196 somewhat higher than at other times and in control areas. The sharp reduction in fertility among these cohorts, however, combined with weak famine effects when conception occurred, indicates that starvation before conception more likely leads to infecundity than to conception with subsequent injury to off-
MATERNAL NUTRITION AND LOW BIRTH-WEIGHT
SIR,-Dr Pasamanick’s insistence (Dec. 6, p. 1145) on a "fatal flaw" in our study of the effects of prenatal exposure to the Dutch famine obliges us to reply. The major hypothesis tested was that nutritional deprivation late in gestation would retard brain growth and depress mental performance. A second hypothesis was that deprivation early in gestation would result in congenital defects and death or handicap. We built our retrospective cohort design chiefly around military induction records. About 120 000 19-year-old male survivors of complete cohorts born in sixteen cities from 1944 to 1946 were assigned to famine exposed and unexposed groups according to place and date of birth, thus controlling simultaneously for place and time. Dr Pasamanick’s first point is that food in the famine area was not randomly distributed. Hence women able to "conceive, maintain pregnancies, and obtain live births", and classed by us as exposed, he asserts were upper class, or Nazi collaborators, or others who obtained more food. This comprises the "fatal flaw". Because the famine lasted only six months, however, such selective food distribution could affect either cohorts born during the famine and conceived previous to it (Bl, B2 in figure) or cohorts conceived during the famine and born subsequent to it (D1, D2).
spring. Pasamanick’s second point is that starvation in "control" cities invalidates them as controls. However, contemporary reports, and the weekly food rations, make clear the more favoured situation of control cities. In sum, cohorts bom in famine cities before and after the famine, and cohorts born in control cities throughout the study period, did not show the fall in births, the retarded fetal growth, nor the rise in infant deaths found in famine-exposed cohorts. None of the birth cohorts, whether in famine or control areas, showed changes over time with respect to mental competence. In our book on this study,’ the data are set out in full in an appendix, and those interested can test the issues for themselves. Division of Epidemiology, Columbia University School of Public Health, 600 West 168th Street, New York, N.Y. 10032, U.S.A. Columbia University and New York State Psychiatric Institute.
MERVYN SUSSER
ZENA A. STEIN
THE ALCOHOLIC DOCTOR
Design of study. Cohorts by month of conception and month of birth, in the Netherlands, 1943-46, related to famine exposure. Solid vertical lines bracket the period of famine, and broken vertical lines bracket the period of births conceived during famine.
Pasamanick’s criticism is
not
germane
to our
main
hypoth-
esis, tested in cohorts exposed to famine in late pregnancy (B1,
B2). As anticipated among cohorts conceived before the famine, neither in number nor in social class distribution is there evidence of changes in fertility. The mothers of these birth cohorts were reduced in weight. Their offspring were reduced in birth-weight, length, placental weight, and head size, and they suffered heavy excess mortality in the first 3 months of life. Despite these effects, adult survivors among the poorest as among the best-off social classes showed no decline in mental competence, nor in physique and health state. Pasamanick’s criticism could be germane to our second hypothesis, tested in cohorts exposed to famine in early pregnancy (Dl, D2). Indeed we considered the point in detail. Fertility among these cohorts, we showed, was socially selective, and births over-represented the upper classes. This, we concluded, resulted from better maternal nutrition at the time of conception. Mean birth-weights were not reduced among these cohorts. Survivors had the mental competence expected from the changed social-class composition of the cohort, but with social class controlled no famine effects were found in time and place comparisons. Rates for stillbirths and c.N.s. defects were ’
SiR,—The subtitle, a Case of Neglect, of Dr Griffith Edwards’ timely article (Dec. 27, p. 1297) applies not only to the treatment of the unfortunate sufferer but also to the coverage of alcohol misuse in the medical curriculum. Partly due to this neglect there is a high prevalence of heavy drinking among doctors and the stigma attached to the diagnosis of alcoholism by the general population is perpetuated. The problem is urgent because alcoholism is clearly on the increase in the U.K., especially among the young. Twenty years ago only 5% of patients admitted to the alcoholic unit at Warlingham Park Hospital were under thirty;2 today, in my unit, some 18% of alcoholic admissions are in this age-group. Alcoholism is not only a treatable illness, but it is also one that is, or should be, preventable. In the future doctors will have an important role to play in prevention as well as in treatment. But the average general practitioner probably knows of no more than 2 out of 20 alcoholics on his list, and the high prevalence of alcoholism among doctors is further evidence of the lack of medical undergraduate education. Liver cirrhosis mortality among doctors, according to the Registrar General’s figures for 1961, was 3ytimes higher than that among the general population, and in line with such estimates is the finding that over the past 25 years the proportion of doctors among our alcoholic patients admitted to the units at Warling. ham Park and St Bernard’s has been 2-%. Doctors are clearly a high-risk group. Various factors may be involved. Social acceptance of heavy drinking among undergraduates may pave the way, and after qualification the doctor may fall back on his familiar "comforter" at times of strain for relaxation, especially since drink is so often freely offered by friends and colleagues. Preventive programmes of must include attempts to reduce consumption, by education the public, beginning in schools. There is an urgent need for education to be directed at high-risk groups, especially medical students, and this should stress the early phases of alcohol rather than the late and relatively rare physical complication "I never heard about alcoholism as an undergraduate except about liver cirrhosis in pathology", an alcoholic consultant remarked last week. Yet medical students can take an interest in the subject, as shown by our experiences of teaching Locoes undergraduates with the help of recovered or still "actil’t alcoholic patients. Doctors often share the misconceptions90 prevalent among the general public. A doctor equating 1.
