1056
mediaries suffice to link any two Americans in a national population of over two hundred million. Some subsidiary comparisons were made, on tonsillectomy and appendicectomy history, socioeconomic status, history of mononucleosis, and siblings without significant findings. No linkage between specific types of leukaemia or lymphoma was evident and GREENWALD and co-workers are cautious in interpretation of their findings. But the results do seem to indicate a greater degree of acquaintanceship among both leukxmia and lymphoma cases than among controls-which is consistent with a transmissibility hypothesis and, in
particular,
one
involving symptomless intermediary
carriers. This fits in with other evidence, at least as regards Hodgkin’s disease.6,13,14 This study in New York State will no doubt stimulate further work in this sphere. The indications are that in Hodgkin’s disease acquaintanceship has to be close and long continued.6,9 When feline leukaemia was shown to be a horizontally transmissible disease the epidemiologists were asked why they had not discovered this. It is good to know that the question of the transmissibility of human leukaemias and lymphomas is now under stringent scrutiny.
Lithium and the Kidney: Grounds for Cautious Optimism WHERE lithium is
well
concerned, psychiatrists
are
of the narrow window between theraand toxic dosage. Adequate management peutic takes trouble. It demands periodic assessment of plasma levels of the drug combined with a careful briefing of the patient of the nature of the possible adverse reactions and toxic effects he may encounter. Nevertheless, in the United Kingdom alone some 50 000-100 000 patients may be under treatment at any one time so the drug enjoys considerable success. The reason is not hard to find. Lithium is the most effective drug for preventing relapses in patients with affective disorders. Thus the report from HESTBECH et al.2 of the presence of chronic nephropathy in patients on prolonged treatment (recently discussed in these columns3) set the alarm bells ringing with a vengeance. Concern became so widespread that the biological section of the World Psychiatric Association saw fit to convene a meeting4 in Copenhagen devoted to this aware
Although six separate groups reported their ability to confirm the renal-biopsy data of HESTBECH and her colleagues, the crucial question was whether
correct
control
had been Most workers had
material
in these investigations. or cadaver kidneys. However, some striking findings of KINCAID-SMITH and her colleagues5 made it clear that non-specific changes similar to those in the lithium-treated group could be identified in patients with affective disorders who had never received lithium, raising the question of whether other drugs used to treat this group
employed
used donor
of diseases might similarly be nephrotoxic. As with structure, so with function. Scientific from Canada, Denmark, Germany, Holland, Sweden, the U.K., and the U.S.A. had for the most part noted some degree of renal deficit but had, with one exception, employed controls without affective disorder. Perhaps some earlier findings of BucHT et a1.6were a pointer to what was really going on: these workers showed that, whilst urinary concentrating ability was subnormal in a group of patients on long-term lithium therapy, the deficit was more severe in a second group treated with a combination of lithium and neuroleptics. Conceptually, the most important study on functional aspects presented at the Copenhagen meeting was that of COPPEN and his colleagues,’ who compared a lithium-treated group with an affective-disorder control group, the members of which were untreated by lithium. There was little difference between the two. teams
What conclusions can be drawn from all these data? Ought the hunt to be on for some as yet unidentified nephrotoxic neuroleptic drug or other form of toxic medication? Not necessarily so. An alternative explanation might be that the non-specific renal damage in these disorders represents a hypersensitive tissue response to drugs-a predisposition connected with some aspect of the affective illness itself, making these patients particularly vulnerable to the nephrotoxic action of various drugs, not just lithium. After all, we already know that depressive subjects, untreated by lithium, concentrate their urine less well than other psychiatric patients or normal subjects.g Moreover, an electrolyte imbalance has been identified9 in this group of
a -single matter. 13. Grufferman S, Cole P, Smith PG, Lukes RJ. Hodgkin’s disease in siblings. N Engl J Med 1977; 296: 248-50. 14. Theiss W, Saner E, Rastetter J. Lymphogranulomatosis in siblings. Munchen Med Wschr 1979; 121: 309-12. 1. Hansen HE, Amdisen A. Lithium intoxication (report of 23 cases and review of 100 cases from the literature). Quart J Med 1978; 47: 123-44. 2. Hestbech J, Hansen HE, Amdisen A, Olsen S. Chronic renal lesions following long-term treatment with lithium. Kidney Int 1977; 12: 205-13. 3. Editorial. Lithium nephropathy. Lancet 1979; ii: 619-20. 4. Lithium Treatment and Kidney Damage. Meeting arranged by the biological section of the World Psychiatric Association, Copenhagen, Oct. 11-13 1979; chairman, Dr Alec Coppen.
