29 db gene show intermediate susceptibility and closely related mice lacking the db gene are relatively resistant. They concluded that genetic predisposition to diabetes in this strain of mice also conveys a greater susceptibility to Coxsackievirus infection. Whether the effect of the db gene is specific, or applies also to other infections, is not yet known. The M variant of encephalomyocarditis virus (E.M.C.), a picornavirus unrelated to Coxsackievirus, infects and destroys pancreatic beta cells in mice, producing a syndrome like juvenile diabetes mellitus.55 Plasmainsulin decreases, plasma-glucose rises, and glucose tolerance declines. Only certain strains of mice show beta-cell destruction and diabetes when infected with the virus, and by examining the progeny of four Fl crosses of susceptible and resistant strains of mice, Ross and his colleagues concluded that the tendency to acquire diabetes after infection is inherited as a recessive trait. Observations in the F2 generation suggested that more than one gene is involved, and environmental factors influenced the extent and frequency of abnormal glucose levels in E.M.c.-infected mice. Another finding was that cultures of pancreatic-islet beta cells from susceptible mice supported replication of the M strain of E.M.C. virus better than did beta cells from resistant strains of mice. The cultures of beta cells from susceptible mice had higher virus titres, more degranulation, and lower concentrations of immunoreactive insulin than beta cells from resistant mice." Immunofluorescence and infectious centre assays showed that the pancreas of susceptible mice contained at least ten times more infected cells than the pancreas of resistant mice. The virus replicated equally well in primary embryo and kidney cell cultures from susceptible and resistant strains of mice. The conclusion was that E.M.C.-virus-infected diabetes is related to genetically determined host differences in the capacity of virus to infect beta cells. Are these findings applicable to man? E.M.C. virus is not a common human pathogen and the M variant which produces diabetes has undergone selection through serial passage in mice. The Coxsackievirus used in the work of Webb et al. 54 had less specific tissue tropism than the M variant of E.M.C. virus but is a common human pathogen and had undergone less selection in the laboratory. Conceivably, Coxsackie-B virus or other virus infections of a few predisposed human beings destroy pancreatic beta cells and produce diabetes mellitus. Investigations of the HLA system in families of patients with juvenile diabetes mellitus58 have shown a statistically significant association between HLA-D identity and the likelihood of acquiring the disease. No association was found with SD antigens. The association between LD identity and juvenile diabetes mellitus is not absolute: seven siblings who had the same antigens as a diabetic patient were free of diabetes. However, in only one family was a second diabetic sib LD-different from the first. This suggests that LD-linked genes are important but not the only determinants of the tendency to acquire juvenile diabetes mellitus. A remarkable finding 55 56
Craighead, J. E., Steinke, J. Am. J. M. 190.
Ross,
Path.
1971, 63,
119.
E., Onodera, T., Brown, K. S., Notkins, A. L. Diabetes, 1976, 25,
Notkins, A. L. J. exp. Med. 1976, 143, 1170 P., Suciu-Foca, N., Nicholson, J. F., Fotino, M., Molinaro, A., Harisiadis, L., Harty, M. A., Reemtsma, K., Allen, F. H. Jr. ibid.
57. Yoon, J-W, 58 Rubinstein, p 1277
increase in the frequency of intra-HLA recombination in these families. The rate of recombination is increased in both fathers and mothers and does not depend on the presence of overt diabetes. In Neurospora and mice the frequency of recombination is known to be under genetic control, and the same may be true of man. The presence of frequent recombinations may be related to the pathogenesis of juvenile diabetes mellitus. Among the many mechanisms that could link the phenomena are loss through recombination of genes required for normal beta-cell function, increased susceptibility to virus infection of certain recombinants, and the possibility that a virus or provirus is itself involved in the increased recombination frequency or altered expression of major histocompatibility antigens.59
was a
highly significant
A WELLCOME BOOST
RESEARCHERS in mental health are accustomed to for scarce resources, but this year the Wellcome Trust added a new dimension to scientific rivalry by widely advertising a £100 000 competitive award for research into mental disorders.60 The Trust is to be congratulated on its unorthodox initiative. The competition and resultant award should provide a stimulus to research, at a time. when psychiatric research in Britain has fallen from the position it occupied a decade ago. By the mid-sixties British psychiatry had pioneered the application of the clinical trial to psychiatry, demonstrated the folly of treating schizophrenics with insulin coma, and clarified the relative roles of electroconvulsive therapy, tricyclics, and monoamine-oxidase inhibitors in depression. It had stood aloof from the American preoccupation with psychoanalysis,61 and maintained rigorous research standards exemplified in the work which emanated from Aubrey Lewis’s department. 62 Unfortunately, the elusive impetus faded, and British psychiatrists have contributed disappointingly little to advances in adult psychiatry over the past five years. Nowhere has this failure been more obvious than in relation to progress
