact. For most of these diseases there is no treatment other than symptomatic and supportive relief, though bacterial infection can be effectively treated with antibiotics. Vaccinations for measles, whooping cough, and diphtheria are feasible and promoted under the Expanded Program on Im- munization of WHO. Vaccines against influenza and pneumococcal pneumonia are available but have reduced usefulness in developing countries: Pneumococcal vaccine is not very effective in children under 2 years old; influenza vaccines must be renewed periodically according to the cur- rently prevalent strain. Improved access to health care is a critical fac- tor, but also needed are field-based epidemiolog- ical studies. ARI control is largely ignored in most developing countries. This is a function of difficult diagnosis (of the etiologic agent), lack of effec- tive treatment, lack of definition as a tropical dis- ease, and as an entity worthy of focused research. Longitudinal studies on the epidemiology of ARI using rapid diagnostic techniques are needed. These studies could simplify the prevention and treatment of ARI by precisely identifying the im- portant etiologic agents in geographic areas and by determining the risk factors which make ARI mortality so high. Practical management of ARI depends on differential diagnosis of viral from other bacterial, chlamydia], and mycoplasmal agents for which specific treatments are effective. With risk factors defined, intervention against them could be initiated. At the same time, such studies would produce baseline prevalence data for subsequent evaluation of intervention meas- ures taken. Diarrheal and Enteric Diseases Diarrhea] diseases are the leading cause of death in children under 5 years of age in over half the countries of Latin America and one of the top five for all other countries. Data from several coun- tries indicate that the typical child below 5 years of age experiences four to eight diarrhea] episodes annually. In some countries, up to 45 percent of all hospital visits during the months of highest diarrhea prevalence are due to childhood diarrhea, and case fatality rates as high as 40 percent have been recorded (76). A comparison of death rates in children under 1 year of age is startling. For North America (United States and Canada), the mortality rate in infants in 1979 was 21.9 per 100,000; for Latin America it was 914.6 per 100,000, 40 times higher, almost 1 in 100 infants dying of diarrhea] disease. Because underreporting from rural areas is still a problem, it is likely that the statistical number of diarrhea] cases will increase as health services are extended to rural populations. 41 Diarrheal diseases constitute a clinical syn- drome of varied etiology, all of which are trans- mitted by human feces. These include bacilli, vi- ruses, and parasitic and helminthic parasites, such as shigellae, salmonellae, Escherichia coli, Cam- ponbacter, Yersinia,_rotaviruses, amoeba, giar- dia, ascaris, and ancylostoma. Poliomyelitis is also a fecal-borne disease. Rotaviruses, which in recent years have been found responsible for almost half of infant diar- rheas in the developing world, were first detected in humans in 1973. Serologic studies have shown that by the age of 2 years, nearly all children have had the infection. A Guatemalan community study indicated that rotavirus accounted for 10 to 20 percent of all diarrhea there. Escherichia coli is a second important cause worldwide of diarrhea] disease. Only certain strains which are classified in three groups cause disease: enterotoxigenic E. coIi, enteroinvasive E. coli, and enteropathogenic E. coli. Each group has a distinctive physiological and pathological symp- tomatology. Serotyping based on bacterial cell wall antigens is a second classification system. Other important diarrheal pathogens are Shi- geIIae, SalmoneIIae (both typhoid and nonty- phoid), Camponbacter, Entamoeba histontica (amebiasis), and Giardia Iamina (giardiasis). Although acute diarrheal diseases remain a leading cause of childhood morbidity and mor- tality in most of the Americas, prospects for their control are steadily improving. Intensive research in recent years into almost all aspects of diarrheal disease has led to a number of breakthroughs and technical innovations, such as oral rehydration therapy (ORT), which has become the main strat- egy of the WHO/PAHO diarrheal disease con— trol program. Therapeutic studies continue to document the effectiveness of this simple, safe method which uses a single specific orally ad— ministered water solution of electrolytes and glucose. An ORT trial project begun in 1978 in Costa Rica has proved an effective lifesaver in both bacterial and rotaviral infant diarrhea (70,72,83). A recent study (95) demonstrated that even in well-nourished children in developed countries, CRT is a safe and effective treatment for acute diarrhea (regardless of etiologic agent) and could replace the use of intravenous fluids in the majority of such children. In addition to CRT, four other major strategies comprise the diarrheal disease control program: 1) improved child care practices, including pro— motion of breastfeeding, proper weaning, and per- sonal hygiene; 2) health education; 3) improved water supply, environmental sanitation, and food hygiene; and 4) epidemiologic surveillance. A medium- to long-term objective is to integrate diarrheal disease activities into existing primary health care systems. With the growing evidence of rotavirus impor- tance in diarrheal disease, further epidemiologic, clinical, and basic research is needed. A major ob- jective now is to develop a vaccine for humans. Such a vaccine exists for animals. Immunological diagnostic testing exists which can be utilized for field studies of prevalence and incidence in geo- graphic localities. Childhood mortality is the highly visible tragic aspect of enteric disease, but the chronic and debilitating effects of these parasitic and infectious diseases (e.g., chronic anemia due to intestinal hookworm) rob a nation of productivity, vitali- ty, and initiative. WHO estimates there are at least 650 million people in the world with roundworm (ascariasis), 450 million people with hookworm (ancylostomiasis), 350 million people with amoe- biasis, and 350 million people with whipworm (trichuriasis) (99). Fecal—oral transmission is the common denominator of all these diseases. Lack of safe and adequate water supply and of proper excreta disposal, two of humankind’s most basic needs, are the critical deficiencies that promote these diseases. In rural Latin America, 68 percent of the population lack access to water supply serv- ice, and 98 percent lack sewage service of any type. In urban areas, 22 percent lack access to water supply service, and 57 percent have no sew- age service. Malnutrition Malnutrition is a primary cause of death of children under 5 years of age in Latin America. Though not a disease per se, it is so intimately involved in disease processes and ill-health to war- rant specific mention in this overview. The Inter- 42 American Investigation of Mortality in Childhood showed that low birth-weight (2,500 g or less) and nutritional deficiency were the direct cause of 6 percent of deaths before age 5 and an associated cause in 57 percent of all deaths (85). Death is the final outcome in a chain of events that begins be- fore birth and then involves the pernicious interac- tion of malnutrition and infectious disease. Mater- nal malnutrition (together with maternal age and parity, two other determinants in infant mortali- ty (86)); produces premature birth and low weight at birth, both serious risk factors for the newborn. Infants who survive the neonatal period tend to thrive for the first 6 months of maternal feeding, but then come to risk from varying degrees of kwashiorkor and marasmus, the two poles of pro- tein-energy malnutrition. According to Gueri (48), in a great majority of cases the problem results not from lack of food in the home but rather from maldistribution of food within the household, from lack of knowledge about child feeding, from an unsanitary physical environment conducive to infectious diseases (particularly gastroenteritis) that increase the child’s energy requirements while decreasing its appetite, from early replacement of breastfeeding with highly diluted and contami- nated milk formulas, and in some cases from sheer neglect. Though malnutrition as a primary cause of morbidity and mortality is less prevalent in adolescents and adults, it still must be considered a major contributing factor in infectious diseases. Immunologic defense mechanisms are seriously compromised by malnutrition. The synergistic in- teraction of malnutrition and disease is well doc- umented. For example, Scrimshaw, Taylor and Gordon (101) observed that, except where popula- tions are malnourished, or otherwise uncommon- ly susceptible to disease, the incidence of tuber- culosis is significantly lower than would be ex- pected by the widespread presence of the tuber- cule baccilus. Mortality due to measles was 274 times higher in Ecuador than in the United States in 1960-61, a time before the development of im- munization to the disease (85). Thus in all analysis of tropical health problems, protein-energy mal- nutrition must be considered a contributing cause in the disease process, and as a primary cause in children under 5 years old. Important research and intervention experi- ments have been carried out under the auspices of PAHO. The principal research centers are the Institute of Nutrition of Central America and Panama (INCAP), the Caribbean Food and Nutri- tion Institute (CFNI), and the Latin American Center for Perinatology and Human Develop- ment. Malaria Malaria is a disease caused by a protozoan blood parasite transmitted by various anopheline species of mosquitoes. It is one of the most wide- spread and destructive diseases in the world and has made a resurgence in the last decade with a more than two-fold increase in world prevalence (127,128). The incidence of malaria in developed nations, such as England and the United States, has also been increasing due to imported cases. Estimated malaria incidence worldwide is 300 mil- lion cases per year. In 1982, 702,000 confirmed cases were reported from the Americas. These statistics are large but undoubtedly underre- ported, because the disease is contracted in rural areas remote from medical facilities. An estimated 64.9 million people live in areas of tropical America where the risk of contracting malaria per- sists. The countries of worst malaria incidence are Haiti, Guatemala, Honduras, El Salvador, Co- lombia, Bolivia, and Brazil. The resurgence of malaria in the last decade is a setback due to the failure of the global eradica- tion campaign based on DDT house-spraying and supplementary mass drug distributions. Early suc- cesses led to overconfidence that ignored the com- plexity of a disease caused by four different species of parasite and transmitted by many different spe- cies of mosquito vectors, each with peculiar be- havior patterns in widely varying ecological and sociological settings. The serious consequences of that failure are insecticide-resistant mosquito vec- tors and drug-resistant strains of the parasite. Malaria research is in a new period of vigorous activity, like most of parasitology. Molecular biol- ogists, geneticists, and biochemists have begun to apply their research skills to the many important questions that were ignored during the eradica- tion era. Metabolic studies can identify parasite- 43 specific enzyme pathways that can be exploited to kill the parasite without harming the human host. Membrane research can reveal how the parasite finds, attaches to, and invades red blood cells yielding important clues for drug therapy and vaccine research. Recent clinical studies have sug- gested better ways of preventing and treating cere- bral malaria, an often fatal complication of severe malaria infection. The spread of drug-resistant malaria (by the species Plasmodium falciparum) is of great con- cern worldwide. Regular monitoring of local para- site strains is necessary to keep abreast of thera- peutic changes that may be needed, both in type of drug and dose. In Latin America, serious drug- resistance has still not moved north of the Panama Canal. Renewed effort to develop new drugs is producing results, but takes years to move from laboratory screening through animal testing to hu- man trials. Vector biology studies are critical to any ra- tional mosquito-control effort. Cytogenetic research which analyzes insect chromosomes has identified species complexes that were previous- ly unrecognized by conventional taxonomy. As an example, Anopheles gambiae, the notorious malaria vector in Africa, is now known to be a complex of several distinct species all identical to the unaided eye. Cytogenetic differentiation of the various species has explained the different behav— ior patterns of the A. gambiae complex and de- fined the important vector species. Research on physiological resistance mechanisms can aid the development of better insecticide methods. Behav- ioral resistance, the avoidance of insecticides by insects, is important for two opposite reasons— the killing effect is reduced, but transmission may still be interrupted, if vectors avoid human habitations. Field— and community-based studies are needed to assess the impact of antimalaria interventions. The ecological impact of vector intervention is critically important. The selection of insecticide- resistant vectors has seriously handicapped cur- rent control efforts. The effect of antimalarial ac- tivities on population immunity levels still needs clarification. Studies in the past have clearly documented the immediate impact of antimalarial projects on morbidity and mortality, but not the long-term consequences when projects cease or fail. Other studies need to evaluate the importance of sociological and human behavioral factors and the usefulness of health education, community self-help, and volunteer collaborators. Significant progress is being made on the de- velopment of a vaccine against malaria, including the identification of surface antigens and their pro- duction by bacteria. If animal testing confirms the feasibility of immunization against this parasite, extensive human and field trials will be required, before there is widespread usage of vaccines in the control of this disease. The wide usefulness of a vaccine is also debated considering the many difficulties associated with implementing other disease immunization campaigns. Chagas’ Disease Chagas’ disease (American trypanosomiasis) is caused by a protozoan parasite of the blood and tissues and transmitted by reduviid bugs (“cone- nosed” or ”kissing” bugs), common blood-sucking insects in the Americas. It is a disease of poor rural areas with substandard housing that provides har- boring sites for the bugs to live and breed. About 150 