- Email: [email protected]
CHOLERA RESEARCH IN BANGLADESH
1207 CHOLERA RESEARCH IN BANGLADESH
SIR,- The
response to my letter of
possibly an attempt is required.
questions than
can
April
be answered in
8 has stirred a
more
single letter,
but
any concerned Bangladeshi known to me is internationalisation of the Cholera Research Laboratory. The issues are developing-country control and the size and scope of the institution. The intense debate in Bangladesh has led to questions about the ethics of research, the involvement of Bangladeshi scientists, and the contribution of the C.R.L. to health services in Bangladesh. I wrote that letter because of my concern and anger over what I felt was excessive pressure from the present donor countries to establish the new institution in a form which would have minimised developing country control and set no real limits on expansion. I chose to submit it and to allow an early draft to be seen in Bangladesh because I believed this was the only way to be sure these views would have an influence on the
Neither I
opposed
nor
to
discussion. There have been important changes here in the past year in the areas of ethical review, participation by Bangladeshi scientists, and the establishment of positions to increase the laboratory’s role in service and training. The director deserves credit for introducing these measures and for pushing them hard against opposition and inertia. The basic structure of the organisation has changed very little, however, and the debate here and outside seemed to me to gloss over past problems and to be often misdirected and misinformed. The real issue is whether medical research can be done at all by foreigners in a developing country without infringing on the rights of human subjects and restricting the development of indigenous research capacity. I believe that it is possible, but only in institutions which recognise these problems as so important and difficult that there must be a primary commitment to their resolution. There are many ways to do this, but the most important seem to me to be:
(1) To conduct all research on human subjects in the context of a clearly visible health benefit to the patient and the community. (2) To subject a patient to no risk which is not justified by the health benefit to the individual undergoing an experimental procedure. (3) To consider the development of indigenous research capacity a primary goal more important than the production research results, however significant these may seem in the short run (4) To put institutional control in the hands of the developing countries.
I have often expressed my views on these questions and the others which arise out of them before and after joining the Laboratory, and I set them out in a memorandum to Dr W. H. Mosley on Dec. 30, 1977. It was no secret to the laboratory leadership that I had serious doubts when I came whether this sort of commitment could be developed. There are several personal questions raised by my letter which I regret very much. The first is the implication which some have read into it that I was questioning the capacity of the Bangladeshi scientists at the laboratory. I do not in any way question the competence of these men, but I am concerned that an expanding laboratory controlled by the developed countries would probably not be able to maintain the present level of contribution from developing-country scientists over time. This would not occur because of any conscious take-over, but simply because of the pressure of highly trained individuals backed by powerful institutions. Equally important, I have no question about the ethical standards of the individuals who conducted the experiments I have cited. As I said in the earlier letter, there was an ethical review board, staffed by prominent scientists, including three from Pakistan. They considered the questions of non-therapeutic research and of informed consent and decided that: "... human experimentation in diseases such as cholera where the disease processes are still not completely known and in which a proven animal model is not available justified appropriate experiments
delineated to discern the disease mechanisms to improve therapy and to enhance knowledge of means of preventing the disease. It was pointed out to the Committee that an overwhelming majority of the patients were illiterate and if they were below the age of consent their parents were illiterate. This made it impossible to obtain informed consent for proposed studies in well over 99% of the patients. The Pakistani members of the Committee agreed that all patients or parents of patients would readily put a mark on a piece of paper acquiescing to experiments but they would have no appreciation of what might or might not be done. In consequence the Committee went on record to the effect that responsibility for experiments rested directly on the Director of the laboratory and his Deputy Diector ... The Director pointed out that it was the general policy of the laboratory to use only procedures which had been well documented by use in University hospitals throughout the world." (Memorandum from R. A. Phillips on meeting of Clinical Investigation Committee, Pakistan-SEATO Cholera Research Laboratory, Nov. 26, 1966.)