competing
in the biological understanding of schizophrenia. 63-66 As so often happens, it has taken an outsider to recognise the malaise. In his pamphlet, The Future of Psychiatry,67 Prof. Hans Eysenck states provocatively that "professional capacity in psychiatry is below that in other specialties within medicine; the ability level of students going into this sphere is lower; and the quality of research is not comparable". There is certainly widespread concern about a fall in the numbers and quality of recruits into psychiatry.68 69 Furthermore, recruits are less in59. Garrido, F., Schirrmacher, V., Festenstein, H. Nature, 1976, 259, 228. 60. Lancet, Jan. 17, 1976, classified advertisements, p. 6. 61. Shepherd, M. Compr. Psychiat. 1971, 12, 302. 62. Shepherd, M., Davies, D. L. (editors). Studies in Psychiatry. London, 1968. 63. Mednick, S. A., Schulsinger, F., Higgins, J., Bell, B. (editors). Genetics, Environment and Psychopathology, Amsterdam, 1974. 64. Mitsuda, H., Fukada, T. (editors). Biological Mechanisms of Schizophrenia and Schizophrenia-Like Psychoses. Stuttgart, 1975. 65. Matthysse, S. W., Kety, S. (editors). Catecholeamines and Schizophrenia. Oxford, 1976. 66. Gancro, R. (editor). Annual Review of the Schizophrenic Syndrome, 1974-75. New York, 1976. 67. Eysenck, H. J. The Future of Psychiatry. London, 1975. 68. Russell, G. F. M. Br. J. Psychiat, 1972, 120, 333. 69. Symposium on Tomorrow’s Psychiatrists. Association of Psychiatrists in Training, 1975.
30 terested in research, and not only on the periphery; at the postgraduate Institute of Psychiatry in London, the number of psychiatrists obtaining M.D. or M.PHIL. degrees fell from 20 in 1971/72 to 6 in 1974/75.70 This widespread decline is all the more remarkable since it followed a decade which saw the establishment not only of many university departments of psychiatry but also of the Royal College of Psychiatrists. But perhaps this is where we should look for the origins of the decline. There are a limited number of people of outstanding merit in psychiatry, and many of these are now preoccupied by university and college politics to the exclusion of research. There are further hazards looming ahead. As in other specialties, most junior research-workers are not eligible for overtime payments, and are therefore at a financial disadvantage to their contemporaries in clinical psychiatry. They may soon find themselves at a similar disadvantage in terms of specialist registration unless the Joint Committee on Higher Psychiatric Training amends its first report. 71This asserts that four years of higher training (i.e., postM.R.c.PSYCH.) are necessary for specialist registration, and that only one year of fulltime research can be counted towards this. Such a regulation would seriously deter young psychiatrists from taking up research. Fortunately, both trainees and directors of research units have protested and the committee may yet change its mind. However, with all these black clouds on the horizon, those interested in psychiatric research should be grateful to the Wellcome Trust for its offer of a silver lining.
affected subjects no pathogens were found, but in some of these cases the negative findings could be attributed to the use of antibiotics. The identification of several pathogens does not necessarily point to a causal relationship, especially where more than one organism is isolated from a single specimen; nevertheless, the results suggest that a variety of organisms must have contributed to the infection, even though the individual culprits (apart from enterotoxigenic E. coli) could not be positively identified. Drinking tap-water and iced beverages is usually thought to be the surest way of acquiring travellers’ diarrhoea in places where sanitary and general living conditions are less than ideal, but in this study visitors who drank only bottled water fared no better than their less cautious colleagues. In fact, they all did rather badly, and the dietary indiscretion which had the most unfortunate consequences (and in which, presumably, both groups of drinkers indulged) was the consumption of salads containing raw vegetables: this was strongly associated with infection by enterotoxigenic E. coli. It would still seem wiser, therefore, to stick to freshly cooked food. Medications such as opiates and diphenoxylate hydrochloride with atropine, which were taken by some of the participants, may actually prolong some forms of infective diarrhoea 72 and are best avoided except in severe cases.