Stein, Z., Susser, M., Saenger, G., Marolla, F. Famine and Human Development: the Dutch Hunger Winter of 1944-1945. New York, 1975. 2. Glatt, M. M. Br. J. Addict. 1955, 52, 55.
197 alcoholic with a "skid-row" drinker or with a psychopath will think it possible that he himself could have this condition. Instead of asking for help he may treat himself with tranquillisers or even barbiturates, and often become dependent on them as well. Alcoholism is the responsibility of a multidisciplinary team, but doctors’ clear acceptance of the alcoholic as a sick person worthy of needing help would in time lessen the stigma and encourage alcoholics and their families to ask for assistance much earlier. But fear of rejection often keeps alcoholics away from their G.P. Similarly, the alcoholic doctor himself feels ashamed of his "weakness" which he "should" be able to control. The covering-up by colleagues, rightly criticised by Dr Edwards and Dr Shribman (Jan. 10, p. 88), only serves to increase the risk to the alcoholic doctor and to his patients. Once the alcoholic doctor faces up to his problem the prognosis is usually good. Those doctors unable or unwilling to avail themselves of the extremely valuable services of Alcoholics Anonymous, the "self-help" alcoholic doctors’ group (which now has 80 members); should be of great value.2 not
St Bernard’s
Renal Unit,
Hospital,
Southall,
M. M. GLATT
Middlesex.
CIRRHOTIC GLOMERULONEPHRITIS AND SECRETORY IMMUNOGLOBULIN A
SiR,—Hyperglobulinxmia is a well-established feature of alcoholic liver cirrhosis, but the origin and the nature of this increased immune response is unknown. Callard et a1.3 found glomerular lesions in nine out of ten cirrhotic patients they investigated. The glomerulonephritis was characterised by the presence in the glomerulus of IgA, often associated with other immunoglobulins and C3. We have investigated twenty-two patients with proven alcoholic cirrhosis and compared them with twelve healthy subjects. Proteinuria was present in six patients with liver cirrhosis. Using discontinuous sucrose-gradient ultracentrifugation and reduction-alkylation of the immunoglobulins, we were able to measure serum monomeric and dimeric IgA levels along with IgM, IgG, and IgA-bound secretory component. By comparison with the controls, the cirrhotic patients presented the following increases of immunoglobulin concentrations: dimeric IgA 7.28 fold, monomeric IgA 2 41 fold, IgM 1.84 fold, IgG 1.56 fold, and IgA-bound secretory component 6.0 fold. As IgA and IgA-bound secretory component increased the most, we suggest that either IgA itself, originating from the gut, or its complex with bacterial, viral or dietary antigens, is deposited in the kidney and induces renal failure. IgA glomerular deposits in some cases of primary glomerulonephritis4 also probably have a mucosal, respiratory, or digestive, origin. Unite de Recherches de Physiopathologie
Digestive, INSERM U 45, Hôpital Edouard Herriot, Pavilion H,
A 42-year-old woman was referred for assessment of hypertension which had developed during her fourth pregnancy. Immediately after delivery the blood-pressure was 200/130 mm Hg lying and 160/120 mm Hg standing. At the same time creatinine clearance was 40 ml/min but rose after 2 weeks to 80 ml/min and has remained stable. An intravenous pyelogram and ultrasound evaluation were compatible with right-sided multicystic disease. The left kidney was elongated, with a duplex collecting system, but otherwise normal. Serum-IgA was undetectable. Blood-pressure was reduced to 150/90 mm Hg lying and standing with guanethidine 100 mg, clonidine 0-3mg, and spironolactone 50 mg daily. There was no past history of sinopulmonary infections, atopy, or use of the contraceptive pill. During follow-up for 20 months serum-IgA has remained undetectable, and the renal impairment has been stable. I wonder if the combination of hypertension, multicystic renal disease, and IgA deficiency is fortuitous or represents a genetic defect in this woman. I would be interested to learn of other cases.