Following these statements, the board approved the experiinvolving radioactive materials, jejunal biopsy, and intestinal intubation. The risk of all these procedures is small, but there is some risk, and since the procedures could not benefit the individual patient, I do not believe this sort of consent procedure conforms to the Helsinki Declarations of 1964 or ments
1975 or that it would have been allowed in the U.S. at that time forexperiments of this nature. Right-heart catheterisation in a sick patient who, again, does not stand to benefit is hard to defend in any circumstances. Ventricular arrhythmias or perforations of the right ventricle with cardiac tamponade can occur and can be fatal. Nevertheless, there can be no doubt that the scientists who did the catheterisations felt the risk was small and the scientific value of the results obtained justified this risk. I have discussed the use of glucagon with epinephrine (adrenaline) for hypoglycaemia in some detail with one of the investigators. He has convinced me that they really felt these drugs would be better treatment than intravenous glucose for hypoglycoemic coma in this situation and changed their minds only after it was shown that they produced less good results than anticipated. Given this belief, I have to concede that they were testing a positive hypothesis-trying to find the best treatment for a difficult clinical situation. It was not correct to use the terms "installation of tubewells" and "experiment" with reference to the study of the incidence of cholera in areas adjacent to the hospital in Matlab. The facts are these. A high incidence of cholera in areas adjacent to the hospital was observed in 1974 (it had been suspected since 1966, and the sanitary system had been known to be defective for about a year). In January, 1975, a study of water use in the high cholera areas was conducted and correlated retrospectively with cholera incidence over the preceding ten years. As a part of this study, it was confirmed that the untreated effluent from the hospital sanitation system was producing contamination of the canals in the area around the hospital. In February, 1975, a requisition was submitted to correct the sanitation problem. In 1976 the problem at the hospital was corrected. The latrine facilities and water supply for patients’ families and others living around the hospital are still not adequate. In all of these instances there is room for argument over whether the same procedures would have been followed given the same situation in the U.S.A. at the same time. I personally believe that they would not. The more important point, however, is that scientists working in developing countries have a particular challenge to attempt to deal with the tremendous cultural gap between themselves and the subjects of their research, and that this challenge holds them to higher ethical standards than would be expected in other situations. This is a personal opinion, but I think it would probably be shared by most of those who carried out the experiments I have cited. I am sure that earnest efforts were made to explain these procedures to patients and relatives and obtain their informed consent, as some have indicated in their letters to me and to The Lancet. It seems to me that the experimenters simply did not
1208 realise that the task was impossible-as the Pakistani members of the ethical review committee did. As for my own responsibility to develop the service programmes I have criticised, I can only say that the understanding when I accepted an appointment six months ago (and the reason that I came) was that I was to develop supportive links with Bangladesh health service organisations outside the existing C.R.L. structure I have not felt that I had the responsibility or the authroity to make changes within the laboratory, although I certainly have been involved in many discussions on this subject. The views expressed on the necessity for physiological studies and the possibility that the "Dacca solution" of glucose, sodium, potassium, and bicarbonate might have obstructed progress, are not those of a physiologist, but of a clinician. Nevertheless, I think they are valid. Salt and sugar are available in almost every village home. Glucose and bicarbonate are not. Since most diarrhoea deaths result from more gradual fluid loss than that seen in classic cholera, it does seem to be likely that it will be more appropriate to recommend salt and gur (unrefined sugar, which contains potassium) for home treatment of most diarrhoea. This is a very important question which needs to be tested more rigorously than it has been up to now. The responsibility for the delay rests as much with those of us who are involved with service programmes as with laboratory scientists at C.R.L. who have now begun some of the needed studies. There is an absolute necessity to test the application of basic scientific findings to clinical situations. There are usually simple and direct ways to do this through carefully observed clinical trials of therapy. Dacca, Bangladesh
COLIN MCCORD
and community service, should not be denounced for the faults of a few individuals. But one must question how, with so many public health and enteric disease experts at the C.R.L., the situations described above could have gone on for so long. Certainly, the C.R.L. leadership, preoccupied with building a research empire, displayed remarkable insensitivity to local health needs in overlooking the most obvious public-health requirements related to their projects. This aspect of McCord’s criticism rings true. Chemical Industry Institute of P. O. Box 12137, Research Triangle Park, North Carolina 27709, U.S.A.
Toxicology, RICHARD
J. LEVINE
SIR,-The Lancet should be commended for its article, Bangladesh: an International Research Centre (Jan. 28, p. on many of the issues involved in changof the Cholera Research Laboratory (C.R.L.) in In the replies to Dr McCord’s letter on the same subject the response to the ethical issues has been intense, but the other issues, which we consider major ones-control by U.S. scientists, the practical relevance to us in Bangladesh of much of the C.R.L.’s research programme, and the effect of this institution on indigenous institutions-are virtually
202), which focused
ing the role Bangladesh.
ignored. Dr Mosley
and the C.R.L. scientific directors describe your Round the World Article as "simply fallacious" (March 18, p. 602). However, in the matter of training, for example, it is evident that, despite the intention to "internationalise", C.R.L. would still serve the interests of the same foreigners. As Mosley proposed in 1976:’ "Establishment of a training program for young investigators from the developed countries such as the United States will require developof direct institutional ties with U.S. or other universities and ties should be encouraged in order that young scientists from the developed countries can gain the skills and the expertise necessary to address health, population and nutrition ment
training institutes. These
SIR,-While Dr McCord (April 8) has overstated his case Mosley’s reply (May 6, p. 991) demands further comment. Mosley maintains that the observation that cholera was occurDr
ring in villages adjacent to the Cholera Hospital in Matlab was made during 1974/75 and that the "first reaction" to this observation was a complete renovation of the sanitary facilities at Matlab. This was not so. Mosley himself, in reference to our paper documenting the fact of cholera transmission along a canal contaminated by the hospital,’ wrote to me on May 13, 1976: "... this is hardly a new observation since those of us who have worked at the Cholera Lab have always been aware of the high frequency of cholera from the villages along the canal near the hospital." Why then were the sanitary facilities not renovated until 1976? When the data were formally presented to the Cholera Research Laboratory the first reaction was not to renovate sanitary facilities but to attempt to prevent publication of the data. Nor was the problem of environmental vibrio contamination limited to the hospital at Matlab. A C.R.L. study of sewerage at the Dacca Cholera Hospital was undertaken in 1973 at the request of Dr K. A. Monsur, then director of health services at the Bangladesh Institute of Public Health. This study noted that fluid containing cholera vibrios was being disgorged directly into a rice paddy from the outflow pipe of a broken hospital septic tank. The report’ goes on to state: "Many people are found cultivating in the area. Besides, this area provides a good ground for catching fish, grazing of cattle and playground for children." Throughout the paddy area and up to an adjoining canal cholera vibrios were cultured from samples of paddy water (M. S. Islam and R. J. Levine, unpublished). Every institution has had some dust swept beneath the carpet, and the C.R.L., truly an international diarrhceal disease resource with an outstanding record of scientific achievement 1. Levine, R. J., and others Lancet, 1976, ii, 84. 2. Islam, M. S Report on Sewerage and Drain Samples: System of disposal at C.R.L. and Institute of Public Health. C.R.L., Dacca, December, 1973.
