- Email: [email protected]
RENAL ALLOGRAFT REJECTION
145 INSULIN RESPONSE IN CHRONIC ALCOHOLISM SIR,-We read with interest the report of Dr. Megyesi and her co-authors.1 In our studies of carbohydrate metabolism in chronic alcoholism we also observed striking hyperinsulinsmia in combination with diabetic glucose-tolerance tests. Typical results obtained in a patient with chronic alcoholism and hepatic disease are shown in fig. 1 (case 1). However, we have also seen striking insulin sensitivity in some chronic alcoholics with hepatic damage and a tendency to spontaneous hypoglycxmia. Fig. 1 (case 2) shows typical results obtained in a patient of this type. Thus some alcoholics display very high insulin values in serum after intravenous glucose loads, whereas others show very slight insulin responses in such tests. Moreover (fig. 1) the patient with poor insulin response metabolised the infused glucose faster than the patient with hyperinsulinaemia. 2 shows intravenous tolbutamide tests in 2 typical Here also, one type of patient (case 1) shows high insulin response after tolbutamide with only slight effect on the blood-sugar level. The other type of patient (case 3) shows, on the other hand, an insignificant rise in serum insulin after tolbutamide but has long-lasting hypoglyceemia.
Fig.
cases.
Summarising, we have observed two principal types of disturbance in carbohydrate metabolism in chronic alcoholics with hepatic disease. One type has a diabetic type of glucose metabolism combined with hyperinsulinasmia and the other has spontaneous hypoglycxmia and extreme insulin sensitivity. These observations are interesting in view of the findings of one of us2 that diabetes as well as hypoglycxmia occurs in
Fig. 1ŃSerum-insulin and Moodglucose levels after glucost infusion by technique oj Cerasi and Luft3 in twc chronic alcoholics with hepatic disease.
Serum-insulin
measured and radioimmunoassay 4 was
by blood-glucose by
a
glucose-
oxidase method. The peroral glucose-tolerance test was of diabetic type (bloodglucose 168 mg. per 100 ml. after 2 hours) in case 1 (continuous lines) and normal in case
2
(interrupted lines).
2-Serum-insulin Fig. blood-glucose levels
and after intravenous administration of tolbutamide (1 g.) in two chronic alcoholics with hepatic disease.
Case 1
(as in fig. 1, continuous
lines). Case 3 (interrupted lines). This patient had a normal peroral
glucose-tolerance
test.
chronic alcoholics. The findings reported here are compatible with idea that increased, as well as decreased, insulin resistance may occur in chronic alcoholics. Medical Department 4, Department of Clinical Chemistry, Sodersjukhuset, Stockholm 38,
Sweden. 1. 2. 3. 4.
R. HED A. NYGREN L. SUNDBLAD.
Megyesi, C., Samols, E., Marks, V. Lancet, 1967, ii, 1051 Hed, R. Acta med. scand. 1958, 162, 3. Cerasi, E., Luft, R. Lancet, 1964, ii, 769. Soeldner, I. S., Sloane, D. Diabetes, 1965, 14, 771.
BACTERIAL ENDOCARDITIS
SIR,-To underline the relative importance of bone-marrow and blood culture in the " investigation of endocarditis and sepsis in general ", Dr. Garcia (Jan. 6, p. 52) compares 17-4% positives out of 223 blood-cultures and 41%positives out of 17 marrow cultures-himself admitting that " this comparison may be biased, because of the small number of myelocultures and because these are done only in selected severe cases ". It would have been more convincing had he cited figures of simultaneous blood and marrow cultures in which only the marrow cultures were positive. Stepping Hill Hospital, K. K. DATTA. Stockport, Cheshire.