FRANÇOISE ANDRÉ CLAUDE ANDRÉ
69374 Lyon, France.
IgA DEFICIENCY, HYPERTENSION, AND MULTICYSTIC RENAL DISEASE
Royal Infirmary,
ROGER GABRIEL
Hull.
ULTRASOUND AND SAFETY
(Oct. 18, p. 770) that the used in connection with the effect of ultra"mutagenic" sound on purified D.N.A. (Oct. 4, p. 662), is inappropriate, but we are not convinced by Dr Thacker’s other criticisms of our work. He argues that we have ignored evidence that does not support our recommendation to minimise ultrasound exposure of fetus. He maintains that degradation arises from hydrodynamic shear forces set up around oscillating or collapsing gas bubbles, but goes on to say that "to generate comparable shear forces in tissue a higher intensity would be required than that which degrades D.N.A. in solution, and were these forces sufficient to disrupt D.N.A. in chromosomes it is likely that damage to other cellular structures will be extensive enough to cause cell disruption and death." Hill’has pointed out that cavitation would happen in the liquid state but probably not in organised tissues, so we tried to work in conditions-frequencies of 2MHz and 0-87 MHz, volume of 7 ml, ambient pressure 1 bar, temperature below 25°C--below the cavitation threshold.3 The mechanism involved in the D.N.A. breaks we have observed is thus not clear. Hill has suggested that ultrasound could produce biological responses directly. The repeated vibrations, transmitted to the long, thin D.N.A. molecules, might produce shearing, and this mechanism might occur in vivo where cavitation is supposed not to happen. We have discussed these points elsewhere,4 taking into account Dr Thacker’s own review.5 We doubt whether cell disruption and death will necessarily happen before D.N.A. shearing. D.N.A., being the longest molecule in living cells, is therefore the most sensitive to shearing. Besides chromosome breaks happen at higher ultrasound intensities (in the W/cm2 range) :6-8 D.N.A. is sheared yet the cells are not dead. The presence of chromosome breaks rather than chromatid breaks means that the cells were sonicated at G,, and later went on to cell division. In our experiments we found that the intensities and durations necessary to break purified D.N.A. were uncomfortSm,—We
agree with Dr Thacker
term
SIR,-Your leading article
on selective IgA deficiency-’ report a patient with hypertension, multicystic renal disease, and absent serum-IgA, but with normal concentrations of IgM and IgG.
prompts me
to
1. Hill, C. R. J. acoust. Soc. Amr. 1972, 52. 667. 2. Hill, C. R. in Ultrasound in Clinical Diagnosis (edited by P. N. T. Wells); p. 165. Edinburgh, 1972. 3. Iernetti, G. Acustica, 1971, 24, 191. 4. Galperin-Lemaître, H., Kirsch-Volders, M., Levi, S. Humangenetik, 1975,
29, 61. 2 Glatt, M M. Lancet, 1975, i, 219. 3 Callard, P., Feldmann, G., Prandi, D., Belair, M. F., Mandet, C., Weiss, Y., Druet, P., Benhamou, J. P., Bariety, J. Am. J. Path. 1975, 80, 329. 4 Berger, J. Transplant Proc. 1969, 1, 939. 5 Lancet, 1975, ii, 1291.
5. Thacker, J. Curr. Topics Rad. Res. 1973, 8, 235. 6. Fischman, H. K., Coleman, D. J., Lizzi, F. L. J. Cell Biol. 1972, 55, 74a. 7. Slotova, J., Karpfel, Z., Hrazdira, I. Biol. Plant. 1967, 9, 49. 8. Coakley, W. T., Hugues, D. E., Slade, J. S., Laurence, K. M. Br. med. J. 1971, ii, 501.