problems in the developing world." The apparent virtue in Mosley and the scientific directors’ that 97% of the C.R.L. employees are Bangladeshi, pales when viewed in the light of their work and positions. Salaries of 17 foreigners (3% of staff) are over 9 million taka, including house rents, transportation, travel, and other expenses ; while the remaining 581 employees receive less than 6 million taka for salaries, housing, and so on. Mosley and his colleagues claim that "At the level of independent research staff, there are 16 Bangladeshis and 15 expatriates ..." (March 18, p. 602). However, buried in another document’ of October, 1977, they admit: "The C.R.L. at present has 33 persons on its scientific staff. Only 15, however, would be classified as Principal scientists or administrators based on their positions of scientific leadership in C.R.L. and recognised status in the national or international community. Five of the principal scientists are Bangladeshi..." Moreover, the C.R.L. annual report of 1977 lists only 4 Bangladeshi investigators statement
of 13. Matlab has been used as a reservoir of human research material. Dr Levine has commented on the frequency of cholera in villages near the hospital. It has also been found4 that 14 (29%) of 48 non-cholera patients admitted to the Matlab hospital in December, 1974, and January, 1975, developed cholera. Investigators concluded that infection did not result from exposure in the hospital, but from bathing in the canal near the hospital. Yet, instead of giving the benefit of sanitary intervention experiments to the people with a high incidence out
H. Proposed Five-Year Plan for the Cholera Research Laboratory; p. 61 Dacca, Bangladesh. April, 1976. 2. C.R.L., Dacca. Draft prospectus: an International Centre for Health Research, p. 36. October, 1977. 3. C.R.L., Dacca. Cholera Research Laboratory Annual Report 1977, p. 68 November, 1977 4. Ryder, R. W. Paper presented at Center for Disease Control meetings in 1.
Mosley, W
Atlanta, 1977; p.45.
1209 of cholera in Matlab, C.R.L. moved these experiments to Teknaf, 150 miles away at the end point of Bangladesh, across a river from the armed political struggle going on in Burma. We accept, in general, Mosley’s claim that "C.R.L. physicians have always conscientiously obtained informed consent from subjects of research by conversations with the patient of guardian" (May 6, p. 991). However, we would point out that Bangladeshi physicians in C.R.L. were paid for every patient protocol they filled out.
surprised that Dr Nalin (May 6, p. 992) did not comthe ethical issues, since, on many occasions, he has raised these with us, one example being his doubts expressed to one of us (Z.C.) about informed consent in the study of nosocomial cholera in a Bangladesh Hospital referred to above.4 Nalin and others may feel that the physiological studies at C.R.L. were essential to the development of oral fluid therapy, but the study in Calcutta5 demonstrated, by a clinical trial (a balance study) in 14 patients, that glucose-linked sodium absorption was intact. In this paper there is no reference to any of the work at C.R.L. on glucose and sodium absorption during cholera. We
are
ment on
The C.R.L. trial of a new cholera vaccine which has 1% urticarial reactions was approved by the Scientific Review Committee of the Bangladesh Medical Research Council although they had no opportunity to see documentation of trials conducted in India and Indonesia. The weekly journal Bichitra pointed out that four out of five members of the Scientific Review Committee were associated directly or indirectly with C.R.L.6 As far as we know, no independent Bangladeshi scientist was consulted in setting up the scientific review committee for internationalisation of C.R.L. until a few weeks before the meeting. Mosley has stressed the quality of the independent, outside ethics review committee (May 6, p. 991), but there was only one Bengali member of this committee. We would like to make some suggestions that we feel would make internationalisation of the laboratory more meaningful:
(1) The institute should do research in diarrhoeal diseases only. (2) In the interests of development of indigenous research, research in other fields such as population, fertility, nutrition, clinical medicine, and social medicine, should be done under the direct control of the five national institutes. As the Bengali proverb says: "Under the Banyan tree, nothing grows". (3) Research should include development of implementation programmes for the solutions of the problems under study. (4) Two-thirds of the senior scientific investigators on the staff (including the director and the scientific directors) should come from de-
veloping countries. (5) At least two-thirds of the board of directors should come from developing countries. To make it effectively (not cosmetically) international, individuals from Western European countries, socialist countries, China, and so on should be included from the early stages of transition. (6) The responsibility of the ethical committee to protect individuals who are in any way subjected to research procedures, should be spelled out in the charter in some detail. (7) All protocols for experimentation should be made public, since human experimentation will be involved, to enable independent Bangladeshi and other scientists to have the opportunity to comment. (8) No more than 25% of the centre’s funds should come from donors of one nationality. (9) Salary levels and benefits must be set so that individuals who come to Bangladesh from other countries are not m a position to derive a large surplus of income over expenses because of their stay in Bangladesh. The attraction inducing individual scientists to come to the centre ought not to be financial but professional opportunities and interest in the health problems of developing countries. (10) All employees of the centre should pay Bangladesh income tax. A fund could be established so that if this tax were greater than that 5
Pierce, N F., Banwell, J., Mitra, R., Caranabos, G., Keimowitz, A., Manji, P. Gastroenterology, 1968, 55, 333. 6. Bichitra Dacca, Feb. 10, 1978.