species of mammals have been incriminated as reservoir hosts, including dogs, cats, guinea pigs, rats, opossums, and other rodents and mar- supials. The parasite has two life stages in the mammalian host, one that circulates in the blood and another that proliferates intracellularly in tissues. In 1974, WHO estimated that out of 50 million exposed, a total of 10 million persons were in- fected with the Chagas’ disease parasite Trypa- nosoma cruzr' (discovered by Carlos Chagas of Brazil). Studies in Brazil have shown Chagas' dis- ease to be a significant cause of mortality in those under 45 years of age (84) and a heavy social burden due to high rates of hospitalization (with unsatisfactory outcome) and disability assistance (78). After initial infection by the reduviid bug, the acute phase of the disease varies in severity ac- cording to age. Cardiac arrhythmias, myocardial insufficiency and collapse, or central nervous 44 system damage may result in death. The younger the individual, the greater the severity. Mortali- ty is high in children under 2 years of age, while adults may show no symptoms. The acute stage may resolve completely in a few weeks or months, or may pass into a subacute or chronic stage. There is no effective cure. Long-term sequelae are cardiomyopathy leading to heart failure and grotesque enlargement of the digestive tract (meg- aesophagus and megacolon). The transmission threat in rural areas is great, but transmission by blood transfusion is also a major problem for blood banks in Latin America. The disease is found in every country of the Western Hemisphere, except Canada and the Car- ibbean. Opossums and other mammals harbor the disease in the Southern United States, and a small number of indigenous human cases have occurred in recent years (e.g., two in California in 1982). Control measures concentrate on insecticide spraying of houses and upgrading of housing con- struction (adobe, mud, cane, thatch, or otherwise poorly constructed rural homes with cracks in the walls are the usual harborage of the insect vector). An effective drug cure is a critical research need. With a therapeutic drug in hand, a simple effec- tive test for early diagnosis would be essential— the long-term effects once they appear are irre- versible. Vaccine research is underway, but this disease has a complicating factor—the long-term pathology seems to result from the body’s immune response reacting against the parasite and cross- reacting to its own heart and nerve tissue. Vec- tor bionomics remain important research topics for defining transmission areas, vector behavioral characteristics, and improved control measures. Leishmaniasis Leishmaniasis is a disease with three clinical presentations depending on the leishamanial para- site species. In each case, the protozoan parasite species is transmitted by bloodsucking phleboto- mine sandflies. Cutaneous leishmaniasis is a self- limiting and usually self-resolving sore at the point of infection. Mucocutaneous leishmaniasis is caused by a different Leishmania species that begins as a sore but commonly metastasizes and proliferates in the nasal and pharyngeal mucous membranes. Gross destructive disfigurement of the nasal passages occurs. Visceral leishmaniasis (kala-azar) is a third type of disease in which spleen, liver, bone marrow, and lymph glands are the sites of parasite proliferation. Fatal outcome in children is common. The disease exists in all Latin American coun- tries except Chile, and in some the number of cases is increasing because of agricultural colonization in jungle areas. In the late 1970’s, cutaneous leishmaniasis seriously impeded a Bolivian scheme to relocate people outside the overcrowded alti~ piano. Many of the colonists abandoned their land. More than 60 percent of those who did said that leishmaniasis was their reason for returning to the mountains. It has also significantly ham- pered both oil exploration and roadbuilding in several Andean countries (76). Epidemiologically, most forms of the disease are transmitted to humans from animals in the jungle (zoonoses), representing a health hazard to anyone working there, and rendering control unsatisfactory or impracticable. Specific treatment is now limited to antimony compounds that are not always effective and often have adverse toxic side-effects. Another disadvan- tage is that they require daily injections over 10 to 20 days, which makes them impractical for pa- tients living in remote and inaccessible areas. Hospitalization for such a period is not only ex- pensive but also a major inconvenience to the pa- tient who cannot afford to leave work or farm for an extended period. For these reasons, im- proved treatment of the tens of thousands of ex- isting cases is a priority research goal. PAHO/ WHO currently has a structured effort to develop new therapeutic drugs. Allopurinol is a promis- ing compound of current research activity (119). In other PAHO investigations of leishmaniasis epidemiology, a seroepidemiologic survey in Panama revealed an apparent focus of leishma- niasis transmission without clinical infection. Completely subclinical leishmaniasis was previ- ously unknown and may be important to vaccine development. Rapid species diagnosis of leish- manial sores may be soon possible by a recently published technique of DNA hybridization (124). 45 This would permit early treatment of the destruc- tive mucocutaneous form of the disease, as well as facilitate precise epidemiologic field studies. Arthropod-Borne Viral Diseases (Arboviruses) This large group of diseases is caused by viruses (currently about 80 in humans) defined by eco- logical, epidemiological, and clinical parameters. Strictly speaking, arboviruses replicate in and are transmitted by arthropods (predominantly mos- quitoes, but also ticks, sandflies, midges and gnats). There are some arbovirus- like diseases Whose vector is still unidentified and some whose early epidemiological profile incorrectly suggested arthropod transmission; their symptoms (e.g., Argentinian and Bolivian hemorrhagic fevers) must be differentiated from those of true arbovi- ruses. The number of arboviruses is growing ra- pidly as research resolves the etiologic agent of many fevers and brain inflammations (encepha- litis) of unknown origin and elucidates transmis- sion cycles. Examples of arboviruses include: yellow fever, dengue fever, eastern equine encephalitis (EEE), western equine encephalitis (WEE), St. Louis encephalitis (SLE), Venezuelan equine encephalitis (VEE), California encephalitis (CE), Colorado tick fever, Chagres fever, and Oropouche fever. (Locality names denote the source of first isolation; range of each is far wider.) Clinically these diseases are classed in four groups (6): 1) acute central nervous system dis- ease usually with inflammation of the brain (encephalitis), ranging in severity from mild asep- tic meningitis to coma, paralysis, and death (WEE, EEE, CE/LaCrosse encephalitis, SLE); 2) acute benign fevers of short duration, many resembl- ing dengue with and without a rash (exanthem), although on occasion some may give rise to a more serious illness with central nervous system involvement or hemorrhage (yellow fever, den- gue, VEE, Oropouche); 3) hemorrhagic fevers, in- cluding complications of acute febrile diseases (previous group), with extensive hemorrhagic in- volvement, frequently serious, and associated with shock and high—fatality rates. One of them, yellow fever, also causes liver damage and jaun- dice; 4) polyarthritis and rash, usually without fever and of variable duration, benign, or with arthralgic sequelae lasting several weeks to months. Most of these infections are diseases of animals (zoonoses) accidentally transmitted to man, though epidemics can occur with man; the prin- cipal source of vector infection. In 1981, an epidemic of dengue fever swept through Cuba with 344,208 cases and 158 deaths. The 1977-80 pandemic of dengue in the Caribbean and Cen— tral America caused a half-million cases. Laboratory diagnosis can identify arboviruses and define antigenically similar groups, but great geographic and climatic diversity is found in each serologic grouping. This emphasizes the complex- ity and challenge of arbovirus research and con- trol. There is no cure for these diseases, only symptomatic and supportive relief. Early diagno- sis of serotype has three important values: to dif- ferentiate ambiguous presenting symptoms; to an- ticipate life-threatening complications, as in yellow fever and dengue fever; and to target the type of vector which then determines control strategies. Current control efforts rely on identi- fying epidemic outbreaks early in order to institute vector-control measures such as insecticide fog- ging. However, disease surveillance is not well developed in many tropical countries of the region. Only yellow fever has an effective vaccine. There are experimental vaccines for certain strains of dengue fever, VEE, and WEE. The general utili- ty of arbovirus vaccination is doubtful, though, because of the complexity involved. The wide va- riety of arboviruses, most occurring only spor- adically in humans, and without inducing cross- immunity, raise many questions about implemen- tation and bring the realization that vaccination is unlikely to be a panacea. Vector control will remain the primary intervention method. Ento- mologic research on vector bionomics together with surveillance of sentinel populations (animal reservoirs and vectors) are activities for emphasis. Especially important is elucidation of the vector- bridge concept—the factors permitting transmis- sion of these zoonoses to humans when the prin- cipal vector arthropod is not a human—biter. 46 Yellow fever was the first arbovirus disease of the Tropics to be recognized and elucidated. It was William Gorgas who eradicated the disease from the Panama Canal Zone and Cuba in the early 1900's. Further success was recorded throughout Latin America against urban yellow fever, such that no cases were documented in the Americas for the past four decades. Jungle yellow fever, however, remains a major threat in tropical Amer- ica. It is the same virus maintained by transmis- sion through a number of jungle mosquitoes with monkeys and possibly certain marsupials serving as reservoirs. Recent research has demonstrated that transovarial transmission (passage of the virus from the female mosquito to the egg) oc- curs in vectors of yellow fever (26) (and other ar- boviruses). Thus, the mosquito may function not only as a vector, but also as a reservoir. Human cases are associated with man invading the jungle habitat. In recent years, however, an outbreak in Colombia appeared where there were no apparent known vectors or reservoirs and in Trinidad where no cases had been detected for almost 20 years. The possibility of unknown reservoirs or vectors is of concern. Aedes aegypti the vector of urban yellow fever remains abundant through- out the hemisphere (including the United States), posing a persistent threat of epidemic outbreaks in large population centers. The disease occurs in periodic cycles stretching over several years which depend on the buildup of nonimmune individuals in a population who are then swept by an epizootic of the virus leav- ing an immune population of survivors. Vaccination of human populations near endem- ic jungle areas is one strategy. Surveillance of monkey populations and jungle mosquitoes by sampling for virus isolation is an important con- trol measure that gives early warning to institute remedial action. Dengue fever is a disease caused by four dif- ferent serotypes of the dengue flavivirus. In re- cent years large epidemics of this virus have swept the Caribbean and Central America. In 1981, the first indigenous cases in the United States since the 1940's occurred. The virus is endemic in the Caribbean and is transmitted by mosquitoes of the genus Aedes, including the common urban vector Aedes aegypti which is found as far north as St. Louis, Mo. It breeds in small containers of water such as discarded tires, cans, and jars. A serious, sometimes fatal, complication of dengue fever is dengue haemorrhagic fever (or dengue shock syndrome). Oropouche fever is emerging as a very impor- tant type of arbovirus disease, because of its de- bilitating symptoms that reduce productivity due to convalesence. The virus is transmitted by biting midges (C uIicoides spp.) in urban and periurban areas. There is probably also a silent transmis- sion cycle in forested areas. Filariasis Several species of filarial nematode worms can inhabit the skin, other tissues, or the lymphatic system causing disease in humans. These parasites are transmitted by bloodsucking insects. In Latin America only two worms are considered public health problems, Wuchereria bancrofti and On- chocerca voIvqus. The bancroftian filariasis was introduced from Africa. It is transmitted by several species of mos- quitoes including common household pest species. The adult worms live in the lymphatic system and cause pathology depending on the immune re- sponse of the host. Inflammation and gross ob- struction results in varying degrees of swelling of the lymph glands up to frank elephantiasis of the legs, breasts, or scrotum. Adult worms release im- mature forms (microfilariae) that circulate in the blood which then infect feeding mosquitoes to complete the transmission cycle. Chemotherapy and vector control are currently imperfect and need more research. Onchocerciasis is also known as river blindness, because the blackflies (SimuIium spp.) that trans- mit it live and breed in or near waterways. The disease occurs in well-defined parts of Africa and in the Americas, in discrete foci in Guatemala, Brazil, Colombia, Ecuador, Mexico, and Vene— zuela. Ecuador’s onchocerciasis focus was only discovered in 1980. A Panamanian blackfly has recently been shown to be a potential vector of O. volvqus. The adult worm lives in the tissues of the body and often forms large nodules where an inter- twined clump of worms localizes. Microfilariae released by the adults migrate through the body in the subcutaneous tissues where they can be picked up by feeding black flies. If microfilariae reach the eye, lesions and blindness can result. Control measures focus on vector control and blindness prevention (imperfectly achieved by chemotherapy and nodule removal). Schistosomiasis This debilitating disease is caused by a fluke. The worm-like adult parasite lives in the human host’s bloodstream. Eggs are deposited in the blood vessels and escape into the bowel or blad- der, or lodge in other organs, where they produce inflammation and scars. The complex lifecycle in- volves excretion of the eggs into water sources, an intermediate snail host in which proliferation occurs, and an immature stage that can penetrate the unbroken skin of persons who enter infected water. Three major species of the fluke occur worldwide, only one in the Americas, Schistoso- ma