RETIREMENT OF DR DOUGLAS-WILSON DR IAN DoUGLAS-WILSON, Editor of The Lancet since 1965, retired on June 30. His successor is Dr Ian Munro; and the Deputy Editors are Dr Robin Fox and Mr David Bharn
MONTEZUMA’S REVENGE
quarter and a half of visitors to Mexico are struck down by "Montezuma’s revenge", the Mexican equivalent of travellers’ diarrhoea ; and a medical conference in Mexico City provided an excellent opportunity for a prospective study of the clinical, epidemiological, and laboratory aspects of the infection.72 True to form, almost half of those 121 physicians and accompanying relatives (mostly from the U.S.A.) who agreed to take part in the survey developed diarrhoea, abdominal cramps, nausea, and associated symptoms between 12 hours after arrival in Mexico and 5 days after departure. In all cases stool swabs taken up to 3 days before arrival had been negative for pathogens. Montezuma must have had a good laugh at this, for the doctors attending the conference were all gastroenterologists, BETWEEN
a
who might reasonably have been expected to be able to avoid such minor but inconvenient afflictions of the
gastrointestinal tract. Diarrhoea
was
associated in 45% of cases with
entero-
toxigenic Escherichia coli, and other potential pathogens included salmonellae, Shigella sonnei and S. flexneri, Vibrio parahcemolyticus, Entamcuba histolytica, Giardia lamblia, and the human reovirus-like agent.
In
37% of
70. Institute of Psychiatry, Report for 1974-75. University of London, 1976. 71. Joint Committee on Higher Psychiatric Training: First Report, 1975. (Obtainable from the Royal College of Psychiatrists). 72. Merson, M. H., Morns, G. K., Sack, D. A., and others New Engl. J. Med.
1976, 294, 1299.
Among the presentations
to Ian and Betty Douglas-Wilson the original of this new drawing by Geoffrey Fletcher of the Lancet office at 7 Adam Street. was
Craighead, J. E., Steinke, J. Am. J. M. 190.
Ross,
Path.
1971, 63,
119.
E., Onodera, T., Brown, K. S., Notkins, A. L. Diabetes, 1976, 25,
Notkins, A. L. J. exp. Med. 1976, 143, 1170 P., Suciu-Foca, N., Nicholson, J. F., Fotino, M., Molinaro, A., Harisiadis, L., Harty, M. A., Reemtsma, K., Allen, F. H. Jr. ibid.
57. Yoon, J-W, 58 Rubinstein, p 1277
increase in the frequency of intra-HLA recombination in these families. The rate of recombination is increased in both fathers and mothers and does not depend on the presence of overt diabetes. In Neurospora and mice the frequency of recombination is known to be under genetic control, and the same may be true of man. The presence of frequent recombinations may be related to the pathogenesis of juvenile diabetes mellitus. Among the many mechanisms that could link the phenomena are loss through recombination of genes required for normal beta-cell function, increased susceptibility to virus infection of certain recombinants, and the possibility that a virus or provirus is itself involved in the increased recombination frequency or altered expression of major histocompatibility antigens.59
was a
highly significant
A WELLCOME BOOST
RESEARCHERS in mental health are accustomed to for scarce resources, but this year the Wellcome Trust added a new dimension to scientific rivalry by widely advertising a £100 000 competitive award for research into mental disorders.60 The Trust is to be congratulated on its unorthodox initiative. The competition and resultant award should provide a stimulus to research, at a time. when psychiatric research in Britain has fallen from the position it occupied a decade ago. By the mid-sixties British psychiatry had pioneered the application of the clinical trial to psychiatry, demonstrated the folly of treating schizophrenics with insulin coma, and clarified the relative roles of electroconvulsive therapy, tricyclics, and monoamine-oxidase inhibitors in depression. It had stood aloof from the American preoccupation with psychoanalysis,61 and maintained rigorous research standards exemplified in the work which emanated from Aubrey Lewis’s department. 62 Unfortunately, the elusive impetus faded, and British psychiatrists have contributed disappointingly little to advances in adult psychiatry over the past five years. Nowhere has this failure been more obvious than in relation to progress
competing
in the biological understanding of schizophrenia. 63-66 As so often happens, it has taken an outsider to recognise the malaise. In his pamphlet, The Future of Psychiatry,67 Prof. Hans Eysenck states provocatively that "professional capacity in psychiatry is below that in other specialties within medicine; the ability level of students going into this sphere is lower; and the quality of research is not comparable". There is certainly widespread concern about a fall in the numbers and quality of recruits into psychiatry.68 69 Furthermore, recruits are less in59. Garrido, F., Schirrmacher, V., Festenstein, H. Nature, 1976, 259, 228. 60. Lancet, Jan. 17, 1976, classified advertisements, p. 6. 61. Shepherd, M. Compr. Psychiat. 1971, 12, 302. 62. Shepherd, M., Davies, D. L. (editors). Studies in Psychiatry. London, 1968. 63. Mednick, S. A., Schulsinger, F., Higgins, J., Bell, B. (editors). Genetics, Environment and Psychopathology, Amsterdam, 1974. 64. Mitsuda, H., Fukada, T. (editors). Biological Mechanisms of Schizophrenia and Schizophrenia-Like Psychoses. Stuttgart, 1975. 65. Matthysse, S. W., Kety, S. (editors). Catecholeamines and Schizophrenia. Oxford, 1976. 66. Gancro, R. (editor). Annual Review of the Schizophrenic Syndrome, 1974-75. New York, 1976. 67. Eysenck, H. J. The Future of Psychiatry. London, 1975. 68. Russell, G. F. M. Br. J. Psychiat, 1972, 120, 333. 69. Symposium on Tomorrow’s Psychiatrists. Association of Psychiatrists in Training, 1975.