5. Kincaid-Smith P, Burrows GD, Davies BM, Holwill B, Walter M, Walker RG. Renal biopsy findings in lithium and prelithium patients. Lancet
1979; ii: 700-01. 6. Bucht G, Wahlin A, Wentzel T, Winblad B. Njurskador vid behandling med litium och neuroleptika. Nord Psykiat Tidsskr 1978; 32: 445-46. 7. Coppen A, Cattell WR, Price R. A comparative study of renal function in lithium-treated and non-lithium-treated patients with affective disorders. Presented at 1979 WPA meeting (ref. 4). 8. Ellis CG, Coppen A, Glen AIM. Urine concentration in depressive illness. J 9.
Neurol Neurosurg Psychiatry 1971; 34: 30-31. Coppen AJ. The chemical pathology of the affective disorders. In: Scientific basis of medicine annual review, 1970; London: Athlone Press, 1970 189-210.
1057
patients which may conceivably stem from renal origins, and there are indications of a higher incidence of death from cardiovascular group3 10 which may not be unrelated.
causes
in this
The putative toxicological effect of lithium on the kidneys must not be confused with the pharmacological nephrogenic diabetes insipidus it gives rise to, whereby the sensitivity of action of antidiuretic hormone on the distal convoluted tubule is
blunted.3 Polyuria,
apparently quite benign,
seems
be a more prominent feature in Scandinavian than British patients, perhaps related to the Scandinavian practice of instructing patients on lithium to drink extra fluids.ll One impressive finding recorded at this meeting was of a five-fold increase of urinary antidiuretic hormone (arginine vasopressin, AVP), presumably compensatory, in patients on lithium.12 It is noteworthy that AVP, apart from its well-known effect on the renal tubule, also appears to act on certain sites in the cerebral vasculature, controlling the movement of water in the brain.13 Might this relationship throw some light on the way lithium works in bipolar affective disorder? Certainly such a mechanism cannot be ruled out. Indeed, the case has been made for a link between AVP and the pathogenesis of affective illness, 14,15 whilst the tricyclic antidepressant drugs seem to have a profound effect on cerebral fluid dynamics. 16 to
What message emerges for the practising psychiatrist out of this reappraisal? As SCHOU 17 pointed out, lithium is a precious drug for which we have
substitute. The consensus at this meeting was that the risk of lithium nephropathy, in the absence of lithium toxicity, is small. GLEN and his colleagues,18 in what must be the clinching argument, showed that there was no increase in mortality in a series of 810 patients exposed to lithium over ten years, compared with expectation. Nevertheless, there remains the problem of the patient with affective disorder who may have pre-existing renal damage and perhaps a history of nephritic illness. In this case nephrological assessment is mandatory
before treatment, and if a deficit is shown to exist, the assessment should be repeated at intervals during treatment. With these precautions, the risk of serious progressive renal damage is likely to be
slight.
,
Safety of Vasectomy VASECTOMY has gained increasing acceptance in the past decade. In the United Kingdom, where even the legality of the operation was in question ,until the 1960s,1 there is a fast-growing trend towards male sterilisation, and at present rates a good 10% of the husbands of women now aged 25-34 will be vasectomised by the time the wife is 35.2 In the United States about a million male sterilisations are now done each year.3 In India six million men were sterilised in 1976.4 Although the procedure is generally regarded as simple, effective, and safe, questions have been raised about possible long-term effects,S-7 resulting from antibody reactions to sperm and from hormonal imbalance or altered blood coagulation. Sperm and their specific antigens are normally sequestered from the 8immune system behind a "blood-testis barrier".g Obstruction of the vas deferens results in the release of sperm antigens, and antisperm autoantibodies appear in the circulation.9-11 These antibodies persist at least 5 years after vasectomy. 12 There have been studies of reactions to antigens other than sperm,13,14 and circulating hormone levels have been measured after vasectomy;15-17 and, despite some conflict of evi-
no
10.
