368 the antihistamine effects of the two drugs were similar.’ Increased appetite and weight-gain during cyproheptadine treatment have been confirmed in other groups of children8 and in adults.9-11 The weight-gain seems to be due to an increase in appetite with increased calorie intake. In cats the lateral hypothalamus shows increased neuronal activity during cyproheptadine administration, suggesting that the drug acts directly on the hypothalamus12—probably by altering serotonin activity in the appetite centre. Cyproheptadine is the first clinically proven appetite stimulant; but indications for its clinical use are few. It has been used successfully to increase the appetite of underweight patients with pulmonary tuberculosis" and may be of some limited value in the management of anorexia nervosa. 14 (Disturbingly, in India cyproheptadine is promoted as a general appetite stimulant or tonic.) Exclusion of organic causes of weight-loss is clearly important before treatment begins. Weight is gained most rapidly during the first few weeks of therapy and is lost again when the drug is stopped.’ There is evidence that serotonin is involved in the control of corticotrophin (A.C.T.H.) secretion, possibly by stimulating corticotrophin-releasing-factor secretion from the hypothalamus,15 and in normal volunteers administration of a serotonin antagonist blocks the release of cortisol during hypoglycæmia.16 Cushing’s disease seems to be due to defective hypothalamic regulation of corticotrophin release from the pituitary. Krieger et al. 17 reported rapid and sustained clinical and biochemical remission in. three cases of Cushing’s disease treated with cyproheptadine and others,18,19 but not all, 20,21 have reported similarly good results. Of 40 patients with Cushing’s disease nearly two-thirds responded well to
cyproheptadine.22
In
A.C.T.H.-dependent Cushing’s
disease cyproheptadine is certainly worthy of trial since it may avert the need for bilateral adrenalectomy and decrease the risk of Nelson’s syndrome. Little is known about the duration of remission with cyproheptadine and the effect of the drug on underlying pituitary tumour activity. In responsive cases the drug may prove valuable as an adjunct to pituitary irradiation. Cyproheptadine has been used successfully in Nelson’s syndrome, where there are very high circulatory levels of A.C.T.H.22,23 although not everyone has found it effective.24 The antiserotonin action may also be useful in migraine,zs and early trials in tardive dyskinesia and 7.
Lavenstein, A. F., Decaney, med. Ass. 1962, 180, 912.
E.
P., Lasagna, L., Van Metre, T. E. J. Am.
8. Bergen, S. S. Am. J. Dis. Child 1964, 108, 270. 9. Drash, A., Elliott, J., Lanes, H., Lavenstein, A. F., Cooke, R. E. Clin. Pharmac. Ther. 1966, 7, 340. 10. Noble, R. E. J. Am. med. Ass. 1969, 209, 2054. 11. Silverstone, T. Schuyler. D., Psychopharmac. 1975, 40, 335. 12. Chakrabarty, A. S., Pillai, R. V., Anand, B. K., Singh, B. Brain Res. 1967,
6, 561. 13. Shah, N. M. Curr med. Pract. 1968, 12, 861. 14. Benady, D. R. Br. J. Psychiat. 1970, 117, 681. 15. Krieger, D. T., Glick, S. M. J. clin. Endocr. Metab. 1974, 39, 986. 16. Plonk, J. W., Bivens, C. H., Feldman, J. M. ibid. 1974, 38, 836. 17. Krieger, D. T., Amorosa, L., Linick, F. New Engl. J. Med. 1975, 293, 893. 18. Middler, S. A. ibid. 1976, 295, 394. 19. Barnes, P., Shaw, K., Ross, E. Lancet, 1977, i, 1148. 20. Tyrell, J. B., Brooks, R. M., Forsham, P. H. New Engl. J. Med. 1976, 295, 1137. 21. Allgrove, J., Husband, P., Brook, C. G. D. Br. med. J. 1977, i, 113. 22. Krieger, D. T. New Engl. J. Med. 1976, 295, 394. 23. Hartwig, W., Kaperlik-Zaluska, A., Wilczynska, J., Migdalska, B. ibid. p. 394. 24. Cassar, J., Mashiter, K., Joplin, G. F., Rees, L. H., Gilkes, J. J. H. Lancet, 25.
1976, ii, 426. Lance, J. W. The Mechanism and Management of Headache; p. 128. Edin-
burgh,
1969.