30 terested in research, and not only on the periphery; at the postgraduate Institute of Psychiatry in London, the number of psychiatrists obtaining M.D. or M.PHIL. degrees fell from 20 in 1971/72 to 6 in 1974/75.70 This widespread decline is all the more remarkable since it followed a decade which saw the establishment not only of many university departments of psychiatry but also of the Royal College of Psychiatrists. But perhaps this is where we should look for the origins of the decline. There are a limited number of people of outstanding merit in psychiatry, and many of these are now preoccupied by university and college politics to the exclusion of research. There are further hazards looming ahead. As in other specialties, most junior research-workers are not eligible for overtime payments, and are therefore at a financial disadvantage to their contemporaries in clinical psychiatry. They may soon find themselves at a similar disadvantage in terms of specialist registration unless the Joint Committee on Higher Psychiatric Training amends its first report. 71This asserts that four years of higher training (i.e., postM.R.c.PSYCH.) are necessary for specialist registration, and that only one year of fulltime research can be counted towards this. Such a regulation would seriously deter young psychiatrists from taking up research. Fortunately, both trainees and directors of research units have protested and the committee may yet change its mind. However, with all these black clouds on the horizon, those interested in psychiatric research should be grateful to the Wellcome Trust for its offer of a silver lining.
affected subjects no pathogens were found, but in some of these cases the negative findings could be attributed to the use of antibiotics. The identification of several pathogens does not necessarily point to a causal relationship, especially where more than one organism is isolated from a single specimen; nevertheless, the results suggest that a variety of organisms must have contributed to the infection, even though the individual culprits (apart from enterotoxigenic E. coli) could not be positively identified. Drinking tap-water and iced beverages is usually thought to be the surest way of acquiring travellers’ diarrhoea in places where sanitary and general living conditions are less than ideal, but in this study visitors who drank only bottled water fared no better than their less cautious colleagues. In fact, they all did rather badly, and the dietary indiscretion which had the most unfortunate consequences (and in which, presumably, both groups of drinkers indulged) was the consumption of salads containing raw vegetables: this was strongly associated with infection by enterotoxigenic E. coli. It would still seem wiser, therefore, to stick to freshly cooked food. Medications such as opiates and diphenoxylate hydrochloride with atropine, which were taken by some of the participants, may actually prolong some forms of infective diarrhoea 72 and are best avoided except in severe cases.
RETIREMENT OF DR DOUGLAS-WILSON DR IAN DoUGLAS-WILSON, Editor of The Lancet since 1965, retired on June 30. His successor is Dr Ian Munro; and the Deputy Editors are Dr Robin Fox and Mr David Bharn
MONTEZUMA’S REVENGE
quarter and a half of visitors to Mexico are struck down by "Montezuma’s revenge", the Mexican equivalent of travellers’ diarrhoea ; and a medical conference in Mexico City provided an excellent opportunity for a prospective study of the clinical, epidemiological, and laboratory aspects of the infection.72 True to form, almost half of those 121 physicians and accompanying relatives (mostly from the U.S.A.) who agreed to take part in the survey developed diarrhoea, abdominal cramps, nausea, and associated symptoms between 12 hours after arrival in Mexico and 5 days after departure. In all cases stool swabs taken up to 3 days before arrival had been negative for pathogens. Montezuma must have had a good laugh at this, for the doctors attending the conference were all gastroenterologists, BETWEEN
a
who might reasonably have been expected to be able to avoid such minor but inconvenient afflictions of the
gastrointestinal tract. Diarrhoea
was
associated in 45% of cases with
entero-
toxigenic Escherichia coli, and other potential pathogens included salmonellae, Shigella sonnei and S. flexneri, Vibrio parahcemolyticus, Entamcuba histolytica, Giardia lamblia, and the human reovirus-like agent.
In
37% of
70. Institute of Psychiatry, Report for 1974-75. University of London, 1976. 71. Joint Committee on Higher Psychiatric Training: First Report, 1975. (Obtainable from the Royal College of Psychiatrists). 72. Merson, M. H., Morns, G. K., Sack, D. A., and others New Engl. J. Med.
1976, 294, 1299.
Among the presentations
to Ian and Betty Douglas-Wilson the original of this new drawing by Geoffrey Fletcher of the Lancet office at 7 Adam Street. was