Glen, AIM, Dodd M, Holme EB, Kreitman N. Mortality on lithium. Neuropsychobiology 1979; 5: 167-73. 11. Amdisen A. Monitoring of lithium treatment, the standardized serum lithium control versus clinical supervision. Presented at 1979 WPA meeting (ref.4). 12. Birch NJ, Hullin RP, Morgan DB. Renal function and plasma arginine-vasopressin during water deprivation in lithium-treated patients, normal controls and patients receiving other psychotropic drugs. Presented at 1979 WPA meeting (ref.4). See also Hullin RP, Coley VP, Birch NJ, Thomas TH, Morgan DB. Br Med J 1979; i: 1457-59. 13. Raichle M, Hartman B, Eichling J, Sharpe L. Central noradrenergic regulation of cerebral blood flow and vascular permeability. Proc Nat Acad Sci USA 1975; 72: 3726-30. 14. Gold PW, Goodwin FK, Reus VI. Vasopressin in affective illness. Lancet 1978; i: 1233-36. 15. Gold PW, Weingartner H, Ballenger JC, Goodwin FK, Post RM. Lancet 1979; u: 992-94. 16. Preskorn SH, Hartman BK. The effect of tricyclic antidepressants on cerebral fluid dynamics. Biol Psychiat 1979; 14: 235-50. 17. Schou M. Concluding remarks. Presented at 1979 WPA meeting (ref.4). 18. Glen AIM, Loudon JB, Swainson CP. Non invasive measures of renal function
following
lithium
therapy.
Presented
at
1979 WPA
meeting (ref.4).
Jackson LN. Voluntary sterilisation for family welfare. Lancet 1966; i: 971-74. 2. Bone M. Recent trends in sterilisation. Population Trends, 1978; 13: 13-16. 3. Hackett RE, Waterhouse K. Vasectomy reviewed. Am J Obstet Gynecol 1973; 116: 438-55. 4. Nortman DL, Hofstatter E. Population and Family Planning Programs, 9th ed. New York: The Population Council, 1978: 63. 5. Roberts HJ. Voluntary sterilisation in the male. Br Med J 1968; iii: 434. 6. Warin RP. Chronic urticaria after vasectomy. Br Med J 1977; i: 1663-64. 7. Alexander NJ, Clarkson TB. Vasectomy increases the severity of dietinduced atherosclerosis in Macaca fascicularis. Science 1978; 201: 1. Blacker CP,
538-41. 8. Setchell BP, Waites GMH. The blood-testis barrier In: Greep RO, Hamilton DW, eds. Handbook of Physiology Section 7: Endocrinology. 1975; 5: 143-72. 9. Phadke AM, Padukone K. Presence and significance of autoantibodies against spermatozoa in the blood of men with obstructed vas deferens. J
Reprod Fertil 1964; 7: 163-70. 10. Ansbacher R. Sperm agglutinating and sperm immobilizing antibodies in vasectomised men. Fertil Steril 1971; 22: 629-32. 11. Bigazzi PE, Kosuda LL, Hsu KC, Andres GA. Immune complex orchitis in
vasectomised rabbits. J Exp Med 1976; 143: 382-404. 12. Hellema HWJ, Samuel T, Rümke Ph. Sperm autoantibodies as a consequence of vasectomy. Clin Exp Immunol 1979; 38: 31-36. 13. Mathews JD, Skegg DCG, Vessey MP, Konice M, Holborow EJ, Guillebaud J. Weak autoantibody reactions to antigens other than sperm after vasectomy. Br Med J 1976; ii: 1359-60. 14. Crewe P, Dawson L, Tidmarsh E, Chanarin I, Barnes RD. Autoimmune implications of vasectomy in men. Clin Exp Immunol 1976; 24: 368-69. 15. Rosemberg E, Marks SC, Howard PJ, James LP. Serum levels of follicle stimulating and luteinising hormones before and after vasectomy in men. J
Urol 1974; 111: 626-29. 16. Purvis K, Saksena SK, Cekan Z, Diczfalusy E, Giner J. Endocrine effects of vasectomy. Clin Endocrinol 1976; 5: 263-72. 17. Skegg DCG, Mathews JD, Guillebaud J, Vessey MP, Biswas S, Ferguson KM, Kitchin Y, Mansfield MD, Somerville IF. Hormonal assessment before and after vasectomy. Br Med J 1976; i: 621-22.