MATERNAL NUTRITION AND LOW BIRTH-WEIGHT
SIR,-Dr Pasamanick’s insistence (Dec. 6, p. 1145) on a "fatal flaw" in our study of the effects of prenatal exposure to the Dutch famine obliges us to reply. The major hypothesis tested was that nutritional deprivation late in gestation would retard brain growth and depress mental performance. A second hypothesis was that deprivation early in gestation would result in congenital defects and death or handicap. We built our retrospective cohort design chiefly around military induction records. About 120 000 19-year-old male survivors of complete cohorts born in sixteen cities from 1944 to 1946 were assigned to famine exposed and unexposed groups according to place and date of birth, thus controlling simultaneously for place and time. Dr Pasamanick’s first point is that food in the famine area was not randomly distributed. Hence women able to "conceive, maintain pregnancies, and obtain live births", and classed by us as exposed, he asserts were upper class, or Nazi collaborators, or others who obtained more food. This comprises the "fatal flaw". Because the famine lasted only six months, however, such selective food distribution could affect either cohorts born during the famine and conceived previous to it (Bl, B2 in figure) or cohorts conceived during the famine and born subsequent to it (D1, D2).
spring. Pasamanick’s second point is that starvation in "control" cities invalidates them as controls. However, contemporary reports, and the weekly food rations, make clear the more favoured situation of control cities. In sum, cohorts bom in famine cities before and after the famine, and cohorts born in control cities throughout the study period, did not show the fall in births, the retarded fetal growth, nor the rise in infant deaths found in famine-exposed cohorts. None of the birth cohorts, whether in famine or control areas, showed changes over time with respect to mental competence. In our book on this study,’ the data are set out in full in an appendix, and those interested can test the issues for themselves. Division of Epidemiology, Columbia University School of Public Health, 600 West 168th Street, New York, N.Y. 10032, U.S.A. Columbia University and New York State Psychiatric Institute.
MERVYN SUSSER
ZENA A. STEIN
THE ALCOHOLIC DOCTOR
Design of study. Cohorts by month of conception and month of birth, in the Netherlands, 1943-46, related to famine exposure. Solid vertical lines bracket the period of famine, and broken vertical lines bracket the period of births conceived during famine.
Pasamanick’s criticism is
not
germane
to our
main
hypoth-
esis, tested in cohorts exposed to famine in late pregnancy (B1,
B2). As anticipated among cohorts conceived before the famine, neither in number nor in social class distribution is there evidence of changes in fertility. The mothers of these birth cohorts were reduced in weight. Their offspring were reduced in birth-weight, length, placental weight, and head size, and they suffered heavy excess mortality in the first 3 months of life. Despite these effects, adult survivors among the poorest as among the best-off social classes showed no decline in mental competence, nor in physique and health state. Pasamanick’s criticism could be germane to our second hypothesis, tested in cohorts exposed to famine in early pregnancy (Dl, D2). Indeed we considered the point in detail. Fertility among these cohorts, we showed, was socially selective, and births over-represented the upper classes. This, we concluded, resulted from better maternal nutrition at the time of conception. Mean birth-weights were not reduced among these cohorts. Survivors had the mental competence expected from the changed social-class composition of the cohort, but with social class controlled no famine effects were found in time and place comparisons. Rates for stillbirths and c.N.s. defects were ’
SiR,—The subtitle, a Case of Neglect, of Dr Griffith Edwards’ timely article (Dec. 27, p. 1297) applies not only to the treatment of the unfortunate sufferer but also to the coverage of alcohol misuse in the medical curriculum. Partly due to this neglect there is a high prevalence of heavy drinking among doctors and the stigma attached to the diagnosis of alcoholism by the general population is perpetuated. The problem is urgent because alcoholism is clearly on the increase in the U.K., especially among the young. Twenty years ago only 5% of patients admitted to the alcoholic unit at Warlingham Park Hospital were under thirty;2 today, in my unit, some 18% of alcoholic admissions are in this age-group. Alcoholism is not only a treatable illness, but it is also one that is, or should be, preventable. In the future doctors will have an important role to play in prevention as well as in treatment. But the average general practitioner probably knows of no more than 2 out of 20 alcoholics on his list, and the high prevalence of alcoholism among doctors is further evidence of the lack of medical undergraduate education. Liver cirrhosis mortality among doctors, according to the Registrar General’s figures for 1961, was 3ytimes higher than that among the general population, and in line with such estimates is the finding that over the past 25 years the proportion of doctors among our alcoholic patients admitted to the units at Warling. ham Park and St Bernard’s has been 2-%. Doctors are clearly a high-risk group. Various factors may be involved. Social acceptance of heavy drinking among undergraduates may pave the way, and after qualification the doctor may fall back on his familiar "comforter" at times of strain for relaxation, especially since drink is so often freely offered by friends and colleagues. Preventive programmes of must include attempts to reduce consumption, by education the public, beginning in schools. There is an urgent need for education to be directed at high-risk groups, especially medical students, and this should stress the early phases of alcohol rather than the late and relatively rare physical complication "I never heard about alcoholism as an undergraduate except about liver cirrhosis in pathology", an alcoholic consultant remarked last week. Yet medical students can take an interest in the subject, as shown by our experiences of teaching Locoes undergraduates with the help of recovered or still "actil’t alcoholic patients. Doctors often share the misconceptions90 prevalent among the general public. A doctor equating 1.
