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The Use of Prophylactic Drugs for Asthma in General Practice A. G. WARD MAN, MRCP (UK), Research Registrar, and N. J. COOKE, BSc, FRCP, Consultant Physician Department of Respiratory Medicine, The General Infirmary Leeds V. BINNS, Statistical Assistant, and A.. D. CLAYDEN, BSc, PhD, Senior Lecturer in Medical Statistics Department of Community Medicine and General Practice, University of Leeds Good control of asthma frequently depends on the correct use of an appropriate prophylactic drug. Enquiries into the circumstances of deaths from asthmafl] suggested that such therapy is often under-used or not used at all in chronic unstable asthma. This has been confirmed in new hospital out-patient referrals; patients with asthma were either not prescribed prophylaxis[2] or used the agents irregularly[3], and supported by a limited study of adult asthma in a single London general practice[4]. These reports indicate a need for improving the care of asthma in the community. Patients and Methods Tn 1982-83 patients (aged 16-80 years) from five group practices in three cities in West Yorkshire were inter- viewed. Patients were selected by two methods: in one practice with a disease index asthmatics receiving drug therapy were included. In the other practices doctors recorded all asthmatics given a prescription for airflow obstruction during a two-month period. Patients were asked to attend their surgery for an interview during which a questionnaire was completed by one author A.G.W. (who worked independently of the practices). Disease severity was assessed by a symptom score (Table 1). This score was modified from a published daily diary for asthma assessment[5]. The patient was asked to grade day and night-time symptoms in the month before inter- view. Statistical analysis was by the standard chi-squared test. Results A total of 201 asthmatics (mean age 45 years, maleifemale 1:1) was interviewed; 134 (67 per cent) used either corticosteroids (inhaled or oral), sodium cromoglycate (SCG) or ketotifen; 32 (16 per cent) did not use these drugs despite a score of 2 or 3 for day or night-time symptoms. Table 1. Symptom score for asthma. Daytime 0 No wheeze. Able to do all activities. 1 Slight wheeze. Able to do most activities. 2 Moderate wheeze. Activities limited regularly by frequent wheeze. 3 Severe wheeze. Activities constantly curtailed by wheeze. Night-time 0 No nocturnal wheeze. 1 Slight nocturnal wheeze. Woken occasionally (<once a week). 2 Moderate nocturnal wheeze. Woken frequently (1-3 times a week). 3 Severe nocturnal wheeze. Woken very frequently (>3 times a week). Table 2. The number and percentage of patients using different types of prophylactic drug. Patients No_ % Total patients 201 Total using prophylactic drugs 134 67 Using inhaled corticosteroids (IC) 79 40 ?via an aerosol 70 ?via a dry powder inhaler 9 Using sodium cromoglycate (SCG) 50 25 ?SCG Compound 28 ?SCG Plain 18 ?SCG aerosol 4 Using systemic corticosteroids (SC) 29 14 Using Ketotifen 3 1 The numbers of patients using prophylactic drugs are shown in Table 2: 26 patients (13 per cent) used combina- tions of drugs, including 15 (7 per cent) using inhaled corticosteroid (IC) and systemic corticosteroid (SC) and 8 (4 per cent) using IC and SCG. Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 45 Problems with the Use of Prophylactic Inhalers Of 121 patients using prophylactic inhalers 13 (11 per cent) took treatment entirely on demand. The rest used regular treatment, but 23 (19 per cent) took extra doses on demand, 27 (22 per cent) omitted at least one pre- scribed dose daily and a further 9 (7 per cent) admitted to both errors. More patients using SCG compound took therapy on demand (either partially or totally) (18 of 28, 64 per cent) than those using SCG Plain (8 of 22, 36 per cent) (i5<0.05). When compared with those who never used prophylac- tic drugs on demand (60 of 76, 79 per cent), significantly fewer (,P<0.01) patients using therapy on demand (total- ly or partially) understood the concept of a prophylactic drug (19 of 45, 42 per cent). In the first group the concept was understood by equal proportions of those who were fully compliant (37 of 49, 76 per cent) and those who omitted at least one treatment daily (23 of 27, 85 per cent). Of 74 patients using aerosol IC or SCG, 10 (14 per cent) had doubtfully efficient and 4 (6 per cent) totally inefficient inhaler techniques[6]. Problems with Prescribing Prophylactic Inhalers Fourteen compliant patients (12 per cent of prophylactic inhaler users) were prescribed below standard doses (<400/ig beclomethasone dipropionate or equivalent, or <4 capsules SCG daily) and 19 (15 per cent only) standard doses, despite both groups having a score of 2 or 3 for day or night-time symptoms suggesting that ad- ditional therapy might have been beneficial. The pres- cribed daily dosage of IC and SCG are shown in Table 3. Combining the problems of use and prescribing, 32 (26 per cent) patients using prophylactic inhalers had a score of 2 or 3 for day or night-time symptoms but all these patients had a poor inhaler technique, used therapy entirely on demand, omitted at least one treatment daily, or were compliant but were prescribed a below standard dose. The Use of Systemic Corticosteroids Twenty-nine (14 per cent) patients used regular SC; 12 (41 per cent) did not use IC and 8 (28 per cent) had never had IC at any time. Of the 29, 27 had been on continuous therapy for at least five years. Previous Out-patient Attendance One hundred and forty-three (71 per cent) of the asthma- tics had attended a hospital out-patient department at some time with chest symptoms and 52 (26 per cent) had attended within the previous year. Discussion Owing to the selection methods employed there was a bias in this study towards symptomatic asthmatics on regular drug treatment. Estimates of the prevalence of adult asthma in the community vary[7] but if a prevalence of 3 per cent is accepted, our study represents a selected sample of 23 per cent. The importance of the general practitioner in the management of asthma is emphasised by the finding that only a quarter of patients had attended a hospital clinic in the previous year. With the advantage of continuity of care general practice management may be preferable[8] and therefore knowledge of the main therapeutic prob- lems in the community is important. SCG Compound was more popular than SCG Plain but there is little evidence to support the use of the combination preparation[9]. Frequent use on demand suggests that the immediate relief obtained by the iso- prenaline in the compound may mean that patients are confused about the role of the drug[10]. Though standard doses are usually sufficient, some patients may improve on larger doses of SCG[11] and IC[12]. It is certainly difficult to defend the prescription of less than standard doses for patients with poorly controlled symptoms. Non-compliance was a major prob- lem with prophylactic inhaler therapy and two main types were found: the use of treatment on demand and the omission of daily doses in an otherwise regular inhaler user. The latter type was not associated with a poor understanding of prophylactic therapy and this may explain why education may fail to improve compli- ance[13]. The prescription of less frequent daily dose regimes may be helpful in these circumstances. The use of inhaled rather than systemic corticosteroids where possible is now established practice and 400/ig of beclomethasone dipropionate and 7.5mg of prednisolone are considered to be roughly equivalent[14]. It was a surprise to find, therefore, that 41 per cent of those on SC did not use IC. It is likely that substantial reductions in the use of SC would be possible in these patients. Table 3. The prescribed doses of inhaled corticosteroid and sodium cromoglycate (2 puffs being 100ng beclomethasone diproprionate or equivalent, 1 capsule being 20mg sodium cromoglycate or equivalent), and the number (%) of patients taking each dose. Daily dose Drug Unknown 4 puffs 6 puffs 8 puffs >8 puffs 2 caps 3 caps 4 caps > 4 caps or less Inhaled corticosteroid 3 (4%) 12 (17%) 22 (32%) 37 (54%) 5 (7%) Sodium cromoglycate 3 (6%) 14 (28%) 17 (34%) 15 (30%) 1 (2%) 46 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 This survey indicates the occurrence of major problems in the use of prophylactic drugs for bronchial asthma in general practice, despite postgraduate education in this field promoted both by the profession and the pharma- ceutical industry in recent years. Clearly this effort must be sustained and attempts made to encourage general practitioners, who have not done so, to attend relevant meetings. Apart from stressing the importance of the recognition of asthma, many general practitioners require re-education in the therapeutics of prophylactic drugs. Acknowledgements We wish to thank: the Yorkshire Regional Health Au- thority and Allen & Hanbury Limited for financial support; Mrs Kathryn Marsden for secretarial assistance; and the general practitioners who allowed us to interview their patients in their surgeries. References 1. British Thoracic Association (1982) British Medical Journal, 285, 1251. 2. Stellman, J. L., Spicer, J. E. and Cayton, R. M. (1982) Thorax, 37, 218. 3. MacFarlane, J. T. and Lane, D.J. (1980) Thorax, 35, 477. 4. Shee, C. D., Poole, D. and Cameron, I. R. (1980) Thorax, 35, 236. 5. Stark, J. E. (1980) In Topical steroid treatment for asthma and rhinitis, p.81. (ed N. Mygind and T.J. Clark). London: Bailliere Tindall. 6. Paterson, I. C. and Crompton, G. K. (1976) British Medical Journal, 1, 76. 7. Gregg, I. (1977) In Asthma, p.214. (ed T. J. H. Clark and S. Godfrey). London: Chapman and Hall. 8. Editorial (1981) Journal of the Royal College of General Practitioners, 31, 323. 9. Godfrey, S. (1977) In Asthma, p.272. (ed T. J. H. Clark and S. Godfrey). London: Chapman and Hall. 10. Gregg, I. (1982) In Child care in general practice, p.283. (ed C. Hart). Edinburgh: Churchill Livingstone. 11. Bernstein, L. (1981) Journal of Allergy and Clinical Immunology, 68, 247. 12. Toogood, J. H., Lefcoe, N. M., Haines, D. S. M. et al. (1977) Journal of Allergy, 59, 298. 13. Sackett, D. L., Haynes, R. B., Gibson, E. S. et al. (1975) Lancet, 1, 1205. 14. British Thoracic and Tuberculosis Association (1975) Lancet, 2, 469.

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The Medical Career Structure in 1985 R.EH. THOMPSON, dm, frcp Consultant Physician, St Thomas' Hospital, London The recent cuts in National Health Service staffjl], small though they may be for doctors, should have stimulated the profession to consider the rapidly increasing problems with its career structure. The Select Committee on Social Services concentrated in its Fourth Report (the Short Report)[2] on medical manpower, and made some perti- nent suggestions for improvements, most of which have been accepted in principle by the Department of Health and Social Security[3], Unfortunately, long-term solu- tions will require greater resources, at a time when unplanned cuts are suddenly imposed, and annual inter- regional relocations of money make 'losing' regions des- perately short of money for maintaining services, let alone allowing for increases of staff. Mr David Bolt has projected that in the year 2000 there will be about 130,000 active doctors in the UK, compared with 89,000 in 1979[4], This increase over 21 years is due to the gradual increase in the number of medical students qualifying, now about 4,000 a year, fewer doctors emi- grating, and substantial immigration. Fears of mass unemployment among doctors are fuelled by the increas- ing number registering as unemployed[5], although this can only be an approximation of the true number unem- ployed. Interestingly, more than half the unemployed doctors are in the four Thames regions, suggesting that a reluctance to move to other regions may be a contributory factor; the DHSS insists that there are at present jobs for everyone, albeit some are less attractive and in less attractive areas of the country. At the end of 1983 the British Medical Association estimated that 3,000 doctors were unemployed[6], al- though this does include temporary unemployment. Will there be large-scale unemployment? Breaking down Mr Bolt's figures, one sees that if the policy of reducing the average list to 1,700 continues, the number of general practitioners will have increased by 50 per cent by the year 2000, leaving perhaps as many as 25,000 extra career (i.e. permanent) posts to be found in the hospital and community services. At the present slow rate of consultant expansion this seems impossible. However, such estimates have in the past frequently been altered by unforeseen events. There are three reasons why the number of extra hospital posts needed may be substantial- ly lower than predicted. First, the age of retirement is likely to continue to fall, owing to hospital doctors being able to increase their pension rights by buying added years, and to the well- founded pressure to prevent any doctor over 65 practising in the Health Service. The statistic that doctors retiring at 60 live to a greater age than those retiring later may also give impetus to earlier retirement. Second, it is projected that 40 per cent of active doctors in the year 2000 will be women, and therefore a number (perhaps also of men) will be working part-time, which will reduce the number of whole-time equivalents. Third, there is scope for a substantial reduction in the number of overseas doctors staying in the UK in career posts. The effect of these three variables together could reduce Mr Bolt's projection for the year 2000 by 30,000 doctors, although this would be optimistic. Most of us concentrate our energies on the problems of our own specialty and our own region. Although there are shortage specialties such as Geriatrics, Histopathology, Anaesthetics and Radiology, in which there are more career posts than suitably trained applicants, most hospi- tal specialties are now full or over-full. For example, in oral surgery there are only 5-7 consultant vacancies annually, but 38 senior registrars[7]. Each senior regis- trar is therefore likely to have to wait about six years in the grade, which is surely a waste of his talent and training. The current slowing down in the creation of new posts makes the future ever more gloomy. The Royal College of Surgeons has analysed the prospects for junior general surgeons[8], and their figures suggest that the number of senior registrars was just about right for the consultant appointments in 1978-9, but since then the fall in the number of consultant appointments[9-l 1] may have upset this balance. The numbers in the more junior surgical grades are more unbalanced, for there are three times as many registrars and senior house officers as senior registrars. However, many registrars move from general surgery into the surgical sub-specialties, and about half of the surgical registrars and SHOs qualified overseas. If overseas doc- tors continue to come for a limited period of training only, it should be possible to retain most of these grades. The College suggested that there should be a substantial reduction in the number of juniors, and consequently more sharing of them between consultant firms, together with an expansion in the number of consultants and senior registrars. Similar or worse problems exist in medical specialties such as rheumatology, gastroenterol- ogy and cardiology[12]. The Short Report[2] suggested, and the DHSS has implemented[13], a standstill in the number of SHO posts in each region. The DHSS insists that there are sufficient SHO posts in the country to allow all UK graduates to spend at least three years in the grade. Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 31 Presumably, therefore, the current difficulties post-regis- tration doctors experience in obtaining SHO posts are due to limiting their choice to the more attractive posts in certain parts of the country. Increasing immobility within the grade may also be due to current SHOs having difficulty in finding registrar posts to which to move. There are even minor problems when placing newly qualified students in House Officer posts, although in 1983 only a handful were without a post[14], and it is understood that these posts are to be protected against manpower cuts. The problem therefore lies in the imbalance between SHO and registrar numbers on the one hand and senior registrar and career posts on the other. This was caused by a rapid expansion of junior posts, the majority of which are now filled by overseas graduates[15], and only a slow expansion of the senior grades. In certain special- ties there is also an imbalance between senior registrars and likely consultant vacancies. What is the solution? First, the General Medical Council has proposed[16] a system of careful sponsorship for overseas graduates (Overseas Doctors Training Scheme) and the BMA has made similar proposals[17]. Overseas doctors would be granted limited registration for up to five years, provided the post offered suitable education and training, and not just service. Full registration, and therefore the possibility of remaining in the UK, would be severely limited, for it cannot be right to take young doctors from developing countries, and encourage them not to return and use their skills there. This scheme of sponsorship should allow overseas doctors to continue the long tradition of medical training in the UK[18]. Second, I oppose reducing the number of SHOs. Under the sponsorship scheme many SHO posts will continue to be filled by overseas graduates, and, provided the posts are properly supervised, their incumbents should gain proper education. It will be more necessary than ever for the College's Sub-Committee on General Professional Training of the Committee on General Internal Medicine to ensure that these overseas incum- bents are not abused. However, the Short Report sugges- tion^], supported by the DHSS[3], that we should no longer rely on their service contribution, must be wrong, for doctors surely know that learning to ride a bicycle or to practise medicine needs personal practice. Standing on ward rounds or behind surgeons' broad backs as a supernumerary is not learning and deludes those coming to the UK for training. However, if there should be a large decrease in the number of overseas graduates coming to the UK, the number of SHO posts will have to be reduced, which will place a severe strain on senior staff, particularly in less well staffed hospitals and in shortage specialties. In my opinion, the number of SHO posts should not be reduced at least until consultant numbers are increased. Another option is for the Colleges to insist on an increased minimum time in the SHO grade before entering general practice. This would probably be unpopular but, with the increased amount of broad knowledge required by to- day's general practitioners, is worth considering. At present the sudden, unplanned freeze of SHO posts has made worthwhile local changes in junior staffing difficult and, like the recent imposition of financial cuts, does nothing to encourage the profession to plan ahead. Third, part-time working should be encouraged, neces- sarily predominantly among women. This will be difficult in some specialties, but easier in others. Fourth, retirement before 65 should be stimulated, if necessary financially by the DHSS, and in my opinion the rule in the hospital service that no doctor should be allowed to practise beyond the 65th birthday should be extended to general practice. Fifth, more flexibility[3] between specialties and be- tween hospital and general practice should be encour- aged. Many younger members of the profession feel that the Colleges and Faculties have acted unwisely in forcing the ramshackle edifice of the Joint Committee on Higher Medical Training on them. It may have been necessary to provide a form of accreditation for entry into the Euro- pean Community, and inspection and approval of posts has helped to force health authorities to improve their educational content, but the rigidity imposed on training programmes has produced junior doctors worried about how to obtain accreditation, and health authorities and appointments committees unsure of how much weight to attach to this new label. A candidate's ability and promise ought to be more important than an approved course of training that may have failed in its objective, and in many cases the new appointee in a career post does work which is quite different from that in his last training post. This rigidity has made it difficult to change from specialty to specialty, or from hospital to general practice, and in particular discourages junior doctors in popular special- ties from moving to shortage specialties. In my view individuals should be accredited only after appointment to a career post. Another form of flexibility might be for part of the work of shortage specialties to be taken on by other specialists. There is a welcome move towards combining geriatrics with general medicine[19]; but the radiology or histopath- ology of a specialty could be combined with clinical work in that specialty, so that a nephrologist, for instance, might examine renal biopsy specimens and intravenous urograms. Some lateral thinking could be beneficial. Finally, there must be a sustained increase in the number of hospital career posts, as suggested in the Short Report[2] and supported by the Secretary of State[3,13] when he asked Regional Health Authorities to plan to double the number of consultants by 1996. But because of shortage of money there is a decreasing number of new consultant posts being created[9,10], although the Health Minister disputes this[20], so there will have to be many new appointments in 1995 if this pledge is to be fulfilled. It is also the policy of the DHSS to increase the number of general practitioners and thus to move to an average list size of about 1,700[4]. Although senior hospital doctors seem to be divided over the need to increase consultant posts, it seems reasonable that more patients should be seen and treated by fully trained doctors; doctors arrange for their colleagues, rather than their colleagues' regis- trar, to treat them or their friends. The fear of a greatly changed consultant style of work without help from Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 juniors is understandable[8, 21-23], but a carefully ex- panded consultant grade will provide a better career structure for a larger number of junior doctors. The concept of a sub-consultant grade was rejected, correctly I believe, in the Short Report[2]. Expansion of the consultant grade requires extra re- sources, for I am not convinced by the suggestion made in the Short Report[2] and later in the debate in the House of Commons[24], that consultants save money by using resources more efficiently. It may be so, but there is no good evidence for or against this. Every comparison of the Health Service with the resources of those of our Euro- pean neighbours or with North America confirms our miserly attitude[25,26]. It may not be possible to increase our gross national product, but the percentage spent on the Health Service[27], the number of doctors[25] and the number of medical students[25] is far below that of most comparable countries. Although successive governments trumpet their financial allocations to the Health Ser- vice[28], repeated analyses of the resources allocated over the years[29-31] and the 1983-84 cash limits[32,33] show that we are not even providing for the increased needs of an ageing population or expensive technology[34,35], let alone allowing for any growth to try to close the gap with other health services[36]. If the UK wants a Health Service that will in future compare in quality with those of other countries, the numbers of consultants and general practitioners will have to be increased, and this will go a long way towards solving the present frozen manpower structure. New money will be required, as well as redistribution within budgets. We must not bury our heads in the sand and hope that the present juniors will somehow all make it to a career post. References 1. Deitch, R. (1983) Lancet, 2, 583. 2. Fourth Report of the Social Services Committee (Short Report) (1981) Medical Education. London: HMSO. 3. Government response to the Fourth Report of the Social Services Committee (1982) DHSS. London: HMSO. 4. Bolt, D. E. (1983) Medical manpower in the year 2000. London: British Medical Association. 5. 'Medical Unemployment'. Information from DHSS, February 1983. 6. Hospital Doctor (1983) Vol. C3, No. 47. 7. Alty, H. M. (1983) Health Trends, 15, 64. 8. Report on surgical manpower and the career structure (1981) London. Royal College of Surgeons. 9. British Medical Journal {1983) 285, 1591. 10. British Medical Journal (1983) 287, 1395. 11. British Medical Journal (1983) 286, 1675. 12. British Medical Journal (1983) 287, 243. 13. DHSS (1982) Health Circular HC/82/4. 14. British Medical Journal {1983) 287, 1152. 15. Todd, G. B. and Sheldrick, K. B. (1983) British Medical Journal, 286, 1997. 16. Williams, D. I. (1983) in Report of General Medical Council for 1982. London: GMC. 17. British Medical Journal (1983) 286, 1916. 18. Williams, D. I. and Paton, A. (1983) British Medical Journal, 287, 1492. 19. Grimley Evans, J. (1983) Lancet, 1, 1430. 20. British Medical Journal (1984) 288, 657. 21, 22. 23. 24. 25. 26. 27. 28, 29. 30 31 32 33, 34. 35 Pentecost, A. (1983) British Medical Journal, 28 7, 305. Batchelor, G. N. (1983) British Medical Journal, 286, 479. Kathel, B. L. ibid, p. 806. Hansard, 18th June 1982. Day, S. C. (1983) Lancet, 2, 339. Lancet (1984) 1, 749. Wilson, M. A. (1983) British Medical Association document (HJS 14a). British Medical Journal (1983) 286, 1079. Hansard, Social Services, 25th April 1983. Deitch, R. (1983) Lancet, 1, 659. Russell, W. (1984) British Medical Journal, 288, 873. British Medical Journal (1983) 287, 374. Ibid. (1983) p. 700. Maxwell, R.J. (1981) Health and Wealth. Lexington, USA: Lexing- ton Books. Royal College of Nursing (1983) British Medical Journal, 287, 1566. Maxwell, R. J. (1984) in Health Care UK 1984 (ed A. Harrison and J. Gretton.) CIPFA.

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Governments may Damage your Health The FitzPatrick Lecture 1984 SIR GORDON WOLSTENHOLME, obe, MB, FRCP Harveian Librarian, Royal College of Physicians For a Harveian Librarian it is a particular honour to give the FitzPatrick Lecture. It was a former Harveian Librar- ian, Dr (later Sir Norman) Moore, who as 'an intimate friend' of Dr Thomas FitzPatrick is credited with the idea of a College lecture on the history of medicine. He declared in fine Victorian style that Thomas FitzPatrick's 'intellectual attainments were the ornament of solid vir- tues, and (that) he deserves to be remembered with honour in this honourable place'fl]. It was another Harveian Librarian, Dr Joseph Frank Payne, who in 1903 gave the first FitzPatrick Lecture, early in which he stated 'this lectureship owes its existence to the munifi- cence of a lady, Mrs FitzPatrick, who desires in this way to honour the memory of her late husband, Dr Fitz- Patrick, member of this College, a physician of great worth, learning and accomplishments'[2]. My brilliant and much-loved predecessor, Dr Charles Newman, gave the lectures in 1954 and 1955 and again in 1968, and also in 1958 gave an 'unofficial' FitzPatrick lecture to mem- bers of the College, in which, characteristically, he summed up the man in these words: 'Dr Thomas FitzPa- trick was a pleasant person, a congenial companion, an able linguist, perhaps a good doctor, but his immortality results from the fact that his wife was fond of him'. Thomas FitzPatrick was born in 1832 at Virginia, a small Irish country town. He qualified in 1856, won the silver medal of the Dublin Pathology Society in the same year, graduated MD at Trinity College, Dublin, in 1862, obtained his MD Cambridge in 1867 and his MRCP in 1868. There are three biographical details of relevance to my subject. FitzPatrick was rather more than 'an able linguist'; in Latin and Greek he was a classical scholar far above the average; he spoke Italian, German, French and Spanish, and had some knowledge of modern Greek, Hebrew, Turkish and Danish; he was clearly a man who made an effort to understand his fellow men and to meet them on their own ground. The second point is that soon after qualifying he joined the East India Company as an Assistant Surgeon, saw service in Bengal, and no doubt would have made his career in India but for a severe illness, after which he was persuaded to enter practice in London; he had therefore some insight into the conditions in which vast numbers of poor people were living in the Indian sub-continent. The third point is that FitzPatrick, although successful in his practice in Sussex Gardens, and supported by English aristocrats with Irish connections, demonstrated his concern for less privileged sections of society by writing about the social and sanitary conditions of the labouring classes in Ireland[3]. The terms of the FitzPatrick Lecture call for the precise subject to be announced beforehand. My title is clear but it is easy to imagine more ways in which governments damage health than the examples given here. Patriotism, Nationalism and World Co-operation My main argument runs as follows: for me, patriotism, towards a native locality, community or country, can be a legitimate and inspiring source of pride in traditions of Fig. 1. Dr Thomas FitzPatrick. Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 17 service, of deep-rooted intellectual and aesthetic culture, of emotional development, of high social standards of behaviour, and of joy in shared experience and compan- ionship. Patriotism in these terms promotes the well- being, the spice, variety and creativity of the human species. In contrast, nationalism, which in our modern world becomes more and more divisive, competitive and intolerant, poses an ever more critical threat to the very survival of humankind. Dr Lewis Thomas[4] recently described the infinite expression of individuality within most, if not all, living species; such 'selfishness' presum- ably has great survival value, but certainly not for our human species when carried to excess in chauvinism, racism, religious bigotry and self-righteous superiority. Aggressive nationalism is as dangerous to the human species as is a cancer, a cardiac infarct, or an inevitably fatal genetic defect to an individual. In our present wretched state of world affairs we may have to accept that it is impossible in our lifetime to achieve peace or non- violence or social and economic justice for the greater part of the earth's population, but in regard to the gross inequalities in the enjoyment of health throughout the world, I suggest that we could do a great deal more than we do already, but that if we leave it to government, we shall wait in vain. I believe that professional, united and non-controversial effort to relieve avoidable ill-health and prevent disease might even put world politics on a new course, away from confrontation and destruction, and towards co-operation and even optimism for, in the words of Addison, 'Health and cheerfulness mutually beget each other'. National Defence against Pestilence Nations learned early in history to fear pestilence coming from foreign lands. For most countries diseases such as plague, cholera, typhus, smallpox and syphilis came from elsewhere, so that strangers and foreigners were readily associated with suspicion and dread. That the fears were justified may be illustrated by the role of plague in the overthrow of Athens, of malaria in the decline of Rome, in the slaughter of at least a quarter of Europe's popu- lation by probably pneumonic plague in the Black Death of the fourteenth century, and by the death of about one- fifth of London's population in the Great Plague of 1665. In the middle of the sixth century, when plague was killing tens of thousands throughout Europe, the Emper- or Justinian, among his many other laws for the better ordering of society, imposed regulations to ensure that travellers arriving in Constantinople from plague-stricken countries should be held in special camps until they were 'purified' and appeared to be free from disease, when they were released with a certificate of health. Protective measures were taken within countries as well as between them: for example, a cordon sanitaire was imposed in the seventh century in Provence, by Padua and in Poland in the fourteenth century, and directed with terror-driven savagery around Marseilles in 1720. In England in 1625 the Court moved to Windsor to escape the plague in London and a gallows was erected to hang anyone who dared to follow. When Napoleon, returning from the Egyptian campaign, disembarked at Frejus in 1799, without permission, the local 'Sante' in Marseilles seriously considered having him shot. Attempts to exclude ship-borne pestilence appear to have been initiated by the island of Rhodes in 1306, followed by the city of Ragusa (now Dubrovnik) in 1377; ships coming from lands where plague was endemic were held under observation at sea, at first for 30 days, and then by Venice from 1403 onwards for 'quaranta' (40) days?a period seemingly arrived at on no more scientific a basis than that that had been the period spent in the wilderness by Moses and by Jesus. The Venetian quaran- tine of 40 days was soon copied by Genoa and Marseilles and then by ports in England. In the eighteenth century two famous Fellows of the Royal College of Physicians became outstanding authorities on quarantine, namely Richard Mead (1673-1754) and Gilbert Blane (1749? 1834). Under the British Quarantine Act of 1710, a ship found to be carrying passengers with plague or cholera could be forfeited and burnt. If sickness was found aboard the victims were isolated in lazarettos where gunpowder smoke and vinegar were used against contamination, and the attendants wore oilskin suits and wooden clogs and handled everything with tongs; the doctors were encour- aged to fortify themselves with a few glasses of wine before seeing the patients, though it was usual for them to employ or blackmail students to carry out the actual examination. But nations were no less self-centred and competitive in those days than they are now. Very soon quarantine became the excuse for exposing the ships and crews of commercial rivals to bureaucratic delays, extortion, accu- sations of spying, and what was known as 'rummaging', that is inspecting the cargo in such a way as to spoil or ruin it. As a major maritime power, England was intoler- ant of delays and inspections; when, at the first Interna- tional Sanitary Conference, a British delegate declared that 'time was money' a Spanish doctor replied 'but public health is gold'. In 1854 Pacini in Italy described the cholera vibrio as an 'organic, living substance of a parasitic nature, which can communicate itself, repro- duce itself, and thereby produce a specific disease' and he worked out the dynamics of dehydration. All of which, he said, was received with 'a sardonic smile of compassion' and 30 years later the vibrio had to be rediscovered by Koch. When the water-borne communication of cholera was clearly described in England by Snow in 1849 and Hassall in 1855, the British led the way in refusing to recognise such inconvenient facts. As The Times put it, 'We prefer to take our chance of cholera and the rest than be bullied into health', and the Royal College of Physi- cians, in a report as late as 1892, dismissed all idea that cholera might be contagious. But the British were the first to impose common-sense regulations for the observation of contacts in preference to the centuries-old and now discredited rules of international quarantine. International Sanitary Conferences The dominating consideration in all the early health measures between countries was national self-preserva- 18 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 -k tion and self-interest. This was still true when nations began to exhibit concern for what was actually happening in other countries in regard to epidemics. For example, in 1847 the French stationed medical men in Constan- tinople, Smyrna, Alexandria, Cairo and Damascus to ; , give France advance warning of the approach of epide- mics of plague and cholera. Later in the century Adrien Proust (1834-1903), the father of Marcel, advocated control of pestilential diseases at their source in endemic centres, in preference to quarantine. It was a Frenchman > also, Segur du Peyron, Inspector of the French Sanitary Service, who proposed in 1834 that an international meeting be held to try to bring some agreed international order into the confusing multitude of both national and individual port quarantine regulations, but this was at t > first vetoed by Austria on the grounds that there was no basis for co-operation. Such a meeting eventually took ) ' place in Paris in 1851, the first of 14 international sanitary conferences[5] to be held, at intervals of two to 15 years, right up to 1938. - V At that first conference, each of the 11 participating nations was represented by one diplomat and one doctor and each had an individual vote, so that a country often ^ , disfranchised itself. After six months it was said in the closing speeches that much had been 'gloriously accom- .-?> plished', and each delegate received the Legion of Hon- our. The practical results, however, were nil. But the French had at least established for the first time that health was a suitable subject for international co- operation. At the Second International Sanitary Confer- ence in 1859 the participating nations were represented only by diplomats, partly because the scientific questions were thought to have been settled and partly because at the first conference 'the doctors had disputed too much'. However, at the Third Conference in 1866, medical scientists were readmitted because in the previous year cholera had spread alarmingly across the Mediterranean to Europe from Egypt. The Fourth Conference, in Vien- na, was called by Russia to protest against vexatious hindrances to Russian shipping in the Bosphorus arising from Turkish abuse of quarantine regulations; and the Fifth was held in Washington in 1881, when the US Congress tried to prevent the introduction of yellow fever into the USA by insisting, though with no international legal justification, that certificates of the sanitary state of a ship must be obtained in all ports of origin before sailing. Only at the Seventh Conference in 1892 was there a measure of practical agreement in the form of an Interna- tional Sanitary Convention. This was expanded to an impressive 184 articles at the Eleventh Conference in Paris in 1903, when the historical decision was taken, on a proposal by Adrien Proust, to create in Paris an Office International d'Hygiene Publique (OIHP). This began work at the end of 1907, at first with nine participating countries, but very soon with no less than 60. For 40 years it was to provide, always in temporary quarters in Paris, a v first world assembly for a new breed of doctors: knowl- edgeable, experienced and concerned about the health of people wherever they were situated in the world, and prepared to communicate directly with each other, and not through governmental and diplomatic channels, in order to achieve improvements in health. On the govern- mental side, the French were still unable to get agreement even on the exercise of moral pressure: for the politicians' sovereignty had to remain sacrosanct, and international co-operation was to be informational only. Health Organisation of the League of Nations At the end of the First World War, when among other woes 15 million people were dying of influenza, when Russia had some 25 million cases of typhus and people there were so starved that they were reduced to cannibal- ism, the president of OIHP, Santoliquido of Italy, com- mented sadly that 'five centuries have passed in five years', and he called for well-organised health services in all countries 'to repair the conscience of the world'. Article 23 of the Treaty of Versailles confirmed that member states of the League of Nations should 'take steps in matters of international concern for the prevention and control of disease'. The League of Nations and its Health Organisation were both boycotted by the USA, which, however, contrived that the work of OIHP should contin- ue, wastefully, in parallel. The USSR also did not recognise the League of Nations until 1934, but well before that time the People's Commissar for Health, Semashko, consulted with the Health Organisation, say- ing that he was satisfied they were 'dealing with humani- tarian and not political questions'[6], The Health Organisation is generally acknowledged to have been the one great success story of the League in the years between the two World Wars. Its work included epidemiological intelligence, collection and collation of medical statistics worldwide, study of methods of organis- ing health services, interchange of skilled health person- nel, joint action on epidemics, and co-ordination of scientific research, especially in regard to the production of therapeutic sera, tests for the diagnosis of syphilis, and the standardisation, efficacy and lack of toxicity of bio- logical products. The Organisation also established ex- pert committees on such diverse subjects as malaria, leprosy, maternal welfare, infant hygiene, nutrition, housing and rural sanitation. Try to imagine what a great stride forward this was in world civilization. Yet during its 20 years of high activity, the Health Organisation is said to have cost the member nations less than the price of one battleship of the time[7], and even then it relied significantly on private financial support from the Rocke- feller Foundation. United Nations Relief and Rehabilitation Administration During the Second World War the United Nations Relief and Rehabilitation Administration (UNRRA) began work in November 1943, on Roosevelt's initiative, main- ly to provide help to the estimated 13 million people in Europe who had been displaced from their own countries, but it also demonstrated, in collaboration with the Rocke- feller Foundation, the feasibility of eradicating malaria from islands such as Mauritius and Sardinia, and it acted for two years as the world centre of information on Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 19 epidemics. UNRRA's efforts were described as 'the greatest act of charity the world has ever seen' [8], but that did not protect it from the attacks made on Roosevelt and all his works, and there were the usual political stupidi- ties; for example, when UNRRA arranged for desperate- ly needed nurses to be trained in the USA, the United States refused visas to the Yugoslav trainees, so Yugo- slavia, badly in need of aid, withdrew from the whole project. I find it sadly fascinating that the great United States should fear political contamination by a few com- munist trainee nurses rather than see the opportunity to impress them with the virtues of democracy and freedom. The World Health Organisation It is common knowledge, I think, that when plans were made at the end of the Second World War for a United Nations Organisation, no specific arrangements were made for health, despite the unique success of the Health Organisation of the League of Nations. The preliminary Dumbarton Oaks proposals referred to 'international economics, social and other humanitarian problems', but it was left to the initiative of the Brazilian and Chinese delegates to insist upon a World Health Organisation (WHO). Over the past 36 years WHO has striven to give reality to its principles: to aim, for all the earth's people, at a state of physical, mental and social well-being, to set clearly in the minds of everybody?perhaps most impor- tantly in the minds of doctors?that the enjoyment of health is a fundamental right of all individual human beings without distinction of race, religion, political belief or economic and social condition; to regard the health of all peoples as essential to long-term peace and security and a matter of co-operative concern among all nations; and to acknowledge that the achievement of better health by any one nation is of value to us all, that inequalities in world health constitute a common danger, that children's health in every country is the basis of the well-being of society, that the informed opinion and active co-operation of the general public everywhere are essential to health; and that every government has a responsibility for the promotion of health. The principles are all that the most idealistic of doctors could desire and WHO has had conspicuous successes, most notably in regard to smallpox eradication?though in that respect I still feel apprehensive, remembering from my own experience the inaccessibility of the high- lands of Ethiopia where the disease was endemic. In practice WHO operates on an annual budget of around 500 million dollars, that is about one-thirtieth of the yearly cost of Britain's NHS, and less than one-thou- sandth of the amount spent annually in the world on arming sections of the human race against each other. Unfortunately, WHO's membership is governmental, and many nations wheel and deal for benefits of direct consequence to themselves, with neither the compassion, imagination nor vision to aim for the good of the world at large. Even health can be viewed by governments with indifference, suspicion and opposition. For instance, the United States' ratification of the WHO agreement was delayed for two years, through fears of internationalism and socialisation of medicine; the Soviet Union and China boycotted WHO for seven and five years respec- tively; and at different times the politics of Taiwan, South Africa, the German Democratic Republic, Vietnam and Zimbabwe have mattered more than any regard for people's health in those countries. Such obsession with politics and economics demonstrates the validity of my contention that even when governments are not actually damaging our health, they often reveal a neglect, even a contempt for what, after all, matters most in life to the individuals and families who together make up the hu- man species. Inequalities in World Health The size of the problems relating to health on this planet are familiar to all: more than a billion people hungry to the point of failure of physical and mental development and resistance to disease; nearly a billion below a poverty line of ?40 a year; a billion also debilitated by infestations with a variety of worms; 500 million exposed to malaria and schistosomiasis; 10-15 million with leprosy; 12 mil- lion blind; child deaths in the worst areas 30 times greater than in the more advanced places; 80 per cent of world diseases caused by lack of clean water; this and much more add to rural desolation, chronic fuel shortage, rapidly spreading urban squalor, widespread illiteracy, and the degree to which manageable afflictions may advance in the absence of medical care. This is surely enough, from a long catalogue of misfortune, to destroy, among doctors at least, any lingering sense of apathy and complacency. What might be done to improve this situation? It is easy to condemn national governments for false priorities. But are we ourselves powerless, helpless in the face of national governments which think of their own people largely in economic terms and which are content, if not even secretly satisfied, to see the economic potentialities of other nations weakened by mass hunger, disability and disease? International Organisations t There are organisations and there have in the past been individuals who have managed to influence a few govern- ments to some extent in regard to medicine and health. I have already mentioned the Rockefeller Foundation, the Sanitary Commission of which did so much early in this century to overcome hookworm in the southern USA and whose International Health Board has so generously supported world health and medical science, including specific aid to at least five British medical schools, and which has claimed to operate its justifiably renowned fellowships 'with freedom from political ends, interna- tional as much as national'. And as just one of many possible examples of important organisational contribu- tions to world health, I must include the United Nations International Children's Emergency Fund (UNICEF) which, when it gained the Nobel Peace Prize in 1965, had an income for that year equivalent to the then world expenditure on arms for two hours. 20 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 Individuals with Remarkable Influence As for remarkable individuals, I can mention only a few of them. At the end of the eighteenth century Johann Peter Frank (1745-1821), working mainly in Baden, Lorraine and Lombardy, recognised that the strength of any nation ultimately depends on the health of its people; he demanded accurate statistics of births, marriages and deaths, and information on the extent of poverty, serf- dom, child labour and the incidence of diseases. Frank also advocated a Supreme Medical Board to regulate the practice of medicine on an international basis, to super- vise medical schools and hence the whole of medical and health systems. For him 'saving one single life must come to be regarded as a deed loftier than the bloody conquest of a province'. Undoubtedly one of the greatest individuals to influ- ence governments beneficially was Henri Dunant (1828- 1910) of Geneva, who witnessed the horrific slaughter of some 40,000 Austrians and Frenchmen at the battle of Solferino, Italy, in 1859, and in particular noted the total inhumanity of the medical staff of the one side to the wounded of the other. Dunant's description of that terrible day, and his personal direct approaches to heads of state led in 1864 to the establishment by himself and five personal friends of the International Red Cross, and the general acceptance of the principle of treatment of casualties 'irrespective of nationality'. Dunant incidental- ly was also a founder of the International YMCA, actively deplored the use by Christians of rum, opium and gunpowder in colonial exploitation, and advocated in the middle of the last century the establishment of a national home for Jews in Palestine under a French mandate. When people had long forgotten him, he won the first Nobel Peace Prize in 1902. Then there, was John Howard (1726-90), the prison and hospital reformer, who deliberately chose to travel on a plague-infected ship to study the operation of quaran- tine, and upon whose tomb in Russia is written: 'Who- ever thou mayst be, thou standest at the grave of thy friend'; and Florence Nightingale (1820-1910), with her passionate concern not only for British soldiers in the Crimean War and in India but also for all the natives in India under British protection, who wrote 'it would be a noble beginning to the new order of things to use hygiene as the handmaid of civilization'. Nikolai Ivanovitch Pirogov (1810-81) was Florence Nightingale's Russian opposite number in the Crimean War, a great anatomist and surgeon, founder of a school for nurses, who intro- duced health education into Russian schools and was also deeply concerned about the education and fate of minor- ities. Such great men as Pasteur (1822-95), Koch (1843- 1910), and Lister (1827-1912), in the words of Sir George Buchanan[9] 'were all good patriotic nationals, but it goes without saying that their work was done for and taken by the whole world . . . their nationalities trouble us as little as those of the great composers'. And I would include Henry Pomeroy Davison (1867-1922) who, having di- rected the American Red Cross extremely well in the First World War, and mistakenly believing that the public would continue to subscribe as generously, set up in 1919 the League of Red Cross Societies 'to anticipate, diminish and relieve the misery produced by disease and calamity, and to devise a world health programme'. Unfortunately, after four good years the money failed, though the League continues to play a valuable international role. Lastly, Dr Mahler, the present Director General of WHO, who has spoken of his wish 'to use health as a lever for social and economic development' and 'more than that, to use it as a platform for peace'. The Role of the Medical Profession Where does the medical profession stand in all this? From 1851 onwards doctors, especially those with research interests, began organising a great many international meetings. After the first International Medical Congress in Paris in 1867 the Lancet[ 10] noted that 'if after this trial an international medical gathering is ever again thought of, it could not take place anywhere but in the French capital' and considered it a pity that Latin was not kept up and spoken as the language of the learned of all countries. After the London Medical Congress in 1881 the Lancet[ 11] felt that 'the welfare of the whole human race was promoted'. No less than 8,000 attended the Medical Congress in Rome in 1894, which called forth another noble statement from the editor of the Lancet[ 12]: Fig. 2. Henri Dunant, founder of the International Red Cross. Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 21 'it was in Rome, according to Suetonius, that professors and practitioners of healing were first given the rank of citizens by Julius Caesar. It is in Rome that the profession is making another stage on its path to that still higher citizenship?the brotherhood of the nations, the citizen- ship of the world\ Most of the congresses and conferences became estab- lished as regular periodic meetings of medical societies and associations. The Yearbook of International Organiza- tions[ 13] for 1981 listed over 200 such bodies in medicine and biology and there are similar numbers of active medical associations in regions such as Western Europe; there are also many biomedical journals which have international boards of editors. The emphasis is naturally on the exchange of information about research, and the practising profession appears to be less internationally or globally concerned. Apart from the interests of the profes- sion itself and regulations for ethical and professional conduct, as discussed in a body like the World Medical Association, or the admirable efforts of such international societies as the Ophthalmologists and Dermatologists, who organise prevention and relief in the Third World, there is little evidence that our profession views the intolerable burden of unnecessary or preventable disease afflicting about a quarter of our fellow humans as an affront to our special skills and our humanitarian princi- ples. We have made some progress in establishing in the European Community at least minimal standards for basic medical education and specialist training, and have given some consideration to common standards of pro- fessional conduct, but we have a long way to go before such standards can be universally applied?and yet, why not? The medical profession is often regarded, as Bernard Shaw saw it, as 'a conspiracy against the public'. No tears are shed over anything which reveals the profession's weaknesses or its financial preoccupations. To secure and deserve a better reputation, and perhaps enjoy an easier conscience, could not the practising profession form an alliance of its members worldwide, preferably together with members of closely allied health professions, not to concern itself with status or conditions of service, but purely to take steps to reduce unnecessary suffering, prevent disease and promote better health? An Alliance for World Health I have in mind not an organisation of well-meaning 'do- gooders', but the highly efficient, multi-disciplinary, technical service of which we are capable[14]. Some two million doctors in the world, and many times that number of other health professionals, are not too small a body to exercise considerable influence, if they cared to co- operate. I have outlined elsewhere how I think such an alliance might be structured and financed[15]. Compared with the potential benefits the costs could, I believe, be comparatively low?a tiny fraction of the huge sum gambled away each year in the UK and almost negligible compared with what is spent daily in adding to already overwhelming armaments. There would surely be a significant role for those who are rich in experience and have retired while still youthful in spirit. Even more importantly, such an alliance for service might well provide the best possible outlet for the undoubted ideals and energies of the otherwise unem- ployed young in all countries, who could act in support of the professionals and greatly extend their competence. We are all sick almost to death of increasing nuclear tension, callous terrorism, criminal violence, racial ha- tred, religious fanaticism, ideological intolerance and nationalistic obstacles to freedom of movement. Migrat- ing birds exploit the whole planet for the survival of their species; can the human species afford to do less? It seems to me that doctors are in a unique position to demonstrate to governments that by this stage in the history of the world nothing less than a global concern for human life is appropriate or acceptable. In determining that care and cure be extended equally to all who need them, we might give all people and governments grounds for a renewal of confidence and hope. References 1. Payne, Joseph Frank (1904) in English Medicine in the Anglo-Saxon Times, FitzPatrick Lecture, RCP, 1903, p. 3. Oxford: Clarendon Press. 2. Ibid., p. 1. 3. FitzPatrick, T. (1862) Transactions of the National Association for the Promotion of Social Science, 1861, pp. 504-509. 4. Thomas, Lewis (1984) 'The Smell of Self: a Link between Olfactory and Immunological Signals'. Lilly Lecture given at the Royal College of Physicians of London (unpublished). 5. Howard-Jones, Norman (1975) In The Scientific background of the International Sanitary Conferences, 1851-1938. Geneva: WHO. 6. Howard-Jones, Norman (1978) In International Public Health between the Two World Wars?the Organizational Problems. Geneva: WHO. 7. Goodman, Neville M. (1971) In International Health Organization, 2nd ed. Edinburgh and London: Churchill Livingstone. 8. Ibid., p. 138. (Noel-Baker, Philip, 1946 quote). 9. Buchanan, Sir George (1934) Lancet, 1, 880. 10. Ibid. (1867) 2, 247. 11. Ibid. (1881) 2, 342. 12. Ibid. (1894) 1, 808. 13. Yearbook of International Organizations (1981) 19th ed. Union of International Associations and International Chambers of Com- merce. Paris and New York: ICC Publishing. 14. Wolstenholme, G. E. W. (1969) In Health of Mankind, pp. 254-61. Ciba Foundation Symposium. London: Churchill. 15. Wolstenholme, G. E. W. (1973) In The Greater Medical Profession. New York: Josiah Macy Jr. Foundation. 22 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985

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Physicians and Infection At the beginning of this century Britain led the world in providing facilities for the isolation and management of patients suffering from contagious diseases. Large fever hospitals were constructed outside most cities and were run by Physician-Superintendents who combined admin- istration with clinical duties; many also acted as the Medical Officer of Health to the adjacent city or town. With the decline in the incidence of the traditional infectious diseases many of these hospitals closed and eventually only one remained as a referral centre and teaching unit in most NHS regions. The number of infectious diseases physicians also decreased. Changes have also occurred outside hospital. At the time of the 1974 reorganisation of the Health Service many exper- ienced Medical Officers of Health retired, and their successors, who commonly have wider responsibilities, have little or no practical experience of infectious dis- eases. Hospital accommodation for patients with suspected or confirmed tropical disease was also gradually reduced as the Empire declined and the influence of war receded, and the numbers of physicians trained in tropical medi- cine fell. As a result of the above, the numbers of clinicians in England and Wales who are trained in communicable and tropical diseases has declined to around 30 and there are many areas where such expertise is no longer avail- able. This is in marked contrast to other countries, most notably the USA and Canada, where every hospital has at least one infectious disease physician. The reduction in the incidence of the traditional conta- gions has been matched by an increase in many other types of infection, which commonly occur in general hospitals where advice on their diagnosis and manage- ment is usually provided by microbiologists. Infections contracted in tropical countries continue to be imported by the ever-increasing numbers of travellers and many of these require a knowledge of tropical medicine for diag- nosis and treatment. The College Committee on Communicable and Tropi- cal Diseases has produced a report recommending an increase in the number of physicians and paediatricians with training and experience in infection, with the aim of providing an improved service to patients, especially those in general hospitals where complex and often life- threatening infections are an everyday and increasing problem. General practitioners and community physi- cians would also benefit from the availability of local expert advice on the diagnosis, management and preven- tion of infection. What should these new clinicians be called? Confusion has resulted from the various titles used at present?these include infectious diseases, communi- cable diseases, microbial diseases, communicable and tropical diseases, and tropical medicine. Perhaps these might all be abolished and replaced by a single designa- tion such as physician or paediatrician with an interest and training in infection. The College Committee might also be re-designated as the Committee on Infection. Names such as those of Jenner, Lister, Nightingale, Manson, Ross and Fleming recall landmarks in the control and management of infection in which Britain has played a leading role. The future will continue to provide challenges from diseases caused by micro-organisms and we must be equipped to deal with them. A. M. Geddes

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Systemic Sclerosis The Watson Smith Lecture 1984 N. R. ROWELL, md, FRCP Consultant Dermatologist, The General Infirmary at Leeds, and Reader in Dermatology, The University of Leeds Sydney Watson Smith, who died in 1950, was Honorary Consulting Physician and Dermatologist to the Royal Victoria and West Hampshire Hospital, Bournemouth, , and in 1934 was President of the British Medical Associ- ation. His bequest to the College, in memory of his wife and himself, stipulated that an annual lecture be given on any subject in medicine, including dermatology. It seemed appropriate to choose a subject which demon- ? strates that dermatology is probably one of the few specialties embracing all aspects of clinical and investiga- tive medicine from childhood to old age. My interest in systemic sclerosis started over 25 years ago. Research has been carried out on many features of this disease but I want to concentrate on three aspects: first, clinical subsets of the disease; second, immunologi- cal abnormalities; third, genetic aspects and possible initiating and precipitating factors. My experience is based on the study of 131 patients at Leeds since 1958. Although systemic sclerosis has been described under various names since the early 19th centuryfl], it was Goetz in 1945 who named the condition progressive A systemic sclerosis[2]. As many patients live for years, I feel that the term progressive is unnecessarily daunting for patients, and prefer the shorter title systemic sclerosis. Scleroderma means sclerosis of the skin, which can occur in various conditions, and to avoid confusion this term should not be used for the disorder. Systemic sclerosis is a multi-system disease and starts * with Raynaud's phenomenon in over 90 per cent of patients. After an interval, which is longer for females than for males, changes occur in the skin. The skin of the face becomes shiny, the nose is beaked, there are radial furrows around the mouth and mat-like telangiectases on the cheeks. Mouth opening is restricted. In the early stages the hands may be swollen but later the skin of the hands becomes tight and shiny with absorption of the terminal phalanges and small ischaemic scars on the tips of the fingers. Calcinosis develops in the soft tissues of the hands and elsewhere. It occurs predominantly in females. The skin of the arms and frequently of the neck below the clavicle becomes tight and shiny. Pigmentation occurs in one-third of cases and may resemble Addison's disease. Changes occur in the feet, with loss of toes due to ischaemia. Ischaemic leg ulcers occur in 30 per cent of patients. The oesophagus is dilated, air-containing and lacking in peristalsis. The results of radiology in 50 Table 1. Radiological observations of the oesphagus in 50 patients with systemic sclerosis. No. % Radiological involvement demonstrated 38 76 Dilatation 30 60 Absent or diminished peristalsis 32 64 Gastro-oesophageal reflux 20 64 Hiatus hernia 13 26 Stricture 6 12 patients are shown in Table 1. Oesophageal reflux is more common than dysphagia. Stricture occurs in 12 per cent. Oesophageal manometry shows abnormalities more frequently than does radiology but it is not required as a routine investigation. The third part of the duodenum may be dilated and aperistaltic segments and strictures occur in the ileum. We evaluated small intestinal involve- ment in 20 patients by jejunal biopsy, small bowel radiology and tests for bacterial overgrowth and malab- sorption, and in 55 per cent found abnormalities which were unrelated to disease in other organs[3]. Malabsorp- tion is not due to poor intestinal permeability. In 17 patients permeability was normal[4]. Malabsorption is mainly due to bacterial overgrowth which is found in one- third of patients[5]. Barium enema shows characteristic wide-mouthed diverticulae of the colon. The extent of the involvement of the gastrointestinal tract is shown in Table 2. The oesophagus, duodenum and colon are most fre- quently involved. Basal fibrosis of the lungs can be shown radiologically in nearly half the patients, but abnormali- ties of pulmonary function occur before radiological changes. Impaired gas transfer is, in our experience, the Table 2. Radiological involvement of the gastrointestinal tract. % Oesophagus 76 Stomach 6 Duodenum 34 Jejunum 11 Ileum 17 Colon 43 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 23 most delicate test and is abnormal in 75 per cent[6], The heart can be involved, electrocardiographic abnormalities being the most frequent findings. Even the teeth show changes. Widening of the periodontal membrane occurs in 30 per cent and is not related to the degree of involvement elsewhere[7]. In my series 73 per cent of patients had radiological oesophageal involvement, 49 per cent had an abnormal ECG, 46 per cent had radiological signs of fibrosis of the lungs and 41 per cent had impaired renal function. The overall five-year survival rates reported are be- tween 34 per cent[8] and 73 per cent[9], the differences between series depending upon different clinical criteria and the proportion of males and females. The prognosis of systemic sclerosis is worse in males than in females[10, 11]. The disease also advances more rapidly in men than in women. The shorter mean interval between the onset of Raynaud's phenomenon and the onset of cutaneous changes, when they can be dated, in my series is shown in Table 3. All the men had developed cutaneous changes Table 3. Mean interval between onset of Raynaud's phenom- enon and onset of cutaneous changes of systemic sclerosis when this could be dated. Males 0.25 + 0.8 years Females 5.10 + 7.0 years P< 0.005 within two years, in contrast to females in whom the interval was as long as 28 years. The criteria for diagnosing systemic sclerosis have recently been considered by a sub-committee of the American Rheumatism Association[12] and are shown in Table 4. These preliminary criteria gave a 97 per cent Table 4. Preliminary criteria for systemic sclerosis 1980[12]. Sole major criterion or Two or more minor criteria Proximal scleroderma Sclerodactyly Digital pitted scars of fingertips or loss of substance of distal finger pad Bilateral basilar pulmonary fibrosis sensitivity and 98 per cent specificity for definite systemic sclerosis in 797 patients seen in 29 American medical centres between 1973 and 1977. Patients with advanced disease are not difficult to diagnose but these criteria do help to provide standards for identifying mild cases and allow comparison between series. Subsets of Systemic Sclerosis Undoubtedly there are subsets of systemic sclerosis and their recognition will become increasingly important in relation to immunological and other factors, to prognosis and to treatment. In 1962 Tuffanelli and Winkelmann studied 727 cases from the Mayo Clinic[13], They consid- ered that systemic sclerosis should be divided into diffuse and acrosclerotic forms. The diffuse form was rare, involving approximately 5 per cent of patients. The sex distribution was equal, as compared with four females to one male in acrosclerosis. In the diffuse group Raynaud's phenomenon was absent or infrequent, sclerosis was generalised and the course was more rapid and likely to be fatal within a few years. It is difficult to be certain whether diffuse systemic scleroderma is an entity or not. Undoubtedly the sex distribution differs and the con- dition has a poor prognosis but some patients with acrosclerosis also have a short course; one of my patients died within two years of onset of the disease. Since 1964 considerable interest has been shown in the so-called CRST syndrome of calcinosis, Raynaud's phe- nomenon, sclerodactyly and telangiectasia^ 4], With the addition of oesophageal involvement this later became the CREST syndrome, the E representing the American spelling of oesophagus. Is this an entity? In an analysis some years ago[ll], 12 of 84 (14 per cent) of my patients with systemic sclerosis showed features of CRST. All had involvement of the internal organs characteristic of sys- temic sclerosis, and two died from malignant hyperten- sion, so all cases do not have a good prognosis, as has been claimed. The male to female sex ratio of patients with CRST syndrome did not differ from that of the whole series and the mean interval between the onset of Raynaud's phenomenon and the onset of cutaneous changes, if these could be dated, did not differ between patients with CRST syndrome and patients without these features. From the clinical point of view I would regard the CRST or CREST syndrome as only mild systemic sclerosis, but I will deal later with some immunological evidence to suggest that it might be a definite subset. In 1972 Sharp[15] described 25 patients with features of systemic lupus erythematosus, systemic sclerosis and polymyositis, using the term mixed connective tissue disease. A haemagglutinating antibody to saline extract- able antinuclear antigen (ENA) could be demonstrated in all. This was RNA-ase sensitive. All had speckled antinu- clear factor (ANF), none had Sm antibody, and anti- DNA antibody, if present, was in low titre. Clinically, renal disease was infrequent, the prognosis was good and patients responded to oral corticosteroids. Further obser- vations showed that 80 per cent were women and one- third present like rheumatoid arthritis, one-third like systemic sclerosis and a few like systemic lupus erythema- tosus. Probably the most characteristic clinical feature is the swelling of the back of the hands with sausage-shaped swelling of the fingers. The face may also be swollen and shiny. The skin manifestations fall into three main groups: those of systemic sclerosis with erosions of the finger tips and disorders of pigmentation; those of lupus erythematosus, either scarring discoid or non-scarring subacute cutaneous lupus erythematosus, and those of dermatomyositis with violaceous appearance of the eye- lids, plaques on the chest and periungual telangiectasia. Raynaud's phenomenon occurs in 90 per cent and vascu- 24 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 lar changes may be very severe, resulting in gangrene which may involve the whole hand. Arthritis is the most common feature and may resemble rheumatoid arthritis. There may be features of muscle involvement, as in polymyositis, and changes in the gastrointestinal tract and other organs identical to those of systemic sclerosis. The immunological abnormalities included speckled ANF and antibody to ribonucleoprotein (RNP), immune complexes in 90 per cent and decreased T cells. Patients with overlap of polymyositis and systemic sclerosis may also have precipitating antibodies recently designated PM-Scl[16] and Ku[17]. In some cases direct immuno- fluorescence of normal exposed skin shows particulate staining of epidermal cells[18] and occasionally nucleolar staining[19], Immunoglobin at the dermo-epidermal junction occurs in one-third. The inflammatory aspects rapidly respond to prednisone but over the course of time about half the patients are left with the features of chronic systemic sclerosis[20]. Is mixed connective tissue disease a subset of lupus erythematosus or of systemic sclerosis? Many patients fulfil the American criteria for systemic lupus erythema- tosus, despite having the digital erosions, oesophageal changes and colonic diverticulae of systemic sclerosis. Anti-RNP antibodies have been demonstrated in one- third of my patients with systemic sclerosis, although only 10 per cent have had other evidence of mixed connective tissue disease. Antibody to RNP is found in 25 per cent of patients with systemic lupus erythematosus and occasion- ally in other patients[21]. Do these patients then have latent mixed connective tissue disease? Examination of nail-fold capillaries suggests a link with systemic sclerosis. Of the patients with mixed connective tissue disease 54 per cent have the capillary changes of systemic scler- osis[22]. Do these abnormal capillaries indicate the patients that go on to systemic sclerosis? Or is mixed connective tissue disease an entity in its own right? Two aspects suggest that it may be. Abnormalities of immuno- regulating T-cell circuits in mixed connective tissue dis- ease are different from those found in systemic lupus erythematosus, systemic sclerosis and rheumatoid arthri- tis[23]. Second, although one cannot define this disorder only by antibody to RNP, there is some evidence that patients with RNP antibodies may be genetically different from patients with uncomplicated systemic lupus erythe- matosus, systemic sclerosis or polymyositis[24, 25]. About 10 per cent of patients with systemic sclerosis have ragged cuticles and nail-fold capillaries visible to the naked eye. Capillary microscopy shows a characteristic pattern of capillary abnormalities in over 90 per cent of patients with systemic sclerosis. Normal nail-fold capillar- ies occur as regular loops evenly spaced, whereas in systemic sclerosis the nail-fold capillaries are enlarged and distorted and there is loss of capillaries and disruption of the normal capillary bed. Haemorrhage is frequent. There does not appear to be any correlation with the extent of cutaneous disease[26], but Maritq, who has done the most work on this subject, suggests that there may be correlation with the extent of visceral involve- ment[27]. Loss of capillary loops characterises the changes in systemic sclerosis and it may be that this vascular ischaemia is the factor related to disease duration and systemic involvement[28]. The systemic sclerotic type of pattern of skin capillaries is also seen in dermato- myositis and mixed connective tissue disease and it has been suggested that the nail-fold capillary changes may indicate some common pathogenic factor. Abnormal nail- fold capillary changes occur in some patients with Ray- naud's phenomenon[29], and future long-term prospective studies may show that nail-fold microscopy is a useful tool in predicting those patients with Raynaud's phenomenon who will develop systemic sclerosis. It is difficult to estimate the proportion of patients with Rayn- aud's phenomenon who will eventually develop systemic sclerosis. From the evidence available, I suggest it may be about 1 per cent of females and 6 per cent of males. Patients with systemic sclerosis do not usually notice any precipitating factor, so what about so-called occupa- tional scleroderma? About 6 per cent of polyvinyl chloride workers develop a syndrome resembling systemic scler- osis[30]. The skin of the face is shiny and tight, the hands are ischaemic with shortened bulbous finger tips. Patients have various immunological abnormalities and immuno- histology of the skin shows an immune complex vascu- litis^]. A genetic susceptibility is indicated by the increased incidence of DR5 in patients compared with controls and of B8 and DR3 in those severely affect- ed[32]. Similar syndromes have occurred after exposure to organic solvents, pesticides and the vapour of epoxy resins, but these are very rare[33]. There is also an association between a systemic sclerosis-like illness and silicosis. Because of the occupational risk?to miners, sandblasters and quarrymen?the condition occurs almost exclusively in men. In East Germany[34] it has been estimated that males exposed to silica dust are 25 times more likely to develop a systemic sclerosis-like illness than are males not exposed to silica. Although visceral symptoms resembling those of systemic sclerosis occur in about half the cases and ANF can be demon- strated in one-third, I am not yet convinced that they suffer from true systemic sclerosis. The incidence is much higher than the suspected gene frequency of classical systemic sclerosis, and the situation is rather similar to the relationship of the systemic lupus erythematosus syn- drome due to drugs like hydralazine and procainamide and true systemic lupus erythematosus. We do not know how silica acts but it may be by stimulating the produc- tion of collagen directly or indirectly by macrophages. Alternatively, occupational substances may inhibit a de- fence mechanism to which I will refer later. These syndromes should alert us, however, to possible unsus- pected environmental triggers. Sclerodermatous skin changes are a late feature of the Spanish toxic oil syn- drome[35], the nature of which is also unknown, but there is some evidence that there are genetic differences between affected and unaffected individuals. Immunological Aspects A variety of humoral and cellular immunological abnor- malities can be demonstrated in the disease. Over 20 years ago, Beck et al., using rat liver as substrate, found Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 25 ANF in 78 per cent of patients at Leeds and Glasgow with systemic sclerosis[36], Homogeneous factor was most frequently demonstrated, but nucleolar factor occurred more frequently in systemic sclerosis than in other con- nective tissue diseases. Recent experience at Leeds using rat liver has given an almost identical figure of 77 per cent but speckled ANF is now more frequent than homogen- eous. In the last few years tissue culture cells have been used as the substrate as an alternative to rat or mouse liver, and antinuclear antibody has been detected in almost all cases of systemic sclerosis. Tan and his col- leagues^], using Hep 2 cells?a human laryngeal carci- noma cell line?showed that 96 per cent of sera were positive for ANF which is similar to our figure of 94 per cent. Various staining patterns have been described[38]. Centromere staining results from the presence of an antibody which reacts with the centromere region of metaphase chromosomes. This is shown as large, bright, round or ovoid granules occurring through the interphase nucleus and on the chromosomes of dividing cells. Other staining patterns using Hep 2 cells include homogeneous, peripheral (specific to systemic lupus erythematosus), fine and gross speckling and a diffuse 'frosted glass' pattern which is seen only in sera containing an antibody to Scl 70 antigen. Scl 70 antibody is usually demonstrated by a precipitin reaction to a soluble nuclear antigen Scl 70 which occurs in about 20 per cent of patients with systemic sclerosis. In addition, three distinct nucleolar patterns have been described?homogeneous, speckled and clumpy. Ninety per cent of patients with anticentromere anti- body have CREST syndrome[38] and 50-70 per cent of patients with CREST syndrome have anticentromere antibody. Anticentromere antibody is associated with long duration of disease, a low incidence of pulmonary involvement and rarity of renal involvement[39]. There is no consistent change in titre with time[40], Anticentro- mere antibody, however, is not always present in patients with the CREST syndrome. It may be present in patients with Raynaud's phenomenon before the clinical features of the CREST syndrome occur[41], and be useful, like nail-fold capillary changes, as a marker to distinguish patients with Raynaud's phenomenon who are likely to develop systemic sclerosis. Anticentromere antibodies occur in about 2 per cent of patients with Raynaud's phenomenon, 6 per cent of patients with systemic lupus erythematosus and 6 per cent of patients with mixed connective tissue disease. Anticentromere antibody has been found in about 9 per cent of patients with primary biliary cirrhosis and these patients had the CREST type of systemic sclerosis[42]. Of patients with primary biliary cirrhosis 17 per cent have systemic sclerosis[43], Anti-Scl 70 antibody occurs in about 20 per cent of patients with systemic sclerosis and appears to be particu- larly associated with a high frequency of lung involve- ment[44]. It may be a marker for systemic sclerosis, as it has not been found in other diseases such as systemic lupus erythematosus or rheumatoid arthritis[37 ]. Tuffanelli and his colleagues[45], using cells from a rat kangaroo epithelial cell line as substrate, reported four patients with an antibody to centriole, which is a repro- ducing cellular organelle that organises the mitotic appa- ratus during cell division. One patient had Raynaud's phenomenon with telangiectasia, another had CREST syndrome and the other two definite systemic sclerosis. The relevance of these and other humoral antibodies to pathogenesis is not known. They may, however, define immunological subsets. Various aspects of cell mediated immune mechanisms have been studied at Leeds and Sheffield in co-operation with Dr Hughes and his colleagues. Delayed skin reac- tions are depressed. Leucocyte migration inhibition oc- curs with a wide variety of autologous and homologous antigens?autologous lymphocytes, liver microsomes and mitochondria, and human myelin basic protein, but not to porcine thyroglobulin[46]. In our experience lympho- cyte transformation to phytohaemagglutinin (PHA) is also depressed and the degree of depression is related to the severity of the disease, elevation of the ESR and the incidence of circulating antibodies[47]. There is a strong correlation between decreased lymphocyte . transforma- tion to PHA and deficiency of circulating T cells. Both total and T lymphocytes are reduced in systemic sclerosis as compared with controls. In our research work we have found it useful to have a grading system to define mild and severe systemic sclerosis (Table 5). Addition of points Table 5. Criteria of systemic involvement in patients with systemic sclerosis. Disease score System (points allotted involved Criteria for involvement) Skin Sclerosis?face 1 hands 1 trunk 1 GI tract Radiological changes 3 Lungs Radiological changes and/or abnormal C02 transfer factor 3 Heart ECG changes 3 Kidneys Creatinine clearance <60ml/min and/or proteinuria 3 Other Sjogren's syndrome, myositis, etc. 3 allocated to the features shown gives a disease score. Using this grading there is a positive correlation between the deficiency of T lymphocytes and the extent of the disease. To what is this deficiency of T lymphocytes due? We do not know, but it may be due to a redistribution of lymphocyte populations, a secondary effect of the disease or the result of chronic antigenic stimulation such as that seen in 'host versus graft' disease. Studies of T-cell subsets by other workers have shown that helper cells are increased[48] and suppressor cell function is decreased in systemic sclerosis. Whiteside and her colleagues have reported that depressed suppressor cell function is not related to severity of the disease or to other immunologi- cal abnormalities[49]. Unlike T cells, B cells are not reduced even in severe disease. 26 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 Reduced lymphocyte cytotoxicity can also be demon- strated in systemic sclerosis. There are several possible lymphocyte tissue damaging mechanisms, first, T lym- phocytes with specific cytotoxicity to target cells, second, a combination of non-T lymphocytes, or killer (K) cells, and antibody to target cell tissue antigens (so-called antibody-dependent cytotoxicity) and third, spontaneous lymphocyte-mediated cytotoxicity produced by natural killer (NK) cells which are mainly T cells; NK cells may take part in immune surveillance. Patients with systemic sclerosis with extensive disease, according to our grading system, and low T cells have both reduced antibody- dependent cytotoxicity and reduced PHA-induced T cell cytotoxicity to Chang liver cells when compared with mildly-affected patients and with controls[50]. We do not know the cause of this defective cell-mediated cytotoxicity but circulating factors capable of blocking or inhibiting these two types of cytotoxicity have been demonstrated in some of our patients and these could be lymphocyte toxins, immunosuppressive globulins or immune com- plexes. We have also demonstrated decreased NK cell cytotox- icity to Chang liver cells in severe systemic sclerosis, but not in mild cases compared with controls[51]. It has been impossible to substantiate the claims of Trayanova et al. [52] and Currie et al. [53] that lymphocytes from patients with systemic sclerosis have increased cytotoxi- city to cultured muscle, fibroblasts and epithelial cells, but this may be due to technical reasons, i.e. to differ- ences in the time of incubation of the lymphocytes with the target cells[54], Dr Hughes and colleagues have allowed me to present some results on antibody-dependent cellular cytotoxicity to human vascular endothelium[55]. Serum from about a quarter of our patients with systemic sclerosis produces cytotoxicity of human umbilical vein endothelium when co-cultured with human peripheral blood mononuclear cells. Sera from normal controls and patients with athero- sclerosis or diabetes do not show similar cytotoxicity. The serum factor(s) in patients with systemic sclerosis is present in IgG fractions and the effector cells have all the characteristics of K cells. There is some evidence that these serum factors may be immune complexes, but antinuclear antibodies could also be involved. This anti- body-dependent cellular cytotoxicity to vascular endothe- lium was found particularly in patients with circulating immune complexes, anti-nuclear and ENA antibodies, and more severe disease. Only one serum causing cyto- toxicity had anticentromere antibody, which is normally associated with the mild CREST variant of systemic sclerosis. Kahaleh et al. [56] have reported direct cytotox- icity of vascular endothelium which they attributed to a circulating protease-like factor in serum from patients with systemic sclerosis. This non-immunological cytotoxi- city has not been confirmed by others. Serum from our patients, with or without added complement, did not cause direct cytotoxicity. We have also studied immune complexes in systemic sclerosis using three techniques: Raji cell radioimmune assay, Ciq binding and K cell inhibition[57]. The Raji cell test is the most sensitive but immune complexes were found in 58 per cent of patients by at least one technique, an incidence similar to that found in systemic lupus erythematosus. Complexes were associated with elevated IgG and IgA levels, a high incidence of auto-antibodies and severe visceral involvement. They occurred in 41 per cent of mild cases compared with 76 per cent of severe cases. Other workers have produced some evidence that C i q binding immune complexes seem to be associated with lung involvement[58]. More recently we studied the mean finger temperatures during a standard vasodilating stimulus in patients with systemic sclerosis[59] and showed that patients with the disease have cooler hands than the controls, with more variation in temperature between digits than in controls. Patients with circulating immune complexes have much lower resting temperatures than those without complexes, and the rate of vasodilation under stimulation was also slower in patients with immune complexes. These two features suggest that immune complexes could be a factor in the production of ischaemia in the hands of some patients with this disease. Other workers, using a differ- ent technique, have shown a relationship between the presence of immune complexes and Raynaud's phenom- enon[60]. How do immune complexes work? We do not know, but they could have a direct action on blood vessel walls, although we have been unable to demonstrate immune complexes in arteries by immunofluorescent techniques in autopsied cases. They are more likely to arm K cells with antibody-dependent cytotoxicity. They could in- crease platelet aggregation or they could inhibit the release of prostacyclin from vascular endothelium. Widespread vascular changes of intimal hyperplasia and endothelial damage occur in systemic sclerosis, and there is considerable evidence to indicate that the micro- vasculature may be the prime target in the disease[61, 62]. It has been suggested that ischaemia or the release of vasoactive substances may initiate the excessive collagen synthesis which leads to the characteristic fibrosis of the disease. Circulating antibodies to collagen Types I and IV occur in systemic sclerosis[63], and Type IV collagen is found in blood vessel walls. It is interesting, however, that anticollagen antibodies appear to be inversely related to the severity of the disease. Genetic Aspects That there is a genetic predisposition to systemic sclerosis has been suggested by the occasional familial cases, by the finding of abnormalities of serum proteins and by the increased incidence of ANF in first-degree relatives of patients. The United Kingdom Study Group studied 50 British patients and their blood relatives and found antibodies to collagen in 49 per cent of patients and in at least one relative in 87 per cent of families, whether or not the patient had anticollagen antibody. Various chromoso- mal abnormalities have also been found in the disease[64, 65], HLA typing has been done in several studies. In 71 of our patients with systemic sclerosis no significant alter- ation in the incidence of HLA type was found when the Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 27 group was considered as a whole. However, further analysis showed that the incidence of HLA-B8 was greatly increased in the severe cases with extensive vis- ceral involvement. Patients with B8 had more rapidly progressive and extensive disease than B8 negative patients[66]. Moreover, the more severely involved patients had a higher mean ESR, decreased circulating T cells and depressed lymphocyte responses to PHA. This association of impaired cell-mediated immunity and ge- netic factors has been confirmed by Kallenberg and colleagues[67], who found an association between haplo- type B8/DR3 and impaired cellular immunity. Recently Black and her colleagues[68] reported an increase in DR2, DR3 and DR5 and a reduced incidence of DR2 in systemic sclerosis. The increased incidence of DR3 was attributed to an increase in the Al, B8, DR3 haplotype. Mild cases, i.e. those with the CREST syndrome, had an increased incidence of DR1 and DR5 and decrease of DR2 when compared with the severe cases. They noted that patients with anticentromere antibody were mainly DR1 or DR5 but there was no relationship between HLA and Scl 70 antibodies. They found no association with any specific organ involvement in their series, but Lynch et al. [69] noted an increase of DR3 and a decrease of DR4 in a subset of patients with systemic sclerosis and pulmon- ary fibrosis. A Unified Concept One of the most neglected aspects of a disease is the interpretation of its age and sex distribution. The age at onset of Raynaud's phenomenon in our patients is shown in Table 6. The onset in males is later than in females. Table 6. Age at onset of Raynaud's phenomenon in 131 patients with systemic sclerosis (Leeds). Age (yr) Females Males 0-9 2 0 10-19 14 2 20-29 19 4 30-39 20 5 40-49 17 11 50-59 17 6 60-69 2 1 70-79 1 0 92 29 Professor Burch carried out a mathematical analysis of age and sex specific incidence rates as a function of age on my original cases over 20 years of age[70]. Plotting the age-specific incidence rates for each sex versus age at onset on log/log scales results in curves which rise to a peak and then fall steeply to zero. The meaning of these curves, which are similar in type but not in detail to those found in other autoaggressive diseases like systemic[71] and discoid lupus erythematosus[72], is that the disease in question is confined to genetically predisposed individuals and that each disease is characterised by one or more specific genotypes. The characteristic female sex pre- dominance in systemic sclerosis, about 3-4 females to every male affected, together with other evidence, sug- gests that the genotype involves one dominant X-linked allele as well as autosomal factors. Mathematical analysis of these curves indicates that the t disease appears to be initiated in predisposed individuals by a small number of random events; the average rate of such events is effectively constant throughout life and is independent of secular and geographical factors. These random events, Burch and I suggest, are somatic muta- tions in predisposed lymphoid stem cells. How does one, or a small number of mutations cause widespread dis- ease? We believe that forbidden clones of lymphocytes synthesising cellular autoantibodies develop and, after a proliferative phase or latent period which is longer in females, attack the primary target tissue, which, in the case of systemic sclerosis, is possibly vascular endotheli- um. The body appears to have an endogenous defence mechanism, probably involving both immunoglobulins and cell-mediated immunity, which can be modified or inhibited by environmental factors which, in the case of systemic sclerosis, could include exposure to vinyl chlo- ride or silica.. This defence mechanism, partly dependent on genetic factors involving the X-chromosome, is thus more effective in females, which accounts for the slower progress of the disease and the better prognosis in females than in males. Other factors, for example HLA B8 and DR3, seem also to govern prognosis. That genetic factors a may be concerned in the progression of disease can also be seen in other conditions. For example, alcoholic cirrhosis occurs more rapidly in patients with HLA B8 and DR3[73], Defective humoral and cell-mediated im- munity may allow forbidden clones to proliferate. The former would account for the high incidence of auto- aggressive disease in agammaglobulinaemia. Clinical and immunological subsets are probably gen- etically determined, and this could be confirmed by studies of the onset patterns of precisely defined groups. The pattern of organ involvement in a particular patient may depend on several factors, for example on particular forbidden clones, on genetic differences in the antigeni- city of target tissues, on local defence antibodies or on local vascular factors. Antinuclear antibodies arise as the result of release of nuclear material by damaged tissues. They may themselves enhance tissue damage, as can be demonstrated in animal experiments[74, 75], The fact that they are not present in all patients may, in part, be due to the genetic inability of certain individuals to produce these antibodies. Patients with overlap syn- dromes probably have the genetic factors for more than one disease or, alternatively, certain alleles may be pleiotropic and predispose to more than one disease. This unified concept (Fig. 1) though obviously contro- versial, is consistent with the sex and age distribution, the spontaneous onset in many cases, environmental factors, clinical and immunological subsets, multiple immunolog- ical abnormalities, differences in prognosis between males and females and overlap with other autoaggressive dis- eases. Our theory, however, is much less controversial but perhaps not so startling as Sir Fred Hoyle's concept of disease being due to viruses, bacteria and genes descend- 28 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 * ing on the earth from outer space[76]. But Hoyle does, however, point out that 'old style genetics . . . failed to give proper emphasis to stochastics . . which we have endeavoured to correct in our consideration of age and specific incidence rates in the disease. At present there is no specific or effective treatment but what of the future? Recombinant DNA technology and drug- or virus-induced gene switching could modify genetic aspects, and in time it may be possible to develop antibodies to specific forbidden clones which will allow a more rational approach to therapy. These aspects high- light the need for more precise definition of clinical and immunological subsets. The outcome of a disease de- pends on the balance between attack and defence. Attack- ing factors have attracted most attention in the past. Perhaps we should now concentrate more on enhancing defence mechanisms. The pace of advance is now so rapid that I can see all these developments occurring in my life- time. Wulff has discussed two philosophical concepts of disease?the nominalistic and the essentialistic (or de- monic)[77]. In the first concept a disease consists of patients with similar clinical, immunological or patho- logical features, that is, a disease is a collection of sick people. In contrast, the essentialistic concept suggests that, like demons, diseases actually attack people. I recognise both concepts in systemic sclerosis, which is not a homogeneous condition but consists of several groups or subsets of patients. Demons also exist and possibly attack primarily the endothelial tissue of blood vessels. 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GENETIC PREDISPOSITION INITIATION PHASE Spontaneous somatic mutation of genes in lymphocytic stem cells DEVELOPMENT PHASE Propagation of forbidden clone(s) in part genetically determined. Phase vulnerable to extrinsic factors such as silica, vinyl chloride, etc. t CLINICAL PHASE Severity depends, in part, on efficacy of the endogenous defence against forbidden clone(s) Fig. 1. General scheme of autoaggressive disease. Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 29 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51 52 53 Bernstein, R. M., Steigerwald, J. C. and Tan, E. M. (1982) Clinical and Experimental Immunology, 48, 43. Steen, V. D., Ziegler, G. L., Rodnan, G. P. and Medsger, T. A., Jr. (1984) Arthritis and Rheumatism, 27, 125. Tramposch, H. D., Smith, C. D., Senecal, J.-L. and Rothfield, N. (1984) ibid., p.121. Fritzler, M. J., Kinsella, T. D. and Garbutt, E. (1980) American Journal of Medicine, 69, 520. Bernstein, R. M., Callender, M. E., Neuberger, J. M., Hughes, G. R. V. and Williams, R. (1982) Annals of the Rheumatic Diseases, 41, 612. Clarke, A. K., Galbraith, R. M. and Hamilton, E. B. D. (1978) Annals of the Rheumatic Diseases, 37, 42. Catoggio, L. J., Bernstein, R. M., Black, C. M., Hughes, G. R. V. and Maddison, P. J. (1983) Annals of the Rheumatic Diseases, 42, 23. Tuffanelli, D. L., McKeon, F., Kleinsmith, D. M., Burnham, T. K. and Kirschner, M. (1983) Archives of Dermatology, 119, 560. Hughes, P., Holt, S. and Rowell, N. R. (1974) British Journal of Dermatology, 91, 1. Hughes, P., Holt, S., Rowell, N. R. and Dodd, J. (1976) British Journal of Dermatology, 95, 469. Krakauer, R. S., Sundeen, J., Sauder, D. N. and Scherbel, A. (1981) Archives of Dermatology, 117, 80. Whiteside, T. L., Kumagai, Y., Roumm, A. D., Almendinger, R. and Rodnan, G. P. (1983) Arthritis and Rheumatism, 26, 844. Wright, J. K., Hughes, P., Rowell, N. R. and Sneddon, I. B. (1979) Clinical and Experimental Immunology, 36, 175. Wright, J. K., Hughes, P. and Rowell, N. R. (1982) Annals of the Rheumatic Diseases, 41, 409. Trayanova, T. G., Sura, V. V. and Svet-Moldavsky, G.J. (1966) Lancet, 1, 452. Currie, S., Saunders, M. and Knowles, M. (1976) British Journal of Dermatology, 84, 400. Wright, J. K., Hughes, P. and Rowell, N. R. (1982) Annals of the Rheumatic Diseases, 41, 414. Penning, C. A., Cunningham, J., French, M. A. H., Harrison, G., Rowell, N. R. and Hughes, P. (1984) Clinical and Experimental Immunology, 57, 548. Kahaleh, M. B., Sherer, G. K. and LeRoy, E. C. (1979) Journal of Experimental Medicine, 149, 1326. 57. Hughes, P., Cunningham, J., Day, M. et al. (1983) Journal of Clinical Laboratory Immunology, 10, 133. 58. Seibold, J. R., Medsger, T. A., Jr., Winkelstein, A., Kelly, R. H. and Rodnan, G. P. (1982) Arthritis and Rheumatism, 25, 1167. t 59. Hughes, P., Day, M., Cunningham, J. et al. (1984) Clinical and Experimental Immunology, in press. * 60. Van der Meulen, J., Wouda, A. A., Mandema, E. and The, T. H. (1979) Clinical and Experimental Immunology, 35, 62. t 61. LeRoy, E. C. (1982) Journal of Investigative Dermatology, 79, 875. 62. Jayson, M. I. V. (1983) Journal of the Royal Society of Medicine, 76, si 635. 63. Mackel, A., DeLustro, F., Harper, F. E. and LeRoy, E. C. (1982) . Arthritis and Rheumatism, 25, 522. 64. Emerit, I. (1979) Clinics in Rheumatic Diseases, 5, 201. j 65. Sherer, G. K., Jackson, B. B. and LeRoy, E. C. (1981) Arthritis and Rheumatism, 24, 1409. < 66. Hughes, P., Gelsthorpe, K., Doughty, R. W., Rowell, N. R., Rosenthal, F. D. and Sneddon, I. B. (1978) Clinical and Experimen- tal Immunology, 31, 351. 67. Kallenberg, C. G. M., Van Der Voort-Beelen, J. M., D'Amaro, ^ J. and The, T. H. (1981) Clinical and Experimental Immunology, 43, 478. y 68. Black, C. M., Welsh, K. I., Maddison, P. J., Jayson, M. I. V. and Bernstein, R. M. (1984) British Journal of Rheumatology, in ^ press. 69. Lynch, C. J., Singh, G., Whiteside, T. L., Rodnan, G. P., J Medsger, T. A., Jr. and Rabin, B. S. (1982) Journal of Clinical Immunology, 2, 314. I 70. Burch, P. R.J. and Rowell, N. R. (1963) Lancet, 2, 507. 71. Burch, P. R. J. and Rowell, N. R. (1965) American Journal of j Medicine, 38, 793. 72. Burch, P. R.J. and Rowell, N. R. (1970) Acta Dermato-venereologica V, (Stockholm), 50, 293. 73. Saunders, J. B., Wodak, A. D. and Williams, R. (1984) Journal of the Royal Society of Medicine, 77, 204. 74. Beck, J. S. and Hughes, P. (1970) Journal of Pathology, 101, 11. ^ 75. Hughes, P. and Rowell, N. R. (1970) ibid., p. 141. 76. Hoyle, F. (1983) Journal of the Royal Society of Medicine, 76, 99. ^ 77. Wulff, H. R. (1979) Journal of the Royal College of Physicians, 13, 219. il College of Physicians of London Vol. 19 No. 1 January 1985