RENAL ALLOGRAFT REJECTION SiR,ŃI have a great deal of sympathy with Dr. Clark and his colleagues (Jan. 6, p. 8) in their attempt to unify the concept of renal allotransplant reaction. The state of the renal alloautotransplant, however, is now quite as chaotic as when Simonsen1 and I2 left it over a decade ago. In our experience, a lethally X-irradiated (600-800r) dog can reject a kidney even when it is nigh impossible to demonstrate a white-blood cell in the peripheral blood. Even so, enough plasma cells get into the kidney to cause rejection. In the lymph-nodes and spleens of such animals there are still plenty plasma cells but no lymphocytes. The assumption, therefore, that an X-irradiated animal rendered leucopenic is that much different from the normal is not valid. I would not have predicted the interesting results reported by Dr. Clark and his colleagues. It would have been helpful if they had cleared up first the mystery of the rejection process of the renal allo-autotransplant. Simonsen reported, and later I agreed, that if a kidney was allotransplanted for 3 days and then returned to the donor it continued to function for several days. At some stage the rejection syndrome developed and the kidney became anuric. Microscopically, a fantastic cell infiltration had occurred. We also agreed that if a kidney was transplanted for a short time (1 hour by Simonsen, and up to 30 hours by myself) and then returned to the original donor it would function indefinitely as an autotransplant. The conclusion that I drew was that although we can often demonstrate that plasma cells are leaching on to the renal endothelial cells within 4 hours, something happens after about 30 hours which is unalterable even when the environment is rendered friendly. The kidney which is returned to the original donor after 3 days as an allotransplant is apparently rejected by the same kind of cellular process which produces acute rejection. But it could be argued that the allo-autotransplant is rejected by self antibodies or by plasma cells from the former recipient or the donor itself. And this autorejection brings us back to the old impasse of the last fifty years of whether cells or antibodies are the mediators of rejection. Rejection processes vary with the conditions of the experi-
immunosuppression, inadequate immunosuppression. temporarily inadequate immunosuppression and its long-term effects, and the second-set kidney. There seems little argument that in the context of the long-term effects of temporarily inadequate immunosuppression, involving apparently successful reversal of rejection episodes, Porter et al. have demonstrated beautifully that first-set kidneys can be slowly destroyed by antigen/antibody complexes deposited in a predictable area-the glomerulus. But the second-set kidney (from the same donor always from a different donor in a high proportion of cases5) is rejected after a few hours of function by potent, actively acquired antibodies, and the cytopathological effects are on the predictable areas-the vessels, and particularly the ment : no
1. 2. 3. 4. 5.
Simonsen, M. Biological Incompatibility in Kidney Transplantation in Dogs. Copenhagen, 1953. Dempster, W. J. Br. J. Urol. 1955, 27, 66. Porter, K. A., Dossetor, J. B., Marchioro, T. L., Peart, W. S., Rendall J. M., Starzl, T. E., Terasaki, P. I. Lab. Invest, 1967, 16, 153. Dempster, W. J. Br. J. Surg. 1953, 40, 447. Nakamoto, S., Straffon, R. A., Kolff, W. J. Transplantation, 1967, 5, 854.
146
glomeruli. In other contexts, transplantation antibodies are not necessarily non-existent when they are not totipotent and, as the late Peter Gorer used to point out repeatedly, this would cause no surprise except to a select band of transplanters. Department of Surgery, Royal Postgraduate Medical School, Ducane Road, London W.12.
W. J. DEMPSTER
MEDICAL STUDENTS AND GENERAL PRACTICE SIR,-We should like to congratulate Dr. Pearson and his colleagues, whose article appeared last week (p. 81), for drawing attention once more to the inadequacies of present methods of teaching in general practice in a large proportion of our medical schools. Their survey leaves one with the impression that most attachment schemes are ill-conceived afterthoughts in which medical students in their 5th or final year are shown something of the peculiarities of general practice in an unstructured, unsupervised way with little participation by the staff of the medical school itself. It is possible that a postal inquiry is not the best method of eliciting facts of the type they sought and in this medical school at least the teaching of general and community practice is not of the type they describe. The 1967 recommendations of the General Medical Council were to a large extent anticipated in Newcastle in 1964 when, despite the absence of a department of general practice or of social medicine, a course in family and community medicine was instituted as a component part of the revised medical curriculum.1 All lst-year clinical students take part, and the course is evolving at regular meetings of the teaching group in the light of experience on the part of the teachers and of the, feed-back of criticism and suggestion by the students. The group consists of 12 general practitioners appointed as clinical tutors in family medicine by the university, 2 doctors from public health, 6 hospital consultants from a variety of disciplines led by a faculty subcommittee which has included 3 general practitioners, and the professors of pxdiatrics, obstetrics, and industrial health, together with other senior members of the