Stein, Z., Susser, M., Saenger, G., Marolla, F. Famine and Human Development: the Dutch Hunger Winter of 1944-1945. New York, 1975. 2. Glatt, M. M. Br. J. Addict. 1955, 52, 55.
197 alcoholic with a "skid-row" drinker or with a psychopath will think it possible that he himself could have this condition. Instead of asking for help he may treat himself with tranquillisers or even barbiturates, and often become dependent on them as well. Alcoholism is the responsibility of a multidisciplinary team, but doctors’ clear acceptance of the alcoholic as a sick person worthy of needing help would in time lessen the stigma and encourage alcoholics and their families to ask for assistance much earlier. But fear of rejection often keeps alcoholics away from their G.P. Similarly, the alcoholic doctor himself feels ashamed of his "weakness" which he "should" be able to control. The covering-up by colleagues, rightly criticised by Dr Edwards and Dr Shribman (Jan. 10, p. 88), only serves to increase the risk to the alcoholic doctor and to his patients. Once the alcoholic doctor faces up to his problem the prognosis is usually good. Those doctors unable or unwilling to avail themselves of the extremely valuable services of Alcoholics Anonymous, the "self-help" alcoholic doctors’ group (which now has 80 members); should be of great value.2 not
St Bernard’s
Renal Unit,
Hospital,
Southall,
M. M. GLATT
Middlesex.
CIRRHOTIC GLOMERULONEPHRITIS AND SECRETORY IMMUNOGLOBULIN A
SiR,—Hyperglobulinxmia is a well-established feature of alcoholic liver cirrhosis, but the origin and the nature of this increased immune response is unknown. Callard et a1.3 found glomerular lesions in nine out of ten cirrhotic patients they investigated. The glomerulonephritis was characterised by the presence in the glomerulus of IgA, often associated with other immunoglobulins and C3. We have investigated twenty-two patients with proven alcoholic cirrhosis and compared them with twelve healthy subjects. Proteinuria was present in six patients with liver cirrhosis. Using discontinuous sucrose-gradient ultracentrifugation and reduction-alkylation of the immunoglobulins, we were able to measure serum monomeric and dimeric IgA levels along with IgM, IgG, and IgA-bound secretory component. By comparison with the controls, the cirrhotic patients presented the following increases of immunoglobulin concentrations: dimeric IgA 7.28 fold, monomeric IgA 2 41 fold, IgM 1.84 fold, IgG 1.56 fold, and IgA-bound secretory component 6.0 fold. As IgA and IgA-bound secretory component increased the most, we suggest that either IgA itself, originating from the gut, or its complex with bacterial, viral or dietary antigens, is deposited in the kidney and induces renal failure. IgA glomerular deposits in some cases of primary glomerulonephritis4 also probably have a mucosal, respiratory, or digestive, origin. Unite de Recherches de Physiopathologie
Digestive, INSERM U 45, Hôpital Edouard Herriot, Pavilion H,
A 42-year-old woman was referred for assessment of hypertension which had developed during her fourth pregnancy. Immediately after delivery the blood-pressure was 200/130 mm Hg lying and 160/120 mm Hg standing. At the same time creatinine clearance was 40 ml/min but rose after 2 weeks to 80 ml/min and has remained stable. An intravenous pyelogram and ultrasound evaluation were compatible with right-sided multicystic disease. The left kidney was elongated, with a duplex collecting system, but otherwise normal. Serum-IgA was undetectable. Blood-pressure was reduced to 150/90 mm Hg lying and standing with guanethidine 100 mg, clonidine 0-3mg, and spironolactone 50 mg daily. There was no past history of sinopulmonary infections, atopy, or use of the contraceptive pill. During follow-up for 20 months serum-IgA has remained undetectable, and the renal impairment has been stable. I wonder if the combination of hypertension, multicystic renal disease, and IgA deficiency is fortuitous or represents a genetic defect in this woman. I would be interested to learn of other cases.