R Mondal,
which should have been would be refunded.
paid
in the country ot
origin,
of Postgraduate Medical Sciences and Research, University of Dacca
Faculty
Institute of Research and Rehabilitation for Diabetes, Endocrine and Metabolic Disorders Dacca
the difference
NURAL ISLAM, Dean
Bangladesh
Community
Health Research
Association,
HAJERA MEHTAB, Medical Director
M. A.
MUTTALIB, President
Dacca
Gonoshasthaya Kendra, P.O. Nayarhat, Dacca, Bangladesh
ZAFRULLAH
CHOWDHURY,
Projects Coordinator
HEREDITARY POLYCYSTIC OSTEODYSPLASIA WITH PROGRESSIVE DEMENTIA IN SWEDEN
SIR,-In the past decade a new hereditary disease characterised by progressive dementia and polycystic bone lesions has been described in Finland’-3 and japan.4,5 The disease manifests itself insidiously at age 20-30 years. The first symptoms usually arise from the skeleton with pain, tenderness, and swelling in the ankles and wrists after minor injury, though fractures have been described as the initial symptom. A characteristic finding at this stage of the disease is symmetrically located cystic bone lesions, especially in the hands and feet. Biopsy of these cysts is virtually pathognomic.1 Serious neuropsychiatric symptoms appear during the fourth decade of life, with decline in mental function, involvement of the upper motor neurons, dyspraxia, epileptic seizures, and myoclomc twitches. The patient dies young (35t5 years), and the climcal picture terminally resembles that of Alzheimer’s disease. Neuroradiological examinations have shown cortical and central atrophy, sometimes before the onset of the neuropsychiatric symptoms.7 Some twenty cases have been found in Finland and Japan, but the disease has never been described in other countries. In the past 6 months we have found two families in northern Sweden, in which seven out of eighteen children have shown a highly uniform clinical picture, with progressive dementia associated with polycystic bone lesions. The first case, a 39-year-old truck driver, presented as a "typical" Alzheimer’s presenile dementia’. However,,previously hyperparathyroidism had been suspected because of a diffuse decalcification of the hand and foot skeleton. On repeat X-rays we observed multiple cysts in the hands and feet and in the metaphysis of the femur. He became severely handicapped due to rigidity and is now totally bedridden. We have not yet found any metabolic abnormality, as in the Finnish cases. The aetiology of this disease is unknown. The disease is inherited via an autosomal recessive gene.2,3 Japanese scientists claim that it is a disturbance of the lipid metabolism,’ and neuropathological examination has shown atrophy of the white-matter and diffuse astrogliosis.8 It seems unlikely that this disease is restricted to Finland, Japan, and Sweden, and we agree with our Finnish colleagues that every new case of unexplained dementia with onset before Järvi, O. H., Hakola, H. P. A., Lauttamus, L. L., Solonen, A. H. Int. Congr. int. Acad. Path. 1968, abstr. p.291. 2. Hakola, H. P. A., Järvi, D. H., Sourander, P. Acta neurol. 1.
K.
A., Vilppula,
scand
1970, 46,
78. 3. 4. 5. 6.
Hakola, H. P.
p 1
A. Acta psychiat. scand. 1972, suppl 232, Nasu, T. , Tsukahara, Y., Teraqama, K Acta path. jap 1973, 23, 539. Harada, K. Folia psychiat. neurol jap 1975, 29, 169. Hakola, H P A., Järvi, O. H., Lauttamus, L. L., Solonen, K. A., Sourander, B. J.P., Vuppula, A. H. Duodecim, 1974, 90, 106 7. Hakola, H. P. A , livanainen, M Neuroradiology, 1973, 6, 162. 8. Sourander, P. Acta path. microbiol scand 1970, suppl. 215. p. 44.