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Editorial Had a nice day? Did every one and thing slot nicely into your clinical programme? If so, then lucky you and congratulations on your organisation. Alas, experience shows that the nitty-gritty of routine hospital work is commonly full, of the gritty. Despite management, administration, operational research and whatever, the pattern of work is usually flawed. We get inured to a level of delay and muddle; and so do the patients. For the patient a hospital visit is too often like war, 95 per cent boredom and 5 per cent fright. An hour's wait for five minutes with the doctor and another hour waiting for blood tests and X-rays is not a programme that would be tolerated by a customer in a shop. So will the new Griffiths-type 'business' managers address this problem? They certainly cannot succeed without considerable effort from the medical profession. We should all be aiming at making patients satisfied customers, not with a transient burst of efficiency but as an accepted routine. So much of today's hospital work concerns the use of its facilities to spare the traditional beds. But even the best-intentioned doctor can still be guilty of disrupting his patient's life by admitting him to a bed without a clear thought as to why he should be in it. Well-run day investigation units and special clinics do give the patient a great deal of benefit with minimal cost in time out from ordinary life. These successes come from a mutually agreed aim enthusiastically pursued by all those involved. The less concentrated efforts in routine practice suffer from a fragmentation of purpose, each person doing his own thing while feeling little responsibility for the whole task. Many doctors see their hospital life through a haze of overwork and over-commitment. Juniors may see themselves as transient prisoners in a system they cannot change. Seniors are too busy battling for more resources to take the time to 'fine tune' those they have. It is indeed a constant struggle for a hospital to deal effectively with the amount of disease that presents; there is little left over to consider the conve- nience of each patient. The public is faced with taking pot luck with the way things go or waiting endlessly for an appointment. So it would seem to be special pleading for a magic administrative wand to save the individual patient's time. But saving that time benefits all those responsible for clinical care. Happy are the clinicians whose administrative colleagues consider their prime task is to make it easy for a doctor to see patients. Yet happier are the patients when administrators and clinicians combine to make it easy for the patient to complete his hospital treatment. It is a pity that we cannot monitor the process by putting a volunteer 'patient' through the system every day, much as a standard is run through an auto-analyser. We can at least ask patients how they fared, a necessary but neglected bit of audit. We also have to realise our responsibility for ensuring each hospital visit is of real value to the patient and that our colleagues the secretaries and clerks have an important role we should acknowledge and applaud. Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985

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Computer-Based Research by Disabled Engineers: A Case Study VIVIEN MORRIS, ma, DPhil Senior Research Assistant, Department of Fluid Engineering and Instrumentation, Cranfield Institute of Technology, Cranfield, Bedford It is well known that unemployment is particularly com- mon among disabled people[l] and even highly trained graduates are often unable to find work appropriate to their qualifications. However, recent advances in com- puter technology mean that, in this area at least, it may be possible to mitigate the physical handicaps imposed by disability. Consequently, disabled people should be better able to achieve their vocational potential in computation- al work than in many other professions. Objectives The aim of the project was to allow a small number of severely disabled technology graduates with skills and interests in computing to work professionally for industry by providing them with training and technical equip- ment. Initially it was hoped that the group would become self-financing, but, in practice, constraints were identified which suggest that a small amount of external funding will probably always be necessary for a group of this kind. Participants It took longer than expected to find suitable participants, probably because highly-trained specialists were needed and such people are not numerous even among the able- bodied. Publicity on TV, in the national and local press, relevant technical journals and appropriate confer- ences^], together with approaches to UK universities and polytechnics, professional institutions, associations concerned with disabled people[3], regional health au- thorities, spinal and rehabilitation units, etc., led to contact with four graduates with appropriate interests and abilities. Their background training covered mechanical engineering, electronic and electrical engineering, math- ematics/computer science and civil engineering, and their respective disabilities were tetraplegia, congenital deaf- ness and limited speech, blindness, and a rare form of muscular disorder. Organisation Cranfield Institute of Technology is a postgraduate uni- versity which works closely with industry, earning ap- proximately half of its income from contract research. Much of the work of the Department of Fluid Engineer- ing and Instrumentation (DFEI) on the analysis of flow is carried out for industrial clients so that it is particularly suitable for an enterprise of this kind, which requires industrial collaboration. Work undertaken by participants was linked to re- search in progress at DFEI, but a period of training was generally necessary before they were able to begin work- ing on commercial contracts. The management of the project was shared between several members of DFEI staff. It would have been preferable to appoint a full-time co-ordinator to arrange training programmes, select and modify computing equipment, liaise with industry, or- ganise contract work, manage financial matters, as well as make some contribution to technical work. In practice, it proved impossible to find such a co-ordinator, possibly because those with relevant technical skills were unwilling administrators. It was particularly disappointing when the appointment of a disabled co-ordinator for a trial period was unsuccessful, though this may have been largely due to factors connected with his illness (multiple sclerosis). Each participant lived and worked as seemed best suited to individual circumstances. Only one of the four was able to live on campus where there is close contact with academic staff and easy access to well-maintained computing equipment. Two participants worked from home, using microcomputers or telephone links to the mainframe computer at Cranfield. The civil engineer's disability required residential care and he lived in the Part III accommodation associated with the Spastics Society's Professional Workshop in Milton Keynes. Nevertheless, he found it difficult to endure the short taxi journey to Cranfield. Equipment Each participant was provided with a microcomputer and accessories but it was sometimes necessary to modify this equipment to take account of disability. The tetraplegic engineer operated his microcomputer very effectively with a mouthstick (Fig. 1) though slight modifications were necessary, e.g. to the shift key. He was also able to load and unload floppy discs by means of a specially designed rack. Small programs, or sections of large programs, were developed on this computer but access to the mainframe computer became necessary at a later 34 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 y! 1 stage to link individual sections together. A commercial v ' company, CASE (Computer'and Systems Engineering), kindly donated additional equipment to allow him to operate a telephone link to the mainframe computer at ?> Cranfield. In addition, a large working surface was installed in his home, allowing access from a wheelchair, with a vertical section to support textbooks, manuals, etc., so that pages could be turned with a mouthstick (Fig. I 2). Manipulation of heavier items was difficult and a microfilm reader was purchased jointly with Imperial College so that he could access large amounts of infor- mation stored on film, according to his particular require- ments, without handling paper copies. Major problems with computing equipment were ex- perienced by the blind mathematician. Although regis- tered blind, he used his residual vision to operate a large scale CCTV magnification system (Fig. 3). The screen had to be continually switched between cameras focused on the VDU and on notes, as a split screen gave insufficient magnification, so the assimilation of infor- mation was slow and laborious. A voice synthesiser was attached to his microcomputer to give an audible record of input and output, but this by no means solved the problem. After discussions with the Royal National Insti- tute for the Blind, the Manpower Services Commission (MSC) provided financial support to allow a sighted assistant to read aloud for 10 hours a week and, at a later stage, supplied a Brailink machine. This machine could be used independently to record and store information in Braille, or with the microcomputer (or telephone link to a mainframe) to provide a tactile record of computer input and output. In view of the laborious process required to access information, it was not surprising that the mathematician worked much more slowly than a sighted person might have done. Research work at Southampton University[4] has suggested that blind subjects using a voice synthesiser take 3-6 times as long as sighted people to obtain information from a Prestel system. A much larger time factor would probably be appropriate if the user were attempting to assimilate complicated technical ideas. It remains to be seen whether the tactile Braille display proves to be more helpful than the audible record from the voice synthesiser or the visual image from the CCTV. At present, it seems appropriate to restrict the work to relatively short programs which can be retained mentally without too much difficulty. No special modifications to computing equipment were necessary for the two remain- ing participants. Research Topics During the period covered by this report, the DFEI undertook a major contract for a commercial manufac- turer of electromagnetic flowmeters. The exact nature of the work is confidential but it accounted almost exclusive- ly for about 18 months of^the electronic engineer's time and produced substantial income for the project. This Fig. 1. Tetrablegic engineer operating microcomputer with mouthstick. Fig. 2. Raised working surface with access from wheelchair. Fig. 3. Computer operation by means of large-scale CCTV magnification system. Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 35 work also formed the basis for his MSc thesis, which was successfully submitted towards the end of 1983. Two other participants also carried out varying amounts of computational work linked to this contract and the com- pany was charged for their time at DFEI's normal rates. The mathematician undertook calculations connected with the design of specially shaped electrodes in an electromagnetic flowmeter for a project funded by the Science and Engineering Research Council (SERC) and began work linked to a flowmeter project carried out jointly by Cranfield and the University of Salford. SERC provided some support for the civil engineer's work on computer modelling of systems of drains which become full during flooding. At the time of writing, this work is not complete so commercial exploitation is not yet feasible. Other research topics involved developments of earlier work by members of DFEI staff and were not supported by external funds. This category includes work on an existing computer program to predict pressure surges occurring in the cooling system of a power station on the Isle of Grain. Recent tests allowed the actual pressures to be measured so that comparison of empirical and theor- etical values became possible. The mathematician modi- fied the orginal program so that it could be used on modern microcomputers. The mechanical engineer was co-author of a report on the effects of installation on a 12-inch turbine flowmeter. The detailed nature of the work is confidential but it involved examination of the effects of sudden changes in flow on the meter's performance. Experimental values of various parameters were compared with theoretical pre- dictions obtained from a computer program developed by this participant. The client was charged for his time at DFEI's normal rates. Since then, various aspects of the work have been developed beyond the scope of the original contract. Output The length of training required before participants were sufficiently expert to cope with work for commercial contracts varied enormously. In some cases, contract work was possible almost immediately, but in others it was still not feasible even after two years of training. Three of the participants registered for higher degrees and continued working for them in addition to contract work. Cranfield's close links with industry mean that thesis topics are directly related to industrial problems and results of contract research can often be used as the basis for a thesis. When necessary, the university accept- ed registration for a higher degree on the basis of part- time work from home. At the time of writing, the registration periods required for the two PhD pro- grammes are still incomplete, while the author of the successful MSc thesis has begun work on a more substan- tial topic suitable for a PhD. This participant's deafness accounted for his enviable ability to concentrate on the task in hand despite the distractions of a noisy environ- ment and, apart from speech therapy and help with telephone calls, little was needed to compensate for his disability. He was the only member able to work a full working week with normal efficiency. For various rea- sons, the other three all had restricted outputs. Difficul- j ties in accessing information reduced the blind mathematician's efficiency to a tenth or a twentieth of that of a fully sighted graduate, and although the tetra- plegic engineer worked effectively, his disability quickly produced exhaustion, so that he was able to spend only about ten hours a week on computational work. The fourth graduate suffered continual periods of sickness, some of which required hospital treatment, so that he made very little progress. It also seemed possible that the powerful drugs required by his disability may have affected his concentration. These restrictions inevitably led to a lower earning capacity than had originally been estimated. Finance The main source of income, apart from the two grants from charitable foundations, was from fees charged to u industrial clients for whom research was undertaken. DFEI's normal practice is to charge customers overheads < of more than 100 per cent, in addition to charges for time, and the same procedure was followed in this case. Thus, the major factor affecting income was the amount of work which could be satisfactorily completed in a given time. There were many sources of expenditure. The initial cost of computing equipment was high, with the possi- bility of extra charges for specialised items to overcome disability. The graduates were paid for their work, but this was not administratively straightforward and the details varied between participants. It was sometimes ' possible to pay a student bursary to cover the initial training period, and to replace this with a salary as expertise developed. Alternatively, participants were paid t as each piece of work was completed. Rates were based on commercial levels applicable to fully able graduates, regardless of the time actually taken to complete the work. Whenever necessary, payments conformed to DHSS requirements for disabled people in receipt of ( social security benefits. These sometimes seemed to be unnecessarily harsh and to actively discourage disabled 1 people from working at home. At present, those whose earnings just exceed the ?22.50 a week allowed as 'thera- peutic' earnings are heavily penalised by withdrawal of benefits. The financial loss can amount to two or three times the earned income. Unless disabled people are able to guarantee earnings which exceed the benefits by at least ?22.50, they lose money by working. The restricted working hours sometimes associated with severe disability mean that it may not be possible to overcome this financial barrier. At present, the DHSS does not recog- nise partial incapacity for work. The assumption is that one is either able to work, or completely unable to work, and no provision is made for those whose disability restricts potential earnings to the difficult band where earned income would exceed 'therapeutic' earnings but fall short of state benefits. Additional charges for time, travel, etc. were incurred by members of staff who provided advice and guidance 36 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 Table 1. Estimated income and expenditure, 1980 83. Year No. of participants Expenditure (?) Income (?) Equipment Other Total Members' Work Student Support Total Income as % of expenditure 1980 1981 1982 1983 2,000 6,000 3,000 3,000 4,000 5,000 13,000 *18,000 6,000 11,000 16,000 21,000 11,000 13,000 4,000 3,000 * includes small contribution from early 1984. 15,000 16,000 0 0 94 76 for disabled participants, co-ordinated research work, modified equipment, managed financial affairs and dealt with other administrative aspects. Table 1 summarises income and expenditure through- out the four-year project. The figures show that a sub- stantial proportion of costs was recovered as the project progressed. However, a large part of the income in 1982 and 1983 arose from one particular contract and it is almost impossible to achieve a steady flow of contract work. A shortage produces a corresponding drop in income, but an excess is undesirable if high standards are to be maintained. Consequently, it would not be realistic to expect to recover as high a proportion of costs as in 1982 and 1983 on a regular basis, particularly if numbers of participants increase. Each new recruit requires ad- ditional expenditure on computing equipment and this may not be offset by an increase in earning capacity until after an initial training period. Discussion The therapeutic value of the work was apparent through- out. Participants stressed the frustration of unemploy- ment and the fulfilment associated with the opportunity of undertaking interesting and stimulating work despite severe disability. During the period of the work, activities such as the International Year of Disabled People pro- duced an increase in general awareness of the problems faced by disabled people and the discrimination to which they are often exposed. The Manpower Services Com- mission (MSC) now administers several schemes to assist disabled workers, e.g. fares to work, aids to employment, etc., but provision in the UK still falls short of that in countries such as The Netherlands and Sweden[5]. The MSC has always been sympathetic to the work but the present group of graduates are highly trained profession- als whose needs do not seem to be effectively served by government-sponsored schemes, such as Sheltered Indus- trial Groups, which cater for workers with a wider range of less specialised skills. This is particularly regrettable, as professional people may well be less handicapped in their work by physical disability than manual workers. Never- theless, help was sought from the MSC, whenever poss- ible, so that precedents and contacts could be established for use in the future when external funds from charitable sources might not be available. The original aim of a self-financing consultancy group was not achieved for the following reasons: 1. Training periods were generally required before com- mercial contract work could be undertaken. These were sometimes unexpectedly long. 2. Severe disability sometimes restricted working hours, e.g. only 10 hours a week were possible for the tetraplegic engineer. Periods in bed or hospital reduced output. 3. Disability sometimes reduced working efficiency, e.g. difficulty in assimilating and retaining information was associated with blindness. Specialised equipment to coun- teract this is relatively expensive, e.g. a Braille computer terminal costs ?5,000. In addition, drugs needed to overcome disability may reduce working ability. 4. Some degree of isolation was associated with work from home. Repairs to computing equipment took longer to arrange and there were sometimes delays while waiting for visits from academic advisers. There was a tendency to spend too long wrestling alone with a particular problem before seeking advice. Nevertheless, the work suggests that it would be realis- tic to expect to recover a substantial proportion of costs. The percentage recoverable by disabled people in intellec- tual disciplines almost certainly exceeds that achieved by similar workers with less specialised skills. For example, Remploy, a government-sponsored organisation in which about 80 per cent of the workers are mentally or physical- ly handicapped, trades in areas such as textiles, furniture, packaging and assembly. In 1981/82 it recovered just under 50 per cent of its costs[6], a figure exceeded by a comfortable margin in the present project. Conclusion It appears that the external funding required to enable these engineers to work professionally is relatively low, probably of the same order of magnitude as the state aid which would automatically be paid if they were unem- ployed. However, the returns in terms of self-fulfilment are high and, in addition, are associated with useful contributions to engineering research. It might well be desirable to modify existing government-sponsored schemes to allow a nationwide network of such groups, possibly based in universities, so that computational research could be undertaken by severely disabled profes- sionals in other parts of the country. Although the interests of the original group were confined to industrial fluid mechanics, there seems to be no reason why the concept should not be extended to computer applications in other disciplines. Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 37 Acknowledgements None of this work would have been possible without the enthusiastic support of Professor Roger Baker, Head of DFEI, who obtained the initial funding. We are grateful to the Nuffield Foundation for the original grant and to the Gatsby Charitable Foundation for additional assist- ance and the opportunity to continue the work for a further three years. We would also like to thank the Aidis Trust for the permanent loan of an Apple microcomputer and accessories. References 1. Kettle,. M. (1979) Disabled people and their employment. Banstead: Association of Disabled Professionals. 2. Enever, K. J. (1981) Distech '81. Proceedings of a conference at / Sussex University, March 30-April 3. London: The Spastics So- ciety. ( 3. Baker, R. C. and Morris, M. V. (1981) Contact, No. 30, p. 15. London: Royal Association for Disability and Rehabilitation. 4. King, R. W. (1983) Personal communication. 5. Greaves, M. and Massie, B. (1977) Work and Disability. London: ; Disabled Living Foundation. 6. Marsh, P. (1982) New Scientist, 95, 218.

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I j i I / ! Observations on Indian Neurology R K. NEWMAN, MB, MRCP(UK), Consultant Neurologist M. SAUNDERS, MB, FRCFJ Consultant Neurologist Middlesbrough General Hospital, Ayresome Green Lane, Middlesbrough, Cleveland The common neurological diseases of the West are, with j - some exceptions, frequently seen in Indian practice, but a further catalogue of neurological affliction is associated ) with the twin factors of infection and malnutrition, and J 4 these conditions must feature prominently in any account of neurology in India. Headache, epilepsy, cervical spon- dylosis, cerebrovascular disease and Parkinson's disease will dominate a neurology clinic anywhere in the world, but the Indian neurologist will also see many other j , diseases regarded as exotic in the UK and as common- place in India. The first generation of immigrants to the % UK from the Indian sub-continent, and to a lesser extent later generations, continue to manifest some of these conditions and, in urban areas of the UK with a high ? immigrant population, the clinician must therefore con- sider these unusual diagnoses. These points are illustrated by a recent study from Leicester[l] in which it was noted that 15 of 17 cases of tuberculous meningitis (TBM) were in Asian patients and that late diagnosis was sometimes a problem. This article highlights some of the neurological diseases which lie outside the routine experience of the English trained doctor, but are familiar to his Indian colleague. Tuberculosis of the Nervous System Tuberculous Meningitis (TBM) The incidence of TBM in the UK is of the order 1.5-2.0 I v cases per million per year[2,3]. Comparable figures for India are not available but a busy neurology unit will see well over 100 cases each year and many more patients will be treated by general physicians and paediatricians. There is no doubt that TBM is over-diagnosed in India; this is inevitable where isolation rates are low[4] and when treatment is urgent. However, late diagnosis can be a problem in the UK, where clinicians may not think of TBM, particularly when the presentation is atypical. The overall clinical picture, laboratory findings and prognosis are similar in India and the UK, but some differences are seen. The Indian patients are more likely to be children, more likely to have miliary or pulmonary disease, and a history of direct tuberculosis exposure is frequently ob- tained. The less usual presentations of TBM are seen in abundance in India, for instance subacute blindness due to chiasmatic and optic nerve arachnoiditis, and acute hemiplegia in which meningeal disease may have oc- eluded major cerebral vessels. The treatment protocols in India have concentrated on the less expensive antibiotics, often without rifampicin, and it is therefore interesting that morbidity and mortality statistics do not differ significantly between the UK and India[3,5,6] and are very similar to those obtained in the early days of anti- tuberculous chemotherapy[7], It is surprising that we are still unclear about the indications for steroid treatment and intrathecal therapy, but prompt initiation of standard anti-tuberculous treatment as soon as the diagnosis is suspected is the main guarantee of a successful outcome. Intracranial Tuberculoma In the UK, intracranial tuberculoma is usually seen in recent immigrants, although rare cases appear in the indigenous population[8]. In India, this condition is common and studies of incidence in neurosurgical units gives a range of 4.1-30.5 per cent of all intracranial tumours[9,10]. Now that CAT scanning facilities are becoming widespread in India, more cases are identified at an early stage, multiple lesions are frequently found and the response to a combined medical and surgical approach, or to medical treatment alone, can be moni- tored precisely[l 1]. The clinical features of intracranial tuberculoma are similar in both countries, lesions may be found in the background of a known tuberculous infection or the presentation may be that of any cerebral space occupying lesion, with a progressive neurological deficit in the presence or absence of symptoms of raised intra- cranial pressure. Adhesive Spinal Arachnoiditis Adhesive spinal arachnoiditis of presumed tuberculous origin accounted for nearly 10 per cent_of paraplegia in a large representative Indian study[12]; a British neurol- ogist will occasionally see this entity. The patient will characteristically be Indian, but of the three cases seen in the UK by one of the present authors, two have been young English males. The condition may arise by spread from a tuberculous basal meningitis or less commonly from spinal tuberculous caries. A subacute progressive myeloradiculopathy, the primary spinal type, is also seen and here a wide differential diagnosis must be exer- cised[13]. Myelography by lumbar or cisternal route and spinal fluid analysis are mandatory, and while treatment Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 13 of the likely underlying active tuberculosis is important, medical and surgical attempts to reduce the deficit due to the arachnoiditis have not met with great success. Recent work with hyaluronidase has suggested a further treat- ment option in both spinal[14] and cranial[15] arachnoi- ditis, although further studies are necessary to evaluate the therapy. Neurological Complications of Leprosy Mycobacterium leprae has a peculiar predilection for the peripheral nervous system, but in India as elsewhere these problems are usually dealt with by the leprologist rather than the neurologist. Nevertheless, a case can be made for the more active involvement of neurologists in the study and treatment of this disease. The Ridley- Jopling classification 16] subdivides leprosy into the polar types of tuberculoid (high resistance) and lepromatous (low resistance), their borderline variants and the inter- mediate forms. The peripheral nervous system is involved in all types of the disease and there is also a controversial pure neuritic variant, in which careful enquiry and examination fail to provide evidence of cutaneous lesions. The facial, ulnar, median, radial and common peroneal nerves are frequently affected in leprosy and the Indian patient with a Bell's palsy or ulnar neuropathy must be meticulously examined for the presence of cutaneous lesions or nerve thickening. Conversely, in Indian prac- tice, the temptation to diagnose leprosy without adequate clinical grounds or biopsy must be resisted, as cases of amyloidosis, porphyria, congenital insensitivity to pain and especially hereditary sensorimotor neuropathy may all appear neurologically similar to leprosy. The tragedy is that such patients may be sent to a leprosy establish- ment and thereby become exposed to the disease. The treatment of leprosy with dapsone and the newer anti- leprotics will arrest the infection, but regrettably continu- ing fibrosis within the nerve may increase the deficit despite otherwise successful treatment, and repeated trau- ma to anaesthetised extremities may result in dreadful deformity. Cysticercosis Cerebral cysticercosis is endemic in the non-Muslim populations of the developing countries and India is no exception[17]. The presence of the cysts of Taenia solium in the brain usually results in one of three symptom groups. The patient may exhibit features of raised intra- cranial pressure, a mental disturbance or convulsions, or a combination of these. Occasionally the disease is identi- fied on radiological examination for other complaints, and rarely cysts may be found in the brain of autopsied patients who have died from other conditions and shown no indication of cysticercosis in life. If cysts are present in the muscle of human hosts a striking muscular hyper- trophy may be seen, and the calcified lesions are readily observed radiologically. The treatment of cysticercosis with drugs or surgery is often unsatisfactory and control of this disease will only be possible through effective public health education. Virus Infections of the Central Nervous System Poliomyelitis remains a relatively common disease in India. Vaccination programmes are widespread, but in this population more booster doses of vaccine than those given in the West appear to be necessary to achieve adequate immunity[18], Cases occur sporadically in the UK but, with the present general trends against vaccina- tion and towards more widespread foreign travel, it seems possible that poliomyelitis may re-emerge and it is wise to consider this infection in the differential diagnosis of cases of post-infective polyneuropathy. Acute haemorrhagic conjunctivitis due to infection with enterovirus 70 has associated neurological features that are in many ways similar to those of poliomyelitis. Widespread epidemics were seen in India in 1971 and 1981, male adults were predominantly affected, and the clinical features were a rapid paralysis of the limbs and the cranial nerve innervated musculature. A detailed study[19] has suggested that the major neurological lesion is at the level of the anterior horn cell, and a permanent poliomyelitis-like disability may follow the acute illness. Japanese encephalitis caused by a Group B arbovirus occurs in epidemics but is also endemic in parts of India, particularly the south. This mosquito-borne infection finds a reservoir in pigs, cattle and some species of bird. A prodromal phase is followed by an acute encephalitis from which only one-third of affected individuals recover, a further third remain neurologically damaged and one- third die[20]. A vaccine is available and, as with acute haemorrhagic conjunctivitis, control of these devastating conditions is theoretically possible. Recently, a tick-borne epidemic encephalitis occurring in the forests of the State of Karnataka has attracted attention. Having bitten infected monkeys, the ticks fall to the forest floor to await the next meal from an unsuspecting human host, in whom haem- orrhagic complications often prove fatal. Other Neurological Infections In a single year there were 227 cases of tetanus seen at the J. J. Group of Hospitals, Bombay[21] and 70 of these patients died of the disease. Improved supportive care may now be reducing the mortality but tetanus remains an important but preventable neurological infection. The scourge of rabies continues in India; few have access to diploid cell anti-rabies vaccine. Imported cases may not become unwell until after entry to the UK[22]. Neurosyphilis, while declining in incidence, may still be seen, especially in the acute or subacute meningovascular forms, but many Indian neurological departments may not have one case in a year. There is an impression that subacute sclerosing panencephalitis is more common in India than in the UK, and it is possible that a widespread measles vaccination programme may reduce the preva- lence of this 'slow virus' disorder. Non-infective Spinal Cord Disorders In South India the most common form of myelopathy is a subacute spastic paraplegia with peripheral sensory 14 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 symptoms, dorsal column involvement and, frequently, bladder disturbance[23]. Identification of known causes of paraplegia will allow categorisation of a few cases, but a large enigmatic group of patients remain. There are similarities to the tropical paraplegia seen elsewhere, notably in Jamaica and Africa, but in all cases intensive study has failed to reveal a nutritional, toxic or infective cause for this entity. Lathyrism Lathyrism, an acute or subacute corticospinal tract de- generation, is common in Central India, and may be found in 4-6 per cent of landless labourers in endemic areas. This disease follows the consumption of the seeds of Lathyrus sativus, and was recognised by the ancients, as illustrated by the 'immortal verse' of lathyrism, thus 'the black pea with its yellow flower, from eating it, comes trouble in the legs, flopping top knot and swaying hips: behold the ill effects of eating matra'[24]. This easily grown crop is used when there is a shortage of conven- tional food but detoxification of the pulse is possible and health education could banish this disorder to the realms of medical history. Endemic Fluorosis The high concentration of fluoride in the drinking water of many parts of India may result in endemic fluorosis, which is particularly likely to occur when the water source is further concentrated by evaporation. Mottling of the teeth is an early sign, but a generalised osteosclerosis may become neurologically manifest when the spinal cord and spinal roots are compressed by vertebral disease[25]. Once again, the major prospect for prevention of this condition lies in appropriate public health activity, in this case the provision of unaffected water supplies, which poses insurmountable engineering and financial difficul- ties in a country as vast and populous as India. Atlanto-axial Dislocation In Western practice, disease of the atlanto-axial joint is likely to be associated with rheumatoid arthritis, but in an Indian population a congenital form of atlanto-axial dislocation is relatively common. This entity may present with cervical pain and stiffness, transient attacks of neurological disturbance or a progressive spinal cord syndrome. Clinical suspicion can usually be confirmed by plain radiology of the cervical spine with attention to the distance between the odontoid and the anterior arch of the atlas, and to the dimensions of the cervical canal, but myelography may sometimes be necessary when the diagnosis is not clear. Surgical reduction of the disloca- tion and lateral fusion are successful, especially in early cases[26]. Other Neurological Diseases common in India Painful ophthalmoplegia, also referred to as the superior orbital fissure syndrome or the Tolosa-Hunt syndrome, is disproportionately common in India and a para-infective aetiology has been postulated where an association with past tuberculous or filarial infection has been found [27], This may be fortuitous and, as in the much rarer UK cases, a dramatic response of the facial pain, ophthalmo- paresis and raised erythrocyte sedimentation rate is seen following corticosteroid treatment. Classical motor neurone disease occurs in India with a frequency similar to that in the UK, but an unusual juvenile variant, with onset before the end of the third decade, is seen in India, particularly the south[28]. Bulbar and asymmetrical limb involvement is characteris- tic and a more benign prognosis can be anticipated. The involvement of the pyramidal tracts and the absence of a family history differentiate this group from cases of spinal muscular atrophy and no association with the polio virus has been found. A further unusual form of motor neurone disease, a monomelic variant, has also been observed, and a number of Indian cases have recently been studied in detail[29]. Cerebrovascular disease afflicts the Indian to the same degree as the Westerner, but there is an impression that strokes in younger patients may be more prevalent in India. An obliterative aortic arch syndrome appears to be quite common and it is possible that a greater proportion of strokes are due to an underlying arteritis, rather than to the familiar embolisation from large vessel arterioscler- osis[30]. Conversely, it was thought that intracranial aneurysm was less common in India than elsewhere, but this observation most likely reflects only the difficulty in collecting statistical data in India. Large scale epidemi- ological studies are under way, both in cerebrovascular disease and in wider aspects of neurology, and the results will be of great interest. A fascinating form of reflex epilepsy has been described in which partial or generalised seizures are induced by bathing with hot water. In a large series of patients with epilepsy[31], 108 (9 per cent) were found to have hot water epilepsy in which attacks were precipitated by pouring mugfuls of hot water on to the head and body, a popular method of bathing in India. This remarkably high fre- quency contrasts with the very rare Western case reports of hot water immersion epilepsy[32]. Treatment may simply be to use tepid water for bathing, although anticonvulsants have been used in some cases. A mention should be made of the high incidence of some of the genetically-mediated neurological disorders in India. Spino-cerebellar degenerations are prevalent in some areas, and mental handicap, caused by obstetric and genetic factors, is a major health problem. Wilson's disease shows remarkable clustering. The personal series of one neurologist in India, collected largely from the local population, stands at 52 cases[33]. It is possible that in rural areas consanguinity is an important factor in the determination of these conditions. Conclusion Neurological disease varies enormously worldwide and this brief review has detailed some of the conditions which are commonly seen in India and the Indian, but rarely Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 15 appear in a British consulting room or ward. The reasons for the high incidence of infective and nutritional disease in India are obvious, but there is no known reason for the superior orbital fissure syndrome or hot water epilepsy being so common in the practice of an Indian neurologist and so rare in the UK. The study of comparative neurology affords fascinating glimpses into the aetiology of these conditions, and the neurologist in training as well as the established clinician should take every opportunity of examining his subject in another environment. Acknowledgements The authors recently re-visited India with the financial assistance of a Medicine-Gilliland Travelling Fellowship. We wish to thank our many colleagues in India who showed us their departments, patients and kindness, and in particular Professor K. Srinivas, Madras; Professor J. Abraham and Dr S. Prabhakar, Vellore; Professor M. Gourie-Devi and Dr H. Swamy, Bangalore; Dr K. Bose, Rourkela, and Dr V. Saxena, Calcutta. References 1. Swart, S., Briggs, R. S. and Millac, P. .(1981) Lancet, 2, 15. 2. Medical Research Council Tuberculosis and Chest Disease Unit (1980) British Medical Journal, 281, 895. 3. Bateman, D. E., Newman, P. K. and Foster, J. B. (1983) Journal of the Royal College of Physicians, 17, 106. 4. Sinclair, S., Prabhamani, V. S., Shrinivas and Ghai, O. P. (1977) Indian Paediatrics, 14, 967. 5. Kennedy, D. H. and Fallon, R. J. (1979) Journal of the American Medical Association, 241, 264. 6. Tandon, P. N. and Pathak, S. N. (1973) in Tropical Neurology, pp. 37-51. (ed J. D. Spillane.) Oxford University Press. 7. Smith, H. V., Vollum, R. L., Taylor, L. M. and Taylor, K. B. (1956) Tubercle, 37, 301. 8. Thrush, D. C. and Barwick, D. D. (1974) Journal of Neurology, Neurosurgery and Psychiatry, 37, 566. 9. Tandon, P. N., Banerji, A. K., Das, B. S. and Dar, J. (1970) Bulletin of the All India Institute of Medical Sciences, 4, 119. 10. Dastur, H. M. and Desai, A. D. (1965) Brain, 88, 375. 11. Bhargava, S. and Tandon, P. N. (1980) British Journal of Radiology, 53, 935. 12. Mani, K. S. (1973) in Tropical Neurology, p. 81. (edj. D. Spillane.) Oxford University Press. 13. Wadia, N. H. and Dastur, D. K. (1969) Journal of the Neurological Sciences, 8, 239. 14. Gourie-Devi, M., Padmini, R. and Satish, P. (1980) Indian Journal of Medical Research, 71, 581. 15. Gourie-Devi, M. and Satish, P. (1980) Acta Neurologica Scandinavica, 62, 368. 16. Ridley, D. S. and Jopling, W. H. (1966) International Journal of Leprosy, 34, 255. 17. Srinivas, H. V., Rao, T. V. and Deshpande, D. H. (1980) Clinical Neurology and Neurosurgery, 82, 187. 18. John, J. (1976) British Medical Journal, 1, 812. 19. Wadia, N. H., Wadia, P. N., Katrak, S. M. and Misra, V. P. (1983) Journal of Neurology, Neurosurgery and Psychiatry, 46, 599. 20. Gourie-Devi, M. and Deshpande, D. H. (1982) in Paediatric Problems, pp. 340-356. (ed L. S. Prasad and L. L. Kulczycki.) New Delhi: S. Chand. 21. Wadia, N. H. (1973) in Tropical Neurology, p. 27. (ed J. D. Spillane.) Oxford University Press. 22. Cohen, S. L., Gardner, S., Lanyi, C. et al. (1976) British Medical Journal, 1, 1041. 23. Mani, K. S., Mani, A.J. and Montgomery, R. D. (1969) Journal of the Neurological Sciences, 9, 179. 24. Srinivas, K., Shivan, U., Saravanan, P. K., Ramachandran, J. and Rajasekharan, E. A. (1983) Proceedings of the Neurological Society of India, p. 153. 25. Singh, A. and Jolly, S. S..(1961) Quarterly Journal of Medicine, 30, 357. 26. Wadia, N. H. (1967) Brain, 90, 449. 27. Mathew, N. T. and Chandy, J. (1970) Journal of the Neurological Sciences, 11, 243. 28. Sundaram, E. M., Jagannathan, K. and Ramamurthi, B. (1970) Neurology (India), 8, Suppl. 1, 104. 29. Gourie-Devi, M., Suresh, T. G. and Shankar, S. K. (1984) Archives of Neurology, 41, 388. 30. Abraham, J. (1973) in Tropical Neurology, pp. 86-91. (ed J. D. Spillane.) Oxford University Press. 31. Mani, K. S., Mani, A.J. and Ramesh, C. K. (1974) Transactions of the American Neurological Association, 99, 224. 32. Szymonowicz, W. and Meloff, K. L. (1978) Canadian Journal of Neurological Sciences, 5, 247. 33. Swamy, H. S. (1984) Personal communication.

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Audit Reviewed: Medical Audit in North America W. VAN'T HOFF, MB, FRCP Consultant Physician, North Staffordshire Hospital Centre, Stoke-on-Trent This review is based on a recent visit to North America during the tenure of a Medicine-Gilliland Travelling Fellowship. I visited a number of hospitals in Ontario, Canada, and in Boston, Massachusetts, which enabled me to study different approaches to medical audit in various centres. Medical audit is now an accepted part of American hospital life; all the hospitals I visited had active pro- grammes. In the USA the Joint Commission on Accredit- ation of Hospitals, which is a Federal institution, visits all hospitals every three years. It demands a rigorous quality assurance by the hospital, and also more specifically by the various medical services. In Canada a similar organi- sation exists, the Canadian Council on Hospital Accredit- ation, which visits hospitals regularly in order to accredit them. Although this is not compulsory, failure to obtain accreditation would result in losing the licence to train junior medical staff (their residents and interns). Most hospitals therefore desire accreditation. As in the USA, a hospital is visited every three years if the report is satisfactory. If the required standards are not met then advice is given and the hospital will be re-surveyed in two years or sometimes after only one year. One of the requirements is that there be a 'process of analysis and evaluation of the performance and outcome of the pro- fessional clinical work of a unit, department or service'. In this particular context the concern is the quality of patient care and, as in the UK, there has been a search for terms other than medical audit. Those suggested are clinical appraisal, clinical assessment, clinical audit and clinical review. Responsibility for seeing that medical audit takes place had been given to an Audit Committee in all the hospitals I visited. In Ontario the Audit Committee is answerable to the Medical Advisory Committee (MAC) which is the executive committee consisting of the executive and medical directors of the hospital, the chiefs of the various medical departments and some other members. The MAC is usually appointed by the Board of Directors of the hospital and is therefore not exactly equivalent to its namesake in the UK. In the USA the Audit Committee is answerable to the Executive or Medical Executive Com- mittee, which is roughly equivalent to the MAC in Canada. The chairman of the Audit Committee is appointed rather than selected, and is usually a motivated and medically qualified member of the hospital staff. The Committee is composed of representatives from the main medical departments, but there is considerable variation, and in some hospitals specialties such as psychiatry are not included. The medical records staff is always repre- sented, there is an administrator or member of the executive staff, and the nursing staff is usually represent- ed, although not in all hospitals. Most Audit Committees meet monthly but the manner of their work and their effectiveness is very variable. Although responsible for seeing that medical audit is practised, the Audit Committee does not usually do all the work itself. Most hospitals have a Tissue Committee which reviews surgical histopathology and, in some cases, all surgical deaths. The main divisions of medicine, surgery, radiology and other specialties are usually responsible for carrying out medical audit within their specialty, and their results or conclusions are reported to the main Committee. The most common pattern is for each department to organise one project a year, which can be a retrospective or a prospective survey. If a department is devoid of ideas a project can be suggested, and in most hospitals Audit Committees welcome suggestions from different sources. The kinds of topic studied can be very variable. A simple one would be length of stay of patients with a particular condition, or the complication rate of a medical or surgical condition, or the effectiveness of communication with patients' own doctors. In some hospitals all deaths are studied, in others various forms of selection are made. In Ontario, in order to help doctors and hospitals, the Ontario Hospital Association and the Ontario Medical Association have jointly prepared a handbook called 'Patient Care Appraisal'. Quite apart from the legal requirements and those of the Canadian Council on Hospital Accreditation, the handbook states that partici- pation in a patient care appraisal programme is 'the ethical responsibility of a self-governing profession. This requires that all physicians be involved in some review process and that this be used as a method for patient care improvement'. A further reason given is that it demon- strates accountability to the public. Patient care appraisal benefits the medical staff by providing feedback on performance or patterns of practice which can encourage a critical attitude to clinical work by identifying topics for inclusion in continuing education programmes, or areas in need of clinical research, and providing useful motiva- tion for physicians to keep up-to-date. The handbook Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 53 gives suggestions and provides help in setting up projects. One useful guide is the definition of useful criteria in a review study and seven steps are listed. 1. Choose a topic. 2. Set objectives. 3. Establish the criteria. 4. Retrieve the data. 5. Collate and present the results of the study. 6. Analyse by peer review and make up a report. 7. Take action and follow it up. In the USA medical audit is organised on similar lines. Hospitals are currently required to carry out at least four audits or quality review studies annually. The Pro- fessional Standards Review Organisation (PSRO), which is mandated by the Federal government, decides on two studies which all hospitals in a particular area are then required to do, and each hospital then decides on two further studies which they choose themselves. Most active hospitals carry out considerably more than the required four, and, as in Canada, most medical divisions or departments also have their own projects. In most hospitals the medical records department plays a considerable role in the organisation and performance of medical audit. The calibre of the staff in medical records departments is considerably higher than is usual in the UK. The Director of Medical Records is normally a graduate, one has a BA in Medical Records and also an MA in Education. In one hospital there were three further graduates, and most records personnel had also taken a two year course in Health Records Adminis- tration. The usual practice is that records of all patients discharged from hospital are coded. Most departments, however, do considerably more than this. One looks through samples of notes such as 25 records of patients admitted as emergencies. Another department looks ev- ery month at 10 records from one service, usually in rotation, critically examining the standard of notes, pro- cedures carried out, length of stay and how long after discharge the summary was sent. This particular job is undertaken by a research medical records librarian. In another hospital every set of notes is studied in detail. In surgical cases this includes checking whether a patient received a transfusion, whether there were any results of a wound swab and, if positive, whether the clinical notes commented on the presence of wound infection. This process can take from 10 minutes to three hours. Records that are considered unsatisfactory are returned to the clinician, and they are not filed until complete. In some hospitals there is a Medical Records Commit- tee which includes medical members, and it decides on the format of notes and standards expected in the depart- ment. The better staffed records departments play an active and major role in both retrospective and prospec- tive surveys conducted by many clinical departments. Results of surveys are reported to the Audit Committee and the chief of the relevant department is informed if any action is required. Where necessary a follow-up survey is done. In Ontario, as in some other provinces, hospitals subscribe to a Hospital Medical Records Institute (HMRI) which receives copies of all in-patient summar- ies. The Institute has medical and lay members and provides a service for hospitals in analysing and dissemi- nating information and statistics. The HMRI has a Medical Audit Advisory Committee which has developed a number of 'Care Appraisal Programs'. These have covered a variety of fields and include the management of overdoses; the diagnosis, management and outcome of acute cerebrovascular disease; the indications for and complications of transurethral prostatectomy; the accura- cy of diagnosis and outcome of myocardial infarction; and the indication, accuracy of diagnosis and outcome of surgical procedures such as appendicectomy, cholecystec- tomy and Caesarian section. These programmes have been researched and prepared and are available for use by hospitals in the province. It is a voluntary scheme and some hospitals prefer to organise their own projects, but the programmes have been designed to help hospitals with limited resources that might have difficulty in setting up projects of their own. The HMRI is able to analyse the programmes it has suggested and return the results to the individual hospital. The HMRI does not establish stan- dards of practice but selects criteria and provides facilities for analysing the results. Individual hospitals are not identified although they themselves are able to make comparisons, and it is up to the hospital to take any action that may be required. The College of Physicians and Surgeons of Ontario is responsible for issuing the licence to practise medicine in the province, and it therefore in part fulfils the role of the General Medical Council in the UK. The Council of the College has recently accepted in principle the establish- ment of a 'Peer Assessment Program'. This consists of the assessment of work done outside hospital, in the offices (consulting rooms) of general practitioners and of a number of specialists in, for example, paediatrics, inter- nal medicine, obstetrics and gynaecology, and general surgery. Assessors are chosen by a committee of the Council and consist of a general practitioner and a specialist. Work assessed has been that of physicians and surgeons who had agreed to take part in the programme. The assessment is made by examining a representative number of case records such as those of the last 30 patients seen. On the whole, both assessors and those assessed considered that records were a reasonable reflec- tion of the care provided. There are five possible categor- ies of finding: A. Satisfactory in all respects. B. Satisfactory with minor suggestions. C. Records deficient but care satisfactory. D. Records of such deficiency that care could not be assessed. E. Inadequate care with or without adequate records. Over the last three years 81.3 per cent of those assessed were considered to be providing satisfactory care and to have adequate records. There was concern about records in 8.7 per cent (Category C). When the practice is considered to be in Categories D or E, copies of the assessment report are sent to the physician concerned who is then invited to an interview with the Peer Assessment Committee; 10 per cent of doctors assessed were invited for interview in the last 54 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 three years; 13.3 per cent of general practitioners assessed were interviewed for this reason as opposed to 2.3 per cent of specialists. Age played an important role in the assessment of general practitioners; 47.6 per cent of those over 70 years were interviewed compared to 11.5 per cent under 70 years, and only 5.7 per cent of those under 40 years were interviewed. Two other significant observations were made. The proportion of female doctors in Categories D and E was 4.0 per cent compared to 14.4 per cent males, and only 2.8 per cent of practitioners who had a Certificate of the College of Family Physicians of Canada were interviewed compared to 16.2 per cent of non-certificants. The majority of those interviewed had corrected the deficiencies when next assessed and in only a small number of cases was there serious concern resulting in reference to the Executive Committee of the College. Medical audit, clinical review, or patient care appraisal is welcomed with more enthusiasm by some doctors than others but it is now generally accepted to be an integral part of hospital life in North America. Nor are doctors the only group to look critically at the service they provide. All hospital departments, including those of adminis- tration and building, are accountable and subject to review. In some hospitals the nursing staff have also initiated projects to evaluate procedures and look at the quality of care they provide. Overall I was much impressed by the way medical audit is organised and carried out and I think in the UK we might well benefit from a much wider acceptance of clinical review, medical audit?call it what you will? responsibility, accountability and constructive self-criti- cism. Acknowledgements This work was carried out during the tenure of a MEDI- CINE-Gilliland Travelling Fellowship, administered by the Royal College of Physicians of London and funded by the Medical Education Trust, a charitable trust founded by The MEDICINE Group, the publishers of MEDI- CINE International. I am very grateful to the large number of people who willingly gave up much of their valuable time in order to discuss medical audit with me.

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The Role of the Pharmacist in the Anticoagulant Clinic M. PEGG, BPharm, Staff Pharmacist J. BOURNE, MSc, BPharm, Staff Pharmacist A. D. MACKAX MD, MRCP(UK), Senior Medical Registrar, Department of Respiratory Medicine, City General Hospital, Stoke-on-Trent W. A. LAWTON, BA, Statistician, Computer Centre, North Staffs Royal Infirmary R. B. GOLE, MD, FRCP, Consultant Physician, Department of Respiratory Medicine, City General Hospital, Stoke-on-Trent Approximately 50,000 patients in Britain receive oral , anticoagulant treatment every day and over two million tests of anticoagulant control are performed in a yearfl, 2]. Close supervision of the patients is necessary because dose requirements are variable and there is an ever- present risk of drug interactions and even major bleed- Jng[3]. Good anticoagulant control is also influenced by diet, intercurrent illness and poor compliance, and recent reviews suggest that in the UK the standard of control is often inadequate [4-6]. One factor which may lead to inconsistent management is the delegation of responsi- bility to junior doctors who do not stay long enough in each training post to learn the patients' idiosyncrasies[4, 51" With the dual objectives of obtaining a consistent standard of anticoagulation control and of bringing the pharmacist more directly into the arena of patient care, an anticoagulant clinic managed jointly by pharmacists and physicians was started in the North Staffordshire Hospital Centre in September 1979. This article describes the management and organisation of such a clinic (the 'combined clinic') and retrospectively compares the re- sults achieved with those obtained by other physicians who retained the supervision of anticoagulant therapy entirely in the hands of medical staff (the 'standard > clinics'). Methods The combined clinic supervises the patients of four consultant physicians and is held twice weekly to run concurrently with the medical clinic of a consultant physician (R.B.C.). The pharmacist has access to the patient's medical file in which anticoagulant control is recorded on a special chart. He counsels the patient, adjusts dosage as necessary, decides when the patient should next attend and dispenses a supply of tablets. To ensure a consistent standard of practice, guidelines (see Appendix) were prepared for the management of the anticoagulant clinic by pharmacists, based on those used in the Division of Clinical Pharmacy at the University of California, San Francisco (Dr Steven Kayser, personal communication). The pharmacist's decisions are checked and initialled by a doctor at the medical clinic to whom patients may be referred if problems arise. Medical review is otherwise limited to one consultation at three months in the case of patients receiving a short course of anticoagulant therapy, or twice yearly consultations for those on long-term treatment. The standard clinics are managed as an integral part of the normal medical out-patient clinics. The patients' anticoagulant control is supervised either by the consul- tant physician or the junior medical staff. The patients are frequently seen by different doctors at successive appointments. The names of 116 unselected patients who had received anticoagulant therapy during the calendar year 1980 were taken from the laboratory records. Sixty-two patients had attended the combined clinic and 54 had been supervised at standard clinics. The following information was ob- tained from the patients' medical records: sex, age, weight, smoking history, alcohol consumption, the indi- cation for anticoagulant treatment, biochemical indices of liver and kidney function, dose and duration of heparin therapy, loading dose of warfarin, length of in-patient stay after commencement of warfarin, and duration of anticoagulant therapy. Treatment with drugs known to interact with warfarin during in-patient and out-patient management, evidence of bleeding or other unwanted effects, and factors which might affect control such as poor compliance and intercurrent illness were also record- ed. In this hospital centre warfarin dosage is adjusted by reference to a prothrombin index (PI) which is the reciprocal of the British Comparative Ratio (BCR), expressed as a percentage. The desired therapeutic range was defined as a PI of between 50-30 per cent (corre- Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 sponding to a BCR of 2-3.3) except for one consultant in the standard clinic group whose chosen range was 40-20 per cent (corresponding to a BCR of 2.5-5). Anticoagulant control was assessed by several methods. 1. The average interval between appointments was cal- culated by dividing the total number of weeks for which a patient received treatment by the number of his atten- dances. 2. The number of occasions on which the PI was above or below the desired therapeutic range (representing under-anticoagulation and over-anticoagulation respec- tively) was totalled and expressed as a percentage of the total number of PI readings for each group. 3. The degree of fluctuation in PI was determined by averaging the PI changes between one attendance and the next throughout each patient's course of treatment. The number of patients experiencing unwanted effects from anticoagulation was obtained from reports of these events in the patients' medical records. Unwanted effects sought included bruising, epistaxis, microscopic haema- turia, haematemesis, melaena, frank haematuria and further episodes of thrombosis or embolisation. The duration of treatment of single episodes of deep vein thrombosis (DVT) or pulmonary embolism (PE) was compared by calculating the mean duration of therapy for these indications in each group. The comparison was carried out retrospectively, since a prospective study would have influenced the management of the patients so as to invalidate the comparison. Results The characteristics of the patients attending the two types of clinic are shown in Table 1. There was no significant Table 1. Patients studied Cases Combined Routine Clinic Clinics Male 24 32 Female 38 22 Age in years (mean and range) 57 (25-77) 52 (23-79) Weight in kg (mean and range) 72 (46-96) 73 (46-101) Renal Function* Normal 44 32 Abnormal 10 11 Unknown 8 11 Liver Function** Normal 43 32 Abnormal 9 14 Unknown 10 8 * Renal function was recorded as abnormal if serum creatinine was outside the normal range. ** Liver function was recorded as abnormal if two or more liver function tests (plasma bilirubin, aspartate transaminase, lactate dehydrogenase, alkaline phosphatase) were outside the normal range. difference between the groups in age, weight, or renal and hepatic function. Similarly, Table 2 shows that the two clinics were comparable with regard to the reasons for which anticoagulant therapy was given. Table 2. Indications for warfarin therapy. DVT?deep vein thrombosis. PE?pulmonary embolism. Cases Combined Routine Indications Clinic Clinics DVT single 11 13 DVT recurrent 8 6 PE single 25 25 PE recurrent 13 8 Mitral valve disease 3 0 Atrial fibrillation alone 0 1 Heart valve prosthesis 2 1 The average actual duration of anticoagulant treatment for single episodes of DVT and PE and the intended duration of treatment as previously declared by the physicians are shown in Table 3. In all cases the actual Table 3. Duration (and range) of warfarin therapy. DVT? deep vein thrombosis. PE?pulmonary embolism. Weeks of Treatment Combined Routine Clinic Clinics DVT (single) Intended 12 6 Actual 13.6 (8-26) 8.2 (3-16) PE (single) Intended 12 12 Actual . 14.2 (9-29) 12.4 (4-20) duration was comparable to the intended duration, but it is also apparent from this table that the clinicians of the combined clinic normally maintained anticoagulation for 12 weeks after a single episode of DVT, while those of the routine clinics did so for only six weeks. Table 4 illustrates Table 4. Control of anticoagulation. PI?prothrombin index. Combined Routine Clinic Clinics Interval between appointments (weeks)* 1.82 (0.3-4.0) 1.81 (0.3-13.0) Percentage of PI readings above desired range (under-anticoagulation) 19% 26% Percentage of PI readings below desired range (over-anticoagulation) 11 % 7 % Difference in PI (%) between attendances* 9.93 (0-58) 9.88 (0-59) *Mean and range our assessment of the management of therapy by the two types of clinic, both of which achieved a similar average standard of anticoagulant control among their patients with a similar range of variation in frequency of attend- ance and PI fluctuation. The number of patients exper- iencing unwanted effects during anticoagulation is 40 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 Table 5. Unwanted effects. PE?pulmonary embolism. Number of Patients Combined Routine Effect Clinic Clinics Bruising 2 0 Epistaxis 1 Microscopic haematuria* 17 10 Frank haematuria 1 0 Haematemesis/melaena 1 ? Further PE 0 1 No. unwanted effects 40 42 Total 62 54 * Detected by reagent strip urinalysis. illustrated in Table 5 which indicates no major differences between the two types of clinic. The most common unwanted effect was microscopic haematuria detected by reagent strip urinalysis. One" patient in the combined clinic group had frank haematuria while the PI was fv within the therapeutic range, and one patient with chronic liver disease had melaena while under-anticoagu- lated (PI 52 per cent), which was subsequently found to be due to gastritis. Discussion Oral anticoagulant therapy is sufficiently hazardous to warrant special measures to ensure safe and effective treatment, and continuity of surveillance is an important factor in avoiding mistakes. Our increasing awareness of the problems coincided with the pharmacists' aspiration to become more directly involved in patient care, and the idea of a joint pharmacist/physician anticoagulant clinic was conceived to satisfy these views. The concept of * pharmacist responsibility for dosage adjustment of anti- coagulants has been tried out in the USA[7-9], and shared responsibility between a physician and a pharma- , cist working together has been described both in the USA[10] and in Britain[ll], but in general such treat- ment is traditionally managed by doctors. The task of supervising treatment and making dosage adjustments is regarded as fairly simple and commonly falls to junior doctors, who periodically move from one post to the next in order to satisfy training requirements. We believe that continuity of care can more easily be maintained by a pharmacist who is interested in applying his knowledge of pharmacology to the practical treatment of patients. ?> Before embarking upon so radical a change in estab- lished practice it was important to ensure that junior doctors should not lose the opportunity of gaining experi- ence in monitoring oral anticoagulation; and that the statutory requirements for the issue of prescribed drugs by qualified medical practitioners should be met. We considered that the training needs of junior hospital doctors were adequately provided for by the experience they gained in initiating warfarin therapy while the patient was still in hospital; and the statutory need for the prescription of warfarin by a doctor would be satisfied by the shared responsibility of the combined pharmacist/ physician anticoagulant clinic, where there would always be a medical presence and where all warfarin prescrip- tions advised by the pharmacist would be checked and initialled by a doctor. Once the new system had been put into practice it became necessary to compare it objectively with the established practice of medically supervised anticoagulant therapy running concurrently. The results of this com- parison between similar groups of patients receiying warfarin therapy for similar indications show that in both sorts of clinic there was considerable variation in the duration of therapy, which was sometimes as much as two months shorter or three months longer than the intended duration. The more extreme variations were due to compliance failure (2 cases), to an alteration in the diagnosis (2 cases), to persistence of the underlying condition which had led to thromboembolic disease such as prolonged immobilisation (2 cases), or to unexplained decisions on the part of the supervising doctors to prolong or cut short treatment (5 cases). These variations were seen equally in the combined and standard clinics, and it was clear that the duration of anticoagulant treatment for a single episode of DVT or pulmonary embolism varied considerably from one physician to the next, lying be- tween six weeks and six months. In the combined clinic we now ask clinicians to state the intended duration of treatment at the outset and the pharmacist draws it to the clinician's attention if treatment appears to be running on too long, but the decision to stop treatment rests always with the clinician and would be taken at a medical follow- up attendance, depending on the medical assessment of that patient's need. The routine three-month medical appointment is intended to prevent inadvertent prolonga- tion of treatment, but a clinician could always decide whether it should be cut short or prolonged according to the clinical situation. The general standard of anticoagu- lant control and the degree of fluctuation in prothrombin index were the same in both combined and standard clinics, and the low incidence of unwanted effects was common to both groups of patients. It should be borne in mind that the comparison was made retrospectively, so that the usual practice of the participating doctors and pharmacists was not modified by a feeling of being overlooked. Our experience in the combined clinic showed that the pharmacist never had any hesitation in consulting his medical colleagues, and would do so, on average, once in 25 patient attendances. Since the doctor and the pharma- cist worked in adjoining rooms access between them was easy, and if the patient complained of any symptoms unrelated to the anticoagulant treatment the pharmacist automatically sought medical advice without further ado. On the strength of these observations it cannot be said that the results obtained by the pharmacist and physician working together were better or worse than the standard clinics managed by clinicians alone, and no significant cost benefit is obtained by substituting a pharmacist to do this work in place of a junior doctor. Critics have argued that the additional cost of assigning a staff pharmacist for 4 hours per week to this role is not justified in the absence of objective evidence of an improvement in the service provided, but this criticism overlooks the subjective bene- Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 41 fits of the combined pharmacist/clinician clinic which we observed, namely: 1. Dual'participation reduces the risk of mistakes. 2. Medical confidence is increased by a system in which the supervision is carried out by a pharmacist with continuing responsibility. 3. The pharmacist's professional role is enhanced. We believe that these are significant benefits, and efforts are being made to expand the clinic to cope with requests for access from other groups of clinicians. The service is limited at present to those physicians whose clinics happen to coincide with the pharmacist's availabil- ity, because the essential principle of this concept is that the pharmacist who runs the clinic should always have at hand a clinician who is responsible for the patients' care. Acknowledgements We acknowledge with thanks the co-operation of the physicians who allowed us to study the records of the patients under their care. We are grateful to Dr John Mucklow who gave us valuable advice and criticism, and to Mrs Helen Theobold for her help with the manuscript and tables. We also acknowledge the help and interest of Professor Malcolm Rowland, Department of Pharmacy in the University of Manchester. References 1. Sharp, A. A. (1982) British Medical Journal, 285, 242. 2. Anon (1983) Drug and Therapeutics Bulletin, 21, 33. 3. Fenech, A., Winter, J. H. and Douglas, A. S. (1979) Drugs, 18,48. 4. Duxbury, B. McD. (1982) British Medical Journal, 284, 702. 5. Mclnnes, G. T. (1981) Lancet, 2, 88. 6. Harries, A. D., Birtwell, A. J. and Jones, D. B. (1981) Lancet, 1, 1320. 7. Reinders, T. P. and Steinke, W. E. (1979) American Journal of Hospital Pharmacy, 36, 645. 8. Nappi, J. M. (1980) The Wisconsin Pharmacist, 49, 164. 9. Chenella, F. C., Klotz, T. A., Gill, M. A. et al. (1983) American Journal of Hospital Pharmacy, 40, 1642. ,, 10. Davis, F. B. and Sczupak, C. A. (1979) Postgraduate Medicine, 66, 100. 11. Kemp, C. G. and Carrington, D. W. (1978) Pharmaceutical Journal, 222, 564. , APPENDIX: MANAGEMENT OF THE ANTICOAGULANT CLINIC BY PHARMACISTS Objectives The objective for pharmacists who are responsible for warfarin anticoagulation therapy is to achieve consistent management and surveillance of therapy in order to promote maximum effectiveness of the drug and minimal risk from adverse effects and over-dosage. Rationale Close supervision of warfarin therapy is considered neces- sary for the following reasons: 1. Warfarin exhibits pronounced inter-individual elimi- nation kinetics. This variation is primarily ascribed to differences in the amount of free fraction of the drug in the serum. 2. There are many drugs, both prescription and over-the- counter preparations, which can produce clinically important interactions with warfarin. 3. There are many diseases which can alter the pharma- cological response to warfarin. 4. The major unwanted effect of warfarin ? bleeding ? is a highly dangerous one. 5. Elderly patients are particularly at risk from problems associated with warfarin therapy because they com- monly suffer from more than one disorder and are receiving several drugs. Methods Organisation of the Clinic (a) On the appointment date the patient will first report to the Haematology Department for a prothrombin test. The result of the test will be entered in the patient's copy of the DHSS Anticoagulant Treatment Booklet by the haematologist. The patient will then report to the Anti- coagulant Clinic and the result of the prothrombin test will be transferred by the pharmacist to the Anticoagulant Treatment Chart (Fig. 1). The Anticoagulant Treatment Chart will remain permanently in the patient's notes. (b) The patient's warfarin dosage will be determined by the pharmacist and will be entered on the Anticoagulant Treatment Chart and also in the patient's Treatment Booklet. The entry in the Treatment Chart will be regarded as a prescription and a physician's signature will be obtained before a supply of warfarin is dispensed. (c) The dispensing of the patient's supply of warfarin will take place at the clinic. The completed prescription will be checked by the pharmacist and the Treatment Booklet will be returned to the patient. (d) All supplies of containers, labels and warfarin tablets will be obtained from the central out-patients pharmacy department by the pharmacist before commencement of the clinic. These supplies will be returned to the phar- macy department for safe-keeping at the end of each clinic. General Responsibilities (a) The pharmacist shall assist the physician in the management of patients on warfarin. (b) The pharmacist will adjust warfarin dose when indi- cated, maintain a record of this information, and educate the patient concerning the use of warfarin. (c) The aim of anticoagulation therapy with warfarin is to maintain a prothrombin index (PI) of between 30 and 50 42 Journal of the-Royal College of Physicians of London Vol. 19 No. 1 January 1985 per cent (i.e. a prothrombin time of between approxi- mately 2 to 3 times the value of the control), unless otherwise required by the physician in charge of the patient's care. (d) Patients whose PI remains stable will be maintained on the existing dosage of warfarin. (e) For Pis outside the desired range, the pharmacist will establish the cause for non-control, decide whether dosage alteration is necessary and schedule the time for the next clinic visit. In all cases when any discontinuation of therapy or the use of vitamin K is indicated the pharma- cist will consult the physician. Specific Responsibilities of the Pharmacist 1. Review of the patient's medical records. Each time a patient is started on warfarin and is to attend the Anticoagulant Clinic, the medical records will be ob- tained and reviewed for the following information: (a) Name, address, sex, date of birth, occupation, unit number and referring consultant. (b) Indication for anticoagulation therapy and anticipated duration of therapy. (c) Concurrent drugs: prescription and over-the-counter preparations. (d) Concurrent diseases and relevant past medical his- tory. (e) Social factors that may influence warfarin therapy (i.e. home medication situation, availability of transportation to clinic, etc). (f) Alcohol use. (g) Name, address and telephone number of patient's GP. The above information will be entered on the patient's Anticoagulant Treatment Chart and amendments made if necessary at each attendance. Dates of the next appoint- ment are placed in the Anticoagulant Clinic appointment book. 2. The Patient-Pharmacist Interview (a) During the first visit to the Anticoagulant Clinic, the pharmacist will, if necessary, interview the patient in order to supplement information gained by review of the medical records. In addition, the pharmacist will ascer- tain the patient's level of understanding of disease and therapy, and assess his ability or willingness to comply with therapy and clinic visits. (b) The second part of the interview will consist of the education of the patient concerning the use of warfarin. Generally, the information in the DHSS leaflet entitled 'For Patients on Anticoagulant Treatment' will be im- parted. The pharmacist will ensure that each new patient has received a copy of the DHSS Anticoagulant Treat- ment Booklet and leaflet. (c) Special instructions will be given to competent persons caring for the patient when the patient is unable to understand or comply with therapy. (d) The pharmacist will note at the time of the medical record review and/or first interview, any potential prob- lems arising from warfarin therapy. These problems will be underlined in red on the Anticoagulant Treatment Chart and will be brought to the attention of the physician at the Clinic. These problems include: (i) Inability of the patient to comply with therapy. (ii) A questionable reason for anticoagulant therapy. (iii) Significant predisposition to bleeding. (iv) History of severe, chronic or intermittent alcohol abuse. (v) Significant drug-warfarin interaction. 3. Patient Follow-up Clinic Visits (a) All follow-up visits to the Anticoagulant Clinic as decided by the pharmacist will be entered in the Anti- coagulant Clinic appointment book on the Anticoagulant Treatment Chart and in the patient's DHSS Anticoagu- lant Treatment Booklet. Follow-up visits to see the physi- cian will be at the discretion of the physician. The Anticoagulant Treatment Chart will be kept in the patient's medical records until the next appointment. (b) Each time a patient is seen in the clinic he is questioned about the following: (i) The current dose of warfarin. (ii) Symptoms of exacerbation of disease. (iii) Suspected side effects of therapy or any bleeding episodes. (iv) Development of any other problems. ANTICOAGULANT TREATMENT CHART CONSULTANT NAME ADDRESS OCCUPATION INDICATION FOR ANTICOAGULANT THERAPY ANTICIPATED DURATION OF Rx CONCURRENT DRUGS (Rx AND OTC) CONCURRENT DISEASES SMOKING HABITS FAMILY DOCTOR ADDRESS SOCIAL FACTORS TEL. INTERVIEW CHECKLIST APPOINTMENTS DATE OF TEST: 7PROTHROMBIN DAILY WARFARIN NEXT APPOINTMENT INDEX DOSAGE (MGI COMMENTS Fig. 1. Anticoagulation treatment chart. Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 43 (v) Addition or cessation of any concurrent medica- tion (this may be recorded in the 'comments' section of the Anticoagulation Treatment Chart). (c) If there has been a significant increase or decrease of the prothrombin time to a value considered out of control, the following questions are asked of the patient in order to determine the cause of^the prothrombin time change: (i) Has the patient started or stopped taking any other medication, including proprietary drugs? (ii) Has there been a change in the patient's alcohol consumption? (iii) Have any other illnesses developed such as infec- tion, acute hepatitis, diarrhoea, CCF, etc? (iv) Is the patient taking the warfarin correctly, i.e. correct dose, omission or addition of doses? (v) Has the patient developed fever? (vi) Has the patient altered his diet significantly? (d) Based on what has been determined to be the cause of the prothrombin time change, the pharmacist, if neces- sary in consultation with the physician, will decide on further warfarin therapy. The pharmacist will convey this information to the patient. (e) In the event of the patient being admitted to hospital, the pharmacist will make at least one check on the patient's anticoagulation therapy. A brief summary of the admission will be indicated in the Anticoagulant Treat- ment Chart. (f) Discharge from the Anticoagulant Clinic will occur after adequate duration of therapy, or where the risks of therapy are considered greater than the benefits, or at the request of the patient, on the decision of the physician. Acknowledgement This appendix is adapted from a document produced by Dr Steven Kayser, Associate Clinical Professor in the Division of Clinical Pharmacy at the University of Cali- ? fornia, San Francisco.

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A Patient of Sir Thomas Browne's G. C. R. MORRIS, dm, mrcp Lately Senior Lecturer in Applied Physiology, Institute of Basic Medical Sciences, London Among three dozen patients mentioned in Sir Thomas Browne's letters of 1670-82 to his son Dr Edward Browne in Londonfl], only a few are described in enough detail to give a clear clinical picture, notably those who were referred for consultation on urinary or venereal condi- tions with 'cosen Hobbes', the anatomist Thomas Hobbs (1648-98), surgeon for the stone at St Bartholomew's Hospital from 1680 (two years before Edward Browne became physician there)[2,3]. One more clinical descrip- tion by Sir Thomas Browne, with the advantage of a parallel account of the same patient by his apothecary, can now be added to those few, from Chancery deposi- tions at the Public Record Office[4]. The background is complicated, but not without its own interest. The patient was Richard Berney (1621?-1680) of Reedham, Norfolk, second son of Sir Richard (d. 1668), first baronet (1620), whose eldest son Thomas (d. 1693) inherited little but the title. Sir Richard's will[5] was one cause of the trouble that led to the Chancery actions. Extending earlier dispositions, it left Park Hall, Reed- ham, and the rest of his real estate to descend in tail male through his second son Richard (the patient) and Rich- ard's only son, also Richard (1650-95), who became the plaintiff. Apart from annuities to the eldest son Thomas and his children, with legacies for the children at 21, Sir Richard's large personal estate was to be divided equally between his second son Richard and Richard's son, who were the executors. The grandson was a minor when Sir Richard died, and did not join in proving the will until 26th June 1671. His father, Browne's patient, was in sole control from January 1669: his handling of the inheri- tance was another cause of the trouble. According to the plaintiff, young Richard Berney[6], grandson of the first baronet, in actions brought within weeks of his father's death on 26th January 1680, his father had allowed him only ?300 a year, which fell far short of his requirements. He was therefore compelled to borrow. Unable to give any other security than his expectations, he was forced to accept increasingly onerous terms for the loans. By February 1677, when he borrowed ?400 from Robert Foster, he had to promise to repay ?1,000 on his father's death. In September of the follow- ing year ?500 from Dr James Fairclough[7] was to cost ?2,000 on the death of his father?when he would also have to pay ?100 a year (since 1678) for Fairclough's life, which the latter said was a retaining fee for his attendance as a physician. The heavy repayments were assured in both instances by penal bonds. The day before he died, Richard Berney senior made a will[8] in which ?10,000 was to be settled on his nephew Richard, eldest son of Sir Thomas Berney, the second baronet, and a further ?500 was to go to each child of Sir Thomas at 21. After ?100, a coach and a horse for his wife, the residue (besides the entailed real estate) was for young Richard, who lost no time in proving his father's will. A week later he instituted proceedings in Chancery against Foster and Fairclough[9], among his numerous creditors[10], claiming that the terms of the loans were harsh and oppressive, considering that his father had been old, ill and likely to die soon. The defendants denied knowledge of the father's illness. Fairclough went further, asserting that old Richard Berney was as healthy as himself, whereas the plaintiff was 'very infirme and subject to greate distempers' and might well die first, when he would lose his money. J Young Richard Berney called for evidence from Nor- folk to support his case. The parish priest who had doled out his 'meagre' allowance quarterly, his father's lawyer, man of business and servant, together with his physician and apothecary, were asked a series of questions designed to elicit answers favourable to the plaintiff[l 1]. The first deposition was taken at the house of John Berney 'comonly called the signe of the Kings head' in the parish of St Peter Mancroft, Norwich, on 20th September 1680. Three more, including the apothe- cary's, were taken there a week later, followed by the deposition of 'Sr Thomas Browne Knt & Dr of phisick . . . aged seaventy yeares or thereabouts', taken at his own house in the same parish[12]. The last witness was heard at the house of John Berney (possibly the plaintiffs uncle) on October 1st. In answer to the first question, Sir Thomas said that he had known the plaintiff for 20 years and his grandfather ' for several years before his death, 'but how long it is since he dyed this deponent now remembreth not'. To the second question he replied that He did know Richard Berney esq1" the Complts father for about twenty six yeares before his death & beleiveth that he was betweene fifty & sixty yeares old when he dyed And saith that when the Complts father was high Sheriffe of the County of Norff at the time of the Assizes in Norwich (being about nine yeares since) he was very short breathed & his leggs were much swelled, & he consulted this dept about the same, & not wthout much difficulty was releived, but for many yeares after he was forced to make use of remedyes against Scurvye & dropsye haveing an ill habit of body which required the same & about two or three yeares Correspondence to: Terrysfield, Downe, Orpington, Kent BR6 7JT. 56 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 before his death he had an ulcer in his legg which (though troublesome) proved beneficiall unto him, but when ever that ulcer stopped or issued not as usually he then fell ill & soe as to be in danger of death, and his legg would sometimes alsoe be soe inflamed & painfull that he was in danger of a gangreene And this dept & most men about him thought that he would live no longer then his ulcer releived him, if it could be kept from a gangreene. And a little before his death it slacked & ran little or nothing soe that considering his long ill habit of body & great uncertainty how long his ulcer would releive him, he lived much longer then this dept expected. Sir Thomas's answer to the third question was that the plaintiff 'was ever of a healthful Constitucon for ought this dept hath heard to the contrary And therefore in a probability to outlive his father', whose only child he was. As Browne went on attending Berney after the initial illness in Norwich in 1670[13], he presumably visited him at Reedham, 15 miles away to the east. That he knew Park Hall earlier, in Sir Richard's time, is shown by his letter to Evelyn in 1663, reporting a large oak in the park[14]. Also, among the notes on the natural history of Norfolk that Browne prepared for Dr Christopher Merret about 1668 was one on the cormorants 'building at Reedham upon trees, from whence King Charles the first was wont to bee supplyed'[15]. However, it is clear from the apothecary's evidence that he was sometimes sent to see the patient on behalf of Sir Thomas Browne. He was Richard Clarke, of Nor- wich, aged about 50, according to the deposition. This is not the 'Dr Clark' whose presence at Browne's house when a dolphin was dissected, during Charles II's visit to Norwich in September 1671, was repeatedly recalled in Sir Thomas's letters to his son five to ten years after- wards. That was Dr Timothy Clarke, FRCP and FRS, physician to the King, whose anatomical studies were being prepared for publication at his death in February 1672. The apothecary ('Mr Clark' in two letters of Sir Thomas's last year) was the Richard Clarke in whose name a silver flagon, bearing his arms, was given to the church of St Peter Mancroft in 1683[16]. He was buried at Marlingford, six miles west of Norwich, where he had bought an estate, as 'Generosus, Medicus, et Pharmaco- peus praestantissimus, utpote Magni Illius apud Norwi- censes ^Esculapii, Thomas Browni, Equitis aurati, fidus Minister et Comes'[17], He died in May 1682, aged 52, five months before Sir Thomas Browne[18]. Clarke deposed that he had known the plaintiff for 20 years and his grandfather for about six years before his death, about 11 years earlier; then that he did know Richard Berney esqr the Complts father for twenty four years before his death (being about fifty six yeares of age when he dyed) & that about nine yeares since when the Complts said father was high Sheriffe of the County of Norff he this dept being an Apothecary was sent by Sr Thomas Browne Dr of Phisick to visit the Complts said father where he found him very sick labouring under a Scorbutick Astma even to that degree that he turned black & was almost suffocated when he stirred from which distemper he was not free to his death, and that many times after the said visit this dept hath gone by the direccon of the said Sr Thomas to the said Complts fathers howse at Reedham to visit him & hath administred to him diverse portions of phisick & medicines & hath con- stantly found him afflicted with that infirmity but especially for two yeares next before his death the said Complts father had a Complicacon of divers other distempers reigning upon him as Catarhs, Dropsye and Scurvye to that height and degree that his life was in danger every day for the said two yeares before his death by which meanes he was confined to his howse for about two yeares before his death for the most part And this dept & others that knewe him never expected he would have lived soe long as he did. The plaintiff had never had any disease or distemper and would probably outlive his father. The other witnesses were asked further questions. Their answers gave estimates of the grandfather's person- al estate (of which the plaintiff should have had half) as about ?30,000 and of the annual value of the father's real estate (entailed to the plaintiff) as over ?5,000. Naturally, none of the witnesses referred to the plaintiff's extrava- gance, which must have been the main cause of all the trouble?and which continued until his death in 1695, deep in debt, with virtually all the real estate, including Reedham, sold or mortgaged and most of the legacies from his grandfather and father to his cousins, the children of Sir Thomas Berney, still unpaid[19]. Perhaps surprisingly, the court considered that the lenders had indeed taken oppressive and unfair advantage of him and decided both cases in favour of Richard Berney, who had to repay only the principal of each loan with interest [20]. Sir Thomas Browne may even have approved. He was clearly sympathetic, a few months after this deposition, to a man aged 54 whose 'old father dyed the last weeke & left him a fayre estate in lands besides good summes of money, which may paye the debts, which the oversparing hand of his father made him contract by borrowing & taking up of money'[21]. Acknowledgement I thank Sir Julian Berney, Bt, for his interest in the publication of this account and for information on the pronunciation of his family's name. References and Notes 1. Keynes, G. (ed) (1964) The Works of Sir Thomas Browne, vol. 4, pp. 48-232. London: Faber & Faber. 2. Morris, G. C. R. (1972) Transactions of the London and Middlesex Archaeological Society, 23, 204. 3. Morris, G. C. R. (1975) Notes & Queries, n.s. 22, 558. 4. Transcripts of Crown-copyright records in the Public Record Office appear by permission of the Controller of HM Stationery Office. 5. Dated 10 Dec. 1667, with a codicil of 19 Dec. 1668, proved (P.C.C.) 21 Jan. 1669: PRO, PROB 11/329, f. 4. 6. Barney in one deposition. That was the usual spelling in the previous century and it is the pronunciation still used by one branch of the family. The word 'barney' for an altercation is unconnected. 7. James Fairclough (1630??1685) was a Cambridge graduate (BA Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 57 1655, MA and licence to practise medicine 1658, MD by Royal letters 1661) who practised in London?largely as a money-lender, to judge by his will (PRO, PROB 11/379, f. 19). 8. Dated 25 Jan., proved (P.C.C.) 6 Feb. 1680: PRO, PROB 11/ 362, f. 14. 9. Bills of complaint dated 14 Feb. with answers 24 and 25 Feb. 1680: PRO, C 7/24/60 (Foster), C 10/201/12 (Fairclough). 10. At least six more similar actions were being heard with these two in 1680-81: Chancery Decrees & Orders, PRO, C 33/255, 257. 11. The interrogatories and depositions are the same in (PRO) C 22/ 225/10 for Foster and C 22/326/16 for Fairclough. 12. Sir Thomas was nearly 75. His letters show that he was immobi- lised by illness in Dec. 1670, April 1677 and Jan. 1679. It was 'a sickly time' on 22 Sept. and 15 Oct. 1680. 13. Richard Berney or Barney was High Sheriff for the year starting 11 Nov. 1669. His father was appointed to the office in 1622, his brother Thomas in 1646 and his son (the plaintiff) in 1691. 14. Keynes, G. (ed) (1964) The Works of Sir Thomas Browne, vol. 4, p. 280. London: Faber and Faber. 15. Ibid., vol. 3, p. 403. 16. Blomefield, F. (1805-10) History of Norfolk, vol. 4, p. 192. London: ,1 Miller. 17. Ibid., vol. 2, pp. 457-8. Gentleman, doctor and outstanding i apothecary, as the faithful assistant and companion of that great /Esculapius among the people of Norwich, Sir Thomas Browne, jT- knight. 18. Buried 18 May; his will dated 16 April, with a codicil of 4 May, was proved 17 June 1682 in the Consistory Court of Norwich (Norfolk Record Office: O.W. 13). Sir Thomas died 19 Oct. 1682, a month before his seventy-seventh birthday: see Morris, G. C. R. (1983) Notes & Queries, n.s. 30, 420. , 19. Will of Richard Berney, dated 28 Jan. 1694, with a codicil of 18 Oct. 1695, proved (P.C.C.) 7 Dec. 1695: PRO, PROB 11/429, f. 227. .20. Chancery Decrees & Orders, 5 March 1681: C 33/255, ff.269, ^ 307. 21. Keynes, G. (ed) (1964) The Works of Sir Thomas Browne, vol. 4, p. 202. London: Faber and Faber.