mansom', which was introduced from Africa. S. mansoni is now established in suitable snail hosts in more than half the States of Brazil, where 10 million people are believed infected, in Suri- nam, where 10,000 people are probably infected, and in parts of Venezuela, where 10,000 more people are thought to have the infection. Foci in the Caribbean occur in the Dominican Republic, Guadeloupe, Martinique, and St. Martin. A few cases have been detected in Montserrat. The dis- ease is declining in Puerto Rico and Saint Lucia due to intervention measures (76). Chemotherapy against the disease is effective and relatively safe. Total and complete coverage in endemic areas can be difficult to achieve re- quiring other measures to complement control ef- forts, particularly attention to water and excreta sanitation and anti-snail treatment of breeding sites (mollusciciding against the snail host). Schistosomiasis is spreading worldwide due to water impoundment and irrigation projects which create and expand suitable environmental condi- tions for snail hosts and increase human-snail con- tact. Areas where large hydroelectric dams are being built especially in South America deserve special surveillance and assessment. Leprosy Leprosy is a chronic bacterial disease that con- tinues to be an important public health problem in the Caribbean and Latin America. A quarter- million cases are registered in the region, perhaps twice that number are prevalent. As case-finding and notification improved, reported incidence in- creased with extension of anti-leprosy efforts. De- pending on the host's immunologic response, lep- rosy can range from the benign tuberculoid form with localized skin lesions and some nerve in- volvement to the malign lepromatous form that causes spreading lesions which become nodular and disfiguring, destruction of the nose, involve- ment of the vocal cords and eyes, and severe nerve damage. Over half the cases in Latin America are the lepromatous form. Research on the epidemiology of leprosy is still needed. A number of useful drugs are now avail- able for treatment. Drug—resistant strains of Mycobacterium Ieprae have resulted in recom- mendations for combination chemotherapy which will shorten the treatment period. If organized and administered well, this will lighten the workload of health services, improve patient compliance, and result in better prognosis. Vaccination against the disease is in human trials but still years from routine use. The PAHO—associated Pan American Center for Research and Training in Leprosy and Tropical Diseases (CEPIALET) in Caracas, Ven- ezuela, carries out a full research agenda on leprosy, as does the US. Public Health Service in Carville, La. Other philanthropic institutions provide support to leprosy control either direct- ly to the countries or through PAHO. Tuberculosis Tuberculosis is a mycobacterial disease trans- mitted mainly by airborne droplets. The lungs are first involved, after which infection can spread to all parts of the body. Though the disease is decreasing slowly in the Americas, it is still a serious problem in most countries of the region. 48 Even countries such as Canada and the United States, with highly developed coverage for diag- nosis and treatment, have significant numbers due to immigrants from tuberculosis-prevalent areas. Control methods based on BCG (bacille Cal- mette—Guerin) vaccination, diagnosis from those with productive cough and treatment for those with sputum positive, is the policy of PAHO and the health ministries of Latin America. BCG vaccination of uninfected persons can pro- duce high resistance to tubercule bacilli, none- theless, the protection conferred has varied greatly in field trials. Because some trials have shown high protection, BCG is still recommended in areas of high-transmission risk. The resolution of the ques- tion of BCG effectiveness needs further evidence. Cancers Cancers deserve mention in the context of this technical memorandum. They are already one of the leading causes of death in Latin America. This is an unhappy indicator of progress against other causes of mortality, because to die of most can- cers, one must survive past middle age. Epidemiologic research has identified varying patterns of site-specific prevalence in the region. This points out areas for research on risk factors as possible causes. Extremely high rates of cervi- cal cancer and penile cancer, compared to the rest of the world, occur in several of the Latin Amer- ican countries, including Panama. RELEVANCE OF RESEARCH AT GORGAS The relevance of GML research may be evalu- ated in comparison to the health problems of Panama, the tropical Americas, the United States, and to biomedical research in general. The broad range of pressing health problems in Latin Amer- ica and the modest amounts of research support available dictate that careful stewardship and ra- tional integration of resources and activities take place so that research programs do not overlap unproductively and that the restricted resources are used efficiently. Historically, GML has concentrated on vector- bome parasitic and infectious diseases. Conse- quently, it is not surprising to note that GML has no active research program on malnutrition, lep- rosy, or tuberculosis. These health problems, however, are under active research and study by other institutions in the region. For example, mal- nutrition is the focus of a longstanding agenda of research and intervention studies by INCAP in Guatemala, by CFNI in Jamaica, and others. Leprosy research is carried out by CEPIALET in Venezuela, and the US. Public Health Service in Carville, La., while PAHO and philanthropic in- stitutions also provide other support for research and intervention in several countries of the region. Tuberculosis research and training is also funded by PAHO. Thus, a lack of GML activities in these areas, by itself, does not indicate low relevance. On diarrhea] disease, GML has researched Campylobacter-caused diarrhea in Panama which was found to be very prevalent in hospitalized cases. Another recent study examined epidemi— ologic features of Norwalk virus and Escherichia coli. This work complements other diarrhea disease work in the region, such as rotavirus research by INCAP and the Caribbean Epidemi- ology Center. A recent GML collaborative clinical study of oral rehydration therapy (95), published in the New EngIand Journal of Medicine and also in Spanish in the Revista Medica de Panama, docu- mented the wide applicability of this technique that was highlighted by an accompanying edito- rial (12). Thus, GML exploited the availablity of a health problem to expand basic scientific un- derstanding, to test clinical therapy, and to dis- seminate the knowledge in Latin America and the United States. Malaria research utilizes the GML monkey col- ony to test experimental drugs. The spread and multiplication of drug-resistant malaria is a cause for concern throughout the world emphasizing the need for discovery and testing of new therapeutic drugs. GML research has identified several prom- ising compounds. This work is not only relevant to the countries with high-malaria prevalence, but also to the US. military, which in fact supports much of this research. The Aotus monkey also appears to be a good animal model for leishmaniasis, which has been used at GML to test therapeutic treatment with allopurinol (119) of this disfiguring, sometimes fatal, disease. The GML monkey colony consti- tutes a resource to conduct screening of promis- ing anti-leishmanial drugs. Cancer is a growing concern in Panama, as well as the rest of Latin America, to which GML has responded by assisting in the development of a cancer registry utilizing the computer facility at GML. One result is the identification of a focus of strikingly high prevalence of cervical and penile cancers. Continuing research has since examined various epidemiological parameters, and has also shown a very high prevalence of a cancer-associ- ated virus (HTLV) in this population. This is being investigated under a grant from the National Institutes of Health (NIH) and the National Can- cer Institute (NCI). This work appears to be highly relevant to the region and especially to Panama. This finding was corroborated by the Minister of Health of Panama (34). Epidemiological capability at GML is available to assist in epidemic outbreaks, such as occurred in 1981, with aseptic viral meningitis and with acute hemorrhagic conjunctivitis. GML’s labora— tory expertise for diagnosis of viruses comple- mented these investigations. GML maintains one of the few viral diagnostic capabilities in the tropical Americas. This type of activity is very important to Panama and the region. Current research on Chagas’ disease is survey- ing the human populations in two geographical areas of Panama in which different vector species transmit the T. cruzi parasite to determine epi- demiological differences in the transmission cycles. This is under a grant from WHO. Arbovirus research, especially on the vectors and reservoirs, is a major GML activity. A large effort is expended to monitor jungle yellow fever, using a system developed by GML, in the belief that surveillance can give early warning of epidemic potential. Urban yellow fever has not occurred for several decades in Latin America, but the vector Aedes aegypti is abundant throughout the region, including the United States. When an epizootic of jungle yellow fever flares, there is a probability of spillover transmission to humans, but, worst of all, would be involvement of A. aegyptr' in the transmission. Furthermore, there still remain questions about reservoirs and vec— tors of this disease. For Panama and Latin Amer- ica, the relevance is obvious. For the United States, too, the relevance is not just theoretical or abstract. There are 20,000 U.S. Government employees and dependents in Panama, another 20,000 US. citizens in neighboring Costa Rica (51). St. Louis encephalitis is another focus of arbo- viral research. GML is attempting to elucidate how the virus is maintained in tropical areas, the vectors and reservoirs, in order to expand know- ledge of this arboviral disease that is prevalent throughout Latin America and the United States. Research on insect vectors and animal reser- voirs of other diseases is carried out as well at GML. Two important functions of entomologic field studies are discrimination of vector and nonvector species in various localities of actual and potential transmission (different species have varying transmission capabilities in different hab- itats), and elucidation of vector behavior and bio- nomics (e.g., biting times, resting habits, insec— ticide susceptibilities) in order to develop interven- tion strategies and to understand the interaction of host, parasite, and vector. Work at GML has recently demonstrated that a common blackfly of Panama, Simulium quadrivittatum, can function as a vector of onchocerciasis, though the disease is currently unknown there. Endemic foci of this disease occur in neighboring countries, thus the disease could spread. Recent work at GML dem- onstrated that transovarial transmission of yellow fever occurs in one of the mosquito vectors. Thus, the vector may also function as a reservoir of the virus, that may explain the persistence of the virus in the absence of disease in animal hosts. Identi- fication of reservoir hosts is an important adjunct activity. Reduction of disease is sometimes feasi- ble through control of animal hosts (e.g., China claims to have reduced leishmaniasis through con- trol of dogs that harbor the parasite.) These ac- tivities have relevance to possible intervention in 50 Panama and the region, as well as to basic un- derstanding of disease processes. GML maintains a reference capability (avail- able to the region as a WHO Collaborative Research Center) for the identification of blood meals in suspected insect vectors. This is used to determine host-preference from field-collected specimens throughout the region. Investigation by isozyme electrophoresis* of disease vectors is carried out by GML. Identifica- tion of these biochemical markers improves the differentiation of vectorial status, especially where species complexes are involved. GML is examin- ing sandfly vectors of leishmaniasis. Isozyme iden- tification was also developed to differentiate the Leishmam’a species isolated from cutaneous sores. This can diagnose the mucocutaneous type before the destructive pathology develops. Recently, ecological studies on the effects of im- poundment of the Bayano River on insect popula- tions and arbovirus activity have been carried out on contract. Also, environmental and disease im- pact assessments were carried out in connection with the Tabasara Hydroelectric Project. Rele- vance seems obvious given that the work was car- ried out under contract with a third party (the Government of Panama), but the relevance is several—fold: 1. the scientific merit and addition to scientific knowledge; 2. that environmental concern is being ad- dressed and promoted in a developing coun- trY; ‘Isozyme electrophoresis is a method of separating and identify- ing variant proteins in apparently similar organisms which then per- mits differentiation and classification. This is most useful when it correlates with geographic, pathogenic, or other varying charac- teristics of the organisms. 3. related to the development of environmen- tal concern in Panama is the significant role that environmental preservation plays in the continued function and maintenance of the Panama Canal, a gravity-flow, natural wa- tershed-fed navigational waterway; and 4. that GML was contracted, recognizing it as a body of expertise, within Panama, compe- tent to do the work. GML's work in sexually transmitted diseases (STDs) has focused on forms of STD that are of high prevalence in Panama, as well as surround- ing countries of the region. STDs are epidemic in tropical America, as they are in the rest of the world, but very little public health activity is cur- rently underway in Latin America or the Carib- bean: With the exception of the four nations men- tioned above [ Canada, United States, Costa Rica, Cuba], few countries have been able to carry out well-organized STD control efforts. Although most countries have developed guidelines and standards for diagnosis and treatment, few pro- grams to carry them out exist, especially outside large cities (76). GML research on STDs in tropical America is an early and unique effort. For a problem of large magnitude with very little current information or other research underway, relevance to the needs of Panama and the region seems to be very high. GML physicians see about 1,000 patients each year. These are people suffering from a variety of tropical diseases for which GML can provide expert and specialized services lacking among local physicians and clinics. This clinical service not only adds to the research effort at GML but also supplies a superb and unique teaching facili- ty, and evidently creates much good will among the general, and health professional, population in Panama. 