university. The general practitioners are carefully selected members of partnership and group practices, able to devote two mornings each week to teaching without too much distraction by routine practice work. They follow a planned, though flexible, teaching programme which emphasises the personal, emotional, and Students are psychological aspects of family medicine. attached in pairs to one of the practices and are expected during their 5 weeks to keep records of the clinical cases they see and in particular to become involved with and study in depth a particular family situation. They present this study at the final seminar of the course held in the teaching hospital and attended by both the community and the hospital based doctors of the group. The student therefore has 10 compulsory sessions in general practice, and in addition attends on a voluntary basis, evening surgeries, antenatal clinics, and emergency calls, as well as spending additional time " working up " his family. Alternate mornings are spent in community medicine. During this time the student is offered experience of a wide range of community services and visits with members of the " domiciliary team "-the health visitor, the district nurse, and the social worker. He studies child-health services in clinic and school, rehabilitation, mental health, public health in the environment, and community geriatrics. Regular seminars during this part of the course, conducted by one of us, enable the student to correlate these two aspects of medicine in the community. In addition to this course, which takes place during the 1st clinical year, the student may spend one of his elective periods in his 2nd or 3rd clinical year in general practice. Over the past 3 years a total of 10 students have been attached full-time for periods ranging from 3 weeks to 3 months to a variety of general practitioners in more distant parts of the region. There is careful briefing by members of the teaching 1.
Walker, J. H., Barnes, H. G. Br. med. J. 1966, ii,
1129.
group, and every effort is made to ensure that there is nothing " amateur or haphazard " about these attachments. In addition to this planned clinical experience in general and community practice, the student meets during the systematiclecture part of his medical training a variety of general practitioners whose special interests are appropriate to the particular topic being taught. During the course dealing with diseases of the respiratory tract, a general practitioner lectures upon and discusses the presentation and management of upper-respiratory-tract infection, another the social consequences of chronic bronchitis, and a third the management of asthma in the home. If our scheme does not constitute " a bold innovation," we feel that in Newcastle at least considerable progress has been made. One valuable by-product has been the establishment of collaborative community research projects: these have involved the university departments of psychological medicine, public health, industrial health and medical statistics, midwifery, and child health, the M.R.C. growth and reproduction unit, and a number of general
practitioners. These activities are creating the atmosphere of a " third faculty", through which students are seeing the challenge and the fascination of practice in the community in all its aspects. University Department of Public Health, Medical School, Newcastle upon Tyne 1
ANDREW SMITH
JOHN H. WALKER.
FOLIC ACID AND NEUROPATHY IN EPILEPSY SiR,ŃIwas interested to read the observations of Dr. Horwitz and his colleagues. Since the inferences drawn are controversial, I should like to present an alternative
interpretation. The incidence of peripheral neuropathy in what I assume be a random group of epileptics, treated for 10 years or more with anticonvulsants, must be very much higher than in patients with any other disorder of unrelated xtiology. Since the anticonvulsant therapy was the most likely common denominator, it would seem reasonable to attribute the neuropathy to the anticonvulsants. The evidence that the dementia, cerebellar degeneration, and neuropathy sometimes seen in drug-treated epileptics may be due to interference with folate metabolism deserves consideration. I, and other observers,2have noted that folic acid sometimes provokes epilepsy in folate-deficient anticonvulsanttreated epileptic patients. Lately a folate-deficient patient (serum-folate 0-75 ng. per ml., red-blood-cell folate 75 ng. per ml., cerebrospinal fluid (C.S.F) folate 5 ng. per ml.) died in uncontrolled status epilepticus after being treated orally with folic acid. These observations suggest that folic acid affects the central nervous system. Moreover there is evidence that anticonvulsants interfere with folate metabolism within the nervous system, since the C.S.F.-folate level in drug-treated epileptics is statistically significantly lower than in control patients.4The only two documented anticonvulsant-treated epileptics with signs and symptoms suggestive of cerebellar degeneration, in whom c.s.F.-folate concentration has been assayed, both had very low c.s.F.-folate levels.46 Clinical reports of patients with neuropyschiatric disorders improving after oral folic-acid therapy are subject to errors of observer bias. The electrophysiological techniques employed by Dr. Horwitz and his colleagues are more objective, and are to be commended. If further studies are contemplated I believe it would be more valuable to compare the electrodiagnostic findings with the c.s.F.-folate activity. D. G. WELLS. Epsom, Surrey.
to
1. 2. 3. 4. 5. 6.