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Use of Hospital Resources by Acute Stroke Patients D. T. WADE, MB, MRCP(UK), Neurology Research Registrar VICTORINE A. WOOD, Research Assistant R. LANGTON HEWER, MB, FRCP) Consultant Neurologist Department of Neurology, Frenchay Hospital, Bristol Stroke is not only a devastating but also an expensive disease. However, there have been very few studies investigating the actual use of hospital resources by stroke patients, and no prospective ones. In 1976 it was estimat- ed[l] that in Scotland, while stroke patients only account- ed for 2.1 per cent of all discharges (including deaths) they occupied 6.2 per cent of all hospital beds at a cost of 6 per cent of the local NHS budget. The effect was largely felt in general medical and geriatric wards, where stroke patients accounted for 12 per cent and 25 per cent of all bed-days respectively. Another study[2] on 1,094 patients with acute stroke admitted to a London hospital over six years found that, for those discharged alive, the average length of stay was 37 days for men and 50 days for women. In Edinburgh[3], minimally disabled patients stayed in hospital for an average of 27 days, while those who were more disabled stayed in for an average of 47 days. Lastly, in a Midlands hospital stroke patients accounted for 8 per cent of all male and 11 per cent of all female admissions to general medical wards[4]. The high use of resources by patients with stroke has prompted suggestions that more economic ways of man- aging these patients need to be investigated[5]. For example, it is possible that patients managed in stroke units may not only spend less time in hospital but may also recover function faster[6]; a second study[7] failed to confirm this. In order to develop new policies, it is important to have some estimate as to the current load on hospitals and present patterns of management. We have conducted such an investigation in our own hospital, trying to look for ways of improving efficiency. In particular we wished to discover: 1. How many stroke patients are admitted with acute stroke? 2. How are they referred to hospital? 3. How long do they stay, and how many are in at any one time? 4. Where do they go at discharge? 5. What use is made of specialised investigations, or of follow-up facilities? Method and Patients Patients were included in this study provided that (a) their clinical diagnosis was of acute stroke (based on the WHO definition[8]), (b) they were admitted within three months of the stroke, or had the stroke while in hospital, and (c) they were in hospital between 22nd June 1981 and 27th September 1982. Those admitted with long-standing strokes were not included, even if the admission related to their old stroke. A three-month cut-off was used because most recovery has occurred by then[9], making it unlikely that admission was related to the acute stroke. Patients were identified by two means. First, one investigator (V.W.) visited the medical wards weekly and compiled a register of all stroke patients. Second, using Regional Health Authority discharge information based upon Hospital Activities Analysis (HAA) coding, all patients discharged with stroke (codes 430-438) were identified. The diagnosis of stroke was based, where possible, upon history and examination (by D.W.). When patients had died or left the hospital before being seen, their notes were scrutinised (by D.W.) to ensure that the clinical diagnosis was stroke. Results Over the 15 months (July 1981?September 1982), 443 patients were admitted with a diagnosis of acute stroke. Because Frenchay Hospital has specialist departments (i.e. neurology, neuroradiology, neurosurgery, and a Stroke Unit), some patients were admitted specifically to use facilities within these units (e.g. CAT scan). We have, therefore, divided these 443 episodes into two major groups. The first, 'Group 1', includes 351 single admissions related to an acute stroke. Four of these 351 admissions were patients admitted with a second acute stroke within the study period. Three patients from Group 1 were re-admitted shortly after their first dis- charge, for reasons relating to their stroke, e.g. failure of a trial home visit. These have been included in the analysis of bed occupancy, but excluded from all other analyses. 'Group 2' included the 88 patients referred for reasons relating to the specialist facilities within this hospital. One patient admitted with an acute stroke 21 48 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 months before the study commenced has been excluded from all analyses. Group 1: General Characteristics The mean age of the 351 stroke patients was 68.2 years, but the 179 men (mean age 65.9 years) were significantly younger than the 172 women (mean age 70.7 years; P<0.001). In total, 59 (33 per cent) men and 90 (52 per cent) women died: the average age of those who died was 71.6 years, with no statistically significant difference between the sexes. Weakness was left-sided in 136 and right-sided in 137 patients; it was difficult to categorise 43 patients because they either died before the side of their weakness could be identified, or they had bilateral symp- toms, e.g. from a brain-stem stroke; 35 (10 per cent) patients had no significant weakness, being admitted, for example, with aphasia. Admission In this study 186 (53 per cent) patients were admitted on the day of their stroke, 42 (12 per cent) the next day and a v, further 48 (14 per cent) during the rest of the first week; 22 (6 per cent) were admitted in the second week, with the remaining 20 being admitted randomly over the next nine weeks. Overall, 156 (44 per cent) patients were referred directly by their GP, with a further 26 (7 per cent) being referred by the Deputising Service; 91 (26 per cent) were admitted through Casualty, 33 (10 per cent) were already in hospital, 33 (10 per cent) were admitted from out- patients or from a domiciliary visit, and 12 (3 per cent) were transferred from other hospitals to be nearer home. Only 248 (71 per cent) of these Group 1 patients came from within the geographically defined Frenchay Health District (population approximately 210,000): 78 (22 per cent) came from neighbouring health districts and 25 came from farther afield. Bed Occupancy -r This was calculated for the 351 acute episodes, together with the three recurrent admissions as described earlier. k The calculation of bed occupancy was based on the dates of admission, or stroke for those already in hospital, and discharge or death. During the study period, the number of stroke patients in hospital ranged from 14 to 33, the average being 22.9 per day. The average number of men was 10.7 (range 6-17), and women 12.2 (range 6-21); this difference is statistically significant (P< 0.001). The aver- age number of patients in hospital under the general ^ physicians was 13.8 per day; under the neurologists it was 4.3 per day. There was no significant monthly variation in the admission rate, death rate, or bed occupancy , throughout the year. During the period of this study, Frenchay Hospital had 542 beds and there was an average of 407 patients in hospital at any time; 67 of these were under the care of general physicians, 36 under the geriatrician, 22 under the neurologists and the rest under other consultants. Thus, stroke patients occupied 5.6 per cent of all occupied beds. Those under the care of general physicians occupied 20.6 per cent of all their beds, while those under neurol- ogists occupied 19.5 per cent of their beds. Outcome: Discharge and Follow-up The outcome of the 351 admissions is shown in Table 1; 149 (42 per cent) patients died, 161 (46 per cent) returned Table 1. Discharge of Group 1 patients. Men Women Discharged alive to: Own home 103 56 Relative's home 1 1 Institutional care 4 2 Hospital care 12 23 Total 120 82 Died in hospital 59 90 home or to live with relatives, and 41 (12 per cent) were transferred to some form of institutional care; none remained in this hospital after October 1983. Women were not only more likely to die (P< 0.001) but were also more likely to need long-term care (/><0.01) if they survived. Of the 167 patients leaving hospital (i.e. includ- ing the six going to Part III accommodation), 88 (53 per cent) returned for at least one medical out-patient ap- pointment and 66 (40 per cent) attended for out-patient rehabilitation. Length of Stay This was calculated from the day of admission (day of stroke for those in hospital) to the day of discharge or death (i.e. those leaving on the day of admission stayed 0 days, those leaving the next day stayed 1 day, etc.). The proportion still in hospital is plotted against time in Fig. 1 for three groups of patients: (a) those dying in hospital (n = 149); (b) those leaving to enter institutional care Fig. 1. Proportion of patients in hospital plotted against time. Days Weeks Months Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 49 (n = 41); (c) those returning home or to relatives (n = 161). Overall, of the 351 patients, those dying occu- pied 3,129 bed-days, those going home 4,717 bed-days and those passing on to institutional care 5,391 bed-days. The length of stay of the 149 patients dying in hospital ranged from 0 to 488 days (median 5; mean 21). Those returning home (mean age 63.7 years) stayed between 0 and 250 days (median 16; mean 29.3). Those discharged to institutional care (mean age 74 years) stayed between 2 and 770 days (median 83; mean 131.5): this group was significantly older (P<0.001) than those going home, which may account for the preponderance of women. For the 161 discharged home, there was no significant corre- lation between age, sex or side of weakness and length of stay. Another way of considering the fate of these patients is to calculate, as a function of the time elapsed since stroke, the likelihood of a patient still in hospital going home, dying or needing long-term care. This is illustrated in Fig. 2 which shows, for example, that of the 129 patients still alive and in hospital at three weeks post-stroke, 55 per cent went home, 26 per cent to long-term care and 19 per cent died. Only 37 patients remained in hospital at 12 weeks after the stroke: 54 per cent went to long-term care, 22 per cent died and 24 per cent returned home or to relatives. Investigations Most of the 351 patients had some routine investigations (e.g. full blood count) while in hospital, but our analysis only considers those likely to be related specifically to stroke. A CAT scan was performed on 189 patients (54 per cent), an arteriogram on 24 (7 per cent) and 25 patients had a lumbar puncture (7 per cent). Other investigations were rare; two patients had an EEG, three had carotid ultrasound scans, one an isotope brain scan, and two had brain biopsies. A post-mortem was carried out on 30 (20 per cent) of those dying. Variations between Consultants The patients were under the care of a variety of consul- tants: 252 (72 per cent) were cared for by the three general physicians, 61 (17 per cent) by the two neurol- ogists, 16 by the one geriatrician, 5 by two neurosur- geons, and 17 by various other surgeons. The patients cared for by the three general physicians were almost all admitted randomly as emergencies under the physician on duty. We have compared the outcomes of patients admitted under each physician (Table 2). Considering Table 2. Comparison of three general physicians General physician No. patients 81 94 77 Average age (yr) 67.4 70.1 70.5 No. who died 42 (52%) 48 (51%) 32 (42%) No. to institutional care 7 (9%) 9(10%) 9(12%) No. to home/relatives 32 (39%) 37 (39%) 36 (47%) Average length of stay (days) of those going home or to relatives 27.0 37.8 19.5* *3 v 2: t = 2.96, PcO.Ol 3 v 1: t = 1.53, NS 3 v 1&2 combined: t = 2.89, P<0.01 those patients who returned home or to relatives, Consul- tant 3 discharged his patients significantly quicker than Consultant 2, and significantly quicker than Consultants 1 and 2 combined. Although fewer of his patients died, this was not statistically significant. Group 2: The Excluded Patients The 88 excluded patients were obviously very different. Most (86) were transferred from other hospitals, most were referred to the neurosurgeons (50) or neurologists (35), most (83) had a CAT scan, 35 (39 per cent) had arteriography and 15 (17 per cent) had a lumbar punc- ture. Only 19 (21 per cent) died in this hospital and the average length of stay for the remaining 69 was 15 days. This group occupied an average of 2.8 beds per day, totalling 1,022 bed-days each year, usually in the neuro- surgical wards. Discussion This study confirms that stroke is still an expensive disease in our hospital. (This refers only to patients in Group 1, as does all further discussion.) During one year 252 patients were admitted with an acute stroke and a further 28 suffered a stroke while in hospital. These 280 stroke patients occupied 8,358 bed-days. The Frenchay District finance department costed a general medical bed Patients dying in hospital I Patients discharged home or to relatives 100-1 o E 90- 80- 70- 60- 50 40- 30- 20- 10- Patients discharged to long-term care Weeks Months Time post-stroke Fig. 2. Discharge destination of patients in hospital plotted against time post-stroke. 50 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 at ?67 per day in 1982, which means that these patients cost ?560,000 for one year or 4 per cent of the Unit's ?14.1 million annual budget for 1981/1982. Of this total, 41 per cent was accounted for by patients who were discharged to instititutional car.e, 36 per cent by patients discharged home alive and 23 per cent by those dying in hospital. Before discussing these findings any further, a v. few comments are needed regarding any bias in the selection of patients. First, our hospital contains specialist departments which might bias the referral of patients. We have attempted to counteract this by excluding those patients who were clearly referred to one of these specialist services, although it was occasionally difficult to be certain of the reasons for referral. Otherwise we feel that our hospital serves a fairly typical Health District, having a catchment area which includes urban, suburban and rural populations. Second, and counteracting the first bias, acute stroke patients from the Health District are admitted to several other hospitals, both within and outside the District. Figures from a community study, conducted throughout the period of this study[10], show that 74 per cent of stroke patients within the Frenchay Health District were admitted to hospital. Of these, 56 per cent were admitted to this hospital, with a further 30 per cent going to one of the other two 'District' hospitals, leaving 14 per cent going to hospitals outside the District. We have not investigated admissions to these other hospitals, but in our study 22 per cent of 'normal' admissions were of y patients from outside the District. Interpretation of these findings is also affected by many factors which will vary from hospital to hospital and area to area. For example, in this hospital stroke patients are accepted as part of the emergency medical 'take', but in some areas more patients may be admitted to geriatric hospitals. In this District, hospital admission is usually easily achieved, but in some areas it can be quite difficult to admit a patient who has suffered a strokefll]. Al- though the majority of patients were admitted under general physicians to general medical beds, some were admitted to other wards or under the care of other consultants. Factors unrelated to the stroke may have prolonged some patients' stay in hospital. One particular item that might have affected our findings was a controlled trial of a domiciliary service for acute stroke being conducted in the Health District[10]. This might have slightly reduced the number of patients y admitted from the trial area, and shortened their length of stay. Any effect was probably small, and only 240 (68 per cent) of the 351 patients came from that study population. It will have reduced the number attending for therapy after discharge. The factors just discussed may affect the absolute findings to a small extent, but the general outlines are probably similar for most hospitals and indeed our find- ings are consistent with other work. For example, patients admitted with an acute stroke can be neatly divided into ?v three outcome categories ? those who die, those return- ing home, and those needing long-term care ? and our study supports others[12,13] which have found that the stay in the acute hospital is shortest for those who die and longest for those needing institutional care. We are unable to demonstrate any influence of either age or sex on the length of stay of those going home. It is likely that the difference in age between those going home and those needing care may account for the correlation between age and length of stay previously reported[2,13]. Similarly, the fact that women seem more likely to need long-term care may account for the earlier observation that they are in hospital longer[2]. The observation that in the USA it is younger patients who stay in longer[14] perhaps con- firms that extrinsic (social) factors influence length of stay more than intrinsic (patient) factors. How can the cost be reduced? There is evidence that the need for nursing support, rather than a need for medical expertise, is the usual reason for hospital admis- sion^]. Therefore, one possible way would be to reduce the number admitted by providing more home support services which might particularly reduce the need for admission of the 35 per cent admitted after the first 24-48 hours. However, as only 44 per cent of patients were referred by their GPs, knowledge of and access to any such service would need to be widely based if the admission rate is to be reduced. A second, complementary, approach would be to re- duce the length of stay of those admitted. In this study about 12 per cent of all patients were referred on to institutional care, a similar proportion to that in North London[2]. These patients were responsible for a dispro- portionate amount of the resources used (41 per cent) and it must be asked whether their stay in the acute hospital needed to be so long. It will be obvious very quickly that many of these patients will never recover sufficiently to return home. For example (see Fig. 2), of those in hospital 10 weeks after their stroke, 51 per cent will need long-term care, 21 per cent will die and 28 per cent will go home. It is likely that those going on to long-term care or going to die will only need the facilities of the acute hospital for a few weeks. Recent studies[15,16] have shown that reasonable prediction of functional recovery is possible within the first 3-4 weeks using simple clinical measures. Assuming that alternative accommodation (long-stay ward or Part III accommodation) is cheaper, one should consider identifying those patients who no longer need the expensive resources of an acute hospital, and transferring them earlier to less expensive places of care. Apart from identifying and moving those destined for long-term care, it may also be possible to reduce the length of stay by concentrating stroke patients into specialised wards[6]. In this hospital there were, on average, enough patients to fill a ward (23 patients). However, there was a considerable fluctuation in the number of patients in hospital at any one time (14-33), which means that any ward dedicated exclusively to stroke patients will either have to turn patients away on occasions or, if it is large enough to cope with every potential patient, it will often have many unused beds. A more practical alternative would be to designate two wards (1 male, 1 female) as being priority wards for stroke patients, taking other general medical patients as Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 51 well. Our figures suggest that such wards would usually be about half full of stroke patients. Such an arrangement would allow staff to gain expertise in managing stroke patients while maintaining a variety of patients, thus lightening the physical and emotional nursing load. This study suggests that it may also be possible to reduce the length of stay of stroke patients going home even without creating 'stroke wards'. Consultant 3 dis- charged patients sooner than his general medical col- leagues. This observed difference may have several explanations: the patients admitted by Consultant 3 may have been less severely affected (particularly if he selec- tively admitted patients to other hospitals in the District), the findings may just be due to chance, Consultant 3's patients may all have done badly at home because they were not fit to be discharged, or his patients may have had better home circumstances. This study has not collected the information necessary to explain the differ- ences which only became apparent after analysis. Fur- ther, even if he does actually discharge patients sooner, any saving of hospital resources he achieves will need to be balanced against extra community costs, any increased stress on the patient and his family, and any reduction in the patient's recovery. Nevertheless, this variation be- tween consultants should be utilised to investigate differ- ent policies. There may also be equally large variations between different districts: in Oxford only 40 per cent of patients suffering a first stroke are admitted to hospital (Sandercock; personal communication), as against 74 per cent in Frenchay. In conclusion, this study highlights the considerable variation in many aspects of the patterns of care of stroke patients; for example, only 46 per cent were admitted by their GP, 35 per cent were admitted more than two days after their stroke, 54 per cent had a CAT scan and 53 per cent came back for medical appointments. This variabil- ity may simply reflect the wide variability in the manifes- tations of stroke. However, it may also reflect uncertainty about the best management of stroke patients, this uncer- tainty leading to different policies being applied to similar patients. If this is the case, there may be scope for reducing the use of hospital resources. For example, in this study one consultant physician discharged his patients considerably sooner than the other two physi- cians; to investigate this further a more complete audit of stroke care would be needed. In addition, it is possible that the development of a 'District policy' would improve the management of stroke patients by, for example, pointing out that a lumbar puncture cannot reliably detect cerebral haemorrhage. This policy would take the form of general guidelines and would need to be widely disseminated both within the hospital and outside it. Such guidelines might profitably be combined with an audit so that variations in policy, whether accidental or deliberate, could be evaluated more fully. Acknowledgements We gratefully acknowledge the considerable help we received from Mrs P. Guyatt, Assistant Patients Services Officer, and all her staff in tracing over 750 sets of medical notes, Miss M. Philpott, District Statistical Officer, for supplying discharge coding information and general hospital statistics, and Miss P. Watts at the Regional Computer Centre for supplying. us with the discharge statistics. We also acknowledge the co-oper- ation of all the doctors and ward staff involved with stroke patients, Mr W. Healing and the finance department in producing the costing information, Dr P. Begley for permission to publish bed occupancy figures and Mr P. Cox for the illustrations. References 1. Carstairs, V. (1976) In Stroke, pp.516-28. (ed F.J. Gillingham, C. Mawdsley and A. E. Williams.) Edinburgh: Churchill Living- stone. 2. Sheikh, K., Meade, T. W., Brennan, P. J., Goldenberg, E. and Smith, D. S. (1981) Community Medicine, 3, 210. 3. Garraway, W. M., Akhtar, A. J., Smith, D. L. and Smith, M. E. (1981) Journal of Epidemiology and Community Health, 35, 39. 4. Acheson, J., Acheson, H. W. K. and Tellwright, J. M. (1968) Journal of the Royal College of General Practitioners, 16, 428. 5. Wade, D. T. and Langton Hewer, R. (1983) Lancet, 1, 807. 6. Garraway, W. M., Akhtar, A. J., Prescott, R.J. and Hockey, L. (1980) British Medical Journal, 281, 827. 7. Stevens, R. S., Ambler, N. R. and Warren, M. D. (1984) Age and Ageing, 13, 65. 8. Aho, K., Harmsen, P., Hatano, S., Marquardsen, J., Smirnov, V. E. and Strasser, T. (1980) Bulletin of the World Health Organisa- tion, 58, 113. 9. Skilbeck, C. E., Wade, D. T., Langton Hewer, R. and Wood, V. A. (1983) Journal of Neurology, Neurosurgery and Psychiatry, 46, 5. 10. Wade, D. T., Langton Hewer, R., Skilbeck, C., Bainton, D., Burns Cox, C. and West, P. (1983) International Journal of Rehabili- tation Research, 6, 510. 11. Warren, M. D., Cooper, J. and Warren, J. L. (1967) British Journal of Preventive and Social Medicine, 21, 141. 12. Gibson, C. J. (1974) Archives of Physical Medicine and Rehabilitation, 55, 898. 13. Granger, C. V., Kaplan, M. T., Jones, B. and Fell, N. (1982) Archives of Physical Medicine and Rehabilitation, 63, 352. 14. Walker, A. E., Robins, M. and Weinfeld, F. D. (1981) Stroke, 12, suppl. 1, 13. 15.' Prescott, R. J., Garraway, W. M. and Akhtar, A.J. (1982) Stroke, 13, 641. 16. Wade, D. T., Skilbeck, C. E. and Langton Hewer, R. (1983) Archives of Physical Medicine and Rehabilitation, 64, 24. 52 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985

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A Plagiarist Plagiarised When the De Fabrica was published in 1543, Vesalius had obtained what privileges he could which theoretically prevented anyone from reprinting his book on much of the continent; but he appears to have failed to do the same for England, or else had not thought it necessary. Imag- ine his dismay, therefore, when two years later there was published in London a work which borrowed not a few, but a majority of the illustrations from the De Fabrica, as well as some from the Epitome?Compendiosa totius anato- miae delineatio, aere exarata: per Thomam Geminum?a title which refers only to the engravings, the text being added perhaps as an afterthought. This Thomas Geminus, also known as Lambrit, came from Flanders, and besides being an engraver, was an empiric, a printer, and a maker of mathematical instruments. His manual of anatomy contains some of the earliest copper plate en- gravings to have appeared in England; its publication may have induced Geminus to practise medicine and surgery. In consequence he was prosecuted by the College for practising without a licence, and fined. John Caius, who was President at the time, was asserting the right of the College to extend its authority over the whole coun- try; to this end he armed its agents with a letter which Geminus had undertaken to print in remission of his fine. This was in 1556. Three years later (1559) the second edition of an English translation of his manual was published. There are two copies in the College library, one of which belonged to a George Frederick Boyd, whose identity presents something of a puzzle. An apothecary of this name served in the 84th Regiment, and in the American War of Independence, and died at Basingstoke in 1801; a surgeon of the same name also served in the 84th Regiment, but died at Halifax in 1789. The previous owner was John Patch, a surgeon of Exeter. An interest- ing note in his hand written 20th May 1728 reads: 'The first Edition of this Book (formerly in my Study) was publish'd in Latin by the same Author at London An? 1545 under the following title Andreae Vesalii Bruxellen- sis suorum de Humani Corporis Fabrica Librorum Epit- ome: this was about two years after that Vesalius obliged the World with his first and one of the famous Basil Editions of his Anatomy, with wooden Cutts, whereof, I think, these are very good Copys.' This 'title' is in fact continued on page 47 44 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 Continued from page 44 the head-title on the first page; perhaps the title page in the copy that once belonged to Mr Patch was lacking, for that makes no mention of Vesalius. When the Barber-Surgeons' Company received their charter of incorporation in 1540, one of the tasks they concerned themselves with was the improvement of the teaching of anatomy. One of the the earliest Readers of Anatomy was John Caius, who is known to have lodged with Vesalius, when in Padua; and it has been suggested that Caius influenced Geminus to publish his manual of anatomy. That it was a success is apparent from the preface to the first English translation published in 1553. The text in the translation bears more resemblance to the Anatomie of Thomas Vicary, a Master of the united company, than to Vesalius. The translator was Nicholas Udall, well-known as the father of English comedy, and the author of Ralph Roister Doister; his translations of Erasmus had gained considerable renown. The transla- tion was made because it 'might greatly availe to ye knowlage of the unlatined Surgeons'. The second edition published in 1559 has two points of interest. In the new title is a portrait of Elizabeth, probably the first published after her accession; in the book itself are two additional woodcuts?seated nude figures of a man and woman? with movable flaps, capable of being lifted to expose the internal organs, one of the first examples of an illustration with movable flaps. The value and success of the Compendious Anatomy quickly resulted in the publication of plagiarisms in England and on the continent, particularly those of Jacques Grevin and Jacob Bauman; but Geminus is never mentioned, and what reference is made to the source of borrowing is always to Vesalius. Nevertheless, the influence of Geminus continued to be felt for at least a century after the publication of his book. Truly has it been said: 'Few plagiarisms have been flattered by so much imitation'. Leonard Payne Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 47

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Correction We apologise for an error in the article 'Metabolic Responses to Beta2 Stimulants' in Vol. 18 No. 3 (July 1984). Page 193, lines 7-10 should have read: . In one report normal subjects were challenged with intravenous salbutamol before and after the administration of 1,600 micrograms of inhaled sal- butamol daily for 2 weeks.' 12 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985

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. . . A Doctor in the House? 'Who would not desire to have a physician always in his house, and one that attends without fee or reward?' asks John Wesley. A rhetorical question, perhaps, but his experience, as he journeyed up and down the country preaching and meeting people, and thus being made aware of the needs of the poor, may well explain in part how he came to compile his Primitive Physic. He began by starting a fund to provide the poor with food and clothing, and then, deciding to prepare and give them physic himself, he opened a dispensary at the Foundery in Moorfields in 1746. Wesley obtained the assistance of an apothecary and an experienced surgeon, 'resolving at the same time not to go out of my depth, but to leave all difficult and complicated cases to such physicians as the patients should choose'. In five months medicines were given to more than 500 persons. This dispensary, a pioneer effort following the closure of the College dispen- sary some 20 years earlier, prospered so greatly that two months later he opened a similar one in Bristol which was no less successful. It was but a natural step for Wesley to write out his prescriptions so that they could become generally available to destitute people. Wesley spent only three months over the composition of Primitive Physic. Published in 1747, it was a pocket-sized volume of 119 pages, nearly a quarter of which was given over to a preface. It is arranged alphabetically, listing 243 condi- tions from 'Ague' to 'Wounds' with 725 'cures'; ailments and cures are numbered consecutively and separately?a device which tends to obscure the alphabetical arrange- ment. It is written in simple English, with the directions concisely given; 'to cure a tooth-ache, put a clove of garlick into the ear'. It was intended to be 'an easy and natural method of curing most diseases'. Wesley had no doubt that identifying the ailment would present no difficulty; 'unless in a complication of disorders, and then you would do well to apply to a physician that fears God'. He generally provides several remedies, which he recom- mends should be tried in order, if necessary. He realised that not all were easy to obtain, and that what cured one would not always cure another. He prefaces his remedies with the advice given by Dr Cheyne in his Essay of Health and Long Life: extolling the virtues of pure air; suit the quality and quantity of food to the strength of the digestion; go to bed at nine and rise at four or five; exercise is indispensible ('Those who read or write much should do it standing; otherwise it will impair their continued on page 58 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 55 Continued from page 55 health'); costiveness cannot long conflict with health; beware the influence of the passions. It was in his early days at Oxford that Wesley first read this book, and later he read Cheyne's Natural Method of Curing Diseases; indeed 'for six or seven and twenty years I had made anatomy and physic the diversion of my leisure hours'. He was acquainted with the writings of Boerhaave, Dover and Sydenham, as well as those of Cheyne. Wesley, however, distrusted the medical profes- sion as a whole because they had introduced into their writings an abundance of technical terms, and into their practice countless compound medicines 'consisting of so many ingredients, that it was scarce possible for common people to know which it was that wrought the cure'. Wesley felt that cures can and should be discovered by accident. Discovering cures and experimenting with them was the primitive way by which was gathered up the whole corpus of healing. Physic was in the first ages chiefly traditional. Hence his title of 'primitive' physic. Within a hundred years of its first appearance no less than 38 editions of Primitive Physic had appeared, 22 of them in Wesley's life-time. It was published in America, and once translated into French; copies of the latter are rare, though there is one in the College library together with the first edition, which was published anonymously. It was not until 1760 that Wesley's name appeared on the title-page. In this edition, too, he added 'Tried' to those remedies which he had found to be of the greatest efficacy, and enthusiastically commended electricity as coming 'the nearest an universal medicine, of any yet known in the world . Leonard Payne 58 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985

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> I I International Epidemiology of Cancer J. A. H. WATERHOUSE, PhD Director, Regional Cancer Registry, and Cancer Epidemiology Research Unit, Department of Social Medicine, University of Birmingham Within the range of this title I have chosen to limit consideration of the subject first to morbidity. Mortality data for many parts of the world are available from WHO, but their quality is very uneven, and the data generally refer to the whole of a country: only the developed countries can claim a reasonable degree of homogeneity of data for such areas. Cancer morbidity data come from cancer registries which, though scattered around the world, are much more plentiful in the more advanced countries, and scarce or non-existent in many places where they would be, for epidemiological and other reasons, very desirable. Nevertheless, they are usually reliable sources of data and more accurate in diagnosis than are death certificates since they will often be support- ed by histological reports or by the results of other investigative or therapeutic methods. My general objective is to examine the variations in the manifestation of cancer across the world, in relation to different ethnic or national groups. As a principal source of data I have taken the latest (fourth) volume of that tabulation of international cancer morbidity data known as Cancer Incidence in Five Continents[ 1]. There are 104 populations or sub-populations included in the volume, each tabulated by sex, age and site for incidence rates, and each subject to checks and quality controls before admission. The volume represents the most comprehen- sive and homogeneous source of such data at present available. Since the various populations differ so much in their structure by age and sex, some common 'denominator' is necessary in order to render them properly comparable. For this purpose the 'world standardised rate' (WSR) is probably the most useful. For any given population and site of cancer, the incidence rates by age are applied to a standard population ? the 'world standard population', constructed originally by the Japanese epidemiologist, Segi, as a form of average between the very young populations of the developing countries and the rather older (in the sense of having a greater proportion of their people in the older age groups) pattern of the developed countries. Applied in this way the rates produce an 'expected' number of cases in the standard population from which the WSR is obtained. These rates can then be properly compared because they all result from the same ( basic population. The list of sites is taken from the second chapter (Neoplasms) of the eighth revision of the ICD[2], which has been condensed to provide just over 40 sites for each sex. I have further condensed it by excluding certain sites mostly of minor importance, such as small intestine, bone, connective tissue, skin, male breast, chorion epith- elioma, other female genital, eye, other endocrine, mono- cytic and other rare leukaemias, polycythaemia vera, myelofibrosis. Skin is an important site which it is unfortunate to have to exclude: melanoma is included but the squamous and basal celled forms of skin cancer are not, since many registries find it difficult to capture all such cases. These varieties seldom cause death, but they are useful indicators of exposure to carcinogenic agents such as ultra-violet light, e.g. intense sunlight, and a number of substances, e.g. hydrocarbons, occurring in various occupations. Basis of Analysis With the limitations mentioned above, the data source is reduced to a WSR for each of 104 populations and rather more than 30 sites, and for both sexes, providing more than 6,000 figures for comparison. In order to heighten the comparison and attempt to typify the patterns rep- resentative of the various groupings, I took first the upper 10 percent of the WSRs for each sex and site, arranged in descending order of magnitude. Later, for greater sim- plicity, I took only the first five populations showing the highest rates within each site by sex, reducing the number of indices to just above 300 (Table 1). Results When placed in rank order, what is lost is the absolute value of the index, here the WSR. Sometimes the five values form a group close together in size and ordered by only small variations; sometimes one may stand out well above the others. In lip cancer, for instance, the WSR for males in Newfoundland is 22.8 per 100,000 and the next figure is 13.3, for Saskatchewan. It has been suggested that the very high rate of 22.8 relates to fishermen accustomed to repair their tarred nets by holding them in their mouths, or alternatively to the reflection of the sun from the water on to their lips. Nasopharyngeal cancer in Singapore Chinese men has a rate of 19.4, the next being 14.6 among Bay Area Chinese men, and then 7.1 for Los Angeles Chinese, the rate for Shanghai, the only rep- resentative of mainland China, being 5.6. Among women, the highest rate for tumours of the gall bladder is 22.2 in the American Indians of New Mexico, the next 10 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 Table 1. World standardised rates for cancerfl]. KEY (Wh) = Whites (Bl) = Blacks Sing. Ind. = Singapore, Indian NWT = North Western Territories (Canada) NW(UK) = North West Region (United Kingdom) Hawaii (Haw) = Hawaii, Hawaiian Hawaii (Ch) = Hawaii, Chinese Jews (E/A) = Jews born Europe or America Hawaii (F) = Hawaii, Filipinos Jews (I) = Jews born in Israel Bay Area (Ch) = Bay Area, Chinese Bay Area (J) = Bay Area, Japanese LA = Los Angeles NSW = New South Wales MALE Tongue Bombay 10.2 Doubs 7.8 Bas-Rhin 7.4 Poona 7.2 Puerto Rico 6.0 Mouth Poona 10.0 Bas-Rhin 9.6 Sing. Ind. 8.8 New Orleans (Bl) 7.0 Sao Paulo 6.8 Oropharynx Bas-Rhin 11.6 Doubs 6.8 Geneva 5.7 Antilles 5.5 Bombay 4.7 Hypopharynx Bas-Rhin 10.2 Doubs 8.7 Bombay 8.0 Neuchatel 4.4 Geneva 4.2 Nasopharynx Sing. (Ch) 19.4 Bay Area (Ch) 14.6 LA(Ch) 7.1 Hawaii (Ch) 6 2 NWT 6.2 Larynx Doubs 17 6 Varese 16.0 Sao Paulo 15.8 Spain Navarra 15.0 Poona 13.6 Oesophagus Shanghai 24.7 Atlanta (Bl) 19.3 Sing. (Ch) 18.9 Hong Kong 18.6 Hawaii (Haw) 18.3 Stomach Nagasaki 100.2 Miyagi 88.0 Osaka 78.0 Fukuoko 75 0 Shanghai 55.7 female Bombay Poona Hawaii (Wh) Puerto Rico Bay Area (Wh) Sing. Ind. Bombay Poona Hawaii (Haw) Hawaii (Wh) Hawaii (Wh) NWT Alameda (Bl) Bay Area (Bl) Bombay Sing. Ind. Bombay Hawaii (Wh) Alameda (Wh) NW(UK) Bay Area (Ch) Sing. (Ch) LA (Ch) Shanghai Hawaii (Ch) Bombay Poona Detroit (Bl) Sao Paulo Bay Area (Bl) Bombay Poona Antilles Sing. Ind. Hong Kong Nagasaki Miyagi Osaka Fukuoko Cali MALE Pancreas 4.1 Bay Area (Bl) 2.4 Alameda (Bl) 1.8 NZ (Maori) 1.6 New Orleans (Bl) 1.5 Detroit (Bl) Bronchus 8.6 New Orleans (Bl) 5.8 Maori 4.3 Scot. West 3.8 Hawaii (Haw) 3.8 Detroit (Bl) Brain and Nervous System 2.7 Jews (E/A) 2.4 Sweden 1.6 Jews (all) 1.4 Nowy Sacz 1.3 Spain Navarra Bladder 3.2 Geneva 2.2 Varese 1.0 New Orleans (Wh) 0.7 LA (Wh) 0.7 Hawaii (Wh) Melanoma 7.7 NSW 7.5 S. Australia 4.0 NZ (Wh) 2.5 Hawaii (Wh) 1.6 LA (Wh) Multiple Myeloma 2.6 Bay Area (Bl) 2.2 Maori 2.0 Hawaii (Haw) 1.9 Detroit (Bl) 1.8 Alameda (Bl) MALE ONLY 10.7 Prostate 10.4 Alameda (Bl) 8.7 Atlanta (Bl) 7.7 Bay Area (Bl) 5.5 LA (Bl) Detroit (Bl) 51.0 Penis 42.0 Jamaica 38.5 Puerto Rico 38.4 Poona 27.3 New Orleans (Bl) Atlanta (Bl) FEMALE 18.3 NWT 18.0 New Mexico (Ind) 14.8 NZ (Maori) 14.3 Alameda (Bl) 12.0 Bay Area (Bl) 107.2 Maori 105.7 Hawaii (Haw) 96.8 NWT 96.2 Bay Area (Ch) 90.7 Bay Area (Wh) 10.0 Sweden 9.2 Jews (E/A) 9.0 Jews (all) 9.0 Jews (I) 8.9 Cracow 30.2 NWT 24.6 New Orleans (Wh) 24.5 LA (Wh) 23.6 Hawaii (Haw) 23.5 Alameda (Wh) 16.6 NZ (Wh) 13.0 NSW 12.3 S. Australia 11.8 New Mexico (Wh) 10.2 Norway 8.4 Hawaii (Haw) 8.2 Alameda (Bl) 7.5 Bay Area (Bl) 7.4 LA (Bl) 7.3 New Orleans (Bl) FEMALE ONLY Breast 100.2 Hawaii (Haw) 95.7 Hawaii (Wh) 92.2 LA (Wh) 79.1 Bay Area (Wh) 73.2 New Mexico (Wh) Cervix 5.7 Cali 4.1 Sao Paulo 3.4 Maori 2.8 NWT 2.1 Poona 11.5 10.8 10.2 9.9 9.9 48.8 40.5 34.7 25.1 24.7 9.1 8.3 8.0 7.9 7.3 7.6 6.5 6.2 6.2 6.1 18.8 18.1 17.6 9.5 9.1 5.9 5.6 5.6 5.6 5.6 87.5 85.6 85.3 83.7 78.7 52.9 37.5 32.6 31.4 30.7 rate being 12.3 for women in Warsaw City. The last example that I give is cervical cancer in Cali, Colombia, with a rate of 52.9, the next being 37.5 in Sao Paulo, Brazil. The populations of Bombay and Poona are the only representatives of India, and in them we find tongue, mouth, oro- and hypopharynx, nose and sinuses, larynx and oesophagus, with cervix and penis also in Poona. Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 These sites, especially the area of the mouth, have long been typical of India, but we find a very similar grouping in France (Bas-Rhin and Doubs), and several in Switzer- land. The Swiss also include high levels of testis, bladder, lymphosarcoma, Hodgkin's Disease, other reticuloses and leukaemia, some of which could be associated with the high standard of living typical of Geneva, Vaud and Neuchatel. The Chinese, represented chiefly by their migrant populations in Hong Kong, Singapore, Hawaii and California, show, in addition to the highest rates for nasopharynx, high rates for oesophagus, stomach, colon, liver, nose and sinuses, and thyroid. There are four registries in Japan itself, and the Japanese have, for both sexes, the highest rate of stomach cancer in the world; after them come Shanghai and the South American towns of Cali and Sao Paulo. Japanese in Nagasaki and Miyagi show high rates of gall bladder carcinoma, while expatri- ate Japanese have an excess of rectal cancer. Jews have high rates for rectum, and also for lip and ovary, but especially, in both sexes, for brain and nervous system. Native Hawaiian women have the highest breast can- cer rate, to which are added mouth, salivary gland, liver, bronchus, thyroid, lymphosarcoma and myeloma; for the men there are oesophagus, bronchus, lymphosarcoma, myeloma and myelocytic leukaemia. The Maoris, of both sexes, have very high rates for pancreas, bronchus, myeloma, myelocytic leukaemia, and for women, cervix. Norway, Sweden and Denmark have high rates for ovary, other urinary, brain and nervous system, and for Denmark the testis, and for Norway, melanoma. In the Antipodes, New South Wales, South Australia and New Zealand whites have the top three rates in both sexes for melanoma, followed by some US whites and the Norwe- gians. Other forms of skin cancer are known to be high there and are likely to result from excess exposure to intense sunlight. The sites found among American whites are breast, colon, melanoma, endometrium, bladder, Hodgkin's dis- ease, and lymphosarcoma, sites which could be said to be characteristic of a high standard of living. Among Ameri- can blacks are found the highest rates of pancreas, prostate, myeloma, and bronchus. For the latter site the New Orleans blacks lead with a rate of 107.2, followed by the Maoris at 105.7, and the west of Scotland at 96.8; among women, the Maoris lead with 48.8. These are the principal highlights, though the cata- logue is far from exhausted. But apparently isolated facts form a poor diet and quickly amount to a surfeit. In some instances it is possible to put forward plausible 'explana- tions' for observed high rates, in others there is no clear ( relationship. A general conclusion would support an environmental rather than a genetic basis for most malig- nant disease, though culture patterns are evidently influ- ential. The work of Haenszel[3] and his colleagues on comparing the pattern of cancer among emigrants with ! both host and parent countries has shown that there can be at least two manifestations of an effect: one that, with increasing period of residence, approximates the risk in ' emigrants towards the host's risk, and another that requires a new generation, born in the host country, before a sizeable change is seen. One of the strongest arguments for the environmental effect is, of course, the large fraction of cancer attributable to cigarette smoking, now increasingly evident among women as male rates have reached saturation. Another is the striking change in the pattern of cancer in Japan as dietary habits change towards a western model. Though we may be able, from analysis of these data, to infer methods that may help to reduce or prevent certain kinds of cancer, there are still many variants that remain unexplained, and secular trends that elude a current rationale. This article is based on a paper read at the Conference on Diseases in Ethnic Minorities held at the Royal College of Physicians in May 1984. I References 1. Waterhouse, Muir, C.S., Shanmugaratnam, K. and Powell, D.J. (1982) Cancer Incidence in Five Continents, Vol. IV. Lyon: IARC. 2. International Classification of Diseases ? Manual of the International Statistical Classification of Diseases, Injuries and Causes of Death (1967) Geneva: WHO. 3. Haenszel, W. (1975) in Persons at High Risk of Cancer, pp. 361-71. (ed J.F. Fraumeni.) New York: Academic Press.

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A Surgeon's Expectations of the Autopsy C.G. CLARK, MD, ChM, FRCS, FRCSEd Professor of Surgery, University College, London, and Director, Department of Surgery, The Rayne Institute In many ways the surgeon may have less apparent interest in the autopsy than the physician. This is because he has already had a preview at operation, made a diagnosis and perhaps found widespread dissemination of a cancer about which he could do nothing except ensure that the patient's remaining days were made as comfort- able as possible. This attitude should not be regarded as showing lack of scientific interest, but more as an accept- ance, after seeing this all too common occurrence, that there is little more to be learned from yet another disseminated cancer. When the primary cancer is un- discovered, efforts are made to obtain permission for autopsy, though this is sometimes thwarted by the rela- tives, who feel that the operation was sufficient opportu- nity, and are reluctant to agree to further mutilation. These two circumstances have some bearing on the degree of enthusiasm with which permission for an autopsy is sought. There are also special problems in any district which has a high proportion of elderly, usually females, who live alone and have either no relatives, or relations who, for various reasons, are reluctant to give permission for further examination. Problems of permis- sion sometimes arise with ethnic minorities such as orthodox Jews or Muslims. The relatives may resent the failure of treatment, or there may have been real or imagined antagonism from the staff, both of which can lead to a request for an autopsy being refused. All these reasons account for up to 40 per cent of requests for autopsy being refused. To some extent the autopsy rate depends upon the method of approach. In a surgical unit it is likely that the person available to meet the relatives is the house sur- geon, whose experience of the situation is one of learning and finding his way. He should be taught to deal with the situation with sympathy and understanding, together with a degree of firmness. It is important that he should explain why an autopsy is necessary, and the degree of conviction with which he does this will largely be deter- mined by the attitude of his seniors. Attitudes to autopsy vary widely. At one time the rule was to try in all cases, but, with a greater understanding of what was likely to be achieved and taking into account the natural resistance of the relatives, permission is usually sought only when a question needs to be answered. The surgeon's guide for an autopsy request might be: (a) Unexplained Death. The patient is admitted and dies before investigations are complete and any diagnosis has been made. (b) Unexpected Death. The diagnosis is established, and perhaps an operation successfully performed, but the patient dies, perhaps from an embolus or a myocardial infarction. (c) Expected Death, but cause unknown as in disseminated malignancy with an unknown primary. (d) Something went wrong. An operation appears satisfac- tory but complications such as septicaemia, fistula forma- tion or undisclosed sepsis such as subphrenic abscess, lead to death. (e) Teaching. There are lessons to be learned by students in comparing the pathology with the results of pre- mortem investigations such as X-rays, CAT scans, etc. (f) Research. It may be valuable to study the effect (or lack) of treatment, as in the case of treatment of malig- nancy by cytotoxic drugs. The attitudes of staff to autopsy can be determined by their response to the question: 'How often is an autopsy helpful?' and by grading the answers into 'usually', 'sometimes' and 'seldom'. Table 1 provides responses Table 1. Responses from different grades of staff from a number of professorial surgical units in the UK to the question: 'How useful is an autopsy?'. No. Usually Sometimes Seldom participating No. % No. % No. % Prof./Reader 27 18 66 6 22 3 11 Sen. Lecturer 28 15 53 10 36 3 11 Lecturer 19 12 63 4 21 3 16 Registrar 29 14 48 8 27 7 24 SHO 16 10 62 4 25 2 12 Houseman 19 10 52 8 42 1 5 Total 138 79 57 40 29 19 14 from different grades of staff in professorial surgical units. All responses are qualified by the fact that selection of autopsy is the mode. Even so, enthusiasm is muted, though reasonably consistent in the different grades. Under 'seldom', registrars appear more cynical than others. Such a survey does little more than provide a general guide to the approach to asking permission for an autopsy. The timing of the approach, the seniority of the staff member, and the particular circumstances of the patient all have a bearing on the response. However, in answer to the question: 'How often do you obtain permission for an autopsy when the professor says "We 72 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 must'", the answer was 'Almost always'. This seems to indicate that success in obtaining permission is deter- mined by attitudes of the senior staff. The number of deaths in the Professorial Surgical Unit at University College Hospital is recorded in Table 2. Table 2. Number of autopsies performed on patients dying ir Surgical Unit, UCH, in 1983. Deaths Autopsies Cancer of stomach 10 Cancer of pancreas Non-malignant 9 2 1 Colo-rectal cancer ' Other cancer 10 10 7 rZr 49 19(39%) Though classed as a general surgical unit, the bulk of the work is gastroenterological, with breast disease as the only other major component of the routine work. It is important to note that the unit maintains a policy of admitting patients with recurrent cancer when it is no longer possible for them to be cared for adequately at home. This may partly account for the fact that, of 49 patients dying, only 19 came to autopsy, though it should also be noted that there were 36 patients who died of malignant disease. Table 3 subdivides the patients into Table 3. Department of Surgery, University College, Autop- sies, 1983. CA = cancer. TUR = transurethal resection of pros- tate. PE = pulmonary embolism. Medico-Legal (Coroner)?3 Assault Anaesthetic (CA breast) Multiple injury Unexplained Hospital Deaths? No Diagnosis Myocardial infarct Myocardial infarct Perforated CA stomach Expected deaths?8 Unknown Primary CA Bronchus CA Bronchus CA Pancreas CA Kidney A utopsy Refused?4 Unexplained Post-op. rectal prolapse Post-op. TUR (myeloma) Post-op Deaths (Pre-mortem diagnosis) Myocardial infarct Pulmonary embolus Faecal peritonitis (obstruction) Faecal peritonitis (resection) Mesenteric infarction (pancreas) Unusual Diagnosis Retroperitoneal sarcoma?PE Leiomyosarcoma Squamous CA chest wall Sup. mes. artery thrombosis Expected Primary unknown Primary unknown unexplained deaths and those in which the disease was known and death was expected, but the case was such that it was hoped to gain further information. The infor- mation which is difficult to provide is: 'How helpful was the autopsy to the understanding of the problem?', and such information, being generally subjective, will be regarded differently by different members of staff. Table 4 shows requests for autopsy, and the number of autop- sies actually performed. Permission was refused in 35 per cent. Table 4. Request for autopsy and number carried out. Request for Autopsy Unknown primary Death within one month of surgery Coroner Unexpected death or no diagnosis More information Total No. Autopsies Performed 6 4 8 6 3 3 7 3 5 3 29 19 It is possible that the need for students to see the ravages of disseminated disease have not been suitably catered for. The alterations to the curriculum are such that students spend much less time than in the past on individual firms, and probably less time on clinical work. Surgical students in particular may be less available to attend the autopsy because of other commitments. The timetable is far too crowded, and the only solution appears to be to arrange for the autopsy to take place at some time when nothing else is programmed, which is usually in the lunch hour. The value of the autopsy is not in doubt. Evidence that the pre-mortem diagnosis is incorrect occurs sufficiently often to warrant autopsy in almost every situation. However, the negative value has not been accurately assessed, and there is little doubt that surgeons, with their 'preview' of the situation, feel that there is little more to be learned in many patients, particuarly those with disseminated cancer. Unfortunately, this view may well deny the students the salutary lesson of seeing the ravages of cancer. It seems likely that the only way to ensure that there are adequate autopsies for the teaching and training of pathologists is by personal liaison between the surgeons and the pathologists. Many already have such a liaison, particularly those with a special interest such as gastro- enterology where good practice usually means a regular weekly meeting to discuss biopsy material. However, this regular meeting may be the only occasion on which surgeons and pathologists meet, and there is room for a meeting in the autopsy room on occasions. This article is based on a paper read at the Conference on Death Certification and the Autopsy held at the Royal College of Physicians in May 1984. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 73

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Organising a Clinical Examination [ JOSEPH PANG, MB, MRCP(UK), Lecturer, Department of Medicine, The Chinese University of Hong Kong Clinical examinations are an important part of under- graduate and postgraduate medicine. Not only do trivial things like the future careers of medical students and junior doctors depend on them, but they also give examiners a chance to meet old friends, make new acquaintances, settle old scores and keep abreast of recent advances. A clinical examination is therefore a double- edged weapon. If it is well organised, it brings immeasur- able prestige to the department as a whole and to the host examiner in particular. On the other hand, if it is chaotic, those responsible may become a laughing stock. Crafty host examiners would of course ensure that they take the credit if things go well, and that their minions take the blame if things do not. It was said that if the New York Yacht Club ever lost the Americas Cup, the skipper's head would replace the trophy on its stand. As it turned out, this did not quite happen, and in any case, the medical profession is far more tolerant of failure than the N.Y.Y.C. Nevertheless, it would not be surprising if the culprits who made a mess of organising a clinical examin- ation were required to relinquish less important parts of their anatomy. These would then be preserved in pots in the anatomy museum and exhibited as warnings to their successors. The fate of the remnants of these culprits is often unknown; rumours suggest that they end their remaining days in disgrace somewhere in outer Mongolia or the steppes of Russia. I had the privilege (misfortune) of being asked (or- dered) to organise two clinical examinations?one for the MRCP(UK) and one for the University of London's Final MB. Lady Luck smiled on me on both occasions: I survived and emerged physically, if not psychologically, intact. It is to those future gladiators who will be asked (ordered) to organise clinical examinations, and to the consumers of these commodities that I dedicate the following 'rules' of survival. Preliminaries Get a good secretary. A good secretary is the key to success. If necessary, beg, borrow or steal one who has previous experience and is mad enough to want to do it again. She should be efficient, highly organised, hard working, charming and understanding, especially when your wife/husband starts complaining that you are spend- ing all your evenings with her, and preferably a good cook (the reasons for this will be apparent later). Under no circumstances must she fall ill before the examination is over. Get a good nurse. A good sister is almost as important as a good secretary, since she will be the one who organises the examination area and makes sure that all the necessary equipment is assembled. Negotiate for time off clinical duties before the examin- ation. Find a suitable area for the examination. The best place is usually a large, well-lit ward, ideally with: 1. Sufficient cubicles where pairs of examiners can grill their victims without disturbance. Examiners function in pairs, not to intimidate, but to observe each other in order to be fairer to the candidates. Also, it is less likely that both of them will fall asleep at the same time. 2. Several 'bays' of 6-8 beds each, with curtains, for patients who need to undress. 3. A large sitting area for patients who do not need to undress. They are usually used as 'short cases'. 4. A room which can be darkened so that a patient's fundi can be examined to best advantage. The alternative of dilating the pupil with topical drugs is not suitable for some patients. 5. An examination room for urine testing. 6. Nearby toilets for all those under stress. 7. A relatively secluded waiting area for candidates. Finally, a sketch map of the examination area, com- plete with bed numbers and chair numbers, is invaluable. About Eight Weeks before the Examination This is the time when the real work begins, namely, the selection of suitable cases. For medicine, there appear to be three modern trends in clinical examinations: 1. Recently admitted patients, who can be used to test the candidate's ability to evaluate and manage their various medical problems, are preferred. 2. Patients with exotic diseases who have been used for examinations from time immemorial ('museum' cases) are to be avoided. 3. Candidates will be examined on all major systems of the body, without reduplication. For example, if someone had a neurological 'long case', he would be taken to patients with diseases in systems other than the CNS in the 'short cases'. Invariably, these trends will have a critical influence on patient selection. My personal 'rules', therefore, are: Try to get an optimum mixture of 'cold' and 'hot' cases. I think their ideal ratio is about 7:3. 'Cold' cases include those 'old faithfuls' who are frequently used for examinations and teaching (most examination-orientated hospitals have lists of these) and, better still, new unused patients who are in the wards several weeks before the Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 93 examination. The latter should be approached before they are discharged, and arrangements made for them to return on the required day(s). 'Hot' cases are those recently admitted patients who are still in hospital during the examination. They have the advantage of being on site so that outside transport arrangements are unneces- sary. However, by definition, most cannot be approached until very near the examination, so there is always a risk of not getting enough patients, or too many with diseases of one system and not enough with diseases of another. A further drawback, perhaps the real one if the truth be known, is that it is exceedingly hard work for both the organiser and the secretary to find these patients and prepare case summaries at the busiest time on the eve of the examination. Aim for a balanced group of patients, (a) There should be enough patients with diseases in each major system, (b) There should be enough patients for the 'long case' and the 'short case' parts of the examination. Some patients are suitable both as a long case and a short case. They are ideal because administration, cost and total patient number can be kept down, (c) Despite the direc- tive on 'museum' cases, it is wise to include one or two. Host examiners can be most upset if their favourite neurosyphilitic is consistently left out, and indeed, the loyal patient can also be displeased if he is no longer invited. You may think that the latter does not matter, but you are wrong because he will surely complain bitterly to your boss the next time he is seen in out- patients. Enlist the help of colleagues. Sending them written requests for suitable patients may help, but tends to be less effective than cornering them and asking them face to face who they have on the wards at the moment. Approach suitable patients for consent with care. Most patients are reasonable and will agree if they are asked tactfully. Some may refuse because they live far away or have other commitments. On the whole, it is probably better not to pressurise reluctant patients because they may agree under duress and then simply not turn up on the day. Prepare brief case summaries, including only the most relevant points. Long discourses waste time and will not be read by the examiners. Needless to say, it is important to check the patient's history and signs before preparing the case summary. A pocket size tape recorder is very useful for on-the-spot dictation, thus saving removing the notes and X-rays from the ward to the secretary's office. Organise the most reliable means of transport for out- patients. Some patients can come on their own, but others require transport. If hired cars need to be used, choose a reliable firm since punctuality is vital. Patients living near one another can come (and leave) in the same car, but allow plenty of time for delays. Two Weeks before the Examination The activities mentioned above intensify during this critical period. In addition, the all-important task of allocating long cases can now begin. Short cases do not need to be assigned. The following rules are helpful. Always use in-patients as long cases at the beginning of each day because they are not dependent on outside transport. All out-patients should be asked to arrive well before the start of the examination, but they should be allocated as long cases later in the day. The reason for this is that even if they come late, or do not arrive at all, there will still be time to find replacements. Take into account patients' personalities as far as rj possible. Human nature being what it is, allowances should be made for patients' prejudices. For example, it is *? obviously inappropriate to assign a patient who is a known male chauvinist pig to the secretary of the local women's liberation society. It is surprising how much you * do know about the candidates, some of whom will have worked with you. Ask the host examiners' advice on case allocation. Their opinion is often very helpful. In addition, most of them do not want to do more work than necessary (and getting to know several brand new long cases each day is hard work), so they may prefer to be given some of their favourite patients whom they know inside out. Always aim to have a few spare patients each day. Liaise with the hospital porters and all relevant depart- ... ments. Porters always know what goes on (often before you do), but details like when their services will be particularly required, positioning of signposts and so on, t need to be discussed with them. Hospital administrators also need to know, but, unlike porters, some of them do not know what goes on even though you have written to them several weeks ago. Perhaps it is the timing; if you * tell them too early, no one will pay any attention; if you tell them too late (like two weeks before the examination), your memo will not be read until the pass list has been i published. A Day or Two before the Examination 1. Finalise patient lists, allocation lists and transport lists. 2. Check on all the arrangements that have been made. 3. Assemble files for the examiners, which should include a map of the examination area with numbered beds and , chairs, list of candidates, list of allocated long cases and summaries of all patients. 4. Work out a timetable for the examination. Sometimes, one will be provided by the examining body. Basically, this is a list of times when certain activities need to be performed. These include introducing the candidates to their long cases, bringing them to the examiners, change- over from long to short cases or vivas, serving coffee during breaks and so on. It is very important, because time-keeping is vital to the smooth running of a clinical examination. On the Days of the Examination r This period is like what is sometimes said of giving anaesthetics?mostly boredom punctuated by spells of blind panic. The major problem occurs when out-patients cannot come or cannot arrive on time for one reason or another. Most responsible patients will ring up the secre- 94 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 tary, who would have established a hot line just for this purpose. Sometimes the problem can be solved but on other occasions it may be necessary to switch patients round or use spare cases. Rarely, even the best laid plans can go astray: this happened when a clinical examination organised by one of my colleagues coincided with a public transport strike so that many patients and candidates found it impossible to be punctual. The chaos that existed before God created the universe was nothing compared to what ensued. Somehow, to their great credit, things were sorted out without too much delay. My colleague gained much respect, and it s now rumoured that he is practising walking on water with some success. Still, there are several rules to be observed. 1. Introduce each pair of examiners to their long cases before the examination starts. They are expected to familiarise themselves with these patients, and a few words about any potential problems the candidates may have with them can be very helpful. 2. Try to put the candidates at ease. Anyone who has gone through the rigours of a clinical examination will undoubtedly have a lot of sympathy for them. However, it is sound to advise them not to discuss patients they have seen with their colleagues. To do so is unhelpful and can be fatally misleading. Examiners detect such exchanges very easily, and many have remarked how successive candidates make identical mistakes on the same patients, or worse still, find the 'correct' signs on the wrong patient while acting on a tip from their predecessors. 3. Keep time strictly. Examiners and candidates must be reminded of their allotted time. Some examiners invari- ably go on longer than they should, and sometimes this will delay the whole examination. All one can do is to try hard to prevent this. 4. Direct examiners towards little-used short cases. It is almost unavoidable that some short cases are much more popular than others. This tends to tire out some patients, and makes others feel totally unloved. 5. Be ready to respond promptly to examiners' and candidates' requests. Candidates usually want to borrow equipment. Requests from examiners are more unpre- dictable. Some examples are: help to find missing specta- cles/stethoscopes, to leave messages for wives/husbands/ secretaries, to confirm signs that you have missed in some patients and to arrange for a call from America to be received during the coffee break. (Those who wish to practise one-upmanship please note.) Sometimes you will need to be in three places at once, but by now this should be no problem. 6. Keep an eye on valuable pocket-size equipment. Many ophthalmoscopes have been unintentionally removed by shell-shocked candidates at the end of their ordeal so that they are unavailable for later use. 7. Thank the patients before they leave, and remind those who have been asked to come on another day when they are required again. Conclusions At the end of it all, organising a clinical examination is not as bad as it sounds. It often gives amusing moments. Two incidents stand out in my memory. In one, I mixed up the case summaries of two patients with identical names, and neither I nor the examiners detected this before the examination started. To their credit, they kept a straight face when the candidate presented a totally different history from the one in the case summary. They then examined the patient, agreed with what the candi- date found, and took great delight in pointing out my blunder to me. In another, when I went round to thank the patients, I found one of them sweaty, pale and talking nonsense. Intravenous dextrose cured his hypoglycaemia, but it was difficult to tell how long he had been in that state. Neither the candidates nor the long case examiners (one of whom was a diabetician) had noticed anything amiss, so one must presume that the patient became symptomatically hypoglycaemic after they had seen him?or can one? In both the examinations I helped to organise, I was extremely fortunate to have an excellent secretary. There were many occasions when I was saved from a fate worse than death by her foresight and organisation. In addition, she provided all the examiners and staff with fresh ground coffee and a different snack every single day, culminating in a farewell tea on the final day which was a gastronomic tour de force. She is now well-known in the marble corridors of the hallowed halls. Without her, I would not have survived to tell this tale. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 95

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Editorial 'How bad is it, doctor?' can be a difficult question to answer. We are all used to the question and tend to accept that we share the patient's concept of badness. But, of course, the concept is too all-embracing to assume agreement. Badness goes from immediate threat to life down to transient discomfort; it ranges through the odds on permanent disability to loss of a job and distress of relatives. It is easy to see that a first epileptic fit will cost a lorry driver his job but will not affect a clerk's income, or that the private hell of schizophrenia encompasses the patient and those who love him. The usual situation is not so clear-cut and our answers tend to combine a good guess with encouragement. We sometimes over-stress the bad to get the patient to accept an unpleasant treatment. Not to be recommended was the ploy of a surgeon long ago who told every patient with a broken wrist that it was the worst fracture he had ever seen; any restoration of function was received with thanks. For some diseases we do have a rational scale of severity. The histological staging of cancers enables us to give informed answers on threat to life and hazards of necessary treatment. We lack such a scale for the less dire illness. In this issue of the Journal Professor Lambert points this out most clearly for whooping cough and shows how he has devised methods to construct an objective scale of distress. This is better than the doctor having to wait until his own children are afflicted before he realises what this infection is all about. We could certainly be helped by more research of this nature in order to build up an all-round view of what is faced by the patient and his relatives. It is indeed very difficult to quantitate the effect of an illness on an individual. Come to think of it, even our vital statistics have to be crude. The epidemiological criteria of health are based on death, which is inevitable. Translation of death rates into tables of life expectancy puts a term to death postponed but adds no hint of medical expectations for that slice of life. Maybe that is far enough on safe ground, for we are not in the business of prophecy. But we are in the difficult position of presenting to people their most probable medical future. No patient can give informed consent to treatment unless adequate information has been supplied. Here we are back to the currently popular concept of perceived risk. At the moment the perception of any risk to health seems to be dominated by pronounce- ments in the media. Accurate assessment is not so publicised. While some wish to decide for themselves on the data presented to them and others still wish to do what the doctor suggests because they feel the expert is primarily concerned with doing his best for them, the only basis for progress is in real knowledge. In these days of retrenchment most of us are involved in making out the strongest case for preserving and extending facilities. This is a poor climate in which to collect objective scientific facts to illuminate the emotive field of badness in illness. But we need the facts for our decisions and to help the patient decide. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

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Cimetidine in the Treatment of Herpes Zoster D. W. LEVX MB, FRCR Consultant Physician A. K. BANERJEE, MB, FRCP! Consultant Physician Department of Medicine for the Elderly, Bolton General Hospital HELEN R GLENNy PhD, Clinical Research Scientist Smith Kline and French Research Ltd, The Frythe, Welwyn, Herts Herpes zoster can be a distressing event in the elderly, causing confusion and distress in the acute phase and incapacitating post-herpetic neuralgia in a high percent- age of cases[l]. The preliminary observations of Van der Spuy et al. [2] suggested that cimetidine may have a beneficial effect in several herpes virus infections, including herpes zoster. In an uncontrolled open assessment of one patient, cimetidine relieved the pain and shortened the course of herpes zoster. A subsequent uncontrolled trial of cimeti- dine in 21 patients with herpes zoster produced encourag- ing results in all but three patients. More recently, Mavligit and Talpaz[3] reported that cimetidine 300 mg q.d.s. for seven days produced a rapid improvement in the pain and pruritus of herpes zoster in four cancer patients whose immune systems were pro- foundly suppressed. Herpes zoster is thought to be associated with a state of depressed cellular immune function[4]. It is theoretically possible for H2 receptor antagonists such as cimetidine to modify cell-mediated immune responses since thymus dependent T-lymphocytes have been shown to possess H2 receptors[5-7]. In addition to a possible direct anti-viral effect[2], cimetidine may augment the immune defences of the body which produce early control of the herpes zoster virus. The present trial, more extensive than that of Van der Spuy et al. [2], was designed to establish whether cimeti- dine was effective in the treatment of herpes zoster. Since herpes zoster has a variable and unpredictable natural history, it was necessary for this study to be placebo controlled. Patients Sixty-three patients aged 27 to 92 years (mean 66.4 years) with herpes zoster, suitable to be treated as out-patients, entered the study. Of these patients 41 were female (mean age 67 years) and 22 were male (mean age 65 years). Local general practitioners and other hospitals in the Bolton area co-operated in recruiting suitable patients. Patients with herpes who had involvement of the ophthal- mic division of the trigeminal nerve were not included in the study. Patients with herpetic infections other than herpes zoster and those who had received cimetidine treatment for other diseases within the past month were excluded from the study, as were patients receiving specific anti- herpetic medications; calamine lotions (for local relief of discomfort) and analgesics such as aspirin and paraceta- mol were permitted. Pregnant or lactating patients, patients with severe renal impairment and those receiving oral anticoagulant therapy were also excluded from entry. Methods The study was conducted in accordance with the Declara- tion of Helsinki. The nature of the trial was fully ex- plained to all patients before entry and their consent obtained. All patients were informed of their right to withdraw from the study at any time. The permission of the hospital ethical committee was obtained and the patients' general practitioners were informed by the investigator. The diagnosis of herpes zoster was made entirely on clinical grounds. The infection was identified by the presence of erythema and/or vesicles corresponding to the unilateral distribution of a sensory nerve. In most patients, pain was experienced at the affected area. In those patients in whom herpes zoster was diagnosed on the basis of erythema and pain, vesicles subsequently developed within 48 hours of entry to the trial. Patients were seen at the earliest possible stage of infection. At the initial visit the distribution, site and stage of the lesions and presence or absence of pain were recorded. Any medications for concomitant disease were noted. Patients were then randomly allocated in a double- blind manner to treatment with either cimetidine 200 mg t.i.d. and 400 mg nocte, or matching placebo tablets. Treatment continued for 28 days. Patients were reviewed daily for the first two days and again at one and four weeks. At each review the distribu- tion, site and stage of the lesions and presence or absence of pain were recorded as for the initial visit. The presence and distribution of any new lesions were also recorded. At the two and four week visits the presence or absence of complications was noted. At three months and six months, patients were assessed for development of com- Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 plications including post-herpetic neuralgia (defined as pain which outlasts the lesions by more than one month). During the treatment period patients were requested to complete diary cards daily to record the presence or absence of pain and its duration. Statistical Analysis Demographic parameters (the number of days lesions and pain were present before the start of the trial) were compared between the two treatment groups using the Wilcoxon two sample rank-sum test. A chi-squared test was used to compare the incidence of healing of lesions and pain after one month of treatment. Two-tailed tests were used throughout. Results Forty-nine patients completed the one month's treatment period as planned; 24 of these patients (18 women, 6 men; mean age 65 years) received cimetidine and 25 patients (13 women, 12 men; mean age 63 years) received placebo treatment. Fourteen of the 63 patients who entered the study were excluded or withdrawn before completion of the treatment period. The reasons for patient withdrawal/exclusion were as follows: default (5 patients); ophthalmic herpes (5 patients); death which was unrelated to treatment (2 patients); inadequate re- cords (2 patients). The two treatment groups were comparable with re- spect to the duration of signs of infection (lesions and pain) before the start of the trial. The median number of days vesicles were present in the cimetidine group was three (1-7), compared to two (range 0.5-6) in the placebo group. The median number of days of pain before the trial in the cimetidine group was three (range 0.5-14), compared to five (range 0-12) in the placebo group. The stage of the lesions in the two treatment groups was roughly comparable at the start of the trial. Efficacy of the treatments was compared by examining the incidence of healing of the vesicles and the incidence of pain at the end of the one month treatment period (Table 1). Table 1. Efficacy of treatments compared by examining inci- dence of healing of vesicles and incidence of pain after 28 days' treatment. H = 100% healed. N = not healed. P = present. A = absent. Cimetidine Placebo Healing of lesions at Day 14 6H, 18N 6H, 19N Day 28 18H, 6N 24H, IN Pain at Day 28 6A, 18P 15A, 10P Incidence of post-herpetic neuralgia at Month 3 12A, IIP 17A, 8P Month 6 16A, 9P 20A, 5P No statistically significant difference between the ef- fects of the two treatments on healing of vesicles was seen. Eighteen out of 24 (67 per cent) healed in the cimetidine group compared with 24 out of 25 (96 per cent) in the placebo group (0.05 < P< 0.1, in favour of placebo). A statistically significant (/3<0.05) difference between the incidence of pain after one month of treatment was found. A higher proportion of patients in the placebo group (15 out of 25, or 60 per cent) experienced no pain, compared with the cimetidine group (6 out of 24, or 25 per cent). There was no statistically significant difference be- tween the two treatment groups with respect to the incidence of post-herpetic neuralgia at 3 months and 6 months (Table 1). No clinically significant untoward events related to cimetidine therapy were reported by any patient. Discussion There is no evidence from the study data that cimetidine relieves the pain or accelerates the rate of healing of lesions in herpes zoster. This conclusion does not support the clinical observations of Van der Spuy et al. [2] and Hayne and Mercer[8], It is possible, though unlikely, that the dosage of cimetidine (1.0 g/day) used in the present study was not sufficient. Van der Spuy et al. [2] reported that relief of pain was the main criterion for judging the success of treatment of herpes zoster with cimetidine (1.6 g/day for the first two days, followed by 1.0 g/day for five days). In our study only the incidence of pain at the beginning and end of treatment was examined statistically. It was not possible to compare the effects of cimetidine and placebo on the relief of pain throughout the period of treatment as only some of the patients completed the diary cards with a record of pain they had experienced. Hayne and Mercer[8] claimed that cimetidine (1.8 g/ day for 8| days) accelerated the rate of healing of lesions of one patient with herpes zoster, on the basis that the duration of the disease can be predicted from the length of time it takes for all the vesicles to erupt[9]. From our data it was impossible to determine the precise time taken for all the vesicles to erupt and therefore to predict the duration of the active phase for each patient. Neither could any effect of treatment on the duration of the active phase be assessed, since the time course of healing of the vesicles after they had crusted was recorded only at days 7,14 and 28 of treatment and was not monitored between these visits. However, as there was no statistically signifi- cant difference between the two treatments given with regard to the number of patients with lesions which were healed, it is unlikely that cimetidine affected the rate of healing of the vesicles. The discouraging outcome of this large controlled trial, unlike that of previous, smaller, uncontrolled tri- als[2,3,8], suggests that further trials of cimetidine in herpes zoster would not be worthwhile. Acknowledgements We are grateful to Caroline Franks and Elisabeth Else for performing the statistical analyses. This study was sup- ported in part by funds from Smith Kline & French Research Ltd. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 97 References 1. de Moregas, J. M. and Kierland, R. R. (1957) American Medical Association Archives of Dermatology, 75, 193. 2. Van der Spuy, S., Levy, D. W. and Levin, W. (1980) South African Medical Journal, 58, 112. 3. Mavligit, G. M. and Talpaz, M. (1984) New England Journal of Medicine, 310, 318. 4. Rand, K. H., Rasmussen, L. E., Pollard, R. B. et al. (1976) New England Journal of Medicine, 296, 1372. 5. Plant, M., Lichtenstein, L. M., Gillespie, E. et al. (1973) Journal of Immunology, 111, 389. 6. Plant, M., Lichtenstein, L. M. and Henney, C. S. (1975) Journal of Clinical Investigation, 55, 856. 7. Rocklin, R. E. (1976) Journal of Clinical Investigation, 57, 1051. 8. Hayne, M. S. T. and Mercer, J. B. (1983) Canadian Medical Association Journal, 129, 1284. 9. Burgoon, C. F. Jr., Burgoon, J. S. and Baldridge, G. D. (1957) Journal of the American Medical Association, 164, 265. Harveian Memorials It must have been a long day's pilgrimage to rural Essex on St Luke's Day, 1883. On that day at Hempstead church the remains of William Harvey, lapt in lead, were transferred to a new sarcophagus inscribed 'The remains of William Harvey, discoverer of the circulation of the blood, were reverentially placed in this sarcophagus by the Royal College of Physicians of London in the year 1883'. Preceded by the vicar of Hempstead, the Rev. Mr Eustace, and his curate, the sarcophagus was borne into the church by Fellows of the College, followed by four members of the Harvey family, the President of the College, Sir William Jenner, robed and carrying the caduceus, and then the College officers, gowned, with Fellows of the College bringing up the rear. The proces- sion went into the Harvey chapel to lay the sarcophagus on its final resting place. After a short service, with hymns sung by the village choir, the President placed in the sarcophagus a bound copy of Harvey's works sealed in a metal box and a scroll describing the event and lauding Harvey as a munificent benefactor of the College. The College had been concerned with the state of Harvey's remains since the first report in 1847 that the lead coffin was damaged. In 1859 a deputation from the College found the coffin was half full of water and further damage was reported in 1878. On 28th January 1882 the tower of Hempstead church and part of the nave col- lapsed, causing further damage. The College forthwith appointed a committee to consider the matter. They rejected a suggestion that Harvey's remains should be reinterred in Westminster Abbey to join such distin- guished Fellows as Thomas Willis, Richard Mead and Thomas Young, and suggested the ordering of an appro- priate sarcophagus which was purchased for ?155. As a matter of history the church at Hempstead was not fully repaired until 1961, the work being aided by substantial sums from the William Harvey Memorial Fund and the Harveian Society of London. The choice of St Luke's Day for the 1883 reinterment was made because for many years that had been the day for the Harveian Oration. Indeed the July Comitia in 1884 resolved that the Oration should henceforth be given on St Luke's Day. The Harveian Oration and Dinner was, of course, instituted by Harvey. Old, infirm, rich and childless, he considered how he could benefit the College. He was the 'anonymous' donor of a library building and, after its ceremonial opening in 1656, the College elected Harvey as President. This offer was received and declined with perfect dignity and with the recommendation that Dr Prujean should continue as President; a recommendation speedily accepted. By an indenture of 21st June 1656, Harvey transferred his patrimonial estate at Burmarsh, Kent, to the College. From the proceeds of this he asked that the College, 'to maintain friendship', should at 'every meeting once a month' prepare a 'small collation' and that 'once every year' there should be 'a general feast for all the Fellows'. The idea of the feast comes before the Oration, as he laid down that 'on the day when such a feast be kept . . . some one person of the said College shall make an oration in Latin publicly'. He exhorted the orator to commemorate the College's benefactors and encourage others to follow their example and he also exhorted 'Fellows and Members to search and study out the secrets of nature by way of experiment'. The first Harveian Oration was given in July 1656, only a month after Harvey's gift, by Dr Edward Emily, a physician to St Thomas's Hospital. This proved a disas- ter. In Comitia of 28th July 1656, Dr Emily 'was accused of having declaimed more bitterly than was proper against military matters, and also of disparaging the present rule of the Commonwealth'. Dr Emily affirmed that 'he had said nothing in a bad spirit'. However, Comitia decided that in future no such oration should be given in the College unless the President and Censors had read and approved the text one month before the oration was due to be given. The College was anxious to remain on good terms with Cromwell's major-generals so the decision to let Emily go without rebuke but to introduce censorship of future orations must have been thought sufficient to ward off official displeasure. What remains puzzling is the choice of Dr Emily as the first Harveian Orator. At the start of the Civil War Emily had hinted in a letter that he sided with the Parliamentarians, so his oration suggests that he had become disillusioned by that cause. Emily's career showed no distinction and any promise of achievement went unfulfilled, as he died in November 1657. 98 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