51 SUMMARY Overall, the work of GML appears to have high relevance to tropical Latin America, especially to Panama, to tropical disease research in general, and to the United States' interests. Not every ac- tivity of GML has obvious relevance. * Nonethe- less, the Office of Technology Assessment finds that there is no major problem relating to the relevance of GML's areas of research. This find- ing is supported by the information presented above, by the personal statements of officials of ‘Clearly stated objectives and goals for the institution, as well as individual projects, together with regular, at least annual, for- malized intramural review procedures could improve this situation. Panama’s Ministry of Health and other health pro- fessionals in Panama, by award of grant and con- tract funding of research projects by NIH, the Department of Defense, WHO, and the Govern- ment of Panama, by Fogarty International Center (FIC) site visit reports, and by NIH/PIC testimony before congressional committee.* ‘House of Representatives, Committee on Appropriations, 98th Congress: Subcommittee on the Departments of Labor, Health and Human Services, Education, and Related Agencies, Appropriations for 1984, National Institutes of Health, Part 43, April 1983, pp. 1635-37, 1641-43. Chapters Findings and Conclusions Chapter5 Findings and Conclusions FINDINGS Previous chapters have presented information on the quality and relevance of tropical medicine research at the Gorgas Memorial Laboratory (GML). At the same time, they were designed to provide enough information about tropical dis- eases, tropical disease research, and research criteria so that research policymakers could place GML’s quality and relevance in the context of the goals and capabilities of any comparable organi- zation. Gorgas cannot be compared to the National In- stitutes of Health (NIH). Neither can Panama’s medical research system be compared to that of the United States. The differences depend on more than simply size. For example, the disease patterns differ, the level and organization of health care delivery differ, and availability of equipment and collaborating scientists differ. Field conditions both create obstacles and present opportunities that cannot be duplicated by an organization such as NIH. OTA thus finds that the evaluation of the quali- ty of an institution such as Gorgas cannot take place without explicit recognition of certain prem- ises. The following are the premises assumed by OTA during this evaluation: 0 There is an inherent value in supporting trop- ical research laboratories in tropical coun- tries. These benefits (see the last section of ch. 1) extend to the tropical country, tropical regions in general, and to the country sup- porting the activities. Evaluations of the quality of research are in- evitably, and properly, made partly on the basis of fairly objective criteria such as publications record and partly on the basis of subjective judgments by qualified individ- uals. The criteria used to judge quality, although similar in type, need to be modified and weighted differently for basic research or re- search performed in well-equipped, state-of- the-art laboratories than for field research laboratories. 0 Relevance is directly dependent on the type and location of institution, and it should be examined from each of the appropriate view- points (e.g., host country, region, United States, general advancement of knowledge). With these premises in mind, OTA examined the quality of GML’s research against a range of objective and subjective criteria. There was very impressive agreement among the results of: 1) the past scientific evaluations of GML, 2) the critical evaluation of the research design and presenta- tion of articles and manuscripts, 3) the survey of expert scientific opinion on GML's quality, 4) in- terviews with Panamanian health officials and professionals, 5) the examination of the GML staff’s publications record, and 6) an examination of GML’s record of competing for grants and con- tracts. All evidence gathered by OTA led to the finding that the overall scientific quality of GML is high, especially when considered in the context of its status as a research laboratory located in the Tropics. Quality was, naturally, not uniform— ly even, but it also appears that the Gorgas Me- morial Institute’s and GML’s management is aware of unevenness and is attempting to make improvements. Relevance is more difficult to judge, but in gen- eral OTA found that the large majority of GML's research is highly or adequately relevant to health concerns and problems of Panama, the tropical American region, US. interests, and the advance- ment of scientific knowledge and the field of trop- ical medicine in general (see tables 1 and 2 in ch. 1). The evidence for this finding lies, for the first two, in the match up between tropical health problems and GML research directed at them, and from strongly expressed opinions and examples by the Panamanian Minister of Health (who is a former Dean of the Panamanian School of Med- icine), his Deputy Minister, the medical director of Panama’s Childrens’ Hospital (a former Min- 55 56 ister of Health and former head of Social Securi- ty in Panama), and numerous officials of the Pan American Health Organization. The importance of GML to Panama cannot be judged solely on the basis of Panama's monetary contribution. Panama is going through a difficult economic period. Even so, the Ministry of Health has arranged a loan to keep GML in operation for the remainder of fiscal year 1983. The value of the land, buildings, and tax-favored status have never been adequately assessed. And to put the often criticized direct financial contribution of $10,000 from Panama in perspective, the research budget of the Panamanian medical school is re- portedly only $20,000 (34'). As one official of the US. Department of State expresses it: Each year, the United States sends a message to Panama and the region by funding GML and supporting activities related to the health of US. and Panamanian citizens alike (51). Activities related to the recent Panama Canal treaty process provide a specific example of the CONCLUSIONS OTA concludes that the benefits of supporting GML justify, on scientific and other grounds, the relatively small amount of funds required. Quality and relevance are high. Withdrawing core sup- port from GML would probably not even save the amount of the appropriation, since other Federal agencies, such as the Department of De- fense, may need to either develop their own ca- pabilities to conduct research now carried out at GML or to fund similar research at other tropical medicine research centers. Gorgas is not ideal; improvements could cer- tainly be made. Some of the shortcomings stem from its uncertain funding. As mentioned earlier, the prospect of unstable funding and perhaps clo- sure may have kept individual scientists from join- ing GML or becoming visiting scientists there and may reduce the desire of US. universities to col- laborate with GML on research projects. As an example, two highly qualified entomologists from the United States discussed with GML the possi- bility of their coming to GML for a period. Uncer- importance of GML to Panama. As part of the treaty, a Joint Committee on the Environment was established. Panama turned to GML, as the only institution in Panama with the necessary skills and experience, for assistance in relation to environ- mental protection and human and animal health, and additionally named Dr. Pedro Galindo, for- merly of GML, as the senior Panamanian on the Committee. Relevance to US. health interests can be found in the surveillance activities, the training activities, and the various research activities undertaken un- der contract to the US. military. Gorgas’ contri- butions in the areas of malaria, yellow fever, and leishmaniasis illustrate its relevance to the general advancement of knowledge. Based on the above evidence, OTA finds that with some exceptions that occur almost entirely within the core-funded activities, the research con- ducted at GML is relevant to the various parties at interest. tainties over the budget and the very future of GML have resulted in not being able to join GML, although one is still considering doing so. The point about uncertainty should be placed in perspective: most research scientists operate under some degree of uncertainty about future funding. In GML's case, the uncertainty applies to the very existence of the entire institution. Thus, the uncertainty is a matter of degree (though perhaps a significant one), and not a situation unique to GML. Another example of the effect of uncertain funding has been the decision by the US. Navy to hold off on the next scheduled training class, because the course would extend a few weeks into fiscal year 1984. Gorgas itself could improve its standing and its relevance by: 0 being more aggressive in its publishing; 0 by making better use of its Advisory Scien- tific Board (e.g., in planning for research di- 57 rections, as part of a more formal and effec- tive peer review process and as visiting con- sultants); 0 by more actively seeking out associations with universities and collaborations with a range of groups from other countries and in- ternational organizations; 0 by making strategic plans to move more fully into the developing areas of modern science (e.g., work with monoclonal antibodies and other immunological diagnostics, and bio— technology approaches to vaccine-related research and development"); 0 by making more of an effort to run vigorous visiting scientist and fellowship programs; and 0 similar types of actions that should be con- sidered by GMI/GML at a very near date. Gorgas has also done a rather poor job of let- ting Congress, Panama, and the public know how much it is doing and what its capabilities are. Its financial base should be broadened. Alternately, or in combination with broadening, some change in the structure (e.g., an international arrange- ment of support) of GMI/GML might be under- taken. Any such step should be taken carefully, in view of the importance of GML and its activi- ties (e.g., its disease surveillance work) to the United States. OTA concludes that the only benefit to the United States of defunding Gorgas would be sav- ing of perhaps significantly less than $2 million. The negative consequences would include loss of one of the few, high-quality, broadly relevant, *The contributions of the International Laboratory of Research on Animal Diseases in Kenya to the molecular biology of African trypanosomes is an example where a field unit has done important work at the forefront of science (68). Other good examples are the centers supported by the Rockefeller Foundation’s Great Neglected Diseases Program. tropical research institutions located in a tropical country. The Army’s malaria research would be hurt, as would disease surveillance in the Central American region. The U.S.’s standing in Panama, and perhaps more broadly in tropical America, would inevitably suffer. For example, the lead editorial on July 7, 1983, in Panama City’s leading newspaper spoke emotionally of the ”incompre- hensible budget policies” of the United States in regard to defunding Gorgas. Ironically, GML is in danger of extinction at the very time that U.S. interest in Latin America is high, and at a time when tropical medicine has never been more relevant to the United States. Health aspects of the increased numbers of refugees in the United States, an increased amount of international travel, and the growth of multina- tional corporations located in tropical regions are examples of this heightened relevance. Loss of the training activities at Gorgas would not only hurt the U.S. Navy but would also preclude the desirable possibility of expanding such training in tropical medicine to include more visiting physicians and students in health sciences* from the United States and to increase the number of Panamanians and others attending. In summary, OTA concludes that the positive consequences of U.S. core support of Gorgas greatly outweigh the amount of funds involved. Defunding now, followed by an appreciation of the loss later and a subsequent attempt to reinstate such a research capability, may result in much larger required investments, an inability to re- create successful conditions for quality research, or both. *For example, GML and Yale University have an ongoing pro- gram whereby students of Yale's School of Medicine go to GML for 2- to 3-month periods for experience in research and clinical aspects of tropical medicine. Appendixes Appendix A Acknowledgments; Pan American Health Organization Liaison Group; OTA Health Program Advisory Committee ACKNOWLEDGMENTS The development of this technical memorandum was greatly aided by the advice and review of a number of people in addition to the Pan American Health Organization Liaison Group, and the Health Program Ad- visory Committee. OTA staff would like to express their appreciation especially to the following individuals: Thomas Aitken Yale University Maj. Richard G. Allen United States Army Medical Research Command Karen Bell National Academy of Sciences Mark S. Beaubien Fogarty International Center Mark Boyer Harvard University Louise Brinton National Cancer Institute Gloriella Calvo The Gorgas Memorial Institute Cdr. Patrick Carney Navy Research 8: Development Command Richard Cash Harvard University Barnett Cline Tulane University School of Medicine William Collins Centers for Disease Control Joseph A. Cook The Edna McConnell Clark Foundation Gustave Dammin Harvard University William Dietz Clinical Research Center Col. Carter Diggs Walter Reed Army Institute of Research Jose Renan Esquivel Medical Director Children’s Hospital Panama City Phyllis Eveleth Fogarty International Center Allan Fleener General Accounting Office Gaspar Garcia de Paredes Minister of Health Republic of Panama Robert J. A. Goodland The World Bank Col. Michael Groves Walter Reed Army Institute of Research Sherman Hinson US. Department of State Rod Hoff Harvard University Donald Hopkins Centers for Disease Control Abraham Horowitz Pan American Health Organization Lee Howard Pan American Health Organization Leon Jacobs The Gorgas Memorial Institute Geoffrey Jeffries Centers for Disease Control Karl M. Johnson Fort Detrick William Jordan National Institute of Allergy and Infectious Diseases Irving Kagan Centers for Disease Control Robert Kaiser Centers for Disease Control Cpt. James F. Kelly Commanding Officer Naval Medical Command Dieter Koch-Weser Harvard University Richard Kreutzer Youngstown State University Austin J. MacInnis Editor, the Journal of Parasitology University of California, Los Angeles Arnold Monto University of Michigan Russell Morgan National Council for