Horwitz, S. J., Klipstein, F. A., Lovelace, R. Lancet, 1967, ii, 1305. Chanarin, I., Laidlaw, J., Loughridge, L. W., Mollin, D. L. Br. med. J. 1960, i, 1099. Reynolds, E. H. Lancet, 1967, i, 1086. Wells, D. G., Casey, H. J. Br. med. J. 1967, iii, 834. Reynolds, E. H., Chanarin, I. Unpublished. Wells, C. Proc. R. Soc. Med. 1965, 58, 721.
Fig.
cases.
Summarising, we have observed two principal types of disturbance in carbohydrate metabolism in chronic alcoholics with hepatic disease. One type has a diabetic type of glucose metabolism combined with hyperinsulinasmia and the other has spontaneous hypoglycxmia and extreme insulin sensitivity. These observations are interesting in view of the findings of one of us2 that diabetes as well as hypoglycxmia occurs in
Fig. 1ŃSerum-insulin and Moodglucose levels after glucost infusion by technique oj Cerasi and Luft3 in twc chronic alcoholics with hepatic disease.
Serum-insulin
measured and radioimmunoassay 4 was
by blood-glucose by
a
glucose-
oxidase method. The peroral glucose-tolerance test was of diabetic type (bloodglucose 168 mg. per 100 ml. after 2 hours) in case 1 (continuous lines) and normal in case
2
(interrupted lines).
2-Serum-insulin Fig. blood-glucose levels
and after intravenous administration of tolbutamide (1 g.) in two chronic alcoholics with hepatic disease.
Case 1
(as in fig. 1, continuous
lines). Case 3 (interrupted lines). This patient had a normal peroral
glucose-tolerance
test.
chronic alcoholics. The findings reported here are compatible with idea that increased, as well as decreased, insulin resistance may occur in chronic alcoholics. Medical Department 4, Department of Clinical Chemistry, Sodersjukhuset, Stockholm 38,
Sweden. 1. 2. 3. 4.
R. HED A. NYGREN L. SUNDBLAD.
Megyesi, C., Samols, E., Marks, V. Lancet, 1967, ii, 1051 Hed, R. Acta med. scand. 1958, 162, 3. Cerasi, E., Luft, R. Lancet, 1964, ii, 769. Soeldner, I. S., Sloane, D. Diabetes, 1965, 14, 771.
BACTERIAL ENDOCARDITIS
SIR,-To underline the relative importance of bone-marrow and blood culture in the " investigation of endocarditis and sepsis in general ", Dr. Garcia (Jan. 6, p. 52) compares 17-4% positives out of 223 blood-cultures and 41%positives out of 17 marrow cultures-himself admitting that " this comparison may be biased, because of the small number of myelocultures and because these are done only in selected severe cases ". It would have been more convincing had he cited figures of simultaneous blood and marrow cultures in which only the marrow cultures were positive. Stepping Hill Hospital, K. K. DATTA. Stockport, Cheshire.