mediaries suffice to link any two Americans in a national population of over two hundred million. Some subsidiary comparisons were made, on tonsillectomy and appendicectomy history, socioeconomic status, history of mononucleosis, and siblings without significant findings. No linkage between specific types of leukaemia or lymphoma was evident and GREENWALD and co-workers are cautious in interpretation of their findings. But the results do seem to indicate a greater degree of acquaintanceship among both leukxmia and lymphoma cases than among controls-which is consistent with a transmissibility hypothesis and, in
particular,
one
involving symptomless intermediary
carriers. This fits in with other evidence, at least as regards Hodgkin’s disease.6,13,14 This study in New York State will no doubt stimulate further work in this sphere. The indications are that in Hodgkin’s disease acquaintanceship has to be close and long continued.6,9 When feline leukaemia was shown to be a horizontally transmissible disease the epidemiologists were asked why they had not discovered this. It is good to know that the question of the transmissibility of human leukaemias and lymphomas is now under stringent scrutiny.
Lithium and the Kidney: Grounds for Cautious Optimism WHERE lithium is
well
concerned, psychiatrists
are
of the narrow window between theraand toxic dosage. Adequate management peutic takes trouble. It demands periodic assessment of plasma levels of the drug combined with a careful briefing of the patient of the nature of the possible adverse reactions and toxic effects he may encounter. Nevertheless, in the United Kingdom alone some 50 000-100 000 patients may be under treatment at any one time so the drug enjoys considerable success. The reason is not hard to find. Lithium is the most effective drug for preventing relapses in patients with affective disorders. Thus the report from HESTBECH et al.2 of the presence of chronic nephropathy in patients on prolonged treatment (recently discussed in these columns3) set the alarm bells ringing with a vengeance. Concern became so widespread that the biological section of the World Psychiatric Association saw fit to convene a meeting4 in Copenhagen devoted to this aware
Although six separate groups reported their ability to confirm the renal-biopsy data of HESTBECH and her colleagues, the crucial question was whether
correct
control
had been Most workers had
material
in these investigations. or cadaver kidneys. However, some striking findings of KINCAID-SMITH and her colleagues5 made it clear that non-specific changes similar to those in the lithium-treated group could be identified in patients with affective disorders who had never received lithium, raising the question of whether other drugs used to treat this group
employed
used donor
of diseases might similarly be nephrotoxic. As with structure, so with function. Scientific from Canada, Denmark, Germany, Holland, Sweden, the U.K., and the U.S.A. had for the most part noted some degree of renal deficit but had, with one exception, employed controls without affective disorder. Perhaps some earlier findings of BucHT et a1.6were a pointer to what was really going on: these workers showed that, whilst urinary concentrating ability was subnormal in a group of patients on long-term lithium therapy, the deficit was more severe in a second group treated with a combination of lithium and neuroleptics. Conceptually, the most important study on functional aspects presented at the Copenhagen meeting was that of COPPEN and his colleagues,’ who compared a lithium-treated group with an affective-disorder control group, the members of which were untreated by lithium. There was little difference between the two. teams
What conclusions can be drawn from all these data? Ought the hunt to be on for some as yet unidentified nephrotoxic neuroleptic drug or other form of toxic medication? Not necessarily so. An alternative explanation might be that the non-specific renal damage in these disorders represents a hypersensitive tissue response to drugs-a predisposition connected with some aspect of the affective illness itself, making these patients particularly vulnerable to the nephrotoxic action of various drugs, not just lithium. After all, we already know that depressive subjects, untreated by lithium, concentrate their urine less well than other psychiatric patients or normal subjects.g Moreover, an electrolyte imbalance has been identified9 in this group of
a -single matter. 13. Grufferman S, Cole P, Smith PG, Lukes RJ. Hodgkin’s disease in siblings. N Engl J Med 1977; 296: 248-50. 14. Theiss W, Saner E, Rastetter J. Lymphogranulomatosis in siblings. Munchen Med Wschr 1979; 121: 309-12. 1. Hansen HE, Amdisen A. Lithium intoxication (report of 23 cases and review of 100 cases from the literature). Quart J Med 1978; 47: 123-44. 2. Hestbech J, Hansen HE, Amdisen A, Olsen S. Chronic renal lesions following long-term treatment with lithium. Kidney Int 1977; 12: 205-13. 3. Editorial. Lithium nephropathy. Lancet 1979; ii: 619-20. 4. Lithium Treatment and Kidney Damage. Meeting arranged by the biological section of the World Psychiatric Association, Copenhagen, Oct. 11-13 1979; chairman, Dr Alec Coppen.