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Ulcerative Colitis in a North Indian Hospital: Current Trends M. E SHARMA, MD, Assistant Professor S. K. SARIN, MD, Lecturer Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India Owing to the frequency and chronic nature of the disease, its propensity for complications and the need for institu- tionalised specialty care, there has been extensive re- search in the field of ulcerative colitis in the Westfl]. Ulcerative colitis is, however, not uncommon in In- f dia[ 2 ]; there have been a number of reports in the past two decades[2-7], Most of them were based on observa- tions made on a limited number of patients and are therefore conflicting. The true incidence and clinical picture of ulcerative colitis in Indian patients is still not clear. Subtle differences have been suggested between patients with ulcerative colitis seen in India and those seen in the West[3,4], This article attempts to highlight the incidence, clinical features and complications based on our experience of observing 218 patients with ulcer- ative colitis in the apex referral hospital of India. A comparison with disease trends as reported from the West is made. Materials and Methods This retrospective study includes 218 consecutive patients with ulcerative colitis seen at the Gastroenterology Ser- vices of the All India Institute of Medical Sciences (AIIMS), New Delhi, between 1972 and 1981. The diagnosis of ulcerative colitis was made on the basis of (a) a history of chronic diarrhoea, with passage of blood and mucus, uncontrolled by adequate anti-bacterial and anti- amoebic treatment, together with (b) negative results from two fresh stools examined for parasites, and sigmoi- doscopic findings of congestion, oedema, ulceration, granularity and fragility of the mucosa[8]. The patients were grouped into mild, moderate and severe disease according to standard criteria[9]. In every patient a thorough clinical evaluation and routine investigations like haemogram, stool for tropho- zoites and cysts, and sigmoidoscopic examination were carried out. In a majority of the patients a plain X-ray of the abdomen, barium enema, amoebic serology, liver function tests and rectal biopsy were also carried out. Results There were 136 males and 82 females, a ratio of 1.6:1. Of the patients, 172 (89 per cent) were between 16 and 45 years of age. Disease was rare below 15 (4 per cent) and above 60 (3 per cent) years of age. The mean age was 33.1 years (Table 1). There were 27 patients (12.4 per cent) with mild, 144 (66.1 per cent) with moderate and 47 (21.5 per cent) with severe ulcerative colitis (Table 2). Table 1. Age and sex distribution of ulcerative colitis in 218 patients. Age (years) Male Female 0-15 6 2 16-30 65 37 31-45 37 33 46-60 22 10 61-75 6 ? >75 ? ? 136 82 Table 2. Duration of the presenting episode Duration Mild Moderate Severe 0-1 yr? 0-6 mth 7 88 32 7-12 mth 6 33 11 1-2 yr 8 12 4 2-3 yr 4 8? 3-4 yr 1 1 ? >4 yr 1 2 ? Total patients 27 144 47 The total duration of the illness varied from three days to 25 years. While 49 per cent of the severe ulcerative colitis patients had the illness for less than one year, 85 per cent of the moderate and 81 per cent of the mild ulcerative colitis had the disease for more than one year (Table 3). Sixty-four patients (29 per cent) presented with their first attack of ulcerative colitis. The remainder (154 patients) had a variable number of relapses during the course of their disease (Table 4). The most important presenting complaint was the history of passage of blood mixed with stools which was seen in 98 per cent of the patients. In 94 per cent the Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 99 Table 3. Total duration of ulcerative colitis. Period (years) Mild Moderate Severe < 1 5 22 23 1-4 5 67 8 5-8 8 33 6 9-12 6 11 6 13-16 1 6 4 17-20 2 4 ? >20 ? 1 ? Total patients 27 144 47 Table 4. Number of relapses experienced by patients with ulcerative colitis. No. of relapses No. of patients % 1 37 17 2 35 16 3 40 19 4 12 6 5 13 6 6 5 2 7 3 1 >7 9 4 stools were loose and frequent. Nocturnal frequency was recorded in 78 per cent. The onset of the illness was mild to moderate in most of these patients. Abdominal pain was present in 53 per cent; it was usually periumbilical or diffuse in distribution and mild to moderate in intensity. Significant weight loss was complained of by 35 per cent of the patients (Table 5). Table 5. Clinical features. Symptoms Mild Moderate Severe Total patients % Blood in stool 26 144 46 214 98 Mucus in stool 26 144 46 214 98 Loose motions 24 135 46 205 94 Increased frequency 24 135 46 205 94 Abdominal pain 9 82 25 116 53 Fever 1 30 9 40 18 Pallor 3 59 27 89 41 Weight loss 2 55 17 75 35 Pedal oedema ? 14 10 24 11 Hepatomegaly ? 22 6 28 13 Splenomegaly ? 5 ? 5 2 Abdominal tenderness ? 18 9 4 Lump in abdomen ? 22 ? 2 1 Physical examination was generally unremarkable. Pallor and pedal oedema were recorded in 41 per cent and 11 per cent of the patients respectively. Hepatomegaly was found in 13 per cent. It was generally minimal and firm, with round edges. Both hepatomegaly and pedal oedema were more common in patients with moderate and severe disease. While mild abdominal tenderness was present in most of the patients, significant tenderness was present in only 4 per cent (Table 5). Important systemic complications of ulcerative colitis were seen in seven patients (3 per cent) and included polyarthralgia in five (2 per cent), ankylosing spondylitis (HLA-B-27 positive) in one and monoplegia of the upper arm without any other neurological sign in another patient. A number of other diseases was found associated y with ulcerative colitis, such as haemorrhoids in 22 (10 per cent), pulmonary tuberculosis in six (2.7 per cent), bronchial asthma in six (2.7 per cent), hypertension in four (2 per cent), etc., as shown in Table 6. Table 6. Complications and diseases associated with ulcerative colitis. Haemorrhoids 22 Polyarthralgia 5 Renal stone 3 Lichen planus 2 Fistula in ano 2 Ankylosing spondylitis 1 Parotid abscess 1 Monoplegia 1 Sigmoidoscopic appearances were graded as I, II, and III, according to Bacon's classification[8]. Sigmoidoscopy was normal in seven cases with clinically mild or moder- ate disease. In all the other cases varying degrees of abnormality were observed. No clear correlation was seen between the clinical severity of the disease and the sigmoidoscopic findings. This was evident, as 27 patients (5 per cent) with severe colitis had only mild to moderate changes on sigmoidoscopy (Table 7). Table 7. Sigmoidoscope findings. Sigmoidoscopy Mild Moderate Severe Normal 4 3 ? Proctitis 2 5 ? Grade I changes 13 17 3 Grade II changes 8 96 24 Grade III changes ? 23 20 Severe anaemia was seen in only 23 patients (15 per cent). Liver function tests, including serum proteins, serum bilirubin and serum transaminases were done in 96 patients. Hypoalbuminaemia (<2.5 g per cent) was found in 27 patients (28 per cent). Mean serum albumin was 2.9 ? 1.13 g. Serum transaminases were abnormally raised in only 3 patients (Table 8). Plain X-ray of the abdomen was done in 184 patients. It showed dilated small and/or large bowel loops in 25 patients (11 per cent). Six patients (2.7 per cent) had marked colonic dilatation (> 7 cm) on plain X-ray of the abdomen and clinically they were consistent with the diagnosis of toxic megacolon. In two other patients, free gas under the dome of the diaphragm was detected, which was sugges- tive of perforation. Barium enema was carried out in 126 patients to see the distribution of lesions (Table 9). In more than half (54 100 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 Table 8. Laboratory investigations. Abnormal investigation Moderate Severe Hb(< 7 g %) 28 4 TWBC (> 12,000/mm3) 8 7 ESR (>20 mm/lst hr) 84 36 * Abnormal plain X-ray abdomen 18 7 tPositive amoebic serology 2 Hypoalbuminaemia (<2.5 g %) 17 16 'Done in 184 patients only fDone in 93 patients only Table 9. Extent of ulcerative colitis as assessed by barium enema (126 patients). Barium enema findings Mild Moderate Severe Normal 8 15 1 Recto-sigmoid 3 Right colon total 15 6 22 5 Descending colon ? Transverse colon ? 22 7 15 5 Ileum ? 2 ? 11 91 24 per cent) of the patients disease was found to be limited to the left side of the colon. Pseudopolyposis was seen in 19 patients (9 per cent). Malignancy was suspected in seven patients with radiologically demonstrated single or multi- ple strictures or an irregular filling defect or a mass in the colon. Malignancy was, however, confirmed at surgery in only one patient. Rectal biopsy was done in all except three patients and the histopathological findings of distortion of glands, cryptitis and crypt abscesses were reported to be compat- ible with the clinical diagnosis of ulcerative colitis. Discussion Though ulcerative colitis is a disease of the West, it is not rare in India[2-7], where its frequency has been reported to be from 9.4 to 24.4 cases per 10,000 hospital admis- sions^]. Two hundred and eighteen cases of ulcerative colitis seen in a single unit of a referral hospital during a period of 10 years is a further indication that the disease is not rare in India. This is comparable with 624 patients in a period of 24 years reported by Edwards and True- love[10]. The observations of the present study show certain differences between Indian and Western patients with ulcerative colitis. In contrast to Western series in which females are equally[ll] or more commonly[12] affected than males, the present and other Indian studies have found a higher male to female predilection[2-5]. This cannot be due to a smaller number of female beds, as a patient with ulcer- ative colitis will definitely seek hospital admission because of the severity of the disease[2,4]. About half of our patients were between 16 and 30 years of age, a signifi- cantly younger group than that found in the West[9]. There are no clear data about the severity of the initial episode of ulcerative colitis in India. Vakil and Mehta[6] reported mild disease in 68.5 per cent, severe in 28.0 per cent and fulminant in 3.5 per cent of the patients. Tandon and co-workers[3] recorded mild ulcerative coli- tis in 43.5 per cent of the patients and severe disease in the rest. In the present series, mild disease was seen in 12.4 per cent, moderate in 66.1 per cent and severe in 21.5 per cent. This is in contrast to the Western series in which the frequency of mild, moderate and severe disease has been reported to be 66.4 per cent, 22.9 per cent and 10.7 per cent respectively[9]. This pattern of disease in our series may not represent the whole picture, as most of our patients were referred cases. In the present study the duration of the illness was looked at from two angles, the duration of the presenting episode, and the total duration of the disease. This gave us valuable information. It was found that about 42 per cent of patients continued to suffer from the disease for a period of more than six months, due either to delayed diagnosis or inadequate treatment before attending the specialty clinic. This proportion is much higher than in the West, where only 22 per cent of patients required such a long period of management. This is probably related both to lack of awareness of the disease and to the widely held belief among the medical fraternity in India that ulcerative colitis is uncommon and these cases are most probably due to chronic amoebic dysentery. Of the patients 71 per cent had more than one attack of ulcerative colitis and only 29 per cent presented during the first episode, compared with the Western figure of 39 per cent. Earlier studies have also suggested that relaps- ing, remitting or chronic continuous ulcerative colitis are the commonest modes of presentation of the disease[7]. Systemic complications related to ulcerative colitis were infrequent (3 per cent) and included polyarthralgia, HLA-B-27 positive ankylosing spondylitis and monople- gia. In earlier studies from our centre[3] and by others[4], systemic complications were not reported. Manifestations like sclerosing cholangitis, uveitis and skin lesions were not seen in our patients as compared to the incidence of 7 per cent[13], 5-10 per cent[14], 3 per cent (erythema nodosum), 1-4 per cent (pyoderma gangrenosum)[15], respectively reported in the Western series. All these reports therefore suggest that ulcerative colitis in India is not usually associated with the extracolonic lesions that have been observed in Western countries. The reason for this is not clear, but it could be due to less frequent and lower levels of circulating immune complexes and auto- antibodies in our patients[16]. The incidence of associated diseases like pulmonary tuberculosis and bronchial asthma was 2.7 per cent in the present series and was comparable with the figures of 2.4 per cent and 2.6 per cent reported by the Oxford group of workers[9]. The incidence of local complications like fistula in ano was less than 1 per cent as compared with 6-20 per cent in Western series[10,17]. None had perirectal abscess. Pseu- dopolyposis was seen in 9 per cent of the radiologically studied cases. The incidence of pseudopolyposis has been reported as being from 10-32.5 per cent in the West[9], Toxic megacolon was seen in 2.7 per cent and colonic Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 101 perforation in 1 per cent of patients, compared with a Western incidence of 1.6 per cent and 3.2 per cent respectively[l 1]. Colonic stricture was found in 3.2 per cent of patients in the present series, which is comparable with other reports from India[5] and much less than the 6.3-11.2 per cent reported from the Westfll], Carcinoma of the colon was detected in only one patient (0.5 per cent). Other Indian studies have not commented on this important complication [2,5], except one report from our centre where carcinoma of the colon was found in 2.9 per cent. In the West, the incidence of carcinoma of the colon has been variably reported from 0.5 per cent to 30 per cent[18,19], Sigmoidoscopic appearances were suggestive of grade I changes in 15 per cent, grade II in 59 per cent and grade III in 20 per cent, and showed normal mucosa or distal proctitis in 6 per cent of the patients. This is in agreement with some of the earlier Indian studies[2,3]. On the whole, sigmoidoscopic changes in the majority of Indian patients are milder as compared with changes seen in Western patients. A rough correlation between the clini- cal severity of the disease and the sigmoidoscopic findings was seen in mild and moderate disease; however, this was not true for severe colitis. Of patients with severe colitis, 57 per cent had only grade II changes on sigmoidoscopy. Moreover, it is worth remembering that normal sigmoidoscopic findings can occasionally be seen in patients with ulcerative colitis[20]. Barium enema studies showed the disease to be limited to the left half of the colon in 75 (60 per cent) of the 126 patients in whom this examination was carried out. Similar observations have been reported in earlier Indian studies[2-5]. This is a much higher rate than that report- ed in the West. On the other hand, total colonic involve- ment was seen in only 17 per cent of patients in the present series, compared to 34 per cent in the West[10], In brief, ulcerative colitis is not an uncommon disease in India. A high index of suspicion will obviate delay in diagnosis. Slight male predominance, younger age, lower incidence of systemic and local complications, rarity of carcinoma, milder sigmoidoscopic changes and localised left-sided involvement of the colon are some of the distinguishing features of patients with ulcerative colitis in India as compared with the West. References 1. Farmer, R. G. (1980) in Clinics in Gastroenterology, Vol. 9, p. 229. New York: Saunders. 2. Maroo, M. K., Nag, N. K., Sortur, S. V. and Patil, R. S. (1974) Journal of the Indian Medical Association, 63, 350. 3. Tandon, B. N., Mathur, A. K., Mohapatra, L. N., Tandon, H. D. and Wig, K. L. (1965) Gut, 6, 448. 4. Chuttani, H. K., Nigam, S. P., Sama, S. K., Dhanda, P. C. and Gupta, P. S. (1967) British Medical Journal, 4, 204. 5. Pimparkar, B. D. (1973)Journal ofthe Indian Medical Association, 61, 217. 6. Vakil, B. J. and Mehta, A. J. (1967) Journal of the Association of Physicians of India, 15, 460. 7. Mehta, S. K. (1981) in Progress in Clinical Medicine in India, Series 4, pp. 275-300. (ed M. M. S. Ahuja.) New Delhi: Arnold Heine- man. 8. Bacon, H. E. (1958) Ulcerative colitis. Philadelphia: Lippincott. 9. Truelove, S. C. and Witts, L. J. (1955) British Medical Journal, 2, 1041. 10. Edwards, F. C. and Truelove, S. C. (1963) Gut, 4, 299. 11. Mendeloff, A. I. (1980) in Clinics in Gastroenterology, Vol. 9, pp. 259-70. New York: Saunders. 12. Goligher, J. C., de Dombal, F. T., Graham, R. G. and Watkin- son, G. (1967) British Medical Journal, 2, 193. 13. Greenstein, A., Janowitz, H. and Sachar, D. (1976) Medicine, 55, 401. 14. Wright, R., Lumsden, K., Luntz, M. H. et al. (1965) Quarterly Journal of Medicine, 34, 229. 15. Johnson, M. L. and Wilson, T. H. (1969) Gut, 10, 255. 16. Sharma, M. P., Kar, P. and Malviya, A. N. (1982) Journal of the Association of Physicians of India, 30, 29. 17. Huizenga, K. A. (1980) in Inflammatory Bowel Disease, 2nd edn, pp. 202-16. (ed J. B. Kirsner and R. G. Shorter.) Philadelphia: Lea and Febiger. 18. Edwards, F. C. and Truelove, S. C. (1964) Gut, 5, 15. 19. Thayer, W. R. (1980) in Inflammatory Bowel Disease, pp. 265-78. (ed J. B. Kirsner and R. G. Shorter.) Philadelphia: Lea and Febiger. 20. Lennard-Jones, J. E., Morson, B. C., Ritchie, J. et al. (1977) Gastroenterology, 73, 1280. 102 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

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The Implications of Demographic Changes on Resource Allocation KEITH ANDREWS, MD, MRCP(UK), Senior Lecturer; Geriatric Medicine, University of Manchester, Clinical Science Building, Hope Hospital, Salford J. C. BROCKLEHURST, MD, FRCP, Professor of Geriatric Medicine, University of Manchester, Withington Hospital, Nell Lane, Manchester Much publicity is given to the provision of a health service relevant to the ageing population. Terms, such as the 'rising tide', express the concern that many feel about the problems of coping with an increase in very old people with complex or chronic disabilities. In spite of this, the DHSS has suggested to the chairmen of Regional Health Authorities that the recommended norm for the number of geriatric beds be decreased from the long-accepted 10 beds to 8.5 beds per 1,000 population 65 years and over. One of the arguments for this seems to be that the projected populationfl ,2] of those aged 65 years and over will not change significantly over the next 20 years (Table 1). Within this group there are, however, very large disproportionate increases of those 75-84 and those 85 years and over. It could be argued that, since there is no change in the total number of elderly people, there will be no alteration in bed requirements. In view of this we felt that it was important to examine how the projected age- sex demographic changes are likely to influence geriatric unit management during the next few years. Method We visited 36 (13 per cent) of the 268 geriatric units in Great Britain, selected to represent different styles of practice (e.g. mixed flow, progressive care and age related patterns), in industrial, urban, rural, retirement Table 1. Projected population changes 1981-2006. Year Population (thousands) 1981 1986 1996 2006 Males 65-74 2160 2075 (-3.9%) 2082 (- 3.6%) 2000 (- 7.4%) 75-84 866 951 ( + 9.8%)' 941 ( + 8.7%) 956 (+ 10.4%) >85 129 140 ( + 8.5%) 177 ( + 37.2%) 180 ( + 39.5%) Total 3155 3166 ( + 0.3%) 3200 ( + 1.4%) 3136 ( -0.6%) Females 65-74 2775 2717 (- 2.1%) 2628 (-5.3%) 2392 (- 13.8%) 75-84 1634 1785 ( + 9.2%) 1759 ( + 7.1%) 1725 ( + 5.6%) >85 422 460 ( + 9.0%) 548 ( + 29.9%) 559 ( + 32.5%) Total 4831 4962 ( + 2.7%) 4926 ( + 2.0%) 4676 (-3.2%) All 7986 8128 (+ 1.8%) 8126 (+ 1.8%) 7812 (-2.2%) and academic settings throughout the country. Infor- mation was obtained from the case notes of a one-in-five sample of patients in these units (2,152 patients altogether) concerning their length of stay for the present admission as well as noting the age and sex of the patient. Results Table 2 shows that the age structure of patients in these units, as a proportion of those 65 years and over, did not follow their distribution in the general population. Fig- ures for the population structure were not available for the study areas and it has been assumed that they follow the national pattern. Although men over 85 years are only 4 per cent of the male population aged 65 years and over, they occupied 19 per cent of male geriatric beds. Similar- ly, females over the age of 85 years, being 9 per cent of the elderly female population, occupied 33 per cent of female geriatric beds. In addition, although the number of bed days per patient does not change much for the male groups, there is an increase with advancing age for females. This is further seen in that whereas 50 per cent of all the beds occupied by patients 65-74 years were used by males, this fell to 19 per cent occupied by males in the 85 years and over age group. The proportion of the bed- days occupied in each age group was lower for the males than the actual proportion of beds they occupied (Table Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 109 Table 2. Age and sex distribution of patients over the age of 65 years in 36 geriatric units. Age 65-74 75-84 >85 All Males (646)? in hospital group 31% 50% 19% 100% in the population 68% 27% 4% 100% bed-days occupied by males 35% 47% 18% 100% Mean days/patient in hospital 306.7 257.5 260.8 285.2 Females (1,391)? in hospital group 14% 53% 33% 100% in the population 57% 34% 9% 100% Bed-days occupied by females 12% 47% 40% 100% Mean days/patient in hospital 361.5 376.8 511.1 426.3 Males/females in each age group in hospital 50% 30% 19% 31% Bed-days in each age group occupied by males 46% 23% 11% 24% 2), further indicating the excessive length of stay of the females. This will be relevant in the presence of differen- tial expected demographic changes for males and females. One further point was that 5 per cent of the geriatric unit beds were occupied by patients under the age of 65 years?with an average length of stay of 686 days. The effect of these demographic changes on future bed requirements may be demonstrated by calculating, from present occupancy and the projected population changes, the number of bed-days for each age-sex group over the next 20 years (Table 3). The decrease in the number of bed-days occupied by people of 65 to 74 years of age is more than compensated for by a striking increase in the bed-days required by those 75 years and over. Based on Table 3. Projected patient bed-days for 36 geriatric units throughout Great Britain. 1981 Bed-days for year: 1986 1996 2006 Males 65-74 75-84 >85 Total 61342 82947 32351 176640 % change from 1981 Females 65-74 75-84 >85 Total 71944 277750 236609 586303 % change from 1981 All 762943 % change from 1981 58950 91076 35101 185127 + 5% 70433 303303 257904 631640 + 7.7% 816767 + 7.1% 59134 90163 44386 193683 + 9.7% 68131 297470 307355 672956 + 14.8% 866639 + 13.6% 56803 91573 45130 193506 + 9.6% 62016 293304 313507 668827 + 14.1% 862333 + 13.0% Table 4. Average length of stay on different types of ward Average days in hospital on wards: Acute Rehabilitation Long-stay Male 31.1 71.9 630.6 Female 34.4 120.2 807.8 Total 33.3 103.5 760.0 these figures 13-14 per cent more bed-days will be required over the next 15-20 years to maintain present standards. Table 4 shows that where the type of ward could be identified in the 36 hospitals, the length of stay was about one month in acute wards, three months in rehabilitation wards and two years in long-stay wards. The age and sex distribution differs for each type of ward. Projecting these figures (Table 5), males will Table 5. Projected change in bed-days required from 1981- 2006 related to the type of geriatric ward. % increase in bed-days from 1981 for year: 1986 1996 2006 Acute ward Male Female All Rehabilitation ward Male Female All Long-stay ward Male Female All 7.1 6.6 6.7 6.6 5.9 6.0 3.6 7.9 7.0 12.0 8.0 9.2 13.4 12.2 12.4 8.1 16.6 14.9 12.9 5.5 7.8 14.1 10.2 10.9 7.5 16.3 14.5 require more acute and rehabilitation facilities, while females will need more long-stay facilities. Overall, the increase required will be 9 per cent for acute, 12 per cent for rehabilitation and 15 per cent for long-stay facilities in the next 15 years. Discussion The future demographic trends show no change in the total number of elderly people in the population over the next 20 years. However, within these figures the 65-74 age group will decrease in numbers but this decrease will be balanced by an increase in the 75 years and over population. If the elderly were a homogeneous group this would not influence future planning in the Health Ser- vice. However, those over 85 years are more likely to be in hospital than those of 65-69 years[3] and the age- specific admission rate increases with age[4]. This study shows that, with present patterns of care, the 36 units visited will require 14 per cent more beds in 15 years' time?with a greater increase in the bed requirements for the females than the males. This is very 110 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 similar to the figure estimated by Clarke for Leicester- shire^]. However, these figures assume that there will be no change in patterns of care. The political solution[6] is that more patients will be treated in the 'community'. The attraction of this policy is that transferring long-stay patients to the community may compensate for the demographic changes, as one long-stay bed is the equiv- alent of treating 24 acute patients or 8 rehabilitation patients (Table 4). Unfortunately, the evidence is that Social Service residential places[7], meals-on-wheels[8] and home help[9] services are already falling far behind the demographic trends. There is already concern[10] that many elderly people do not receive satisfactory support in the community. Residential homes are now caring for heavily dependent individuals and require a considerable increase in resources to maintain present service levels[ll]. It is, therefore, unlikely that there will be a significant shift from the hospital long-stay services to Social Service care. Private rest and nursing homes are contributing to long-term support, though there is concern[12,13] about the control of standards of care and the tendency to accept the less disabled at the expense of those most in need. How significant a role these homes will continue to play will depend largely on political encouragement and Social Security funding. Even if they are to play a significant role the figures from this study show that, to cope with the present long-stay bed requirements, the equivalent of 15 per cent of the long-stay beds in geriatric units will have to be available in the 'community'. As the increased need for rehabilitation and acute services can only be met by a further decrease in long-stay beds, this figure will have to be much larger than 15 per cent. There is certainly evidence that an increased turnover can be achieved by more efficient use of beds[14] and by better discharge planning[15,16]. This, of course, de- pends on patients being reasonably fit for discharge. Unfortunately, the major cause of long-stay care is dementia; social and physical disability play a relatively small rolef 17,18], A poor mental state is badly tolerated by families[19] and extremely difficult to cope with in the community. Support of heavily disabled individuals in their own homes depends on very large increases in district nursing and Social Service resources. As 0pit[20] has shown, the cost of community support of the heavily disabled person is probably as expensive as institutional care, while the quality of care decreases as the amount of support required increases. These problems of demographic change are not only applicable to geriatric and psychogeriatric units. The length of stay in medical, surgical and orthopaedic units is also increased in the elderly[21-23]. In 1977 one-fifth of medical and surgical beds were occupied by people 75 years and over[24]. In addition, blockage at any point in the hospital system inevitably results in pressure on other services and this applies especially to geriatric units, which have a high transfer rate from other departments. Figures presented here indicate that, taking demo- graphic changes into account, a norm of 8.5 geriatric beds per 1,000 population of 65 years and over will be the equivalent of 7.3 beds by 1996. We suggest that the planning of future services must take into account the differential requirements of the age-sex distribution of the elderly population for different periods throughout the next 20 years. Acknowledgements We wish to thank the King Edward's Hospital Fund for London for their generous financial support and our colleagues in the geriatric units visited for their time and help. References 1. OPCS (1983) Census 1981. National Report, Part 1, London: HMSO. 2. OPCS (1975) Population Projections No. 5. London: HMSO. 3. Downie, B. N. (1972) The elderly in Scottish Hospitals 1961-1966. Scottish Health Services Studies No. 21. Scottish Home and Health Department. 4. Evans, G. J., Hodkinson, H. M. and Mezey, A. G. (1971) Lancet, 2, 539. 5. Clarke, M. (1984) Journal of the Royal College of Physicians of London, 18, 128. 6. Department of Health and Social Security (1981) Care in the Community. London: DHSS. 7. Grundy, E. and Arie, T. (1982) British Medical Journal, 284, 799. 8. Department of Health and Social Security (1979, 1981) Personal Social Services Local Authority Statistics: Meals Services. A/F79/2, A/F81/ 2. London: DHSS. 9. Department of Health and Social Security (1979, 1981) Personal Social Services Local Authority Statistics. Staff of Local Authority Social Service Departments. S/F79/1, S/F81/1. London: DHSS. 10. Hunt, A. (1979) Health Trends, 11, 21. 11. Clarke, M., Hughes, A. O., Dodd, K.J. etal. (1979) Health Trends, 11, 17. 12. Godber, C. (1984) British Medical Journal, 288, 1473. 13. Andrews, K. (1984) ibid., p. 1518. 14. O'Brien, T. D., Joshi, D. M. and Warren, E. W. (1973) British Medical Journal, 4, 277. 15. Cable, E. P. and Meyers, S. P. Jr. (1983) Archives of Physical Medicine and Rehabilitation, 64, 57. 16. Shrager, J., Halman, M. and Myers, D. (1978) Social Work Health Care, 4, 65. 17. Rainey, C. G. E., Russell, W. F. and Silver, C. P. Age and Ageing, 4, 247. 18. Rosin, A. J. (1970) Gerontologia Clinica, 12, 40. 19. Sanford, J. R. A. (1975) British Medical Journal, 3, 471. 20. Opit, L. J. (1977) British Medical Journal, 1, 30. 21. Seymour, D. G. and Pringle, R. (1982) British Medical Journal, 284, 1921. 22. Rubin, S. G. and Davies, G. H. (1975) Age and Ageing, 4, 142. 23. Medical Manpower Steering Group (1980) Developments in health services for the elderly?implications for medical manpower. London: HMSO. 24. Office of Population Censuses and Surveys for Government Actu- ary's Department (1977) Hospital In-Patient Enquiry, London: DHSS. Journal of ihe Royal College of Physicians of London Vol. 19 No. 2 April 1985

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Oral Anticoagulants: a Cost-Effectiveness Approach / E. J. STAMF! B Med Sci, Medical Student S. J. JONES, M Phil, Research Assistant Department of Community Health, University Hospital and Medical School, Nottingham D. R. RYRIE, MB, FRCPEd, FRCPath, Senior Lecturer and Consultant Haematologist, Department of Haematology, City Hospital, Nottingham A. J. HEDLEX MD, FRCPEd, FFCM, Professor of Public Health, Ruchill Hospital, Glasgow Oral anticoagulants have been adopted for general use in venous thromboembolic and arterial thrombotic diseases [1-3], The aim of treatment is to achieve a stable reduced blood coagulability within a desired therapeutic range. This is maintained by regular standardised laboratory testing of the patient's blood at appropriate intervals. In this study a conventional method of achieving anticoagulant control was compared with two alternatives using a cost-effectiveness technique. Cost-effectiveness studies demand (a) definition of the objective of treatment or programme being studied; (b) definition of the various options for available management; (c) a measure of outcome which is valid and applicable to all the options, and (d) an estimation of all the costs involved [4], The Options for Treatment Option 1: This was the conventional system in operation at the hospital in which patients attend a clinic approxi- mately every four to six weeks for adjustment of their dose of anticoagulants. Changes in treatment are recorded on a patient-held card and clinic record; no direct contact is usually made with the GP except at the onset and cessation of treatment. Option 2: This alternative is in operation in two general practices in Nottingham. Patients attend their local sur- gery for venepuncture. Blood is then sent to the hospital laboratory for testing and adjustment of dose; patients obtain the results by telephoning the surgery the same day. Option 3: This was a theoretical model based on the Dutch Thrombosis Service [5]. A nurse would visit the patients in their home, collect a blood sample by vene- puncture and take it to the hospital laboratory for testing and assessment of drug dose. Patients and GPs would be informed of the results and recommended dose by post the next day. The aims of this study were to calculate and compare the total cost for each system; to measure the level of effectiveness for the two 'operational' alternatives (op- tions 1 and 2) and determine if this was affected by the 'decentralisation' of treatment control; and to assess the acceptability of the three alternatives to patients and their GPs. The measure of effectiveness used was the proportion of 'Thrombotest' [6] results within the therapeutic ranges of 5-10 per cent and 5-14 per cent. This was found for all tests performed over the past year; for patients treated for less than a year the value was found for the period of time they had been on treatment. It was assumed that the effectiveness of the theoretical model (option 3) would be the same as that found in the conventional clinic system (E. A. Loeliger, personal communication). Patients and Methods Clinic Patients Clinics are held twice weekly, with an average of 63 patients attending each clinic. A l-in-3 systematic sample of patients attending 12 consecutive clinics was selected. This comprised 236 of the total of 419 patients currently attending for anticoagulant treatment. The sample was similar to the total clinic population in age (mean = 56 years) and sex (M:F = 1:1.3) distribution. Practice Patients All 24 patients being anticoagulated at one urban general practice were included in a detailed study. The mean age was 57 years and the male/female ratio was 1.4:1. The records of a further 23 patients at a second practice were Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 105 available for measurement of effectiveness of anticoagu- lant control. Information Collection Information was extracted from medical records about dose of anticoagulants, level of control, frequency of checks and reason for treatment. For patients attending the hospital and general practice clinics a self-adminis- tered questionnaire was used to obtain information about patient costs, knowledge of anticoagulant therapy and other treatments, patient attitudes and their preferred choice for monitoring anticoagulant control. Twenty substitutions were made at the clinic for patients who did not wish to complete the questionnaire (6 due to illness, 9 due to poor sight and 5 refusals). Non- attenders, from the original sample, were sent a question- naire and all of these were returned. In the health centre, 22 out of 24 (92 per cent) patients completed the question- naire. A random sample of the GPs of clinic patients was sent a questionnaire to assess their attitudes, choice of system and reason for their choice. Costs The total average cost for a patient visit was calculated for each option, including costs incurred by both the NHS and patient. The directly attributable NHS costs included were pharmaceutical costs, equipment and tests, staff and administration costs and ambulance costs. These were obtained from published sources and relate to 1980 prices [7-9], Estimates were made of costs incurred by patients including consultation, waiting and travel time, costs of travel and any escort costs. Under the theoretical option, patients had no travel time cost but a waiting time of one hour was assumed which was comparable with that found in the hospital clinic (1.2 hours). In estimating patient time costs for the theoretical model, the employment status of the clinic patients was assumed to be similar to that of the general population. Results Effectiveness The mean proportion of tests in the range 5-10 per cent was 58 per cent for all clinic patients, and 59 per cent for the 47 patients in the GP-operated systems; the difference was not significant. If the acceptable therapeutic range was extended to 5-14 per cent there was an improvement of 20 per cent in the proportion of tests in the range for all patients (Table 1). These results are comparable with other recent studies of levels of control in anticoagulated patients [10-12]. Costs For the sample studied, the distributions of total cost, time cost and travel cost were negatively skewed with between 60 per cent and 81 per cent of values below the Table 1. Effectiveness of anticoagulant therapy in clinic and health centre setting as measured by Thrombotest. Mean proportion (%) of tests in Thrombotest range Category of patient 5-10% 5-14% Clinic 58 78 (n = 236) Health centres 59 84 (n = 47) mean. Patients in the high cost category tended to be those who were employed (high time cost) or who used the ambulance service (high travel cost). The NHS and patient costs are itemised in Table 2, the mean total cost is analysed in Table 3. Table 2. NHS costs Hospital Clinic ? Treatment 0.22 Staff and Administration 0.72 Ambulance* 3.62 Total 4.56 *28% of patients travel by ambulance at ?1.00 per mile Average return trip is 13.5 miles. Domiciliary-based system Treatment 0.27 Staff and Administration 2.04 Nurse Travel 3.14 Total 5.45 Health Centre Treatment 0.27 Staff and Administration 1.12 Total 1.39 Table 3. Mean total cost per attendance by occupation and method of travel for patients using different types of care. Option 2 Option 3 Option 1 (Health (Domiciliary (Clinic) centres) visit) Patient category (n = 236) (n = 47) (n = 236) ? ? ? All 11.43 3.89 6.75 Occupation: Employed 13.55 5.68 8.59 Other 10.87 2.46 5.73 Method of travel to clinic or health centre: Walk 4.82 2.53 5.82 Bus 6.61 3.19 5.94 Car 11.09 4.54 6.78 Ambulance 16.05 ? 7.34 Option 1. Of clinic attenders, 25 per cent were employed and their mean time cost was ?7.97 compared with ?1.92 106 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 for those not in employment. Patient mean time costs were ?3.44. The 28 per cent of patients who required an ambulance had a mean travel cost of ?12.94 compared with ?4.52 for car users and ?1.76 for bus users. The mean ambulance cost (NHS cost) per attendance was ?3.62 and patient mean travel costs were ?2.46. The mean NHS cost per attendance for drugs, tests, staff and administration was ?0.94, so total NHS costs per attend- ance were ?4.56. Mean total patient costs, including escort costs of ?0.97, were ?6.87. Therefore, the mean total cost per attendance was ?11.43. Option 2. No patients used an ambulance to attend the health centre and the mean patient travel cost of ?0.72 was low because no patient travelled more than three miles. Seven patients (29 per cent) were employed, with a mean total cost of ?5.68, compared with ?2.22 for those not employed. NHS costs, based on an average of 10 tests performed each week, amounted to ?1.39. Thus the mean total cost per patient visit was ?3.89 which was cheaper than either of the other two systems. Option 3. NHS costs for the theoretical model, calculated for an average clinic of 63 patients, were ?5.45 (?0.90 drug treatment, administration and staff costs, ?1.41 nurse wages, ?3.14 nurse travel costs). The distribution of costs was affected by a few high values for those patients living farther from the hospital. The decrease in patient time, escort costs and use of the ambulance service, led to a reduction in mean total cost (?6.75) of 40 per cent compared with the clinic system (t = 23.39; degrees of freedom = 235; P<0.001). Discussion As in many economic studies of health care the costs used are the best available estimates and as such are only indicative of the absolute and relative costs. Nevertheless, the results show that for some patients the management of anticoagulant treatment could be carried out in the community with no decrease in the standard of control but with considerable savings to both the NHS and patients. Although the number of patients studied in the health centre was small, other comparisons of hospital care and community care have also found the latter to be cheaper and more convenient for patients [13-16]. In this study the assumption was made that no alter- ation in the level of control would occur in the theoretical model although in the Leiden Thrombosis Service 83 per cent of all Thrombotests were within the range 5-10 per cent compared with 58 per cent in this study (E. A. Loeliger, personal communication). This may be import- ant in taking decisions to implement other systems al- though other factors may be involved such as the age structure of the population, reasons for anticoagulation, therapeutic regimen and dosage schedule. Certainly de- centralisation of care in Leiden has not resulted in a decrease in standard of control. This study clearly shows that, from the NHS view- point, high cost patients are those requiring ambulance transport. With 28 per cent of patients using an ambu- lance the mean NHS cost for a clinic attendance is ?4.56 compared with ?5.45 for the theoretical model using a nurse. However, if 35 per cent or more of patients require an ambulance the theoretical model becomes cheaper. At the same time patient costs are ?6.87 for clinic atten- dances and ?1.30 for domiciliary visits by the nurse. Table 3 classifies patients by employment status and their mode of travel to the hospital clinic or health centre and shows the difference in mean total costs for each group for the various options. The actual costs for clinic and health centre attenders are shown along with the projected mean costs for the 236 current clinic attenders if they were transferred to the domiciliary visiting scheme. Cost-effectiveness ratios, comprising the cost of a single clinic visit and the proportion (%) of patients in the Thrombotest range 5-10 per cent, were ?11.43/58 per cent for the hospital clinic, ?3.89/59 per cent for the health centre and ?6.75/58 per cent for the domiciliary- based service. Acceptability Seventy per cent of the 236 patients put the clinic as their first choice; 17 per cent (of whom 45 per cent were employed) chose the GP system, and 32 per cent (of whom over 60 per cent were aged over 60) chose the theoretical domiciliary system. Nearly two-thirds found attendance at the clinic 'inconvenient but necessary'. A total of 63 (76 per cent) out of 83 GPs returned question- naires after two reminders. More than half (57 per cent) of these GPs did not know how many of their patients were undergoing anticoagulant treatment. Ten (16 per cent) preferred the GP-centred model, 14 (22 per cent) the theoretical model and 39 (62 per cent) put the clinic system first. Reasons given against the alternatives to the present clinic system were lack of facilities (21 per cent); too complicated (19 per cent); risk of error in communi- cating results (19 per cent) and extra work for the GP (16 per cent). The reasons given in favour of the alternative chosen included more convenience for patients (19 per cent), more GP involvement (14 per cent) and more economical use of resources (16 per cent). Perhaps more importantly, if the theoretical model were to be implemented, the nurse would not return to the hospital between each patient-visit (which was as- sumed here as the most convenient way to calculate and compare costs), thus reducing the cost still further to the NHS. It should be borne in mind that the costs quoted in this study are average costs. Consideration of the implemen- tation of any particular model of care would concentrate on the marginal costs. For example, there will be a miminum number of patients that would make the em- ployment of a specialist nurse worthwhile. Once that number is achieved the marginal cost of each extra patient will be relatively low until the point at which another nurse needs to be recruited, who may then have spare capacity. However, if resources, such as nurses, can be reallocated as required, marginal costs may be close to average costs. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 The major component of patient costs was time costs for employed patients. The reduction in total costs of care, if such patients were seen outside the hospital clinic setting, would be high. Since all the employed were assumed to use work time, if the change from hospital clinic to general practice clinic meant a change to use of leisure time, then patient costs would be further reduced as leisure time is generally assumed to be worth less. Implementation of the two alternative options would decrease the burden on crowded out-patient clinics and release resources in an over-burdened ambulance service. Although it is unnecessary, at present, for all patients to be transferred to alternative forms of care, nearly 40 per cent of general practitioners appear willing to adopt these methods of working and patients already provided with such facilities do not wish to change. The best practical solution would probably be to offer a mixture of options, with interested general practitioners taking over care of their patients, particularly those in employment, while a nurse could care predominantly for those who require an ambulance. In this way, maximum savings in the provision of anticoagulant control services could be made by making the most efficient use of available resources. Acknowledgements This work is based on a B.Med.Sci. dissertation by E.J.S. in the Department of Community Health, University of Nottingham. We thank Professor Gavin Mooney and Mr John Henderson, Health Economic Research Unit, Depart- ment of Community Medicine, University of Aberdeen, for helpful advice, and the hospital clinic staff and Doctors Alan Murphy and John Skinner and their gen- eral practitioner colleagues for support and collaboration. References 1. Owen, C. A. (1974) Mayo Clinic Proceedings, 49, 912. 2. Prentice, C. R. M. (1976) Prefcribers Journal, 16, 116. 3. Taberner, D. A., Poller, L., Burslem, R. N. and Jones, J. B. (1978) British Medical Journal, 1, 272. 4. Fordyce, I. D., Mooney, G. H. and Russell, E. M. (1981) Health Bulletin, 39, 21. 1 5. Jordan, F. L.J. (1958) Thrombosis et diathesis haemorrhagica, 2, 527. 6. Owren, P. A. (1959) Lancet, 2, 754. . 7. Department of Health and Social Security (1981) Health Services costing returns 1978/1979. London: HMSO. 8. Department of Employment (1981) New earnings survey. London: HMSO. 9. Automobile Association (1982) Yearly statistics on car running costs. London: Automobile Association. 10. Harries, A. D., Birtwell, A.J. and Jones, D. B. (1981) Lancet, 1, 1320. 11. Mclnnes, G. T. (1981) Lancet, 2, 88. 12. Duxbury, B. McD. (1982) British Medical Journal, 1,702. 13. Lester, J. P. (1980) Journal of the Royal College of General Practitioners, 30, 230. 14. Mooney, G. A. (1978) Scottish Journal of Political Economy, 25, 149. 15. Gallow, R. J. (1979) Journal of the Royal College of General Prac- titioners, 29, 478. 16. Jones, S. J., Hedley, A. J., Curtis, B. et al (1982) Lancet, 1, 1229. 108 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

PMC005xxxxxx/PMC5371009.txt

j The Thyroid and Osier SIR RAYMOND HOFFENBERG, KBE, MD, PRCP, William Withering Professor of Medicine, University of Birmingham Medical School, Birmingham Osier made no major contribution to the study of the thyroid but he was at the peak of his career at the most exciting time of thyroid, indeed endocrine, conceptual development and he was characteristically quick off the mark in recognising the importance of contemporary work and in adding his own observations to the burgeon- ing literature of the time. The scene has to be set roughly 150 years ago. In 1835 Robert Graves[l] described the condition of hyperthyroi- dism which still bears his name, despite the fact that, as with so many diseases, Parry's description had preceded his by 10 years. Caleb Hillier Parry[2] was of Welsh descent, the name being derived from ap Harry, and incidentally a lifelong friend of Edward Jenner with whom he was at school in Cirencester. Both were mem- bers of the Gloucestershire Medical Society which met in the parlour of the Fleece Inn, Rodborough, and became known as the Fleece Medical Society. It was before this society in July 1788 that Parry presented his famous paper entitled 'An Inquiry into the Symptoms and Causes of the Syncope Anginosa, commonly called An- gina Pectoris' in which he clearly stated the coronary origin of the symptom. He failed to publish his observa- tions until 11 years later (1799), a delay that also characterised his publication on exophthalmic goitre, for he had seen his first case in 1786 and correctly recognised it to be a new and distinct syndrome; publication did not take place until 1825, three years after his death, but still well in advance of Graves' description of the disease. The first edition of Osier's textbook of 1892 discusses exoph- thalmic goitre under the eponyms of Graves and von Basedow, whose description followed in 1840. The third edition of 1898 refers to it as Parry's disease and contains a defence of Parry's right to the eponym. Both Parry and Graves recognised the important triad of the disease?exophthalmos, palpitations and goitre? but they failed completely to appreciate the role of the thyroid in its genesis. The goitre was regarded as a swelling or diverticulum designed to siphon off the superfluous blood in the circulation, thereby preventing a serious flooding of the brain. Graves, in fact, referred to the thyroid as 'analogous to those tissues properly called erectile'. At the time there was no comprehension of the role of endocrine glands as organs which secreted materi- als into the circulation and certainly not of disease which might follow excessive secretion. The fact that these organs were known to be ductless must have contributed to this lack of comprehension. I should like to review how the light gradually dawned. The story is sometimes said to have started with John Hunter, but his experiments on transplantation of a cock's testis appear to have been carried out as experi- ments in transplantation rather than studies of the or- gan's function and there is nothing to suggest that he comprehended their endocrine significance. Arnold Adolf Berthold published in 1849 the results of similar experi- i ments[3] in which he removed the testes from four young cocks, transplanted them to another site in two of the birds, keeping two as controls in the best scientific mode. He showed that the cock's comb developed normally in the transplanted birds but did not do so in the non- transplanted pair. To us, today, it would seem incompre- hensible in the face of this evidence that the role of the testes as secreting organs was not immediately under- stood. Yet Berthold did not directly express this opinion. Indeed, he favoured the view that they functioned by extracting matter from the bloodstream. In the same year (1849) Addison[4], somewhat imper- fectly, described the features of the hypoadrenal state that now bears his name. In 1855 he produced a more accurate, less confused and still pertinent clinical descrip- tion of the consequences of adrenal failure[5]. He, too, failed to appreciate the significance of his findings al- though he recognised that destruction of the adrenal glands constituted an integral part of the disease. Brown- Sequard, the eminent neurophysiologist, followed up Addison's report with a superb set of experiments, analo- gous to those of Berthold, in which he showed that removal of the adrenal glands was followed by severe disease and death, and that this could be prevented by transplantation of the adrenals to another site[6]. Both he and Addison attributed to the adrenals a role in detoxify- ing substances which, in the absence of adrenal function, led to severe or fatal consequences. Brown-Sequard, of course, later achieved notoriety through his publication of 'The Pentacle of Rejuvenes- cence', in which he ascribed his own youthful exuberance at the age of 72 years to regular injections of testicular extract, a practice which rapidly became fashionable and may be seen as the beginning of the organotherapy movement. It was through the thyroid that a proper appreciation was gained of the role of endocrine glands and their secretions and Brown-Sequard's organotherapy was given more acceptable scientific support. The story really starts with the clinical descriptions of hypothyroidism. Cretinism was one of the earliest diseases ever to be delineated, and its endemic nature was fully appreciated 80 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 in the Middle Ages. But endemic cretinism had largely died out in Britain by 1850, the year in which Thomas Blizzard Curling read a paper before the Royal Medical and Chirurgical Society, with Thomas Addison in the chair, on 'Two Cases of Absence of the Thyroid Body and Symmetrical Swellings of Fat Tissue at the Sides of the Neck, connected with Defective Cerebral Develop- ment'^]. He noted the absence of the thyroid gland at postmortem examination and said: 'I am not acquainted with any case on record in which a deficiency of the thyroid gland has been observed in the human body.' Again, he and others might previously have been misled by the association of the cretinoid condition with goitrous enlargement, not absence of the thyroid gland. It would have required great perspicacity, indeed clairvoyance, to have appreciated at the time that an enlarged gland was functioning too little, not too much. In 1874 Sir William Gull[8] presented to the Clinical Society of London five cases of 'A cretinoid condition supervening in adult life in women', to which four years later Ord[9] applied the name 'myxoedema' in recognition of the characteristical- ly mucoid oedema shown by the patients. This led to separation of the well-known endemic cretinism with goitre from a sporadic disorder of similar clinical presen- tation but characterised by absence of the thyroid gland. Hilton Fagge could claim priority in clearly recognising this distinction in a paper he wrote in 1871 [10]. At about this time, through improvements in anaes- thesia and advances in aseptic technique, European surgeons were beginning to carry out thyroidectomy for large endemic goitres. The Reverdin cousins in 1883 noted the postoperative sequel of a myxoedematous syn- drome in many of their patients [11] and in the same year Theodor Kocher, the Swiss surgeon, presented the results of his operations to a Berlin conference; 30 of his first 100 thyroidectomised patients developed a similar syndrome, to which he gave the name cachexia thyroprival2]. Kocher attributed this syndrome to operative damage to the trachea with consequential disturbance of cerebral oxygenation. In the same year at a clinical presentation of a case of myxoedema to the London Clinical Society, Sir Felix Semon[13], aware of Kocher's publication, sugges- ted that his postoperative cachexia thyropriva, Curling's cretinism and Gull's adult myxoedema might all be related and he established a committee to investigate this. Ord was chairman of this committee and Victor Horsley, about whom more will be said, was a member. The famous report of the London Clinical Society in 1888[14] concluded that all three diseases were in fact related and due to deficiency of the thyroid gland. This was a stupendous conceptual advance?that a gland which was known not to possess a duct was able to secrete something into the circulation, and that this secretion was necessary for health. But, the committee concluded, there was no hope of cure; its recommended treatment included a warm room, a warm climate, tonics and so on. In 1890 Victor Horsley proposed transplantation of the thyroid gland from a sheep as a means of arresting the progress of myxoedema[15] but this idea was superseded by the far simpler solution of George Murray of Newcastle, a pupil of Horsley's, who in 1891 [ 15] reported the successful treatment of a patient by injection of an extract of sheep's thyroid. Brown-Sequard's organotherapy was on its way. Within a very short time it was appreciated that Graves' disease was the antithesis of sporadic myxoe- dema. In the latter the thyroid was usually absent; in Graves' it was enlarged. In myxoedema there was torpor, slow pulse, dry skin, coldness, etc.; in Graves' hyperacti- Fig. 1. Robert Graves. Fig. 2. C. H. Parry. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 vity, tachycardia, heat intolerance and sweating. And, most convincingly, over-enthusiastic treatment of myxoe- dema with thyroid extract was soon shown to reproduce the clinical picture of Graves' disease. It was then gener- ally accepted that the disease resulted from excessive secretion by the thyroid gland. Again, this was a remark- able conceptual breakthrough?the recognition that se- cretion from a gland was not only necessary for health but, if excessive, could lead to disease. Osier included a section on exophthalmic goitre in the first edition of The Principles and Practice of Medicine. He accepted that worry, fright and depressing emotions preceded the disease in some cases but admitted that its true nature was unexplained. He lent some support to the nervous hypothesis of its cause, originally propounded in 1860 by Trousseau, and discussed the possibility of sympathetic paralysis or 'affection of the medulla oblon- gata'. In retaining this view he lagged behind the growing acceptance that the thyroid gland was the primary seat of trouble. In the third edition of 1898 he cites Moebius and Greenfield who regarded Graves' disease as a primary thyroidal disturbance (hyperthyrea as opposed to the athyrea of myxoedema). Osier's reluctance to accept this view may have been influenced by statements such as those of the pathologist McCullum, who held that 'organs hypertrophy only to meet the needs of the body, not to insult it' [ 16]. Excluding chapters for textbooks, I have counted ten contributions by Osier, which are related to the thy- roid[ 16-25]; three of these are unsigned editorials in Medical Atezw[16-18]; there are a few case reports and clinical notes[ 19-23], and two substantive publications on sporadic cretinism in America, that of 1893 presented to the Association of American Physicians[24] and of 1897 to the Washington Congress of American Physicians and Surgeons[25], It is to the earliest of his unsigned editorials that I wish to turn. Headed 'The Thyroid Gland and Myxoedema' it refers to the work of Professor Victor Horsley, a man with whom Osier formed a close associ- ation, about whom he was later to contribute an obituary for the British Medical Journal, and of whose biography by Stephen Paget[26] he was to write a review from his bed during his last illness in 1919. Victor Horsley was a remarkable man, probably the best experimentalist of his time. He was, regrettably, a surgeon, but would have endeared himself to present-day Fellows of the Royal College of Physicians by the article he wrote for the Students' Medical Society in 1883 (the year he was admitted FRCS) 'on the evil effects of tobacco'. His later crusade against alcohol might have been less well received. The following year (1884) he was appointed Professor-Superintendent of the Brown Insti- tute which had been established in 1871 as a result of a legacy from Mr Thomas Brown of Dublin 'for investigat- ing, studying and, without charge beyond immediate expenses, endeavouring to cure maladies, distemper and injuries, any quadriped or birds useful to man may be found subject to'. The Brown Institute preceded the Lister and, at that time, there were no research depart- ments in our medical schools. It was thus an important new venture and, through a succession of distinguished investigator-superintendents (Burdon Sanderson, Green- field, Roy, Horsley, Sherrington, Rose Bradford and Brodie), it came to exert great influence and authority on British medicine. Horsley stayed there from 1884 to 1890 and pursued three lines of research?localisation of func- tion within the brain, protection against rabies, and the relation of myxoedema and cretinism to thyroid function. He was a member of the London Clinical Society's Committee on Myxoedema .and was asked by the Com- mittee to study the function of the thyroid gland by experiment. It was through these studies that he devel- oped the idea of treating myxoedema by thyroid gland transplantation that I referred to earlier; despite the success of injections of thyroid extract and later oral therapy for myxoedema, Horsley held on to his idea of transplantation for over 20 years. In his obituary[27] on Horsley, who died in 1916, Osier refers to a meeting that had taken place one summer evening in 1878 with 'two young students (of University College) whose bright eyes held the light of high promise'; one of these was Victor Horsley, whose 'upward path', Osier says he followed 'from afar with an affectionate interest'. In 1885 Osier came to London to give his Goulstonian Lectures and he visited Horsley at the Brown Institute. It is an analysis of Horsley's work as Osier must have seen it that is presented in the first of his unsigned editorials on the thyroid. In it he says?and this precedes the report of the London Clinical Society by three years?'it seems reasonable to attribute . . . cretinism, myxoede- ma . . . and cachexia strumipriva?to disturbance or ar- rest of the functions of this gland, and the possibility of the supervention of this state will make the operation of thyroidectomy almost unjustifiable'. Osier's dismissal of ?> thyroid surgery was, to say the least, a trifle hasty. Horsley and Osier met several times thereafter and remained excellent friends. In 1892 Osier attended the annual meeting of the British Medical Association in Nottingham. Horsley was then President of the Section of Pathology and with his pupil, Murray, provided what was generally regarded as the outstanding contribution of the meeting on 'The Pathology and Treatment of Myxoe- , dema' which included a report of the first four cases cured by the juice of thyroid glands. When Sir John Burdon Sanderson later approached Osier to come to Oxford, he mentioned in his letter, presumably in an attempt to influence Osier's decision, that Sir Victor Horsley would * approve. Osier, in his obituary on Horsley, equated his technical skill as a surgeon to the brilliant diagnostic skill of Gowers. The two men clearly shared great liking and respect for one another. Osier's two papers on sporadic cretinism in America contained characteristically clear clinical descriptions of the disease: 'The stunted stature, the semi-bestial aspect, the blubber lips, retrousse nose, sunken at the root, the wide-open mouth, the lolling tongue, the small eyes, half closed with swollen lids, the stolid, expressionless face, the squat figure, the muddy, dry skin, combine to make the picture of what has been well termed the "pariah of nature".' In the first paper he quotes extensively from Horsley, provides a detailed review of the history of 82 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 cretinism and criticises the confusion of cretinism with other forms of idiocy. He attempted a survey of both endemic and sporadic forms of the disease based on the literature, inquiries made of superintendents of asylums for the insane throughout the country, 'as well as of many friends'. He found 11 cases but on the basis of such a limited and selective survey wisely avoided any firm statistics about its prevalence in America. By 1897 he had collected 60 cases and reported on the results of treat- ment: 'not the magic wand of Prospero, or the brave kiss of the daughter of Hippocrates ever effected such a change as that which we are now enabled to make in these unfortunate victims, doomed heretofore to live in hope- less imbecility, an unspeakable affliction to their parents and to their relatives'. How excited he would have been by the modern approach to the diagnosis of cretinism by neonatal screening and measurement of TSH on the Guthrie filter paper strips used for the detection of phenylketonuria. Neonatal hypothyroidism affects about one in 3,500 births and, it seems, this 'unspeakable affliction' may now be prevented by early detection and treatment. Two of his case reports are of interest. The first[20] concerns an acute myxoedematous condition with goitre affecting a 23-year-old man possibly, in retrospect, a case of autoimmune thyroiditis of rather rapid onset and short duration: the history of 3^ months and lack of mention of thyroidal tenderness make a viral subacute thyroiditis less likely. Osier treated this myxoedematous patient with ergot but wisely refrains from commitment about its efficacy. Followers of Osier might have been a little confused in that year because the concurrent first edition of his textbook offers ergot as a treatment for exophthal- mic goitre. The second report[23] is entitled 'An acute myxoede- matous condition, with tachycardia, glycosuria, melaena, mania and death'. He starts this report by referring to the patient of his first report who, he now says, had 'for a period of five or six months a myxoedematous condition of the hands and face, which disappeared completely'. Not a word about ergot. The subject of the second report was a 31-year-old male who six months earlier had rapidly increased in size, to the extent that he had to get 'a completely new outfit of underclothes and outer garments'. His weight went up from 145 to 182 pounds in four months. 'Everyone remarked on the extraordinary increase in his size, and a personal friend asked him if he had been drinking as he looked so bloated'. There was a stage when he got 'queer in his head' and developed delusions, some paranoid. His face became almost purple. When Osier saw him he noted large supraclavicular pads but could not feel the thyroid. The abdomen was large and full and 'the skin presented in concentric lines on either side on the flanks and in the iliac regions the most extraordinary atrophic lineae, six on either side'. The largest 'was fully three-fourths of an inch in breadth at its widest part'. 'All were curved and presented a purplish red colour'. Osier does say 'while he was bloated and puffy, the general appearance was not at all that of a case of myxoedema'. And, of course, Osier was right, for the combination of rapidly increasing truncal obesity, supraclavicular fat pads, a swollen purple face, purplish-red abdominal striae, mania and (as later described) severe muscular weakness and glycosuria makes the diagnosis of Cushing's Syndrome ineluctable. Did Harvey Cushing, his pupil and later biographer, know of Osier's early recognition of his syndrome, more than 30 years before his classical report? We all know of Osier's great gift of firing the enthusi- asm and imagination of colleagues and students. He influenced many physicians, some of whom were later to become eminent endocrinologists?Harvey Cushing, William S. Halsted, James H. Means. David Marine was another of these[28]. He entered Johns Hopkins Medical School in 1900 to study zoology and chemistry, and the Hospital in 1901 as a medical student. Here he fell under Osier's spell. Dr Josip Matovinovic, of Ann Arbor, writes that David Marine confided to him that he was influenced by Osier's brilliant education, general and professional, his kindness and his dignity[29]. Osier suggested to Marine that he should institute a study of pregnant women and treat them with iodine or dessicated thyroid. This early interest in the thyroid burgeoned when Marine was appointed to Cleve- land, a famous epicentre of endemic goitre. Writing about this to Matovinovic in 1968, Marine, then 88 years old, described how on the morning he arrived in Cleve- land from Baltimore, walking from his hotel to the hospital he saw many dogs with swollen necks; he stopped three or four of them and found that the swelling was due to enlargement of the thyroid gland. This decided him to follow up the early interest in goitre induced by Osier's influence, and to make this his major research. Iodine treatment of goitre had long been practised in Europe (Switzerland, Germany, France) but had fallen into disrepute because of the high incidence of iodism and, especially, of hyperthyroidism due to excessive iodine intake (Jod Basedow). Marine spent six months in 1913- 14 with Theodor Kocher who strongly opposed the use of iodine in goitre therapy and whose prestige at that time was such that the practice was all but abandoned. Despite this Marine remained convinced as a result of his own experiments that endemic goitre was due to absolute iodine deficiency. Marine initiated the first proper goitre prevention trial in Akron, Ohio, from 1917 to 1920, and showed conclu- sively that iodine was able to prevent endemic goitre and, indeed, cure many of those that had already developed. By using small doses of iodine he minimised the incidence of iodism and obviated the hazard of hyperthyroidism. It has been estimated that 200 million people throughout the world currently suffer from endemic goitre, often with cretinism or the neurological syndrome of iodine de- ficiency. Through the use of injections of slowly-released organic iodide-containing oils much of this is now being prevented, a benefit we can attribute directly to David Marine, in whose early work we may discern the guiding hand of Osier. In his writings on the thyroid, Osier showed all of his familiar characteristics. He was quick to spot the import- ance of research that was going on in the field, especially in Horsley's laboratory; he was able to place it in its Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 historical perspective and to discern the connection with cretinism, his clinical descriptions of which could not be bettered today; he spoke and wrote about it only after his own reading, observation and surveys had provided a sound and thoughtful basis for speculation. His contribu- tion to the field was not large but it exemplified his oft- quoted statement: 'That man can interrogate as well as observe nature, was a lesson slowly learned in his evolu- tion'. This article is based on the Oslerian Oration delivered to the Osier Club of London in July 1984. References 1. Graves, R. J. (1835) In Medical Classics (1940) pp. 25-43. (Com- piled by E. C. Kelly.) Baltimore: Williams and Wilkins. 2. Parry, C. H. (1825) Collections from the Unpublished Papers of the Late Caleb Hillier Parry, Vol. 2, pp. 111-128. London: Underwood. 3. Berthold, A. A. (1849) quoted by Rolleston, H. D. (1936) The Endocrine Organs in Health and Disease. London: Oxford University Press. 4. Addison, T. (1849) London Medical Gazette, 43, 517, 562. 5. Addison, T. (1855) In A Collection of the Published Writings of the Late Thomas Addison, MD, p. 209. (ed Wilks and Daldy 1868.) London: The New Sydenham Society. 6. Brown-Sequard, C. E. (1856, 1858) quoted by Rolleston (see reference 3). 7. Curling, T. B. (1850) Medical and Chirurgical Transactions, 33, 303. 8. Gull, W. W. (1874) Transactions of the Clinical Society of London, 7, 180. 9. Ord, W. M. (1878) Medical and Chirurgical Transactions, 61, 57. 10. Fagge, C. H. (1871) Medical and Chirurgical Transactions, 54, 155. 11. Reverdin, J. L. and Reverdin, A. (1883) Revue medicale de la Suisse romande, 3, 360. 12. Kocher, T. (1883) Archiv fur klinische Chirurgie, 29, 254. 13. Semon, F. (1888) Transactions of the Clinical Society of London, XXI, (suppl.), 10. 14. Clinical Society of London (1888) Transactions of the Clinical Society of London, XXI, (Suppl.), 21. 15. Murray, G. R. (1891) British Medical Journal, 2, 796. 16. Editorial (by Osier, W.) (1886) Medical News, 49, 661. 17. Editorial (by Osier, W.) (1885) The Medical News, XLVI, 381. 18. Editorial (by Osier, W.) (1887) Medical News (Philadelphia), 1, 523. 19. Osier, W. (1889) Medical News (Philadelphia), lv, 257. 20. Osier, W. (1892) Johns Hopkins Hospital Bulletin, 21, 42. 21. Osier, W. (1898) Journal of Cutaneous and Genitourinary Disease, xvi, 127. 22. Osier, W. (1895) Archives of Pediatrics, New York, xii, 105. 23. Osier, W. (1899) Journal of Nervous and Mental Disease, xxvi, 65. 24. Osier, W. (1893) Transactions of the Association of American Physicians, viii, 380. 25. Osier, W. (1897) American Journal of the Medical Sciences, 114, 377. 26. Paget, S. (1919) Sir Victor Horsley: a study of his life and work. London: Constable. 27. Osier, W. (1916) British Medical Journal, 2, 165. 28. Matovinovic, J. (1978) Perspectives in Biology and Medicine, 21, 565. 29. Matovinovic, J. (1984) Personal communication.

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Recruitment and Training in Community Medicine ? A Decade's Experience ROSEMARY RUE, CBE, MB, FRCFJ Regional Medical Officer and General Manager, Oxford Regional Health Authority; Chairman, Midlands and South Western Inter-Regional Training Scheme in Community Medicine A. G. W. WHITFIELD, CBE, MD, FRCFJ Assistant Director, Royal College of Physicians Research Unit; Convener, Midlands and South Western Inter-Regional Training Scheme in Community Medicine It is now ten years since the inaugural meeting of the Faculty of Community Medicine of the Royal Colleges of Physicians, the first MFCM examinations and the first registration of Fellowships and Memberships of the Fac- ulty with the General Medical Council. With the help of Lord Rosenheim the Faculty had however been estab- lished and many of its foundation Fellows and Members elected two years earlier. The new specialty comprised several heterogeneous groups of doctors including medical officers of health, those administering the hospital service, those employed at the Department of Health and Social Security, the Scottish Home and Health Department, the Welsh Office and Northern Ireland Department of Health and Social Services, those in the medical services of the armed forces and those in academic departments of community medi- cine whose main interest was usually epidemiology or operational research. To assimilate doctors with such divergent areas of responsibility into one specialty was a daunting task. In addition, community physicians have had to guide the profession through two reorganisations and help it to adjust to a period of severe recession in place of continuous expansion and limitless finance which had been its staple diet since the establishment of the National Health Service in 1948. Although the specialty has developed an attitude of extreme modesty and self-criticism, its contribution has been remarkable considering the lack of proper training available until a decade ago. Moreover, it has had to face and live with much disharmony within the Health Ser- vice, which has led to the rapid growth of private medical care. Although some doctors wishing to pursue a career in community medicine prepare themselves for the Part I MFCM examination and largely arrange their own Part II project and service training, the majority in England and Wales are employed as registrars by health authori- ties and attend the MSc course at the London School of Hygiene and Tropical Medicine or the University of Manchester, the MPH course at Leeds or one of the three consortia training schemes. The 1983 report of the joint working party set up by the Regional Medical Officers and the Community Medicine Consultative Committeefl] indicated that a minimum intake into the specialty of 80 trainees per year is necessary to fill the 200 existing career vacancies for Specialists in Community Medicine (SCMs) and those which will arise from death or retirement in England and Wales. This article describes the work of one of the three consortia, the Midlands and South Western Inter-Re- gional Training Scheme, which the joint working party suggested should aim at an intake of 26 trainees per year. The Scheme Geographically, the scheme covers the Oxford, South Western, Wessex and West Midlands Regions and the whole of Wales apart from Clwyd and Gwynedd. The participating universities are Oxford, Bristol, Wales, Southampton, Exeter and Birmingham. Reading also contributed until the DHSS withdrew the funding of its operational research unit. Twenty weeks of modular training, covering Appendix I of Specialist Training in Community Medicine [2], is provided by the universities and a further week by the DHSS. Between modules, registrars receive in-service training as outlined in Ap- pendix II of Specialist Training in Community Medicine [2]. Approximately one-third of the in-service training is at the Regional Health Authority and the remaining two- thirds is normally split between two disparate but geo- graphically adjacent districts. During in-service training registrars spend about half a day each week with their academic tutor. The scheme is of two years' duration and after passing the Part I MFCM and approval by a Senior Registrar Assessment Committee the trainees are up- graded to senior registrar. Recruitment Since the scheme started in 1973, 132 doctors have been accepted for training (Table 1). It will be seen that it has never been possible to reach the target of 26 per year; in fact even if this number of suitable candidates applied it is at present doubtful whether so many posts could be 112 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 Table 1. Entrants to Midland and South Western Inter-Regional Training Scheme in Community Medicine by year, age and sex. 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 Total M 7 11 8 5 11 10 9 9 14 12 18 18 10 4 4 4 2 4 4 5 1 5 4 10 Mean age (years) Total M F 35.4 37.9 36.3 31.2 33.1 32.8 31.3 34.6 33.6 32.8 30.7 31.1 35.0 36.1 33.5 27.0 34.0 33.3 28.8 34.5 35.1 33.5 29.5 32.9 35.8 38.5 39.0 37.5 31.5 32.0 32.4 25.0 31.2 31.8 31.7 29.0 20-29 3 2 3 3 4 4 4 2 7 4 10 Age range (years) 30-39 40-49 2 5 2 1 6 4 4 5 3 6 7 10 50-59 132 77 (59%) 55(41%) 32.8 32.9 32.7 53 55 18 6 funded or satisfactory service placements arranged. In- itially there was a great shortage of acceptable applicants but over the last four years the number and quality of candidates have improved greatly. This is thought to be due to several factors. First, greater undergraduate expo- sure to the specialty, second, the intense competition in the major clinical specialties together with worldwide over-production of doctors, third, a growing appreciation that community medicine is an interesting, challenging and important specialty, and fourth, the increased female intake into the profession, many of whom find com- munity medicine best suited to their professional aspira- tions and family commitments. However, more male (59 per cent) than female (41 per cent) doctors have entered training; it will be seen that the mean age of males and females has been similar and that entrants are a little younger now than they were when the scheme started. This is due mainly to the diminishing numbers of mature senior clinical medical officers wishing to obtain the MFCM and become community physicians and to fewer older general practitioners seeking to transfer to com- munity medicine. Of the 132 entrants, 66 had obtained higher qualifica- tions before starting training in community medicine; 21 held the MRCP, FRCS, FRCOG, MRCOG or MRCGP, 6 had doctorates of medicine and 2 of philos- ophy, 21 had degrees of BSc or B Med Sci, 4 had obtained the DPH, 16 the DCH, 17 the DRCOG and 8 held other diplomas. Wastage Seventeen (12.9 per cent) of the 132 entrants have left the specialty; 13 of the 17 transferred to general practice before vocational training became mandatory. In two the change resulted from failure to pass the Part I MFCM examination and in another two because of difficulty over the Part II dissertation; 6 of the 13 had already passed the Part I examination and the demands of Part II coupled with a reluctance to relinquish clinical work and the attraction of the higher income and tax allowances in general practice appeared to be the major influences. The other 4 of the 17 lost to the specialty included one who has transferred to audiological medicine, one to genito-uri- nary medicine and two to occupational medicine. One of the latter was working in the Employment Advisory Service when he joined the scheme in order to obtain the MFCM, but he was unsuccessful in the examination. He has since obtained the MFOM and DIH. A wastage of 12.9 per cent is considerably lower than that envisaged by the joint working party of the Regional Medical Officers and Community Medical Consultative Committee[l] and in the 1980 report of a Joint Working Group entitled Recruitment to Community Medicine[3], who assumed a trainee wastage rate of 45 per cent. The low wastage is thought to reflect increasingly stringent selec- tion of entrants. Progress of Trainees Of the 132 trainees, 36 have not yet been in the scheme long enough to sit the Part I examination, 48 have completed Part I but have not yet obtained Part II, while 26 have obtained Part II. Eleven have not passed either Part I or Part II but are still in the specialty and 11 of those who have left the specialty had not passed any part of the examination. Of the 115 remaining in the specialty, 37 have already achieved SCM (consultant equivalent) status, of whom one has died and 3 are overseas; 6 who have SCM or equivalent status were unsuccessful in the Part I MFCM examination despite repeated efforts, being appointed SCM because it was felt that the scheme had given them sufficient knowledge and experience to enable them to fulfil their duties and that their personal qualities fitted them for the job (Table 2). The interval between passing the Part I examination and completing Part II is shown in Table 3. The delay has been a source of some anxiety and appears attributable to several factors; first, with the present staff shortage in the specialty senior registrars have been overburdened with service work and are often called upon to fill vacant DMO posts on a locum basis. Second, some projects chosen have by their nature required several years to elapse Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 113 Table 2. Progress of 132 entrants into scheme Passed Part I MFCM Completed MFCM Not passed Part I MFCM but still in specialty? as consultant or equivalent 6 as SCMO 3 Left specialty? with Part I MFCM without Part I MFCM Consultants (DMOs, SCMs, Senior Lecturers or equivalent) Senior Registrar or Lecturer Registrar? Not yet 2 years in post Failed Part I MFCM once Failed Part I MFCM twice Passed Part I MFCM and awaiting Senior Registrar Assessment Committee Passed Part I MFCM gaining further clinical experience in general practice 1 / 'Includes 1 died, 3 abroad and 5 not yet completed Part II and special salary scale nl 36 1 1 48 26 17 44 Table 3. Interval between passing Part I and obtaining Part II of the MFCM examination. Years Number of Trainees Mean age at entry to scheme 0 1 43.0 1 1 32.0 2 5 38.0 3 4 30.0 4 10 32.2 5 1 28.0 6 1 37.0 7 1 26.0 before the information sought could be available. Third, other projects have been intended to serve also as MD theses and their magnitude has inevitably involved sev- eral years' work. Fourth, some senior registrars have not decided on a Part II project until they have been in post some little time and fifth, within the Faculty there has been some delay in granting approval to project protocols and in assessing dissertations. Delay in obtaining Part II did not appear to be age-related. Senior registrars are currently urged to give priority to and to complete their Part II during their first year in post and to select their project and get its protocol approved immediately they pass Part I or before. Failure to pass Part I is age-related, the mean age of those who are successful being 31.7 years as compared with 41.5 years in those who fail. It appears more difficult for the mature general practitioner or senior clinical medical officer to grasp the skills required of a community physician today. Discussion The current situation suggests that recruitment to com- munity medicine is improving and that the trend is likely to continue and accelerate. The Faculty of Community Medicine is to be congratu- lated upon setting up a satisfactory Membership Examin- ation in only a little over ten years. It is hoped that the Faculty will continue its efforts to reduce delays in the second part of the examination and that its assessors will adopt realistic standards. If this can be achieved, there should be no delay in advancement to SCM status for the foreseeable future and the use of the special salary scale should rarely be required. While in general it is probably wise and kind to dissuade mature doctors from entering the specialty because of the examination difficulties that they may encounter, a mean age at entry of over 30 indicates that nearly all those recruited to the specialty will have had much more than the one mandatory year of post-registration clinical experience. In these circum- stances four or five years of training in community medicine should suffice. Even this means that the average trainee will be about 37 before becoming an SCM and will have only 28 years in a career post before him, or 23 if he retires at 60 as so many do. While the standard of the National Health Service will always depend on the skill and devotion of its clinicians, nurses and paramedical personnel, it is unrealistic to think of any increase in the funds that can be made available to it for many years, if ever. In these circum- stances the community physicians' skills of epidemiology, statistics, health services management and research, in- formation systems, planning, manpower, health care evaluation and the behavioural sciences provide the es- sentials of good housekeeping. The Royal Colleges of Physicians of London, Edinburgh and Glasgow have every reason to be proud of the progress and achieve- ments of the Faculty they helped to establish ten years ago. References 1. Recruitment and Training in Community Medicine (1982) Report of Regional Medical Officers/Community Medicine Consultative Committee Working Party. 2. Specialist Training in Community Medicine (1982) The Faculty of Community Medicine. 3. Recruitment to Community Medicine (1980) Report of Joint Working Group from the Profession and Central Government Departments. 114 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