RENAL ALLOGRAFT REJECTION SiR,ŃI have a great deal of sympathy with Dr. Clark and his colleagues (Jan. 6, p. 8) in their attempt to unify the concept of renal allotransplant reaction. The state of the renal alloautotransplant, however, is now quite as chaotic as when Simonsen1 and I2 left it over a decade ago. In our experience, a lethally X-irradiated (600-800r) dog can reject a kidney even when it is nigh impossible to demonstrate a white-blood cell in the peripheral blood. Even so, enough plasma cells get into the kidney to cause rejection. In the lymph-nodes and spleens of such animals there are still plenty plasma cells but no lymphocytes. The assumption, therefore, that an X-irradiated animal rendered leucopenic is that much different from the normal is not valid. I would not have predicted the interesting results reported by Dr. Clark and his colleagues. It would have been helpful if they had cleared up first the mystery of the rejection process of the renal allo-autotransplant. Simonsen reported, and later I agreed, that if a kidney was allotransplanted for 3 days and then returned to the donor it continued to function for several days. At some stage the rejection syndrome developed and the kidney became anuric. Microscopically, a fantastic cell infiltration had occurred. We also agreed that if a kidney was transplanted for a short time (1 hour by Simonsen, and up to 30 hours by myself) and then returned to the original donor it would function indefinitely as an autotransplant. The conclusion that I drew was that although we can often demonstrate that plasma cells are leaching on to the renal endothelial cells within 4 hours, something happens after about 30 hours which is unalterable even when the environment is rendered friendly. The kidney which is returned to the original donor after 3 days as an allotransplant is apparently rejected by the same kind of cellular process which produces acute rejection. But it could be argued that the allo-autotransplant is rejected by self antibodies or by plasma cells from the former recipient or the donor itself. And this autorejection brings us back to the old impasse of the last fifty years of whether cells or antibodies are the mediators of rejection. Rejection processes vary with the conditions of the experi-
immunosuppression, inadequate immunosuppression. temporarily inadequate immunosuppression and its long-term effects, and the second-set kidney. There seems little argument that in the context of the long-term effects of temporarily inadequate immunosuppression, involving apparently successful reversal of rejection episodes, Porter et al. have demonstrated beautifully that first-set kidneys can be slowly destroyed by antigen/antibody complexes deposited in a predictable area-the glomerulus. But the second-set kidney (from the same donor always from a different donor in a high proportion of cases5) is rejected after a few hours of function by potent, actively acquired antibodies, and the cytopathological effects are on the predictable areas-the vessels, and particularly the ment : no
1. 2. 3. 4. 5.
Simonsen, M. Biological Incompatibility in Kidney Transplantation in Dogs. Copenhagen, 1953. Dempster, W. J. Br. J. Urol. 1955, 27, 66. Porter, K. A., Dossetor, J. B., Marchioro, T. L., Peart, W. S., Rendall J. M., Starzl, T. E., Terasaki, P. I. Lab. Invest, 1967, 16, 153. Dempster, W. J. Br. J. Surg. 1953, 40, 447. Nakamoto, S., Straffon, R. A., Kolff, W. J. Transplantation, 1967, 5, 854.
146
glomeruli. In other contexts, transplantation antibodies are not necessarily non-existent when they are not totipotent and, as the late Peter Gorer used to point out repeatedly, this would cause no surprise except to a select band of transplanters. Department of Surgery, Royal Postgraduate Medical School, Ducane Road, London W.12.
W. J. DEMPSTER
MEDICAL STUDENTS AND GENERAL PRACTICE SIR,-We should like to congratulate Dr. Pearson and his colleagues, whose article appeared last week (p. 81), for drawing attention once more to the inadequacies of present methods of teaching in general practice in a large proportion of our medical schools. Their survey leaves one with the impression that most attachment schemes are ill-conceived afterthoughts in which medical students in their 5th or final year are shown something of the peculiarities of general practice in an unstructured, unsupervised way with little participation by the staff of the medical school itself. It is possible that a postal inquiry is not the best method of eliciting facts of the type they sought and in this medical school at least the teaching of general and community practice is not of the type they describe. The 1967 recommendations of the General Medical Council were to a large extent anticipated in Newcastle in 1964 when, despite the absence of a department of general practice or of social medicine, a course in family and community medicine was instituted as a component part of the revised medical curriculum.1 All lst-year clinical students take part, and the course is evolving at regular meetings of the teaching group in the light of experience on the part of the teachers and of the, feed-back of criticism and suggestion by the students. The group consists of 12 general practitioners appointed as clinical tutors in family medicine by the university, 2 doctors from public health, 6 hospital consultants from a variety of disciplines led by a faculty subcommittee which has included 3 general practitioners, and the professors of pxdiatrics, obstetrics, and industrial health, together with other senior members of the university. The general practitioners are carefully selected members of partnership and group practices, able to devote two mornings each week to teaching without too much distraction by routine practice work. They follow a planned, though flexible, teaching programme which emphasises the personal, emotional, and Students are psychological aspects of family medicine. attached in pairs to one of the practices and are expected during their 5 weeks to keep records of the clinical cases they see and in particular to become involved with and study in depth a particular family situation. They present this study at the final seminar of the course held in the teaching hospital and attended by both the community and the hospital based doctors of the group. The student therefore has 10 compulsory sessions in general practice, and in addition attends on a voluntary basis, evening surgeries, antenatal clinics, and emergency calls, as well as spending additional time " working up " his family. Alternate mornings are spent in community medicine. During this time the student is offered experience of a wide range of community services and visits with members of the " domiciliary team "-the health visitor, the district nurse, and the social worker. He studies child-health services in clinic and school, rehabilitation, mental health, public health in the environment, and community geriatrics. Regular seminars during this part of the course, conducted by one of us, enable the student to correlate these two aspects of medicine in the community. In addition to this course, which takes place during the 1st clinical year, the student may spend one of his elective periods in his 2nd or 3rd clinical year in general practice. Over the past 3 years a total of 10 students have been attached full-time for periods ranging from 3 weeks to 3 months to a variety of general practitioners in more distant parts of the region. There is careful briefing by members of the teaching 1.