Parkinson’s disease suggest possible benefit. Hyperphagia and weight-gain may be a disadvantage when the drug is used in the treatment of Cushing’s disease and neurological disorders. Other less troublesome effects are drowsiness (with large doses), anticholinergic effects (dry mouth, glaucoma, and urinary retention in predisposed subjects), and very occasionally central-nervoussystem stimulation with agitation, confusion, and visual hallucinations. Cyproheptadine has considerable theoretical and therapeutic possibilities. USES AND ABUSES OF OCCUPATIONAL-MORTALITY FIGURES THE Office of Population Censuses and Surveys has its latest decennial survey of occupational the data being tied in with the Census of 1971.’ No-one should complain at the interval between the reference years and the appearance of the report, for it must have been a formidable task to plan and execute the correlations here recorded, often in great detail. The report can be used to instruct or to generate hypotheses (or at least highlight areas where time spent on speculation seems warranted); and to some it will be a political weapon. With the first use none can quarrel, for the early pages provide excellent summaries of the methods and pitfalls in the study of death certificates and the occupations written on them. It is even possible to get a glimmer of understanding on the vexed question of direct and indirect standardisation. The direct method is purer, but involves more arithmetic and requires knowledge of the ages at which people died. The simpler and more familiar standardised mortality ratio (S.M.R.) seems to do perfectly well for most purposes, the result of the two approaches being much the same. But not always: the S.M.R. for pilots, navigators, and flight engineers, for example, is 86 but direct standardisation yields a figure of 151. For comparative studies care is needed when the age distribution is unusual. The search in these tables for hypotheses about the causes of diseases is encouraged by the finding of confirmation at a population level of many associations already known from prospective or other epidemiological work. Examples are bladder cancer in rubber workers, mesothelioma in those who could have been exposed to asbestos, and lung cancer in occupations where men are known to smoke a lot. Other associations are less interesting to the researcher but make sense all the same-cirrhosis among innkeepers and suicide by those who have easy access to painless and certain ways of ending life. Woodworkers have (the hazard is possibly historical) an increased mortality from nasopharyngeal carcinoma; butchers are exposed to sawdust at work and their death-rate from cancer of the maxillary sinus is higher than usual. This is one possible area for thought. Another, fraught with difficulties in interpretation and paucity of numbers, is deaths from arthritic conditions and anæmia, both of which are raised in men who do detailed work with their hands but in a sitting position. Do the anti-inflammatory drugs given for the arthritis contribute to the anaemia ?
published mortality,
1.
Occupational Mortality Office. £4·75.
1970-72.
England
and Wales. H.M.
Stationery
369
"Social class" sounds as though it ought to mean something-nowadays the standing of the family breadwinner’s occupation within the community rather than the job itself or the pay that goes with it. A television straw poll a few years ago rated nurses and miners more useful people than merchant bankers, and take-home pay is probably a less reliable guide than ever. It is not clear just what element in that intangible entity "social
class" it is that contributes A
to
the very real differences
of
mortality. graph mortality against earnings a precipitate fall over subtle changes in income followed by slower changes when pay packets become much larger. Perhaps it is how people spend rather than what they have to spend that counts, but either way the relationship cannot be simple. Housing and nutrition are not taken into account by the O.P.C.S. Education, another likely candidate, will be reflected in occupation. The O.P.C.S. falls back on the concept of "way of life", but whatever it is it is real enough, as suggested by figures for childhood deaths-i.e., deaths after infancy, when social-class influences on maternity may have a residual effect, but before occupation can be directly relevant. Childhood mortality doubles from social class in
shows
v, and for violent deaths of all types the differential is shattering and contributes greatly to the lower life expectancy of the unskilled worker’s child. The differential, at birth between classes I and v is around 10% (7-17 years). Differences are present at school, before school, and in the womb, and they probably persist after retirement; yet those discernible during the working years can rarely be tied in with specific occupational risk. Figures for trends in death-rates between 1931 and 1961 showed a widening gap between the banker and the labourer: the rich were living longer, and the poor were by implication getting relatively less healthy. However, figures for 1971, especially with the necessary adjustment for changes in classification, show a less striking picture, and the O.P.C.S. warns of the confounding problems of comparing social-class gradients over the years: "Generally attempts to overcome these problems have been unsuccessful and the resultant measures of trends remain unconvincing." i to
PREVENTION OF CHEST DISEASE A SYMPOSIUM last month on Progress in the Prevention of Chest Disease paid tribute to the work of Dr Horace Joules, who was physician and medical director at Central Middlesex Hospital from 1937 to 1962. Twentyone years ago Joules wrote to The Lancet, "Unless trends are modified, a million people in England and Wales will die of [lung cancer] before the end of the century".’ At present rates this figure will be reached by
1987. Sir Richard Doll cited the latest evidence from the Swedish Twin Study which suggested that, in monozygotic as well as dizygotic twins, the heavier smoker had a greater liability to lung cancer. If this finding was confirmed by longer observation, it would add substantially to the already massive evidence that cigarettes cause lung cancer. Doll also stressed that different constituents 1. Joules, H. Lancet, 1956,
ii, 1171.