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The Enigma of Pertussis * The Marc Daniels Lecture 1984 // '/ ??J H. P LAMBERT, md, frcr ffcm Professor of Microbial Diseases, St George's Hospital Medical School, London Marc Daniels died at the age of 46, in 1953. Most of his working life was spent in the study of tuberculosis. After the Second World War he worked in many European countries in which tuberculosis was rife and then, in 1946, joined the Medical Research Council. The work in which he was so deeply involved, on the emerging forms of chemotherapy and on BCG vaccination, set a gold standard for the conduct of clinical trials, which still operates. These early MRC studies were the first proper- ly controlled trials in tuberculosis but had an impact far beyond this particular disease. They showed the import- ance of such trials, the need for their careful planning, the solution of the many statistical and ethical problems and the organisation required. It is hard now to remember how relatively recent these ideas are; one reason why the work of innovators is easily forgotten is that it becomes so firmly embedded in the ideology of science that later generations assume that the ideas have existed for ever. Another lesson is that trials need to be done quickly and early: the first MRC report on isoniazid was published a mere six months from its start. We are still sadly short of much important information about pertussis, some of it susceptible to the kind of study of which Marc Daniels was such an effective protagonist. By the mid-1970s it was possible for the author of an extensive review of pertussis to say that the disease had become something of a medical curiosity. Even at that time this was certainly not true in the developing coun- tries. In several of the wealthier countries, notably Brit- ain, the situation was just about to change in a very dramatic way, which brought pertussis back into promi- nence as a subject of great public health importance and led to a resurgence of studies on many basic aspects of the disease. The Recent History of Pertussis At the beginning of this century pertussis was a major cause of childhood mortality, causing more deaths than any of the infective diseases of children except measles. In infants, it was a more frequent cause of death than measles. Then, throughout the century there followed a major decline in case fatality, long before immunisation was introduced and continuing after its general introduc- tion in the post-war decades. Notifications, however, fell sharply only after the mid-1950s and other countries, for example the USA, experienced similar changes, one of the many controversies being whether this decline could be related in any way to vaccination programmes, or whether it represented a continuation of previous trends unrelated to immunisationfl]. In 1974 the question of possible brain damage follow- ing pertussis-containing vaccine was brought into sharp public focus as a result of a television programme and many articles in newspapers, leading to a loss of confi- dence in the vaccine among parents and Health Service staff, and a steep fall in vaccination rates. So, in 1975-76, pertussis posed several very important practical ques- tions. The first one, was the vaccine having any effect, was answered by two large epidemics of pertussis, the largest since a general programme of immunisation against the disease was introduced in 1957. The sequence of events does not, of course, itself prove that a previous vaccine had an effect, but there is much detailed epidemi- ological evidence which makes this conclusion inescap- able. The question of whether the vaccine carried a risk of neurological damage was answered about as fully as it was possible to do by the National Childhood Encephalo- pathy Survey carried out by Miller et al. [2]. The unan- swered questions were: What impact does pertussis have on the current generation of patients who develop the disease? What sort of an illness is it, how serious is it, what complications may ensue? Does it cause long-term pulmonary damage? The reasons why these questions could not be answered were twofold. First, the steep fall in mortality and more anecdotal evidence about decline in severity made it clear that the disease had changed in recent decades so that older studies could not be validly used in any cost-benefit equation. The same argument applied to the problem of long-term damage, but here a second difficulty also emerged; the older studies address- ing this question were few in number and, by modern standards, lacking in control data which would ensure their epidemiological validity. The Illness and its Complications The main features of pertussis are well known, the paroxysmal bouts of coughing and choking often culmi- nating in vomiting and cyanosis, which may occur as many as 50 times in 24 hours. The apnoeic attacks, especially common in infancy and at that age often Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 occurring without a preceding coughing bout, and the generally long duration of the illness make an intensely unpleasant experience. There is much misunderstanding between affected families and doctors because the patients generally look well and have few or no abnormal signs on examination between the attacks, and the attacks are seen by mothers at home and by nurses in hospital but less often by doctors in either case. There is a great list of complications, and clinical or radiographic evidence of lung involvement is quite common. In the series collected at St George's Hospital, 24 per cent had abnormal chest radiographs and similar findings have been reported from many other countries. Fits are not uncommon and encephalopathy still occasionally occurs. However, although chest complications especially are potentially important, we believe that attempts to measure the impact and severity of pertussis merely by enumerating complications are misleading. Some so- called complications are of little or no importance, the definition of a complication being to some extent arbi- trary and, most importantly, the use of complications as an index of severity diverts attention from the central features of the disease which give it its chief impact. Impact on the Patient and Family Another aspect of severity to which little attention has usually been paid is the extent to which the illness affects the life of the patient and his family. There have been many studies of this kind in relation to chronic illness, but few have focussed on acute illnesses and none on whoop- ing cough. As part of a group of studies carried out recently at St George's Hospital, we decided to examine this aspect of the disease[3]. Dr I. D. A. Johnston and Miss M. Hill, an MSc student in clinical psychology, interviewed the parents of 21 children admitted to hospi- tal with pertussis. They did this on two occasions, the first shortly after admission and the second during convales- cence at the patients' homes. The questions were of a structured but relatively open-ended kind, useful in pro- viding a systematic approach without unduly limiting the scope of the answers, and were aimed at providing information about the illness and the problems it posed for patient and family, at determining the effect of the illness on the behaviour of patient and family and at identifying the parents' attitudes and fears. They includ- ed behaviour checklists for the patient and the family which could be roughly quantified. One incidental find- ing, which the late convalescent interview made possible, was confirmation of the prolonged nature of the illness, with a mean duration of 11.7 weeks but lasting over 16 weeks in more than a quarter of the children. The behaviour of the children was severely affected during the illness and had still not returned to normal at the second interview about two months later; the effect of admission to hospital, which has been extensively studied in other contexts, may have contributed at this later stage. Famil- ies, too, were greatly affected in their behaviour patterns, although these had generally returned to normal by the time of the second interview. There is no doubt that pertussis was an intensely distressing experience for the parents as well as for the patient. Not surprisingly, the apnoeic or choking attack was most distressing and many parents commented on their feeling of helplessness at these times. During the acute stage most parents were concerned that their child might die; later their main worry was of permanent chest damage. The possibility of brain damage was also of concern in the acute stage. There was much physical stress, too, particularly the extensive disruption of sleep and consequent fatigue of the parents. Most parents were being woken at least five times every night, for a mean of 24 nights (range 7-60) before the patient's admission. Some were awakened 10-15 times each night or sat up with their child all night. It is not surprising that in these circumstances strains on the marriage often emerged especially as some husbands, like some doctors, doubted the severity of the illness, as they were often away when the child had its worst episodes. Pertussis in Adults These patients were all children, but pertussis is not uncommon in adults. In Dr W. O. Williams' study in South Wales 10 per cent of the cases were adults [4] and even the crude notification figures showed adults as 3.3 per cent of cases in the 1977-79 epidemic. Pertussis is often said to present atypical features in adult life and some of the few studies of adults indicate that whooping is uncommon. Others, however, show a picture very similar to that found in children and it seems that the disease often goes undiagnosed because it is unexpected in adults. Certainly it can be severe at any age. In the recent epidemics a general practitioner in his thirties developed cough syncope following the paroxysms; Williams saw grandparents aged 77 both with the disease and I have seen a woman of 65 with its typical features. Nevertheless, the disease in adults may be atypical or mild and this is of epidemiological importance, since Nelson in the USA has provided evidence that, in his community, adults may be the main source of infection for susceptible children[5]. One reason why adult pertus- sis may have become more common is the decline in immunity in the population generally. At the turn of the century the median age for pertussis was < 4 years and 85 per cent of the population had had the disease by the age of seven years, so that few adults were susceptible. The spread of pertussis from and to adults in hospitals has been observed on several occasions. Pertussis in the Third World A final clinical point is the contrast between pertussis in wealthy and poor countries. Some years ago Morley[6] showed that whooping cough in Nigeria was very severe and that, as for measles, the mortality rate approximated to that found in fever hospitals in London in the first decades of this century; the actual figures were 15.5 per cent of 479 admissions in Nigeria from 1957 to 1981, and 11.9 per cent deaths of 17,003 admissions to the London Fever Hospital between 1911 and 1929. Certainly this fits 68 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 in with the records of the Grove Fever Hospital, now the site of St George's Hospital and Medical School. The postmortem books show many records of children who died there of pertussis well into the 1940s. Recent data on pertussis in the Third World is, however, much more scanty and much less information is available than in the case of measles. A study in Kenya[7] in the mid-1970s estimated the infant fatality rate at 3.2 per cent and WHO figures of the late 1970s estimated that pertussis accounted for the deaths of 250,000-450,000 child deaths P-a., making it about as important as tuberculosis as a cause of death in childhood [8]. Accurate recent records about Third World pertussis are very definitely needed, but the data we have suggest that, as in other infections, the impact of the disease is greater than it is in wealthier countries. Treatment Can pertussis be treated? A multitude of treatments has been employed at various times and it is sad to note, many decades after clinical trial methods were firmly established, that the evidence for many of the more modern remedies is little greater than for the traditional ones. One reason for this was the decline of interest in the disease before its recent resurgence, another is the great difficulty in assessment of severity, making pertussis a peculiarly difficult disease to measure. As regards antibiotics, MRC trials in the 1950s[9] established that the number of coughing spasms was lessened by the use of chloramphenicol or chlortetra- cycline both given in high doses. The effect was, however, a small one and could be detected only in the patients treated early in the disease. The disease has changed since these trials were done, and in any case these two agents, for well-known reasons, are not now considered suitable for childhood infections. There is now some evidence that erythromycin mitigates the severity of the disease but no adequate trials of substantial size have been carried out and any effect is likely to be small[10]. Some anti- microbial drugs, including erythromycin, have been pro- posed as chemoprophylaxis for family or institutional contacts as an alternative to control by immunisation. This could be especially useful in young infants who are both susceptible to the disease yet too young to have been fully immunised against it. Scattered reports have ap- peared suggesting that erythromycin could be used in this way but two recent placebo controlled trials showed no benefit from this method. The treated contacts showed no advantage over their controls and the method was in fact difficult to apply in field conditionsfll, 12]. Indeed, one reason for failure may have been the problem of timing since in the larger study an average of two weeks elapsed between the first sympton in the index case and the administration of drug, or placebo, to the contact. Whether or not antibiotic treatment has any effect on established disease or in preventing it in contacts, some, especially erythromycin, do reduce naso-pharyngeal car- riage of the organism, so that one justification for their use is that the risk to contacts may be diminished. This may be so, but many failures to prevent infection in this way have also been described, perhaps because the effect of erythromycin in reducing naso-pharyngeal carriage is not as rapid or as complete as is sometimes supposed. More studies of these relationships are needed, especially in closed communities in which a point source of infection is sometimes identifiable. Does Pertussis damage the Lungs? The paucity of previous controlled observations and the changes in the disease in recent decades have deprived us of valid information on possible long-term lung damage caused by pertussis. This problem has now been studied by I. D. A. Johnston working jointly in the Department of Communicable Diseases and the Department of Social Medicine and Clinical Epidemiology at St George's Hospital Medical School. The study involved the identifi- cation, from both hospital and from community sources, of children who had had whooping cough in 1971-79, and the use of controls, two for each index case, randomly selected from the same class as the index case. Groups of cases and controls were studied at their schools, at the same session, the observer being 'blind' to their identity as cases or controls. This school-based study had the great advantage of eliminating many potentially confounding variables such as local exposure to respiratory infection, air pollution and, to some extent, socio-economic varia- bles. Respiratory questionnaires were used, employing well-validated questions from the large body of previous work on childhood respiratory disease, together with other relevant questions, giving information on such matters as breast feeding, previous hospital admission, vaccination, family size, parental smoking, social class and aspects of family history. The questionnaire was blandly entitled to avoid any particular attention to whooping cough. At the school visits the groups of children were measured to obtain weight, height, skin- fold thickness at four sites and arm circumference, and the chest was inspected and auscultated, including assess- ment of the 'loose cough' sign. Spirometry was performed using an 'S' model spirometer, measuring the FEVo.75, FEVi and FVC and deriving the FEV/FCV%, the FEF25-75; the mean transit time was read on a printout from the microprocessor. The opportunity was taken to apply the respiratory questionnaire to all children in the classes containing an index case plus control group, so that, on completion of the study, we had 360 cases and 711 controls but, in addition, about 4,000 additional questionnaires which acted as another set of control data underpinning this aspect of the survey. The results have been published elsewhere[13], but, in brief, questionnaire data revealed a significant excess, in children who had whooping cough, of previous chest illnesses, hay fever and eczema, especially marked in the group who had been in hospital for whooping cough, who showed a two- to three-fold excess of past respiratory illness (Table 1). The same trends were observed in the tendency to current symptoms, that is, within the preced- ing year (Table 2). In the lung function tests, however, although there Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 69 Table 1. Reported chest symptoms at any age (%). Croup Pneumonia Bronchitis Wheezy bronchitis Wheeze Asthma Hay fever Eczema * PC0.05 ** /><().01 *** P<0.001 Cases Controls n = 360 n = 711 18 9 8 3 16 8 15 8 17 9 7 4 12 7 19 12 Table 2. Reported chest symptoms in last year (%) Morning cough Day/night cough Morning phlegm Day/night phlegm Wheeze Breathlessness Cough/cold lasting 2 weeks * /><0.05 *** P<0.001 Cases Controls n = 360 n = 711 23 13 6 3 8 4 25 12 16 7 38 33 were small differences in some of the sub-groups, none was significant and, overall, the mean measurements were the same in test and control groups, with the observations sharing narrow confidence limits (Tables 3 and 4). Table 3. Lung function tests Adjusted Difference 95% confidence Lung Function* between cases limits for Test Cases Controls and controls difference FEVo.75 1-571 1.564 FEV, 1.689 1.686 FVC 1.904 1.896 FEF 1/s 2.119 2.127 * Lung function adjusted to height = 128 + 0.007 -0.017 to 0.030 + 0.003 - 0.022 to 0.028 + 0.008 -0.021 to 0.036 -0.008 -0.058 to 0.073 Table 4. Lung function tests. Forced expiratory ratio and mean transit time (MTT). Cases Controls FEV,/FVC % n = 333 n = 670 89.2 89.1 MTT (sec) n = 211 n = 458 0.47 0.47 It appears, therefore, that children who have had pertussis have had and do now suffer an excess of respiratory illnesses compared with their controls. Is this excess caused by whooping cough or does it precede it, indicating a susceptibility to respiratory infection which might include an increased likelihood of developing per- tussis, or pertussis of increased severity? Or, of course, both these factors might be operating. We cannot answer this question with complete confidence but an analysis of the ages at which the cases had whooping cough suggests that the undue susceptibility to chest illness shown by these children preceded their attack of whooping cough and then continued after it. The lung function tests do exclude any possibility that, in the present generation of British children, whooping cough has any substantial effect on ventilatory function. Two caveats are necessary. First, the size of the study would not suffice to detect reliably rare pulmonary complications: for example, if, as was long ago supposed, whooping cough was followed by bronchiectasis in one in 200-300 children, such an effect could only have been detected in a much larger study. Second, in view of the abnormal experience of respiratory infections of these children and the controversy about methods of testing for small airways disease, could important findings be missed by our measurements? This seems unlikely but, in col- laboration with Dr J. Warner, we have carried out another study, now being analysed, in which a number of children who had pertussis in infancy, together with suitable controls, have been tested at Brompton Hospital for bronchial sensitivity to histamine, together with skin tests and detailed lung function studies including flow- volume curves and nitrogen washout tests. Advances in Pathogenesis Bordetella pertussis shows an astonishing variety of bio- logical effects in experimental animals (Table 5), some of Table 5. Biological activities of Bordetella pertussis Pertussigen Lymphocytosis-promoting factor histamine sensitisation islet activation Filamentous haemagglutinin Agglutinogens Endotoxin (lipopolysaccharide) Dermonecrotic toxin Adjuvant effects Extracytoplasmic adenylate cyclase the most striking being the induction of lymphocytosis, a high degree of sensitivity to the lethal effects of histamine, and resistance to the hyperglycaemic action of adrenaline, and there Ws been much effort to characterise these effects more fully, both chemically and by analysis of their precise physiological mechanisms[14]. In addition to the well-established actions, a recent addition is the finding of an extracytoplasmic adenylate cyclase which is ingested by leucocytes and diminishes their phagocytic ca- pacity[15]. At one level these actions may seem obscure experimental findings of no practical importance but they do point to actions which might have some significance in accounting for the strange pathogenesis of pertussis and 70 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 perhaps too for the unwanted effects of vaccine. It is still, however, not possible to make a clear line of explanation between the experimental findings and the human dis- ease, although it is hard to escape the conclusion that the lymphocytosis is likely to have the same origin in man as in the experimental animal. A major advance has been the isolation in crystalline form of a material which carries three of the best recognised actions of the organism. This has been named pertussigen or pertussis toxin. Its sub- unit structure is beginning to be analysed. There is certainly enough evidence to include pertussis as a 'toxin disease analogous to cholera or tetanus. There are pro- found general and systemic effects, yet only local activity of the organism on the respiratory mucosa, with no evidence of systemic invasion. So obvious targets to be borne in mind in improved vaccines are the main pertus- sis toxin, and other toxins shown to be relevant in experimental systems. Another focus of interest is the earliest stage of infec- tion, when the organism attaches to human ciliated respiratory epithelium to which it shows a specific attach- ment. This has been known from morphological data for a very long time but the mechanisms and antigens involved are now being elucidated in much greater detail. Workers at the Centre for Applied Microbiology and Research are studying a number of pertussis components as candidates for a subcellular vaccine. In Japan two infants died after pertussis vaccination in 1974 and 1975, so vaccination was discontinued and then reintroduced for older children only. As in the UK a large epidemic followed, with a peak of 41 deaths from the disease in 1979. Japanese workers have now developed a com- ponent vaccine containing two main protective antigens; the filamentous haemagglutinin, thought to be concerned with attachment to cilia, and the leucocytosis promoting factor haemagglutinin, thought to represent the main toxin[16]. This has now been given to four million Japanese children and, with help from WHO, is being tested in several other countries. There are problems in assessing the results, as few infants have been included in the series so far, and other questions of the appropriate- ness of different laboratory models for the newer vaccines are still to be defined. There are hopes, too, for vaccines from recombinant DNA techniques, since E. coh plas- mids have been inserted into B. pertussis and transforma- tion of plasmid-derived DNA has been demonstrated. Conclusion In summary, over the last decade we have found that pertussis is still an important disease in many countries and that current vaccines, although imperfect, are strong- ly protective. Our study has shown that children who have had pertussis have an abnormally high morbidity from respiratory disease. This may well precede or in part precede, the attack of pertussis, but whatever the mixture of pre-existing susceptibility and effects of the disease itself, we see a group of children who warrant special attention in preventive programmes. Progress on analysis of the active components of B. pertussis has been rapid. One component vaccine has been extensively tested and others are on the way. The ethical and administrative problems involved in efficacy and safety testing of these vaccines are great. There are still great gaps in our understanding of how the pertussis toxins relate to the human disease. In particular the pathophysiology of the choking bouts and the apnoeic attacks which give the disease its particular character is still mysterious, and our capacity for making useful interventions in the progress of this distressing disease is still sadly limited. The epidemiological data make it clear that, until extremely effective vaccines can be universally and continuously used, pertussis will re- main with us and continue to deserve study both for its public health importance and for its fundamental interest as a model of a particular kind of host-parasite relation- ship, the pathogenesis of which is at last becoming susceptible to detailed analysis in biochemical and im- munological language. At present, parents of children with whooping cough are as distressed as Mary Barker, who wrote to her husband Abel on 26th May 1661, to say, 'I am in a sad condition for my pore children who are all so trobled with the chincough that I am afraid it will kill them. I am fane to have a candell stand by me to go into them when the fitt comes', and a few days later, '. . . all sadly troubled by the chincough. Moll is much the worst. They have such fitts that it stopes theare wind, and puts me in such frits and feares that I am not myselfe'. References 1. Department of Health and Social Security (1977) Whooping Cough Vaccination. London: HMSO. 2. Miller, D. L., Ross, E. M., Alderslade, R., Bellman, M. H. and Rawson, N. S. B. (1981) British Medical Journal, 282, 1595. 3. Johnston, I. D. A., Hill, M., Anderson, R. and Lambert, H. P. (1985) British Medical Journal, In press. 4. Royal College of General Practitioners (Swansea Research Unit) (1981) British Medical Journal, 282, 23. 5. Nelson, J. D. (1978) American Journal of Disease of Childhood, 132, 371. 6. Morley, D., Woodland, M. and Martin, W.J. (1966) Tropical and Geographical Medicine, 18, 169. 7. Mathieu, J. M., Muller, A. S., Voorhoeve, A. M. and Dikken, H. (1978) Bulletin of the World Health Organisation, 56, 773. 8. Walsh, J. A. and Warren, K. S. (1979) New England Journal of Medicine, 301, 967. 9. Medical Research Council (1953) Lancet, 1, 1109. 10. Lambert, H. P. (1979) Journal of Antimicrobial Chemotherapy, 5, 329. 11. Grob, P. R. (1981) Lancet, 1, 772. 12. Spencely, M. and Lambert, H. P. (1981) Lancet, 1, 772. 13. Johnston, I. D. A., Anderson, H. R., Lambert, H. P. and Patel, S. (1983) Lancet, 2, 1104. 14. Manclark, C. R. and Cowell, J. L. (1983) In Bacterial Vaccines (ed R. Germanier.) New York: Academic Press. 15. Confer, D. L. and Eaton, J. W. (1982) Science, 217, 948. 16. Satq, Y., Kimura, M. and Fukumi, H. (1984) Lancet, 1, 122. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

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The Short Report ? What Next? The time is right for yet another push to solve our career imbalance with all its implications for medical manpower. This saga is similar to The Mousetrap, as both have complicated plots, have had an exceedingly long run and a fairly obvious solution when it is revealed. Whereas The Mousetrap gives up its secret every night, the solution to our career imbalance is revealed at less frequent intervals but is always greeted with surprise by the audience, although the remedy has remained unchanged for almost as long as The Mousetrap has been running. The problem remains, at heart, a very simple one. For one reason or another too many junior hospital posts were created, particularly at SHO and registrar level, so that the career prospects for medical graduates entering these posts are now very poor indeed. As in The Mousetrap, a red herring is drawn across the stage, as the sub-plot of student numbers is often produced to explain how best to deal with the problem. Unfortunately, this is misleading and misconceived, as the apparent excess of student numbers is a product of the career imbalance with only a very small contribution from financial stringency. The growth in investment and output from medical schools is well within our sluggish national economic means and is required to enable a greater spread of trained doctors into those parts of the health service still short of medical skills. Increased numbers of graduates are necessary to cut waiting lists and increase the consultation time that patients have in general practice. There is no perceived need for fewer doctors from the viewpoint of the patient. The apparent excess at junior level arises mainly from the great competition for the better training posts which ensure that graduates progress quickly to career posts within the health service. We now have a system where there are two classes of junior hospital post: the first, mainly occupied by British graduates, leads reasonably quickly to a consultant post or to general practice, whereas the second, mainly in shortage specialties and occupied by overseas graduates, leads nowhere. These two classes of post have obscured the problem of career imbalance but the increased number of British graduates and a continuing failure to expand consultant posts has brought the problem into the open. If there is an import- ant sub-plot, it is not student numbers but the need to upgrade or abolish many of these so-called training posts occupied by juniors with no future. Any solution to our career imbalance demands an answer for this problem. If reducing student numbers will not solve the problem, or only solve it at a cost to patient care, we are left with two other options which are as well known as the plot of The Mousetrap. The first is to have a sub-consultant grade, suitably disguised and probably particularly tail- ored to the part-time married woman, and the second is to expand the consultant grade either as such or with two levels of responsibility and activity. These solutions have been repeatedly debated in the past, and on every occasion the profession preferred to see consultant expan- sion. More consultants and fewer juniors will inevitably change the pattern of work in hospitals and sooner or later this nettle will have to be grasped. The prospect is uncertain for medical graduates, whichever decision is reached. Either a substantial proportion of them will not achieve a full career post and will become a sub-consult- ant of one form or another or they will enter consultant ranks with the job somewhat different from today. The present system cannot continue for much longer although it has defied gravity for so long that it may have life left in it for a few more years. Apart from the unwillingness of the profession to grasp the nettle, there is another more difficult problem. Even when the profession and the central government agree on the solution, which they do from time to time, it has proved virtually impossible to translate this agreement into action. This is because the link between central exhortation from the DHSS and execution of health service policy by the Health Authorities is inadequate for its task. It is like having a powerful car with no clutch therefore the engine cannot drive the wheels. Until we find a clutch mechanism it remains difficult to translate national agreements on manpower and career structure into realistic hospital and general practice staffing at district level. It is unrealistic to expect District Health Authorities to organise their staffing as if they were self- sufficient nations concerned with medical student train- ing and career structure as well as health care, so the initiative is unlikely to come from them to find a mechan- ism for ensuring that they conform to a centrally agreed policy. A clutch mechanism is badly required and prob- ably requires more urgent attention than finding a solu- tion to the career imbalance, which is to hand and has been debated almost to death in the past. The not too recent expansion of our medical school output, coupled with a financial slow-down, has made it more urgent than ever to correct our career imbalance. One of the these days The Mousetrap will be taken off, but I hope before then we will have rung down the final curtain on the career imbalance saga. We all know how to solve this problem; now is the time to roll up our sleeves and finish the job. T. J. H. Clark 66 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

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In Sickness and in Health A. G. W. WHITFIELD, cbe, md, frcp Emeritus Professor of Medicine, University of Birmingham Honorary Consultant Physician, United Birmingham Hospitals In less than ten years after his death virtually all that the Prince Consort had done to increase the popularity and importance of the monarchy had been dissipated. The Queen's self-imposed seclusion and refusal to carry out her public duties were the main factors. Though physical- ly well, she lived chiefly at Osborne and her people rarely saw her. They felt they were not getting value for money and posters appeared outside Buckingham Palace: 'These commanding premises to be let or sold, in consequence of the late occupant's declining business'. Sir William Jen- ner, her physician and President of the College 1881-88, repeatedly pronounced the Queen unfit to accept engage- ments when he must have known that continued seclusion would make her worse. Perhaps he feared to cross her. On All Fools Day 1864 The Times included a paragraph: 'Her Majesty's loyal subjects will be very well pleased to hear that their sovereign is about to break her protracted seclusion'. She did not open Parliament until 1866 and then with little grace and only because she wanted a Civil List allowance for Prince Alfred, who had just come of age, and money for Princess Helena, who was about to marry the impoverished Prince Christian of Schleswig- Holstein. The same year she did visit Aldershot, held garden parties and attended the Braemar Gathering but in 1868 it required all the diplomacy and powers of persuasion of her old friend and physician, Sir James Clark, to obtain a promise to open the new St Thomas' Hospital. Her obsession with her Highland servant John Brown was a source of further criticism and for a time she was referred to as 'Mrs Brown'. The extravagant pleasure-seeking way of life of the Prince of Wales and his love of racing, shooting, cards and beautiful women was an additional source of public dissatisfaction. This was greatly increased in 1870 when he was subpoenaed to give evidence in an action for divorce by Sir Charles Mordaunt, who cited two of the Prince's friends, Sir Frederick Johnstone and Lord Cole, as co-respondents. The Prince had known Harriet Mor- daunt, a beautiful woman of 21, since childhood, as her father, Sir Thomas Moncrieffe, lived close to Balmoral. Harriet confessed to her husband that she had committed adultery with Cole, Johnstone and others, including the Prince of Wales, and it transpired that the Prince had visited Lady Mordaunt on several occasions and written her a dozen letters. There was, however, no corrobora- tion of her confession in respect of the Prince. A counter petition was filed on the grounds of Lady Mordaunt's insanity and the Prince was not cited, but he was understandably worried about being cross-examined by Mr Serjeant Ballantine, Mordaunt's counsel. By the time the action began on 16th February 1870 before the full Court of Divorce and Matrimonial Causes Lady Mor- daunt required institutional care. The Prince of Wales gave evidence for only seven minutes and said that there was 'never any improper familiarity between him and Lady Mordaunt'. The jury found that Lady Mordaunt was not of sound mind, an opinion shared by Lord Penzance and Lord Justice Keating but not by the third judge, Chief Baron Kelly. Mordaunt's action therefore failed. However, for some time after the trial the Prince was hissed in the streets and at the theatre in London and some four months later when he drove up the course at Royal Ascot. In 1871 the Queen was physically ill. A sting on her arm at Osborne led to an axillary abscess at Balmoral and Jenner summoned Lister, then Professor of Surgery at Edinburgh and the previous year appointed Surgeon in Ordinary to the Queen in Scotland, to incise it. Lister was kept at Balmoral for a week and Dr William Marshall of Crathie was appointed resident medical attendant to Her Majesty. The Queen doubtless experienced great pain, felt very ill, and lost considerable weight and, though her doctors professed great concern, there was little public sympathy. A few weeks later the Queen's health and the ever- decreasing respect for the monarchy were transformed by the grave illness of the Prince of Wales. Returning from Abergeldie the Prince and Princess of Wales stayed from October 30th to November 4th with Lord Londesborough at Londesborough Lodge in Scarborough. From there the Prince went to Marlborough House for two days before returning to Sandringham. A week later, after a day's shooting, he developed fever and a whitlow appeared on the index finger of his right hand. He was seen by Dr John Lowe of King's Lynn, medical attendant to the Prince and Princess of Wales at Sandringham, and the following day he went to stay with Lord Carrington at Gayhurst but as the whitlow became more troublesome Mr Oscar Clayton, Extra Surgeon in Ordinary to the Prince of Wales, was summoned from London and remained at Gayhurst until November 17th when the Prince went to Marlborough House. He saw a play in the evening and returned to Sandringham the following day. The whitlow had subsided, as had a second whitlow on the left hand, but the Prince was still very unwell and when Dr Lowe saw him on November 20th he diagnosed Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 115 typhoid and again sent for Mr Oscar Clayton who agreed with Lowe's opinion. Jenner was detained with the Queen at Balmoral so Dr William Gull, the Guy's Hospital physician, whom the Prince had previously consulted, was sent for and when he saw the Prince on November 22nd he too agreed that it was typhoid, as did Jenner when he arrived from Scotland the following day. Jenner had had long experience of typhoid at the London Fever Hospital and was the first to differentiate typhoid and typhus fevers. He had been one of the four physicians attending the Prince Consort when he died from typhoid in 1861. A bulletin signed by Jenner, Gull, Clayton and Lowe was issued, stating that the Prince had typhoid but that there were no unfavourable symptoms, and there- after Jenner and Gull remained at Sandringham. For the next two weeks the illness appeared to be running a normal course apart from a persistently high respiration rate. However, on December 7th there was an increase in fever, delirium and marked deterioration due to a chest infection, which was hardly a surprising complication in view of the vast number of cigars and cigarettes smoked by the Prince. For some days his life was in imminent danger and there was intense anxiety in London in particular but also all over the country and in India, Canada, Australia and America. The Prince Con- sort had died from typhoid at Windsor Castle on Decem- ber 14th ten years previously and as the anniversary of his death approached it appeared impossible that the Prince of Wales would survive. The Archbishop of Canterbury issued a form of prayer to be used on or after December 10th in all chapels and churches of the Establishment and a slightly altered version was used in Catholic churches and in the synagogues. Jenner, Gull and Lowe issued bulletins five times a day, which crowds clamoured to read. Inevitably they were very repetitive, hence the future Poet Laureate, Alfred Austin's, lines: 'Flashed from his bed, the electric tidings came. He is not better; he is much the same'. The bellringers were summoned to St Paul's Cathedral to toll out the Prince's death but miraculously that weekend he began to improve and thereafter made slow but continuous progress towards recovery. The royal children were sent to Windsor early in the illness but the Princess of Wales and Princess Alice of Hesse were at Sandringham throughout, and the Duke of Edinburgh, Prince Leopold, Princess Louise, Princess Beatrice and the Duke of Cambridge for the critical period. The Queen travelled from Balmoral to Windsor as soon as she heard the news of the Prince's illness and from there she went to Sandringham, which she had never visited previously, on November 29th. She stayed two days and returned when she heard of the severe deterioration that had taken place, in deep snow and intense cold, on December 8th. On Boxing Day she wrote a letter to her people from Windsor, to be published in the newspapers, thanking them for their prayers, sympathy and support. Jenner and Gull were both at Sandringham for five or six weeks. The development of periostitis at the upper end of the femur, accompanied by fever, necessitated their return to Sandringham at the close of the year and Sir James Paget was called in. Not surprisingly the bony complication took some time to settle down and caused temporary lameness; a mild exacerbation towards the end of February necessitated Paget seeing the Prince again. Paget himself had been gravely ill at the beginning of 1871 with septicaemia from an autopsy infection. Jenner and Gull were among the ten doctors attending him and after his recovery he resigned from St Bartholomew's Hospital and Christ's Hospital. The Prince of Wales, as President of St Bartholomew's, had thanked him for his services and in July 1871 he had been created a baronet. From Sandringham in letters to Lady Paget he wrote of 'the Prince's patience and courtesy' and remarked that 'the Princess is the sweetest nurse you ever saw'. The Earl of Chesterfield had occupied the bedroom used by the Prince of Wales at Londesborough Lodge from October 7th?21 st. He returned to Scarborough on October 31st, staying at 3 Belvoir Terrace and leaving on November 4th, returning in due course to his home at Bretby Park near Burton-on-Trent where about Novem- ber 17th he too developed typhoid. He was attended by Dr George Evans, a Fellow of the College, who had been physician at the General Hospital, Birmingham, for over 30 years and Evans called in Dr Charles Murchison, a Fellow of the College and of the Royal Society and physician first to the Middlesex and later to St Thomas' Hospital. He had had much experience of typhoid at the London Fever Hospital and had published 'A treatise on the continued fevers in Great Britain'. Unfortunately, Lord Chesterfield developed a perforated bowel and died from peritonitis on December 1st. He was only 40 years of age and had never married. Blegg, one of the Prince of Wales' grooms, also died from typhoid at Sandringham on December 14th, despite a visit from Queen Victoria and Princess Louise. How- ever, he had travelled direct from Abergeldie to San- dringham and was not at Londesborough Lodge or at Scarborough. In addition, Mr Christopher Sykes' under- butler, who deputised for Lord Londesborough's butler during the royal visit, staying at the Royal Hotel, also developed typhoid on November 19th. The press showed even less sense of responsibility than they do today, hounding poor Lord Londesborough mercilessly on the grounds that defective drainage and sewer gas at Londesborough Lodge were responsible for causing the illnesses of the Prince of Wales, the Earl of Chesterfield and the butler. Fortunately, Lord Londes- borough had taken the precaution of having the sanitation and drainage at Londesborough Lodge carefully exam- ined before the royal visit and everything had been found to be in perfect order. Mr G. P. Dale, FRCS, a general practitioner at Scarborough, sprang to the defence of Lord Londesborough and the town in a letter to the Lancet. Moreover, Lord Londesborough had taken care to provide only Bristol water for drinking during the royal visit. The Eberthella typhi was not isolated until 1880 and it was several years later before the mode of spread of the disease was fully understood. In 1871 sewer gas was thought to be responsible and it was erroneously reported that there was a sewer beneath the floor of the Prince of Wales' bedroom at Londesborough Lodge. The Lancet 116 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 and the British Medical Journal both appointed sanitary commissioners to investigate the matter and Lord Londesborough generously allowed them to examine his house in any way they wished and Mr Dale and the builders and plumbers employed in the maintenance of Londesborough Lodge gave every assistance. Though everything was found to be as perfect as anywhere in the country at that time both journals condemned Lord Londesborough. Moreover, it is significant that no impu- rities were found in Scarborough water, the water at Londesborough Lodge or the Bristol water which the guests drank. The British Medical Journal appointed Dr John Murray as their sanitary commissioner but there is no record as to who James Wakley, then editor of the Lancet, employed to stir the pot. At that time there were 120,000 cases of typhoid each year in England, and of these one in six died. The Times, the Lancet and British Medical Journal gave much gratuitous advice as to the honours that should be awarded to Jenner and Gull for their care of the Prince. Jenner received a KCB and Gull a baronetcy. In addition Gull was appointed Physician Extraordinary to the Queen and Physician in Ordinary to the Prince of Wales. Poor Lowe, who had made the diagnosis and attended the N Prince most assiduously, got nothing, while Clayton in due course collected the CB, CMG and a knighthood and when he died left ?150,000. Although a Fellow of the Royal College of Surgeons he was essentially a fashion- able general practitioner. Lowe did not even get the full credit for his early diagnosis of the Prince's illness. The British Medical Journal stated that Clayton had first recognised that it was typhoid and on 4th January 1872 Gull wrote to Clayton saying that there was a rumour about that Lowe had not suspected typhoid and Clayton had diagnosed it. Clayton replied ackhowledging that this was not so but he said he had not heard the rumour. Thirteen years later an article about the illness, written by Dr W. H. Russell, appeared in the April number of Harper's Magazine. It stated that Clayton and not Lowe had made the diagnosis. Lowe approached Clayton about it and Clayton arranged for the mistake to be corrected in the July issue. Even when Clayton died in 1892 the British Medical Journal reiterated in his obituary that it was he who had first recognised that it was typhoid, showing how difficult it is to correct erroneous press reports. When Lowe saw the obituary he wrote a very restrained letter to the British Medical Journal, enclosing copies of Gull's and Clayton's letters written in 1872, which they published. A thanksgiving service for the Prince's recovery, held in St Paul's Cathedral on February 27th, was attended by 13,000 people. The Prince was still lame, could only walk slowly and looked pale and drawn but he, the Princess of Wales and the Queen were given a rapturous reception by a huge crowd who went mad with joy. Sweet are the uses of adversity. Though the Prince nearly died, the Queen's health and the standing of the monarchy had been restored. After two weeks at Osborne the Prince went to the south of France on March 9th for three months' convales- cence. He was accompanied by Dr George Vivian Poore, a Member of the College and a keen sanitarian, who had just been appointed an assistant physician and lecturer in jurisprudence at Charing Cross Hospital at the age of 29 and had previously travelled with Prince Leopold as his medical attendant. In 1876 he became an assistant physi- cian at University College Hospital and the following year was elected a Fellow of the College. To what extent it was recognised by the doctors or the Prince that the respiratory complication which so nearly proved fatal was largely attributable to smoking is uncer- tain. However, after his recovery the Prince resumed smoking cigars and cigarettes incessantly. His regular habit was 12 large Havana cigars and 20 cigarettes daily. In addition he was throughout adult life considerably overweight due to four or five very large meals every day, including a dinner often of 12 courses. The College reports on Smoking and Obesity were not published until nearly a century later but in 1897 the Prince accepted an Honorary Fellowship of the College and though Punch depicted him looking down a microscope, with a caption 'HRH Dr Wales FRCP The popular physician', he found it quite impossible to follow advice to reduce his consumption of food and tobacco. In consequence in his later years he was never free from cough and in 1890 a severe attack of bronchitis prevented him from going to Germany. In 1891 Sir Morell Mackenzie saw him six times at Marlborough House on account of huskiness of the voice and was rewarded with a gift of a jewelled breast-pin. Mackenzie was a Member of the College who had attended Queen Victoria's son-in-law, Prince Fred- erick William of Prussia, later Emperor Frederick III of Germany, when he died from carcinoma of the larynx. His book The Fatal Illness of Frederick the Noble was so Fig. 1. Sir Felix Semon, KCVO, MD, FRCP, Physician Extraordinary to King Edward VII. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 117 critical of his German colleagues that Sir Henry Pitman, the Registrar of the College, wishing to save Mackenzie the ignominy of having his Membership withdrawn, tactfully suggested that he should resign from the College, which Mackenzie very sensibly did. After Mackenzie's death in 1892 the Prince consulted his friend, Sir Felix Semon, and Professor Sir St Clair Thomson on a number of occasions regarding his recurrent laryngitis. Semon and Thomson, though laryngologists, were both Fellows of the College and Semon was Physician Extraordinary to the Prince. There were frequent attacks of bronchitis and the Prince became short of breath on stairs and hills; later, when king, he developed glycosuria and an inci- sional hernia through the scar of his appendicectomy, which had necessitated postponement of his coronation in 1902. During his later years violent paroxysms of cough- ing caused intense cyanosis and he developed a tendency to fall asleep at lunch or dinner or at the theatre. On 8th February 1909 he had an episode of cough syncope at the British Embassy in Berlin. Sir James Reid, his physician and a Fellow of the College, managed the situation with the utmost skill and tact but everyone could see the deterioration in the King's condition. In February 1910 he had a further attack of bronchitis at Biarritz, with severe breathlessness, and although when he returned to Buckingham Palace at the end of April he endeavoured to continue all his normal duties and activities, he steadily deteriorated and died on May 6th. In his last days he was attended by Sir Francis Laking (who was a Member of the College but never a Fellow and who had risen from r being Surgeon Apothecary to much respected and trusted Physician in Ordinary), Reid, Sir Douglas Powell, who had been President of the College from 1905 to 1910, Dr 1 Bertrand Dawson, later Viscount Dawson of Penn, Se- 'j mon and St Clair Thomson. Sir Thomas Barlow, who had attended the King when he had his appendix removed in 1902, succeeded Powell "'( as President of the College and at Comitia on May 26th moved that messages of condolence from the College j should be sent to King George V and to Queen Alexan- > dra. The change in management of royal illness was strik- ing. When the King, as Prince of Wales, nearly died in 1871, Jenner and Gull issued up to Five bulletins in 24 hours. There were only two in all when the King died. The first was issued on May 5th because he was not fit to meet the Queen at the station on her return to England. 'The King is suffering from bronchitis and has been confined to his room for two days. His Majesty's con- dition causes some anxiety'. The second was issued on the following day, before he died at 11.45 p.m. 'The King has passed a comparatively quiet night, but the symptoms have not improved and His Majesty's condition gives rise to grave anxiety.' Bibliography Annual Register, 1870, 1871 and 1872. British Medical Journal, 1871, 1872, 1879, 1885, 1892, 1902 and 1910. Sir James Clark's Diaries. Debrett's Peerage, Baronetage, Knightage and Companionage. Godlee, R. J. (1917) Lord Lister. London: Macmillan. Hibbert, Christopher (1976) Edward VII. London: Collins. Lancet, 1871, 1872, 1879, 1885, 1892, 1902 and 1910. Longford, Elizabeth (1964) Victoria RI. London: Weidenfeld and Nicol- son. Magnus, Philip (1964) King Edward the Seventh. London: John Murray. Medical Directory. Medical Times and Gazette, 1871 and 1872. Munk's Roll. Paget, Stephen (1901) Memoirs and Letters of Sir James Paget. London: Longmans. Plarr's Lives of the Fellows of the Royal College of Surgeons of England. Punch, 1897. St Aubyn, Giles (1979) Edward VII. London: Collins. Stevenson, R. Scott (1946) Morell Mackenzie. London: Heinemann. The Times, 1864, 1870, 1871, 1872 and 1910. Whitfield, George (1981) The First Thirty-Seven Registrars of the College, Birmingham University. Whitfield, George (1983) Beloved Sir James. Birmingham University. Fig 2. Sir Francis Laking, Bart., GCVO, MD, MRCP, Physician in Ordinary and Surgeon Apothecary to King Edward VII. 118 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

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Psychiatric Illness in Expatriates PETER DALLY MB, FRCR FRCPsych Department of Psychological Medicine, Westminster Hospital, London Men and women and their families, whose work involves living abroad, are said to be more likely to break down than those who stay at home. Because of this it is estimated that one in seven Americans working overseas have to return home earlier than expected. If this is so, what are the particular stresses encountered abroad which make expatriates more vulnerable to psychiatric disorder? A number of factors need to be considered; the expatri- ate's personality; his or her expectations; the nature of the foreign country, its climate, political and ethnic press- ures, and the availability of social and leisure activities; their status, whether he or she is married, and with or without a family. The strains felt by a wife and children are inevitably different from those met by the husband. There have been virtually no studies of the psychiatric health of expatriates in the last 20 or 30 years, a period during which the life of foreigners, in Africa, the Middle East and the Far East especially, has changed rapidly and often unpredictably. Studies of immigration do not throw much light on the expatriates' problems. To look more closely at the matter I collected data from 50 consecutive British white expatriates referred to me (men, women and children) who had returned home because of psychiatric disorders. These examples came from all over the world; 52 per cent were in Far or Middle Eastern countries, 10 per cent in Africa, 8 per cent South America, 12 per cent in North America and the Caribbean, 14 per cent in Europe and Scandinavia, and 4 per cent from Iron Curtain countries. The strains of living behind the Iron Curtain are very different from those of Bangkok, Malawi or Bermuda. The people involved worked for a variety of organisations and institutions. Most expected to move every three or four years, but 6 per cent were static and intended to stay in the same place until they retired. Sample The sample was made up of 22 men (two-thirds married) and 6 women employees (all unmarried) whose ages ranged from 26 to 53. Forty-four per cent were depen- dents: 17 wives (not of course of the men in the sample) and 5 teenage females. The ages of the wives ranged from 28 to 50 years. The teenagers were between 13 and 17. Findings Depression was the most common condition among men and wives, followed by psychosomatic disorders and anxiety states. Alcoholism as a primary problem was rare, although alcohol abuse occurred in 23 per cent of expatri- ates with affective disorders. A paranoid psychosis devel- oped in half the female employees and one man. All five teenage children had anorexia nervosa. (This reflects my known interest in the illness.) Clearly there is likely to be a difference, both in presentation and course of the illness, between those who break down soon after going abroad and those who do so later. I have taken three time intervals: (a) the first nine months, (b) between nine months and four years and (c) after more than four years. I have chosen nine months because it is during this period of their new life that students who have neurotic or inadequate personalities are most likely to break down and give up. Nearly one-third collapsed in the first nine months (41 per cent male and half the female employees, but only one wife). Half the sample became ill in the second period. This included 41 per cent of the men, the rest of the female employees, and 70 per cent of the wives, a significant difference. Only 20 per cent of expatriates became disabled after four years. The majority of the men and women employees who broke down in the first nine months did so because they were unable to adjust to their new life abroad. They felt homesick, were disappointed with what they found, and increasingly missed the support of family and friends. Some withdrew into themselves, others tried the distrac- tion of living hectically and beyond their means, but all eventually became liabilities and had to be sent home. For most it was their first posting abroad. These people were emotionally insecure and lacking in confidence, although this was often disguised by their efficiency and drive at work. They had difficulty in communicating socially and in establishing friendships. The single expatriate in par- ticular had unrealistic expectations about life abroad. After nine months the remaining expatriates had, for the most part, settled down and adapted. The exceptions were the three women and one man who developed paranoid psychoses. Their social isolation and communi- cation difficulties continued. Their perception of events became increasingly distorted, and eventually psychotic. In the second period other factors began to assume increasing importance, notably marital dissatisfactions, which were responsible for 88 per cent of the breakdowns of wives, and played a part in 40 per cent of male illness. The expatriate wife syndrome is probably a universal one, developing out of the emptiness and frustration of her life. Her husband is ambitious and successful, ab- Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 103 sorbed in his work, popular with his colleagues and in demand socially. She cannot work, either because she has small children, or is unable to obtain a work permit, or her husband says 'No' for fear of lowering his status. She seeks friendship with other expatriate wives, but this is rarely satisfactory. She feels isolated and unhappy. She looks to her husband for understanding, but he is too busy with his professional life to respond other than perfunctorily. He expects her support rather than vice versa ? to entertain his boss and important friends, to enhance his reputation, and ensure that his life at home is as easy as possible. As this truth dawns on her so her demands on her husband increase. There are frequent rows. He spends more and more time at work, relieved to be away from his querulous wife. Their sexual relation- ship deteriorates. She may start an affair, attempting to boost her morale and attract his attention, but this is rarely helpful. Often, when reduced to a state of des- pair and near collapse, she returns home with the children. Work itself occasionally became an intolerable strain. Negotiations with government representatives over con- cessions and agreements, particularly when prolonged and difficult, resulted in disabling anxiety. Nepotism and xenophobia sometimes created frightening situations. A middle-aged man who had enjoyed working in an African state for 12 years ran into trouble with a black employee. The latter believed that he had been refused promotion out of malice and complained to friends in the govern- ment. For almost a year the Englishman was repeatedly investigated and threatened with expulsion. He was eventually able to prove that he had not discriminated against his employee, but the strain had been so great that a subsequent minor car accident caused him to collapse with acute depression and he had to be flown home for treatment. What happened to the expatriates after recovery? In 13 per cent the marriage ended; this is twice as likely when the wife is the patient. Of the employees, 16 per cent, all of whom had broken down in the first nine months, had their employment terminated; 31 per cent were trans- ferred to jobs in the UK, two-thirds of them to be reviewed after two years to decide their fitness for further posting overseas; 40 per cent returned to their jobs after treatment, but more than half continued on medication, sometimes prolonged. One wife remained on imipramine for 16 years; her husband insisted that she continue on the drug 'for as long as I need to work'. Family tensions often contribute to the development of anorexia nervosa in adolescents. Many mothers were depressed long before their daughters dieted and lost weight. Of the five teenagers who were sent home because of anorexia nervosa, four came from unhappy families. None of the mothers worked, all were dissatisfied with their lives and angry with their husbands. They felt trapped. The picture was that of the expatriate wife syndrome, complicated by the daughter's reaction to her mother's unhappiness. In at least two of the five cases the daughter's illness resulted in the mother leaving her husband. Discussion It is difficult to assess how great the psychiatric morbidity of expatriates is, compared to that of those who stay at home. Anxiety and depression are common conditions but, in one's own country, with friends and relations to turn to for support and comfort, and competent psychia- trists at hand, the sufferer can be helped and treated, often without serious disruption to either working or private life. The strains encountered abroad differ in degree rather than in kind from those at home. The first nine months are a time of adjustment, and those who broke down during this period did so mainly because of an inadequate personality structure. It has been suggested that candi- dates for posts abroad should be screened, and sub- sequently excluded if they seem vulnerable. But this is easier said than done. Only half those expatriates who broke down in the first nine months would have shown clear signs of vulnerability at interviews, and in any case, to rule out everyone with a neurotic personality from working abroad would be like throwing out the baby with the bathwater. Every neurotic is not necessarily subject to breakdowns and many are highly talented, successful and reliable. Marital difficulties were a common source of strain. Tensions developed, often in subtle ways at first, and eventually began to affect both partners, but particularly the wife, who all too often abroad, in predominantly male-orientated cultures, is prevented by consideration for her husband's career from pursuing her own interests. It must be admitted that many wives cannot, or will not, take advantage of the new situations in which they find themselves. Nevertheless, it is unrealistic to suggest that employers try to analyse the quality of their employees' marriages. Few couples are likely to co-operate honestly with a stranger over what goes on between them, particu- larly if they are keen to go abroad, but a friendly discussion of the problems that they may have to face in the other country could be useful. It is salutary to note that the majority of expatriates develop no serious psychiatric problems abroad. On the contrary, the lives of many are greatly enhanced and enriched by the experience. In general they are financial- ly better off, have servants and maybe a pleasant climate, new diversions and a ready-made social life among the other expatriates. Afterwards, returning home for good can often be something of a let-down. It is then that their troubles can start. 104 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

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Endothelium Derived Relaxant Factor T. M. GRIFFITH, MB, MRCP(UK), Registrar in Radiology D. H. EDWARDS, British Heart Foundation Technician E COLLINS, MB, MRCP(UK), British Heart Foundation Junior Research Fellow M. J. LEWIS, MB, PhD, Senior Lecturer in Pharmacology A. H. HENDERSON, MB, FRCF! Professor of Cardiology (BHF Sir Thomas Lewis Chair) University of Wales College of Medicine, Heath Park, Cardiff The phenomenon of endothelium mediated vasodilata- tion has become apparent only in the last few years. It is likely to be of considerable physiological importance, though there is much that is yet unknown about it. We first became aware of it when we were developing an isolated coronary artery preparation, as a more appro- priate model than conventional strip preparations, with which to investigate vasomotor control mechanisms in large coronary arteries. It is, of course, the large coronary arteries that are particularly relevant to the pathogenesis of coronary artery disease in man. The preparation consisted of an isolated intact left coronary artery of the rabbit, perfused at constant flow, with monitoring of pressure as a measure of constrictor tone. Initially we observed the expected increase in perfusion pressure upon infusion of a variety of vasoconstrictor agents, but as we gained experience with the preparation we became less able to elicit these conventional constrictor responses. We then noted that localised damage to the arterial wall in an otherwise unresponsive artery would result in a localised response[l]. The nature of this phenomenon became clear when in 1980 Furchgott published his evidence that endothelium possesses vasodilator proper- ties^]: he showed that acetylcholine, generally regarded as an arterial constrictor, exerted a paradoxical dilator effect if the vessel wall endothelium was carefully pre- served during preparation (Fig. 1). We therefore devel- oped ways of preserving or removing endothelium in our preparation, validated always by en face silver staining, and proceeded to study its contribution to vasomotor control. Using the perfused coronary artery preparation of the rabbit we compared concentration-response curves, with and without endothelium, to a number of physiologically relevant constrictors?histamine, acetylcholine, 5-hy- droxytryptamine and phenylephrine. The influence of the endothelium was striking: it markedly suppressed, to the point of almost abolishing, the constrictor responses (Fig. 2). We also found that deliberate localised damage to the artery made it susceptible to localised constriction? reversible, reproducible and non-specific. Local endothe- lial damage had converted one dose-response into the other and, in effect, had reproduced a model of 'coronary spasm'. Parallel experiments were performed in conventional isometrically mounted aortic strip preparations of the rabbit?again with and without endothelium (Fig. 3). In this preparation, by contrast to the perfused coronary preparation, the endothelium exerted relatively little in- fluence on the responses. Statistical comparison showed that there was nevertheless a significant difference be- tween the responses with and without endothelium, albeit in the opposite direction with all the constrictors except acetylcholine which was known from Furchgott's work to stimulate the endothelium-dependent dilator response. The paradoxically greater constrictor response to the other three agents in the presence of intact endothelium was subsequently explained by the fact that the response starts from a lower baseline in the presence of endotheli- Fig. 1. Effect of acetylcholine (Ach) (10~6M) in aortic strips preconstricted by 5-hydroxytryptamine (5HT). In preparations with an intact endothelium (left panel) relaxation occurs: in preparations denuded of endothelium (right panel) further constriction occurs. 74 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 um, due to basal activity of the endothelium-dependent dilating effect, and that the ceiling of the constrictor response is the same with or without endothelium, as the constrictor response over-rides the basal endothelium derived relaxant factor (EDRF) actitivity[ 1 ]. The phenomenon of endothelium-dependent vasodila- tation is likely to be of general physiological relevance: it has been demonstrated in all mammalian species so far studied, including man, and in all types of blood vessel. Our data with the coronary arteries show furthermore that it can be very potent. Its underlying mechanism has become a subject of intensive investigation. The Nature of EDRF Furchgott postulated that the phenomenon was mediated by a humoral agent released from endothelial cells. To test such a hypothesis we developed a bioassay for the putative vasodilator substance (or EDRF)[3], Figure 4 shows the bioassay system schematically. An intact aorta possessing endothelium is perfused in series with a coron- ary artery which has been denuded of endothelium and preconstricted by the infusion of a constrictor agonist. The pressure response of the coronary artery allows detection of vasomotor substances in the coronary perfu- sate. The length of the intervening tubing can be altered to give a range of transit times between aorta and No endothelium Intact endothelium Fig. 2. Coronary artery responses to histamine (A), acetylcho- line (M)t 5-hydroxytryptamine ( 6 ) and the -agonist phenyl- ephrine (+) are markedly depressed by the presence of intact endothelium (right panel), compared to responses in prepara- tions denuded of endothelium (left panel). _8 -7 -6 -5 -4-3-2 Logio molarity No endothelium 16OO-1 Intact endothelium -9 -8 -7-6-5 -4 Logio molarity Fig. 3. Aortic responses to histamine (A), acetylcholine (W), 5-hyd.roxytryptam.ine (* ) and phenylephrine (+) are relatively similar in the presence of endothelium (right panel) and in its absence (left panel). Responses to acetylcholine are depressed in the presence of endothelium, but those to the other agents are (paradoxically) enhanced by the presence of endothelium. Flow I ,4k AORTA Intact endothelium G> CORONARY No endothelium preconstricted Y ?Proximal (P) -Distal (D) Fig. 4. Diagram of bioassay system, t = pressure transducer. Fig. 5. Representative trace of a bioassay experiment. The coronary artery is preconstricted by infusion of 5HT (10'5M) and acetylcholine (Ach) (10~6M). a, = introduction of unstimu- lated aorta into circuit. A, = stimulation of aorta by Ach, infusion of which is transposedfrom post- to pre-aortic (see Fig. 4). Basal release from an unstimulated aorta and enhanced release from stimulated aorta are shown. ai \ \ f ) Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 198o coronary artery. Drugs can be infused into the interven- ing tubing either proximally or distally to allow different interaction times with EDRF in transit. Figure 5 shows a typical experiment, where the coron- ary has been preconstricted by infusion of 5-hydroxytryp- tamine plus acetylcholine. When an aorta possessing intact endothelium is introduced into the circuit a small fall in pressure is seen, due to basal release of EDRF into the aortic effluent. When the aorta is perfused by acetyl- choline, the fall in pressure is much larger, as acetylcho- line stimulates EDRF release from the aortic endothelium. Such experiments demonstrate that EDRF is indeed a humoral agent released continuously in the basal state and whose release can be stimulated by acetylcholine (for up to an hour in good preparations). By altering the transit time between the aorta and coronary it was possible to measure the half-life of EDRF (Fig. 6). From the straight line relationship between the logarithm of dilatatiomand transit time, the half-life of EDRF was calculated as about six seconds. Other workers have subsequently performed similar experi- ments using different experimental models and different mammalian species, and found an almost identical half- life: 5.4 + 0.4 sec for EDRF from cultured bovine cells[4], and 6.3 ?1.2 sec with EDRF from dog femoral arte- ries[5]. Recent data indicate that the exact half-life is influenced by molecular oxygen and has been obtained as 24 + 3 sec with EDRF from rabbit aorta[6] and 49 + 5 sec with EDRF from dog femoral arteries[6] at lower oxygen tensions than used in the above experiments. The present evidence suggests that the EDRF molecule is similar if not identical in all mammalian species. To characterise the chemical nature of EDRF, different agents were tested to see which might inhibit its action. A large number of compounds was screened in aortic strip preparations. Those found to be effective were then studied using the bioassay system (Fig. 7) to distinguish those which interacted chemically with EDRF in transit from those which influenced its production or its action on smooth muscle. The two chemical properties that emerge as common to agents which inhibited endotheli- um-mediated relaxation by direct chemical interaction with EDRF are that they are either antioxidants or combine with carbonyl groups?properties that are mutu- ally consistent. Analysis of concentration-inhibition curves provides evidence that the interaction of EDRF with the four inhibitors?phenylhydrazine, potassium borohydride, dithiothreitol and phenidone?obeys first- order kinetics[7]. We were also able pharmacologically to exclude the possibility that EDRF is a cyclo-oxygenase product, such as prostacyclin, or a lipoxygenase product, such as a leucotriene. We conclude that EDRF probably possesses a carbonyl group at or near its active site[3]. However, the chemical identity of this unstable agent remains to be defined. Mechanisms of Action of EDRF There is now a substantial body of evidence that nitrodi- lators such as glyceryltrinitrate and nitroprusside act by elevating smooth muscle cyclic guanosine monophos- Fig. 6(a). Increasing transit time between aorta and coronary artery from 4 to 21 sec causes a marked fall off in EDRF induced vasodilatation, (b) A logarithmic plot of dilatation against transit time yields a straight line allowing calculation of EDRF half-life as 6.3 ? 0.3 sec. Fig. 7. Bioassay experiment, showing dilator response to EDRF released from stimulated aorta (A,) and the effect of infusing the EDRF inhibitor, potassium borohydride, into the intervening tubing. Distal infusion (D) to allow 0.5 sec interaction time has little effect. Proximal infusion (P) to allow a 4 sec interaction time results in complete inhibition. Phenylhy- drazine and antioxidant inhibitors gave similar results. 76 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 phate (cGMP) levels[8, 9]. Their physiological and bio- chemical effects can be inhibited by methylene blue (which inhibits the enzyme guanylate cyclase)[8, 9] and potentiated by MB22948 (which prevents cGMP hydroly- sis by inhibiting the enzyme cGMP phosphodiesterase)^, 10]. Evidence that EDRF might act in an analogous manner appeared when Austrian and American workers demonstrated elevation of arterial cGMP when endotheli- um was stimulated to produce EDRFfll, 12]. Further- more, EDRF and nitrodilator-induced relaxation are associated with identical alterations in the phosphoryla- tion!^] ?f proteins, including contractile proteins. Using these pharmacological probes infused at different sites into the bioassay system, we have confirmed that they influence the action of EDRF at the level of the smooth muscle response (Fig. 8) and shown that they do not exert an additional effect on EDRF release or by interacting with EDRF in transit[14], It thus appears that EDRF behaves functionally as an endogenous 'nitrite'. Relevant to our hypothesis that EDRF contains a carbonyl group is the finding that carbonyl agents stimulate guanylate cyclase[15]. The intracellular control of tension development in smooth muscle is inadequately understood. cGMP is thought to mediate one mechanism of relaxation through altered phosphorylation of contractile proteins. We have recently shown that EDRF-mediated dilatation is also associated with a reduction of net influx of calcium, which might contribute to its mode of action[16]. This finding may explain the apparently greater sensitivity of the coronary artery than the aorta to the dilator action of EDRF[1]: vasoconstriction in the rabbit coronary artery is very largely dependent on influx of extracellular Ca+ +, whereas in the aorta it is more dependent on mobilisation of Ca+ + from intracellular sites (unpub- lished observations). Production of EDRF Basal release can be demonstrated from the rabbit aortic preparation, and its stimulated release can likewise be maintained for up to an hour. Endothelium-dependent relaxation has been found to be stimulated by a large number of agents, with some differences between differ- ent vessels and different species (Table 1). Consideration of the naturally occurring substances which appear in this list must provide pointers to the possible physiological role of EDRF. It should perhaps be noted that not all observed endothelium-dependent dilatation has yet been confirmed by bioassay as indeed being due to EDRF, though this seems likely. Notably, EDRF release is stimulated by the calcium ionophore A23187. We have confirmed that it is depen- dent on the presence of extracellular calcium[33]: in bioassay experiments its production can be abruptly stopped by removal of extracellular calcium and equally rapidly restored by its replacement (Fig. 9). It is not known if calcium is required for de novo biosynthesis or for release of stored EDRF from intracellular vesicles. The presence of some oxygen also appears to be a necessary requirement[2]. Duration of Effect The half-life of EDRF in well oxygenated aqueous buffer at 37?C is 6 sec. The duration of its effect in the vascular compartment in vivo is almost certainly much shorter. We have shown that a heat labile component of plasma blocks EDRF activity in aortic strips (unpublished observa- tions). Endothelial permeability is increased under these unphysiological in vitro conditions so that plasma proteins probably penetrate the endothelial barrier[34]. The im- plication is that EDRF will be rapidly inactivated in the intravascular compartment in vivo, so localising its effect to adjacent smooth muscle, with no downstream effect. Therefore EDRF may be regarded as an autocoid. It has recently been observed that the vascular effects of EDRF can be inhibited by > 10" 7M free haemo- globin^], an observation which may be relevant in a number of pathological conditions. Possible Endogenous Analogues of EDRF It is of considerable interest that an inhibitory neurotrans- mitter isolated from retractor penis and anococcygeous muscle of a number of species has many characteristics in common with EDRF[36], It relaxes both vascular and non-vascular smooth muscle[37], and is thought to do so by elevating smooth muscle cGMP levels[38]. It is also known to be unstable and appears to be a carbonyl compound[39]. EDRF may therefore represent one of a family of physiologically important and previously unde- scribed substances. 1 min X -i105 E E J80 i?. I D j 5HT 10~5M + ACh 1Q-6M ,100 50 ACh 3.10"6M ?L Methylene blue 10"6M MB22948 10~6M Fig. 8. Bioassay experiment showing effect of (a) methylene blue and (b) MB22948. Left traces show negligible effects of adding these agents solely to the coronary perfusate (control, C). Right traces show EDRF mediated dilatation by effluent from a stimulated aorta (A;), with addition of agents distally (D) or proximally (P) into the intervening tubing. In each case the effects of proximal and distal infusion are identical (unlike those of direct EDRF inhibitors, Fig. 7). Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 77 Table 1. EDRF stimulation in different species. Receptor type/ EDRF Stimulant mechanism Species A23187 (calcium ionophore) acetylcholine adenosine diphosphate (ADP) adenosine triphosphate (ATP) clonidine ergometrine ergometrine histamine hydrallazine 5-hydroxytryptamine noradrenaline thrombin Peptides: vasoactive intestinal polypeptide bradykinin substance P cholecystokinin Electrical stimulation Non-specific: saturated/unsaturated fatty acids (may stimulate or block) ? increased calcium influx muscarinic P2 Pa 0i2 not 5HT or a p H, p ?5HT, a2 heparin-sensitive receptor VIP bradykinin substance P ? substance P ? increased calcium influx ? membrane fluidity man[17], rabbit[3, 18, 19] man[17], rabbit[2], guinea-pig[2], cat[2], rat[2], dog[20] rabbit[3, 21], dog[20], pig[22] rabbit[3, 21], dog[20], pig [22] dog[23] rabbit[24] man[l 7] dog[25], rat[26], NOT rabbit[l] rabbit[27] dog[24, 28], NOT rabbitfl] dog[24], pig[24] dog[29] rat[30] man[31], dog[31], NOT cat[31] rabbit[21], dog[21], cat[21 ] rabbit[21] rabbit[32], cat[32], monkey[32] rabbit[2], dog[21] Physiological and Pathophysiological Role for EDRF The physiological role of this newly recognised and potent dilator substance remains to be established, as does its potential role in disease states. The vasomotor control I mechanisms that exist in the intact circulation are clearly multiple and complex. We may nevertheless speculate on the physiological and pathophysiological roles of EDRF, mindful of the number of naturally occurring agents capable of influencing EDRF activity. In large arteries EDRF is likely to act as a physiological regulator in response to intravascular events. Thrombosis will expose the endothelium to agents such as adenosine diphosphate (ADP) and 5-hydroxytryptamine (5HT) which are released from platelets and are known to stimulate EDRF. This would represent a short-term negative feedback. That such a phenomenon may be important in vivo is suggested by tissue bath experiments 1 showing that arterial smooth muscle relaxes in response to aggregating platelets when intact endothelium is present and contracts when the endothelium is removed[40], The possibility of local spasm where endothelium is function- ally impaired, particularly in arteries susceptible to its action such as the coronary, may be relevant to pathoge- netic mechanisms in variant angina. We have shown that ergometrine maleate, an agent used to provoke coronary , artery spasm in susceptible patients, is able to stimulate EDRF release[25]; functional impairment of endothelium and consequent lack of EDRF effect may therefore ex- plain its usefulness in this test. Inactivation of EDRF by haemoglobin and plasma proteins may be relevant to the > prolonged arterial spasm which is sometimes seen after subarachnoid haemorrhage. Endothelium-dependent dilatation has been described in relation to flow rate[41], acting presumably through shear stress on the endothelium, though it has not yet been proved that this phenomenon is mediated by EDRF itself. Flow-dependent endothelium-mediated dilatation I 1 min i ACh 10-5M Fig. 9. Bioassay experiment demonstrating dependence of EDRF production on extracellular calcium: left trace shows a control experiment demonstrating EDRF mediated vasodilata- tion by effluent from the stimulated aorta (At) while this is in circuit (horizontal bar). Right trace shows loss of vasodilator response when calcium is omitted from the aortic perfusate (but infused into intervening tubing to maintain normal calcium in coronary perfusate) and demonstrates the immediate recovery of dilator responses (with overshoot) on re-introduction of calcium into aortic perfusate. 78 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 may be an important homeostatic mechanism coupling large artery calibre to changes in microvascular resis- tance, thus optimally distributing shear stress at the blood-intimal interface throughout the vascular tree. The influence of EDRF activity on resistance vessels has not been adequately investigated. Peptides such as vasoactive intestinal polypeptide (VIP), whose action is endothelium-dependent in large arteries at low concentra- tions[30], have been demonstrated histochemically in nerve endings found in the adventitia around small vessels[42]. It is possible therefore that there is neurogeni- cally-mediated control of EDRF in the microvasculature, the stimulus in this case arriving from outside these small vessels where diffusion distance is small. Concentrations of VIP known to stimulate EDRF release in vitro can be detected in the effluent from some isolated organ prepara- tions when their nerve supply is stimulated and there is accompanying vasodilation[43]. This action may be a component of the complex neurogenically mediated vaso- motor mechanism of penile erection[44]. Substance P, derived from sensory nerve terminals, is also a stimulant of EDRF and has been shown in rat hind limb prepara- tions to mediate neurogenic vasodilatation[45]. Acetyl- choline and VIP have been shown histochemically to co- exist in the same nerve terminals[42] and of course both are potent stimulants of EDRF. Does EDRF participate in the ultimate mechanism of the neurogenic vasodilata- tion that results from vagal activity, as in vasovagal syncope? It is intriguing to speculate whether alterations in EDRF activity play any part in atherogenesis. Experi- mental atheroma is associated with increased calcium influx, can be induced experimentally by alteration of calcium metabolism and prevented by calcium antagon- ists^, 47], We have shown that EDRF reduces calcium influx in vitro as measured with 45Ca flux studies. Con- versely, the presence of atheroma, an intimal disease, may itself affect EDRF activity, either by altering its production or by interposing a physical barrier between the endothelium and the smooth muscle. Indeed, it has recently been reported that endothelium-dependent relax- ation is diminished by atheroma in both human coronary arteries[17] and in rabbits fed a cholesterol-supplemented diet[48]. This article is based on a paper read by Dr T. M. Griffith at the College Regional Conference in Oxford in September 1984. ^excrences 1. Griffith, T. M., Henderson, A. H., Hughes Edwards, D. and Lewis, M.J. (1984) Journal of Physiology (London), 351, 13. 2- Furchgott, R. F. and Zawadzki, J. V. (1980) Nature, 288, 373. 3. Griffith, T. M., Edwards, D. H., Lewis, M. J., Newby, A. C. and Henderson, A. H. (1984) Nature, 308, 645. 4. Cocks, T. M., Angus, J. A., Campbell, J. H. and Campbell, G. R. Journal of Cellular Physiology (in press). 5. Vanhoutte, P. M. (personal communication). 6. Forstermann, U., Trogisch, G. and Busse, R. European Journal of Pharmacology (in press). 7. Griffith, T. M. (1984) European Heart Journal (in press). 8. Gruetter, C. A., Gruetter, D. Y., Lyon,J. E., Kadowitz, P.J. and Ignarro, L. J. (1981) Journal of Pharmacology and Experimental Thera- peutics, 219, 181. 9. Kukovetz, W. R., Holzmann, S. and Poch, G. (1982) Naunyn- Schmiedeberg's Archives of Pharmacology, 319, 29. 10. Nemoz, G., Prigent, A. F., Picq, M. and Pacheco, H. (1982) Biochemical Pharmacology, 31, 3353. 11. Holzmann, S. (1982) Journal of Cyclic Nucleotide Research, 8, 409. 12. Rapoport, R. M. and Murad, F. (1983) Circulation Research, 52, 352. 13. Rapoport, R. M., Draznin, M. B. and Murad, F. (1983) Nature, 306, 174. 14. Griffith, T. M., Henderson, A. H., Hughes Edwards, D. and Lewis, M. J. (1984) Journal of Physiology (London), 350, 46P. 15. Sobolev, A. S., Tertov, V. V. and Rybalkin, S. D. (1983) Biochimica et Biophysica Acta, 756, 92. 16. Collins, P., Griffith, T. M., Lewis, M.J. and Henderson, A. H. Journal of Physiology (London) (in press). 17. Ginsburg, R. and Zera, P. H. (1984) Circulation, 70, Suppl II, 122. 18. Furchgott, R. F. (1981) Trends in Pharmacological Sciences, 2, 173. 19. Singer, H. A. and Peach, M. J. (1983) Journal of Pharmacology and Experimental Therapeutics, 226, 796. 20. De Mey, J. G. and Vanhoutte, P. M. (1981) Journal of Physiology (London), 316, 347. 21. Furchgott, R. F. (1983) Circulation Research, 53, 557. 22. Gordon, J. L. and Martin, W. (1983) British Journal of Pharmacology, 79, 531. 23. Cocks, T. M. and Angus, J. A. (1983) Nature, 305, 627. 24. Griffith, T. M., Hughes Edwards, D., Lewis, M.J. and Hender- son, A. H. (\9M) Journal of Molecular and Cellular Cardiology, 16, 479. 25. Toda, N. (1984) British Journal of Pharmacology, 81, 301. 26. Van De Voorde, J. and Leusen, I. (1982) Archives Internationales de Pharmacodynamic, 256, 329. 27. Spokas, E. G., Folco, G., Quilley, J., Chandker, P. and McGiff, J. C. (1983) Hypertension, 5, Suppl I, 107. 28. Cohen, R. A., Shepherd, J. T. and Vanhoutte, P. M. (1983) American Journal of Physiology, 245, HI 07 7. 29. De Mey, J. G., Claeys, M. and Vanhoutte, P. M. (1982) Journal of Pharmacology and Experimental Therapeutics, 222, 166. 30. Davies, J. M. and Williams, K.I. (1983) Journal of Physiology (London), 343, 65P. 31. Cherry, P. D., Furchgott, R. F., Zawadzki, J. V. and Jothianan- dan, D. (1982) Proceedings of the National Academy of Sciences of the United States of America, 79,2106. 32. Frank, G. W. and Bevan,J. A. (1983) American Journal of Physiology, 244, H793. 33. Singer, H. A. and Peach, M.J. (1982) Hypertension, 4, Suppl II, 19. 34. Schneeberger, E. E. and Hamelin, M. (1984) American Journal of Physiology, 247, H206. 35. Furchgott, R. F., Cherry, P. D., Zawadzki, J. V. and Jothianan- dan, D. (1984) Journal of Cardiovascular Pharmacology, 6, S336. 36. Ambache, N., Killick, S. W. and Zar, M. A. (1975) British Journal of Pharmacology, 54, 409. 37. Bowman, A. and Gillespie, J. S. (1983) Journal of Physiology (London), 341, 603. 38. Bowman, A. and Drummond, A. H. (1984) British Journal of Pharmacology, 81, 665. 39. Gillespie, J. S., Hunter, J. C. and Martin, W. (1981) Journal of Physiology (London), 316, 111. 40. Cohen, R. A., Shepherd, J. T. and Vanhoutte, P. M. (1983) Science, 221, 273. 41. Holtz, J., Busse, R. and Giesler, M. (1983) Naunyn-Schmiedeberg's Archives of Pharmacology, 322, R44. 42. Lundberg, J. M., Fahrenkrug, J., Hokfelt, T. el al. (1984) Peptides, 5, 593. 43. Andersson, P. O., Bloom, S. R. and Jarhult, J. (1983) Journal of Physiology (London), 334, 293. 44. Andersson, P. O., Bloom, S. R. and Mellander, S. (1984) Journal of Physiology (London), 350, 209. 45. Lembeck, F., Donnerer, J. and Bartho, L. (1982) European Journal of Pharmacology, 85, 171. 46. Fleckenstein-Grun, G., Frey, M. and Fleckenstein, A. (1984) Trends in Pharmacological Sciences, 5, 283. 47. Blumlein, S. L., Sievers, R., Parris, K. and Parmley, W. W. (1984) American Journal of Cardiology, 54, 884. 48. Habib, J. B., Wells, S. L., Williams, C. L. and Henry, P. D. (1984) Circulation, 70, Suppl II, 123. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

PMC005xxxxxx/PMC5371016.txt

r- Are Calcium Antagonists Cardioprotective? M. J. KENDALL, MD, FRCP, Senior Lecturer R. C. HORTON, BSc, Medical Student Department of Therapeutics and Clinical Pharmacology, Queen Elizabeth Hospital, Edgbaston, Birmingham Calcium antagonists are establishing themselves as major therapeutic agents in the management of hypertension and angina. Both conditions put the patient at risk from a myocardial infarction (MI) and treatment should ideally reduce this risk. Beta-blockers, perhaps the major class of drugs used in these two conditions, have acquired a reputation for being cardioprotective. In this context, the term is used to indicate that they reduce heart work, decrease arrhythmias and modify platelet function, effects which may diminish the adverse effects of coronary artery disease. In addition, beta-blockers have been given pro- phylactically to animals whose coronary arteries are to be ? occluded[l,2], to hypertensives[3], and, both acutely[4,5] and chronically[6,7], to patients after cardiac infarction. - ? In each situation they appear to improve the prognosis. If calcium antagonists are to become first-line treatments for angina and hypertension, should they also have a cardioprotective role? Clinical data on cardioprotection can only be obtained from large-scale trials. In the case of calcium antagonists such data may not be available for many years. However, since these drugs are already in widespread use, it seems ? _ reasonable to ask now: (a) Are there theoretical reasons for supposing they may reduce the adverse effects of ischaemic heart disease? (b) Are there animal data suggesting that these drugs reduce infarct size? (c) Are there any clinical data on the use of calcium antagonists in patients at or after a myocardial infarction? ^ - These questions will be considered in turn. Possible Cardioprotective Actions of Calcium Antagonists Calcium antagonists could reduce infarct size by their impact on the supply and demand imbalance in the myocardium. This may be achieved by improving coron- < ary blood flow or by reducing heart work. Calcium antagonists might also reduce mortality by reducing the damage caused by hypoxia and by having an anti- arrhythmic action. Coronary Blood Flow (a) Vasospasm. Calcium antagonists reduce coronary ar- tery spasm[8,9] and act as vasodilators[10]. These effects have been of interest in recent years as it has been increasingly appreciated that angina and infarction are by no means always the result of a fixed obstruction. The fact that recurring anginal episodes occur at rest, when there is no increased demandfl 1-13], and take place despite considerable variability in fixed coronary le- sions[14], shows that another, spontaneous, process is operating. Such vasospasm may be assumed to play a role in Prinzmetal's angina, in situations where angiographic evidence or ergonovine injection testing is positive and where anti-vasospastic drug treatment is helpful. In their investigations into the pathophysiology of MI, Maseri's group[15] showed that infarction occurred in 37 of 76 patients with rest angina involving coronary spasm as shown by angiography. The infarcted area was closely associated with the region supplied by the vessel undergo- ing spasm. Calcium antagonists have been repeatedly shown to possess anti-vasospastic properties. Through their block of excitation-contraction coupling in coronary artery smooth muscle[8] they reduce vascular tone, and there- fore resistance, with a subsequent increase in coronary blood flow[9]. (b) Platelets. Platelet aggregation exacerbates the effects of diseased coronary arteries by predisposing to occlusive thrombus formation[16] and by the release of vasocon- strictor substances[17,18]. Calcium antagonists reduce platelet aggregation, a calcium dependent process[19], an effect which has been demonstrated both in vitro[20] and in patients with angina[19,21]. (c) Viscosity and Flow. Some drugs are reputed to improve tissue perfusion by modifying the flexibility of red blood cells and thereby facilitating their flow down narrow blood vessels. There is evidence that an increase in red cell calcium decreases deformability[22] and that calcium antagonists increase it[23]. Heart Work The ability of calcium antagonists to improve cardiac haemodynamic efficiency and thereby reduce demand on the heart is well known. By their actions on cardiac muscle and arterial smooth muscle, calcium antagonists may reduce wall tension and peripheral resistance. Of these, the dilating effect on the peripheral arteries is probably the most important[10]. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 Protection from Hypoxic Damage At the onset of a myocardial infarct several processes may lead to an increase in intracellular calcium which may be the cause of cell death[24,25]. First, catecholamines released at this time will markedly increase calcium uptake into myocardial cells[26]; this causes activation of the calcium-dependent myofibrillar ATPase and results in an abnormally high consumption of energy-rich phos- phates. In addition, the mitochondria try to take up calcium ions from the cytosol and so consume energy. This causes decoupling of oxidative phosphorylation and structural damage. A reduction in the cellular uptake of calcium across the cell membranes could therefore be expected to produce a protective effect. This may be achieved by blockade of the slow calcium channels[10] and also by an effect on calmodulin[27,28]. If calcium antagonists have this effect on the hypoxic cells in a human myocardial infarct, it is possible that they might reduce muscle damage. Anti-arrhythmic Action Beta-blockers reduce the risk of sudden death from myocardial re-infarction and this might be due to their ability to reduce the extent of ischaemia and to block the development of arrhythmias[29]. This is of interest since beta-blockers do not have a major therapeutic role in the treatment of ventricular tachyarrythmias. The hope that calcium antagonists may reduce mortality in the same way has received little attention. Correction of calcium influx into ischaemic myocardial cells can retard the development of ventricular fibrilla- tion[30]. Originally, the retardation was ascribed to increased coronary blood flow and reduced cardiac work, as shown by studies of verapamil in dogs with com- plete^ 1] or temporary[32] coronary artery occlusion. Recently, however, it has been demonstrated that cal- cium antagonists can directly suppress ventricular fibril- lation induced by ischaemia[30,33,34]. Nifedipine, widely thought to have few anti-arrhythmic actions, reduces the incidence of ventricular fibrillation, ventricu- lar tachycardia and ventricular ectopic activity in rats[35] and inhibits calcium-dependent myocardial excitability in dogs with one-day-old infarcts[36]. Evidence of Cardioprotection from Animal Studies The three major calcium antagonists currently in clinical use?verapamil, nifedipine and diltiazem?have all been investigated in a wide variety of animal models. The data from these have to be interpreted with caution. Drugs which act as vasodilators must be expected to have different effects in animals which readily form a collateral circulation, such as dogs[37], compared with those which do not, such as pigs and baboons[38]. Second, where infarct size is the end point, care must be taken to ensure that the time allowed for its development is compar- able^]. Third, the effects of surgery and anaesthesia have to be considered[40]. Finally, different calcium blockers have very different actions[41-43]. Nifedipine causes coronary and peripheral vasodilatation while hav- ing few chronotropic effects. Verapamil and diltiazem prolong atrioventricular nodal conduction and have less effect on vascular smooth muscle. In addition, verapamil and nifedipine are negative inotropic agents, while diltia- zem is probably not. Verapamil and its Analogues In open chest anaesthetised dogs, pre-treatment with verapamil reduces the extent of tissue necrosis as measured histologically following left circumflex artery occlusion[44]. DaLuz[45] found that treatment both be- fore and after occlusion increased collateral blood flow to the ischaemic myocardium, reduced heart rate, thus reducing metabolic demand, and reduced ST elevation, indicating a decrease in infarct size. In addition, Wende[46] demonstrated that verapamil infusion during coronary artery ligation reduced infarct size as measured by epicardial ST segment changes. Verapamil also selec- tively depressed ischaemic myocardium, thereby reduc- ing injury to the ischaemic tissue[47]. However, the favourable effects of intravenous verapamil treatment after ligation have been challenged[48,49]. In conscious dogs, DeBoer[50,51] was the first to find that verapamil administered one hour after infarction produced a short-term significant decrease in infarct size. Yellon[52] extended this by showing the longer term tissue sparing effect of verapamil treatment. Urqu- hart[40], using physiologically equipotent doses of vera- pamil, nifedipine and diltiazem, showed that all three drugs caused coronary and systemic vasodilatation, re- duced heart rate and reduced myocardial contractility following left circumflex artery ligation. Two other studies have yielded negative results[53,54]. Cardioprotective effects have also been demonstrated in other animals including the open chest anaesthetised baboon[55], rabbits[56] and in the isolated rat heart[34]. Verapamil and its analogues clearly appear to have significant cardioprotective effects in most animal mod- els, but a number of studies[47,57] have emphasised the need to use low doses of verapamil since higher doses will precipitate heart failure with consequent extension of the infarcted area. Dihydropyridines (nifedipine and related compounds) Using open chest anaesthetised dogs to assess cardiopro- tection, the dose of dihydropyridines, like that of verapa- mil, was found to be important. Low doses improve regional myocardial blood flow and cause reduced cre- atine kinase (CK) release while higher doses cause an increased heart rate and hypotension, with resultant extension of the infarcted area[58-60]. Heart rate and blood pressure readings should therefore be used to monitor dosage. Henry[61] demonstrated the efficacy of nifedipine in producing increased collateral perfusion to ischaemic myocardium and reduced vascular resistance distal to the occlusion, and Clarke[62] showed a reduction in the injury volume. Weintraub[63] emphasised the direct effects of nifedipine on myocardial cells and found 86 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 an increase in sub-endocardial blood flow in non-ischae- mic tissue with improved muscle function in the ischae- mic zone. In conscious dogs it has been shown that nifedipine increased collateral blood flow to ischaemic myocardium and reduced ischaemic injury as measured by enzyme < losses[64,65], Melin[66] attempted to mimic the clinical situation further by delaying nifedipine intervention until three hours after coronary artery occlusion. Even then ? ^ there was a reduction in infarct size combined with an increased collateral blood flow. ** As with verapamil, studies using the baboon, rabbit and rat hearts[67-69] have confirmed the results found in the dog. The cardioprotective actions of dihydropyridine cal- cium antagonists have been demonstrated in many differ- ent centres. Geary[70] is the only worker to have shown no effect of nifedipine on infarct size. He used the open chest anaesthetised baboon, an animal with little potential for developing a collateral supply. Diltiazem Diltiazem, given soon after coronary occlusion, improved > ischaemic muscle function in anaesthetised open chest dogs[71,72]. In the same preparation, diltiazem reduced infarct size as measured by ST elevation and percentage of tissue at risk, increased regional myocardial blood flow, increased tissue ATP, reduced lactate levels and - > improved ischaemic muscle function[73,74]. In chronically instrumented dogs, Franklin[75] showed that diltiazem improved collateral blood flow to the ischaemic tissue. Clozel[76] reinforced this finding by demonstrating improved function of hypokinetic muscle segments after treatment with diltiazem. Confirmatory studies on the efficacy of diltiazem have also been performed on pigs[77], rats[78] and isolated preparations[79]. These studies and those in dogs indi- cate that diltiazem is a useful protective agent. A number of authors have actually stressed the advantages of diltia- zem over the other calcium antagonists. In comparative studies, Urquhart[40] examined left ventricular function in healthy conscious dogs and showed that at equipotent doses diltiazem did not alter the indices of left ventricular ^ -> contractility, whereas verapamil and nifedipine reduced them. Evidence from Clinical Trials Verapamil Several studies have been reported, but as yet no long- term clinical trial has been completed. Over a three- <> month period Hansen[80] found no reinfarctions in 28 patients randomised for intravenous verapamil therapy, compared with four of 23 patients in the control group. r Verapamil had no adverse effects on cardiac conduction. Brachetti et al. [81] showed that treatment within eight hours of the occurrence of symptoms reduced ST segment vector magnitude, implying a reduced myocardial infarct size. Chew[82], in 25 patients, subsequently distin- guished between two groups. One involved subjects with mild cardiac disease, defined haemodynamically, in which the vasodilatory actions of verapamil exceeded its depressant actions. However, in patients with more severe cardiac disease, the depressant actions became important, causing reduced stroke volume and reduced mean arterial blood pressure. Blood pressure therefore needs to be monitored closely during such therapy. Similar findings have also been reported by Singh and colleagues[83]. Hasin's group[84] found that intravenous verapamil therapy for 16 patients admitted with imminent subendo- cardial or transmural myocardial infarction caused a reduction in transmural ischaemia as measured by ST segment elevation. Heikkila and Neiminen[85] conducted the first study of the effect of verapamil on myocardial contractile perform- ance in patients. They found that verapamil given intra- venously caused increased regional contractile function without inducing a more widespread depression of nor- mal myocardial tissue. Finally, one study[86] has shown that intravenous treatment in the range of 0.5-12 hours (with a mean of 4 hours) after onset of pain produced no evidence of a reduction in infarct size (as measured by CK release) in 119 patients. The authors attributed this negative finding to the delay in treatment. Dihyd.ropyrid.ines Several studies of nifedipine given to patients soon after infarction[87-89] have shown that the drug is well tolerat- ed and tends to have beneficial haemodynamic effects, but the studies have been too small to demonstrate any cardioprotective effect. Muller et al. [90] have conducted the only randomised double-blind, placebo-controlled multicentre trial, using a 20 mg oral dose of nifedipine. In 181 patients selected from a sample size of 3,143, no prevention of progression of threatened myocardial infarction or limitation of necro- sis in patients with acute MI was found. The study sample was not large enough to make any estimates of effects on mortality. This discouraging result may have been because treatment was not given early enough (4.6 ? 0.1 hr after onset of pain). As previously described, early treatment is required to obtain myocardial salvage. Diltiazem In view of the comparatively recent addition of this drug to the list of calcium antagonists, very few human studies have been conducted. In patients who have had a recent MI it has been found that diltiazem treatment has no deleterious haemodynamic effects[91] and Nakamura[92] has shown that in 12 patients, diltiazem reduced rest angina after MI. No reports of definitive cardioprotection have yet been produced. Conclusion On the basis of the evidence considered in this review the following conclusions may be drawn about the possible Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 cardioprotective actions of the calcium antagonists. First, there are a number of well-documented mechanisms by which these drugs might reduce the size of an infarct and the complications that may result from it. They may improve flow, reduce demand and help to control poten- tially lethal ventricular arrhythmias. 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J. (1983) European Heart Journal, 4, (Suppl. C), 43. 38. Newman, D. E. (1981) American Heart Journal, 102, 431. 39. Yellon, D. M., Hearse, D. J., Maxwell, M. P., Chambers, D. E. and Downey, J. M. (1983) American Journal of Cardiology, 51, 1409. 40. Urquhart, J., Patterson, R. E., Bacharach, S. L. et al. (1984) Circulation, 69, 382. 41. Henry, P. D. (1980) American Journal of Cardiology, 46, 1047. 42. Low, R. I., Takeda, P., Mason, D. T. and DeMaria, A. N. (1982) American Journal of Cardiology, 49, 547. 43. Millard, R. W., Lathrop, D. A., Grupp, G., Ashraf, M., Grupp, I. L. and Schwartz, A. (1982) ibid., p. 499. 44. Reimer, K. A., Lowe, J. E. and Jennings, R. B. (1977) Circulation, 55, 581. 45. DaLuz, P. L. DeBarrows, L., Leite, J. J., Pileggi, F. and Decourt, L. V. (1980) American Journal of Cardiology, 45, 269. 46. Wende, W., Bleifeld, W., Meyer, J. and Stuhlen, H. W. (1975) Basic Research in Cardiology, 70, 198. 47. Smith, H. J., Goldstein, R. A., Griffith, J. M., Knet, K. M. and Epstein, S. E. (1976) Circulation, 54, 629. 48. Anand, I. S., Sharma, P. L., Chakravarti, R. N. and Wahi, P. L. (1980) Advances in Myocardiology, 2, 425. 49. Chakravarti, R. N., Sharma, P. L., Anand, I. S., Manga, P. A. and Wahi, P. L. (1981) Indian Journal of Medical Research, 73, 625. 50. DeBoer, L. W. V., Strauss, H. W. and Kloner, R. A. (1980) American Journal of Cardiology, 45, 485. 51. DeBoer, L. M. V., Strauss, H. W., Kloner, R. A. et al. (1980) Proceedings of the National Academy of Sciences, 77, 6119. 52. Yellon, D. M. (1984) European Heart Journal, 5, Suppl. 1, 735. 53. Karlsberg, R. P., Henry, P. D., Ahmed, S. A., Sobel, B. E. and Roberts, R. (1977) European Journal of Pharmacology, 42, 339. 54. Baur, H. R., Calder, O. N. and Pierach, C. A. (1984) European Heart Journal, 5, Abst. Suppl. 1, p. 734. 55. Rogers, G. G., Rosendorff, C., Shimell, C. J. and Coull, A. (1982) Cardiology, 69, 58. 56. Nayler, W. G., Ferrari, R. and Williams, A. (1980) American Journal of Cardiology, 46, 242. 57. Saini, R. K. and Antonaccio, M.J. (1982) Journal of Pharmacology and Experimental Therapeutics, 221, 29. 58. Welman, E., Carroll, B. J., Lawson, J. S., Selwyn, A. P. and Fox, K. M. (1978) European Journal of Cardiology, 7, 379. 59. Selwyn, A. P., Welman, E., Fox, K., Horlock, P., Pratt, T. and Klein, M. (1979) Circulation Research, 44, 16. 60. Yamasawa, I., Nohara, Y., Konno, S. et al. (1983) Arzneimittel Forschung, 33, 389. 61. Henry, P. D., Shuchleib, R., Clark, R. E. and Perez, J. E. (1979) American Journal of Cardiology, 44, 817. 62. Clarke, R. E., Christlieb, I. Y., Henry, P. D., Nora, J. D., Fischer, A. E., Williamson, J. R. and Sobel, B. E. (1979) American Journal of Cardiology, 43, 361. 63. Weintraub, W. S. (1982) Circulation, 65, 49. 64. Henry, P. D., Shuchleib, R., Borda, L. J., Roberts, R., William- son, J. R., and Sobel, B. E. (1978) Circulation Research, 43, 372. 65. Clarke, R. E., Christlieb, I. Y., Henry, P. D. etal. (1979) American Journal of Cardiology, 44, 825. 66. Melin, J. A., Becker, L. C. and Hutchins, G. R. (1984) Circula- tion, 69, 131. Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 67. Alps, B. J., Calder, C. and Wilson, A. (1983) Arzneimillel Fors- chung, 33, 868. co Rosen, R., Kleuren, B., Heider, A., Panzner, B. and Klaus, W. (1984) European Heart Journal, 5, Abstr. Suppl. 1, p. 291. Dejong, J. W., Harmsen, E., De Tombre, P. P. and Keijzer, E. (1982) European Journal of Pharmacology, 81, 89. Geary, G. G., Smith, G. T., Suehiro, G. T. and McNamara, J. J. (1982) American Journal of Cardiology, 49, 331. Perez, J. E., Sobel, B. E. and Henry, P. D. (1980) American Journal of Physiology, 239, H658. Nagao, T., Matlib, M. A., Franklin, D., Millard, R. W. and Schwartz, A. (1980) Journal of Molecular and Cell Cardiology, 12, 29. Weishaar, R. Ashikawa, K. and Bing, R. J. (1979) American Journal of Cardiology, 43, 1137. Bush, L. R., Romson, J. L., Ash, J. L. and Lucchesi, B. R. (1982) Journal of Cardiovascular Pharmacology, 4, (2), 285. 75. Franklin, D., Millard, R. W. and Nagao, T. (1980) Chest, 78, (July Suppl.), 200. 76. Clozel, J. P., Theroux, D. and Bourassa, M. G. (1983) Circulation Research, 52, I, 120. 77. Klein, H. H., Schubothe, M., Nebendahl, K. and Kreuzer, H. (1984) Circulation, 69, 1000. 78. Flaim, S. F. and Zelis, R. (1981) Pharmacology, 23, 281. 79. Bush, L. R., Li, Y. P., Shlafer, M., Jolly, S. R. and Lucchesi, B. R. (1981) Journal of Pharmacology and Experimental Therapeutics, 218, 80. 81. 82. 83. 84. 85. 86. 87. 88 89 90 91 92 Hansen, J. F., Sigurd, B., Mellemgaard, K. and Lyngbye, J. (1980) Clinical and Investigative Medicine, 3, 159. Bracchetti, D., Cantelli, I. and Lombardi, G. (1980) Arzneimittel Forschung, 30, 1907. Chew, C. Y. C., Hecht, H. S., Collett, J. T., McAllister, R. G. and Singh, B. N. (1981) American Journal of Cardiology, 47, 917. Singh, B. N., Chew, C. Y. C., Hecht, H., Collett, J. and Ormiston, J. (1980) Clinical and Investigative Medicine, 3, 73. Hasin, Y., Freiman, I., Schwarz, T., Weiss, A. T. and Gotsman, M. S. (1983) Clinical Cardiology, 6, 487. Heikkila, J. and Nieminen, M. S. (1984) American Heart Journal, 107, 241. Thuesen, L., Jorgensten, J. R., Kvistgaard, H. J. et al. (1983) British Medical Journal, 286, 1107. Marra, S., Paolillo, V., Baduini, G., Spadaccini, F. and Ange- lino, P. F. (1983) Chest, 83, 50. Roberts, R., Jaffe, A. S., Henry, P. D. and Sobel, B. E. (1981) Herz, 6, 90. Gordon, G. D., Mabin, T. A., Isaacs, S., Lloyd, E. A., Eichler, H. G. and Opie, L. H. (1984) American Journal of Cardiology, 53, 1228. Muller, J. E., Morrison, J. and Stone, P. H. (1984) Circulation, 69, 740. Koiwaya, Y. (1982) Clinical Therapeutics, 4, 381. Nakamura, M. and Koiwaya, Y. (1983) Circulation Research, 52, I, 158.