International Health Ladene Newton Centers for Disease Control Clifford Pease Agency for International Development Martha G. Peck Executive Director Bourroughs-Wellcome Fund Col. C. J. Peters USAMRIID Medical Division William C. Reeves Gorgas Memorial Laboratory D. S. Rowe The World Health Organization Special Programme for Research and Training in Tropical Diseases Ira Rubinoff Smithsonian Tropical Research Institute Col. Phillip K. Russell Director Walter Reed Army Institute of Research 61 Rolando E. Saenz Gorgas Memorial Laboratory Warren R. Sanbom Portable Rapid Diagnostic Technology, Inc. John E. Scanlon American Society of Tropical Medicine and Hygeine Robert E. Shope Yale Arboviral Research Unit Reuel A. Stallones University of Texas Ronald St. John Pan American Health Organization Jose Teruel Pan American Health Organization Paul Tiggert Gorgas Memorial Institute Ronald Vogel University of Arizona Kenneth Warren The Rockefeller Foundation Raymond H. Watten Director Gorgas Memorial Laboratory Thomas Weller Harvard University Karl A. Western National Institute of Allergy and Infectious Diseases Kerr L. White The Rockefeller Foundation Roy Widdus National Academy of Sciences Frank S. Wignall United States Navy Phillip Winter Walter Reed Army Institute of Research Martin Wolfe US. Department of State Martin Young University of Florida of PAN AMERICAN HEALTH ORGANIZATION LIAISON GROUP OTA would like to thank the members of the group formed by the Pan American Health Organization to provide advice on OTA's study of the Gorgas Memorial Laboratory and the main project on the status of research for tropical medicine in tropical America. Gloria Coe, Ph. D. Liaison Group Coordinator Dr. Gabriel Schmunis Dr. Juan Cesar Garcia Dr. Rafael Cedillos Mr. Jorge Pena Mohr . Francisco J. Lopez-Antunano . Fernando A. Beltram Hernandez . George Alleyne . Pedro Acha 63 HEALTH PROGRAM ADVISORY COMMITTEE Sidney S. Lee (Committee Chair) Michael Reese Hospital and Medical Center Carroll L. Estes Department of Social and Behavioral Sciences School of Nursing University of California, San Francisco Rashi Fein Department of Social Medicine and Health Policy Harvard Medical School Melvin A. Glasser Health Security Action Council-Committee for National Health Insurance Patricia King Georgetown Law Center Joyce C. Lashof School of Public Health University of California, Berkeley Margaret Mahoney The Commonwealth Fund Frederick Mosteller Department of Health Policy and Management School of Public Health Harvard University Dorothy P. Rice Department of Social and Behavioral Sciences School of Nursing University of California, San Francisco Richard K. Riegelman George Washington University School of Medicine Walter L. Robb Medical Systems Operations General Electric Milwaukee, Wis. Frederick C. Robbins Institute of Medicine Rosemary Stevens Department of History and Sociology of Science University of Pennsylvania Appendix B Tropical Disease Research Activities This appendix is a brief profile of tropical medicine research support, concentrating primarily on activities with which the United States is involved, either through direct research activities or by block contribu- tions, but also containing several examples of other supporting organizations. Table 8-1, at the end of this appendix, summarizes the tropical medicine research funding levels of the organizations covered. This dis- cussion should not be regarded as a comprehensive re- view. For example, many U.S. universities maintain tropical biomedical research programs. In addition, most developed and some developing countries have national agencies or institutes which in some way fund tropical disease research. These are not covered. For more detail on the range of support for tropical medi— cine research, see the General Accounting Office report on Gorgas, to be completed in August 1983. Multinational Programs The United Nations Development Program/ World Bank/ World Health Organization Special Programme for Research and Training in Tropical Disease (TDR) has targetted six specific diseases for biomedical research: malaria, schistosomiasis, filariasis, African and American trypanosomiasis, leishmaniasis, and lep- rosy. Essentially a grant institution, TDR also funds projects on vector biology and control, biomedical sci- ences, epidemiology, and social and economic research (126). Of the more than $30 million spent by TDR in 1981, appproximately $5.6 million went to research activities in the Americas (77). Total US contributions to the TDR in 1982 were more than $5 million, ap- proximately 22 percent of all TDR fundings (105). The Pan American Health Organization (PAHO), regional office of the World Health Organization, sponsored 131 research projects during 1980-81 for a total of $5.2 million. Direct monetary contributions from PAHO/ WHO comprised 32 percent of that sum, the remainder coming from the 30 institutions, inter- national organizations, agencies, and governments that collaborate with PAHO. Research efforts were primar- ily directed towards the diarrhea] diseases, a reflection of the Special Programme for the Control of Diarrheal Disease. PAHO-funded programs also researched other infectious diseases, parasitic diseases, foot and mouth diseases and vesicular stomatitis, zoonoses, nutrition, and other areas (77). In 1982-83, U.S. con— tributions to PAHO of $57.1 million constituted 61.3 percent of the organization’s funding (18). 64 PAHO maintains nine centers, including the Car- ibbean Epidemiology Center (CAREC) located in Port- of-Spain, Trinidad, the Institute of Nutrition of Cen- tral America and Panama (INCAP) in Guatemala City, the Caribbean Food and Nutrition Institute in Kings- ton, ]amaica, and the Pan American Center for Re— search and Training in Leprosy and Tropical Diseases, in Caracas, Venezuela (76). PAHO provides scientists and researchers to each of the centers, and with the exceptions of INCAP, which is semi-independent, and CAREC, which receives moneys from 19 different countries and institutions, the centers are primarily PAHO— funded. It is important to note that the centers are by no means exclusively devoted to research. CAREC, for example, provides extensive training, epi- demiological surveillance, and laboratory services for much of the English-speaking Caribbean (100). United States Agencies The majority of Agency for International Develop- ment (AID) funding for tropical diseases research comes from its Office of Health. In fiscal year 1982 the office allotted $5.8 million for research in malaria immunology and vaccine development, $5 million to the TDR, and $1.9 million as part of the core support for the International Center for Diarrheal Diseases Re- search/ Bangladesh. The AID Africa Bureau spent ap- proximately $1.3 million on the biomedical research components of three projects—onchocerciasis control, combatting communicable childhood diseases, and schistosomiasis activities in the Cameroons and the Sudan. The remainder of AIDS tropical diseases ac- tivities, some $1 million, was channeled through the Office of the Science Advisor for collaborative research between U.S. universities and developing countries. All AID funding may be considered “extramural,” with moneys given out on a competitive basis to univer- sities, profit, and nonprofit institutions (79). Nearly all tropical diseases research at the National Institutes of Health (NIH) is carried out at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID spent more than $9.5 million in fiscal year 1982 for research on trypanosomiasis, schistosomiasis, leish- maniasis, malaria, filariasis, and leprosy. The General Tropical Medicine Program spent $7.7 million for re- search involving virology, bacteriology, vector path— ogens, and other disciplines; NIAID’s General Para- sitology Program expended an additional $3.5 million. The NIAID International Collaboration in Infectious 65 Diseases Research (ICIDR) Program allies institutions in tropical countries with universities in the United States for joint research on specific diseases. The ICIDR fiscal year 1982 budget was $2.2 million. An- other $800,000 was directed towards NIAID Tropical Research Units (112). Approximately $9.5 million of the NIAID’s Tropical Medicine Program expenditures went towards intramural research, including salaries and administrative costs. Extramural research ac- counted for the remaining $25 million, awarded to in- stitutions around the world on a competitive grant basis. The NIAID Tropical Medicine and fiscal year 1982 total came to $34.8 million. Also within NIH, the Fogarty International Center administers the appropriation of the Gorgas Memorial Institute (as the core support for the Gorgas Memorial Laboratory). The Department of Defense (DOD) is active in areas of research into diseases which pose a threat to American troops stationed in tropical regions. Activ— ities within DOD are coordinated by the Medical Research and Development Commands of the Army and Navy. Within the Army, tropical disease research is managed by the Research Area Manager for Military Disease Hazards; the Infectious Diseases Program Manager oversees the Navy’s activities. In fiscal year 1983, DOD expenditures are estimated at $31.2 mil- lion, more than half of which ($17.6 million) was di- rected towards “basic" research (2). The Walter Reed Army Institute of Research is the center for most of the Army’s tropical disease ac- tivities. In the Navy, the Naval Medical Research In— stitute is the major U.S.-based center for tropical dis- eases research. Infectious diseases research includes a wide range of tropical diseases. The Army's anti- malaria drug development program and the Navy's vaccine effort are part of the Department's emphasis on malaria. In addition, the United States Army main- tains tropical medicine research units in Brasilia, Kenya, Malaysia, and Thailand. The Naval Medical Research Units are located in Manila, Jakarta, Lima, and Cairo. In fiscal year 1983 DOD funding for these overseas units came to $9.7 million. The department’s overall tropical disease program total of $31.2 million does not include salary or housing expenses for mili- tary personnel, which fall into other areas of DOD obligations; however civilian salaries, local employees, maintenance, and supplies do come out of tropical dis- ease program budgets. The Centers for Disease Control (CDC) (of the US. Public Health Service) does not have an autonomous tropical disease program, but conducts tropical disease research primarily through its Center for Infectious Diseases and its Parasitology Division. CDC also serves as a worldwide resource center and is frequently called on by tropical countries to provide emergency assistance. The Medical Entomology Research and Training Unit in Guatemala is funded by CDC. In fiscal year 1983, total CDC tropical diseases research funding, including salaries, administration, and other costs, came to an estimated $5.5 million (53). Other Institutions The following are a few examples of non-US. Gov— ernment supporters of tropical medicine research and related activities. Through its Tropical Diseases Research Program, the Edna McConnell Clark Foundation funds a varie- ty of research projects in both developed and develop- ing countries. Primarily concerned with schistosomi- asis, the foundation's program awarded approximately $2.5 million for more than 60 competitive grants dur— ing fiscal year 1982, and accounted for 18 percent of all Clark Foundation activity (27). The Great Neglected Diseases of Mankind (GNO), a major component of the Rockefeller Foundation Health Sciences Program, examines vaccine and drug development, improvement of diagnostic testing, and appropriate targeting of therapy. The GND Network currently maintains 14 units at institutions around the world. These units, primarily universities, carry out research projects concentrating on malaria, schistoso- miasis, and diarrhea] diseases; furthermore, in 1982 the units trained a total of 84 researchers from devel- oped and developing countries. The GND program cost came to $1.9 million in 1982 (90). The International Development Research Centre (IDRC), an Ottawa—based public corporation created by the Canadian Parliament, disbursed approximate- ly $4.9 million Canadian on tropical medical research grants to institutions in 1982 from its Health Sciences Division. The grants went for projects ranging from sexually transmitted diseases to malnutririon to leprosy. The division also provided additional funding for some health care delivery and water supply and sanitation projects in tropical countries. Along with its four other divisions, IDRC issued $36.5 million in grants during 1982 (56). In London, a portion of the profits profits from the Burroughs-Wellcome pharmaceutical company go to the Wellcome Trust. During 1980-82, the Trust distributed 3.6 million pounds Sterling (roughly $6 mil- lion U.S., approximately 15 percent of the Trust’s total allocations) for research and fellowships for investiga- tion into cerebral malaria, schistosomiasis, leishma— niasis, rabies, and other tropical medicine concerns. About 30 percent of these funds were used to help run the Trust's Tropical Units in India, Brazil, Thailand, Kenya, and Jamaica. Approximately 20 percent of the allocations were used for special lectures and fellow- ships with the remaining 50 percent awarded to re- searchers and research institutions around the world on an individual project basis (122). In addition, the Burroughs Wellcome Fund, an entirely separate enti- ty supported by profits from the US. branch of the company, awarded $406,000 in support of molecular parasitology research in fiscal year 1982. This sum represented 18 percent of the Fund’s awarded grants during that period (80). Table B-1.—A Profile of Funding for Tropical Medical Research} Millions Organization of dollars Year Reference World Health Organization: Special Programme for Research and Training in Tropical Diseases (T DR) ...................... 23.832 Pan American Health Organization ................. 5.2 Agency for International Development .............. 15.0 National Institutes of Health: NIAID ........................................ 34.856 Fogarty international Center .................... 1.8 Department of Defense ........................... 31.246 Centers for Disease Control ...................... Edna McConnell Clark Foundation ................. Great Neglected Diseases Program ................ International Development Research Centre ......... Burroughs-Wellcome ............................ aApproximately equal to 4.9 million Canadian dollars. bApproxlmately equal to $600,000 U.S plus 3.6 million pounds Sterling. NOTE: The definitions of tropical diseases and tropical disease research activity used in compiling these data are not unliorrn. For example, CDC totals Include activity In research which Is not covered by the Department of Defense. TDRIWHO totals are for research and development and research capability strengthening only. The DOD data are only restricted to those diseases which are of concern to American troops stationed In tropical countries. As part of the Department of State, AID contributes funds for tropical disease research to both the TDFIIWHO and the PAHO; these funds then lose their “American" label. In addition, more than 81 million was given by AID to NIAID. Only 32 percent of PAHO activities came directly from PAHOIWHO, the remainder coming from matchlng contributions from local governments. 81 80-81 FY82 102 77 79 FY82 1 1 1, 1 12 FY83 1 14 FY83 2 FY83 53 82 27 82 89 82 56 80-82 80, 122 Appendix C Bibliography of Publications by the Gorgas Memorial Laboratory Staff 753* 754 755* 756* 757* LISTA DE LAS PUBLICACIONES DEL LABORATORIO CONMEMORATIVO GORGAS DE 1975 A 1979+ (EN Los so Afios DE su FUNDACION) CON ADICIONES PARA 1930 Prof. Manuel Victor De Las CasasM Blandén R, Edgcomb JH, Guevara jF,johnson CM: Electro- cardiographic Changes in Panamanian Rattus rattus Natu- rally Infected by Trypanosoma cruzi. Am Heart j 88 (6): 758-764, 1974 Kourany M, Martinez R: La Situacion de la Shigelosis en Pa~ nama’(Parte B, pp, 71-73). En: Sz'mposio Sobre Disenten'a Shiga en Centroamérica (Ciudad de Guatemala, 27 y 28 de julio de 1971), Washington, D.C: OPS, 1974 (Publicacién Cientifica No. 283) Baerg D.C: Boreham MM: Experimental Rearing of Chagasia bathana (Dyar) Using Induced Mating, and Description of the Egg Stage (Diptera: Culicidae).J Med Entomol 11(5): 631-632, 1974 Baerg DC, Boreham MM: Anopheles nez'vai Howard, Dyar 8c Knab: Laboratory Observations on the Life Cycle and Des- cription of the Egg Stage (Diptera: Culicidae). j Med En- tomol 11(5): 629-630, 1974 Boreharn MM, Baerg DC: Description of the Larva, Pupa and Egg of Anopheles (Lophopodomyia) squamzfemur Antunes with Notes on Development (Dipterea: Culicidae). J Med Entom0111,(5): 564-569, 1974 + Segundo Suplemento. La presentacién de esta bibliografia (Nos 753 at 846) difiere de nuestra Bibliografia Bésica y sus Suplementos en que, para ahorrar espacio, se supri- mio la sangn’a y se usaron tanto las abreviaturns como el estilo de la Seccién dc Mate- ria del CIM, normas adoptadas por la Revista Médica de Panamé. ++ Bibliotecologo Médico del Laboratorio Conmemorativo Gorgas y Profesor de Biblio- tecologia en la Facultad de Filosofia, Letras y Educacién, de la Universidad de Pann- mi. El asterisco que sigue a] nfimero de um publicacion indica que, at momento dc pre- parar esta bibliografia, hay disponiblcs reimpresos de la misma. 67 68 £2 .22 ”$2 bzamfiz SEE row—tons .afimcnm E 9.3.2.85“: 3&6» 3x502 noun...— -8£3 05 mo :ofiozuoaom £3300 HUG whumm .ZM dammed £2 film "33 in E: 225 a :2 .335 2: 2o oocoummfium E8095 4: fins—Em E 3358.7.va 250:3 .30 we 2:32am ioEEEEoEmm " £2 .omo_-mm2 ”GVE 2,: E: mofi. 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Macdonald, under contract to OTA, conducted a telephone survey of experts knowledge- able about the Gorgas Memorial Laboratory (GML). OTA supplied Mr. Macdonald with a list of approxi- mately 70 potential interviewees. He attempted to con- tact each of them, and was able to complete 23 inter- views. (The individuals contacted are among those in- cluded in the Acknowledgments for this memoran- dum.) The original list of potential interviewees was com- piled by OTA staff. It included the names of individ- uals known to have specific knowledge of GMI/GML. The names were gathered during the previous 2 months of preliminary work on this technical mem- orandum. During that process, solicitations were con- tinually made for additional people who would have useful information on this subject. Names were added to the list regardless of whether biases of the in- dividuals were known or unknown to OTA, and re- gardless of the nature of those biases. The wide range of responses, positive and negative, gives some assur- ance that a spectrum of viewpoints was expressed, though OTA does not claim the survey to be global or entirely representative of opinion about Gorgas. Most of those contacted by Mr. Macdonald had some firsthand knowledge of Gorgas. They had either worked there, collaborated with Gorgas investigators, participated in site visits, or had experience with Gorgas grants or contracts. Nearly all those who par- ticipated in the survey are technical specialists in tropical diseases, including experts in infectious dis- eases (mainly arboviruses and other viruses); malaria, leishmaniasis, helminthic, and other parasitic diseases; traditional tropical disease and cancer epidemiology; vector biology; microbiology; nutrition; and the gen- eral fields of clinical research, tropical medicine, pre- ventive medicine, and international health. Ten of the participants hold positions in U.S. aca— demic institutions, five are in the military, six are employed by other U.S. Government departments (Department of Health and Human Services and De- partment of State), and two are with an international health organization. The results of the survey are summarized in the re- mainder of this appendix. Opinions and quotes are not attributed to specific individuals. 1. How would you rate the work of GML? The respondents generally rated the quality of work at GML high. Most felt that some programs were ex- cellent, especially the work on arboviruses, malaria, and medical entomology, while other programs, such as the bacteriology, were of lower quality. Three respondents said that GML has done excellent work. The most solid endorsement came from one who said that it was “outstanding, the best in the world." Two others who have spent many years in tropical medicine stressed that the location of GML makes it an excellent site for training, as a place for visiting scientific groups, and for field situations that are not available elsewhere. Other responses were less enthusiastic but still gen- erally positive. Some programs were considered ex— cellent, others less so. One person commented, "Like any large institution which has existed for many years, it has its weak points, but on a scale of 1 to 5, I would give it a 4 (high).” Another offered a similar rating. He felt that while some of the research may not be ori- ginal, it is technically very good. Certain programs, including the entomology, virol- ogy, and malaria work got high marks. Other pro- grams that were rated as excellent were the cancer and sexually transmitted diseases programs, trypanosomi- asis and leishmaniasis studies, and the ecology and en- vironmental studies. One respondent said that while the arbovirus and ecology studies were excellent, some of the other pro- grams were ”mediocre." Another individual com- mented, “some of the work was excellent, some rou- tine, but you can expect that in any institution that has existed for so many years." The bacteriology and some parasitology programs were sometimes said to be the weakest points. Two respondents characterized some of the parasitology studies as slow but steady. 77 78 Many chose to qualify their answer and said that one must consider the setting when rating the work of GML. The field conditions make it a much different situation than that of the National Institutes of Health (NIH), for instance. One person commented, ”I would rate the work as high. As a person who has worked in the field for many years, I know what tropical medicine work is like. Its only weak point is the decrease in support which makes it difficult to attract top scientists." Another also rated the work as ”un- dersupported.” 2. How should GML be judged? The quality of publications and GML's impact on the public health of the region were the most frequently offered criteria for evaluation. Other responses in- cluded judging how GML fared in grant competition; on the productivity of researchers; on the reputation of the staff; on the training provided at GML; and by the contributions to progress against specific diseases. Those respondents with the most experience in the field stressed that one should not make a direct com- parison between an institution such as GML and uni- versity or NIH laboratories. Some felt that it should be judged on a regional basis, in comparison to lab- oratories in other countries in the region. One in- dividual pointed out that because many of the pro- grams are involved in vector control, it is inap- propriate to look simply at short-term output. The benefits of surveillance accrue in the long term. 3. Has the quality of research changed over the years? Most of the participants agreed that this was a dif- ficult question, since the emphasis of the research has changed. Many chose not to answer. Three thought that there was no change. Two said there had been a positive change. Four others said that there were fluc- tuations in the quality of research, but through all of the fluctuations, some programs, such as entomology, continued to meet a very high standard. A number of people responded that there has been a general decline in the quality of the research over the years. All of those who said that there has been a decline blamed the uncertain funding, citing an in- ability to buy sophisticated equipment or attract top- notch scientists. 4. Are you aware of the Peer Review Process at GML? Few had any knowledge of the peer review process at GML. There was a general lack of consensus about whether such a process exists. It seems that respond- ents felt that sometimes the peer review process was operating, while at other times it was not, possibly depending on who was in charge. One person com- mented that a process exists, but it needs strengthening. 5. What is the relevance of GML to research in: Panama, Latin America, the United States, and Biomedical Research in general? In various ways, GML research is perceived to be relevant to Panama, the region, and the United States. A number of individuals noted that Panama benefits from activities such as the surveillance field studies and the environmental impact assessments of hydroproj- ects. Another respondent, familiar with the cancer re- search, noted that GML has been a great help in in- creasing the sophistication of Panamanian cancer researchers. In terms of the region, GML served as a serum and data bank during the recent dengue epidemic. It was also the only laboratory in the region that was capable of looking into the resurgence of yellow fever. Another aspect of its importance as a regional center is that it is a place where researchers in Central and South America can call and receive answers in Span- ish. Everyone contacted mentioned that GML is partic- ularly important to the United States, specifically for the military. Since NIH no longer has its own labora- tory in Central America, it is the only place for the military to commission work in the region. One respondent said that if GML did not exist, then the military would have to build its own tropical lab- oratory. Many respondents stressed the potential impact of GML work. Some said it should be more closely linked to the Panamanian Ministry of Health, that it should be a leader in the region and that it could be more pro— ductive. One respondent, however, felt that political barriers presently limit its importance as a regional center. 6. What is the value of the training in tropical medicine carried out at GML? Most of those who commented gave GML training a high rating. They felt that it was a unique setting and very important to maintain, since there are so few other places available for training in tropical medicine. One person said that a training center in a place such as Puerto Rico, for example, would not be as valuable because of a different disease ecology. Two respond- ents offered the same quote by General Douglas Mac- Arthur that in the Philippines he needed three divi- sions to do the work of one, since two would always be in the hospital with malaria or dengue. Not all of the responses to this question were posi- tive. Two felt that the level of training had gone down- hill over the past few years because of financial con- straints. Another felt that the trainers were not sophis- ticated enough. He noted that there were more Pana- manians involved in the training now and that the pro- gram was hurt when NIH cut back on funding for young American scientists to go to GML. A third neg- ative opinion was offered by a university scientist who felt that there should be more civilians involved in training programs at GML. 7. What is the value to research of the animal population kept at GML? Nearly all of the responses to this question were very positive about the animal populations. This question evoked the most immediate and strongest reactions of any on the survey. The colonies were variously termed “Crucial, Critical and Unique, cannot be duplicated elsewhere.” One noted that this function is becoming even more important with the increasing prevalence of malaria strains resistant to current drugs. A number of respondents noted that it was much more cost ef- fective to keep the colonies in Panama than in the United States. Besides malaria, the colonies are very important in the study of diseases such as trachoma and hepatitis. One person stressed that the work on antimalarials must be carried out. He said that if GML cannot do it then the Army would have to build its own lab to screen the antimalarial drugs. Others concurred that this was one of the most important functions of GML. "The screening of antimalarials must continue." ”The monkey colonies are invaluable to our study of human malaria." It was mentioned that to an outsider the col- onies seem to be dull and routine work, but they pro- vide a very important service. One who is quite knowledgeable about malaria felt the value of the Aotus population had declined over the years and that there was some difficulty in meshing the colony to current research needs. He felt that the colony was not reaching its potential. In addition to the monkey colony, it was menioned that the wild animals in the area also provide a very valuable resource for the study of disease ecology of such diseases as leishmaniasis, the arboviruses, and Chagas' disease. 