of tobacco could lead to different types of cancer. A reduction of tar in cigarette smoke might not be associated with a reduction of nitrosamines and might therefore produce different effects. The 43% reduction of tar in cigarettes since 1965 was probably the main reason for the fall of male lung-cancer rates. But the carbonmonoxide content of cigarettes was not falling, which could be one reason why the death-rates (in Britain) from coronary heart-disease in men continue to rise. However, Doll was encouraged that, as well as doctors and other health workers, teachers, writers, journalists, and university students were also reducing their cigarette
consumption.
a letter to the British Medical Journal in 19532 Joules said, "Our long continued national smoking
In
are associated with a bronchitis morbidity or morwhich is the highest in any country where statistics are kept. The irritant effects of cigarettes combines with the general atmospheric pollution of our industrial cities and the vitiated atmosphere of factory, foundry, and mine to produce a chronic and deteriorating lung condition which is made worse by each winter’s virus infections". Prof. Charles Fletcher reviewed present-day views on the cause of chronic bronchitis and Prof. Patrick Lawther spoke on atmospheric pollution. The importance of smoking in the production of chronic bronchitis had been abundantly confirmed in numerous studies, as had the benefits of -giving up cigarettes. Air pollution, formerly very important, was now a much less important factor. Joules had seen clearly the importance of air pollution, but perhaps he had focused his attack too strongly on the power-station chimneys and cooling towers; the major culprit had been the domestic fire. Evidence to support the role of infection as a major cause of chronic bronchitis was lacking, but factors related to social class still seemed to have an unex-
habits
tality
plained importance. Turning to disease control in the local community, Dr Martin McNicol discussed the increasing incidence of tuberculosis in Brent. Recently arrived immigrants were the most severely affected, and the domiciliary approach pioneered under very different conditions by Toussaint and Joules remained relevant. A domiciliary chemotherapy programme now made possible not only effective therapy but also a reduction in need for hospital beds, despite a very substantial increase in incidence of tuberculosis. Finally, Sir George Godber pointed to the philosophic changes which had occurred in preventive medicine. From its earlier successes in reducing food and water pollution and other environmental hazards, it was now trying to persuade people to change their life-styles; but to further this aim he believed that Government would need to apply restrictions on the promoters rather than on users, especially with regard to tobacco and alcohol. Successive health ministers had been left to negotiate from weakness, while the tobacco industry skilfully fought a delaying action. Smoking was currently the largest avoidable factor causing premature death and excess invalidity in our society. Despite this the practice was promoted extensively for commercial gain. The control of smoking had become the paradigm of health promotion by voluntary change. 2. Joules, H. Br. med.
J. 1953, ii, 441.
cyproheptadine.22
In
A.C.T.H.-dependent Cushing’s
disease cyproheptadine is certainly worthy of trial since it may avert the need for bilateral adrenalectomy and decrease the risk of Nelson’s syndrome. Little is known about the duration of remission with cyproheptadine and the effect of the drug on underlying pituitary tumour activity. In responsive cases the drug may prove valuable as an adjunct to pituitary irradiation. Cyproheptadine has been used successfully in Nelson’s syndrome, where there are very high circulatory levels of A.C.T.H.22,23 although not everyone has found it effective.24 The antiserotonin action may also be useful in migraine,zs and early trials in tardive dyskinesia and 7.
Lavenstein, A. F., Decaney, med. Ass. 1962, 180, 912.
E.
P., Lasagna, L., Van Metre, T. E. J. Am.