FRANÇOISE ANDRÉ CLAUDE ANDRÉ
69374 Lyon, France.
IgA DEFICIENCY, HYPERTENSION, AND MULTICYSTIC RENAL DISEASE
Royal Infirmary,
ROGER GABRIEL
Hull.
ULTRASOUND AND SAFETY
(Oct. 18, p. 770) that the used in connection with the effect of ultra"mutagenic" sound on purified D.N.A. (Oct. 4, p. 662), is inappropriate, but we are not convinced by Dr Thacker’s other criticisms of our work. He argues that we have ignored evidence that does not support our recommendation to minimise ultrasound exposure of fetus. He maintains that degradation arises from hydrodynamic shear forces set up around oscillating or collapsing gas bubbles, but goes on to say that "to generate comparable shear forces in tissue a higher intensity would be required than that which degrades D.N.A. in solution, and were these forces sufficient to disrupt D.N.A. in chromosomes it is likely that damage to other cellular structures will be extensive enough to cause cell disruption and death." Hill’has pointed out that cavitation would happen in the liquid state but probably not in organised tissues, so we tried to work in conditions-frequencies of 2MHz and 0-87 MHz, volume of 7 ml, ambient pressure 1 bar, temperature below 25°C--below the cavitation threshold.3 The mechanism involved in the D.N.A. breaks we have observed is thus not clear. Hill has suggested that ultrasound could produce biological responses directly. The repeated vibrations, transmitted to the long, thin D.N.A. molecules, might produce shearing, and this mechanism might occur in vivo where cavitation is supposed not to happen. We have discussed these points elsewhere,4 taking into account Dr Thacker’s own review.5 We doubt whether cell disruption and death will necessarily happen before D.N.A. shearing. D.N.A., being the longest molecule in living cells, is therefore the most sensitive to shearing. Besides chromosome breaks happen at higher ultrasound intensities (in the W/cm2 range) :6-8 D.N.A. is sheared yet the cells are not dead. The presence of chromosome breaks rather than chromatid breaks means that the cells were sonicated at G,, and later went on to cell division. In our experiments we found that the intensities and durations necessary to break purified D.N.A. were uncomfortSm,—We
agree with Dr Thacker
term
SIR,-Your leading article
on selective IgA deficiency-’ report a patient with hypertension, multicystic renal disease, and absent serum-IgA, but with normal concentrations of IgM and IgG.
prompts me
to
1. Hill, C. R. J. acoust. Soc. Amr. 1972, 52. 667. 2. Hill, C. R. in Ultrasound in Clinical Diagnosis (edited by P. N. T. Wells); p. 165. Edinburgh, 1972. 3. Iernetti, G. Acustica, 1971, 24, 191. 4. Galperin-Lemaître, H., Kirsch-Volders, M., Levi, S. Humangenetik, 1975,
29, 61. 2 Glatt, M M. Lancet, 1975, i, 219. 3 Callard, P., Feldmann, G., Prandi, D., Belair, M. F., Mandet, C., Weiss, Y., Druet, P., Benhamou, J. P., Bariety, J. Am. J. Path. 1975, 80, 329. 4 Berger, J. Transplant Proc. 1969, 1, 939. 5 Lancet, 1975, ii, 1291.
5. Thacker, J. Curr. Topics Rad. Res. 1973, 8, 235. 6. Fischman, H. K., Coleman, D. J., Lizzi, F. L. J. Cell Biol. 1972, 55, 74a. 7. Slotova, J., Karpfel, Z., Hrazdira, I. Biol. Plant. 1967, 9, 49. 8. Coakley, W. T., Hugues, D. E., Slade, J. S., Laurence, K. M. Br. med. J. 1971, ii, 501.