SIR,- The
response to my letter of
possibly an attempt is required.
questions than
can
April
be answered in
8 has stirred a
more
single letter,
but
any concerned Bangladeshi known to me is internationalisation of the Cholera Research Laboratory. The issues are developing-country control and the size and scope of the institution. The intense debate in Bangladesh has led to questions about the ethics of research, the involvement of Bangladeshi scientists, and the contribution of the C.R.L. to health services in Bangladesh. I wrote that letter because of my concern and anger over what I felt was excessive pressure from the present donor countries to establish the new institution in a form which would have minimised developing country control and set no real limits on expansion. I chose to submit it and to allow an early draft to be seen in Bangladesh because I believed this was the only way to be sure these views would have an influence on the
Neither I
opposed
nor
to
discussion. There have been important changes here in the past year in the areas of ethical review, participation by Bangladeshi scientists, and the establishment of positions to increase the laboratory’s role in service and training. The director deserves credit for introducing these measures and for pushing them hard against opposition and inertia. The basic structure of the organisation has changed very little, however, and the debate here and outside seemed to me to gloss over past problems and to be often misdirected and misinformed. The real issue is whether medical research can be done at all by foreigners in a developing country without infringing on the rights of human subjects and restricting the development of indigenous research capacity. I believe that it is possible, but only in institutions which recognise these problems as so important and difficult that there must be a primary commitment to their resolution. There are many ways to do this, but the most important seem to me to be:
(1) To conduct all research on human subjects in the context of a clearly visible health benefit to the patient and the community. (2) To subject a patient to no risk which is not justified by the health benefit to the individual undergoing an experimental procedure. (3) To consider the development of indigenous research capacity a primary goal more important than the production research results, however significant these may seem in the short run (4) To put institutional control in the hands of the developing countries.
I have often expressed my views on these questions and the others which arise out of them before and after joining the Laboratory, and I set them out in a memorandum to Dr W. H. Mosley on Dec. 30, 1977. It was no secret to the laboratory leadership that I had serious doubts when I came whether this sort of commitment could be developed. There are several personal questions raised by my letter which I regret very much. The first is the implication which some have read into it that I was questioning the capacity of the Bangladeshi scientists at the laboratory. I do not in any way question the competence of these men, but I am concerned that an expanding laboratory controlled by the developed countries would probably not be able to maintain the present level of contribution from developing-country scientists over time. This would not occur because of any conscious take-over, but simply because of the pressure of highly trained individuals backed by powerful institutions. Equally important, I have no question about the ethical standards of the individuals who conducted the experiments I have cited. As I said in the earlier letter, there was an ethical review board, staffed by prominent scientists, including three from Pakistan. They considered the questions of non-therapeutic research and of informed consent and decided that: "... human experimentation in diseases such as cholera where the disease processes are still not completely known and in which a proven animal model is not available justified appropriate experiments
delineated to discern the disease mechanisms to improve therapy and to enhance knowledge of means of preventing the disease. It was pointed out to the Committee that an overwhelming majority of the patients were illiterate and if they were below the age of consent their parents were illiterate. This made it impossible to obtain informed consent for proposed studies in well over 99% of the patients. The Pakistani members of the Committee agreed that all patients or parents of patients would readily put a mark on a piece of paper acquiescing to experiments but they would have no appreciation of what might or might not be done. In consequence the Committee went on record to the effect that responsibility for experiments rested directly on the Director of the laboratory and his Deputy Diector ... The Director pointed out that it was the general policy of the laboratory to use only procedures which had been well documented by use in University hospitals throughout the world." (Memorandum from R. A. Phillips on meeting of Clinical Investigation Committee, Pakistan-SEATO Cholera Research Laboratory, Nov. 26, 1966.)