8. Bergen, S. S. Am. J. Dis. Child 1964, 108, 270. 9. Drash, A., Elliott, J., Lanes, H., Lavenstein, A. F., Cooke, R. E. Clin. Pharmac. Ther. 1966, 7, 340. 10. Noble, R. E. J. Am. med. Ass. 1969, 209, 2054. 11. Silverstone, T. Schuyler. D., Psychopharmac. 1975, 40, 335. 12. Chakrabarty, A. S., Pillai, R. V., Anand, B. K., Singh, B. Brain Res. 1967,
6, 561. 13. Shah, N. M. Curr med. Pract. 1968, 12, 861. 14. Benady, D. R. Br. J. Psychiat. 1970, 117, 681. 15. Krieger, D. T., Glick, S. M. J. clin. Endocr. Metab. 1974, 39, 986. 16. Plonk, J. W., Bivens, C. H., Feldman, J. M. ibid. 1974, 38, 836. 17. Krieger, D. T., Amorosa, L., Linick, F. New Engl. J. Med. 1975, 293, 893. 18. Middler, S. A. ibid. 1976, 295, 394. 19. Barnes, P., Shaw, K., Ross, E. Lancet, 1977, i, 1148. 20. Tyrell, J. B., Brooks, R. M., Forsham, P. H. New Engl. J. Med. 1976, 295, 1137. 21. Allgrove, J., Husband, P., Brook, C. G. D. Br. med. J. 1977, i, 113. 22. Krieger, D. T. New Engl. J. Med. 1976, 295, 394. 23. Hartwig, W., Kaperlik-Zaluska, A., Wilczynska, J., Migdalska, B. ibid. p. 394. 24. Cassar, J., Mashiter, K., Joplin, G. F., Rees, L. H., Gilkes, J. J. H. Lancet, 25.
1976, ii, 426. Lance, J. W. The Mechanism and Management of Headache; p. 128. Edin-
burgh,
1969.
Parkinson’s disease suggest possible benefit. Hyperphagia and weight-gain may be a disadvantage when the drug is used in the treatment of Cushing’s disease and neurological disorders. Other less troublesome effects are drowsiness (with large doses), anticholinergic effects (dry mouth, glaucoma, and urinary retention in predisposed subjects), and very occasionally central-nervoussystem stimulation with agitation, confusion, and visual hallucinations. Cyproheptadine has considerable theoretical and therapeutic possibilities. USES AND ABUSES OF OCCUPATIONAL-MORTALITY FIGURES THE Office of Population Censuses and Surveys has its latest decennial survey of occupational the data being tied in with the Census of 1971.’ No-one should complain at the interval between the reference years and the appearance of the report, for it must have been a formidable task to plan and execute the correlations here recorded, often in great detail. The report can be used to instruct or to generate hypotheses (or at least highlight areas where time spent on speculation seems warranted); and to some it will be a political weapon. With the first use none can quarrel, for the early pages provide excellent summaries of the methods and pitfalls in the study of death certificates and the occupations written on them. It is even possible to get a glimmer of understanding on the vexed question of direct and indirect standardisation. The direct method is purer, but involves more arithmetic and requires knowledge of the ages at which people died. The simpler and more familiar standardised mortality ratio (S.M.R.) seems to do perfectly well for most purposes, the result of the two approaches being much the same. But not always: the S.M.R. for pilots, navigators, and flight engineers, for example, is 86 but direct standardisation yields a figure of 151. For comparative studies care is needed when the age distribution is unusual. The search in these tables for hypotheses about the causes of diseases is encouraged by the finding of confirmation at a population level of many associations already known from prospective or other epidemiological work. Examples are bladder cancer in rubber workers, mesothelioma in those who could have been exposed to asbestos, and lung cancer in occupations where men are known to smoke a lot. Other associations are less interesting to the researcher but make sense all the same-cirrhosis among innkeepers and suicide by those who have easy access to painless and certain ways of ending life. Woodworkers have (the hazard is possibly historical) an increased mortality from nasopharyngeal carcinoma; butchers are exposed to sawdust at work and their death-rate from cancer of the maxillary sinus is higher than usual. This is one possible area for thought. Another, fraught with difficulties in interpretation and paucity of numbers, is deaths from arthritic conditions and anæmia, both of which are raised in men who do detailed work with their hands but in a sitting position. Do the anti-inflammatory drugs given for the arthritis contribute to the anaemia ?
published mortality,
1.
Occupational Mortality Office. £4·75.
1970-72.
England
and Wales. H.M.