5. Kincaid-Smith P, Burrows GD, Davies BM, Holwill B, Walter M, Walker RG. Renal biopsy findings in lithium and prelithium patients. Lancet
1979; ii: 700-01. 6. Bucht G, Wahlin A, Wentzel T, Winblad B. Njurskador vid behandling med litium och neuroleptika. Nord Psykiat Tidsskr 1978; 32: 445-46. 7. Coppen A, Cattell WR, Price R. A comparative study of renal function in lithium-treated and non-lithium-treated patients with affective disorders. Presented at 1979 WPA meeting (ref. 4). 8. Ellis CG, Coppen A, Glen AIM. Urine concentration in depressive illness. J 9.
Neurol Neurosurg Psychiatry 1971; 34: 30-31. Coppen AJ. The chemical pathology of the affective disorders. In: Scientific basis of medicine annual review, 1970; London: Athlone Press, 1970 189-210.
1057
patients which may conceivably stem from renal origins, and there are indications of a higher incidence of death from cardiovascular group3 10 which may not be unrelated.
causes
in this
The putative toxicological effect of lithium on the kidneys must not be confused with the pharmacological nephrogenic diabetes insipidus it gives rise to, whereby the sensitivity of action of antidiuretic hormone on the distal convoluted tubule is
blunted.3 Polyuria,
apparently quite benign,
seems
be a more prominent feature in Scandinavian than British patients, perhaps related to the Scandinavian practice of instructing patients on lithium to drink extra fluids.ll One impressive finding recorded at this meeting was of a five-fold increase of urinary antidiuretic hormone (arginine vasopressin, AVP), presumably compensatory, in patients on lithium.12 It is noteworthy that AVP, apart from its well-known effect on the renal tubule, also appears to act on certain sites in the cerebral vasculature, controlling the movement of water in the brain.13 Might this relationship throw some light on the way lithium works in bipolar affective disorder? Certainly such a mechanism cannot be ruled out. Indeed, the case has been made for a link between AVP and the pathogenesis of affective illness, 14,15 whilst the tricyclic antidepressant drugs seem to have a profound effect on cerebral fluid dynamics. 16 to
What message emerges for the practising psychiatrist out of this reappraisal? As SCHOU 17 pointed out, lithium is a precious drug for which we have
substitute. The consensus at this meeting was that the risk of lithium nephropathy, in the absence of lithium toxicity, is small. GLEN and his colleagues,18 in what must be the clinching argument, showed that there was no increase in mortality in a series of 810 patients exposed to lithium over ten years, compared with expectation. Nevertheless, there remains the problem of the patient with affective disorder who may have pre-existing renal damage and perhaps a history of nephritic illness. In this case nephrological assessment is mandatory
before treatment, and if a deficit is shown to exist, the assessment should be repeated at intervals during treatment. With these precautions, the risk of serious progressive renal damage is likely to be
slight.
,
Safety of Vasectomy VASECTOMY has gained increasing acceptance in the past decade. In the United Kingdom, where even the legality of the operation was in question ,until the 1960s,1 there is a fast-growing trend towards male sterilisation, and at present rates a good 10% of the husbands of women now aged 25-34 will be vasectomised by the time the wife is 35.2 In the United States about a million male sterilisations are now done each year.3 In India six million men were sterilised in 1976.4 Although the procedure is generally regarded as simple, effective, and safe, questions have been raised about possible long-term effects,S-7 resulting from antibody reactions to sperm and from hormonal imbalance or altered blood coagulation. Sperm and their specific antigens are normally sequestered from the 8immune system behind a "blood-testis barrier".g Obstruction of the vas deferens results in the release of sperm antigens, and antisperm autoantibodies appear in the circulation.9-11 These antibodies persist at least 5 years after vasectomy. 12 There have been studies of reactions to antigens other than sperm,13,14 and circulating hormone levels have been measured after vasectomy;15-17 and, despite some conflict of evi-
no
10.