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Book Review Advanced Medicine 20. Edited by Anne Ferguson. Pitman Publishing, London, 1984. Price ?20. I enjoyed reading this book. The Advanced Medicine Conferences organised by the College are an important part of its educational activities, particularly so since there is now a tradition of rapid publication in book form. Advanced Medicine 20 contains papers presented at the meeting held in London in February 1984, and has been edited by Dr Anne Ferguson of the Western General Hospital, Edinburgh. The eight sections cover inflamma- tory bowel disease, general gastroenterology, the preven- tion of cardiovascular disease, chronic disease in adolescence, clinical immunology, an assessment of four 'new' diseases, four papers on cancer management and finally two papers on breast cancer. In trying to assess the value of this book for the general physician I found myself looking for discussions on controversial or difficult areas of current practice; for articles which encourage 'lateral thought' (by discussing a topic in a field outside my own interests but leading me to new thoughts about my own patients); for comprehensi- ble reviews of the 'state of the art' in current research fields; and for 'interface' articles exploring the fascinating ways in which different fields within medicine interact with each other. From these standpoints this volume has much to commend it. Clearly, the comments that follow are personal reflections, but I have tried to give a flavour of the contributions. Of the two sections on gastroenterology, I particularly enjoyed firstly the paper on the varied presentations of coeliac disease which illustrates neatly how textbook descriptions of disease can become out of date, and secondly the chapter on the oesophagus as a cause of chest pain which one might characterise as a new explanation for an old symptom. There is a comprehensive review by Misckiewicz of H2 antagonist treatment for peptic ulcer- ation, and the general points made by Lennard-Jones in his discussion of corticosteroid and immunosuppressant treatment in inflammatory bowel disease are sure to be of interest to physicians in other specialties. From a total of five papers discussing the epidemiolog- ical evidence for the value of preventive measures in cardiovascular disease, one would have hoped that a clear picture would emerge of the pathological processes which it is hoped to prevent, and of the 'best buys' from the candidates for programmes. However, this is not the case and one has instead a thought-provoking article about pathogenesis, and two somewhat opposing views about coronary heart disease screening from Professor Oliver and Professor Marmot. I think the article upon mild continued on page 89 84 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 Continued from page 84 n hypertension might have been better deferred until the >, full results of the MRC study are known. Adolescence is an example of an interface area where both paediatricians and general physicians might have reason to feel somewhat out of their depth. I found the rather unlikely subject of retarded growth and develop- ment in teenagers by Dr Preece an interesting example of how careful simple clinical measurements (in this case height and family history) can lead to important conclu- sions and diagnoses. In this respect it reminds me of the use of peak expiratory flow rate charts in chest medicine. Margaret Mearns' and Dr Taylor's comments on the psychological difficulties of chronically ill teenagers are surely important reviews for any doctor dealing with such ?s patients. The section on clinical immunology was clearly intend- ^ -> ed to summarise research fields and was easily the most difficult to comprehend. There are, however, comprehen- sive reviews for the erudite, and Professor Kay's overview -> of the mediator maze in asthma is an example. Professor LessoPs paper on mediators in food intolerance might have been better supported by, for example, a separate ^ discussion of the important difference between food intol- erance and food allergy which has recently been high- lighted so admirably by the Working Party Report prepared by the College and chaired by him. Factitious illnesses are surely not 'new' diseases, and \ one would imagine that Munchausen patients have pre- sented to physicians for centuries. However, Professor Meadow's article rightly fascinates one with his account of parents who fabricate symptoms and illnesses in their children. One remains as baffled as ever to understand the motivation of, for example, parents who deliberately suffocate their children to induce epileptic fits. I also much enjoyed Dr Lacey's description of the hyperphagic syndrome (bulimia) as a counterpoint to the more notori- ous anorexia nervosa, and the comprehensive account of AIDS by Harris and Weber. The last two sections concentrate on cancer therapy. Several of these articles are of direct interest to the general physician since most of us now deal with cancer either frequently or rarely, and I found in this respect a discussion of cancer care delivery, the lucid account of breast screening by Dr Chamberlain, and particularly the thought-provoking article by Maguire on the psychologi- cal difficulties which patients experience when they un- dergo cancer chemotherapy, were the most memorable. There is now, perhaps belatedly, intense interest in oncology in the measurement of >the quality of life that these patients experience. Dr Maguire once again forces us to remember the importance of the whole patient when we apply treatment, and I thought it an apposite way to end this valuable collection of papers. MARTIN MUERS Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985

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Conference on Sports Medicine J. H. ROSS, MC, MD, FRCjR Retired Physician, Hereford It is time that the profession appreciated that sports medicine is not just about the treatment of injuries and that those concerned with the subject are not only figures in track suits who run on to sports fields carrying little bags and icepacks. The present interest in improving performance by the study of the physiology and the effects of exercise has received little publicity. There are now of course numerous sports enthusiasts, marathon runners and joggers in every general practice and hospital popu- lation, and it has become important to know to whom to turn to for expert advice when unusual medical problems arise. A valuable step in stimulating interest in the subject as well as educating those already interested and helping them to exchange ideas was taken by the College in arranging a 'Conference on Sports Medicine' in March of this year, organised by Dr J. Howel Jones from Coventry, an Honorary Medical Adviser to the Commonwealth Games Federation. The President chaired the first morning's session on 'Exercise Physiology'. The working of muscles is obvi- ously of prime interest to athletes and their doctors and it was right that the first two lectures were devoted to this subject. Dr N. C. Craig Sharp from the Motor Perform- ance Laboratory in the University of Birmingham spoke about the development of muscle strength. He stressed the need, in research with sophisticated methods, to simulate as accurately as possible the use to which the athletes being studied put their muscles, and to discover from coaches exactly what is to be achieved. Muscular strength can be improved by recruiting the percentage of fibres in use at any one time and also increasing metabolic activity within the fibres. These aims are achieved not only by repeated contraction of the muscles against resistance but also by slow controlled relaxation after contraction. Traditionally, training for strength has been carried out every other day but there is evidence now that daily training is better and that for maintenance a programme one third as active as the initial training is needed. The speed of muscle activity necessary to achieve optimum results in various sports has been studied in detail and is determined by the different types of muscle fibre. Marathon runners have 79 per cent of slow twitch Type 1 fibres and 21 per cent of fast twitch fibres in their running muscles, and sprinters have almost exactly the opposite. These studies have influenced training and have led to more careful attention to muscle loading and to variation in the training exercises. Nowadays the longer careers of athletes and sportsmen and the large cash sums involved make avoidance of injuries most important. It was interesting to hear that nervousness leads to muscles over-acting, especially early in games or competitions, and that this can be of benefit to sprinters but not to others; also that, on the whole, an athlete's specific ability is determined genetically. For we are born with set populations of-slow and fast muscle fibres but these are capable of some modification. Increasing the endurance of muscle activity has also been studied; muscle capillaries can be increased as can myoglobin content, and mito- chondria can multiply up to 300 per cent. Professor Clyde Williams from the University of Technology, Loughborough, went into more detail about muscle metabolism with particular reference to energy yields from aerobic and anaerobic metabolism. The different substrates used by muscle can alter energy production but require varying consumption of oxygen. The amount of oxygen required by different individuals to achieve the same speed of running can also vary considerably. Blood lactate accumulates earlier in untrained individuals; the amount produced by an indi- vidual at a given stage of training is reproducible and determination of this can indicate the optimum running speed. Type 2 fibres have a greater oxidative capacity than Type 1 and are recruited as activity continues with anaerobic metabolism complementing aerobic. Lactate accumulation and the consequent fall in pH influences enzyme performance and is responsible for fatigue in muscles. Many factors can influence the development of muscle endurance, particularly diet and training. Elite runners can thus develop a capacity for promoting aerobic metab- olism and can manage to metabolise lactate and to buffer the fall of pH in muscle. They have a surprising ability to reproduce good performances after only short recovery periods, but studies can be confusing as treadmills do not accurately simulate marathon conditions because they produce a 'softer' activity. The physiological session concluded with 'Thermo- regulation in Athletes' by Professor C. T. M. Davies. A former Director of the MRC Muscle Research Group in Nottingham, he is now Head of the Department of Physical Education and Sports Science in Birmingham. The study of heat dissipation is obviously fascinating, but perhaps not of immediate value to sportsmen, although we learned that cold spongeing when overheated is sound practice physiologically. The maximal aerobic power and maximal evaporative (cooling) capacity of an individual are closely matched under normal conditions. Endurance athletes operate at over 75 per cent of their maximum aerobic power; at levels of work over 85 per cent there is evidence of vasoconstriction, the skin remains cool and as exercise progresses there is a spiralling increase in core 294 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 temperature. Thermal control during the later stages of such exercise (equivalent to elite marathon running) appears to be 'passive' and thus extremely sensitive to small changes in climatic conditions. Trained athletes control their temperature better at high work loads than do the untrained. The low skin temperature may actually suppress sweating and in thin endurance athletes a major portion of the heat produced by the muscles may be transferred directly to the environment through overlying skin and subcutaneous tissue. It is also possible to train to produce more sweat but this does not alter exercise capacity. Oxygen consumption becomes greater in cold conditions whilst exercise capacity decreases. Children are less efficient mechanically. The speakers during the first afternoon considered some of the consequences of exercise and sport in a session chaired by Professor P. Fentem, a physiologist from Nottingham and an aviation medicine consultant. Mr J. S. Fox, consultant obstetrician and gynaecologist and a member of the British Athletic Board, discussed the menstrual cycle and sporting activities. It is no longer considered that exercising during menstruation is harmful and performance at that time is unchanged but the premenstrual phase does seem to be associated with poorer performance both in training and competition. Dysmenorrhoea and midcycle pain can also cause problems. Oral contraceptives can reduce menstrual problems but may impair performance and increase body fat and weight. The menarche may be delayed in athletes and they may have more menstrual disturbances than non-athletes but this could be related to the type of individual rather than be a consequence of the training. There does appear to be a relationship between exercise taken and amenorrhoea and amenorrhoeic runners are said to have greater endurance. Possibly the psychological and physical stresses associated with competition, low body weight, reduced percentage of body fat and hyper- prolactinaemia are factors leading to a progression from deficient luteal activity through anovulation to amenorr- hoea. Progesterone may not be produced and endo- metrium and breast could be subjected to unopposed oestrogens with an increased risk of malignant change. Oestrogen deficient states may arise if there is profound gonadal suppression with a possibility of osteoporosis developing. Athletic activities can lead to infertility, but this is reversible. Dr D. Tunstall-Pedoe, Chairman of the British As- sociation of Sport and Medicine and President of the International Marathon Medical Directors Association, spoke on 'Normal and Abnormal Cardiac Responses to Exercise' and covered a broad field. He believes that the present increased exercising of the public is a reaction to 'automobile culture' and that there is a variety of reasons for running in marathons: 1. To see if you can do it for the first time; 2. To improve performance; 3. To deny illness, (a worrying reason); 4. To raise money; 5. Exhibitionism. The limiting factor in middle distance running is maxi- mum oxygen consumption. This can be increased by training, with consequent greater cardiac stroke volume and enlargement of the heart, a physiological hyper- trophy accompanied by bradycardia. There is a great variation in this response and it may be associated with unusual physical signs and a range of ECG changes that can disturb doctors unfamiliar with such manifestations. There can occasionally be worrying responses to exercise with excessive tachycardia, bradycardia or other arrhyth- mias which can lead to sudden death. Dr M. Harries, from Northwick Park, explained that lung function, unlike that of the heart, changed little with training. He had studied airways obstruction in athletes using portable devices capable of measuring air flow and volume changes. Exercise induced asthma may occur, probably due to the release of mediators from mast cells and to vagal action; a variety of irritants can also precipitate bronchoconstriction in athletes. Studies in cold chambers have shown that subjects exercising at +14?C exhibit slight bronchodilation but at -10?C and below bronchoconstriction occurs. Asthmatics develop bronchoconstriction with exercise even at +14?C and at the lower temperatures without exercise. There is no reason however why asthmatics should not take part in competitive sports; antispasmodics are acceptable if their use is declared before an event. Dr John Ross reviewed the renal and haematological changes occurring with exercise with particular reference to studies made during selection courses for an army unit. These studies had been initiated following the treatment of acute renal failure in a participant who developed rhabdomyolysis. Very severe increasing exercise over a three week period was associated with considerable elevation in serum myoglobin and some enzymes, the elevation becoming less with training. No light was thrown on the mechanism of renal failure that can arise with myoglobin elevation. 'Sports anaemia' was also discussed and considered to be, for the most part, a 'pseudoanaemia' occurring with plasma volume expansion. Erythropoietin production is probably not stimulated as the oxygen requirements of the tissues are satisfied and the decreased haemoglobin concentration is not corrected. Haemolysis and iron deficiency may arise during training but are not usually of importance. The next session concerned with 'Sports Injuries and Sport in an Abnormal Environment', was chaired by Dr. C. R. A. Clarke, the neurologist and mountaineer. Dr P. Sperryn, Consultant in Physical Medicine at Hillingdon Hospital and Medical Officer to the British Amateur Athletic Board, gave a comprehensive talk on 'Sportsmen and Soft Tissue Injuries'. Much can be done by doctors to advise sportsmen and their trainers about avoiding injury. In the first place, careful history taking is essential in order to discover exactly what muscles the sportsman uses and what he does with his body and his time, then advice can be given about modifying equip- ment, clothing, shoes, spectacles and even indoor run- ning tracks. Sport will inevitably become more dangerous as the public and the media display more interest in what can only be described as gladiatorial exhibitions, and stress to competitors will continue to increase in view of the financial rewards. Dr. Sperryn thought that 'Sports Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 295 Medicine' was a poor name for what is really 'Medicine and the Science of Health and Fitness in Exercise'. Dr Wendy Dodds, a rheumatologist from Bradford, a runner, swimmer and skiing orienteer, told us that the aims of the 'Treatment of Soft Tissue Injuries' were to relieve pain, resolve inflammation, and promote healing. She described the simple first aid use of ice, compression and elevation and the various non-invasive methods of treatment now available. Analgesics and non-steroidal anti-inflammatory drugs can be valuable, the use of corticosteroid injections is controversial and enzyme preparations are not recommended. Many methods for physical rehabilitation are used, helping muscle function to be restored, mobility to be regained and propriocep- tion, which can be impaired by injury, to be retrained. We elderly physicians in the audience wondered why our knocks and blows took so much longer to settle down than they used to and were sorry to hear that little can be done to help this state of affairs, the slow recovery of our aged tissues being due to many factors including changes in collagen structure and probably relative ischaemia. Dr J. S. Milledge, of Northwick Park Hospital, an experienced climber who has made many studies on exercise and altitude at the famous 'Silver Hut' high altitude laboratory, in the Western Cwm on Everest and elsewhere spoke about 'Exercise Limits at Altitudes'. The barometric pressure at the top of Everest is only one third of that at sea level and it was not surprising to learn that it is possible to climb only one hundred feet in an hour at that height. If ventilation did not change, the alveolar oxygen would become intolerably low. Pa02 decreases to 35 mm Hg with the induced changes in ventilation, about the lowest level that can be tolerated. Arterial oxygen falls to a far greater extent as work increases at high altitudes than it does at sea level, equilibration with oxygen being much slower along the alveolar capillaries; this is the crucial limitation to exercise at such heights. Those climbers with naturally low hypoxic ventilatory rates drop their alveolar oxygen more than those with high rates and did not do so well on Everest. However one climber who reached the summit without oxygen had a low hypoxic ventilatory rate, having been born and bred at a high altitude, as had some Sherpas who also had low rates but nevertheless reached great heights. The handling of oxygen from atmosphere to pulmonary vessels has been studied in detail, work which must have been difficult under such extreme conditions. Dr. Milledge's clear description made it all sound very easy. From problems at high altitudes we descended to the 'Clinical Problems of Sports Diving' described by Dr N. K.I. Mclver, a general practitioner who also works with the North Sea Medical Centre at Great Yarmouth giving medical advice to commercial and Scuba divers. The subject is clearly important: in 1985, 165 diving 'inci- dents' were reported including 14 deaths and 57 episodes of decompression sickness occurring in 1,500 North Sea commercial and 50,000 British Scuba divers. Joint pains, pruritus, skin rash, oedema and general malaise with fatigue and anorexia are the symptoms associated with Type I decompression sickness; the more severe Type II is manifested by peripheral neuropathy, respiratory symptoms and hypovolaemic shock. Localised pain is the single most common presenting complaint. Problems can arise at comparatively shallow depths, only 5 metres descent being accompanied by an increase of half an atmosphere. Early recognition of the condition and the correct action are extremely important, the initial presen- tation sometimes being mild and many unfortunate cases have been recorded as a result of lost time. As with so many hazardous activities, good training and discipline can minimise accidents. The final session was chaired by Sir Roger Bannister, Master of Pembroke College, Oxford, whose famous mile was mentioned several times by previous speakers. The four papers were concerned with 'Sports Problems and Prospects'. The damage which can be done to children by demanding too much physical exertion from them had been referred to by earlier speakers but was dealt with fully by Dr I. D. Adams, an accident and emergency physician from Leeds. It is easy to ask too much of children and adolescents who try to please their parents and coaches; they must be thought of as children first and athletes second. We heard some extraordinary facts from Dr. Adams. Marathons have been run by a 15-year-old boy in 2 hours 29 minutes and by a 16-year-old girl in 2 hours 46 minutes, sports injuries constitute 4 per cent of new accident and emergency cases of which 17.4 per cent are in children, and a 16-year-old swimmer may need a diet of over 7000 kcals, but work and training may leave little time for swallowing this large amount of food. Such facts, and the knowledge that growing bones are so vulnerable to damage, make the care and protection of competing children a matter of concern to many doctors other than sports experts. Much can be done in the way of helping them by arranging general rather than specific training, by safety devices particularly in gymnasia, proper maintenance of facilities, matching of opponents, adaptation of rules and avoiding unreasonable pressure to win. Dr J. Howel Jones started his talk on 'Doping in Sport' by giving an example of drug abuse in which an individual had used seven different substances, some possibly to help him and some to counter consequent side effects?a depressing story. The International Olympic Committee Medical Commission produces lists of banned drugs and most individual federations do adhere to them. There are however problems; some banned drugs may be present in preparations used therapeutically in a perfectly acceptable way. There is conflicting evidence about the benefits to be gained from some drugs; amphetamine for example may only lead to small physical effects. But as Dr. Howel Jones pointed out very minor improvements can make con- siderable differences to athletes' success. This was illus- trated by the fact that after Sir Roger Bannister ran the mile in 1954 in 3 minutes 59.4 seconds, 10 new records were set in the next 11 years with an overall reduction of only 10 seconds. Studies on caffeine show that it probably does improve sub-maximal long-term exercise perform- ance. It was removed from the banned list in 1972 but is now prohibited again because of its abuse by injections and suppositories. It is known that androgenic steroids do 296 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 not help aerobic performance but do increase strength and decrease fatigue, knowledge that has unfortunately led to their increased use. It is shocking to hear that, in order to avoid detection, gradually increasing daily doses of steroids and testosterone derivatives are taken for some weeks and then reduced in the week prior to competition when human chorionic gonadotrophin is also taken: a diuretic is used on the final day to produce dilute urine for testing. Beta blockers are now banned from shooting contests in which they could reduce tremor, unfortunate for some hypertensives. Athletic training at high altitudes increases oxygen transport by the blood and improves performance on return to lower levels; this is permitted by the Olympic Authorities. 'Blood doping', the transfusion of whole blood or packed cells, has the same effect and is banned; but now that storage methods have been improved autologous reinfusion can be used and is not easily detected. It was sad but interesting to hear how much deceit has been introduced by competitiveness in sport. Dr R. Budgett, an Olympic Gold Medallist who had stroked the victorious coxed four in 1984, gave the competitor's view of the preparation for such a contest. This took him four years during which there was the constant anxiety that he might be sacrificing time, money and the formation of a career with the possibility of not eventually being selected to compete. He emphasised the need to use stress and the 'adrenaline surge' to improve performance, to work and think as a team and to maintain motivation by envisaging the joys of winning. The advice of sports doctors throughout training was valuable to help avoid injuries which could wreck ambitions. It all sounded incredibly hard work and the winners of any event deserve lasting admiration. Dr B. B. Lloyd, former Chairman of the Health Education Council, looked at the future of athletic records. He had found that the records for various running events, expressed as metres per second, rose as straight lines over many years. It appeared that women's records were now improving faster than men's but it seemed unlikely that improvement would continue in a linear fashion. The recently formed London Sports Medicine Institute has produced a pamphlet which states '. . . there has been no base for sports medicine in Great Britain and the average athlete is less well served than in many other countries where there is government money for sports medicine and where well established sports medicine clinics and research institutes exist'. At this conference I do not think that the speakers were just addressing the converted; there were many non-sports doctors and students from all over Great Britain who will have taken home with them the message that more attention to the subject is needed. More sports clinics, perhaps in university settings, are required. These might stimulate more research in departments of physiology, orthopaedics and physical medicine. Well controlled trials of treatment for injuries are much needed. More doctors should be affiliated to sports clubs. There do seem to be experts throughout the country who would be happy to give advice on these matters and to be included in coordinated projects.

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Editorial Events change the impact of words. Add 'nuclear' to 'power' or 'bomb' and you will stir the emotions, if not the reason, of all. Fifty years ago these words would have been greeted with incomprehen- sion. On a lower plane of disturbance is that ambivalent word 'drug'. In the 18th century it had a comfortable existence as 'a general name for all spices and other commodities brought from distant parts and used in the business of medicine, dyeing and the mechanical arts.' In the business of today's medicine we use, and seek, curative medica- ments but call them drugs, the same word we use for agents of addiction brought from distant parts and the so-called drug culture. The pharmaceutical industry is handicapped by their representatives being called 'drug reps', an abbreviation that hints at drug pedling. Semantics do matter whenever a matter of medicine is the subject of public discussion. Public perception can so easily be based on misconception. Any kind of drug can be perceived as a symbol having power over a person, as something that can save or enslave. The term 'drug dependence' has a sinister ring to it. So the act of prescription can be construed as a dispensation of power. A prescription is both desired and feared. If it is only a substitute for communication the patient will feel rejected. If the drug prescribed has an adverse effect then the doctor may be seen as an adversary. Fortunately, these considerations seldom arise in the humdrum world of daily prescrib- ing but they can easily be invoked and exploited. We have not learnt an accepted language to explain the benefits and risks of each prescription. Merely reciting a litany of all possible adverse effects is of little help to the patient, particularly if there has not been a recital of the benefits to be derived from the prescription. To mount a private hobby-horse, adverse effects are inherent in the drug's structure, they are not 'on the side'. The rare catastrophe of drug-induced death has to be called 'adverse' rather than by the trivialising term 'side effect'. Adversity can be quantified in terms of frequency of occurrence and severity of event. But numbers, however useful to the doctor, do little to adjust public perspective. The one disaster stays in the imagination long after its rarity is forgotten. In the continuing public debate on medicines there is a noticeable lack of information on the positive benefits of drugs. People need to be reminded over and over again of the morbidity and mortality that is prevented by modern medicines. Of course, giving due praise to certain treatments needs the backing of correct prescription. Every doctor knows that no drug should be prescribed unless it is necessary and proper for both disease and patient, and given in the right dose for the right time. Why every prescription does not fulfil these obvious criteria remains a mystery that needs a solution if the public are to trust the doctor's medicine. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 233

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Senior Registrars' views on Geriatric Medicine PAUL V. KNIGHT, mb, mrcp(UK) University Department of Geriatric Medicine, Southern General Hospital, Glasgow The ideal relationship between geriatric and general medicine, in terms of training and service commitment, has been frequently contested[l,2]. The practice of geriat- rics and its association with general medicine at present remains diverse[3,4]. This study attempts to describe the attitudes of senior registrars (SRs) in geriatrics to the specialty's affiliation with general medicine. Method Questionnaires were mailed to 157 SRs whose names were obtained from the British Geriatrics Society trainee list. The questions were phrased in a pragmatic form and the replies were made anonymously. There was space in the questionnaire for additional comments. Results One hundred replies suitable for analysis were received; a 64 per cent response rate. The answers are detailed in Tables 1-3. Table 1. Length of registration and experience in geriatric medicine; job description. Years registered with GMC: Months (post-GMC registration) of experience in geriatrics prior to SR appointment SR job description: Full-time geriatrics Integrated with general medicine Mean 7.4 No. of people 0 28 1-6 26 6-12 17 >12 29 59 41 More than half the sample had less than 6 months' geriatric experience before being appointed SR. Although a majority (68) felt that further training in general medicine as an SR was desirable, a minority of 35 were unable to undertake it. In contrast, 62 respondents preferred the career option of whole-time geriatrician and the same number wished geriatric medicine to remain separate from general medicine. Approximately 15 per cent of the respondents made further comments, independent of the questionnaire. Many of these views overlapped and most were related to the integration of geriatric and general medicine. Table 2. Accreditation and rotation with general medicine. (Number of answers received) In training future consultant geriatricians, do you believe dual accreditation with general medicine is desirable, in contrast to training (at SR level) mainly or wholly in geriatrics'. Desirable 68 Undesirable 9 Irrelevant 23 Would one year's experience in general medicine, at SR level, enable you to apply for dual accreditation? Yes 62 No 33 Don't know 5 Can you to rotate to general medicine during SR training, if desired? Yes 65 No* 35 *15 in Thames Regions. 5 lecturer posts in University Departments. Table 3. Career choice; future of specialty. Choice of consultant post: Whole-time geriatrician 62 Physician with an interest 30 No stated preference 8 How geriatrics should proceed? Separate specialty 62 Total with general medicine 21 Other 17 Of those favouring some form of integration, several expressed some confusion at what this implied, i.e. whether it was sharing of beds, staff, or resources such as radiology. A popular view was that in rural or semi-rural areas integration would be more logical than in urban environments; however, specialist university departments should continue to exist to guide research and policy. Other people believed that geriatrics would be more viable as an age-related speciality like paediatrics, and interestingly only two respondents wished geriatrics to be a medical sub-specialty like cardiology. A further two respondents stated that other reasons for dual accredit- ation were to give them as wide as possible a career choice and to silence critics of the calibre of trainees in geriatric medicine. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 271 The more entrenched 'separatist' attitude was that wholesale integration would once more lead to general physicians with neglected and unsupervised long-stay beds. Indeed, they felt that far from encouraging geriatric medicine SRs to train further in general medicine, it should be made compulsory for general medical SRs to spend a period in geriatrics. One respondent expressed concern that some senior geriatricians now seemed to believe that training as a pure geriatrician was in some way inferior to the integrated approach. The replies of the 28 respondents who had no previous geriatric experience prior to SR appointment were exam- ined. It transpired that 15 had integrated SR posts, 19 only required one further year in general medicine to qualify for dual accreditation (providing two years of geriatrics was also completed), and four had already claimed accreditation in general medicine prior to SR appointment. The majority (23) believed further training in general medicine at SR level to be desirable, but equal numbers were in favour of each career choice. Only nine wished geriatrics to integrate totally with general medi- cine. Discussion The response rate of 64 per cent seems small. However, theJCHMT gives an approximate figure of 120 approved geriatric medicine training posts in the UK. Some are not necessarily funded, and others may be vacant because the incumbent has moved on to another post and a replace- ment has yet to be appointed. Thus the true reply rate may be in excess of 85 per cent, which makes the views expressed more representative of the general SR popu- lation. It is disappointing that there remains a minority of SRs (28) who have no previous geriatric .experience on ap- pointment. This number includes over one third of those in designated integrated SR posts and almost one half (13) of those wishing to become physicians with an interest in the elderly. They are not significantly longer registered with the GMC than other respondents nor do they necessarily wish for the integration of geriatrics into general medicine. There are more integrated SR posts than likely consult- ant vacancies of this sort. Only a minority (30) wish to have their consultant practice integrated in this fashion. The desirability of further training in general medicine appears to have as much to do with its possible political implications as with its probable training content. In my opinion the suggestion that geriatric medicine is an ideal career option for surplus trainees from other general medical specialities[3] is fraught with difficulties. To imply that surplus-to-requirements purely means failed candidate would be grossly unfair to the many excellent recruits geriatrics has gained in this way. A recent survey by Donaldson has clearly shown that trainees who arrive by this route would still rather be doing something else[5], Donaldson's survey had a sub- stantially different SR population from my own study, but both show that these people wish, in the main, to keep in touch with their general medical roots by choosing a consultant post as a physician with an interest in the elderly. It is possible that applicants with longer general medical training may be considered more favourably for these integrated posts. However, as their SR training is often integrated with general medicine, their geriatric experience may not always be of sufficient duration. It is a worrying, although perhaps an over-pessimistic view that, in suggesting all geriatric departments should be a subset of general medicine we will recruit a cadre of dissatisfied general physicians who may in the future be inclined to give a lower priority to their elderly patients. As these types of departments work almost exclusively on acute admissions with little or no home visiting it is inevitable that a high turnover of patients will be achieved. What then becomes of the difficult rehabili- tation problems, who do not fall into the acutely-ill category? I believe that closer liaison with general medicine brings benefits. However, I suggest these lie in having assessment beds in the main hospital with access to all investigative facilities and perhaps also a common pool of staff. I think that, because of its development from the chronic care wards, the very modus operandi of geriatric practice in the UK, precludes it from being treated in the same way as another medical subspeciality. If a consult- ant is busy doing general medical out-patient clinics, specialist clinics and practising skills such as endoscopy, there will simply be little or no time to do day hospital, chronic care and rehabilitation rounds and domiciliary assessments. Geriatricians should co-operate very closely with their general medical colleagues. Regular visits to the general medical ward, to advise on problems and not just to provide a 'take-away' service, can be particularly beneficial[6]. The majority of SRs in geriatric medicine would, for a variety of reasons, welcome the opportunity of having further training in general medicine, although at present some are unable to achieve this. Despite this, the majority of SRs in geriatrics wish to be whole-time consultant geriatricians. Therefore, such training, however desirable it may be for the trainee, should not intimate to trainers that geriatric medicine requires wholesale integration with general medicine. This represents a diametrically opposite view to that of other policy makers[7]. Acknowledgements I would like to thank Professor F. I. Caird for his help. References 1. Evans, J. G. and Graham, J. M. (1984) Journal of the Royal College of Physicians of London, 18, 18. 2. Williamson, J. (1984) Guinness Lecture to the British Geriatrics Society. 3. Irvine, R. E. (1984) Journal of the Royal College of Physicians of London, 18, 21. 4. Horrocks, P. (1982) In Recent Advances in Geriatric Medicine, No. 2, p.259 (ed B. Isaacs) London: Churchill Livingstone. 5. Donaldson, M. (1985) Age and Ageing, 14, 8. 6. Burley, L. E., Currie, C. T., Smith, R. C. and Williamson, J. (1979) British Medical Journal, 2, 90. 7. Royal College of Physicians (1977) Report of a working party on medical care of the elderly. London: Royal College of Physicians. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986

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The Female Life Span SIR RICHARD BAYLISS, kcvo, md, frcp SIR CYRIL CLARKE, kbe, md, frcr frs A. G. W. WHITFIELD, cbe, md, frcp Royal College of Physicians Research Unit, London There is widespread awareness of the increased longevity of the population of Great Britain and of the socio- medical problems which the care of those no longer capable of an independent life impose upon the nation. The actual numbers involved and the progressive in- crease in those living to an advanced age are not so fully appreciated. Figure 1 and Table 1 show the position in England and Wales over the last half century. In 1981 there were more than four times as many women over the age of 85 as there had been 40 years earlier in 1941, while over the same period the number of males of this age trebled[l-5]. The proportion of very old people relative to the total population of each sex has steadily increased and by 1991 may for women exceed 2 per cent. This demogra- phic and social change was considered in an earlier publication[6] which this contribution endeavours to am- plify and to take a step further. The factors underlying increased life expectation are multiple. Progressive improvement in social conditions is probably the most important. Better housing, better nutrition, clean air, central heating and improved water supply and sanitation have become available to the majority. In addition, free medical care, the advent of Table 1. Population of England and Wales over age 85 by Decade and Sex. Number over 85 Percentage over 85 of total of sex Male Female Male Female 1941 42,000 89,000 0.24 0.41 1951 59,000 132,000 0.28 0.58 1961 92,000 205,000 0.41 0.86 1971 107,000 313,000 0.45 1.25 1981 125,500 410,700 0.52 1.61 Fig. 1. Population of England and Wales over age 85 by sex and percentage of the total population of their sex. 500, 000-, Females Males 400,000-1 5 300,000^ 200,000H ioo,oooH ? ? ??" r~1' 5 M -0 r0'5 1941 1951 ?I? 1961 Year -0-0 1971 1981 290 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 antibiotics and improved surgical and anaesthetic skill must have played their part. The virtual conquest of great killers of a bygone age such as tuberculosis and smallpox and the effective prophylaxis of poliomyelitis, whooping cough, diphtheria and other infections have reduced the death rate from these diseases while the enormous reduc- tion in perinatal mortality has allowed more babies, who previously would not have survived, to live to swell the population in their second and subsequent years. The extent to which life span can continue to increase may have a finite limit. To date, authentic records show the longest surviving male^in England and Wales to have died at 111 in 1968 and the longest surviving female at 112 in 1973[7], It may well be that in the future a few will live for longer than this but the probable trend will be for more men and women to live to extreme old age and for there to be more centenarians; but the numbers living beyond 110 are likely to remain small. That more females than males survive to an advanced age has long been known. In 1841 there were 78 female and only 36 male centenarian deaths[8] and in 1910 the numbers were 43 female and 22 male[9]. The extent of the increasing female preponderance is shown in Figure 1 and Table 1. Figure 2 shows the number of men and women aged 100 or more who died in England and Wales in 1982[ 10]. The causes underlying the sex difference in longevity are complex. In the years 1941-81 the total population of England and Wales contained a million more women Table 2. Population England and Wales Male Female *1941 17,228,000 21,515,000 1951 21,049,000 22,751,000 1961 22,346,000 23,820,000 1971 23,797,000 25,097,000 1981 24,121,000 25,472,000 * Figures influenced by 1939-45 war Table 3. Number and sex of babies born in 1941-81 in England and Wales. Female M/F ratio 1941 280,000 268,000 1.045 1951 346,000 328,000 1.055 1961 403,000 382,000 1.055 1971 401,500 380,100 1.056 1981 324,900 309,500 1.050 than men (Table 2) although at birth there was a slight male preponderance (Table 3) which was maintained until the age of 50-54 years. This was despite a higher perinatal mortality in males than in females and despite a higher death rate in male infants from congenital malfor- mations. Indeed more male than female deaths occurred until the age of 80 years (Table 4) when the reduction in the number of male deaths resulted chiefly from the fact that there were fewer men than women of that age available to die rather than a smaller proportion of the Table 4. Number of deaths in 1981 in England and Wales by sex. Age 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94 95-99 100-104 105-109 110 + Male 4,770 447 573 1,734 1,576 1,427 1,754 2,143 3,392 5,920 10,969 19,688 27,170 40,298 51,891 50,959 35,815 19,406 7,357 1,563 161 8 1 Female 3,431 302 368 650 642 718 1,103 1,451 2,291 3,820 6,693 11,268 15,943 25,100 37,662 49,320 54,234 43,416 22,827 6,627 940 60 2 Total 289,022 288,068 Fig. 2. Centenarian deaths England and Wales 1982 (actual number) over Age Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 male population in that age group dying[l-5]. In 1976, and earlier, the death rate in women overtook that in men in those aged 75-79 and this upward change reflects the enhanced life expectation for men. It is remarkable that with the wide differences in the number of male and female deaths from birth onwards the numerical supremacy of men in the population is not finally eroded until the age of 50-54, but with a total population of 50 million in England and Wales it requires a disproportion of deaths between the sexes of half a million to produce a one per cent change in the sex structure of the population. It must be emphasised too that in the fourth and fifth decades the difference in the sex population is small and before 1981 the change over in numerical sex supremacy occurred at an earlier age, being in the age group 45-49 in 1971 and 35-39 in 1961 [1-5]. The recent upward trend again reflects the improved life expectancy of men and possibly also the receding effects of the 1939-45 war. From birth up to quite an advanced age, therefore, more men than women die each year. Each death, male or female, depletes the numbers entering the next and subsequent years and the excess of male over female deaths up to the age of 80 means that each year there are more women going forward to the next year than men. From the age of 80 onwards there are even more females than males surviving to enter the subsequent year because the male population over the age of 80 is so small. The causes of the higher male death rate are shown in Table 5 which lists the diseases in which there is a significant sex difference in the numbers dying. Tubercu- losis, neoplasms (particularly of the lung and bronchus), ischaemic heart disease, chronic obstructive airways dis- ease, accidents and suicide are largely responsible. These deaths remove large numbers of males in middle life, leaving fewer to progress with their contemporaries and with females of the same age to the next and subsequent years. The excess of some 27,000 male over female deaths in 1981 is paralleled in other years but is often less in degree. It occurs despite the large numbers of women dying from breast, uterine and ovarian cancer and the predominance of females among those dying from cere- brovascular disease. However, most females who die from strokes do so between the age of 70 and 95: of the 43,047 women who died of a stroke in 1981, 35,467 were aged 70 or over[5]. It is obvious that the age at death plays a crucial part in determining the numerical disproportion between the sexes. If the years lost by death are considered in the principal causes of death in men and women, the extent to which the male population is depleted in middle life will be immediately evident (Table 6). While cerebrovas- cular disease causes marginally more years lost in women than in men, the years lost to age 65 and to age 85 from deaths due to neoplasms, ischaemic heart disease, chronic obstructive airways disease, accidents, and suicide are very much greater in men than in women[5]. It must be emphasised that a larger female population and a higher male than female mortality rate have been a feature of England and Wales since accurate records have been kept[8,9,11-13], Currently, a considerable number Table 5. Major causes of death where there is marked dispro- portion between the sexes England and Wales 1981. Number of deaths Male Female Tuberculosis 385 172 All neoplasms 69,920 61,771 Oesophagus (2,242) (1,613) Stomach (6,305) (4,347) Colon (4,428) (5,940) Rectum (3,281) (2,772) Lung & bronchus (26,297) (8,430) Female breast (12,513) Cervix, uterus & ovary (7,239) Prostate (5,151) Diabetes 1,994 2,632 Thyroid disorders 76 375 Mental disorders 1,137 2,304 Senile dementia (534) (1,441) Rheumatic heart disease 896 2,224 Ischaemic heart disease 89,104 66,092 Hypertensive heart disease 2,458 2,955 Cerebrovascular disease 26,604 43,047 Chronic obstructive airways disease 17,587 7,309 Musculoskeletal disorders 823 2,289 Congenital anomalies 1,665 1,374 Perinatal 1,605 1,054 Injury and poisoning 11,588 8,200 Road traffic accidents 2,889 1,156 Suicide 2,761 1,658 Total 231,582 204,612 Note: Items in parenthesis are part of 'All neoplasms' or Mental disorders' and so do not add to the total. of the male deaths in middle life appear likely to have resulted from smoking. How then can a similar situation in respect of male mortality be explained during a long period before the cigarette arrived? Table 7 shows some of the causes of death in 1911 where it will be seen that infections, particularly tuberculosis and pneumonia, sui- cide and violence, and perinatal mortality were respon- sible for very many more male than female deaths[14], A similar pattern was seen throughout the second half of the nineteenth and early decades of the twentieth centuries. Why perinatal death claims more male than female infants is uncertain. The higher congenital malformation rate in males only explains a small part of the difference. If the consumption of tobacco is reduced by health education it is possible that in a decade or so men may have a life expectation similar to women. Of the 1,975 deaths certified in 1981 as due to senile dementia 574 were male and 1,441 female[5]. It will be of interest to see whether, when men live longer, they experience the same incidence of senile dementia as do women now, or whether women are particularly prone to this disorder. It may well be, however, that in blaming tobacco for male attrition one is tending to overlook other factors which may be of equal or greater importance. Under good laboratory conditions the male mole rat lives longer than the female, probably as a result of protection from predators (see also a similar situation in mice[15]), and 292 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 Table 6. Mortality rates per 10,000 population, age at death and years lost by death?England and Wales 1981 All neoplasms Ischaemic heart disease Cerebrovascular disease Chronic obstructive airways disease Accidents Road traffic accidents Suicide Male Female Mortality Mean age Years lost Mortality Mean age Years lost rate at death to age 65 to age 85 rate at death to age 65 to age 85 29 68.8 37 69.8 11 74.1 6 73.4 3 45.1 1 37.4 1 48.1 1131.5 4663.3 229.1 1371.2 38.0 298.4 20.6 159.4 173.9 303.4 84.1 137.7 51.4 101.9 24 69.3 26 76.8 17 78.6 2 73.6 2 65.7 0 49.1 1 55.7 687.3 1124.0 49.9 577.6 33.3 307.6 12.9 67.3 52.9 113.2 22.9 41.6 20.4 48.6 Table 7. Some major causes of death in England and Wales in 1911. Male Female All causes 272,512 255,298 Infections 49,551 43,377 Tuberculosis (29,227) (23,893) Pneumonia 21,582 16,060 Perinatal mortality 19,560 15,144 Violence and suicide 14,405 5,929 not having to compete for food and living space[16]. In the Hutterite and Amish communities in the USA males live longer than females, 55.6 per cent of the Amish over 60s being male. This is thought to result from their large family size, their self sufficient agrarian existence and their social and cultural isolation. It certainly appears to be environmental rather than genetic for the Amish came to the USA from Berne via Alsace Lorraine only about two and a half centuries ago[17]. Among humans in this country those with Down's syndrome are probably the most protected group; they do not have to serve in wars, they are not often exposed to the risk of accidental death and they are provided with food and a home either by their parents or by the state. Their life expectation has increased since 1929 from nine years[18] to about 50 years now[19-23] and today the major cause of death is premature senility (Alzheimer's disease). While it may reasonably be argued that much of this improvement stems from the prevention or control of infections there seems little doubt that the unavoidable pattern of living imposed on patients with Down's syndrome favours their increasing life span and male survival. There is a male preponderance among mongols born alive[20,21]. Al- though earlier writers report the majority dying in their first year to be female, this is no longer evident[23] and after one year there is no clear difference between male and female mortality. In consequence, a male preponder- ance remains until death. So, therefore, it may be with normal humans. The female has a more sheltered life than the male and is under less risk of physical injury; other indirect factors which threaten life affect her less and so she usually lives longer than her male counterpart. Evidence currently available strongly favours environmental rather than genetic influences in female longevity and it may well be that a more wholesome lifestyle for the male might result in his living as long as the female. References 1. Registrar General's Statistical Review of England and Wales for the year 1941. (1945). London: HMSO. 2. Ibid, for the year 1951. (1953). London: HMSO. 3. Ibid, for the year 1961. (1963). London: HMSO. 4. Ibid, for the year 1971. (1973). London: HMSO. 5. Office of Population Censuses and Surveys. (1983), Mortality Statistics England and Wales 1981. London: HMSO. 6. Clarke, Sir Cyril. (1986). Journal of the Royal College of Physicians of London, 20, 122. 7. Thatcher, A. R. (1981). Population Trends, 25, 11. 8. Fourth Annual Report of the Registrar General of Births, Deaths and Marriages in England. (1842). London: HMSO. 9. Seventy-third Annual Report of the Registrar General. Abstract of 1910. (1912). London: HMSO. 10. Office of Population Censuses and Surveys. (1985), Mortality Statistics England and Wales 1982. London: HMSO. 11. Fourteenth Annual Report of the Registrar General of Births, Deaths and Marriages in England. (1855). London: HMSO. 12. Supplement to the Thirty-fifth Annual Report of the Registrar General of Births, Deaths and Marriages in England. (1875). London: HMSO. 13. Registrar General's Statistical Review of England and Wales for the year 1931. (1932). London: HMSO. 14. Registrar General's Statistical Review of England and Wales for the year 1921. (1923). London: HMSO. 15. Miihlbock, O. (1957) In Ciba Foundation, Colloquia on Ageing. Vol. 3. London: J. and A. Churchill. 16. Nevo, E. (1985). Personal communication. 17. Cross, H. E. and McKusick, V. A. (1978) In Medical Genetic Studies of the Amish. Baltimore: Johns Hopkins University Press. 18. Penrose, L. S. (1932) Journal of Genetics, 25, 407. 19. Penrose, L. S. (1949) Journal of Mental Science, 95, 685. 20. Record, R. G. and Smith, A. (1955) British Journal of Preventive and Social Medicine, 9, 10. 21. Carter, C. O. (1958). Journal of Mental Deficiency Research, 2, 64. 22. Collmann, R. D. and Stoller, A. (1963). Journal of Mental Deficiency Research, 7, 53. 23. Gill, M., Murday, V. and Slack, J. (1986). Submitted for publication. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 293

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Graves of Graves' Disease, 1796-1853 SELWYN TAYLOR, dm, MCh, frcs Dean Emeritus, Royal Postgraduate Medical School, London It is just over 150 years since Graves described the disease which we associate with his name. The description ap- peared in the London Medical and Surgical Journal for Saturday, 23rd May, 1835 and was part of his clinical lectures at the Meath Hospital in the 1834/35 sessions[l]. He reported three cases of tachycardia and thyroid enlargement in young women and added a fourth with severe exophthalmos who had been referred by a col- league. He was not the first to identify the symptoms and the eponym should properly have been claimed by Parry. To digress, Caleb Hillier Parry was born in Gloucester- shire, studied medicine in Edinburgh and practised in fashionable Bath. He went to school with Jenner, who remained a lifelong friend, and dedicated his famous book on vaccination to him. Parry's account[2] of eight cases of the disease was published posthumously by his son in 1825. Basedow, whose name is used for hyperthyroidism in most of the other member countries of the European Community, came from an aristocratic German family and practised in Merseburg. He described, but not until 1848, the postmortem appearances of a patient dying with exophthalmic cachexia. There is no doubt, however, that Robert James Graves should be remembered for his immense contributions to medicine. He revolutionised the clinical instruction of medical students in the UK. He wrote a standard two- volume work[3] on medical treatment, which was trans- lated into French, German and Italian and also published in the USA. In it he described many conditions for the first time; for example, intermittent pallor of the fingers and toes is clearly defined 10 years before Raynaud and so is angioneurotic oedema, 30 years before Quincke. Robert Graves was born on 28th March 1796, the sixth of the 10 children of the Reverend Richard Graves, a Fellow of Trinity College, Dublin, who later became Regius Professor of Divinity and Dean of Ardagh. His mother was Elizabeth Drought, the daughter of another Professor of Divinity also of TCD, as it is affectionately called. The Irish branch of the Graves' family, who hailed from Mickleton in Gloucestershire, was founded by Wil- liam Graves, a colonel commanding a horse regiment in Cromwell's army which wrought such havoc in Ireland, who as a reward received a grant of land in 1650. The family over the years have been distinguished for their contributions to learning, especially theology, and to the Government services, from admirals and governor-gener- als to professor of divinity, authors and poets. Young Graves had a happy childhood and after being tutored by an uncle of Oscar Wilde, passed into TCD at the top of the entry list. He subsequently took the highest award, the Gold Medal, when he graduated, as did two of his brothers. This was a degree in the classics and for the rest of his life he enjoyed quoting from his knowledge of Latin and Greek authors. Qualifying in medicine three years later in 1820, he made the most important decision of his career, which was to go abroad, and he spent the next three years in postgraduate study travelling round Europe. Training to be a doctor in the 1820s, be it in Dublin or London was at best haphazard and at worst scandalous. Eoin O'Brien in his biography of Dominic Corrigan[4] paints a graphic picture of the scene in Ireland, and it is little wonder that the General Medical Council for Edu- cation and Registration, our own GMC, was set up in 1858 albeit after 18 years of parliamentary debate, for the reform of the medical profession. As the Council stated, the two chief reasons for legislation were 'the deep felt necessity for a radical improvement in the education for the main body of medical practitioners, and reciprocity of professional privileges in the three divisions of the king- dom'[5]. Fig. 1. Graves as a young man. 298 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 Graves had been disappointed at the poor training, especially in clinical medicine, he received in Dublin; indeed, many of his contemporaries went to Edinburgh which at that time offered more systematic instruction. Even at this early age Graves was probably contemplating setting up a better eductional programme in his own city, because his first stop was with Sir William Blizard who had founded The London Hospital Medical College in 1785. He must have enjoyed Blizard's company with his great respect for anatomical knowledge, his meticulous attention to detail, not least in his personal appearance, and his gifts as a teacher. He moved on to Gottingen where Stromeyer (1776-1835) was professor of what today we would call clinical pharmacology. Graves was after- wards in the forefront of therapeutics, always describing in his publications precisely what he used and why. The other attraction in Gottingen was Blumenbach (1752- 1840) the father of anthropology, about whom Dr Freed- man[6] wrote in 1984 describing how he introduced the term Caucasian, a term still in current use in America. Graves moved on to Berlin to study with Hufeland (1762-1840) who was pre-eminent in infectious diseases and epidemiology. This was to stand him in good stead when he returned to Ireland and was almost immediately confronted with a typhus epidemic and later one of Asiatic cholera; typhoid was then endemic. He also spent some time with Colsman (1771-1830) in Copenhagen and concluded his tour in Edinburgh. He never missed a chance to travel further afield and had an exciting time, as young travelling fellows in medicine still do. He spent a couple of weeks in prison in Austria suspected of spying, for he was a great linguist. He met and sketched with Turner in the Alps and had a remarkable escape in a Sicilian brig which was caught in a storm in the Mediter- ranean^]. Returning to Ireland he made an enormous impact on the Dublin medical world. As a young man he was a striking figure, tall, dark haired, with flashing eyes and a very animated way of expressing himself. To these rich gifts must be added that of eloquence, to which the Irish brogue adds a certain golden timbre. His daily lectures at Sir Patrick Dun's Hospital at four o'clock were the talk of the town, and this in Dublin in the 1820s was praise indeed. He was of a serious frame of mind and apart from his great affection for his brother Hercules, seems usually to have preferred the company of older men. He was never a lady's man, nor a frequenter of the drawing-rooms of Dublin, which in his day were like courts for anyone who was socially conscious. His three years of postgraduate study in Europe, a true hegira in those days of difficult travel, moulded his character and influenced the rest of his professional life more than anything else he ever did. Indeed, he continued for the rest of his life to correspond with distinguished colleagues overseas and occasionally made further visits abroad to talk to them. At heart he was a true natural philosopher in a period when that subject was just beginning to blossom. He loved to use his classical knowledge, and was equally at home discussing problems in biology, geology, chemistry or epidemiology; he was a natural enquirer. However, as a true physician, when confronted with a patient he became totally in- volved with the individual and thus his contributions to medical literature were not only very practical in terms of treatment, but showed that he never lost the common touch; he was involved in every detail of prescribing and nursing and even with the psychology of coping with relatives. When epidemics of typhus, cholera and typhoid struck the undernourished population in the West of Ireland he immediately went to their help with a team of medical assistants[8], He was fearless in this regard, at a time when many doctors were dying from these conta- gions. His return to Dublin in 1821 caused quite a stir in the rather closely-knit medical profession of the day. Here was a brilliant and talented young man with good connec- tions and better informed about the progress of medicine in Europe than anyone else. His gift of eloquence and his powerful presence would have swept most people off their feet and he was elected almost at once to the staff of one of the city's most prestigious hospitals, the Meath, which had just been rebuilt. Within two years he had been elected a Fellow of the Irish College of Physicians and a year later was co- founder with his colleagues of a new medical school in Park Street. Simultaneously he became a lecturer in the Institutes of Medicine. With his burgeoning private medical practice, and many patients will always flock to a new doctor because he is new, he was at once a force to reckon with in both town and gown. With his excellent papers appearing in the medical journals and his lectures each evening at Sir Patrick Dun's, he was the leading light in those golden years of Irish medicine which positively scintillated with men of talent whose names are still household words from their eponymous links with disease: Stokes, Adams, Corrigan, Colles, to mention only the most famous. He had not been back a year in his home city when he married Matilda Jane Eustace, but within four years she was dead and so was their daughter Eliza. A year later he again plunged into matrimony with Sarah Jane, the daughter of John Brinkley, the Professor of Astronomy and an outstanding mathematician who had come to Dublin from Cambridge. A stimulating intellectual, he became a friend of Graves with whom he co-operated in the field of probability in relation to epidemic diseases, but tragedy struck again and Sarah Jane died within a year, as did her baby daughter. He clearly immersed himself in work at this time but once again he essayed matrimony, and his choice of Anna, daughter of the Reverend Grogan of Slaney Park, very much the county family, seems perhaps out of character. However, they had six children and she outlived him by 20 years. I have the impression that as a young man Graves was mildly hypomanic, a not uncommon occurrence among individuals as brilliant as he was, and that his wonderfully ebullient out-going character suffered a sea-change in the early 1840s, for in 1841 he resigned his chair of medicine and although he accepted the Presidency of the Royal College of Physicians of Ireland in 1843, he forthwith resigned from the Meath Hospital. It must have been an unexpected step, as the hospital minutes record that a Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 299 deputation should wait on him and try to persuade him to change his mind. But he stuck to his decision. For the next 10 years, apart from his election to the Royal Society, his contributions to the academic world were small and his portrait at that time shows a tired, rather cross individual, indeed one who looks depressed?and there is a coarsening of his features. What contributed to this change of mood from one so sparkling to one of depression is difficult to say. Could it have been that slowing of the faculties which accompanies a falling-off in activity of the thyroid gland? That would indeed have been a tragic fate for one whose name was to be afterwards identified with over-activity of the thyroid. There were of course flaws in Graves' character and the greater the man, the greater the attention and condemna- tion they are likely to receive. He did not suffer fools gladly and he sometimes spoke out far too clearly with his strictures. But to his credit he never bore a grudge and even his slanging match with Corrigan in the pages of the Dublin Quarterly Journal of Medical Science[4] contained a generous admission of the latter's great contribution to the organisation of improved health services in the com- munity. In his deductions he was probably too quick to draw analogies which really did not exist, but his ap- proach to natural phenomena was often one of his strengths, and his essays, whether on such diverse sub- jects as the Dead Sea or the progress of Asiatic cholera, always showed the impact of an original mind. His greatest gift to the medicine of his day was his system of clinical teaching which was a subject long neglected. He treated senior students as colleagues and the manner and quality of his instruction was greatly enhanced by his continuing involvement in research, allied with warm compassion for his patients. The clarity of his written word produced a standard text on clinical medicine that was used for many years, not only in the British Isles and North America, but, through transla- tion, in much of Europe. He pioneered studies on the spread of infectious diseases in his own country and, on a broader canvas, worldwide. He was a pioneer in the nutrition of the sick patient and hoped that his epitaph might be 'he fed fevers'. Above all, he was the epitome of a good physician. He succumbed after a long period of pain and discom- fort to cancer of the liver and died on 20th March 1853. His great friend and pupil William Stokes[7] gave a touching account of his death in his biographical notice and his tomb is in the cemetery of Mount Jerome in Dublin. This article is based on a biography of Robert Graves to be published. References 1. Graves, R. J. (1835) London Medical and Surgical Journal, 7, (pt/2), 516. 2. Parry, C. H. (1825) Collections from the Unpublished Papers of the late Caleb Hillier Parry, Vol. 2, pp. 11-128. London: Underwood. 3. Graves, R. J. (1843) Clinical Lectures on the Practice of Medicine, 2 vols. Dublin. 4. O'Brien, E. (1983) Conscience and Conflict. A Biography of Sir Dominic Corrigan. Dublin: Glendale Press. 5. Pyke-Lees, W. (1958) Centenary of the General Medical Council 1858- 1958. London: GMC. 6. Freedman, B. J. (1984) British Medical Journal, 288, 696. 7. Stokes, W. (ed) (1863) Studies in Physiology and Medicine by the late R. J. Graves. 'The life and labours of Graves'. London: John Churchill. 8. Graves, R. J. (1824) Transactions of the Association of the King and Queen's College of Physicians, 4, 408. Fig. 2. Graves as an older man. (Courtesy the National Gallery of Ireland). 300 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986

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Anomalies and Ambiguities in the Disposal of the Dead S. LEADBEATTER, MB, ChB, DMJ (Path), Lecturer in Forensic Pathology. B. KNIGHT, MD (Wales), MRCFJ FRCPath., DMJ, Barrister-at-Law, Professor of Forensic Pathology. University of Wales College of Medicine, Institute of Pathology, Royal Infirmary, Cardiff During the past 150 years legislation relating to the disposal of the dead has developed in a somewhat piece- meal fashion, causing several inherent anomalies that reduce its efficiency and the accuracy of information derived from it. The Medical Certificate of Cause of Death It is the statutory duty[l] of the registered medical practitioner who has been in attendance upon the de- ceased to issue the medical certificate of cause of death. This duty includes deaths which fall within the coroner's jurisdiction although it is standard practice in such cases to withhold the 'death certificate'. The Registrar General recommends that the statutory duty should be strictly observed[2] but the death certificate in such cases is of little practical use because the Registrar of Births and Deaths must register the details as provided by the coroner. For those deaths falling within the coroner's jurisdiction because their causes are unknown, any death certificate completed by the attending doctor obviously would be meaningless. There is no obligation to view the body of the deceased in respect of whom the death certificate is to be issued; such a view of the body is a legally acceptable alternative to having seen the deceased within 14 days before death[3]. The fact of death, the identity of the deceased and the absence of signs of extraneous violence cannot be ascertained without seeing the body. Examination of the external surface of the body, in the absence of recent clinical attendance, is inadequate evidence upon which to base an opinion of the cause of death. In National Health Service hospitals most death certifi- cates are completed by pre-registration house officers, the least experienced members of the clinical staff. Many of these certificates do not contain a true cause of death, merely unqualified modes of death[4], and it is not uncommon for these certificates to escape the notice of the Registrar of Births and Deaths despite his statutory duty to report such deaths to the coroner[5]. Imprecise or inadequate recording of causes of death may lead to requests for further information from the Office of Popu- lation Censuses and Surveys; there is no statutory duty to reply to these requests. No matter how firm the opinions upon which causes of death are based or how accurate their wording, subsequent autopsies reveal an appreciable proportion to be incorrect[6]. It is apparent that data derived from medical certificates of cause of death may be subject to considerable error. The Medical Act 1956, s.29, states that 'a certificate required . . . from any physician ... or other medical practitioner shall not be valid unless the person signing it is fully registered'. It is standard practice, however, for the provisionally registered house officer to issue the death certificate. It would appear that this certificate is not only frequently inaccurate but also always invalid. Still-birth A certificate of still-birth may be issued by a registered medical practitioner (or registered mid-wife) who has seen the body of a still-birth but was not present at that birth; if a certificate is requested by a qualified informant in these circumstances it cannot be withheld. It is difficult enough to ascertain the 'cause of death' at autopsy; a mere view of a still-birth cannot be considered adequate for certification. It remains a legal alternative, where a certificate of still-birth cannot be obtained, for a qualified informant to make a statutory declaration that a child was not born alive[7]. A qualified informant is allowed 42 days in which to register a still-birth; there may be much delay before a need for further enquiry becomes appar- ent. The Registrar of Births and Deaths, unlike the medical practitioner or mid-wife, has a statutory duty to report to the coroner any case where he has reason to believe that the child may have been born alive[8]; he is not required to report a case in which the cause of death is unknown[9]. Such legislation is hardly a deterrent to subtle child destruction or infanticide. The format of the cause of death on the certificate of still-birth is different from that on the medical certificate of cause of death: it has three parts, divided into five sections labelled (a) to (e). There is an apparent lack of appreciation of the principles underlying death certifica- tion[4]; it seems somewhat sanguine to increase the complexity of the cause of death when the certifying Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 273 medical practitioner or mid-wife may have made only an external examination of the still-birth. There is no obligation to notify the Registrar of Births and Deaths of the disposal of the body of a still-birth. Cremation The Acts and Regulations pertaining to cremation date from 1902, the latest regulations having come into force on 1st April, 1985; these latter regulations, which dis- pense with the necessity for the confirmatory Form C in certain circumstances, represent the only major departure from the essence of the original Regulations of 1903. Before the Births and Deaths Registration Act 1926 there was no legal obligation to obtain a certificate of disposal from the Registrar of Births and Deaths before disposing of a body and it was therefore possible to dispose of that body before the death had been registered; it was also possible to register a death without a medical certificate of cause of death having been issued by a registered medical practitioner. The original Cremation Regulations were designed to prevent the near-total destruction of a body before the appropriate authority was aware of any need for investigation. Since the Act of 1926 any need for investigation should be indicated during the process of certification and registration of a death: the fundamental argument upon which the necessity for the cremation certification procedure was based has not existed for the last 60 years. The Cremation Regulations 1930, upon which all later regulations are based, refer to the 'registered medical practitioner'. Provisional registration was introduced in the Medical Act 1950; it is the opinion of the Home Office that those duties which may be carried out by a provision- ally registered practitioner as though he were fully regis- tered do not include duties imposed under the Cremation Regulations. As mentioned in relation to death certifica- tion, s.29 of the Medical Act 1956 implies that it is not legal for the provisionally registered house officer to issue Form B. There appears to be some ambiguity as to whether the practitioner who issues Form C is under obligation to view the body of the deceased. At the time of the Brodrick Report (1971)[ 10] there was no necessity to view the body; no new regulation regarding this has been issued since that time but it is now stated in the rubric of Form C that 'the doctor must see the body of the deceased'. The Brodrick Committee gave its opinion that '. . . a certificate in Form C not given by a pathologist after an autopsy is, in our views, no more than a statement of confidence in the judgement of the Form B doctor'. Home Office guidance that the practitioners issuing Forms B and C should be clinically independent would tend to reinforce this opinion: it seems strange to continue to charge a fee for a mere statement of confidence but to dispense with that fee when a post-mortem examination, which provides verification or otherwise, is performed[l 1], The situation of the Medical Referee is similarly ambivalent. Regulations require him to be 'satisfied that the fact and cause of death have been definitely ascer- tained'^]; such satisfaction is impossible to obtain without post-mortem examination. Even post-mortem examination may fail. The Coroner's Certificate E for Cremation, Form 102, may be issued when an inquest has been opened but does not state the cause of death: the bodies in five of nine cases known to the authors in which the cause of death remained unascertained at the close of the inquest were cremated! The Regulations state that when a death 'might be due to poison, to violence, to any illegal operation, or to privation or neglect' the Medical Referee 'shall require a post-mortem examination to be held'[12]. Except when directed by the coroner all post-mortem examinations are subject to the Human Tissue Act 1961: the Medical Referee cannot 'require a post-mortem examination' without ensuring that there is lack of objection on the part of the deceased or his nearest relative. Even when there is no objection to such an examination, the Regulations do not empower the Medical Referee to pay for one. More- over he has no statutory duty to report such deaths to the coroner. Her Majesty's Coroner There is no statutory duty upon a medical practitioner to report a death to H.M. Coroner although, as 'a person about the deceased', there is a common law duty 'to give information which may lead to the coroner having notice of circumstances requiring the holding of an inquest'[13], This common law duty, long fallen into desuetude, applies to any 'person about the deceased'; a medical practitioner may be considered to be better placed than the man in the street to know what circumstances require the holding of an inquest but the current decline in education in medico-legal matters[14] does not permit confidence in such an opinion. The Registrar of Births and Deaths has a statutory duty to report such deaths as are cited in his Regulations[15]. The information available to him upon which to make a decision is limited to the medical certificate of cause of death and the answers to questions he may put to the qualified informant: he may be at a disadvantage in comparison with the medical practitioner. He must report to the coroner any death 'the cause of which appears to be unknown'[5], Many medical certificates of cause of death do not contain a true cause of death[4] and, therefore, should be reported to the coroner. However, the coroner has no jurisdiction over a death the cause of which appears to be unknown unless it is 'a sudden death'[16]; there is no legal definition of the word 'sudden'. If a death is reported by the Registrar of Births and Deaths because of inaccurate or imprecise wording on a death certificate, but the coroner, after preliminary en- quiry, does not assume jurisdiction, the Registrar must nevertheless register that imprecise or inaccurate cause of death[17], H.M. Coroner may direct[18] or request[19] any legally qualified medical practitioner to carry out a post- mortem examination although such an examination 'should be made, when ever practicable, by a pathologist with suitable qualifications and experience and having access to laboratory facilities'[20], A recent report[21] 274 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 suggests that such an examination has not always been 'practicable'. An inquest may be held without a post-mortem exam- ination. The only situation in which the coroner must direct that a post-mortem examination be performed is on the written requisition of his jury[22]; by the time such a requisition may be made there has been usually both release and disposal of the body. In the absence of a post- mortem examination, the inquest might be quashed on the grounds of insufficiency of enquiry. There is little evidence that the 'psychological autopsy' developed in the USA in the investigation of 'equivocal deaths'[23], forms a part of the medico-legal investigation of death in the UK. Might not the lack of such an autopsy sometimes be described as insufficiency of enquiry? Comment Much of the legislation pertaining to disposal of the dead is anachronistic, ambivalent and ambiguous. Medical undergraduates (and post-graduates) find it difficult to grasp even when tuition is adequate. These qualities detract from the accuracy of death certification and may permit inadequate enquiry into equivocal deaths. There should be both consolidation and streamlining in new legislation which would: (a) make it the statutory duty of the fully registered medical practitioner, who had attended during the last illness, to view the body and to either issue the death certificate (if the cause of death can be stated with accuracy and precision) or report the death to H.M. Coroner. Still-births should be treated in an identical manner; (b) define precisely the circumstances in which a practitioner cannot issue a death certificate and thus clarify the role and duties of H.M. Coroner; (c) abolish cremation certification. It is a final anomaly that these recommendations were made 15 years ago by the Brodrick Committee when education in the legal aspects of medical practice was more prominent in the curriculum that it is today. References 1. Births and Deaths Registration Act 1953, s. 22 (1). 2. Forms for Medical Certificates of the Cause of Death (1985) Notes for Medical Practitioners. 3. The Registration of Births, Deaths and Marriages Regulations 1968, reg.51 (1) (c). 4. Leadbeatter, S. (1986) Journal of the Royal College of Physicians of London, 20, 129. 5. The Registration of Births, Deaths and Marriages Regulations 1968, reg. 51 (1) (d). 6. Cameron, H. M. and McGoogan, E. (1981) Journal of Pathology, 133, 273. 7. Births and Deaths Registration Act 1953, s. 11 (as amended by Population (Statistics) Act 1960 s.2 and Nurses, Midwives and Health Visitors Act 1979, s.23 (4) and Sch.7.) 8. The Registration of Births, Deaths and Marriages Regulations 1968, reg. 43. 9. Forms for Certificates of Still-Birth (1985), Statement of the Cause of Death. 10. Brodrick Committee (1971) Report of the Committee on Death Certifica- tion and Coroners. Cmnd No. 4810. London: HMSO. 11. The Cremation (Amendment) Regulations 1985, reg. 3. 12. Cremation Regulations 1930 (as amended by Regulations of 1952 and 1965) reg. 12(4). 13. Knapman, P. A. and Powers, M. J. (1985) The Law and Practice of Coroners. Chichester: Barry Rose. 14. Knight, B. and Thompson, I. M. (1986) Journal of Medical Education (in press). 15. The Registration of Births, Deaths and Marriages Regulations 1968, reg. 51 (1) (a)-(g). 16. Coroners Act 1887, s.3 (1). 17. Form 100, Notification to the Registrar by the Coroner that he does not consider it necessary to hold an inquest, Part A, Instructions to Registrar. 18. Coroners Act 1887, s.21 (2). 19. Coroners (Amendment) Act 1926, s.22 (1). 20. The Coroners Rules 1984, r.6 (1). 21. Scott, K. W. M. (1986) Lancet, i, 277. 22. Coroners Act 1887, s.21 (3). 23. Litman, R. E., Curphey, T., Shneidman, E. S., Farberow, N. L. and Tabachnik, N. (1963) Journal of the American Medical Association, 184, 924.