Stationery
369
"Social class" sounds as though it ought to mean something-nowadays the standing of the family breadwinner’s occupation within the community rather than the job itself or the pay that goes with it. A television straw poll a few years ago rated nurses and miners more useful people than merchant bankers, and take-home pay is probably a less reliable guide than ever. It is not clear just what element in that intangible entity "social
class" it is that contributes A
to
the very real differences
of
mortality. graph mortality against earnings a precipitate fall over subtle changes in income followed by slower changes when pay packets become much larger. Perhaps it is how people spend rather than what they have to spend that counts, but either way the relationship cannot be simple. Housing and nutrition are not taken into account by the O.P.C.S. Education, another likely candidate, will be reflected in occupation. The O.P.C.S. falls back on the concept of "way of life", but whatever it is it is real enough, as suggested by figures for childhood deaths-i.e., deaths after infancy, when social-class influences on maternity may have a residual effect, but before occupation can be directly relevant. Childhood mortality doubles from social class in
shows
v, and for violent deaths of all types the differential is shattering and contributes greatly to the lower life expectancy of the unskilled worker’s child. The differential, at birth between classes I and v is around 10% (7-17 years). Differences are present at school, before school, and in the womb, and they probably persist after retirement; yet those discernible during the working years can rarely be tied in with specific occupational risk. Figures for trends in death-rates between 1931 and 1961 showed a widening gap between the banker and the labourer: the rich were living longer, and the poor were by implication getting relatively less healthy. However, figures for 1971, especially with the necessary adjustment for changes in classification, show a less striking picture, and the O.P.C.S. warns of the confounding problems of comparing social-class gradients over the years: "Generally attempts to overcome these problems have been unsuccessful and the resultant measures of trends remain unconvincing." i to
PREVENTION OF CHEST DISEASE A SYMPOSIUM last month on Progress in the Prevention of Chest Disease paid tribute to the work of Dr Horace Joules, who was physician and medical director at Central Middlesex Hospital from 1937 to 1962. Twentyone years ago Joules wrote to The Lancet, "Unless trends are modified, a million people in England and Wales will die of [lung cancer] before the end of the century".’ At present rates this figure will be reached by
1987. Sir Richard Doll cited the latest evidence from the Swedish Twin Study which suggested that, in monozygotic as well as dizygotic twins, the heavier smoker had a greater liability to lung cancer. If this finding was confirmed by longer observation, it would add substantially to the already massive evidence that cigarettes cause lung cancer. Doll also stressed that different constituents 1. Joules, H. Lancet, 1956,
ii, 1171.
of tobacco could lead to different types of cancer. A reduction of tar in cigarette smoke might not be associated with a reduction of nitrosamines and might therefore produce different effects. The 43% reduction of tar in cigarettes since 1965 was probably the main reason for the fall of male lung-cancer rates. But the carbonmonoxide content of cigarettes was not falling, which could be one reason why the death-rates (in Britain) from coronary heart-disease in men continue to rise. However, Doll was encouraged that, as well as doctors and other health workers, teachers, writers, journalists, and university students were also reducing their cigarette
consumption.
a letter to the British Medical Journal in 19532 Joules said, "Our long continued national smoking
In
are associated with a bronchitis morbidity or morwhich is the highest in any country where statistics are kept. The irritant effects of cigarettes combines with the general atmospheric pollution of our industrial cities and the vitiated atmosphere of factory, foundry, and mine to produce a chronic and deteriorating lung condition which is made worse by each winter’s virus infections". Prof. Charles Fletcher reviewed present-day views on the cause of chronic bronchitis and Prof. Patrick Lawther spoke on atmospheric pollution. The importance of smoking in the production of chronic bronchitis had been abundantly confirmed in numerous studies, as had the benefits of -giving up cigarettes. Air pollution, formerly very important, was now a much less important factor. Joules had seen clearly the importance of air pollution, but perhaps he had focused his attack too strongly on the power-station chimneys and cooling towers; the major culprit had been the domestic fire. Evidence to support the role of infection as a major cause of chronic bronchitis was lacking, but factors related to social class still seemed to have an unex-
habits
tality
plained importance. Turning to disease control in the local community, Dr Martin McNicol discussed the increasing incidence of tuberculosis in Brent. Recently arrived immigrants were the most severely affected, and the domiciliary approach pioneered under very different conditions by Toussaint and Joules remained relevant. A domiciliary chemotherapy programme now made possible not only effective therapy but also a reduction in need for hospital beds, despite a very substantial increase in incidence of tuberculosis. Finally, Sir George Godber pointed to the philosophic changes which had occurred in preventive medicine. From its earlier successes in reducing food and water pollution and other environmental hazards, it was now trying to persuade people to change their life-styles; but to further this aim he believed that Government would need to apply restrictions on the promoters rather than on users, especially with regard to tobacco and alcohol. Successive health ministers had been left to negotiate from weakness, while the tobacco industry skilfully fought a delaying action. Smoking was currently the largest avoidable factor causing premature death and excess invalidity in our society. Despite this the practice was promoted extensively for commercial gain. The control of smoking had become the paradigm of health promotion by voluntary change. 2. Joules, H. Br. med.
J. 1953, ii, 441.