Walker, J. H., Barnes, H. G. Br. med. J. 1966, ii,
1129.
group, and every effort is made to ensure that there is nothing " amateur or haphazard " about these attachments. In addition to this planned clinical experience in general and community practice, the student meets during the systematiclecture part of his medical training a variety of general practitioners whose special interests are appropriate to the particular topic being taught. During the course dealing with diseases of the respiratory tract, a general practitioner lectures upon and discusses the presentation and management of upper-respiratory-tract infection, another the social consequences of chronic bronchitis, and a third the management of asthma in the home. If our scheme does not constitute " a bold innovation," we feel that in Newcastle at least considerable progress has been made. One valuable by-product has been the establishment of collaborative community research projects: these have involved the university departments of psychological medicine, public health, industrial health and medical statistics, midwifery, and child health, the M.R.C. growth and reproduction unit, and a number of general
practitioners. These activities are creating the atmosphere of a " third faculty", through which students are seeing the challenge and the fascination of practice in the community in all its aspects. University Department of Public Health, Medical School, Newcastle upon Tyne 1
ANDREW SMITH
JOHN H. WALKER.
FOLIC ACID AND NEUROPATHY IN EPILEPSY SiR,ŃIwas interested to read the observations of Dr. Horwitz and his colleagues. Since the inferences drawn are controversial, I should like to present an alternative
interpretation. The incidence of peripheral neuropathy in what I assume be a random group of epileptics, treated for 10 years or more with anticonvulsants, must be very much higher than in patients with any other disorder of unrelated xtiology. Since the anticonvulsant therapy was the most likely common denominator, it would seem reasonable to attribute the neuropathy to the anticonvulsants. The evidence that the dementia, cerebellar degeneration, and neuropathy sometimes seen in drug-treated epileptics may be due to interference with folate metabolism deserves consideration. I, and other observers,2have noted that folic acid sometimes provokes epilepsy in folate-deficient anticonvulsanttreated epileptic patients. Lately a folate-deficient patient (serum-folate 0-75 ng. per ml., red-blood-cell folate 75 ng. per ml., cerebrospinal fluid (C.S.F) folate 5 ng. per ml.) died in uncontrolled status epilepticus after being treated orally with folic acid. These observations suggest that folic acid affects the central nervous system. Moreover there is evidence that anticonvulsants interfere with folate metabolism within the nervous system, since the C.S.F.-folate level in drug-treated epileptics is statistically significantly lower than in control patients.4The only two documented anticonvulsant-treated epileptics with signs and symptoms suggestive of cerebellar degeneration, in whom c.s.F.-folate concentration has been assayed, both had very low c.s.F.-folate levels.46 Clinical reports of patients with neuropyschiatric disorders improving after oral folic-acid therapy are subject to errors of observer bias. The electrophysiological techniques employed by Dr. Horwitz and his colleagues are more objective, and are to be commended. If further studies are contemplated I believe it would be more valuable to compare the electrodiagnostic findings with the c.s.F.-folate activity. D. G. WELLS. Epsom, Surrey.
to
1. 2. 3. 4. 5. 6.
Horwitz, S. J., Klipstein, F. A., Lovelace, R. Lancet, 1967, ii, 1305. Chanarin, I., Laidlaw, J., Loughridge, L. W., Mollin, D. L. Br. med. J. 1960, i, 1099. Reynolds, E. H. Lancet, 1967, i, 1086. Wells, D. G., Casey, H. J. Br. med. J. 1967, iii, 834. Reynolds, E. H., Chanarin, I. Unpublished. Wells, C. Proc. R. Soc. Med. 1965, 58, 721.