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Pain Control in Advanced Cancer: Pharmacological Methods G. W. HANKS BSc, mrcp(UK) Consultant Physician E J. HOSKIN BSc, MRCP(UK), FRCR Cancer Research Campaign Research Fellow and Honorary Senior Registrar Royal Marsden Hospital, Sutton, Surrey Pain is a major symptom in some 60 per cent of patients managed in a general oncology unit[l] and up to 85 per cent of patients referred for hospice care[2]. Pain control is therefore an essential component of the modern man- agement of malignant disease. Pain is a complex subjective experience, combining the perception of a painful stimulus with a variable emotional response to it. Chronic pain associated with progressive malignancy is quite different from acute pain following trauma or surgery, or the minor acute pains (headache or toothache) of normal day to day life. Unlike acute pain, chronic pain is of unpredictable duration and is maladap- tive: it has no positive function. Thus a major component of chronic cancer pain is the associated emotional reac- tions of fear, anxiety, anger or depression. Invariably the patient is also troubled by other symptoms such as anorexia, nausea, constipation, fatigue and sleep disturb- ance, all contributing to a lowered pain threshold and impaired pain tolerance. The clinical picture of the patient with chronic cancer pain is a summation of the physical effects of the original nociceptive stimulus, the patient's emotional response to this, and other symptoms associated with the underlying malignancy or caused by the pain. The situation is further complicated by the fact that 80 per cent of patients in pain will have more than one pain and approximately 20 per cent will have four or more separate pains[3]. Management of Chronic Cancer Pain As the nature of chronic cancer pain is so complex it is necessary before embarking upon treatment to identify each individual pain and its underlying aetiology, to appraise the patient's mental state and to evaluate any associated physical symptoms. A body chart is often helpful and will also provide a valuable baseline for future assessments. Once the underlying nature of the patient's pain has been identified a logical treatment strategy can be de- vised. The mainstay of treatment will be pharmacologi- cal. It is, however, important not to neglect the role of other treatment modalities and at this early stage to identify those pains which may respond to specific non- drug measures, such as the use of radiotherapy for localised bone pain. A further important step at the outset of treatment is careful explanation to the patient and reassurance that pain control can be achieved. Realistic goals should be set, with three stages of pain control in mind: to be pain free at night, pain free at rest and pain free on movement. The first two of these will almost always be possible to achieve and confidence will be built up as each objective is realised. Complete pain control on movement may be more difficult and sometimes simple modifications to life style, in addition to specific treatment, are needed. Drug Treatment of Chronic Cancer Pain Effective drug treatment is founded on the regular use of an appropriate analgesic given in an adequate dose. Initial choice of drug is based on the severity of the pain and its response to previous treatment. In general, a simple scheme using a limited number of drugs familiar to the prescriber is recommended, ranking drugs accord- ing to analgesic strength with a range from simple non- opioid analgesic, to weak opioid, to strong opioid. One drug in each class should be used routinely, for example paracetamol, dextropropoxyphene/paracetamol, and morphine; only rarely will an alternative be necessary. If a drug is no longer effective there is no value in using alternatives from the same group, and it is inappropriate to use two drugs of similar strength in the hope of an additive or synergistic action. Proprietary tablets contain- ing combinations of drugs, in particular those combining several simple analgesics, are best avoided unless careful consideration has been given to the individual constitu- ents and their doses. There is no place for intermittent 'as required' anal- gesia in the management of chronic cancer pain. The aim of treatment is to control and prevent further symptoms by regular medication, maintaining constant effective blood concentrations in the steady state. A recommended scheme of drug use in chronic cancer pain is outlined in Table 1. 276 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 Table 1. Recommended scheme of drugs for use for chronic cancer pain Pain Mild pain Analgesic group Drug of choice Simple peripherally-acting analgesic Paracetamol 1 g 4-hourly Alternative drugs Soluble aspirin 600-1200 mg 4-hourly Drugs to avoid Compound preparations Other measures Co-analgesic Unresponsive to simple analgesics Unresponsive to weak opioids Weak opioid Dextropropoxyphene/paracetamol 2 tabs. 4-hourly Dihydrocodeine 30-60 mg 4-hourly Pentazocine Co-analgesic Strong opioid Morphine or diamorphine. orally 5-200 mg 4-hourly Phenazocine, levorphanol, oxycodone suppositories Short-acting opioids, combinations, opioids with cumulative toxic effects Co-analgesic Simple Analgesics Paracetamol is the preferred simple analgesic where no anti-inflammatory action is required. A derivative of para-aminophenol, it has analgesic and antipyretic effects similar to those of aspirin at equivalent doses up to 1 g. Paracetamol is rapidly absorbed from the small bowel but hardly at all in the stomach: hence gastric emptying may significantly affect the overall rate of absorption. Peak plasma concentrations are reached at 30 to 60 minutes after a single oral dose[4]. In addition to tablets a suppository for rectal use is available for those patients unable to take drugs by mouth. The plasma elimination half-life is 1.5-3.0 hours[5], and regular 4-hourly oral administration of 1 g (two tablets) is the recommended dose. The principal advantage of paracetamol over other simple analgesics is that it is well tolerated by most patients with no gastric irritant effect. Serious toxicity is not seen when it is used in the above doses. The alkylating metabolite responsible for hepatotoxicity in overdosage is produced only in small amounts at normal therapeutic doses and is rapidly detoxified by conjugation with reduced glutathione[6]. Alternative simple analgesics are not usually required since intolerance to paracetamol is unusual. Failure of a simple analgesic to control pain is an indication for a drug with a stronger analgesic action. Aspirin (acetylsalicylic acid) is recommended by some authors[3] as the simple analgesic of choice. It has the advantage, in high dosage (4-6 g/day), of additional anti- inflammatory action which may be of value, particularly in the treatment of bone metastases. However, side- effects, including gastric intolerance and metabolic dis- turbances, are much more common at these doses and the use of one of the newer non-steroidal anti-inflammatory drugs is generally preferable when an anti-inflammatory action is required. At low doses aspirin has no advantage over paracetamol and is generally less well tolerated. Weak Opioids These drugs are recommended where simple analgesics are ineffective or in mild to moderate visceral pain which often does not respond to paracetamol. Dextropropoxyphene/paracetamol (Coproxamol) is our drug of choice in this group, despite continued controversy over its efficacy and potential dangers[7,8], Dextropro- poxyphene is a synthetic opioid structurally related to methadone and a weak opioid agonist. It is readily absorbed from the gastrointestinal tract with peak serum levels at about two hours after administration. The mean elimination half-life is about 15 hours with steady state levels being reached after three to four days of regular 6 to 8-hourly administration. In elderly patients the half-life may be very long (over 50 hours)[9], Dextropropoxy- phene undergoes extensive first pass metabolism, its principle metabolite being norpropoxyphene which also has analgesic activity and a longer half life (about 23 hours) than dextropropoxyphene itself. This metabolite therefore accumulates in plasma[10]. Both dextropro- poxyphene and norpropoxyphene reach plasma concen- trations in the steady state which are five to seven times greater than those found after the first dose. It follows from this that studies using single doses of dextropropoxyphene are assessing a very different situ- ation to that which exists in the steady state during regular administration for chronic painfll]. This may explain why extensive clinical experience with a dextro- propoxyphene/paracetamol combination in patients with chronic pain due to malignant disease and in patients with rheumatic disorders[12] suggests that the prep- aration is effective and well tolerated, but controlled clinical trial data are conflicting. There is, however, substantial evidence to support the efficacy of dextropro- poxyphene itselff 13] and a single published controlled study in rheumatology patients[14] which indicates the superiority of a dextropropoxyphene/paracetamol combi- nation over paracetamol alone. The recommended dose is up to two tablets of Coprox- amol 4-hourly (each tablet contains dextropropoxyphene 32.5 mg and paracetamol 325 mg). At these doses serious side effects are unusual but confusion, dysphoria and lightheadedness may occur, particularly in the elderly. Nausea and vomiting are infrequent and constipation is less troublesome than with other opioids. Addiction has been reported[15] but is rare and does not arise in the treatment of chronic pain. Coproxamol will potentiate the effects of warfarin, carbamazepine and central nervous system depressants. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 277 Alternative weak opioids should be restricted to pure opioid agonists such as codeine or dihydrocodeine. Dihydrocodeine is probably the alternative drug of choice being a semi-synthetic analogue of codeine and approxi- mately 30 per cent more potent than the parent drug. Both drugs are chemically closely related to morphine (codeine is 3-methylmorphine). After an oral dose of codeine some 10 per cent is converted by demethylation to morphine, which may contribute to the analgesic effect. The principal disadvantage of codeine or dihydro- codeine compared with Coproxamol is that they tend to be more constipating at equi-analgesic doses[3]. Pentazocine is a mixed opioid agonist and antagonist which, although in common use, is not recommended for chronic pain due to malignant disease. It is a derivative of phenazocine, a strong opioid agonist. An evaluation in patients with chronic pain[16] showed an analgesic poten- cy of one sixth that of morphine, and another single dose study[17] has suggested that standard doses are less effective than standard doses of dextropropoxyphene with paracetamol. Thus no clear advantage of pentazocine exists in terms of analgesic efficacy and there are two major drawbacks; first, it may antagonise opioid agonists and, second, there is a high incidence of psychotomimetic effects, occurring in 20 per cent of patients in one series[18], half of which resulted in a major disturbance. Strong Opioids When pain is no longer controlled by a weak opioid in standard doses, then a strong opioid should be used in its place, titrating the dose to the patient's pain. Morphine sulphate is the drug of choice for oral use, most readily taken in aqueous solution or in chloroform water as morphine elixir. Morphine is the pharmacologi- cally active constituent of opium. Despite its widespread use, dating from the third century B.C., accurate data on the pharmacokinetics of morphine are sparse, primarily due to the difficulties in measuring morphine distinct from its metabolites in serum[19]. Absorption from the gastrointestinal tract occurs readily (mainly in the upper small bowel) but oral bioavailability varies considerably (between 15 and 64 per cent in one study in cancer patients[20]). The effect of an oral dose is significantly less than that of the same dose given intravenously due to a considerable first pass effect. In rats, 85 per cent of an oral dose is eliminated due to metabolism in both gut wall and liver[ 21 ]. While a role for the kidney has been recently proposed[22], the relative importance of renal glucuronidation is disputed[23]. Almost certainly the metabolism of morphine is principally hepatic, the main pathway resulting in the formation of morphine-3-glucur- onide and morphine-6-glucuronide. The elimination half life also shows considerable variation from one to hours after low single oral doses in cancer patients[20], although it is not clear how this relates to steady state conditions after chronic high dosage. During chronic dosing, accumulation of the main metabolites occurs, the average ratio for morphine-3-glucuronide to morphine being 35:1 and for morphine-6-glucuronide 4:1 [24], There is evidence to suggest that morphine-6-glucuronide also has significant analgesic activity[25]. The presence of high concentrations of morphine-6-glucuronide may ex- ? plain the apparent increased sensitivity to morphine of patients with renal impairment and the possible misinter- pretation of kinetic data obtained using an assay method which could cross react with this metabolite[26, 27], Despite the variation in plasma half-life, in clinical practice regular 4-hourly administration provides con- stant analgesia in doses ranging from 5 mg to 200 mg every four hours, although occasionally much higher doses are required. The dose is titrated to achieve pain control and around 70 per cent of patients will not require more than 30 mg 4-hourly[28]. The need for a dose to be given in the middle of the night can usually be avoided by a double dose at bedtime. The use of a slow release preparation of morphine sulphate (MST Continus) has gained increasing popular- ity over recent years. Peak concentrations of morphine in the blood are not achieved until up to four hours after administration[29], but there are claims that overall bioavailability may be better than with 4-hourly oral morphine sulphate[30]. Although a useful means of deli- vering regular morphine in a stable situation, it is important to emphasise that this preparation should not be used for acute exacerbations of pain, nor, because of uncertainty over the time to achieve steady state plasnia levels, is it ideal for patients starting morphine or requir- ing regular dose adjustments. MST does appear to be effective when given twice a day, and used appropriately it allows a more convenient regimen for patients requir- ing long-term morphine therapy[31]. The principal side effects of morphine in chronic use are drowsiness, constipation, nausea and vomiting. Most patients experience drowsiness initially which may cause considerable concern for both patients and relatives, particularly if associated with confusion. However, this is usually transient and not an indication to reduce an effective pain-relieving dose of morphine, but rather should be dealt with by careful explanation and reassur- ance. Constipation is universal and regular laxatives such as Dorbanex (containing a faecal softener, poloxamer, and a peristaltic stimulant, danthron) should be given from the outset. Nausea and vomiting are not inevitable, up to one third of patients receiving regular oral mor- phine requiring no anti-emetics[32]. In those patients who do become nauseated, haloperidol taken once or twice daily is usually effective with fewer side effects than the phenothiazines. Where a more sedative anti-emetic is required, prochlorperazine or chlorpromazine taken 8- or 4-hourly is suitable. Other reported side effects, including pupillary con- striction, biliary spasm, increased bladder tone and peri- pheral vasodilatation, do not usually present a clinical problem in chronic cancer pain patients. Respiratory depression does not occur in patients who are in pain[28] and is not a justification for using inadequate doses. Addiction does not occur in patients receiving long term opioids for chronic cancer pain. Addiction is based on three separate components: physical dependence, psychological dependence and habituation (Fig. 1). De- spite prolonged treatment with high doses of opioids 278 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 neither psychological dependence nor habituation is seen. Tolerance to the physical effects of opioids may occur and physical dependence may develop after continuous use for periods of longer than about two weeks. Despite this, in patients whose pain improves or resolves, dose reductions and discontinuation of the opioid may be achieved with- out difficulty [3]. Diamorphine (diacetylmorphine) is the strong opioid of choice for use by subcutaneous or intravenous adminis- tration, and may also be substituted for morphine orally. It is a semi-synthetic derivative of morphine and is rapidly deacetylated m the body to monoacetyl-morphine and morphine. Its onset of action after intravenous injection is more rapid than that of morphine and it is associated with less vomiting and less sedation. There is some evidence that diamorphine is better absorbed from the gastrointestinal tract than morphine. However, dia- morphine is essentially a prodrug for morphine, diacetyl- morphine and monoacetylmorphine being undetectable in blood after an .oral dose[33]. Diamorphine has no unique advantages or disadvantages for the relief of pain[34, 35] and its effects are indistinguishable from those of morphine when given 4-hourly for chronic pain[36]. The principal advantage of diamorphine lies in its much greater degree of solubility, enabling high doses to be administered by injection in small volumes suitable not only for intravenous use but also for subcutaneous injec- tion or infusion. The limit of solubility is about 400 mg/ ml although a concentration of 250 mg/ml (25 per cent w/ v) is probably the maximum that should be used for continuous subcutaneous infusion[37]. It is important to consider the differences in bioavaila- bility when changing from an oral morphine preparation to parenteral diamorphine, dividing the oral dose of morphine by three to obtain an equivalent parenteral dose of diamorphine. Because of the better oral bioavaila- bility of diamorphine, an oral dose of diamorphine should be divided by two to obtain the equivalent parenteral dose. Alternative Strong Opioids None of the alternative strong opioids possess particular advantages which make them preferable to oral morphine or parenteral diamorphine. Commonly used drugs in this group are shown in Table 2 together with their equivalent Table 2. Alternative strong opioids Drug Dose Oral morphine sulphate (mg) equivalent dose (mg) Buprenorphine (Temgesic) Dextromoramide (Palfium) Dipipanone (Diconal when combined with cyclizine 30 mg) Nepenthe Papaveretum (Omnopon) Pethidine Phenazocine (Narphen) Methadone (Physeptone) 0.2" 10 lml (10ml of 10% solution) 10 50 5t 10-15 10 5 12 5 6 25 5 "Usually given 8-hourly; the equivalent dose of morphine indicated is a 4-hourly dose. tin single doses only; diie to accumulation considerably more potent in chronic usage. oral morphine doses. As can be seen, some are consider- ably more potent than morphine and this can cause problems in changing from one to another. Buprenorphine is a partial opioid agonist which means that it may have both agonist and antagonist effects. It may be given sublingually or by injection. In acute pain postoperatively it appears effective, but in chronic use it has a high incidence of side effects, in particular nausea and vomiting, dizziness and drowsiness[38]. This limits its effective dose range and together with its potential antagonist action outweighs the advantage of sublingual absorption which may in any case be delayed and unrelia- ble in patients with malignant disease who frequently have dry sore mouths. Dextromoramide is a potent analgesic but usually has an effective duration of action of only lj-2 hours. It is unsuitable for the treatment of chronic cancer pain. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 Dipipanone has no specific advantages and the import- ant drawback of being available only in a fixed dose combination tablet containing dipipanone 10 mg with cyclizine 30 mg. Nepenthe used to be an alcoholic tincture of opium but is now formulated almost entirely as morphine hydrochlo- ride)^]. Since it can be made up in various strengths this can cause confusion as to the equivalent dose of morphine and it has no advantages over morphine sulphate. Pethidine is a synthetic opioid agonist which is generally shorter acting than morphine, its duration of effective analgesia being two to four hours. Its other main draw- back for chronic use lies in its conversion to norpethidine by 7V-demethylation. Although this metabolite does not reach detectable levels after a single dose of pethidine, it accumulates with chronic usage, particularly where there is renal impairment[40]. The elimination half-life of norpethidine is about 17 hours compared with 3.5 hours for pethidine[41],Norpethidine differs from pethidine in its effects on the central nervous system, having predomi- nantly excitatory effects which are manifest in patients by tremor, twitching, agitation and convulsions. Clinically significant accumulation of norpethidine is seen with doses of pethidine greater than 200-300 mg given 3- hourly, and at lower doses when there is renal impair- ment. Methadone is marginally more potent than morphine in single doses. When given regularly, however, its half life increases considerably, with cumulation; plasma concen- trations may take two to three weeks to reach a steady state[42]. Furthermore, no clear relation exists between plasma levels and analgesic activity. This tendency to cumulation in regular use can be particularly troublesome in the debilitated and elderly in whom sedation, confusion and, occasionally, respiratory depression may be seen. Opioid mixtures have been advocated in the past, based on the traditional 'Brompton Cocktail', and the current British National Formulary[43] still contains four such formulations containing morphine or diamorphine with cocaine in a sweetened alcoholic base. Use of such cocktails confers no advantages but has a number of disadvantages. The inclusion of cocaine appears to in- crease side effects particularly in the elderly, and the use of any combination preparation reduces flexibility in dosage. Route of Administration The majority of patients will have their pain well con- trolled on oral medication until the final hours or days of their illness, and over 50 per cent will never require an injection[44]. Some patients, however, will be unable to tolerate oral drugs, because of nausea and vomiting, general debility, or impaired consciousness. Rectal administration is a good alternative but may be unacceptable to some patients. Morphine suppositories are given 4-hourly in the same dose used by mouth and are widely available in a range of strengths. Oxycodone suppositories are an alternative which have the advantage of a longer duration of action (6 to 8 hours). Oxycodone 30 mg is equivalent to morphine 20 mg. As discussed above, when parenteral medication is required, diamorphine is preferred. The optimum means of administration is by subcutaneous infusion using a syringe driver which avoids the need for repeated skin punctures. An anti-emetic such as haloperidol can be included in the subcutaneous infusion if necessary. Parenteral opioid analgesics are not inherently better than oral medication when given in equi-analgesic doses, and in practice the indications for the use of subcutaneous infusions are relatively limited. Co-analgesics A co-analgesic is any therapeutic agent which may not have intrinsic analgesic activity but which will contribute significantly to pain relief when used with a conventional analgesic[45]. Table 3 gives some common examples. Table 3. C o-analgesics. Drug Type of pain NSAID Musculoskeletal pain, e.g. bone metastases or soft tissue infiltration. Corticosteroid Raised intracranial pressure Nerve root compression Soft tissue infiltration Hepatomegaly Diuretic Lymphoedema ( + compression sleeve, massage) Antibiotic Infected ulcer Discharging sinus Muscle relaxants Muscle spasm Anticonvulsants Nerve root pain Post herpetic neuralgia Non-steroidal anti-inflammatory drugs (NSAIDs) do not have a place as primary therapeutic agents but when used in conjunction with an opioid may be very effective particularly in the relief of bone pain. Prostaglandins are involved in peripheral nociceptive mechanisms, sensitis- ing free nerve endings to pain-inducing vasoactive amines and kinins and hence facilitating pain transmission. They are also specifically involved in the development of bone metastases, stimulating osteoclastic bone resorption. Some tumours produce prostaglandin-like substances which may promote their metastatic potential in bone; the use of a prostaglandin synthetase inhibitor has a rational basis in the treatment of bone pain. NSAIDs have a considerable potential, however, for producing adverse effects particularly on the gastrointes- tinal tract and in elderly patients[46]. It is important to closely monitor the therapeutic response of each patient and discontinue the drug at an early stage if no clear-cut benefit is seen. Despite a wide range of drugs in this class, none appears to have specific advantages in this indi- cation. Soluble aspirin 600-1200 mg 4-hourly, may be appropriate for patients receiving 4-hourly morphine. In general, drugs which require less frequent administration are preferable for other patients, such as piroxicam 20 mg nocte or flurbiprofen 100 mg b.d. 280 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 Benorylate is an ester of paracetamol and aspirin which can be administered as an oral suspension. It has fewer side effects than aspirin used alone and has the additional advantage of 12-hourly dose intervals. It is de-esterified in vivo, each gram of benorylate producing 600 mg aspirin and 440 mg paracetamol. It may be a suitable alternative in certain patients where gastrointestinal tolerance is a problem with anti-inflammatory doses of aspirin, or with other NSAIDs. A dose of 10 ml (4g) b.d. is equivalent to 4.8 g/day of aspirin. Corticosteroids are of use in headache due to raised intracranial pressure, nerve root pain due to compression or tumour infiltration, and may also reduce pain due to soft tissue infiltration. Dexamethasone has advantages over prednisolone because of its weaker mineralocorticoid (salt and water retaining) effects, with a lesser tendency to cause oedema and weight gain. Diuretics may be useful in conjunction with massage and compression for painful lymphoedema. Antibiotics are helpful for pain from an infected ulcer or discharging sinus, and for dysuria due to a urinary tract infection. Muscle relaxants are indicated where pain is due to increased muscle tone, spasm or clonus. Baclofen 5-20 mg three times daily is the preferred drug, having less sedative action than diazepam. Some patients, however, have intolerable gastrointestinal side effects and in these diazepam 2 to 5 mg t.d.s. may be used as an alternative. Anticonvulsants may be helpful in some patients with lancinating or stabbing dysaesthetic pains associated with nerve compression or infiltration, and post-herpetic or post-traumatic neuralgias. Carbamazepine 100 mg t.d.s., sodium valproate 200 mg t.d.s. or clonazepam 0.5-2.0 mg once or twice daily, may all be helpful. Individual patients may respond better to one particular drug. Clonazepam tends to cause more sedation and the choice of drug should be tailored to the individual patient. Conclusion The principles of effective pain control are: make a diagnosis; individualise the treatment; and keep it simple. Familiarity with a simple analgesic ladder will facilitate rational changes in analgesic and dose modifications as appropriate. Predictable side effects such as constipation should be prevented. The appropriate use of co-analgesics including non-drug treatments such as radiotherapy or nerve blocks should also be considered. With this ap- proach it should be possible to control pain in almost all patients with malignant disease without the need for exceptional measures. Acknowledgement We are grateful to Mrs F Fleetwood for the typing of this manuscript. References 1. Foley, K. M. (1979 Advances in Pain Research and Therapy, 2, 59. 2. Twycross, R. G. (1974) International Journal of Clinical Pharmacology, Therapy and Toxicology, 9, 184. 3. Twycross, R. G. and Lack, S. A. (1983) Symptom Control in Far Advanced Cancer: Pain Relief London: Pitman Books. 4. Gwilt, J. R., Robertson, A., Goldman, L. and Blanchard, A. W. (1963) Journal of Pharmacy and Pharmacology, 15, 445. 5. Cummings, A. J., King, M. L. and Marti, B. K. (1967) British Journal of Pharmacology and Chemotherapy, 29, 150. 6. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Davis, D. C., Gillette, J. R. and Brodie, B. B. (1973) Journal of Pharmacology and Experimental Therapeutics, 187, 185. 7. Miller, R. R., Feingold, A. and Paxinos, J. (1970) Journal of the American Medical Association, 213, 996. 8. Anonymous (1983) Drug and Therapeutics Bulletin, 21, 17. 9. Crome, P., Gain, R., Glurye, R. and Flanagan, R. J. (1984) Human Toxicology, 3, 415. 10. Inturrisi, C. E., Colburn, W. A. and Verebely, K. et al. (1982) Clinical Pharmacology and Therapeutics, 31, 157. 11. Hanks, G. W. (1985) Cancer Topics, 5, 54. 12. Gumpel, J. M (1979) British Medical Journal, 1, 551. 13. Beaver, W. T. (1984) Human Toxicology, 3, 1915. 14. Owen, M. and Hills, L.J. (1980) Medical Journal of Australia, 1, 617. 15. Whittington, R. M. (1979) Lancet, 2, 743. 16. Beaver, W. T., Wallenstein, S. L., Houde, R. W. and Rogers, A. (1966) Clinical Pharmacology and Therapeutics, 7, 740. 17. Robbie, D. S. and Samarasinghe, J. (1973) Journal of International Medical Research, 1, 246. 18. Taylor, M., Galloway, D. B., Petrie, J. C. et al. (1978) British Medical Journal, 2, 1498. 19. Aherne, G. W. (1983) Royal Society of Medicine International Congress and Symposium Series, 58, 21. 20. Sawe, J., Dahlstrom, B., Paalzow, L. and Rowe, A. (1981) Clinical Pharmacology and Therapeutics, 30, 629. 21. Dahlstrom, B. E. and Paalzow, L. K. (1978) Journal of Pharmacokine- tics and Biopharmaceutics, 6, 505. 22. McQuay, H. J., Moore, R. A., Bullingham, R. E. S., Sear, J. W. and Symonds, H. W. (1984) Royal Society of Medicine International Congress and Symposium Series, 64, 111. 23. Hanks, G. W. and Aherne, G. W. (1985) Lancet, 1, 221. 24. Sawe, J., Kager, L., Svensson, J. O. and Rane, A. (1985) British Journal of Clinical Pharmacology, 19, 495. 25. Shimomura, K., Kamato, O., Ukei, S. rfa/(1971) TohokuJournal of Experimental Medicine, 105,45. 26. Sawe, J., Svensson, J. O. and Odar-Cederlof, I. (1985) Lancet, 2, 211. 27. Aherne, G. W. and Littleton, P. (1985) Lancet, 2, 210. 28. Hanks, G. W. and Twycross, R. G. (1984) Lancet, 1, 1477. 29. Hanks, G. W., Rose, N. M., Aherne, G. W. et al. (1981) British Journal of Anaesthesia, 53, 1259. 30. McQuay, H. J., Moore, R. A., Bullingham, R. E. S. et al (1984) Royal Society of Medicine International Congress and Symposium Series, 64, 149. 31. Hanks, G. W., Trueman, T. (1984). Royal Society of Medicine International Congress and symposium Series, 64, 103. 32. Hanks, G. W. (1982) Lancet, 1. 1410. 33. Inturrisi, C. E., Max, M. B., Foley, K. M. et al. (1984) New England Journal of Medicine, 310, 1213. 34. Kaiko, R. F., Wallenstein, S. L., Rogers, A. G., Grabinski, P. Y. and Houde, R. W. (1981) New England Journal of Medicine, 304, 1501. 35. Leading Article (1985) Lancet, 1, 1449. 36. Twycross, R. G. (1977) Pain, 3, 93. 37. Jones, V., Murphy, A. and Hanks, G. W. (1985) Pharmaceutical Journal, 235, 426. 38. Anonymous (1982) Drug and Therapeutics Bulletin, 20, 74. 39. British National Formulary (1985) Number 9, p 169. 40. Szeto, H. H., Inturrisi, C. E., Houde, R. et al. (1977) Annals of Internal Medicine 86, 738. 41. Edwards, D. J., Svensson, C. K., Visco, J. P. and Lalka, D. (1982) Clinical Pharmacokinetics, 7, 421. 42. Twycross, R. G. (1984) Clinics in Oncology, 3, 123. 43. British National Formulary (1985) Number 9, p 172. 44. Lamerton, R. (1979) British Medical Journal, 2, 443. 45. Twycross, R. G. and Hanks, G. W. (1984) Clinics in Oncology, 3, 153. 46. Somerville, K., Faulkner, G. and Langman, M. (1986) Lancet 1, 462. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 281

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The Relationship between Physicians and the Pharmaceutical Industry A REPORT OF THE ROYAL COLLEGE OF PHYSICIANS Membership of the Working Party Sir Raymond Hoffenberg (President and Chairman) Dr O. L. Wade (Honorary Secretary) Dr Barbara M. Ansell Sir Douglas Black Dr A. M. Breckenridge Dr T. L. Chambers A. J. Collier Esq Dr M. J. Denham Miss Patricia Lamburn Dr S. P. Lock Dr D. R. London Dr M. F. Muers Dr P. C. Reynell The Rt Hon Sir Kenneth Robinson Dr P. P. Turner Dr D. W. Wall Dr D. A. Pyke (Registrar) In attendance Mr G. M. G. Tibbs (College Secretary) Mrs Myra Dawson , . ? . c ? \ ? 7 , (Working Party Secretaries) Mrs Sarah Green v Contents Page Introduction 236 Evidence Received 237 Drug Prescribing 237 Clinical I^search and Trials 237 Recommendations 238 Meetings 238 Hospitality and Gifts 239 Research Projects and Clinical Trials 239 Appendices 1. Evidence Given 241 2. Relationship between Postgraduate Medical Centres and Pharmaceutical Houses 241 3. Statement by The British Journal of Clinical Pharmacology 242 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 235 INTRODUCTION There needs to be a close and constructive relationship between the medical profession, which prescribes drugs for patients and the pharmaceutical industry, which produces and markets them. Such a relationship brings benefit to patients, the pharmaceutical industry and our nation. It furthers the well-informed and safe use of the drugs which are available and it encourages the co- operative research that is essential in the development of new drugs. It contributes to our national economy be- cause our research-based pharmaceutical industry has an enviable record of innovation and success in its export trade. New drugs can be properly developed only if doctors evaluate them in patients. The pharmaceutical industry depends on independent and impartial clinical assessment of their drugs by physicians. This brings chemists and scientists in pharmaceutical companies into a relationship with doctors which is necessary and constructive. It must, however, be conducted on strictly professional lines and neither party should abuse its position for financial or other gain or mislead the other on factual evidence about the drugs under trial. Once a drug is developed and marketed, a new re- lationship comes into existence between pharmaceutical companies and doctors; a relationship in which compan- ies in a competitive industry are trying to persuade the medical profession to prescribe their products while at the same time seeking the views of the profession about their efficacy and safety. This Report has been produced by a Working Party and approved by the College as a guide to practising physicians. It is not a critique of the pharmaceutical industry, nor an examination of recent, well-publicised cases of apparent misdemeanour on the part of doctors although its origin lies in anxiety over those cases. It is intended to help doctors when they have to decide how best to handle their complex relations with the pharma- ceutical industry. There has been increasing concern in recent years about the relationship between doctors and the pharma- ceutical industry in two respects: 1. Prescribing. Doctors spend large sums of public money with fewer restrictions than in almost any other area of public expenditure. In return for the trust placed in him the doctor is expected to prescribe for his patients on the basis of the known efficacy and safety of drugs and it is essential that there should be no suspicion that his professional judgement may have been impaired by the receipt of gifts, hospitality, payment or subsidy from pharmaceutical companies. Consultant physicians have an additional responsibility inasmuch as they are opinion leaders in drug usage and influence the prescribing patterns of their junior staff and of general practitioners in their area. 2. Clinical Research and Clinical Trials. There has been concern that some of the interactions between companies and physicians who are clinical investigators could com- promise the autonomy and independence of the doctors in a way that might reflect adversely on the integrity of the profession. That these concerns in both fields are widely shared is apparent from comments made in three published docu- ments: 1. The General Medical Council's booklet Professional Conduct and Discipline: Fitness to Practise (1985) states 'doctors should avoid accepting any pecuniary or ma- terial inducement that might compromise, or be regarded by others as likely to compromise, the independent exercise of their professional judgement in prescribing. The seeking or acceptance by doctors of unreasonable sums of money or gifts from commercial firms which manufacture or market drugs or diagnostic or therapeutic agents or appliances may be regarded as improper.' 2. The Department of Health and Social Security (DHSS) has recently re-issued a notice on the acceptance of funding, gifts and hospitality which states that 'it is a basic principle in all parts of the public service that staff should not only be scrupulously impartial and honest but beyond the reach of suspicion.' The notice goes on to state that 'whenever an officer wishes to attend an educational conference or other occasion that is to be financed wholly or partially from promotional or com- mercial sources he should seek approval from the employ- ing authority . . .' 3. The Code of Practice for the Pharmaceutical Industry (1984) published by the Association of the British Phar- maceutical Industry (ABPI) states (section 19) that 'no gift or financial inducement shall be offered or given to members of the medical profession', but excepts inexpen- sive gifts, which in this context are presumably pens, diaries, books, rulers or similar articles related to a doctor's work. The Code also states (section 20) that 'entertainment or hospitality offered . . . should always be secondary to the main purpose of the meeting . . not extend beyond members of the profession, be appropriate and not out of proportion to the occasion . . . not exceed that level which the recipients might normally adopt when paying for themselves'. Comments in television and radio programmes, in The Times, the Guardian, the Economist, a number of medical journals and by the Consumers' Association demonstrate that the media and the public expect and demand that the conduct of doctors, both as prescribers and investigators of drugs, should be above criticism. In the light of this concern, and because of the responsi- bilities that physicians have for the care and treatment of patients, the President called a meeting of Fellows on 15 February 1984. It was agreed that a College Working Party should be established to examine the relationship between physicians and the pharmaceutical industry. The emphasis of the enquiry was to be on the behaviour of physicians and not on the relationships between commer- cial organisations and clients. The Working Party met twelve times and received both documentary and oral evidence (see Appendix 1.) 236 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 EVIDENCE RECEIVED Drug Prescribing We found that there was widespread acceptance that a pharmaceutical company has a duty to inform doctors of its products and collect information on clinical experi- ence, but the provision of social functions for doctors or other inducements to use its products was not considered to be part of that duty. We were reassured by the general standard of the relationship between physicians and the pharmaceutical industry but were aware of frequent examples of minor infringements of the accepted codes and a few examples of gross abuse. Sponsored Meetings There has been considerable and welcome development of postgraduate centres and of graduate medical edu- cation in the last 20 years. Possibly because the DHSS was slow in giving adequate support to these activities, drug companies began to sponsor educational meetings many years ago. This help was welcomed, but in some postgraduate centres almost every meeting now held is financially dependent upon funding by a pharmaceutical company. We were informed that the National Associ- ation of Clinical Tutors was concerned that at these meetings there was not always appropriate separation of promotional and educational activities. Hospitality We were given evidence that many doctors receive hospi- tality on a scale beyond that recommended in the ABPI Code. We were informed that doctors occasionally de- mand hospitality before agreeing to receive a pharma- ceutical representative, and that this demand has even on occasions included hospitality for the doctor's spouse. We heard of instances in which a company wished to show a promotional and/or informational film but doctors had made it clear they would not attend unless the film was shown with a meal organised at a restaurant of their choice. If such a film is to be shown to resident medical staff at a hospital it is often understood that there should be accompanying hospitality from the pharmaceutical company which may vary from in-house food and wine to a more formal dinner at a restaurant. Gifts and Inducements The offer of small gifts such as diaries, memo pads or pens by pharmaceutical representatives to doctors is commonplace and acceptable but occasionally hints or demands for more substantial gifts may be made. We heard evidence of doctors being offered gifts or cash payments for every patient started on a product and of a recent approach to a number of physicians who were offered the sum of ?500 for each five patients treated with a new non-steroidal anti-inflammatory drug; offers of even larger sums are apparently made at times. We are concerned that such inducements might influence the prescribing patterns of doctors. Visits Abroad We were informed that pharmaceutical companies re- ceive many letters from doctors soliciting funds to attend meetings abroad. The majority of such requests are refused. Sometimes requests are accompanied by state- ments which indicate that the doctor is a frequent pre- scriber of the company's products and one doctor even stated that unless his request was granted he would stop prescribing the company's products. A television programme (Panorama) showed some doc- tors agreeing that their attendance at conferences was influenced by their being held in locations of interest and the likelihood that hospitality would be generous. Justifi- cation for holding meetings abroad is sometimes based on their ease of international accessibility and lower costs, but we were told of a meeting of physicians who all lived in one NHS Region which was organised by a pharma- ceutical company to take place on a Mediterranean island, which could not have had the advantage of convenience, and of other meetings abroad in which the professional and scientific content was minor in compari- son with the social content and hospitality. Clinical Research and Clinical Trials We were given much evidence concerning the conduct of research projects and clinical trials. For the most part these studies are carried out with a great sense of responsibility by members of the medical profession and the medical and scientific staff of the pharmaceutical companies. In such work the companies are usually seeking co-operation with physicians of high scientific and clinical repute; there is considerable mutual respect. We wish to continue to encourage a close working relation- ship between physicians and research workers in the pharmaceutical industry, but are concerned about certain new developments in the conduct of clinical trials which have little scientific value and are of the nature of promotional exercises, designed to modify prescribing by doctors or to influence hospital formulary committees. Such trials threaten to undermine the trust of patients, and the respect of the public for the profession. Large sums of money are now being paid to clinical investiga- tors to conduct drug trials, and we are aware of compan- ies, partnerships and individual doctors who contract to carry out clinical trials. These organisations or individ- uals arrange clinical trials and recruit healthy subjects or patients to take part in them. They act as links between the pharmaceutical companies and members of the medi- cal profession and are often set up in association with hospital clinic units or university departments. Other companies are purely commercial enterprises, indepen- dent of hospital or university associations. In some Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 instances physicians are directors of or have a significant financial interest in the success of the company. Some trials are carried out making use of Health Service or university facilities, without proper recompense to the Authorities. Physicians may receive payment which is not made through the appropriate employing authority, whose facilities are being used. The use of healthy volunteers for the testing of pharma- ceutical products is increasing. This special problem has been examined in the Royal College of Physicians' Report on Research in Healthy Volunteers (J Roy Coll Phycns 20, p. 243). Our Report should be read in conjunction with this. Publishing Some research workers expressed concern about their right to publish data being sometimes unduly restricted to serve the commercial interests of the companies with whom they had collaborated. Dissatisfaction was also expressed at the way some companies arranged for the proceedings of symposia to be published as supplements to the normal circulation run of a journal: the papers in these supplements are not always subject to the peer review process of the journal and the reprints are used by the company for promotional pur- poses. Such papers also contribute to undesirable duplica- tion of published work. CONCLUSION AND RECOMMENDATIONS We believe that a close relationship between doctors and the pharmaceutical industry is important for the treat- ment of patients and for the future development and assessment of new drugs. Because this relationship is so important both to medicine and to the pharmaceutical industry, we recommend that Fellows and Members of the College ensure that their behaviour in relation to the pharmaceutical industry is always seen to be scrupulously impartial and honest. The overriding principle is that any benefit in cash or kind, any gift, any hospitality or any subsidy received from a pharmaceutical company must leave the doctor's independence of judgement manifestly unimpaired. When it comes to the margin between what is acceptable and what is unacceptable, judgement may sometimes be difficult: a useful criterion of acceptability may be 'would you be willing to have these arrangements generally known?' Meetings At Postgraduate Centres The establishment of postgraduate centres, the develop- ment of graduate education and the increasing joint participation of doctors in scientific and educational meetings is much to be commended. It is convenient for many of these meetings to take place at lunch time or in the evening and it is reasonable that light refreshment should be available. We regret that this refreshment is so often sponsored by pharmaceutical companies. As a regular practice this degrades our profession. We believe that the DHSS should encourage Health Authorities to contribute to the support of meetings attended by hospital staff as they do for general practitioners and GP trainees who attend educational and scientific meetings. We commend to all physicians the Code of Practice of the National Association of Clinical Tutors (see Appendix 2). The Code insists that the selection of programmes and the choice of speakers are in the hands of clinical tutors. We believe that these selections should be independent of any sponsor. The Code insists that any display of promotional material by a pharmaceutical company is limited and kept apart from the educational and scientific part of the meeting. It allows a pharmaceutical company which sponsors a meeting to provide modest refreshment in the form of a working lunch or a buffet supper. As stated earlier, we regret the need for this and do not accept that the cost of entertaining non-medical guests should fall on a sponsor. The expenses and fees paid to lecturers must be moderate. The Code recommends that no film be shown without a consultant whose specialty is featured in that film being present and allowed to com- ment. For Resident Medical Staff in Hospitals We are concerned about meetings and interviews that take place between pharmaceutical representatives and junior hospital doctors because these junior doctors have considerable influence on prescribing patterns in hospi- tals and may not yet have the experience necessary for the critical assessment of new products. These meetings often take place on an ad hoc basis in which representatives come to a hospital hoping to find doctors who are free to be interviewed. We recommend that such ad hoc meetings and interviews should be discouraged; meetings should take place only by appointment. We recommend that meetings with pharmaceutical representatives should be arranged in advance and at- tended by both senior and junior staff to encourage open and critical discussion, and that pre-registration house doctors should never be approached by pharmaceutical representatives except with the permission of a supervi- sory consultant. Other meetings of scientific or educational merit for junior medical staff should be arranged in accordance with the Code of Practice of the National Association of Clinical Tutors and should take place within a hospital or university setting. If promotional material is displayed an independent consultant should be present. If such scienti- fic or educational meetings are held outside a university or hospital they should conform with the above recom- mendations. 238 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 Meetings and Conferences organised by or with the help of Pharmaceutical Companies These vary from conferences of high scientific value to meetings which are patently promotional exercises. The distinction rests primarily on the quality and indepen- dence of the scientific programme. Physicians should participate in and attend only meetings of educational or scientific value, the content of which has been selected independently of the sponsor. International meetings may be held at locations which, although exotic, are convenient for access of doctors from a number of countries, but the attractiveness of the venue is not of itself a good reason for attendance. The criteria of educational or scientific value and independent selec- tion of contributions should be paramount. A physician may accept fees for travelling or other expenses of attending a meeting but the primary invita- tion should come from the organising body or delegate of an organisation, e.g. a university department. Support from the pharmaceutical industry for scientific and educational meetings is invaluable, but sponsorship of speakers and attenders should be decided independent- ly and payment should not be arranged directly between a pharmaceutical company and a physician. Companies should be encouraged to make their donations for these purposes to the organising committees and proper ac- knowledgement of their support should be made. If a company offers travel funds in the form of scholarships, its name may be indicated but applications for such support should be submitted to the organisers and the selection made independently by them and not by the company. Payment of travelling or other expenses by the organ- isers for the spouse of a physician attending a meeting is not normally acceptable. Hospitality, Gifts, Payments and Investments Hospitality A physician should not accept inordinate or excessive hospitality from any pharmaceutical company. The bor- derline of acceptability is not easy to define. The pro- vision of modest refreshment at a conference should be construed as reasonable; a lavish private dinner party at a restaurant should not. A pharmaceutical company should not be expected to extend hospitality to the spouse of a physician. We believe that medical students, pre-registration house officers and all trainees should be made aware during their training of the dangers of compromising their professional judgement by accepting or demanding inordinate hospitality or other favours from pharma- ceutical companies. Gifts It is unacceptable for a physician to receive any gift or other inducement from a pharmaceutical company be- yond those specified in the Code of Practice for the Pharmaceutical Industry (ABPI 1983) which are 'inex- pensive and relevant to the practice of medicine'. Payments Reasonable payment to a physician for giving an ad hoc expert opinion to a company is acceptable if the physician takes time and trouble in dealing with it. If such work is carried out in normal working hours for which the physician is already being paid, no additional payment should be accepted. He should not receive payments from a pharmaceutical company for seeing their representative, for sending letters to journals or for reporting adverse reactions to drugs, such reporting being part of normal clinical prac- tice. Consultancy Fees A physician may act more formally as consultant to a pharmaceutical company. The arrangements, which should be agreed in advance, should be those of any business contract and may include fees and reimburse- ment of travel and other expenses. If he is an employee of a Health Authority, university or Research Council, he must obtain permission from his employer to enter such a contract. It is inappropriate for a physician to receive payments unless the work for the company is done in his own time or unless he is specifically allowed by his employer to do the work during normal working hours. It is always necessary for a physician to declare a relevant financial interest in a company, to remove any suspicion about the relationship; this applies whether money is received personally or paid into a departmental account. Research Projects and Clinical Trials Contracts, Payments and the Responsibility of Physicians Physicians, pharmaceutical companies and ultimately our patients have much to benefit from the close co-operation of physicians with the officers of pharmaceutical compan- ies in research projects and clinical trials of drugs. In providing opinions and services to companies the princi- ples of confidentiality, honesty and decorum must prevail as in other professional activities. Formal arrangements are essential and should be negotiated through pro- fessional colleagues in the pharmaceutical companies, not informally by loose arrangement with a company rep- resentative. The physician responsible for the project or trial is responsible for informing his employer, for ensur- ing that proper accounting procedures are adopted with independent audit and for fulfilling all legal require- ments. We recommend that the financial arrangements should be made through the finance office of a Health Authority or a university and the accounts supervised by their financial officers. The monies may be used to finance the execution of the Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 239 studies which may include salaries of research workers, technicians, nurses or secretaries. They may be used to purchase equipment or expendables, to meet hospital or university overheads, to fund other research projects or to fund attendance of staff at scientific or educational meet- ings. It is undesirable for a physician to have any personal financial interest in studies carried out on patients under his care, and it is reprehensible to advertise the availabil- ity of his own or his colleagues' patients for use as research subjects. Payments must be reasonable in terms of the time and effort given to the trial and openly declared. It is also the responsibility of the physician to ensure that: 1. The studies are of scientific merit, are competently planned and will be carried out wherever possible in properly equipped hospital or university premises. 2. The studies have the approval of an independent research ethical committee to whom all details of the financial arrangements are reported. 3. There is prior agreement with the company that the results may be submitted to journals of the physicians' choice and that the company will not seek to influence the publication of the results of the trial. Physicians might however accede to reasonable requests by companies to delay publication if, for instance, patent rights might otherwise be jeopardised. When the results of multi- centre trials are to be published, all physicians participat- ing in the trial should see and agree the final draft of any paper. 4. Appropriate arrangements are made by the company to indemnify healthy subjects or patients in the event of untoward harm arising because of the trial. (Negligence is, of course, covered by existing law.) Companies Research companies or organisations which contract to carry out clinical trials or studies on normal volunteers should be willing to have their laboratories, or other places where studies are performed, open to inspection in order to ensure that high standards are maintained (see the Royal College of Physicians Report on Research on Healthy Volunteers). Arrangements with such companies should be con- sidered with particular care by Ethical Committees in view of their intrinsic commercial nature. It is important that physicians responsible for the care of the patients or subjects in these studies should not have a significant financial interest in the company or organisation. Some research companies have recently advertised their capability of supplying patients suffering from specific diseases, e.g. of the liver or kidney. Any such practice should be monitored most carefully by the Ethical Committees and the welfare of patients must be safeguarded as recommended in the Guidelines to Ethics Committees published by the Royal College of Physicians in 1984. Declaration of Interest We believe that a physician has a duty to declare his interest in a pharmaceutical company or contract re- search company to ensure that opinions or decisions are seen to be free of bias. This is particularly important if: 1. He is a member of a committee, national, regional or local, considering matters relating to the pharmaceutical industry, e.g. purchase of drugs, decisions on drug safety etc. 2. He publishes data that are the result of work with a company. Publishing We approve of the views expressed by the Editorial Board of the British Journal of Clinical Pharmacology, concerning the publishing in medical or scientific journals of papers presented at sponsored meetings (see Appendix 3). It is our view that offprints of such papers should clearly indicate that the papers were presented at a sponsored meeting and were not routinely published papers. It is desirable that the pagination of such papers is distinct from the normal journal pagination. Such submissions should only be published if the meetings were of edu- cational or scientific value and the content was selected independently of the sponsors. Conclusion We believe that our recommendations substantially re- present the present practice of most physicians and of those in training as physicians. However, in the light of the evidence we have received, we believe that the publication of these recommendations will be welcomed. 240 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 APPENDICES 1. Evidence given to the Working Party The following gave oral Dr V. R. Bloom Dr A. Bowyer *Dr D. M. Burley Mrs Ruth Bycroft *Dr J. Clifford Mr Philip Cox QC Dr C. T. Dollery Dr J. G. Domenet Mr J. J. Dower Rev Prof G. R. Dunstan *Dr O. Gillie Dr E. L. Harris *Dr A. Herxheimer Dr B. H. Mascie Taylor *Dr O. Morton *Dr M. D. Rawlins Dr P. R. Read Dr E. S. Snell Dr A. Thillainayagam Dr P. Turner Sir John N. Walton evidence to the Working Party Editor, Journal of the Royal Society of Medicine Association of Clinical Tutors Association of Medical Advisors to the Pharmaceutical Industry Chairman, National Association of Postgraduate Educational Centres Administrators Association of Medical Advisors to the Pharmaceutical Industry Chairman, ABPI Code of Practice Committee Department of Clinical Pharmacology, Royal Postgraduate Medical School Ciba Geigy Deltakos (UK) Ltd Department of Theology, University of Exeter Medical correspondent of the Sunday Times Deputy Chief Medical Officer, DHSS Department of Clinical Pharmacology, Charing Cross and Westminster Hospital Medical School St James's University Hospital, Leeds Association of Medical Advisors to the Pharmaceutical Industry Department of Clinical Pharmacology University of Newcastle upon Tyne Hoechst, UK, Ltd Association of the British Pharmaceutical Industry (ABPI) Manchester Royal Infirmary Department of Clinical Pharmacology, St Bartholomew's Hospital Medical School General Medical Council *Also supplied documentary evidence. The following provided documentary evidence for the Working Party Dr S. Brandon Dr G. M. Besser Dr B. W. Cromie Dr B. McConkey Dr R. N. Smith Department of Psychiatry, University of Leicester Chairman of Ethical Committee, St Bartholomew's Hospital, London Hounslow Dudley Road Hospital, Birmingham Glaxo Group Research Ltd The Working Party also received a copy of A Guide to Ethical Principles in the Relationship between Physicians and the Pharmaceutical Industry prepared by a sub-committee of the Royal Australasian College of Physicians in 1984. 2. The Relationship between Postgraduate Medical Centres and Pharmaceutical Houses Representatives of the Association of the British Pharma- ceutical Industry, the National Association of Clinical Tutors and the Advisory Committee of Deans of the Council for Postgraduate Medical Education in England and Wales have agreed that: 1. Meetings sponsored by a pharmaceutical house may be allowed in a postgraduate medical centre subject to the decision of the clinical tutor. 2. Arrangements for all sponsored meetings should al- ways be made through the clinical tutor. Staff from the sponsoring pharmaceutical house should be invit- ed to attend. 3. Some vetting of lecture material and films should always be undertaken. 4. An independent opinion by a doctor sufficiently ex- perienced in the topic should always be available at such meetings. 5. Publicity by the pharmaceutical house is allowed but should be separate from the educational content of the meeting. 6. Sponsorship by the pharmaceutical house should be limited to a grant paid to the Postgraduate Dean or to the provision of light refreshments and the printing of programmes. Meetings sponsored in other ways can- not be approved under Section 63, but may be recognised for the postgraduate training allowance on application by the Postgraduate Dean to the Depart- ment of Health and Social Security. Council for Postgraduate Medical Education in England and Wales 7 Marylebone Road Revised May 1978 London NW1 5HH Reaffirmed 1985 We are grateful to the Council for their permission to publish these guidelines. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 241 3. Statement by the British Journal of Clinical Pharmacology Supplements The British Journal of Clinical Pharmacology is willing to consider publishing Supplements at the request of a sponsoring organisation. The papers included will nor- mally have been prepared for oral presentation at a symposium, but manuscripts submitted for publication should adhere to the format of original papers published within the Journal itself. However, review papers cover- ing the background of an area of pharmacology or therapeutics and serving as an introduction to original papers can be included where appropriate in a Sup- plement. Sponsors and authors are asked to give some thought to the potential problem of duplicate publication in preparing a manuscript on data that have already been published or are being prepared for publication else- where. Although the Editors realise the advantages of collecting together up-to-date information on a new drug, they are committed to minimising duplicate or repetitive publication. Problems which are anticipated in this area should be discussed with the Editorial Secretary. The Editorial Board insists upon retaining editorial control of Supplements with the right to reject any paper considered to be of an inadequate scientific standard. The sponsors are therefore asked to discuss with the Editorial Secretary nomination of a member of the Editorial Board to act as one of the editors of the Supplement (most Supplements have two or three editors, but at least one should represent the Journal). This can be most easily achieved by ensuring that an appropriate member of the Board participates in the symposium, and problems would therefore be avoided if an approach to the Editorial Secretary is made at the time of planning the symposium, rather than at a later stage. We are grateful to the Editorial Board for permission to publish this statement.

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Local Arterial Complications of Left Heart Catheterisation GRAHAM A. H. MILLER, dm, frcp Consultant Cardiologist, Brompton Hospital, London It is axiomatic that comparisons between two techniques, both of which have a low complication rate, will be meaningful only if based on a large experience of those techniques. In a recent issue of this Journalfl] Chiverton and Murie contrasted the local arterial complications following a brachial arteriotomy for left heart catheteris- ation with those that followed the percutaneous, trans- femoral (Seldinger) approach. While the low (0.1 per cent) local complication rate for the trans-femoral approach was based on a large experience of 2,602 procedures during the five year study period, the much higher (3.8 per cent) local complication rate for brachial arteriotomy was based on an experience of only 158 such procedures. It is the purpose of this brief communication to report the incidence of local arterial complications associated with the two techniques based on an experience of 5,278 brachial arteriotomies and 2,648 percutaneous trans-femoral procedures over a 10-year period. Material and Methods At the Brompton Hospital a computer-based data logging and retrieval system has been employed since 1970 for recording details of all cardiac catheterisations per- formed. Among a total data base of 17,407 procedures there were 7,926 which fulfilled the following criteria; patient aged 20 years or more, procedure performed in the 10-year period from 1975 to 1985 and a procedure which included arterial catheterisation either via a brachial arteriotomy or via a percutaneous approach from the femoral artery. These patients form the data base for this report. The system allows retrieval of all patients in whom any complication had been logged; in this instance the search was limited to local arterial complications. The records of these patients were then studied for details of the complication which had occurred and the patient's subsequent progress. Results 1. Brachial arteriotomy. There were 5,278 brachial arterio- tomies performed in patients aged 20 years or more during the 10-year period. Local arterial complications were recorded in 43 of these studies; a complication rate of 0.8 per cent. Of the 43 local complications that occurred, 18 were dealt with by re-exploration in the catheterisation laboratory, 16 were referred to the surgical teams for re-exploration in theatre and 9 were dealt with 'conserva- tively' by heparin infusion. A good radial pulse was restored in 15 of the 18 re-explored in the laboratory (83 per ceht) and 12 of the 16 dealt with in theatre (75 per cent). Seven patients (3 dealt with in the laboratory and 4 in theatre) had no palpable pulse at the time of discharge but had a good peripheral circulation and no symptoms. Of the 9 patients treated conservatively, 7 (78 per cent) had a good radial pulse at the time of discharge but 2 did not and one of these patients still has mild postural claudication in the limb?the only patient with a residual disability following brachial arteriotomy. Of the 5,278 brachial arteriotomies, 1,559 were per- formed by an experienced operator with local compli- cations occurring in 9 (complication rate 0.5 per cent); for all other operators combined the complication rate was 0.9 per cent. 2. Percutaneous trans-femoral approach. There were 2,648 percutaneous trans-femoral arterial procedures performed in patients over the age of 20 during the same 10-year period. Local arterial complications requiring treatment occurred in 12 (complication rate 0.45 per cent). Ten of the 12 patients were referred to the surgical teams with a good outcome in 8. One patient required evacuation of a two-pint retroperitoneal haematoma fol- lowing perforation of the femoral or iliac artery and died on the table?possibly as a result of an intercurrent myocardial infarct. A second patient sustained a deep venous thrombosis leading to (non-fatal) pulmonary embolism following evacuation of a large haematoma in the groin. The surgical procedures performed were (a) evacuation of haematoma/arterial repair?4 patients, (b) repair of false aneurysm?3 patients, (c) thrombectomy for loss of leg pulses?2 patients and (d) repair of arterio- venous fistula?1 patient. In two patients, one with prolonged bleeding which eventually responded to local compression and one in whom hypotension following partial dissection of the femoral artery lead to the procedure being abandoned, surgical intervention was not needed. Discussion In any study of the complications of cardiac catheteris- ation a number of factors will influence the reported incidence of local arterial complications. These will 288 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 include the experience of the operators, the technique used to obtain haemostasis and the reporting system employed for recording the occurrence of complications. It is impossible to discover, from published reports, the complication rates produced by individual operators, experienced or inexperienced, but the total number of studies from which the complication rate is derived provides insight into the experience of the unit. Studies based on a large number of cases are likely to reflect the results obtained by experienced personnel as well as being of more value from a statistical point of view. Thus a local arterial complication rate from brachial arteriotomy has been reported to be as high as 28 per cent[2] and as low as 0.56 per cent[3]. The former study was based on an experience of 96 procedures in 1972 and the latter, a multicentre prospective study reported in 1982, on 23,040 brachial arteriotomies. The technique employed for brachial arteriotomy is of the utmost importance if local complications are to be avoided. Good technique includes (i) a transverse (not vertical) incision in the artery (ii) repair by interrupted 6/0 (or finer) sutures (not a 'purse-string' suture) and (iii) whole body heparinisation (1 mg/kg body weight); instil- lation of small quantities of heparin into the distal vessel is quite inadequate. In addition, trauma due to clumsy catheter or guide-wire insertion must be avoided as must the use of too large a catheter for the calibre of the vessel. Other details include the trimming of any free intimal flaps[4] and, most importantly, rejection of the concept of 'spasm' as the cause of an absent or weak radial pulse following the repair. Spasm does, sometimes, occur and is always the result of introducing too large a catheter with resulting pain. But spasm is too often used as an excuse for an inadequate technical repair. No patient should be allowed to leave the laboratory after brachial arteriotomy unless there is a good volume arterial pulse. If a good pulse is not present the most experienced available oper- ator should be called to re-fashion the repair. The results reported above suggest that re-exploration of the artery in the laboratory by an experienced physician is at least as effective as a repair by the surgical team, although it is probably true that it was the more difficult or 'failed' repairs which were referred to the surgical teams. The nature of the reporting system used to determine the complication rate is of crucial importance. In the report by Chiverton and Muriefl] the recording of only the complications that resulted in referral to the surgical team for operative repair will certainly underestimate the true complication rate. In the present study, 63 per cent of the local brachial complications that occurred were dealt with in the laboratory or resolved spontaneously so that the complication rate, as seen by the surgical team, would have appeared to be much lower (0.3 per cent) than the true figure of 0.8 per cent reported here. It is probable that almost all studies (including the present one) underestimate the complication rate since only those complications that have been recorded will be counted; and recording is unlikely to be without some omissions. This is particularly true if a complication occurs after the patient has left the laboratory (or the hospital) and the laboratory personnel are not informed. On the other hand the reported complication rate based on immediate events is much higher than the late complication rate. Only one patient in the present series had long standing (mild) disability following a brachial arteriotomy. The approach used will also affect the accuracy with which compli- cations are reported. A 'lost pulse' following a brachial arteriotomy is immediately noticeable and reported; a large haematoma in the groin is not reported unless needing surgical evacuation or repair but is not an infrequent complication?particularly as whole-body heparinisation is widely practised to prevent coronary embolisation during coronary arteriography. The close similarity between our own overall arterial complication rate of 0.69 per cent and that of 0.57 per cent reported in another large recent series, the Registry study[3], suggests that there is a minimum complication rate of between 0.5 and 1.0 per cent and that a lower figure is unlikely to be achieved in any laboratory where operators include physicians in training. The lower figure of 0.5 per cent complications for brachial arteriotomy achieved by an experienced operator, as reported here, points to the importance of experience in reducing com- plications and the importance of assessing the risk on the basis of studies involving large numbers of patients. It is probable that the local arterial complication rate following the trans-femoral approach is slightly lower than that following the trans-brachial approach; of the 291 patients with local vascular complications (0.57 per cent incidence) reported in the Registry study[3], 62 per cent were associated with the brachial approach. Our own results also show a slightly higher complication rate for the brachial approach (0.8 vs 0.45 per cent) though non- reporting of haematoma formation makes the latter figure artificially low. However the difference is so small as to be outweighed by other considerations. These include the greater ease with which a stenotic aortic valve may be crossed when the approach is from the arm as well as the ability to perform studies on a 'day case' basis when haemostasis is obtained by repair of an artery, as against the need for the patient to remain in bed until a stable fibrin plug has formed at the site of a femoral artery puncture. It is generally agreed that the trans-femoral approach is contraindicated when there is known ilio-femoral disease and relatively contraindicated in the presence of gross obesity (especially in females). Similarly, the brachial approach is best avoided in those in whom the artery is likely to be of small calibre?female patients or Asians of slender build. The wise operator will suit the approach to the patient and to the problems to be solved and will make sure that he is equally adept at both the brachial and femoral approach. References 1. Chiverton, S. G. and Murie, J. A. (1986) Journal of the Royal College of Physicians, 20, 126. 2. Brener, B. J. and Couch, N. P. (1973) American Journal of Surgery, 125, 521. 3. Kennedy, J. W. et al. (1982) Catheterisation and Cardiovascular Diag- nosis, 8, 5. 4. Grossman, W. (1986) Cardiac Catheterisation and Angiography, Third Edition. Philadelphia: Lea and Febiger. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 289

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Medical Problems of Cold Weather The Oliver-Sharpey Lecture 1985 WILLIAM KEATINGE, MB, BChir, PhD, MRCFj Professor of Physiology, The London Hospital Medical College, London Mortality caused by cold weather among elderly people has been one of the most widely discussed of all medical problems in Britain in recent years. In the public mind, this mortality has come to be associated almost exclusive- ly with hypothermia. Hypothermia does cause some deaths and it contributes to others, but, although it has been a major cause of losses of life in special situations in the past, current evidence suggests that it is not a major factor in approximately 40,000 excess deaths that occur every winter in England and Wales, mainly among elderly people. The public interest shown in these prob- lems has helped to direct attention to the problems of elderly people in winter. A negative side of the public interest is that popular preoccupation with hypothermia came to affect scientific thinking, and delayed the investi- gation of other, and more large-scale, causes of death in cold weather. Winter mortality is, in fact, only the latest example of popular beliefs diverting investigation of cold- induced problems, and much of the misconception on this occasion resulted from initial successes in identifying hypothermia as the cause of earlier problems. The most striking of these was death in the water after shipwreck. Observant individuals throughout history re- alised that shipwreck victims often died of cold rather than by drowning. The earliest known example both of this and of seasonal influence on mortality was recorded by Herodotus in the first book written on the mainland of Europe, in the Fifth Century BC[ 1 ]. In recording the wreck of Darius's fleet invading Greece, early in the year, he states that cold rather than drowning caused many of the deaths, but at the Battle of Salamis, fought in summer, the Greeks lost few men as they were able to' swim to safety if their ships were sunk. Later, however, by a kind of international literary and journalistic conven- tion, people lost after shipwreck were routinely assumed to drown. Shakespeare gives an example of this in the opening scene of The Tempest. In more recent times, 'drowned at sea' was the phrase almost exclusively used in newspaper accounts of people lost at sea up to 1960, and is sometimes used today. Although this was little more than a verbal convention, it affected people respon- sible for lifesaving equipment at sea, to the extent that they seldom considered anything except the need for flotation equipment. It was only towards the end of the Second World War that the consequences of this became clear, when a Committee under Rear-Admiral A. G. Talbot reported that most of the Royal Navy men lost in that war, some 20-30,000 men, died in the water rather than from battle injuries, and that without thermal protection they had often died from simple body cooling rather than drowning. This was further documented a decade later[2]. It was largely due to this realisation that extensive studies were made during the next two decades of the internal factors that control body heat loss and heat production in cold water[see 3, 4 for reviews]. The results of that work provided a useful background to consider- ation of other hazards of cold, since immersion largely eliminates external thermal insulation, leaving survival dependent on the uncomplicated operation of internal mechanisms of heat conservation and heat loss. The results showed that once people were in cold water, and vasoconstriction developed, most of the internal insula- tion of the body was provided by subcutaneous fat (Fig. 1), so that fat people could maintain body core tempera- ture indefinitely in water at 12?C, while thin people often cooled progressively in water as warm as 25-29?C. Figure 1. Effect of subcutaneous fat on body cooling during 30-minute immersions in water at 15?C (Courtesy Journal of Physiology). Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 283 Children usually cooled rapidly in cold water[5], partly because young children, particularly boys, are usually thinner than adults, and partly because the small size of young children gives them a high surface area/mass ratio. Another point of practical importance was that exercise greatly accelerated heat loss by increasing blood flow to limb muscles; in cold water, with little external insula- tion; this outweighed the increase of heat production in exercise, thus increasing the rate of fall of body tempera- ture. It was also found that in water colder than 12?C cold vasodilatation caused blood flow to return to the limbs and so led to rapid body cooling even in relatively fat people. This reaction, which was largely due to cold paralysis of blood vessels of the extremeties, seemed to put a lower limit on the environmental temperature that even fat people could survive for long periods. However, an unusually fat Icelandic fisherman recently survived for five hours swimming in water at 5-6?C, and was brought to London by Professor Johann Axelsson; in laboratory experiments, we found that he could stabilise body temperature in such water with little cold vasodilatation, apparently because an unusually thick layer of limb fat protected the limb arteries from serious cooling[6]. For other people exposed to such a degree of cold, extended survival depends on the wearing of clothing or other external protection to keep skin temperature above the threshold for cold vasodilatation. Even with deaths in water, cold does not produce hazards solely by causing lethal cooling of the body core. Some result from cardio- vascular and respiratory reflexes induced by cooling of the skin[7]. The most important of these is inhalation of water due to inability to control respiration during the intense inspiratory drive caused by the reflexes, which readily causes drowning in waves that splash over the head. In addition, reflex drive to the heart occasionally causes sudden death from ventricular fibrillation during the first few minutes of cold immersion[8]. Apart from this, the high viscosity of cold water near 0?C can combine with the reflex effects of cold to cause death from drowning as even fit, healthy young people become rapidly exhausted as they try to swim short distances to shore in very cold water without buoyancy aids[9]; that may be the most important cause of immersion death in inland waters. Insidious Hypothermia and Memory It has recently become clear that in special circumstances minor degrees of hypothermia can occur without much discomfort during quite mild exposures to cold, and can indirectly be a serious hazard to life in people carrying out demanding work in potentially dangerous circumstances. We have seen that the rate at which an individual's body core temperature will fall in water at 15?C can be predicted quite accurately from fat thickness alone. How- ever, if people are immersed in relatively warm water, and then in progressively colder water until they become just unable to stabilise core temperature, the size of their metabolic response to cold is as important as fat thickness in determining the coldest water in which they can stabilise. Experiments[10] showed that although such people's fat thickness did correlate with the temperature of the coldest water allowing them to stabilise, the relationship was not a close one. On the other hand, the subjects' body insulations at the time they stabilised in the coldest possible water were closely related to fat thickness, both at rest and in exercise. The discrepancy was due to metabolic rates, which were very varied and had no,clear relationship to fat thickness, so that while body insulation and heat loss could be predicted, metabolic rate and minimum water temperature for stability in this marginal situation could not. This marginal situation for heat balance is one with wide applications, but the most striking example of these has been in deep commercial diving. Loss of heat to the respiratory gas and from the body can be lethal at depths greater than about 100m, where pressure is more than 10 times atmospheric, and where water on the seabed is at 4-6?C, even in the tropics. Heating is therefore supplied to the diver, usually by an open-circuit hot-water system in which warm water pumped from the surface is used to flood the inside of the diving suit. The popularly accepted principle that if people do not feel cold they are not seriously cold, often led to the assumption that as long as divers were within their limits of voluntary tolerance, cold could be discounted as a cause of any serious problems. By 1976, it became clear that something was causing serious and unexplained problems. The report of the Science Research Council taskforce on marine technology in that year[ll] gave unexplained losses of consciousness and confusional states in divers as the problem of top priority for research to assist development of North Sea resources. Childs and Norman[12] obtained notes of 114 such incidents up to 1978. There was also a high rate of fatalities, usually six or seven each year in a diving population of only a few hundred. Although the cause of death could usually be given as diver error, there was often no explanation why a highly skilled man had made some gross mistake, leading to a fatal result. In 1979, we had the co-operation of a North Sea diving company in making measurements of divers' temperatures, as urine temperature, when they returned to the bell at the end of saturation diving shifts[ 13]. In four of 13 cases, tempera- ture was below 36?C, and one diver was in hypothermia at 34.7?C. At the same time, another was seriously overheated at 38.3?C. Some of the divers felt cold, so the heating water was then clearly on the cool side, and the hot-water system sometimes failed, whereupon the dives were continued without heating for a time while attempts were made to restart the hot-water supply. However, two of the coldest of the divers had neither felt particularly cold nor experienced any failure of heating. A diver being supplied by water that is a little on the cool side for comfort is essentially in a bath of lukewarm water. Laboratory experiments showed that people in lukewarm water always suffered falls in core temperature, sometimes to hypothermic levels, and again often with little sensation of cold[14]. Figure 2 shows the most dramatic case, in which the subject was a thin man who had undergone considerable recent cold exposure. His rectal temperature fell steadily to 34.7?C with very little shivering and only slight feelings of cold. At this point, he 284 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 developed atrial fibrillation, which reverted to sinus rhythm when he was rewarmed. However, the main hazard that these levels of body cooling presented to divers was that they impaired memory and reasoning[15]. When volunteers' body temperatures were lowered ex- perimentally by immersion in cold water, cold discomfort could be abolished immediately by transferring them to warm water. The deep body temperature remained low and even fell more rapidly for a few minutes in the well- known afterdrop. So it was possible during this time to test reasoning and memory with low core temperature but without the complication of distraction by cold discom- fort. Such experiments showed that ability to memorise facts was greatly reduced at body core temperatures below about 36?C. Ability to recall facts learned at normal body temperature was, interestingly, not im- paired, but there was marked slowing of the speed at which complex reasoning tasks could be performed. For example, the time needed to perform a series of double- digit sums was increased by about 50 per cent at body temperatures below 35?C. These difficulties in memoris- ing new facts-and in reasoning could obviously be danger- ous to a diver facing an unexpected, complex and demanding situation on the seabed. We cannot say in retrospect how many diving incidents in the 1970s were due to low body temperature, but during the last six years, care has been taken to adjust water temperatures so as to keep divers thermally comfortable and to bring them in at once if heating fails. During that time, such incidents have become uncommon in the North Sea, and measurements by urine temperature at the end of dives from the diving ship Arctic Seal in the North Sea in 1982, at 75 and 135m, showed no cases of core temperature below 36.8 or above 37.5?C (nine cases; personal observations). Careful control of the hot-water supply to maintain full thermal comfort can therefore prevent hypothermia, even with an even skin temperature, but more reserve can be provided by allowing the hands and feet to cool and so provide the sensory input needed to activate shivering and vasoconstriction if core temperature does fall. This restores the kind of thermal gradients normally present in cold air, which the human thermoregulatory system is geared to deal with, and it can restore normal thermore- gulation to people who otherwise cool progressively with an even skin temperature around 29?C[16]. This prob- lem of mild hypothermia leading to dangerous misjudge- ments is a hazard specifically to people working in potentially dangerous situations with an even pattern of mild skin cooling. It may be important in a number of occupations in cold weather, but it obviously raises the question whether such insidious cooling could lead direct- ly to death from hypothermia in people exposed to such patterns of skin cooling in air. Winter Mortality in the Elderly The hazards of hypothermia had become firmly fixed in the public mind by the early 1960s, so it was perhaps inevitable that when increased mortality among elderly people in cold weather started to attract marked public attention, this mortality should come to be associated with hypothermia. It had been realised at least since 1841 that mortality in Britain increases in winter[17]. Mortal- ity statistics over the last two decades show that this winter mortality is tending to become less, but that there are still about 40,000 excess deaths in an average winter in England and Wales. Analyses of these deaths, particu- larly by Bull and Morton[18] show strokes and myocar- dial infarcts accounting for most of them, while hypothermia causes only about one per cent of the excess deaths in winter. It can be argued that the mortality statistics may be distorted by failure to recognise deaths that are due to hypothermia and it has been suggested that the latter might, in fact, be common[19]. Sublingual readings often give an indication of low body temperature in cold surroundings, but sublingual readings give false low indications of body core temperature in cold sur- roundings, mainly because of parotid saliva entering the mouth via parotid ducts in cold cheeks[20]. The most reliable measurement of core temperature in this situation is by a thermoelectric rectal probe at an adequate depth (>80 mm), and reports that rely on this or on another dependable measure seldom show low core temperatures in people either at home or entering hospital. Most cases of hypothermia admitted to an intensive care unit in Glasgow[21] (from a total of 44 cases in 15 years) were a result of collapse in cold surroundings. The commonest cause of this collapse (25 cases) was poisoning or intoxi- cation by alcohol, drugs or carbon monoxide. Severe physical illnesses such as cerebrovascular accident, myo- cardial infarct, malignancy or broken limb caused another eight such cases. Another seven of the cases of hypothermia were a result of hypothyroidism or other endocrine disease, or of malnutrition and dehydration, often combined with alcohol. Only two were attributable to cold exposure combined with old age or mental disability alone. It could be argued that this low incidence of hypother- Figure 2. Progressive fall in body temperature during immer- sion in water at 29? C (Courtesy British Medical Journal). Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 mia was due to failure to detect low body temperature in many patients entering hospital. Accordingly, routine measurements of sublingual temperature, with rectal readings if sublingual values below 36?C were obtained, were made on all new patients entering the Emergency and Accident Department of The London Hospital, Whitechapel in January and February 1985. Only three (0.04 per cent of all patients) had core temperatures below 35?C; one of these had suffered a cerebrovascular acci- dent, one a fractured hip, and one with mental impair- ment had fallen out of bed and been unable to get back onto the bed[22]. Such observations suggest that hypo- thermia is not only uncommon but, when it does occur, is usually a secondary, and not always important, compli- cation of a serious underlying condition. Effective treat- ment is, of course, particularly important in those cases in which hypothermia does play a major role in the illness, such as hypothyroidism. People with mild myxoedema are prone to cool in cold surroundings because of defec- tive heat production, while undernutrition can both reduce heat production in the cold[23, 24], and increase heat loss[25]. It is likely that malnutrition has been responsible for rare cases of elderly people with clearly defective responses to cold, who are prone to cool rapidly as a result[26]. Elderly people are often slow to act to correct changes in their thermal environment[27]. There are rare cases of grossly defective thermoregulation caus- ing hypothermia in otherwise normal and well-nourished adults, who are often not elderly, perhaps due to hypotha- lamic defects. It is less clear whether elderly people in general have impaired responses to cold; reduced re- sponses have been reported in groups of elderly people[28, 29], but variability in the response of both young and old is very great[30] and normal metabolic response to cold has been found in well-nourished elderly people[24]. The present evidence indicates that deaths caused directly by all types of hypothermia in cold environments, though individually important, represent only a small part of the overall excess mortality in cold weather in Britain, even among the elderly. The problem then is to explain the large number of excess deaths that occur in winter, particularly from arterial thrombosis. We made experiments[31] on eight young adults to see whether any relevant changes were produced by mild surface cooling with rapidly moving air at 24?C. This rapidly lowered skin temperature to near air temperature, while rectal temperature fell slowly by 0.4?C, and then stabilised before the end of the 6-hour experiments. Shivering developed with increased meta- bolic rate but, even at the end, was only moderate. This was therefore a mild, sustainable and closely controlled cold stress with little fall in core temperature. Systolic and diastolic arterial pressures both increased in the cold, on average by 12 and 18 mmHg respectively. Pulse rate fell, probably due to baroceptor reflexes as arterial pressure rose, while cardiac output did not change significantly. The increase in arterial pressure, which occurs to at least this degree in elderly adults[32], could have some long- term effect on increasing arterial thrombosis, but seemed insufficient to explain the rapid cold weather mortality from coronary thrombosis which Bull and Morton[18] showed to reach a peak within 24 hours on a cold day. The probable explanation of this was provided by in- creases in platelets, as well as red cell count and haemato- crit, during the exposure to cold (Table 1). An increase in haematocrit is a known effect of cold, though it does not previously seem to have been associated with cold weath- er mortality. It was of particular interest, since arterial thrombi in their early stages are largely formed by deposition of platelets, that the mean size of circulating platelets, as well as platelet count, increased in most cases. The increase in platelet number, like the increase in red cells, could be partly attributed to haemoconcen- tration following vasoconstriction, but the tendency to increased size of platelets suggests addition of large and therefore young and active platelets to the circulation. These changes in platelet size and numbers would clearly tend to increase arterial thrombosis, in cold weather, among elderly people with atheromatous vessels. There is recent evidence that increases in red cell count also markedly increase platelet deposition, probably by phys- ically driving platelets against the vessel wall, so the increase in red cells in the cold is also important. There was also an increase in neutrophil polymorphs during Table 1. Changes in blood cells and platelets. Values are means (SE in parentheses)[31]. Before experiment (n = 8) Change during 1st hour (n = 6) Change during 6 hours (n = 8) Red cell count (1012/1 blood) Packed cell volume Platelet count (1071 blood) Platelet volume (fl) Platelets as fraction of plasma by volume (10~3) Neutrophil count (1071 blood) Cold Control Cold Control Cold Control Cold Control Cold Control Cold Control 4.65 4.63 0.395 0.391 291 287 8.8 8.7 4.12 4.01 3.79 3.45 (0.23) (0.15) (0.025) (0.017) (27) (28) (0.5) (0.4) (0.21) (0.22) (0.31) (0.33) + 0.11 (0.06) -0.15 (0.05)c + 0.007 (0.004) -0.012 (0.004)c - 10 (4) - 15 0.0 0.0 -0.07 -0.23 + 0.42 -0.17 (5)c (0.2) (0.1) (0.11) (0.07)c (0.28) (0.06)c + 0.35 (0.07)M -0.03 (0.03) + 0.029 (0.005)b,e 0.000 (0.003) + 23 (9)c + 7 (5) + 0.2 (0.1) 0.0 (0.1) + 0.61 (0.13)M + 0.12 (0.11) + 2.04 (0.47)a>d + 0.74 (0.29)c Difference from control: a p < 0.05; b p < 0.01 Difference from initial value: c p < 0.05; d < 0.01; e p < 0.001 286 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 these exposures to cold, and these changes together caused an increase in whole blood viscosity which rose by 20 per cent in the cold. Very little of these changes took place in the first hour but they were well developed in six hours. Plasma protein ratios of high-to-low-density pro- tein did not change in the cold, but plasma cholesterol, in all its fractions, increased. The increases in platelets, red cells, blood viscosity, arterial pressure and plasma choles- terol could clearly all contribute, to different degrees, to the increase in arterial thromboses in cold weather. Other Problems in Hot and Cold Weather An explanation is incidentally also needed for the fact that mortality increases if minimum daily temperature rises above about 20?C[18, 33], This heat-induced mortality is a much greater problem in North America than in Britain, but even in Britain heatwaves produce marked rises in mortality every two or three years[34]. Again, although most work[35] on heat-induced mortality has concentrated on the effects of simple overheating of the body, mortality statistics show arterial thrombosis as responsible for about half the deaths in major heat-waves, and heat-stroke for rather few. Although changes in blood composition and arterial pressure offer a straightforward explanation for the increased mortality from arterial thrombosis in the cold, many questions remain to be answered on this as well. Efforts to optimise the level of home heating are obviously desirable, if only for the sake of general comfort and welfare. However, it is by no means certain that this alone will prevent excess mortality in winter, and substantially more information may be needed to find ways of minimising this mortality. References 1. Herodotus. Translated by A. de Selincourt, revised by A. R. Burn (1972) The Histories. Harmondsworth: Penguin Books. 2. McCance, R. A., Ungley, C. C., Crosfill, J. W. L. and Widdow- son, E. M. (1956) The Hazards to Men in Ships Lost at Sea, 1940-44, Medical Research Council, Special Report Series no. 291. 3. Burton, A. C. and Edholm, O. G. (1955) Man in a Cold Environment. London: Edward Arnold. 4. Keatinge, W. R. (1969) Survival in cold water. The physiology and treatment of immersion hypothermia and of drowning. Oxford, Blackwell Scientific Publications. 5. Sloan, R. E. G. and Keatinge, W. R. (1973) Journal of Applied Physiology, 35, 371. 6. Keatinge, W. R., Coleshaw, S. R. K., Millard, C. E. and Axelsson, J. (1986) British Medical Journal, 292, 171. 7. Keatinge, W. R., Mcllroy, M. B. and Goldfien, A. (1964) Journal of Applied Physiology, 19, 1145. 8. Keatinge, W. R. and Hayward, M. G. (1981) Journal of Forensic Sciences, 26, 459. 9. Keatinge, W. R., Prys-Roberts, C., Cooper, K. E., Honour, A.J. and Haight, J. S. J. (1969) British Medical Journal, 1, 480. 10. Hayward, M. G. and Keatinge, W. R. (1981) Journal of Physiology, 320, 229. 11. Birks, J. (Chairman) Marine Technology (1976) The report of a task force of the engineering board. London: Science Research Council. 12. Childs, C. M. and Norman, J. N. (1978) Medecine Subaquatique et Hyperbare, 17, 127. 13. Keatinge, W. R., Hayward, M. G. and Mclver, N. K. I. (1980) British Medical Journal, 1, 229. 14. Hayward, M. G. and Keatinge, W. R. (1979) British Medical Journal, 1, 1182. 15. Coleshaw, S. R. K., van Someren, R. N. M., Wolff, A. H., Davis, H. M. and Keatinge, W. R. (1983) Journal of Applied Physiology, 55, 27. 16. van Someren, R. N. M., Coleshaw, S. R. K., Mincer, P.J. and Keatinge, W. R. (1982) Journal of Applied Physiology, 53, 1228. 17. Alderson, M. R. (1985) Health Trends, 14, 87. 18. Bull, G. M. and Morton, J. (1978) Age and Aging, 7, 210. 19. Taylor, G. (1964). Practitioner, 193, 761. 20. Sloan, R. E. G. and Keatinge, W. R. (1975) British Medical Journal, I, 718. 21. Ledingham, I. McA. and Mone, J. G. (1980) British Medical Journal, 280, 1102. 22. Coleshaw, S. R. K., Easton, J. C., Keatinge, W. R., Floyer, M. A. and Garrard, J. (1986) Clinical Science, 70, Suppl. 13, 93. 23. Bastow, M. D., Rawlings, J. and Allison, S. P. (1983) Lancet, 1, 143. 24. Fellows, I. W., MacDonald, I. A., Bennett, T. and Allison, S. P. (1985) Clinical Science, 69, 525. 25. Keatinge, W. R. {I960) Journal of Physiology, 153, 166. 26. MacMillan, A. L., Corbett, J. L., Johnson, R. H., Crampton Smith, A., Spalding, J. M. K. and Wollner, L. (1967) Lancet, 2, 165. 27. Collins, K. J., Exton-Smith, A. N. and Dore, C. (1981) British Medical Journal, 282, 175. 28. Krag, C. L. and Kountz, W. B. (1950) Journal of Gerontology, 5, 227. 29. Wagner, J. A., Robinson, S. and Marino, R. P. (1974) Journal of Applied Physiology, 37, 562. 30. Collins, K. J., Easton, J. C. and Exton-Smith, A. N. (1981)Journal of Physiology, 320, 76. 31. Keatinge, W. R., Coleshaw, S. R. K., Cotter, F., Mattock, M., Murphy, M. and Chelliah, R. (1984) British Medical Journal, 289, 1405. 32. Collins, K. J., Easton, J. C., Belfield-Smith, H., Exton-Smith, A. N. and Pluck, R. A. (1985) Clinical Science, 69, 465. 33. Heyer, H. E., Teng, H. C. and Barris, W. (1953) American Heart Journal, 45, 741. 34. Macfarlane, A. and Waller, R. E. (1976) Nature, 264, 434. 35. Sprung, C. L., Portocarrero, C. J., Fernaine, A. V. and Wein- berg, P. F. (1980). Archives of International Medicine, 140, 665. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 287