Glen, AIM, Dodd M, Holme EB, Kreitman N. Mortality on lithium. Neuropsychobiology 1979; 5: 167-73. 11. Amdisen A. Monitoring of lithium treatment, the standardized serum lithium control versus clinical supervision. Presented at 1979 WPA meeting (ref.4). 12. Birch NJ, Hullin RP, Morgan DB. Renal function and plasma arginine-vasopressin during water deprivation in lithium-treated patients, normal controls and patients receiving other psychotropic drugs. Presented at 1979 WPA meeting (ref.4). See also Hullin RP, Coley VP, Birch NJ, Thomas TH, Morgan DB. Br Med J 1979; i: 1457-59. 13. Raichle M, Hartman B, Eichling J, Sharpe L. Central noradrenergic regulation of cerebral blood flow and vascular permeability. Proc Nat Acad Sci USA 1975; 72: 3726-30. 14. Gold PW, Goodwin FK, Reus VI. Vasopressin in affective illness. Lancet 1978; i: 1233-36. 15. Gold PW, Weingartner H, Ballenger JC, Goodwin FK, Post RM. Lancet 1979; u: 992-94. 16. Preskorn SH, Hartman BK. The effect of tricyclic antidepressants on cerebral fluid dynamics. Biol Psychiat 1979; 14: 235-50. 17. Schou M. Concluding remarks. Presented at 1979 WPA meeting (ref.4). 18. Glen AIM, Loudon JB, Swainson CP. Non invasive measures of renal function
following
lithium
therapy.
Presented
at
1979 WPA
meeting (ref.4).
Jackson LN. Voluntary sterilisation for family welfare. Lancet 1966; i: 971-74. 2. Bone M. Recent trends in sterilisation. Population Trends, 1978; 13: 13-16. 3. Hackett RE, Waterhouse K. Vasectomy reviewed. Am J Obstet Gynecol 1973; 116: 438-55. 4. Nortman DL, Hofstatter E. Population and Family Planning Programs, 9th ed. New York: The Population Council, 1978: 63. 5. Roberts HJ. Voluntary sterilisation in the male. Br Med J 1968; iii: 434. 6. Warin RP. Chronic urticaria after vasectomy. Br Med J 1977; i: 1663-64. 7. Alexander NJ, Clarkson TB. Vasectomy increases the severity of dietinduced atherosclerosis in Macaca fascicularis. Science 1978; 201: 1. Blacker CP,
538-41. 8. Setchell BP, Waites GMH. The blood-testis barrier In: Greep RO, Hamilton DW, eds. Handbook of Physiology Section 7: Endocrinology. 1975; 5: 143-72. 9. Phadke AM, Padukone K. Presence and significance of autoantibodies against spermatozoa in the blood of men with obstructed vas deferens. J
Reprod Fertil 1964; 7: 163-70. 10. Ansbacher R. Sperm agglutinating and sperm immobilizing antibodies in vasectomised men. Fertil Steril 1971; 22: 629-32. 11. Bigazzi PE, Kosuda LL, Hsu KC, Andres GA. Immune complex orchitis in
vasectomised rabbits. J Exp Med 1976; 143: 382-404. 12. Hellema HWJ, Samuel T, Rümke Ph. Sperm autoantibodies as a consequence of vasectomy. Clin Exp Immunol 1979; 38: 31-36. 13. Mathews JD, Skegg DCG, Vessey MP, Konice M, Holborow EJ, Guillebaud J. Weak autoantibody reactions to antigens other than sperm after vasectomy. Br Med J 1976; ii: 1359-60. 14. Crewe P, Dawson L, Tidmarsh E, Chanarin I, Barnes RD. Autoimmune implications of vasectomy in men. Clin Exp Immunol 1976; 24: 368-69. 15. Rosemberg E, Marks SC, Howard PJ, James LP. Serum levels of follicle stimulating and luteinising hormones before and after vasectomy in men. J
Urol 1974; 111: 626-29. 16. Purvis K, Saksena SK, Cekan Z, Diczfalusy E, Giner J. Endocrine effects of vasectomy. Clin Endocrinol 1976; 5: 263-72. 17. Skegg DCG, Mathews JD, Guillebaud J, Vessey MP, Biswas S, Ferguson KM, Kitchin Y, Mansfield MD, Somerville IF. Hormonal assessment before and after vasectomy. Br Med J 1976; i: 621-22.