8. Do you have any suggestions for change? Nearly all respondents had suggestions for change: stabilization of funding and increased funding were the most common answers. It was felt that the constant budget problems eroded the confidence of the staff and GML’s attraction to top scientists. One respondent who had worked there for many years said that it was demoralizing to hear at every weekly meeting that, “Funding might be cut next week." He said that uncertain funding was a major rea— son for failing to attract top university scientists. One said that GML cannot continue in such a precarious financial position and that it should either be funded properly or closed. Others felt that GML/GMI should look for more international support and operate more like the cholera research institution in Dacca or the International Laboratory of Research on Animal Dis- eases in Kenya. Another respondent suggested that GML should col- laborate more with labs in the United States, but bureaucratic changes would be needed for travel money and arrangements for cooperative agreements with other institutions. Some felt that major changes should be made in the management structure of GML/GMI, expressing the opinion that even with solid core support, they would not be able to compete with other tropical medicine units. ”The current direction must change" noted one individual. The need for a strong executive was rec- ognized by many other respondents. One felt that they should pay the high salary needed to get a good direc- tor in the United States and in Panama. Two other sci- entists with many years of experience in tropical med- icine felt also that it was important to develop closer ties to the region. Other suggestions were for more long-range plan- ning, a firmer peer review process and pruning the dead wood. Two felt that there should be closer links to basic science and a greater use of more sophisticated immunologic and diagnostic techniques. 80 9. What do you think is the overall value of GML? All the respondents, without exception, felt that it would be a terrible mistake to lose GML. “For better or worse, it is the only one we have, and we are bet- ter off with something than nothing. If it did not exist [the military] would have to build one there." It is a resource that cannot be duplicated. “It is irreplaceable in the panorama of tropical disease research related to Latin America and the United States." A number of other respondents noted the unique setting of GML. "While it does have its weaknesses, it would be a terri- ble mistake to let it go.” “The relative cost is peanuts compared to the benefits, and it would be insane to reduce our limited involvement in the area.” "If lost now, we would never get it back.” Many spoke in terms of GML’s potential. One felt that GML’s value now was only marginal but that it could be great, if it had stable funding. GML is also viewed as a front line defense against certain diseases that could spread to the United States. Panama Canal forms a barrier to many diseases at this point. But now that the Pan American Highway is opening up it is even more essential that diseases such as foot and mouth disease, swine fever, yellow fever, Venezuelan and eastern equine encephalitis be confined at this point. Besides its importance in traditional tropical medi- cine, GML is very important in cancer research in the region. It is unique in that it is capable of doing sophisticated cancer research in a place which is in the process of modernization. GML was also felt to be very important politically. It would be an affront to Panama if we pulled out as it is a very important indicator of US. concern with nonpolitical problems in the region. The general feel- ing was that with the current direction of events in the region, GML is becoming more important than ever, if constructive changes are made. Appendix E Glossary of Acronyms and Terms Glossary of Acronyms AFRIMS AID ARI BCG CAREC CCCD CDC CE/LAS —Armed Forces Research Institute of Medical Sciences —Agency for International Development (US. Department of State) —acute respiratory infections —bacille Calmette-Guerin Vaccination ——Caribbean Epidemiology Research Center (PAHO) —Combatting Communicable Childhood Diseases (AID) ——Centers for Disease Control (PHS) —California Encephalitis/LaCrosse Encephalitis CEPIALET —Pan-American Center for Research CFNI DOD DRG EEE EPI FIC GAO GMI GML GND HHS HTLV ICDDRB and Training in Leprosy and Tropical Diseases (PAHO) —Caribbean Food and Nutrition Institute (PAHO) —U.S. Department of Defense —Division of Research Grants (NIH) —eastern equine encephalitis —Expanded Program on Immunization (WHO) —Fogarty International Center (NIH) —General Accounting Office (US. Congress) —Gorgas Memorial Institute of Tropical and Preventive Medicine, Inc. —Gorgas Memorial Laboratory (of GMI) —Great Neglected Diseases of Mankind (Rockefeller Foundation) —U.S. Department of Health and Human Services —human T-cell leukemia virus —International Center for Diarrheal Disease Research/ Bangladesh ICIDR IDRC ILRAD INCAP IRG MARU —International Collaboration in Infectious Diseases (NIAID) —International Development Research Centre (Canadian) —International Laboratory of Research on Animal Diseases —Institute of Nutrition of the Caribbean and Panama (PAHO) —Internal Review Group (NIH) ——Middle American Research Unit (NIAID) MERTU/G—Medical Entomology Research and NAMRU NCI NIAID NIH ORT OTA PAHO PHS SLE STD TDR UNDP USAMRU VEE WEE WHO WRAIR YARU Training Unit in Guatemala (CDC) —Naval Medical Research Unit —National Cancer Institute (NIH) ——National Institute of Allergy and Infectious Diseases (NIH) —National Institutes of Health (PHS) —ora1 rehydration therapy —Office of Technology Assessment (US. Congress) —Pan American Health Organization —U.S. Public Health Service (HHS) ——~St. Louis encephalitis —sexually transmitted diseases —United Nations Development Program/World Bank/ World Health Organization Special Programme for Research and Training in Tropical Diseases —United Nations Development Programme —United States Army Medical Research Unit ——Venezuelan equine encephalitis —western equine encephalitis —World Health Organization —Walter Reed Army Institute of Research —Yale Arboviral Research Unit (Yale University) 81 82 Glossary of Terms* acute: Having a sudden onset, sharp rise, and short course; not chronic. Aedes (ah-ee’dez): A genus of mosquitoes. A. aegyp- ti, the tiger mosquito, is a common urban species that breeds near houses and transmits urban yellow fever and dengue fever. amebiasis (am-ee-bi’ah-sis): Infection by amebae, es- pecially, infection with Entamoeba histolytica, an intestinal parasite, characterized by diarrhea with blood and mucous and also causing abcesses in the intestine and liver (sometimes called amebic dysen— tery). See AMEBA. ameba (ah-me’bah), also, amoeba: A protozoan; a minute single-celled life form. One species, Entamoe— ba histolytica, is a parasitic pathogen producing amebiasis in man. See AMEBIASIS. ancylostomiasis (an-ki’los—to-mi'ah-sis): Infection with Ancylostoma duodenale, the human intestinal hook- worm. Causes chronic anemia. Anopheles gambiae (a-nof’a-leez gam-bee'ee): A spe- cies of mosquito in Africa that transmits malaria; also, a group of closely related species of mosqui- toes. See SPECIES COMPLEX. antigen (an'ti-jen): Any substance that stimulates the production of antibodies. Aotus (ay-o’tus): A genus of monkey; the owl monkey. arbovirus (ar’bo-vi-rus): An abbreviation for arthro- pod-bome virus, virus transmitted by arthropods. Argentinian hemorrhagic fever: An acute, sometimes fatal disease caused by a virus, transmitted through contamination by urine or feces of infected rats. Characterized by chills, fever, severe headache, hemorrhagic symptoms, shock, kidney involve- ment, and neurologic involvement. arthropods (ar'thro-podz): Invertebrate animals of the phylum Arthropoda that includes insects, ticks, spiders, and crustaceans. arthropod-borne: Transmitted by arthropods. ascariasis (as-kah-ri'ah-sis): An infection with worms of the genus Ascaris, especially, Ascaris lumbri- coides, the human intestinal round worm, charac- terized by intestinal pain and diarrhea. “SOURCES: 1. The American Heritage Dictionary of the English Language, W. Morse (ed.) (Boston, Mass.: Houghton Mifflin Co., 1976). 2. Control of Communicable Diseases in Man, 13th ed., A. S. Benensen (ed.) (Washington, D.C.: American Public Health Association, 1981). 3. Dorland’s Illustrated Medical Dictionary, 25th ed. (Philadelphia: W. B. Saunders, 1974). . Office of Technology Assessment, US. Congress, Washington, D.C. . Roper, N., Pocket Medical Dictionary, 13th ed. (Edinburgh, Scotland: Churchill Livingstone, 1978). 01:5 aseptic meningitis (a-sep'tik men-in-ji'tis): Viral-caused inflammation of the membranes surrounding the brain and spinal cord. bacille Calmette-Guerin, abbr. BCG: An attenuated (weakened) strain of tuberculosis bacteria used to vaccinate against virulent tuberculosis. bacillus (ba-sil’us), pl. bacilli: Any of various rod- shaped, aerobic bacteria of the genus Bacillus. bacteriology (bak-tir’ee—ol’o-ji): The scientific study of bacteria. bacterium (bak-tir’ee-um), pl. bacteria: Any of numer- ous unicellular micro-organisms (class Schizomy- cetes), occurring in a wide variety of forms, existing either as free-living organisms or as parasites, and having a wide range of biochemical, often patho- genic, properties. bilharzia (bil-har'zi-ah): See SCHISTOSOMIASIS. bilirubin (bi-li-roo'bin): A pigment largely derived from the breakdown in the spleen of hemoglobin from red blood cells. Bolivian hemorrhagic fever: An acute, sometimes fatal disease caused by a virus, transmitted through con— tamination by urine or feces of infected rats, occur- ring in Bolivia. Characterized by chills, fever, severe headache, hemorrhagic symptoms, shock, kidney involvement, and neurologic involvement. California encephalitis: An acute encephalitis caused by an arbovirus, transmitted by mosquitoes. Campylobacter (kam’pil-o-bak’ter): A genus of bacteria, one of which, C. jejuni, causes an acute diarrhea] disease. cellulose acetate electrophoresis: A type of isozyme electrophoresis. See ISOZYME; ISOZYME ELEC- TROPHORESIS. cervical cancer (ser’vi-kal): Cancer of the cervix (the neck of the uterus). Chagas’ disease (sha’gus): Infection by Trypanosoma cruzi, transmitted by reduviid bugs. Discovered and described by Carlos Chagas of Brazil. Characterized by an acute course in children with fever, encepha— litis, and inflammation of the heart muscle (often life-threatening or fatal), and a chronic course in adults leading to heart disease and heart failure. Widely distributed in Central and South America. Also called American trypanosomiasis. See TRYP- ANOSOMIASIS. Chagres fever: A febrile disease caused by an arbovi— rus, transmitted by phlebotomine sandflies. Also called “Panama fever.” chemotherapy (kee-mo-ther’a-pi): The use of specific chemical agents to arrest the progress of, or eradi- cate, disease in the body without causing irreversi- ble injury to healthy tissues. chorioretinitis (kawr-i—o-ret-in-it’is): Inflammation of the choroid and retina of the eye. 83 chronic: Lingering, lasting, as opposed to acute. Colorado tick fever: A febrile disease without rash caused by an arbovirus, transmitted by a tick, oc- curring in the Rocky Mountain region of the United States. cytogenetics (si'to—je-net'iks): Laboratory examination, usually microscopic, of chromosomes. dengue fever (deng'gee): An acute febrile disease caused by an arbovirus, transmitted by mosquitoes of the genus Aedes, characterized by fever, severe pains in the head, eyes, muscles, and joints, and a skin eruption. Occurring in Japan, Southeast Asia, the South Pacific, India, the Caribbean, Middle and South America. Sometimes called ”breakbone fe- ver." dengue hemorrhagic fever: Life-threatening complica- tions of dengue infection; syn. DENGUE SHOCK SYNDROME. See DENGUE FEVER. dengue shock syndrome: Life-threatening complica- tions of dengue infection; syn. DENGUE HEMOR- RHAGIC FEVER. See DENGUE FEVER. diarrhea (dy-a-ree’a): Pathologically excessive frequen- cy and fluidity of fecal discharges. Adj., diarrhea]. diphtheria (dif-theer’ee—a): An acute infectious disease caused by the bacterium Corynebacten'um diphther- iae. Characterized by grey, adherent, false mem- brane growing on mucous surface of the upper res- piratory tract. Locally there is pain, swelling, and may be suffocation. Systemically the toxins attack the heart muscle and nerves. DNA hybridization: Laboratory method for species and strain identification based on matching of DNA from an unknown organism with DNA from known organisms. eastern equine encephalitis, abbr. EEE: An arbovirus disease of horses and mules, possibly other verte- brates, with a reservoir of infection in birds, trans- mitted by mosquitoes. Can be transmitted to hu- mans and cause death. Occurring in the United States in a region extending from New Hampshire to Texas to Wisconsin, in Canada, Mexico, the Car- ibbean, and parts of Central and South America. Characterized by encephalomyelitis. elephantiasis (el-ef-an-ti’a-sis): The swelling of a limb, usually a leg, as a result of lymphatic obstruction, followed by thickening of the skin and subcutaneous tissues. A complication of filariasis in tropical coun- tries. See FILARIASIS. encephalitis (en-sef-a-li’tis): Inflammation of the brain. encephalomyelitis (en-sef’-al-o-mi-e-li’tis): Inflamma- tion of the brain and spinal cord. endemic (en-dem’ik): The constant presence or persist- ence of a human disease or infectious agent within a given geographic area. Cf. EPIDEMIC; ENZOOT- lC. enteric (en-ter’ik): Pertaining to the intestine. entomology (en-to-mol’o—ji): The science dealing with insects. enzootic (en-zo-ot’ik): The constant presence or per- sistence of an animal disease or infectious agent within a given geographic area. Cf. ENDEMIC; EPI- ZOOTIC. epidemic (ep—i-dem'ik): The occurrence of a human ill- ness in excess of usual frequency in a particular area. Cf. ENDEMIC; EPIZOOTIC. epidemiology (ep-i-de-mi-ol'o-ji): The scientific study of the distribution and occurrence of diseases and health conditions. epizootic (ep-i-zo-ot'ik): The occurrence of an animal disease in excess of usual frequency in a particular area. Cf. EPIDEMIC; ENZOOTIC. Escherichia coli (esh-er-ik’i-a ko’li): A species of bac- teria; motile, rod-shaped bacterium which is ubiq- uitous in the intestinal tract of vertebrates. Some strains are pathogenic to humans, causing intestinal disease and diarrhea. etiology (ee-ti-ol’o-ji): The scientific study of disease causation; the causation of a disease. filariasis (fil-a-ri’a-sis): Infection with Filaria, parasitic thread-like worms, found mainly in the tropics and subtropics, transmitted by mosquitoes. Adults of Wuchereria bancrofti' and Brugi'a malayi' live in the lymphatic system and connective tissues, where they may cause obstruction, but the embryos (microfil- ariae) migrate to the blood stream. Completion of the lifecycle is dependent on passage through a mos- quito. See ELEPHANTIASIS. genus (jen'us): The taxonomic category next greater than species. granulomatous (gran-u—lom’ah-tus): Composed of tumor-like mass or nodule of tissue, due to inflam— matory process associated with an infectious disease, such as tuberculosis. helminth (hel’minth): Parasitic worm. Adj. helminthic. hemorrhage: The escape of blood from a blood vessel. hemorrhagic fever: Severe complication of some viral diseases involving internal or external bleeding. host: Human or other living animal, including birds and arthropods, that affords subsistence or lodg- ment to an infectious agent under natural condi- tions. human T-cell leukemia virus, abbr. HTLV: A recent- ly identified virus that induces a specific type of can- cer of the blood-forming organs. immunity (i-myoo’ne—ti): Nonsusceptibility, or relative resistance, to a specific infection, due to antibodies produced against that specific antigen. immunology (im'yoo-nol'o-ji): The scientific study of immunity. Adj., immunologic, immunological. 