Following these statements, the board approved the experiinvolving radioactive materials, jejunal biopsy, and intestinal intubation. The risk of all these procedures is small, but there is some risk, and since the procedures could not benefit the individual patient, I do not believe this sort of consent procedure conforms to the Helsinki Declarations of 1964 or ments
1975 or that it would have been allowed in the U.S. at that time forexperiments of this nature. Right-heart catheterisation in a sick patient who, again, does not stand to benefit is hard to defend in any circumstances. Ventricular arrhythmias or perforations of the right ventricle with cardiac tamponade can occur and can be fatal. Nevertheless, there can be no doubt that the scientists who did the catheterisations felt the risk was small and the scientific value of the results obtained justified this risk. I have discussed the use of glucagon with epinephrine (adrenaline) for hypoglycaemia in some detail with one of the investigators. He has convinced me that they really felt these drugs would be better treatment than intravenous glucose for hypoglycoemic coma in this situation and changed their minds only after it was shown that they produced less good results than anticipated. Given this belief, I have to concede that they were testing a positive hypothesis-trying to find the best treatment for a difficult clinical situation. It was not correct to use the terms "installation of tubewells" and "experiment" with reference to the study of the incidence of cholera in areas adjacent to the hospital in Matlab. The facts are these. A high incidence of cholera in areas adjacent to the hospital was observed in 1974 (it had been suspected since 1966, and the sanitary system had been known to be defective for about a year). In January, 1975, a study of water use in the high cholera areas was conducted and correlated retrospectively with cholera incidence over the preceding ten years. As a part of this study, it was confirmed that the untreated effluent from the hospital sanitation system was producing contamination of the canals in the area around the hospital. In February, 1975, a requisition was submitted to correct the sanitation problem. In 1976 the problem at the hospital was corrected. The latrine facilities and water supply for patients’ families and others living around the hospital are still not adequate. In all of these instances there is room for argument over whether the same procedures would have been followed given the same situation in the U.S.A. at the same time. I personally believe that they would not. The more important point, however, is that scientists working in developing countries have a particular challenge to attempt to deal with the tremendous cultural gap between themselves and the subjects of their research, and that this challenge holds them to higher ethical standards than would be expected in other situations. This is a personal opinion, but I think it would probably be shared by most of those who carried out the experiments I have cited. I am sure that earnest efforts were made to explain these procedures to patients and relatives and obtain their informed consent, as some have indicated in their letters to me and to The Lancet. It seems to me that the experimenters simply did not
1208 realise that the task was impossible-as the Pakistani members of the ethical review committee did. As for my own responsibility to develop the service programmes I have criticised, I can only say that the understanding when I accepted an appointment six months ago (and the reason that I came) was that I was to develop supportive links with Bangladesh health service organisations outside the existing C.R.L. structure I have not felt that I had the responsibility or the authroity to make changes within the laboratory, although I certainly have been involved in many discussions on this subject. The views expressed on the necessity for physiological studies and the possibility that the "Dacca solution" of glucose, sodium, potassium, and bicarbonate might have obstructed progress, are not those of a physiologist, but of a clinician. Nevertheless, I think they are valid. Salt and sugar are available in almost every village home. Glucose and bicarbonate are not. Since most diarrhoea deaths result from more gradual fluid loss than that seen in classic cholera, it does seem to be likely that it will be more appropriate to recommend salt and gur (unrefined sugar, which contains potassium) for home treatment of most diarrhoea. This is a very important question which needs to be tested more rigorously than it has been up to now. The responsibility for the delay rests as much with those of us who are involved with service programmes as with laboratory scientists at C.R.L. who have now begun some of the needed studies. There is an absolute necessity to test the application of basic scientific findings to clinical situations. There are usually simple and direct ways to do this through carefully observed clinical trials of therapy. Dacca, Bangladesh
COLIN MCCORD
and community service, should not be denounced for the faults of a few individuals. But one must question how, with so many public health and enteric disease experts at the C.R.L., the situations described above could have gone on for so long. Certainly, the C.R.L. leadership, preoccupied with building a research empire, displayed remarkable insensitivity to local health needs in overlooking the most obvious public-health requirements related to their projects. This aspect of McCord’s criticism rings true. Chemical Industry Institute of P. O. Box 12137, Research Triangle Park, North Carolina 27709, U.S.A.
Toxicology, RICHARD
J. LEVINE
SIR,-The Lancet should be commended for its article, Bangladesh: an International Research Centre (Jan. 28, p. on many of the issues involved in changof the Cholera Research Laboratory (C.R.L.) in In the replies to Dr McCord’s letter on the same subject the response to the ethical issues has been intense, but the other issues, which we consider major ones-control by U.S. scientists, the practical relevance to us in Bangladesh of much of the C.R.L.’s research programme, and the effect of this institution on indigenous institutions-are virtually
202), which focused
ing the role Bangladesh.
ignored. Dr Mosley
and the C.R.L. scientific directors describe your Round the World Article as "simply fallacious" (March 18, p. 602). However, in the matter of training, for example, it is evident that, despite the intention to "internationalise", C.R.L. would still serve the interests of the same foreigners. As Mosley proposed in 1976:’ "Establishment of a training program for young investigators from the developed countries such as the United States will require developof direct institutional ties with U.S. or other universities and ties should be encouraged in order that young scientists from the developed countries can gain the skills and the expertise necessary to address health, population and nutrition ment
training institutes. These
SIR,-While Dr McCord (April 8) has overstated his case Mosley’s reply (May 6, p. 991) demands further comment. Mosley maintains that the observation that cholera was occurDr
ring in villages adjacent to the Cholera Hospital in Matlab was made during 1974/75 and that the "first reaction" to this observation was a complete renovation of the sanitary facilities at Matlab. This was not so. Mosley himself, in reference to our paper documenting the fact of cholera transmission along a canal contaminated by the hospital,’ wrote to me on May 13, 1976: "... this is hardly a new observation since those of us who have worked at the Cholera Lab have always been aware of the high frequency of cholera from the villages along the canal near the hospital." Why then were the sanitary facilities not renovated until 1976? When the data were formally presented to the Cholera Research Laboratory the first reaction was not to renovate sanitary facilities but to attempt to prevent publication of the data. Nor was the problem of environmental vibrio contamination limited to the hospital at Matlab. A C.R.L. study of sewerage at the Dacca Cholera Hospital was undertaken in 1973 at the request of Dr K. A. Monsur, then director of health services at the Bangladesh Institute of Public Health. This study noted that fluid containing cholera vibrios was being disgorged directly into a rice paddy from the outflow pipe of a broken hospital septic tank. The report’ goes on to state: "Many people are found cultivating in the area. Besides, this area provides a good ground for catching fish, grazing of cattle and playground for children." Throughout the paddy area and up to an adjoining canal cholera vibrios were cultured from samples of paddy water (M. S. Islam and R. J. Levine, unpublished). Every institution has had some dust swept beneath the carpet, and the C.R.L., truly an international diarrhceal disease resource with an outstanding record of scientific achievement 1. Levine, R. J., and others Lancet, 1976, ii, 84. 2. Islam, M. S Report on Sewerage and Drain Samples: System of disposal at C.R.L. and Institute of Public Health. C.R.L., Dacca, December, 1973.