84 incidence (in'se-dens): The frequency of new occur- rences of disease within a defined time interval. In- cidence rate is the quotient of new cases of a speci- fied disease divided by the number of people in a population in a defined period of time. inflammation (in-flam-ma’shun): The reaction of liv— ing tissues to injury, infection, or irritation; char- acterized by pain, swelling, redness, and heat. influenza (in-floo-en'za): An acute viral infection of the nasopharynx and upper respiratory tract. in vitro (vi’tro): In glass, as in a test-tube. in viva (vi’vo): In living tissue. isozyme (i'so-zime): Two or more forms of the same enzyme having identical chemical function but dif- fering physical structure, which can be separated and identified. isozyme electrophoresis (i’so-zime el-ek-tro-for—ee’sis): Laboratory method of separating isozymes (cf.) based on their migration distance in an electric field applied across a standardized inert material (poly- acrylamide gel, agarose gel, or cellulose acetate). jaundice (jawn’dis): A condition characterized by yellow appearance due to raised bilirubin level in the blood resulting from: 1) obstruction in the biliary tract, 2) excessive rupture of red blood cells, 3) tox- ic or infective damage of liver cells. kwashiorkor (kwash-ee-or’kor): A nutritional disease produced by persistent deficiency in essential dietary protein. Characteristic features are anemia, wasting, edema, potbelly, depigmentation of the skin, loss of hair or change of hair color. Untreated, it pro- gresses to death. LaCrosse encephalitis: An acute encephalitis caused by an arbovirus, transmitted by mosquitoes. Closely related to California encephalitis. Leishmania (Ieesh-may’ni-a): A genus of flagellated parasitic protozoans causing several clinical diseases. See LEISHMANIASIS. leishmaniasis (leesh-man-i’a-sis): Infection by Leishmania, transmitted by sandflies. Cutaneous leishmaniasis is a skin ulcer caused by L. mexicana (New World) or L. tropica (Old World). Mucocu- taneous leishmaniasis is an ulceration of the nose and throat caused by L. braziliensis, occurring in tropical America. Visceral leishmaniasis, also called kala-azar, is a generalized and internal disease caused by L. donovani (New and Old World). leprosy (lep'ra-si): A chronic, infectious, granuloma- tous disease occurring almost exclusively in tropical and subtropical regions, caused by the bacillus Mycobacten'um Ieprae, and ranging in severity from noncontagious and spontaneously remitting forms to contagious, malignant forms with progressive anesthesia, paralysis, ulceration, nutritive disturb— ances, gangrene, and mutilation. Also called ”Han— sen’s disease." leptospirosis (lep-to-spi-ro’sis): Disease caused by spi- rochete (finely coiled bacterium), commonly trans- mitted in water contaminated by urine of infected animals. Characterized by inflammation of the spi- nal cord, the nervous system, and liver. lifecycle: The progressive stages of development of an organism. lymphatic system (lim-fa'tik): The system of vessels in the body that carry lymph fluid. lymph glands (limf-glanz): The organs at various points of the lymphatic system that filter the lymph fluid. malaria: A disease caused by protozoan parasites that infect red blood cells, transmitted by mosquitoes of the genus Anopheles. Four species of the parasite cause disease in humans: Plasmodium falciparum, P. vivax, P. malariae, and P. ovaIe. P. vivax and P. ovale have a persistent stage in the liver that causes relapses. Many other species infect monkeys, rodents, birds, and reptiles. Characterized by fever, chills, and sweating that occur at intervals depend- ing on the time required for development of a new generation of parasites in the body. See PLASMO- DIUM FALCIPARUM. marasmus (ma-raz’mus): Wasting away of the body due to gross lack of calories in the diet. measles (meez’lz): An acute infectious disease caused by a virus. Characterized by fever, a blotchy rash, and inflammation of mucous membranes. metabolic: Pertaining to metabolism, the series of chemical changes in the living body by which life is maintained. metastasize (me-tas’ta-syz): Tranfer of a disease from one part of the body to another, usually by blood or lymph, leading to secondary growth or lesions. molluscicide (mol-lusk’i—side): Any chemical agent used to kill molluscs, especially snails. morbidity: Disease or illness. mortality: Death. onchocerciasis (on-ko-ser-ki’a-sis): An infection of hu- mans with Onchocerca worms, transmitted by the bite of blood-sucking blackflies (Simuliidae). Adult worms become encapsulated in subcutaneous nod- ules. Immature worms (microfilariae) migrate in the tissues and can cause ”river blindness” if reaching the eye. Occurring in western Africa and discrete foci in tropical America. oral rehydration therapy: The treatment of fluid-loss due to diarrhea by a specific water solution of elec- trolytes and glucose taken by mouth. Oropouche fever (or-o-poosh): An arbovirus disease transmitted by biting midges (CuIicoides spp.). 85 Characterized by fever, headache, aches and pains, and occasionally encephalitis. Found in Trinidad and Brazil, but recognized range in tropical America is expanding. Occurrence is primarily rural or forest, but explosive urban and suburban outbreaks occur. parasitology (par-a-sit-ol’o-ji): The scientific study of parasites. pathogen (path’o-jen): A disease-producing agent. pathological: Of or pertaining to disease processes. Phlebotomus (fle-bot'o-mus): A genus of sandflies, many of which are vectors of leishmaniasis. Adj. phlebotomine. physiological: In accordance with natural processes and normal function of the body. Plasmodium falciparum (plaz-mo'de-um fal-sip’ar- um): One of the four species of protozoan parasites causing malaria in humans. Only P. faIciparum causes life-threatening complications; only species with drug—resistant characteristics. See MALARIA. pneumoccocal (nyoo-mo-kok’al): Referring to the bacterium, Diplococcus pneumoniae, that causes pneumococcal pneumonia. pneumonia (nyoo-mon’ya): Inflammation of the lung, usually the lower respiratory tract. poliomyelitis (po’lee—o-my’a-li’tis): An infectious viral disease occurring mainly in children and in its acute, more virulent form attacking the central nervous system and producing paralysis, muscular atrophy, and often deformity. Transmitted by the oral-fecal route. prevalence (prev'a-lens): The number of existing cases of a disease in a defined population at a particular time. protozoa (pro-to—zo’a): Unicellular organisms, the smallest type of animal life. Adj. protozoan, pro- tozoal. protozoology (pro-to-zo-ol’o-ii): The scientific study of protozoa. Adj. protozoologic. reduviid (re-du’vi-id): Belonging to the family Reduviidae, winged, “true" bugs (Order Hemiptera), including blood-sucking vectors of Chagas' disease. See CHAGAS’ DISEASE. reservoir: Any person, animal, arthropod, plant, soil or substance (or combination of these) in which an infectious agent normally lives and multiplies, on which it depends primarily for survival, and where it reproduces itself in such manner that it can be transmitted to a susceptible host. rotavirus (ro-ta-vi-rus): Any of a group of viruses (round in shape) causing gastroenteritis in infants and children. St. Louis encephalitis, abbr. SLE: An arbovirus dis- ease transmitted by mosquitoes, with the reservoir of infection in birds. Can be transmitted to humans and cause death. First observed in Illinois in 1932. Occurring in most of the United States, Trinidad, Jamaica, Panama, and Brazil. Mild cases character- ized by aseptic meningitis; severe infection usually marked by acute onset, headache, high fever, coma, convulsions, and paralysis. schistosomiasis (shis’to-so-mi’a—sis): An infection of the human body by worms of the genus Schistosoma (“blood flukes”), from drinking or bathing in in- fected water. Infected humans pass eggs in urine or feces (depending on parasite species) into water source. Immature form (miricidia) hatchs and infects suitable snail host. After multiplication, interme— diate form (cercariae) is shed from snail into water, where penetration of human skin occurs. Adult worm develops in human, localizing in veins of bladder or intestine. Schistosoma mansom’ occurs in Africa, the Caribbean, and Brazil; 5. japonicum occurs in the Far East; in both, adult worms localize in veins of intestine; deposited eggs cause tissue scar- ring of intestine and liver; S. haematobium occurs in Africa and the Middle East producing the urinary form as adult worms localize in veins of the blad- der; characterized by obstruction due to scar for- mation, inflammation, and possibly cancer. Also called “bilharzia.” sequelae (se-kwel'ee): The pathological consequences of a disease. seroepidemiologic: Pertaining to a branch of epidemi- ology that studies antigens from humans to delineate epidemiologic patterns of a disease. See EPIDEMI- OLOGY; SEROLOGY. serology (se-rol’o-ji): The scientific study of sera (the fluid portion of blood). Adj. serologic, serological. sexually transmitted diseases: A group of infectious diseases defined by transmission through intimate contact, including gonorrhea, syphilis, chancroid, lymphogranuloma venereum, granuloma inguinale, chlamydia, herpes simplex, trichomonas, as well as hepatitis virus and intestinal parasites such as giar- dia, entamoeba, ascaris, and trichuris. species: A taxonomic subdivision of a genus. A group of individuals having common characteristics dis- tinguishing them from other categories of individ- uals of the same taxonomic level. Always carries the implication of reproductive isolation, i.e., members of a species only reproduce successfully with one another. species complex: A group of two or more closely related insect species that can only be differentiated by cytogenetic analysis or cross-breeding experi— ments. strain: A group of organisms of the same species (cf.) having a distinctive quality or characteristic (bio— 86 chemical, pathogenic, or other feature) that can be differentiated, but not different enough to constitute a separate species. subacute: Mild or moderately severe. Often the stage between the acute and chronic phases of disease. symptomatic: Of or pertaining to the symptoms, rather than the causes of a disease. symptomatology: The branch of medicine concerned with symptoms. The combined symptoms typical of a particular disease. therapeutic: Dealing with the treatment of disease. toxoplasmosis (toks—o-plas-mo’sis): Infection by the protozoa] parasite Toxoplasma gondii. Many mam- mals can harbor the parasite which encysts in tissue after ingestion (oral-fecal route), but only in cats is the lifecycle completed, with the infective form shed in feces. Characterized by lesions of the central ner- vous system, which may lead to chorioretinitis, blindness, brain defects, and death. trachoma (tra-ko’mah): A chronic, infectious disease of the eye caused by the bacterium Chlamydia tra- chomatis, characterized by inflammation, pain, wa- tery eye, then scarring, and finally blindness. triatomine (tri-a-to-meen): Pertaining to the genus Tri- atoma, blood-sucking bugs important as vectors of Chagas’ disease. See CHAGAS’ DISEASE. trichuriasis (trik-u-ri’ah-sis): Infection with the intes- tinal parasitic whipworm, Trichuris trichiura. Tryparlosoma (tri-pan-o-so’ma): A genus of parasitic protozoans. Their lifecycle alternates between blood-sucking arthropods and vertebrate hosts. See TRYPANOSOMIASIS. trypanosomiasis (tri-pan’a-so-my’a-sis): Disease pro- duced by infection with Trypanosoma. In man this may be with Trypanosoma cruzi, transmitted by blood-sucking reduviid bugs in the Americas (also called Chagas’ disease); or with T. rhodesiense in East Africa or T. gambiense in West Africa, both transmitted by the tsetse fly, causing ”sleeping sick- ness.” See CHAGAS’ DISEASE. tubercle bacillus (tu’ber-kl ba-sil’es): A bacillus caus- ing tuberculosis; usually refers to Mycobacterium tuberculosis, the principal cause of human tubercu- losis. tuberculosis (tu-ber-ku-lo’sis): An infectious disease caused by any of several species of mycobacteria. Usually begins with lesions in the lung, but can me- tastasize to other parts of the body. vector: A carrier of disease; usage commonly refers to arthropods or rodents. vector bionomics: The relationship between organisms and their environment. vector-borne: Transmitted by a vector. vector control: Intervention aimed at disease reduc- tion by action against vectors. Venezuelan equine encephalitis, abbr. VEE: An ar- bovirus disease of horses and mules, possibly other vertebrates, with a reservoir of infection in birds, transmitted by mosquitoes. Can be transmitted to humans and cause death. Endemic in northern South America, Trinidad, Middle America, Mexico, and Florida. Characterized by severe headache, chills, fever, pain in muscles and eyes, nausea and vomit- ing, possibly with severe central nervous system complications leading to convulsions, coma, and death. western equine encephalitis, abbr. WEE: An arbovirus disease of horses and mules, possibly other verte- brates, with a reservoir of infection in birds, trans- mitted by mosquitoes. Can be transmitted to hu- mans and cause death. Occurring in Western and Central United States and Canada and in scattered areas further east. Characterized by encephalomy- elitis. whooping cough: Pertussis; an infectious respiratory disease of children with attacks of coughing which reach a peak of violence ending in an inspiratory whoop. Caused by BordeteIla pertussis. Prophylac- tic vaccination is responsible for a decrease in case incidence. yellow fever, abbr. YF: An acute febrile disease caused by an arbovirus, transmitted by mosquitoes. Char- acteristic features are fever, jaundice, black vomit, and anuria (absence of urine excretion). 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N., “Studies With Induced Malarias in Aotus Mon- keys,” Laboratory Animal Science 26(6),Part 11:1131-1137, 1976. Office of Technology Assessment The Office of Technology Assessment (OTA) was created in 1972 as an analytical arm of Congress. OTA's basic function is to help legislative policy- makers anticipate and plan for the consequences of technological changes and to examine the many ways, expected and unexpected, in which tech- nology affects people’s lives. The assessment of technology calls for explora- tion of the physical, biological, economic, social, and political impacts that can result from applications of scientific knowledge. OTA provides Con- gress with independent and timely information about the potential effects—~ both beneficial and harmful—of technological applications. 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