problems in the developing world." The apparent virtue in Mosley and the scientific directors’ that 97% of the C.R.L. employees are Bangladeshi, pales when viewed in the light of their work and positions. Salaries of 17 foreigners (3% of staff) are over 9 million taka, including house rents, transportation, travel, and other expenses ; while the remaining 581 employees receive less than 6 million taka for salaries, housing, and so on. Mosley and his colleagues claim that "At the level of independent research staff, there are 16 Bangladeshis and 15 expatriates ..." (March 18, p. 602). However, buried in another document’ of October, 1977, they admit: "The C.R.L. at present has 33 persons on its scientific staff. Only 15, however, would be classified as Principal scientists or administrators based on their positions of scientific leadership in C.R.L. and recognised status in the national or international community. Five of the principal scientists are Bangladeshi..." Moreover, the C.R.L. annual report of 1977 lists only 4 Bangladeshi investigators statement
of 13. Matlab has been used as a reservoir of human research material. Dr Levine has commented on the frequency of cholera in villages near the hospital. It has also been found4 that 14 (29%) of 48 non-cholera patients admitted to the Matlab hospital in December, 1974, and January, 1975, developed cholera. Investigators concluded that infection did not result from exposure in the hospital, but from bathing in the canal near the hospital. Yet, instead of giving the benefit of sanitary intervention experiments to the people with a high incidence out
H. Proposed Five-Year Plan for the Cholera Research Laboratory; p. 61 Dacca, Bangladesh. April, 1976. 2. C.R.L., Dacca. Draft prospectus: an International Centre for Health Research, p. 36. October, 1977. 3. C.R.L., Dacca. Cholera Research Laboratory Annual Report 1977, p. 68 November, 1977 4. Ryder, R. W. Paper presented at Center for Disease Control meetings in 1.
Mosley, W
Atlanta, 1977; p.45.
1209 of cholera in Matlab, C.R.L. moved these experiments to Teknaf, 150 miles away at the end point of Bangladesh, across a river from the armed political struggle going on in Burma. We accept, in general, Mosley’s claim that "C.R.L. physicians have always conscientiously obtained informed consent from subjects of research by conversations with the patient of guardian" (May 6, p. 991). However, we would point out that Bangladeshi physicians in C.R.L. were paid for every patient protocol they filled out.
surprised that Dr Nalin (May 6, p. 992) did not comthe ethical issues, since, on many occasions, he has raised these with us, one example being his doubts expressed to one of us (Z.C.) about informed consent in the study of nosocomial cholera in a Bangladesh Hospital referred to above.4 Nalin and others may feel that the physiological studies at C.R.L. were essential to the development of oral fluid therapy, but the study in Calcutta5 demonstrated, by a clinical trial (a balance study) in 14 patients, that glucose-linked sodium absorption was intact. In this paper there is no reference to any of the work at C.R.L. on glucose and sodium absorption during cholera. We
are
ment on
The C.R.L. trial of a new cholera vaccine which has 1% urticarial reactions was approved by the Scientific Review Committee of the Bangladesh Medical Research Council although they had no opportunity to see documentation of trials conducted in India and Indonesia. The weekly journal Bichitra pointed out that four out of five members of the Scientific Review Committee were associated directly or indirectly with C.R.L.6 As far as we know, no independent Bangladeshi scientist was consulted in setting up the scientific review committee for internationalisation of C.R.L. until a few weeks before the meeting. Mosley has stressed the quality of the independent, outside ethics review committee (May 6, p. 991), but there was only one Bengali member of this committee. We would like to make some suggestions that we feel would make internationalisation of the laboratory more meaningful:
(1) The institute should do research in diarrhoeal diseases only. (2) In the interests of development of indigenous research, research in other fields such as population, fertility, nutrition, clinical medicine, and social medicine, should be done under the direct control of the five national institutes. As the Bengali proverb says: "Under the Banyan tree, nothing grows". (3) Research should include development of implementation programmes for the solutions of the problems under study. (4) Two-thirds of the senior scientific investigators on the staff (including the director and the scientific directors) should come from de-
veloping countries. (5) At least two-thirds of the board of directors should come from developing countries. To make it effectively (not cosmetically) international, individuals from Western European countries, socialist countries, China, and so on should be included from the early stages of transition. (6) The responsibility of the ethical committee to protect individuals who are in any way subjected to research procedures, should be spelled out in the charter in some detail. (7) All protocols for experimentation should be made public, since human experimentation will be involved, to enable independent Bangladeshi and other scientists to have the opportunity to comment. (8) No more than 25% of the centre’s funds should come from donors of one nationality. (9) Salary levels and benefits must be set so that individuals who come to Bangladesh from other countries are not m a position to derive a large surplus of income over expenses because of their stay in Bangladesh. The attraction inducing individual scientists to come to the centre ought not to be financial but professional opportunities and interest in the health problems of developing countries. (10) All employees of the centre should pay Bangladesh income tax. A fund could be established so that if this tax were greater than that 5
Pierce, N F., Banwell, J., Mitra, R., Caranabos, G., Keimowitz, A., Manji, P. Gastroenterology, 1968, 55, 333. 6. Bichitra Dacca, Feb. 10, 1978.
R Mondal,
which should have been would be refunded.
paid
in the country ot
origin,
of Postgraduate Medical Sciences and Research, University of Dacca
Faculty
Institute of Research and Rehabilitation for Diabetes, Endocrine and Metabolic Disorders Dacca
the difference
NURAL ISLAM, Dean
Bangladesh
Community
Health Research
Association,
HAJERA MEHTAB, Medical Director
M. A.
MUTTALIB, President
Dacca
Gonoshasthaya Kendra, P.O. Nayarhat, Dacca, Bangladesh
ZAFRULLAH
CHOWDHURY,
Projects Coordinator
HEREDITARY POLYCYSTIC OSTEODYSPLASIA WITH PROGRESSIVE DEMENTIA IN SWEDEN
SIR,-In the past decade a new hereditary disease characterised by progressive dementia and polycystic bone lesions has been described in Finland’-3 and japan.4,5 The disease manifests itself insidiously at age 20-30 years. The first symptoms usually arise from the skeleton with pain, tenderness, and swelling in the ankles and wrists after minor injury, though fractures have been described as the initial symptom. A characteristic finding at this stage of the disease is symmetrically located cystic bone lesions, especially in the hands and feet. Biopsy of these cysts is virtually pathognomic.1 Serious neuropsychiatric symptoms appear during the fourth decade of life, with decline in mental function, involvement of the upper motor neurons, dyspraxia, epileptic seizures, and myoclomc twitches. The patient dies young (35t5 years), and the climcal picture terminally resembles that of Alzheimer’s disease. Neuroradiological examinations have shown cortical and central atrophy, sometimes before the onset of the neuropsychiatric symptoms.7 Some twenty cases have been found in Finland and Japan, but the disease has never been described in other countries. In the past 6 months we have found two families in northern Sweden, in which seven out of eighteen children have shown a highly uniform clinical picture, with progressive dementia associated with polycystic bone lesions. The first case, a 39-year-old truck driver, presented as a "typical" Alzheimer’s presenile dementia’. However,,previously hyperparathyroidism had been suspected because of a diffuse decalcification of the hand and foot skeleton. On repeat X-rays we observed multiple cysts in the hands and feet and in the metaphysis of the femur. He became severely handicapped due to rigidity and is now totally bedridden. We have not yet found any metabolic abnormality, as in the Finnish cases. The aetiology of this disease is unknown. The disease is inherited via an autosomal recessive gene.2,3 Japanese scientists claim that it is a disturbance of the lipid metabolism,’ and neuropathological examination has shown atrophy of the white-matter and diffuse astrogliosis.8 It seems unlikely that this disease is restricted to Finland, Japan, and Sweden, and we agree with our Finnish colleagues that every new case of unexplained dementia with onset before Järvi, O. H., Hakola, H. P. A., Lauttamus, L. L., Solonen, A. H. Int. Congr. int. Acad. Path. 1968, abstr. p.291. 2. Hakola, H. P. A., Järvi, D. H., Sourander, P. Acta neurol. 1.
K.
A., Vilppula,
scand
1970, 46,
78. 3. 4. 5. 6.
Hakola, H. P.
p 1
A. Acta psychiat. scand. 1972, suppl 232, Nasu, T. , Tsukahara, Y., Teraqama, K Acta path. jap 1973, 23, 539. Harada, K. Folia psychiat. neurol jap 1975, 29, 169. Hakola, H P A., Järvi, O. H., Lauttamus, L. L., Solonen, K. A., Sourander, B. J.P., Vuppula, A. H. Duodecim, 1974, 90, 106 7. Hakola, H. P. A , livanainen, M Neuroradiology, 1973, 6, 162. 8. Sourander, P. Acta path. microbiol scand 1970, suppl. 215. p. 44.