PMC005xxxxxx/PMC5371044.txt

Audit of the Assessment of Mental Impairment in the Elderly J. P IREDALE, Medical Student A. J. SYMONS, SRN, Research Assistant R. S. J. BRIGGS, MB, MRCP(UK), Senior Lecturer in Geriatric Medicine Faculty of Medicine, University of Southampton, Southampton General Hospital. The accurate assessment of mental state in elderly patients admitted to hospital has long been recognised as essential in the identification and management of demen- tia and toxic confusional states. The failure to diagnose such syndromes is associated with the misplacement of patients[l]; mental impairment itself is associated with difficulty in discharge from hospital[2] and increased mortality[3]. A Royal College of Physicians Report rec- ommended in 1981 the administration of a mental test score to all elderly patients admitted to hospital[4]. There has been considerable interest over the last few years in the role of medical audit, not only in the identification of poor practice but also as a means towards improving the effectiveness and efficiency of care. Al- though studies may show that the initiation of audit coincides with improvements in outcome[5], the extent of the change attributable to audit remains doubtful. A recent review suggested that 'it would appear that simply feeding back information on performance has almost no impact on changing clinical behaviour'[6]. We have attempted a controlled study of the effect of audit on the assessment of impairment in elderly patients admitted to hospital wards. Methods Over a two-month period the case notes of 195 patients were reviewed. These patients were consecutive admis- sions over the age of 65 years to three medical wards under six general physicians, four orthopaedic wards under six surgeons, or three wards used by three geriatric firms. The information sought in the notes comprised whether or not a formal mental test score had been carried out, whether there was any statement describing the patient's mental state, and whether any corroborative history had been obtained from a third party. One of the investigators then performed a simple mental test score with the patient[7], as shown in Table 1. Using ward registers, each patient was followed up at one month to Table 1. Abbreviated mental test score of Hodkinson (1972); (each question scores 1 mark). 1. Age 2. Time (to nearest hour). 3. Address for recall at end of test ? this should be repeated by the patient to ensure it has been heard correctly: 42 West Street. 4. Year. 5. Name of hospital. 6. Recognition of two persons (doctor, nurse). 7. Date of birth. 8. Year of First World War. 9. Name of present monarch. 10. Count backwards, twenty to one. determine the date and destination of discharge. The purpose of the study was concealed from ward staff at this stage; each consultant involved had given permission for an audit of case notes of elderly patients under his care to be performed, but had been asked not to divulge this to junior medical or nursing staff. After the results of this initial audit had been collated, a summary of the findings was sent to the consultants in charge of one general medical firm and one geriatric firm in one ward block ? the 'audit-wise' group. No specific suggestions were made as to how the results should be interpreted or acted upon, other than a request to discuss them with their own junior staff but not with staff on other firms. One month later, a repeat audit was conduct- ed on the notes of 17 consecutive elderly patients admitted to the audit-wise general medical firm and 21 patients to the audit-wise geriatric firm. For comparison, a control group of 27 patients under the care of an 'audit-blind' geriatrician (who had no knowledge of the results of the first audit) was studied in a separate ward block. Results Initial Audit Considerable variation was seen between the different ward groups in terms of age, sex ratio and mean level of Correspondence to: Dr R. S. J. Briggs, Senior Lecturer in Geriatric Medicine, Centre Block, Level E, Southampton General Hospital, Southampton, Hampshire S09 4XY. 268 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 mental impairment. To simplify comparisons, patients were grouped according to their mental test score as 'mentally normal' (7-10 points), 'mentally impaired' (4- 6) and 'severely mentally impaired' (0-3). The distribu- tion of the patients between the geriatric, medical and orthopaedic wards is shown in Table 2. The fact that Table 2. Age, sex and mental test score in patients over 65 years admitted to geriatric, medical and orthopaedic wards: initial audit. Ward group (n) Mean (S.D.) % Female Mean (S.D.) age years mental test score Geriatric medicine (100) 83 (6.9) 71 5.6 (2.7) General medicine (50) 75 (5.9) 52 7.6 (3.2) Orthopaedic surgery (45) 82 (6.3) 96 6.1 (3.3) admissions (in the over 65 age-group) to geriatric wards tended to be older, were more likely to be female and had a higher prevalence of mental impairment than on gen- eral medical wards is not surprising in view of an 'age- related' admission policy. The orthopaedic wards studied were devoted to acute admissions, and the data reflect the preponderance of elderly women with fractured neck of femur. Analysis of the case notes on geriatric wards showed that only 8 per cent of patients had had a formal mental test score, and none on more than one occasion (to determine progress). In the absence of formal testing, 17 per cent had a documented corroborative history from a third party, and 69 per cent a reference in the notes to their mental state. However, in 17 of these 69 patients the statement in the notes was misleading: for example, the notes recorded 'not confused' but a formal mental test score by the investigator showed severe mental impair- ment. Of the 23 patients with no reference at all to mental state, five had some degree of mental impairment on formal testing (severe in three). Of the 50 general medical patients, none had received a formal mental test score, six (12 per cent) had a corrobo- Table 4. Mental assessment in casenotes of elderly patients admitted to general medical and geriatric wards, on initial audit and on repeat audit. Patient Formal mental Corroborative Appropriate Misleading Impaired, but group (n) test (%) history (%) description (%) description (%) no description % Geriatric wards: initial audit (100) 8 17 52 17 5 Medical wards: initial audit (50) 0 12 30 8 12 Geriatric 'audit-blind' repeat audit (27) 7 7 33 15 7 Geriatric 'audit-wise' repeat audit (21) 5 10 71 0 5 Medical 'audit-wise' repeat audit (17) 0 24 60 0 6 rative history, and 19 (38 per cent) some description of their mental state, four of which were misleading. Of the 31 (62 per cent) with no reference to their mental state, six showed impairment on formal testing (severe in four). The notes of 45 orthopaedic patients revealed no formal mental testing, two (4 per cent) corroborative histories and 24 (53 per cent) references to mental state (misleading in four). Of the 21 patients (47 per cent) with no assessment of mental state documented in the notes, five were impaired (two severely so). Taking these 195 patients overall, 18 had died within one month of admission; 15 per cent of those severely mentally impaired, compared with only 4 per cent of those who were mentally normal (p<0.01, chi-squared test). Similarly, the degree of intellectual impairment was a significant (0.01 >p>0.001) adverse prognostic indica- tor for discharge (Table 3). Table 3. Proportion of patients successfully discharged from hospital one month after admission, compared with mental test score (MTS). Patient group (MTS) n % Successful discharge Severely impaired 42 31 (0-3 points) Impaired 43 47 (4-6 points) Mentally normal 110 64 (7-10 points) Repeat Audit The further audit of case notes one month after the results of the initial audit had been collated, is shown in Table 4; the findings of the repeat audit on 'audit-wise' and 'audit- blind' firms are compared with the original results. As before, no formal mental testing was carried out by the 'audit-wise' general medical firm, whilst the geriatric firms continued to test at a rate close to that of the original audit, whether 'blind' or 'wise'. However, misleading comments were now absent from the notes of both 'audit- wise' firms, and there was a significant increase in the frequency with which appropriate descriptions of mental Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 269 state were made on both the geriatric (52 to 71 per cent; 0.01>p>0.05) and general medical (30 to 60 per cent; 0.05 >p> 0.02) 'audit-wise' firms, which was not seen in the geriatric 'audit-blind' ward. Discussion Although 85 of the original 195 patients studied (43 per cent) had evidence of mental impairment, only eight patients (4 per cent) had formal mental test scores recorded in the notes. This is disappointing in view of the recommendations of the Royal College of Physicians Report, in 1981 [4], Copies of a longer mental test are available on our geriatric wards, but even after the initial audit their use did not increase. Since the completion of the study, the 'audit-wise' general physician has request- ed copies of the short mental test score used, which was contained in an appendix to the 1981 College Report. 'Passive feedback' of the results of initial audit did not change the practice with regard to formal mental testing, consistent with the view that 'active feedback' is more successful in modifying clinical behaviour[6] ? perhaps, in this case, by supplying wards with a copy of this paper together with copies of the mental test score. However, even in the absence of recording of formal mental test score (or of documenting a corroborative history), what is most important is that misdiagnosis should not result in mistaken management decisions[8]. Thus the fact that a mentally normal elderly person is not recorded as such in the notes may not be of any conse- quence, but to miss cognitive impairment in a dement who is socially well-preserved may lead to unexpected difficulties. In this context it is important to note that the original audit showed 22 per cent of geriatric and 20 per cent of medical admissions to be misdiagnosed in terms of an absent or a misleading description, when subsequent formal mental testing revealed mental impairment. The rate of such misdiagnosis remained at 22 per cent on the 'audit-blind' geriatric firm, but it is encouraging that the rates fell significantly to 5 and 6 per cent on the geriatric and general medical 'audit-wise' firms respectively. All these latter errors would have been obviated had a mental test score been done, there being no misleading descrip- tions recorded in the notes at the repeat audit in the 'audit-wise' groups: only the 'audit-blind' group missed any cases of severe mental impairment. The Birmingham audit group have placed emphasis on the adequacy of admission notes and the documentation of the subsequent course of illnesses, reporting that the poor quality of notes seen initially on audit quickly improves and that a high standard is maintained[9]. Such changes are limited to 'audit-wise' clinicians[ 10], as in our present study. We would support the view that regular audit is helpful in the development and mainten- ance of good clinical standards, and have instituted in the geriatric unit regular audit meetings modified from the Birmingham model. We further suggest that assessment of mental function is an important aspect of the manage- ment of elderly patients, and our study has shown improved identification of mentally impaired subjects simply as a result of audit. However, to sustain such improvement in the longer term may also require more positive educational measures[6]. As a first step, we recommend that copies of a mental test score are available on all wards dealing with elderly patients, and that consultants ask their junior staff the results of such tests ? in the knowledge that successful treatment, rehabili- tation and discharge of mentally impaired elderly may prove difficult, particularly where impairment is unrecog- nised. References 1. Langley, G. E. and Simpson, J. H. (1970) Gerontologia Climca, 12, 149. 2. Leif, C. and Thogren, K. (1982) Lancet, 2, 1097. 3. Hodkinson, H. M. (1973) Journal of the Royal College of Physicians of London, 7, 305. 4. College Committee on Geriatrics (1981) Journal of the Royal College of Physicians of London, 15, 141. 5. Gruer, R., Gordon, D. S., Gunn, A. A. and Ruckley, C. V. (1986) Lancet, 1, 23. 6. Mitchell, M. W. and Fowkes, F. G. R. (1985) Journal of the Royal College of Physicians of London, 19, 251. 7. Hodkinson, H. M. (1972) Age and Ageing, 1, 233. 8. Denham, M.J. and Jeffreys, P. M. (1972) Modern Geriatrics, 2, 275. 9. Heath, D. (1980) Journal of the Royal College of Physicians of London, 14, 200. 10. Heath, D. (1981) Journal of the Royal College of Physicians of London, 15, 197. 270 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986

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?) Research on Healthy Volunteers A REPORT OF THE ROYAL COLLEGE OF PHYSICIANS Members of the Working Party Sir Raymond Hoffenberg (Chairman) Dr W. van't Hoff (Honorary Secretary) Dame Elizabeth Ackroyd Sir Douglas Black Mr I. Dodds-Smith (Legal Adviser) Dr V. Dubowitz Dr R. E. Gillon Dr M. J. S. Langman Dr D. R. Laurence Dr P. Richards Dr K. B. Saunders Dr E. S. Snell Dr J. D. Swales Dr D. A. J. Tyrrell Observer from the Medical Research Council Dr Barbara J. Rashbass In attendance Dr D. A. Pyke (The Registrar) Mr G. M. G. Tibbs (The Secretary) Miss Alice Overton (Committee Secretary) Miss Ann Cowell (Committee Secretary) Mrs Janet Vernon (Secretary to the Hon. Secretary) Contents Page Introduction 244 Justification for Research on Healthy Volunteers 244 Description of a Healthy Volunteer 245 Definition of Risk 245 Recruitment and Selection 245 Special Groups Women 246 Children 246 The Elderly 247 The Mentally Handicapped 247 Prisoners 247 Students 247 Junior Colleagues 248 Other Groups 248 Financial and Other Inducements 248 Safeguards 248 Design and Protocol 249 Ethics Committees 250 Consent, Contract and Liability 251 Personal Insurance 252 SUMMARY OF RECOMMENDATIONS 253 APPENDICES 1. Check list for healthy volunteer consent and contract forms 254 2. Oral Evidence 255 3. Written Evidence 256 4. Edited abstracts of the Royal College of Physicians Guidelines on the Practice of Ethics Committees in Medical Research. 256 BIBLIOGRAPHY 257 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 243 Introduction This Working Party was set up in April 1984 at the request of the Medicines Commission which had become concerned about the testing of new drugs on healthy volunteers. We are aware of and uneasy about the growing commercial interest in the establishment of units doing drug research, not only in private institutions, but also in university and National Health Service (NHS) premises. It appears that early drug development studies on healthy volunteers have increased in volume over recent years. A factor in this may be the belief in industry that the Licensing Authority will look more favourably on applications for a Clinical Trial Certificate (CTC), or for an exemption from the need for holding such a Certificate (CTX), if studies on large numbers of healthy volunteers form part of an application, rather than the small studies precisely designed to produce essential information for scientific and regulatory purposes. The Licensing Au- thority should consider this matter and should state clearly its policy regarding the role and scope of drug studies on healthy volunteers in the development of medicines. Although the primary stimulus for this Report came from the Medicines Commission's concern about the use of drugs, we decided to examine research on healthy volunteers in general and not to confine ourselves to pharmacological studies. Thus the Report also covers products that might be used in surgery and diagnostic procedures as well as drugs. Our deliberations have been independent of the Medicines Commission and our Re- port reflects views taken after receipt of written and oral evidence from a wide selection of individuals and organi- sations. Previously published documents and guidelines (see Appendix 3 and Bibliography) have been helpful. We accept and emphasise the need for research on healthy volunteers, but we are concerned about their health, their safety and their rights. We have described the healthy volunteer, defined the possible risks, and the safeguards required for the subject and for the investigator. Safeguards for the healthy volunteer are concerned with selection, consent, conduct of the research and compensation for any injury that may result. We have produced guidelines for the volunteer, the investigator, the sponsor, Research Ethics Committees and for all institutions where research on healthy volun- teers takes place and have suggested a check list that may be useful when compiling healthy volunteer consent and contract forms (Appendix 1). We have also made sugges- tions regarding compensation for injury. These guide- lines should be read in conjunction with the Royal College of Physicians Guidelines on the Practice of Ethics Committees in Medical Research (1984), edited abstracts of which appear in Appendix 4. In this Report we make specific recommendations about various aspects of research on healthy volunteers. In many cases we have not provided detailed solutions or mechanisms for their implementation. For instance, we recommend that clinical research departments of com- mercial organisations be subject to external scrutiny, and that there be a register of approved institutions; but we do not specify who might take on this responsibility. Justification for Research on Healthy Volunteers Most research into disease is done on patients rather than on healthy volunteers and is therefore outside the scope of this Report. Research on healthy volunteers, however, is required in order to gain knowledge in two main fields. Physiology and Psychology Further knowledge of human physiology and psychology is important in its own right and also because it increases understanding of disease. Research may be by obser- vation or experiment. The latter may involve simple procedures such as measuring heart rate or blood press- ure before and after exercise, taking blood samples, or more complex and invasive procedures such as catheteri- sation of blood vessels or muscle biopsy. Similarly, psychological research may consist of simple observations, tests of memory or aptitude, or more complex experiments sometimes involving stress and emotion. Observations on healthy volunteers play an important part of medical and scientific training. Drugs and Medicines, Cosmetics and other Substances New drugs intended for use in man ultimately need to be tested in man to discover whether they are effective medicines, because the response to drugs in humans may be different from that in laboratory animals. Further, effects on, for example, mood and sleep are difficult to assess in animals. It is, therefore, essential to discover at an early stage the dose range, possible side effects and short-term tolerance of a drug in humans. It could be argued that it is more ethical to test drugs on patients who might stand to benefit rather than in healthy volunteers, but there are advantages in doing initial (Phase I) studies on healthy volunteers. In healthy per- sons there is less physiological variation and their re- sponses are likely to be more uniform. Healthy persons are often better able to collaborate in more complex experiments, and the ethical dilemma of starting treat- ment with an inadequate dose (e.g. in acute infections), or of stopping or withholding potentially effective treat- ment does not arise. In cases where harmful effects of a drug may be anticipated at therapeutic dose levels it is unethical to use healthy volunteers. With certain drugs such as those used for cancer or leukaemia, it is more ethical to undertake initial studies on patients who may stand to benefit. Cosmetics and other substances, e.g. domestic washing powders, used on or by man, may need to be tested on healthy volunteers and so come within the scope of this Report. It is useful in this context to refer to the 1982 Report produced by the Committee on Toxicity of the Department of Health and Social Security, Guidelines for the Testing of Chemicals for Toxicity. 244 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 Description of a Healthy Volunteer Although the definition may at first sight appear to be obvious, we think it important to define what we mean by a healthy volunteer in the context of research. A healthy volunteer is an individual who is not known to suffer any significant illness relevant to the proposed study, who should be within the ordinary range of body measurements such as weight, and whose mental state is such that he is able to understand and give valid consent to the study. Although it may be scientifically appropriate to use patients as control subjects for a condition from which they do not suffer, they should still be regarded as patients and not as healthy volunteers. Many patients have a sense of obligation towards doctors, particularly those respon- sible for their treatment, that could influence them to take part in a study which in other circumstances they might decline. Great care should be taken when recruiting volunteers from patients in or attending a hospital or other medical institution, and Ethics Committees should pay particular attention to this. On the other hand we see no reason why a volunteer, who is found incidentally to have an abnormality, such as congenital displacement of the hip, should be excluded from a study that is not related to this disorder. However, a subject in remission from a relapsing condition such as bronchial asthma cannot be a healthy volunteer for a study relating to that condition, and should be regarded as a patient volunteer for studies involving the immune or respiratory systems. Furthermore, such a subject should not be enrolled as a healthy volunteer for other studies in which there is any risk of affecting or precipitating the condition. Definition of Risk Any activity or even inactivity is associated with some risk, and we accept a concept of minimal risk in healthy volunteer studies. A risk greater than minimal is not accept- able in a healthy volunteer study. In some procedures, studies or experiments, the risk is so small that it can be ignored. We would equate this with the sort of risk accepted in everyday life. In medical terms we include here simple physiological experiments involv- ing exercise, e.g. on students, procedures such as collect- ing urine, taking measurements of height and weight, or a single venous blood sample. In more complex or invasive physiological and phar- macological studies it is helpful to consider not only the seriousness of an adverse effect that might result from a procedure, but also the probability of it happening. We therefore use the term 'minimal risk' to cover two types of situation. The first is where there is a small chance of a recog- nised reaction which is itself trivial, e.g. a headache or feeling of lethargy. The second is where there is a very remote chance of a serious disability or death. We regard this second risk to the healthy volunteer as comparable, for example, to that of flying as a passenger in a scheduled aircraft. Before new chemical entries are administered to healthy volunteers, they are first examined by pharmaco- logical and toxicological studies in animals. Thus only substances of low toxicity and so predicted to have low hazard are given to healthy volunteers. Furthermore, the experimental design of studies on new drugs requires them to be administered in low and graded doses, and so the risk to the volunteer is minimal. In studies of established drugs, the drug will have been tested in animal experiments and already administered to many patients. With many such drugs the risk may be regarded as minimal, provided that the proper procedures and adequate safeguards are followed. The Guidelines of the British Psychological Society (BPS) state: 'Where it is reasonable to suppose that research procedures may result in undesirable conse- quences for participants, psychologists have a responsi- bility to detect and remove or correct these consequences including, where relevant, long-term after effects.' While accepting this responsibility to treat affected subjects, it would be wrong to take the words 'reasonable to suppose' as justifying research procedures with more than trivial risk. The Guidelines of the British Psychological Society should be consulted whenever psychological research is undertaken and both we and the BPS believe that experi- ments that cause more than minimal anxiety, distress, lowering of self-esteem or long-term harm should be avoided. Recruitment and Selection of Volunteers Volunteers for physiological and other class demonstra- tions or experiments usually come from within a teaching department and are normally invited to participate by the head of the deparrtment or his deputy. Most of these experiments are for teaching students, and we consider it reasonable and ethical for students to be recruited in this way as they have been for a century or more. Class teaching experiments or demonstrations involving healthy volunteers should be approved by a Research Ethics Committee. Once this has been done it is not necessary for further approval to be sought each time the same demonstration is repeated, but the decision might be reviewed at intervals, perhaps every five years. Recruitment of healthy volunteers for research projects may involve conscious or subconscious pressures both on the investigator and the volunteer. For the investigator there are obvious advantages in ease and availability in using volunteers within the department, faculty, com- pany or other organisation. The motives that prompt people to volunteer are various. They may be scientific or idealistic but investigators should be aware of and try to minimise factors such as the desire to please or not wishing to displease possible patrons, to gain favourable notice or promotion. Financial incentives in particular may over-persuade individuals, including students, who have low incomes, and may promote the 'professional volunteer'. There should, therefore, be no coercion, overt or covert, of anyone to volunteer for research, whether the pressure be financial, for academic or employment advantage, for job security, or for other reasons. Initial Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 245 recruitment should be through circulars, notices or an- nouncement to groups and not by individual approach. The amount of any financial reward should not be stated on the initial notice. In the case of a university department, staff of the department may reasonably be invited to volunteer for studies, and it is common practice for the clinical pharma- cology departments of large pharmaceutical companies to use volunteers from within the company. We consider it reasonable for these practices to continue under supervi- sion of Ethics Committees and there may well be advan- tages to subjects and to research in forming groups of volunteers who are willing to participate regularly, will be under particularly close supervision, and who will be informed to a relatively high level. Psychological experi- ments are referred to on page 251. All departments or institutions where research on healthy volunteers is conducted should keep careful re- cords and avoid excessive use of any volunteer. It is difficult to stipulate the maximum amount any individual should volunteer because of the variety of procedures and drugs involved, but no person should take part in more than one study at a time. Account should be taken of factors such as the total time spent in any one year, the total exposure to drugs, and the total volume of blood taken in a year (not normally more than 1.5 litres in men and 1.0 litre in women). We recommend that healthy volunteers who partici- pate in drug trials more than once should be provided by the investigator with cards or booklets which record details of the studies in which they took part. If conscien- tiously completed by the investigator and shown to the next investigator, such a record would safeguard the volunteer. The proposal would also apply to the adminis- tration of radioactive substances for which there are safety limits. We have considered the desirability of a central register but think the logistic problems would outweigh any potential benefits. The method of recruitment and source of healthy volunteers should be included in the study protocol submitted to the Ethics Committees. In Britain there is a long tradition of investigators doing research on themselves. We would not wish to discourage this, but anyone who desires to experiment upon himself should seek the guidance of the Ethics Committee before doing so. If any other individual is to participate, e.g. by administering a drug or test, this also should be approved by the Ethics Committee. Special Groups Special consideration needs to be given to certain groups of volunteers and some of these are outlined below. Women A study which could be harmful to pregnancy should be avoided in women of child bearing potential, and particu- lar care should be taken in studies involving radioactivity in women. Women of childbearing potential should not normally be accepted as healthy volunteers in initial pharmacological studies without special consideration by an Ethics Committee. Children In law, individuals below the age of 18 years are regarded as children or minors. The Family Law Reform Act 1969 states that the consent of a minor who has attained the age of 16 years to medical treatment is as effective as it would be if he were of full age and it is, therefore, not essential to obtain consent from his parent or guardian for a thera- peutic procedure. The position regarding younger children was unclear until the recent House of Lords ruling (Gillick 1985) which stated that the parental right to determine whether or not their child below the age of 16 would have medical treatment terminates if and when the child achieves sufficient understanding and intelligence to enable him to understand fully what is proposed. Therefore, if a child is capable of understanding what is proposed there is no reason why he cannot give legally valid consent and authorise medical examination or treatment. Nevertheless, the Court noted that it would be 'most unusual' for a doctor to treat a child under 16 without the approval of his parent or guardian. The specific issue of parental consent with regard to research on a healthy child has not been considered by the courts but is probably covered by the wider principle that a minor's capacity to make his own decision depends upon the minor having sufficient understanding and intelligence to make that decision and is not to be determined by reference to any judicially fixed age limit (Gillick 1985). It is therefore appropriate to consider the procedure to adopt depending on whether a healthy child is or is not considered able to give legally valid consent to a research procedure. Children competent to give consent Even if an investigator believes that a child is capable of giving legally valid consent we advise that the approval of a parent or guardian should still be obtained before any research procedure is contemplated on a healthy child under the age of 16 years, and preferably under the age of 18 years. Details of the research procedure, including any dis- comfort involved, should be explained in terms capable of being understood both by the parent or guardian and by the child. We advise that the older child, as well as the parent of guardian, should sign a consent form for more than trivial procedures. Objection to taking part in a research procedure either by such a child or his parent or guardian should always be respected. Children not competent to give consent The position of the child who does not have the under- standing and intelligence to make such a decision is less clear. The investigator must look to the parent or guard- ian for consent to proceed but the question arises as to whether a parent can properly consent in law to his child 246 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 being subjected to a procedure which carries no prospect of direct benefit and some (if only minimal) risk. The law is unclear, but the prevailing view appears to be that the duty of a parent to act in the best interests of the child can reasonably be interpreted as an obligation not to do anything clearly against the interests of the child. This seems sensible to us and we believe that where the research is for the benefit of children generally, and the child is incapable of giving legally valid consent, the investigator can properly rely upon the consent of a parent or guardian. If, when the parental approval has been obtained, a child were to object to the procedure itself, e.g. taking a blood specimen, the investigator and the parent or guardian should reconsider whether it would be appropriate for the procedure to be undertaken. In the past, doubt about the legal position has inhibited research on children, but the British Paediatric Associ- ation Guidelines (1980) now accept the need for non- therapeutic research on children which benefits other children, although research which could equally well be done on adults should never be done on children. We agree with this because research that may add to our basic biological and psychological knowledge, such as the es- tablishment of reference ranges, and thereby benefit other children, can only be done on children. Pharmacological studies on healthy children should on the whole be avoided. In the case of a drug to be used in children, appropriate studies should be done on adults first unless scientifically valid results can only be obtained by the inclusion of children. There must be no financial or other reward either to the parent or guardian, or to the child, although reim- bursement of expenses is obviously acceptable. As in all research on healthy volunteers, projects should be approved by an Ethics Committee, and when children are involved particular attention should be paid to the issues outlined above. The Elderly There are some inherent problems in carrying out re- search in the elderly. For example, it is difficult to establish the criteria for health in older people and to determine their mental ability to give valid consent initially and thereafter to withdraw it if appropriate. Also, the effects of drugs and their metabolism in the body may be different in the elderly. However, it may be appropri- ate to conduct in the elderly physiological or pharmaco- logical studies relevant to their age providing particular care is taken to confirm their fitness for the proposed study. It may be important to study a drug in the elderly if it is likely to be used as a medicine in this age group. Pharmacological studies on the elderly who do not need the drug should on the whole be avoided unless the re- quired information cannot be obtained from other sources such as elderly patients or younger healthy volunteers. The Mentally Handicapped Special consideration needs to be given to mentally handicapped subjects, who are not always patients, and who will frequently not be able to give valid consent. As with children, studies should not be done in the mentally handicapped if they could be done in any other group. Research that is likely to benefit or prevent mental handicap, and is only possible in mentally handicapped people, would be ethical provided precautions like those outlined in the section on 'children' were taken, even when the subject is adult. The present legal position would appear to be that a relative cannot give a legally valid consent on behalf of an adult who is unable at the time to give consent because of mental disability. It is prudent in all circumstances for research proposals to be discussed with the volunteer's immediate family. Prisoners In the past, prisoners in Britain have not normally been invited to participate as healthy volunteers in research but we do not consider it inherently unethical to carry out research on prisoners. There might be a reason to believe that a certain hormonal, genetic, psychological or other condition was associated with violence or other pattern of behaviour likely to lead to criminal action. It would be reasonable to study such a condition in prisoners as they constitute a group likely to be relevant to the study. All the usual safeguards, which include obtaining valid con- sent, would apply and Ethics Committees might need to take special advice. Particular care needs to be taken to avoid coercion in any form including any impression that inducements such as reduction of sentence or pardon or other favours could be given. Nevertheless we appreciate that there is no precise point where a recompense be- comes an inducement. It should also be appreciated that for some prisoners the opportunity to contribute positive- ly to the well-being of society may be of help in re- establishing self-esteem and therefore in rehabilitation. Students Students are likely to volunteer as subjects for research for various reasons. Sometimes they are motivated by scienti- fic interest and they may have much to gain in terms of knowledge and experience from taking part in research projects. Financial reward may be an added incentive or even the sole motive. As students are normally young, healthy, numerous, and have low incomes, they are easily recruited by university departments and other organisa- tions. They are, however, particularly vulnerable to academic, personal and financial pressures. They may also be tempted to spend more time than is desirable away from their studies. Unless the study is educational it is normally undesira- ble to recruit students who are in close contact with the investigator, e.g., on his medical teaching 'firm' or in his class. This is because students are, or may feel, vulner- able to pressure from someone in a position to influence their careers, by assessment in an examination or other- wise. Ethics Committees should be aware of and pay particular attention to this. When students of an institu- tion are recruited for other than educational studies, the Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 Dean of that institution or other designated person should be informed in writing and the student should be aware of this. The information given should include details of the research project, the names of those taking part and which Ethics Committee has approved the study. Junior Colleagues It is a time honoured and well-established practice for junior colleagues to co-operate with their seniors in research. When the research involves volunteers this may include doing studies on each other. In this context the junior colleague is in a vulnerable position, on the one hand because of overenthusiasm, and on the other be- cause any lack of eagerness to participate might be thought to prejudice his future career. The Ethics Committee should be made aware of the fact if colleagues are involved as subjects in research. Other Groups Volunteers may be recruited from other groups and there is no reason, for instance, why unemployed people should not be invited to volunteer for research. Financial re- wards are likely to be a particular incentive for them, however, and care needs to be taken that they to not take part in an excessive number of studies. Volunteers in the armed or other Services might also be subject to coercion and this again should be guarded against. There may, however, be good reasons for re- cruiting healthy volunteers in the armed forces, e.g. in experiments designed to help servicemen in action. Financial and Other Inducements There is a long tradition that both investigators and healthy volunteers in research are motivated by the desire to advance knowledge and help society and this spirit of altruism is to be admired and encouraged. Students, particularly in the medical and psychological sciences, frequently take part in experiments in the course of their training where the prime object is to enable them to make their own observations. This we regard as educational and entirely acceptable. However, many studies, particularly in pharmacology, are lengthy and tedious, and may involve urine collec- tion, multiple venepunctures or other procedures associ- ated with some discomfort. It is reasonable that volunteers in this type of research should be paid, over and above reimbursement of expenses incurred. These payments are for inconvenience or discomfort and in- creased payments may be reasonable for procedures requiring extra care on the part of the subject or involving more discomfort. Payments should never be for undergoing risk. Payments should not be such as to persuade people to volunteer against their better judgement, nor to induce them to volunteer more frequently than is advisable for their own good. While appreciating that any given sum would be viewed differently by a student or person who is unem- ployed than by a person in full paid employment we suggest that payment should range somewhere between rates equivalent to current student grants and a daily rate equivalent to the average wage, but time involved and inconvenience incurred should be taken into consider- ation. All payments to volunteers should be approved by the Ethics Committee. When a volunteer withdraws for medical reasons re- lated to the study full payments should be made. When the volunteer leaves the study and exercises his right not to give a reason or is required to leave for non-compli- ance, no payment need be made if the consequences of leaving the study in these circumstances have previously been explained to him. If a volunteer withdraws for other reasons, including non-related medical reasons, the in- vestigator or sponsor should make a proportional pay- ment. Some investigators receive personal payment, or mem- bers of their staff, the department, or laboratory equip- ment may be funded by a sponsoring company or other organisations. Any or all these payments should also be disclosed to the Ethics Committee. This is commented on in the Royal College of Physicians Report on The Re- lationship between Physicians and the Pharmaceutical Industry. (1986, J.Roy.Coll.Physic 20, 235) Safeguards It is the responsibility of the investigator to confirm that a volunteer is healthy. How detailed this confirmation requires to be depends on the type of study. When using a volunteer in minor procedures such as a simple physiol- ogy class demonstration or equivalent research it is normally adequate to accept the volunteer's assurance about his health. A more thorough assessment of the volunteer's health is required in more complex studies including most pharmacological studies. When giving consent the volun- teer should state that as far as he knows he is in sound physical and mental health and should give details of any previous medical history. It is advisable to inform the volunteer's general practitioner and in industry the medi- cal officer of the company or institution. This is to let a doctor know that his patient has volunteered for a particular study and to obtain, if approriate, any past medical history that could, for instance, increase the risk of his participation. The volunteer's agreement is re- quired for this and if he does not agree it would be wise not to use him. A history of smoking, alcohol or other drug consumption should be obtained from the volunteer. He should also be asked if he is taking any medicines, whether prescribed or not and if he has participated in any previous studies. Where appropriate the volunteer should be medically examined and relevant blood or other tests, e.g. a cardiogram, should be performed. These tests would normally comprise a blood count and routine biochemical analysis, but screening for alcohol and other drugs may sometimes be advisable. If any tests shows an abnormality that could be associated with an increased risk for the individual if he participated in the study, the volunteer should be excluded. Where appropriate, safe- guards regarding communicable diseases should be taken to protect the volunteer, the investigator and his staff. 248 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 Further examination and tests may need to be done after the study. If at any time a significant abnormality is discovered the volunteer's general practitioner should be informed. The volunteer should have agreed to this in advance of the study; and he should also have given consent if it is the intention or if it is advisable to inform anyone else, e.g. the medical officer of a company or other institution. The volunteer should be provided with a written account of the study describing simply and clearly what is involved, including risks that may be incurred and the probability of their occurrence. The degree of supervision required and the suitability of premises and equipment where research takes place should depend on the type of study and risk involved. The Ethics Committee should always consider whether a suitably qualified medical person should supervise and be responsible for a study. This would be desirable particularly for drug studies and invasive procedures. Further safeguards may be required in studies using drugs that are new chemical entities or new combinations of established drugs. Where there is any possibility of serious adverse reactions there should be facilities for full resuscitation including appropriate drugs, a cardiac defi- brillator and apparatus for intubation and assisted venti- lation. The medical and ancillary staff should be trained and experienced in resuscitation and for some types of study further medical help and intensive care facilities should be available within a few minutes. In some circumstances (see p246) we recommend that volunteers carry a booklet stating the nature of the study, any drugs that have been taken, and the name of the investigator or other appropriate person to contact should this be necessary. If at any time a healthy volunteer develops more than a minor reaction the investigator should stop the study in that individual and consider whether it is advisable to stop the whole study. As well as informing the Ethics Committee and the volunteer's general practitioner the investigator should, where neces- sary, take appropriate action to safeguard the volunteer's health. All laboratories or other places where studies are performed on healthy volunteers, whether they may be in university or other academic departments, in NHS hospi- tals, pharmaceutical companies or contract companies, should be open to inspection in order to assure all concerned that high standards are maintained and the guidelines in this Report are followed. In the case of NHS hospitals university and other academic departments we think this inspection could, where necessary, be done by or on behalf of properly constituted Ethics Committees. These Committees should consider carefully whether it might not be advisable for units carrying out substantial and sustained research on healthy volunteers (particularly departments investigating drugs under development) to be inspected. Clinical research departments of pharmaceutical com- panies, contract companies and other commercial institu- tions that perform research on healthy volunteers should be subject to external scrutiny as they are vunerable to criticism because of commercial pressures. We further recommend the establishment of a register of all commercial institutions approved as maintaining appropriate standards. Design and Protocol Research involving healthy volunteers should conform to the same ethical standards that apply to all medical research, as indicated in the Royal College of Physicians Guidelines on the Practice of Ethics Committees in Medical Research (1984). There should be an intention to benefit society by doing research, and also an obligation to protect subjects of research from harm, and to preserve their rights. Since healthy volunteers will not benefit medically from their participation it is particularly im- portant to respect their autonomy, right of self determi- nation and safety. All research on healthy volunteers should be based on sound scientific principles, should not involve more than minimal risk and should be conducted or supervised where necessary by a qualified medical person with the training and experience appropriate to the particular study. Before stating the present position of a healthy volun- teer in drug studies it is useful to consider the scope and limitation of the Medicines Act (1968). The Act regulates medicines, and does not use the term 'healthy volunteer'. It is concerned with 'medicinal products' administered for a 'medicinal purpose' (this includes contraception and anaesthesia) and excludes from its concern any substance that is administered by or on behalf of a manufacturer 'solely by way of a test for ascertaining what effects it has when so administered', and 'in circumstances where the manufacturer has no knowledge of any evidence that those effects are likely to be beneficial to human beings'. Therefore the administration of a contraceptive to a healthy person and the administration of a drug to prevent heart attacks would both have a 'medicinal purpose'. The subject would be treated as a patient and the administration would be regulated by the Medicines Act. But the administration by (or on behalf of) a manufacturer of a drug to healthy people to find out what it does to the blood pressure or blood sugar would not be controlled by the Act because it is not regarded as the administration of a medicinal product since there is no medicinal purpose. Thus the majority of drug studies on healthy volunteers are excluded from regulation under the Act. Under the Act, a medicinal product cannot normally be supplied by a manufacturer for the purposes of a clinical trial (in patients) unless the manufacturer has applied to the Licensing Authority for a Clinical Trial Certificate (CTC) or for exemption from the need to hold such a Certificate (CTX). In either case submission of details of laboratory studies in animals (pharmacology, including studies on absorption, distribution and elimina- tion, and appropriate studies on safety, including acute and chronic toxicity and mutagenicity) is usually re- quired. There are special provisions for investigators to obtain clearance where they wish to carry out studies on patients other than on behalf of a manufacturer or other third party. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 249 Therefore in the case of almost all healthy volunteer studies there is currently no statutory requirement for such prior laboratory work to be done or assessed inde- pendently, although the common law duty to take proper care almost certainly imposes an obligation to do such work, indeed the Association of the British Pharma- ceutical Industry (ABPI) has advised its members that the same background work and information should be avail- able before healthy volunteer studies are undertaken. We take the same view as the ABPI but recommend a further safeguard. Although we are aware of problems caused by delay and of the extra work it will involve, we recommend that proposals for all drug studies on healthy volunteers involving new chemical entities and new com- binations of drugs should be reviewed independently. This is because Ethics Committees need assurance on the adequacy and appropriateness of the highly specialised preclinical laboratory studies both with regard to safety and potential efficacy, in the assessment of which they themselves do not usually have the necessary expertise. The DHSS Medicines Division would appear to be a suitable organisation to undertake this review, and the CTX scheme under the Medicines Act (1968) provides a possible model. The protocol of any research of any project involving the use of healthy volunteers should give full details of the scientific background and the objectives of the study. It should give the number, age and sex of volunteers required and how they are to be recruited. It should give details of how the study is to be performed, where it is to be done, and where appropriate, the arrangements for emergency medical care. Volunteers should give valid consent and should also be told that they may withdraw from the study at any time without giving a reason. The protocol should also state what financial arrangements have been proposed including payment of compensation to a healthy volunteer in the event of accident, injury or ill health during the course of or following the study. If a volunteer drops out of a study, for whatever reason, the investigator should take reasonable steps to find out whether harm has come to him as a result of his participation, e.g. by keeping in touch with the volunteer for an appropriate time. Some psychological research involves deception of the subject and would be invalid were this not so. The deception that is considered necessary in a study should not involve the volunteer in any risk, nor should healthy volunteers be deceived about any possible risk caused by participation in a psychological research project. Possible risks are unexpected anxiety or distress, lowering of self esteem, or any form of long-term psychological or physi- cal harm. Deception on any aspect that might affect the subject's willingness to participate is as unacceptable in psychological as it is in any other kind of research. Ethics Committees All research, studies and experiments on healthy volun- teers must have been approved by an Ethics Committee. Ethics Committees should be properly constituted and should follow the 'Guidelines on the Practice of Ethics Committees in Medical Research' issued by the Royal College of Physicians in 1984. Most universities, medical schools and larger hospitals already have properly constituted Ethics Committees. It is essential that research at all hospitals, academic institu- tions, pharmaceutical companies and any other institu- tions undertaking research on healthy volunteers should be supervised by such a Committee and that independent lay and scientific judgement should be available. Some drug studies on healthy volunteers are done by contract companies unassociated with universities, hospitals or pharmaceutical companies. It is important that these studies should be made subject to the same conditions and scrutiny. It is the responsibility of the investigator to ensure that any proposed research on healthy volunteers is considered by an Ethics Committee. If a small company or institu- tion has difficulty in obtaining assessment of its research by a local or regional Ethics Committee we suggest it should seek the advice of the Committee on Ethical Issues in Medicine of the Royal College of Physicians of Lon- don. The Ethics Committee should satisfy itself that studies are scientifically sound because this is an essential ingre- dient of ethical research. It should also ensure that volunteers are fully aware of the details, implications and possible risks of a study and are able to give valid consent. The Committee should also satisfy itself that there is adequate provision for compensation independent of proof of negligence in case of injury or illness arising from the study. The Committee should be made aware of payments made not only to healthy volunteers, but also to the investigator, his staff or department, including grants for equipment, travel, etc. In studies involving drugs, the Ethics Committee needs to ensure that pharmacological and toxicological data have been properly appraised. New chemical entities and combinations of drugs pose special problems (see page 250). If the Committee does not have the necessary expertise to evaluate the scientific merit of proposals it is advisable to obtain expert advice or co-opt suitably qualified and informed persons. An Ethics Committee might also have difficulty in deciding on moral issues when considering studies involving groups such as prison- ers, children or the mentally handicapped. Here again the Committee would be well advised to seek advice or co-opt a person with special experience of such groups. Ethics Committees should be informed promptly of any significant untoward event occurring in the course of a study, and be consulted about material changes in a project. They should be told when a project is completed, and see resultant publications. It is desirable that Ethics Committees should be made aware of any significant ethical problems involving re- search on healthy volunteers that arise in this country and elsewhere, whether or not they have been reported in the medical journals or press. Consideration should be given to the possibility that the Committee on Ethical Issues in Medicine of the Royal College of Physicians of London should take responsibility for supplying Ethics Commit- tees with relevant information that comes its way. 250 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 We understand that the British Psychological Society is unwilling to accept that psychological experiments should be scrutinised by Ethics Committees which do not include at least one properly qualified psychologist as a full member. While we have some sympathy with their views, and realise that they accept the general principal of independent scrutiny of such experiments, we think that such review should take place in precisely the same way as for other experiments using healthy volunteers. Consent, Contract and Liability By implication a volunteer taking part in an activity has given consent, but before agreeing to participate in a research project it is important that the volunteer should be properly informed and have given valid consent. In the present state of the law we believe that the investigator's obligation in this regard is to explain in understandable terms the nature and purpose of the study and to provide sufficient information and advice on possible risks to which the volunteer is exposing himself so as to give meaning to the volunteer's right to self determination. In practice this means that the investigator must disclose the risks he believes, as a matter of professional judgement, are material to the volunteer's decision on whether to participate or not, and all other information that might be considered relevant. Even a remote risk is important to a healthy person who does not stand to gain any compen- sating benefit from the study. As well as being told about possible risk the volunteer should be aware of other relevant details of the study, such as its duration and what is required of him, whether this be taking exercise, drugs, having blood tests or other procedures. He should also be told whether any intended procedures will be associated with discomfort and whether there are any restrictions on, say, driving or drinking alcohol. He should be assured of confidentiality, and the financial reward, if any, should be clearly stated. We recommend that all relevant information about a project be given to the volunteer in writing, preferably as a Subject Information Sheet. Ethics Committees should decide when written information could be dispensed with, e.g. for trivial studies. Only when the volunteer has been so fully informed by the investigator do we believe that the ethical and legal requirements have been met. Although not essential in law, it is usual and desirable, except in trivial cases, that a consent form be signed by the volunteer, and the investi- gator should state that he has explained the nature of the investigation to the volunteer. It is useful if the Subject Information Sheet and the consent form are kept together. Having agreed to participate, a volunteer also has a commitment. He should disclose his full medical history, comply conscientiously with the protocol, and report any symptoms that may occur during or after a study. On the other hand, as already stated (p.250), he should know he can withdraw from the study at any stage without giving a reason. The healthy volunteer will also need to know what his position is in the event of an accident, injury or the development of ill health as a result of having taken part in the research project. The current strict legal position is that an individual in this situation is only entitled to compensation if he can show there was negligence on the part of the investigator, the institution where the study took place, the sponsor of the research or their respective staff. (We are aware that the position may change in the light of the EEC Directive on Product Liability, 1985). This puts the onus on the volunteer and could make the investigator an adversary; the volunteer has no legal redress if he is unable to show negligence. However carefully a research project has been planned and carried out, the possibility of an unforeseen event resulting in injury or ill health and not due to negligence, can never be eliminated. In the case of research conducted in and sponsored by universities, National Health Service hospi- tals, Medical Research Council and other establishments the healthy volunteer is then dependent on an ex gratia payment. We believe that universities and other institu- tions should make binding commitments to provide com- pensation, because we consider it unacceptable that a healthy volunteer should have to rely on an ex gratia payment. A similar conclusion was arrived at both by the Royal Commission on Civil Liability and Compensation for Personal Injury (Cmnd 7054)?the Pearson Report, March 1978?and by a Ciba Foundation Study Group, Medical Research: Civil Liability and Compensation for Personal Injury, 1980. They made, however, rather differ- ent recommendations. The Pearson Report recommended 'that any volunteer for medical research or clinical trials who suffers severe damage as a result should have a cause of action, on the basis of strict liability, against the authority to whom he has consented to make himself available.' (Para. 13.41). The Ciba Foundation Study Group concluded: 'The Group has considered the most appropriate means of compensating participants (or their relatives) for injuries received as a consequence of medical research. The Group recognises that injury may occur despite the exercise of the highest degree of skill and care by the investigator. It recommends the establishment of a cen- trally operated Fund to provide compensation on a no- fault (i.e. insurance) basis.' We are not in favour of the imposition of strict liability by legislation because this still retains the need to com- mence legal proceedings in order to establish responsi- bility and determine compensation. The Ciba Group suggested establishing a Fund provided by organisations such as the Medical Research Council, the universities, the DHSS, the pharmaceutical industry, the medical protection societies and private organisations funding research. We think a no-fault scheme is more attractive but ultimately impractical in the special case of healthy volunteers because the problems of funding and adminis- tration would be unnecessarily burdensome, bearing in mind the limited number of claims that are likely to arise. The ABPI recommends the use of a combined consent and contract form in which the sponsor agrees to pay compensation independent of proof of negligence in the event of the volunteer suffering any deterioration in Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 251 health or well being as a result of participating in their research project, unless there was negligence on the part of a third party. We agree in the main with the ABPI and consider this approach should be used generally in re- search, but we suggest further safeguards for the volun- teer. We suggest a simple form of contract under which the sponsoring institution or company agrees to pay compensation for injury, accident, ill health or death caused by participation in the research in question. Normally causation is based on the balance of probabil- ity. In the case of healthy volunteers the reasonable inference should be that any unexpected injury or harm suffered during or shortly after the study is due to participation in the study. In marginal cases we believe the benefit of the doubt should be given to the volunteer. We think it is the responsibility of the institution or organisation responsible for the research to provide com- pensation where this is indicated. We advise them to consider whether they are prepared to cover such an eventuality out of existing funds or whether to take out an appropriate insurance policy. Many organisations and institutions already have third party liability policies that cover negligence. We recommend that policies be ex- tended to cover compensation payable under such con- tracts independent of proof of negligence. The number of claims is likely to be small and the extra insurance premium should be acceptable. Where medical research on healthy volunteers is undertaken by contract compan- ies on behalf of a pharmaceutical company it should be made clear whether the sponsor or contract company is responsible for compensation. If these suggestions are implemented it is important that the organisation or institution responsible for com- pensation be named in the protocol and the contract form, and that Ethics Committees ensure that this has been done. In the event of a dispute or difference of opinion regarding a claim including the issue of negli- gence by a third party, we advise following the procedure suggested by the ABPI?that reference be made to an arbitrator or arbitrators appointed by the President of the appropriate medical Royal College, the arbitrator having the power to consult a barrister of 10 years' standing with regard to any issue of law including the amount of compensation. As the law stands, if injury or ill health occurs as a result of failure to take care by the investigator or anyone else, the volunteer still has the alternative of pursuing a claim for negligence. The wording of the contract should be such that the volunteer would not waive any existing legal rights he might have against the organisation or institution or any person involved in the research. If the contract excludes the right to compensation by the sponsor where a third party's negligence may have caused the injury, and if there were a difference of opinion regarding the issue of negligence, then the volun- teer would be entitled to ask the Arbitrator to consider whether there was any evidence to support the sponsor's case that the injury resulted from a third party's negli- gence. However, if the Arbitrator decided that there was such evidence, he could not make any final ruling that the third party was negligent or bound to compensate the volunteer because there is no agreement that any dispute between the third party and the volunteer shall be determined by Arbitration. The volunteer would have to commence legal proceedings against the third party and the delay in resolving whether the third party or the sponsor should pay compensation might be quite long. We believe that a healthy volunteer sustaining ill health or injury as a result of participation in a research project is entitled to compensation, and also that justice requires that the parties promoting the research so organise their affairs that he receives this compensation without delay. Although it is a complex area involving both insurance practice and the law we suggest that it is reasonable to expect the sponsor of research to undertake to pay the volunteer independent of proof of negligence, even negli- gence of a third party, such as the investigator. Compen- sation could than be paid to the volunteer by the sponsor without delay. Before giving such an undertaking, the onus would be on the sponsor to protect his right to claim against the other parties to the research so that if a payment is made in circumstances where one of those parties was negligent, the sponsor has a right to recover the full amount of the payment, or a contribution, depending upon the facts of the case. As already stated, we believe it is the responsibility of Ethics Committees to ensure that adequate arrangements for compensation have been made before a project involv- ing healthy volunteers is approved. In the, we hope unlikely, event of institutions or organisations responsible for the research either not being able to obtain appropri- ate insurance cover, or not being prepared to underwrite compensation themselves, then the future of research on healthy volunteers might be in jeopardy. If this were to be the case, thought should be given to the establishment of a centrally operated fund as suggested by the Ciba Founda- tion Study Group. The College is not equipped to make a detailed proposal for such an arrangement but rec- ommends that it be explored. Appendix 1 set out the matters that we believe should be considered for inclusion in the form of contract that provides evidence of consent and other matters that have been agreed between the volunteer and the investigator. Obviously not all these provisions will be relevant to every type of study, nor can our list be exhaustive given the infinite number of special situations that might arise. However, this check-list may be helpful to investigators wishing to develop a consent form to suit their own circumstances. Personal Insurance It is unlikely that a healthy volunteer would take out a life, sickness or accident policy in contemplation of taking part in medical research. It is, however, possible that he may already have a policy. The advice we have had from the Association of British Insurers (Life Insurance Coun- cil) is that an existing policy is unlikely to be affected, but that it would be prudent for the volunteer to study the wording of his policy to see whether cover is provided in respect of accidents arising in connection with research, or to contact the insurance company for clarification. 252 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 More significantly, when effecting a new life or health insurance policy the Association has advised that any intention to participate in medical research should be disclosed, on the grounds that such participation might affect the insurer's attitude to accepting the proposal or fixing the premium. We note the views of the Association but we think it unrealistic to expect volunteers to do as suggested, even if so advised on a consent form. Therefore we recommend that the Association of British Insurers should take the broad view and advise its member companies not to treat an intention to participate in research that has been passed by an Ethics Committee and is considered to involve no more than minimal risk as constituting a material fact that must be disclosed by the healthy volunteer. SUMMARY OF RECOMMENDATIONS Ethical Considerations I. All research involving healthy volunteers should be approved by an Ethics Committee (p. 245, 250). , 2. All studies should be scientifically and ethically justi- fied (p. 249, 250). 3. Confidentiality of healthy volunteers should be main- tained (p. 251). 4. The recruitment of some groups, (e.g. students, i women, children, the elderly, the mentally handicapped, prisoners), raises scientific and ethical issues which should v be given special consideration (p. 246-248). 5. If the Ethics Committee does not feel competent to consider difficult scientific data or difficult ethical issues (e.g. the use of prisoners) it should seek appropriate advice or co-opt people with the necessary expertise (p. 250). 6. There shall be no deception that might affect a volunteer's willingness to participate in research, nor should there by any deception about the possible risks involved (p. 250). 7. Relevant information about significant ethical prob- lems should be supplied to Ethics Committees by a central body such as the Committee on Ethical Issues in Medicine of the Royal College of Physicians (p. 250). Recruitment and Financial Considerations 8. Initial recruitment of healthy volunteers should be via a notice, or if verbally, through a group approach rather than to individuals (p. 245, 246). 9. The Ethics Committee should be given full details of the background, nature and object of the study, how healthy volunteers are to be recruited and their age and sex. It should also be informed from which section of the community it is proposed to recruit them in case this raises ethical issues (p. 246-248, 250). 10. When students are used as healthy volunteers, the Dean or designated alternate should be informed in writing, given details of the students, the project and which Ethics Committee has approved the study (p. 247). II. It is normally undesirable to recruit students in close contact with the investigator, e.g. on his medical teaching firm or in his class, unless the project is educational (p. 247). 12. There should be no financial inducement or any coercion that might persuade a volunteer to take part in a study against his better judgement (p. 245, 248). 13. Any payment to a healthy volunteer should be for expenses, time, inconvenience or discomfort, and never for risk. Increased payments may be reasonable for procedures requiring extra care or involving more dis- comfort (p. 248). 14. There should be no financial reward when children are used as healthy volunteers (p. 247). 15. All payments should be declared to the Ethics Com- mittee; not only those to healthy volunteers, but also those to the investigator, his staff or his department (p. 248, 251). Safeguards 16. No study on healthy volunteers should involve more than minimal risk (p. 245). 17. For most medical research, particularly drug studies, the investigator responsible should be medically qualified and with experience appropriate to the study concerned (p. 249). 18. Any significant untoward event occurring during or after a study affecting a volunteer should be communi- cated promptly to the Ethics Committee and the volun- teer's general practitioner. Appropriate action to safeguard the volunteer's health should be taken, and the study should be stopped in that individual (p. 249, 250). 19. If a volunteer drops out of a study, for whatever reason, the investigator should take reasonable steps to find out whether harm has come to him as a result of participation in the study (p. 250). 20. The premises where research takes place should be appropriate to the type of study and to the risk involved (p. 249) 21. Where drugs are new chemical entities, or new combinations of established drugs, and where there is any risk of serious adverse reactions, there should be facilities and appropriately trained staff for full resuscitation (p. 249). 22. For some types of study further medical help and intensive care facilities should be available within a few minutes (p. 249) Design, Consent and Contract 23. An investigator should keep full records of all studies performed and should keep a register of healthy volun- teers used (p. 245). 24. An investigator should give full details in writing to a Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 healthy volunteer explaining the nature, object and dur- ation of a study. The volunteer should be informed of any risk, and told what the study will involve, e.g. number of blood tests or injections, and whether there are any restrictions on, e.g. driving or drinking alcohol (p. 249, 251). 25. The volunteer should be asked for permission to contact his general practitioner, and if appropriate a company or other medical officer, for details of past history. Where necessaary, e.g. in the event of any ill health as a result of the study, there should be further communication. If this permission is not given it is advisable not to use the volunteer (p. 248). 26. Having been given appropriate information and having given his consent the volunteer should sign a consent form (p. 251). 27. Where appropriate, but particularly before taking part in any drug trial, a healthy volunteer should be asked about relevant medical history, which should include smoking, taking of alcohol, drugs and medicines, and whether he had participated in previous studies (p. 248). 28. Where appropriate a healthy volunteer should be medically examined and have relevant blood, urine or other tests. These may need to be repeated during or after the study (p. 248). 29. The volunteer should give a commitment to the study and also report any unexpected or unusual symptoms but he should have the right to withdraw from the study at any time without giving a reason (p. 250, 251). 30. Volunteers who participate more than once in drug trials should be provided with a card or booklet giving details of studies in which they have participated (p. 246, 249). 31. The Ethics Committee should be informed when a study has been completed and be supplied with any relevant publications (p. 250). Compensation and Insurance 32. The sponsor, whether this be a commercial organis- ation, university, NHS or other institution, should agree to pay compensation for injury, accident, ill health or death caused by participation in a research study without regard to proof of negligence and without delay. Pro- vision for arbitration of disagreement should be included (p. 251-252). 33. Where there is any doubt about causation the benefit of the doubt should be given to the volunteer (p. 252). 34. Where necessary the sponsor should take out appro- priate insurance to cover compensation independent of proof of fault (p. 252). 35. Where ill health in or injury to a healthy volunteer may be due to negligence by a third party, the sponsor should compensate the volunteer. The sponsor should protect his right to claim against other parties in the research (p. 252). 36. Whether or not they have been notified insurance companies should honour life and sickness policies of healthy volunteers affected by participation in research that has been passed by an Ethics Committee and considered to involve no more than minimal risk (p. 252- 253). Standards and General Recommendations 37. The Licensing Authority (Medicines Act, 1968) should state its view of the role and scope of drug studies in healthy volunteers in the development of new medi- cines (p. 244). 38. The laboratory data obtained in animals that are deemed to justify drug studies involving new chemical entities and new combinations of drugs should be re- viewed independently (p. 250). 39. Ethics Committees should be satisfied that there has been adequate evaluation of background pharmacologi- cal, toxicological data, etc., in all drug studies, particu- larly in the case of new chemical entities or combinations, e.g. by the DHSS. Medicine Division (p. 250). 40. All establishments or laboratories where studies on healthy volunteers are performed should be open to inspection in order to assure all concerned that high standards are maintained and the guidelines in this report are followed. Research departments of NHS hospitals, university and other academic institutions could, where necessary, be inspected by or on behalf of properly constituted Ethics Committees. In units where substantial and sustained research on healthy volunteers is carried out, and particu- larly in those departments where drugs under develop- ment are being investigated, Ethics Committees should consider carefully whether it might not be advisable for them to be inspected. Commercial institutions performing research on healthy volunteers should be subject to independent scrutiny (p. 249). 41. A register of approved commercial institutions that perform research on healthy volunteers should be estab- lished (p. 249). APPENDICES Check List for Healthy Volunteer Consent and Contract Forms This is a check list and not a specimen consent or contract form. It is not possible to produce a form that covers all types of research nor does this check list set out to be comprehensive. Consent Confirmation is required of the fact that: 1. The volunteer is willing to take part in the study and this should be clearly stated. 2. The investigator has explained the nature and purpose of the study and has informed the volunteer of any risk to health that the investigator foresees. 254 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 3. The volunteer has received the Study Information Sheet describing the essential features of the study which acts as an aide memoire in relation to attendance, etc. (Depending upon the type of study involved such a sheet may be considered unnecessary). 4. The volunteer has been given the opportunity to question the investigator and has understood the investi- gator's advice. 5. The volunteer has been told he is free to withdraw consent at any time without the need to justify that decision. Medical Information given by Volunteer prior to Participation Confirmation that the volunteer has informed the investi- gator of: 1. Previous or current participation in healthy volunteer studies. 2. Significant previous or present illnesses together with details of consultations with a doctor whether or not they resulted in treatment. 3. Medicines (whether prescribed or not) being taken or which have been taken in the recent past (this period can be defined according to the nature of the study) and that the volunteer is expecting to take during the course of the study. 4. History of previous or present use of tobacco, alcohol and other drugs. 5. The volunteer's readiness to keep the investigator informed of any additions to the above information. Authority to Consult the Volunteer's General Practitioner Confirmation that the investigator is authorised to consult the volunteer's general practitioner and that the latter is authorised to disclose any information concerning the volunteer's health that he considers relevant to the pend- ing study. Continuing Obligations of the Volunteer Confirmation that the volunteer will: 1. Follow the reasonable instructions of the investigator and not to do anything that the volunteer knows or might reasonably suspect will affect the integrity of the study. 2. Inform the investigator of any unexpected symptoms or deterioration in his health during or immediately following the study. 3. Not restrict the use to which the study results are put (including submission to drug regulatory authorities) provided that any document relating to the Study passed to a third party does not identify him by name. Obligations of the Person initiating the Research Confirmation by the sponsoring institution, company or other person or body initiating the research or their respective agents of: 1. Any payment that will be made in consideration of a volunteer's participation and the terms that have been agreed regarding payment in the event of withdrawal from the study. 2. Arrangements made concerning compensation for in- jury which will include an undertaking by the person or body initiating the research that compensation will be paid independent of proof of negligence and without delay. There should be provision for arbitration in the event of dispute including the manner of appointment of the arbitrator and his right to consult a barrister. 3. To provide a simple form of contract giving effect to the above. Formalities 1. The volunteer should sign to confirm his consent on the terms set out but it is not necessary that his signature be witnessed. 2. The investigator should sign a statement at the bottom of the document or on a separate attachment confirming that he has explained the nature, purpose and possible risks of participation to the volunteer. 3. The person responsible for the payment of compen- sation (above) or his agent should sign the document. In some cases it may be more practicable to have the issue of compensation dealt with in a separate document where the person supervising the conduct of the study is not giving the undertaking concerning compensation. 4. The document should be dated. 2. Oral Evidence The following gave oral evidence and most also submitted written evidence to the Working Party: Professor A. W. Asscher, Department of Renal Medi- cine, University of Wales College of Medicine. Associate Members' Group of the British Medical Associ- ation (Miss J. Smith and Mr. C. Valentine) Association of Provincial Medical Schools (Mr. J. Marr) Bowring London Ltd. (Mr. M. D. Jones, Divisional Director) British Pharmacological Society, Clinical Section (Profes- sor M. L'E. Orme) British Psychological Society (Professor A. Gale and Dr. A. Manstead) Charterhouse Clinical Research Unit Limited (Dr. S. J. Warrington, Executive Medical Director) The Committee of Professors of Clinical Pharmacology and Therapeutics (Professors C. F. George and D. W. Vere) The Faculty of Anaesthetics, Royal College of Surgeons (Dr. Aileen Adams and Professor J. W. Dundee) The Faculty of Occupational Medicine, Royal College of Physicians (Dr. J. F. L. Aldridge) Health and Safety Executive (Dr. David Gompertz, Deputy Director Medical Services) Imperial Chemical Industries PLC (Dr. J. D. Fitzgerald, Medical Director, Pharmaceuticals Division) Dr. Gerald Jones, Department of Health and Social Security, Medicines Division Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 255 Dr. Robert Mahler, MRC Clinical Research Centre, Northwick Park Hospital Dr. A. E. M. McLean, Professor of Toxicology, School of Medicine, University College, London National Union of Students (Messrs. J. Fallon and P. Woolas) Trades Union Congress (Dr. Ronald Owen, Medical Adviser) 3. Written Evidence The following gave written evidence to the Working Party: The Association of British Insurers, Life Insurance Coun- cil (Mr. T. H. M. Oppe) The Association of the British Pharmaceutical Industry The Association of Medical Advisers in the Pharma- ceutical Industry (Dr. I. Lennox-Smith) Dr. L. S. Bernstein: for Clinical Research Physicians of: Beecham Pharmaceutical Research Division, Glaxo Group Research Ltd., Imperial Chemical Industries PLC and The Wellcome Foundation Ltd. Biomedical Sciences (Dr. E. H. L. Harries) Professor Ronald Dworkin, University College, Oxford Huntingdon Research Centre Ltd. (Dr. D. Mansel- Jones) Professor June K. Lloyd, Department of Child Health, St. George's Hospital Medical School The Medical Research Council Professor Alan Richens, Department of Pharmacology and Therapeutics, University of Wales College of Medicine The Wellcome Protocol Review Committee (Professor J. R. Trounce, Chairman) 4. Edited Abstracts of the Royal College of Physicians Guidelines on the Practice of Ethics Committees in Medical Research Because of the importance of Research Ethics Commit- tees to the protection of research subjects we append some edited extracts from the Royal College Physicians Guide- lines on the Practice of Ethics Committees in Medical Research (1984) to supplement the main text of this report. The Objectives of Ethics Committees. The objectives are to facilitate medical research in the interest of society, to protect subjects of research from possible harm, to preserve their rights, and to provide reassurance to the public that this is being done. Commit- tees also protect research workers from unjustified attack. Decision The nature of the decision that the Committee has to make is largely defined above. But the question of the extent to which scientific quality, design and conduct should be considered continues to cause difficulty. It has been pointed out that badly planned, poorly designed research that causes inconvenience to subjects and may carry risk without producing useful or valid results, is unethical. A Committee should feel free to refuse an application on grounds of inadequate scientific quality. Mandatory Review The institution setting up an Ethics Committee should provide that all research projects affecting human subjects come before it. The legitimate concern of the public and the profession that led to the setting up of Ethics Commit- tees cannot be satisfied by anything less than mandatory review. Definition of Project Definition of a research project that should be put before an Ethics committee continues to present difficulties. Any investigation in man designed to develop or contribute to knowledge raises ethical issues, though these may some- times be quite small. Since any such study may involve subordination of at least the immediate interest of the individual participant to the objective of the advancement of knowledge all should be subject to ethical review. Membership and Appointment of Ethics Committees Membership should comprise at least:- (a) Medical: both those occupied chiefly with clinical care as well as experienced clinical investigators; a general practitioner should be included whether or not the Com- mittee reviews projects in general practice. (b) Nursing: a nurse who is in active practice with patients. (c) Lay: i.e. one, or perhaps better, two persons not trained in or practising any medical or paramedical discipline. It is important that the community should have confi- dence in Ethics Committees and provided that the mem- bership is seen to be broad and not exclusively medical and the lay members to be persons of responsibility and standing who will not be overawed by medical members, such confidence should be forthcoming. Experience has shown that lay members, though they may not grasp some of the niceties of some research projects (nor do some of the medical members), are invaluable, particularly on issues of consent and infor- mation to subjects. A lay member with legal training can be of great value and his/her role should be a general one, not simply to answer questions of law. Both sexes should be represented. The nominations should be made by a responsible Authority, District Health Authority, Hospital Commit- tee or Academic Executive and the Committee will report to this Authority, though details of its considerations of applications will be confidential. An established Commit- tee, knowing its own needs may propose names where this is appropriate. The appointment of lay members may need wider consultation than the appointment of pro- fessional members. Ethics Committees have no direct sanctions, but in the event of their discovering that their advice is unheeded or 256 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 that clinical investigations are being conducted without reference to them, then they should report the facts to the body that set them up, e.g. an NHS district or hospital authority or a university board. Plainly, an investigator who bypasses or ignores the recommendations of a prop- erly authorised Ethics Committee creates a potentially serious situation. Declaration of interest by Committtee members. Just as applicants should declare an interest, so members of an Ethics Committee should declare their interests, e.g. where an application relates to testing a product of a company to which the member is an adviser. The complete Report can be obtained from the Royal College of Physicians. BIBLIOGRAPHY 1. Association of the British Pharmaceutical Industry The report of the committee to investigate medical experi- ments on staff volunteers (1970) (the Stuart-Harris Report). Updated as: Guidelines for medical experiments on non-patient volunteers (1984). 2. Association of the British Pharmaceutical Industry (1985) Guidelines on data needed to support the adminis- tration of new chemical entities to non-patient volunteers. 3. British Medical Association (1984) The Handbook of Medical Ethics. British Medical Association. 4. British Paediatric Association (1980) Guidelines to aid ethical committees considering research involving children. Archives of Diseases in Children, 55, 75-77. 5. British Psychological Society (1983) Guidelines for the professional practice of clinical psychology Issued by the British Psychological Society. 6. Ciba Foundation Study Group (1980) Medical Re- search: Civil liability and compensation for personal injury. The Ciba Foundation. 7. DHSS Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (1982) Guidelines for the testing of chemicals for toxicity, Appen- dix 10: Human Studies. Report on Health and Social Subjects 27. HMSO. 8. Faculty of Occupational Medicine (1982) Guidance on ethics for occupational physicians. 2nd edition, Royal College of Physicians. 9. Family Law Reform Act 1969. 10. General Medical Council (1985) Professional conduct and discipline: fitness to practice. General Medical Council. 11. Gillick v. West Norfolk and Wisbech Area Health Authority and the Department of Health and Social Security. House of Lords, 1985. 1985 3 All ER 402. 12. Medical Research Council Responsibility in investi- gations on human subjects. Report of Medical Research Council 1962-63 (Cmnd 2382). 13. Medicines Act 1968. 14. Medicines (Exemption from Licences) (Special Cases and Miscellaneous Provisions) Order 1972. 15. Medicines (Exemption from Licences) (Clinical Trials) Order 1981. 16. World Health Organisation (1982) Proposed inter- national guidelines for biochemical research involving human subjects: Geneva CIOMS. (The Declaration of Helsinki, 1964, revised by the World Medical Associ- ation, Venice 1983). 17. Report of the Royal Commission on Civil Liability and Compensation for Personal Injury (Cmnd 7054). The Pearson Report 1978. 18. Royal College of Physicians (1984) Guidelines on the practice of ethics committees in medical research. Royal College of Physicians. 19. Royal College of Physicians (1986) Relationship be- tween physicians and the pharmaceutical industry. Jour- nal of the Royal College of Physicians, 20, 235. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 257

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Antiviral Strategies and Vaccines against HTLV III/LAV A. G. DALGLEISH, BSc, MB, MRCF| FRACR Consultant Medical Oncologist, Clinical Research Centre, Northwick Park Hospital, Harrow The Virus, its Origins and Nomenclature The causative agent of the acquired immune deficiency syndrome (AIDS) and related conditions was reported in September 1983 by Barre Sinoussi et al. [1] working in Montaignier's Laboratory (Pasteur Institute). At that time there was no evidence that this virus had any causal role in AIDS or related conditions. It was Robert Gallo and his colleagues[2] at the National Cancer Institute (NCI) Washington who first reported (May 1984) the successful isolation and production in a permanent cell line of a new retrovirus which induced specific serum antibodies in the majority of AIDS and AIDS at risk persons[3]. The causal nature of this new retrovirus was quickly confirmed by workers in London, who also confirmed that the French and American isolates were serologically identical[4]. The first French isolates were known as LAV (lympha- denopathy virus) or IDAV (immunodeficiency associated virus). Workers in Gallo's laboratory had previously isolated the first human retrovirus now shown to be the causal agent of the adult T cell leukaemia lymphoma syndrome (ATLL) and this was already known as the human T cell leukaemia?lymphoma virus?I (HTLV- I)[5]. A second similar yet different isolate called HTLV- II has yet to be associated with any specific disease[6]. The French group recognised that 'LAV' and 'IDAV' were new human retroviruses and that they had a procliv- ity for T4 + T lymphocytes. They therefore referred to them as human T cell lymphotrophic viruses. It was not surprising that Gallo referred to his new isolates as HTLV-III, the 'L' standing for lymphotrophic as op- posed to leukaemia or lymphoma. Further isolates report- ed from San Francisco added to the confusion as they were called AIDS retroviruses (ARV)[7], The confusion has recently been compounded with an international committee declaring the viruses as 'human immunodefi- ciency viruses' (HIV)[8], This decision is not unanimous, but in this article I refer to the viruses as HIV if for no other reason than it is shorter than HTLV III/LAV. The isolation and establishment of a permanent cell line was not an easy feat, as the virus is cytopathic for most host cells. Permanent T4 + leukaemic T cell lines were eventually used to isolate and produce large quanti- ties of the virus which could then be used as antigen for widespread serological screening. The major 'hold up' in establishing the French isolate as a causal agent was the inability to establish it in a permanent cell line. It was initially isolated in a low producing B cell line and it was not until workers in Prof. Weiss's laboratory in London established 'LAV' in the T4 + leukaemic line?CEM that the causative role could be investigated. The CEM/LAV line was sent back to Montaignier in March 1984[9], The availability of the virus in a permanent cell culture is a prerequisite for investigating antiviral stratagems in vitro, although it is now possible to 'clone' virus isolates from primary culture without the establishment of a permanent cell line. The Retrovirus Life Cycle HIV is a retrovirus which means that it is an RNA virus capable of making double DNA copies of itself which may then intercalate into the hosts cell genome or remain within the cytoplasm. Replication is directed by the enzyme reverse transcriptase (RT) which uses the host's cell replicative mechanism for replication (Fig. 1). In order for a virus to enter a cell it must enter through an appropriate receptor. The presence or absence of this receptor will establish the host cell range. The virus must first bind to the appropriate receptor before gaining entry to the cell as part of the virus receptor complex. Most retroviruses enter by the endocytic pathway from whence the virus is 'delivered' to lysosomes which are able to 'uncoat' the virus, thus releasing the infectious core into the cell. Further replication depends on the RT enzyme and post-translational events include glycosylation of the envelope proteins. Antiviral stratagems may be aimed at any one of these steps, which may be grouped as follows for possible therapeutic manipulation: 1. Binding to the receptor; 2. Endocytic pathway; 3. Reverse transcriptase inhibitors; 4. Post translation modification. The Receptor Viruses use specific receptors which may only be present on a very limited number of cells, or they may use a receptor that is present on a broad range of cells some- times from many species. The host cell range is often established by performing plaque assays and/or infectiv- 258 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 Table 1. Therapeutic sites of intervention. 1. Plasma ? complement 2. Neutralising antibody 3. Anti receptor/binding, antibody ? idiotype 4. Drugs affecting the endocytic pathway NH4C1 Amantadine (Chloroquine) (Monensin) 5. Reverse transcriptase inhibitors HPA-23 Suramin Phosphonoformate AZT ? others 6. Cytotoxic T cells 7. Anti-sense RNA variants ity assays on various cells. As retroviruses do not readily lend themselves to plaque assay systems[10], alternative assays have been devised. The simplest is the syncytial induction assay (Fig. 2) which utilises the ability of viruses to fuse receptive cells so that giant or multi- nucleate cells are seen by light microscopy[l 1], Replica- tion within a cell can be assessed by measuring the reverse transcriptase levels. Cells may 'fuse' and form syncytia in the presence of various physical or chemical conditions other than a virus, and conversely not all cells infected with retroviruses necessarily form syncytia. In order to investigate further the viral membrane antigens and the host cell receptors the ability of viruses to combine randomly has been usurped in the form of the pseudotype assay (PT)[ 12,13]. Briefly, a virus which can readily be used in a quantifiable plaque assay (VSV) is grown through cells producing the retrovirus under investi- gation. Some of these viruses will form hybrids, being VSV cores with retroviral membrane antigens. Non- hybrid viruses can be 'neutralised' using anti-VSV monoclonal antibody. Such pseudotypes can. then be titrated onto various cells, and provided they have recep- tors for the retroviral antigens they will allow the hybrid virus to enter the cell, thus enabling the VSV core to undergo replication which can then be measured quanti- tatively by applying an overlay of cells suitable for a VSV plaque assay. Using these assays we were able to show that most HIV infectable cells were T4 + leukaemic cell lines[ 13], and that those that were not expressed the T4 antigen. Furthermore, using a range of monoclonal anti- bodies made against various leukocyte surface antigens (1) Virus (2) Virus bound to receptor (3) Virus/receptor in endosome (4) 'Released RNA' (5) Linear DNA (6) Circular DNA (7) Proviral (integrated DNA) (8) Other protein products (9) Virus budding from cell membrane Fig. 1. Retrovirus: replication and life cycle. Replication GAG POL ENV AWWVWMAAAV MWW AWWV /WWW GAG POL ENV ? ? \ Viral genome Linear DNA Closed circular DNA Proviral DNA Viral DNA Primary translation products Mature proteins Fig. 2. Photograph of syncytia or multi-nucleate giant cells formed by the viral fusion' of JM T4 + cells. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 obtained from Peter Beverely (ICRF) we were able to show that all anti-T4 (CD4) monoclonal antibodies were able to block both the SI and PT assays[13]. We con- cluded that the T4/CD4 antigen was an essential com- ponent of the HIV receptor. The possibility that T4 is the only receptor is exciting as this may lead to a therapeutic handle against viral replication. Unfortunately, studies on animal retroviruses have shown us that retroviruses may learn to use more than one receptor[10]. Our further studies showed that no other T cell antigen acts as a component of the receptor (Dalgleish et al., unpublished observations) and that not all epitopes of T4 block infection, i.e. OKT4 as well as some other antibodies to epitopes of T4 in the OKT range do not block infection (Sattentau et al., submitted). The definitive experiment to show that T4 is the HIV receptor would involve the transfection of the cDNA T4 clone into various cell lines that do not normally express the T4 antigen. The recent cloning of the cDNA of T4 by Maddon et al. [14] has allowed the construction of a wide range of cells expressing human T4 antigens. Results of these studies are in press[15] and show that human cells expressing T4+ antigen are infectable with HIV. Fur- thermore it has been shown that T4 and the gp 110-120 envelope antigen of HIV not only bind but also specifi- cally immunoprecipitate together[16]. What is important is that no cellular antigen other than T4 is brought down. These results are exciting in that they suggest that a specific binding site may be preserved among different isolates (they all appear to use the T4 antigen as a receptor) and that further studies may identify this site. As the sequence of both T4 and many HIV isolates are now known[14,17] it could be possible to synthesise a peptide and raise an antibody against this site. This would clearly be a very important therapeutic strategy, providing the virus did not learn to use an alternative receptor. Post-receptor: the Endocytic Pathway Following binding to the receptor the virus/receptor complex has to enter the cell if infection is to take place. In the case of many viruses this is achieved via the endocytic pathway[18] (Fig. 3). Fusion of the virus requires an acidic environment, without which the virus does not reach the lysosomes and get 'decoated'. Prelimi- nary data have shown that in keeping with other retrovir- uses, inhibitors of intracycloplasmic acidification such as ammonium chloride and amantadine, appear to reduce the infectability of HIV. The absence of a one viral- replication cycle assay makes those experiments techni- cally difficult and therefore difficult to interpret. We have yet to confirm that carboxylic ionophores such as chloro- quine and monensin (which inhibit endocytosis in some animal retrovirus systems) inhibit HIV infection (Dalg- leish and Marsh, unpublished observations). Further studies are in progress. In the meantime it may be worth considering amantadine, or similar compound, in a pilot therapeutic trial, as it is readily available. A combination of amantadine with another drug which acts at a different stage of replication, for example reverse transcriptase (RT) inhibitors, may be even better. Reverse Transcriptase Inhibitors Reverse transcriptase inhibitors may act at different sites in the enzymatic reaction, as enzyme-binding com- pounds, template-binding compounds, substrate or prod- uct analogues, divalent cation binding agents and miscellaneous compounds[19], A large number of com- pounds are known to be inhibitory against the RT of many animal retroviruses[20]. These include (1) suramin that binds directly to the enzyme and other diasylimida- zoline derivatives which bind to the template such as Evans blue and direct yellow 50, adenosine analogues such as Ara-A, ribavirin, antimoniotungstate, (HPA-23), pyrazofurin and 5-iodo-2'-deoxy cytidine, thiosemicarba- zone R (a cation binding agent) and phosphonoformic acid (PFA). Following the report that suramin was active against HTLV-III in vitro[21], we screened a number of suramin analogues which were found devoid of anti-HIV activity. We then tested PFA in vitro and found it to be an extremely active inhibitor of reverse transcriptase at doses of 100-200 /ig/ml which are readily attainable in vivo (Fig. 4) (Dalgleish et al., unpublished observations). The in Fig. 3. Endocytosis. 1. virus attached to receptor; 2. virus receptor complex crowd together ('cap') and undergo invagination; 3. Endosome, where virus undergoes fusion in an acidic environment and is transferred to a lysosome. 260 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 vitro findings that PFA inhibited HIV have since been confirmed by other workers[22,23], As PFA is licensed for use against cytomegalovirus (CMV) and appeared to improve the overall condition of some AIDS patients to whom it was given for CMV infection, we undertook a pilot study of PFA in patients with AIDS and AIDS related conditions, the results of which will be published shortly (Farthing et al.). In vivo studies with suramin[24], HPA-23 [25] and AZT[26] have now been reported. HPA-23 (antimonio- tungstate) has been given to three patients with AIDS and one with prodromal symptoms. Although considerable clinical improvement was reported after a short follow-up period, the ability to isolate the virus was reduced during therapy but returned following cessation. A large trial is at present in progress, although considerable toxicity (to marrow) and the inability to cross the blood/brain barrier will limit its further usefulness. Similarly, suramin has been used on 10 patients with AIDS and ARC. Toxicity is also a major limitation, although there is some evidence that this drug is much better tolerated in African patients, and, again, it is not able to cross the gut or blood/brain barrier. Viral isolation studies concur with those for HPA-23. More recently, a new drug known as azido deoxythymidine (AZT)[26] an analogue of thymidine (Fig. 5) has been used in vivo. The advantages of a high therapeutic index, oral administration and easy access across the blood/brain barrier make this an attractive therapeutic candidate for long-term administration. A multi-centre pilot study[26] reports significant improve- ment in clinical parameters, T4 positive lymphocyte counts and delayed-type hypersensitivity skin reactions, as well as a failure to isolate virus from patients given a high dose of parenteral and oral AZT for six weeks. The reported short term toxicity was limited to headaches and leukopenia. Only 19 patients were investigated in this study which needs to be extended to more patients with longer treatment and follow-up periods. Other Drugs What is exciting about the results seen with AZT is that similar substitutions in either purines (adenosine, guano- sine inosine) or pyrimidines (cytidine, thymidine) could also prevent RT transcription. Therefore a wide variety of possible compounds may lead to an ideal in vivo, anti- HIV formulation. Other drugs have been reported to have potential anti- HIV activity. Ribavirin, an analogue of guanosine, is able to inhibit HIV replication in vitro[27] but is unable to protect against cytopathic effects in vitro and appears to have no obvious clinical benefit[28], Dithiocarb (sodium diethyldithiocarbamate) and ino- sine pranobex (Isoprinosine) also inhibit HIV expression in infected cells[29]. Both drugs are said to increase the number of T4 lymphocytes and are used as 'immunomo- dulators'. The antiviral effect is weak and is thought to occur at the stage of virus transduction through the membrane and/or DNA integration in the nucleus. A novel lipid compound AL 721 has also been claimed to inhibit HIV replication in vivo by altering the cell mem- brane cholesterol content[30]. Other parts of the cell cycle may also be susceptible to interference such as post translation modification e.g. proteolytic cleavage, glycosylation, acylation and phos- phorylation (Fig. 1). I am unaware of any clinical studies of drugs known to affect this end of the pathway. Tunicamycin is known to interfere with glycosylation and is at present being studied in vitro. Time (days) Fig. 4. The effect of varying doses of PFA on an in vitro infectivity assay using high virus producing cells (H93) and very susceptible T4 + cells (JM). These results show that PFA at a dose of 100 fim/litre and above inhibit viral replication. 3' azido 3' deoxythymidine Thymidine analogue HN CH3 hoch2 Competitive inhibition with thymidine at 1-10/xM in vitro. These doses do not cause significant immunological depression or toxicity. Fig. 5. The structure of AZT showing the similarity with thymidine with only N3 replacing OH at the 3' position. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 261 What Determines Infectability? A number of studies are presently looking at sero- negative partners of HIV-positive patients. What is sur- prising is that some patients have had continual exposure for several years with infected persons and yet remain sero-negative (IVD Weller et al., unpublished observa- tions). Nearly all of these patients including sero-negative haemophiliacs who have had large doses of known infect- ed blood products, have no evidence of virus detectable by virus isolation and molecular hybridisation techniques (E. Miller et al., unpublished observations). It therefore seems likely that some patients are able to 'deal' with the virus before it gets a chance to enter the replication cycle. Human sera have been shown to activate the compliment pathway against most animal retroviruses[31]. The hu- man T cell leukaemic-lymphoma virus (HTLV-I) is not susceptible to destruction by complement[31] and neither is HIV (Clapham et al., unpublished observations). It would appear that HTLV-I and HIV may be infectious because they are not lysed by the plasma. Clearly it would be interesting to see if there is any difference in susceptibility to complement between sero- positive and sero-negative persons. Neutralising Antibodies (or lack of) Following infection and replication antibodies are raised against both core and envelope antigens (Fig. 6). In many virus systems these antibodies are capable of neutralising the virus. Whereas patients infected with HTLV-I have high titres of neutralising antibody[12], patients infected with HIV have low or absent neutralising antibodies (NAB), although they may have high titres of non- neutralising antibodies[12,32]. The small variation in the low titre of neutralising antibodies does not correlate with clinical status and is therefore unlikely to have any protective function. Why then is there no significant neutralisation present in HIV infected patients? A num- ber of possibilities exist. The neutralising epitope may be masked by other epitopes or may be altered by base pair antibodies against other more prominent epitopes. The secondary and tertiary structures of antigens may be altered by base pair changes, far removed linearly from the binding site regions in other virus systems such as polio virus[33] where neutralisation may be changed by a single base pair change up to 300 base pairs away from the binding site. Similarly, the three dimensional struc- ture of virus antigens may contain many epitopic sites as well as binding sites[34] (e.g. influenza virus, see Fig. 7). Antibodies may therefore detect some epitopes but not others which may be masked by being recessed, or masked by antibodies attached to more immunogenic epitopes (or even that several NABs may be required). Fig. 6. Immunoprecipitation of HTLV III antigens. a b gp 110 p 55 gp 41 p 24 p 19 ? Envelope proteins With a = infected serum b = normal serum Fig. 7. Hypothetical illustration showing how an antibody may be raised against a binding site and not neutralising epitopes and vice versa, (based on the haemagglutinin antigen of the influenza virus). 262 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 There is a recent report of a new mechanism for the neutralisation of enveloped viruses by anti-viral antibody, whereby binding of a flavi-virus to its receptor does not preclude neutralisation at the endosomal acid catalysed fusion step[35]. Clearly, any of these factors could be present in the case of HIV. Another possibility is that of antigen misrepresentation by the antigen presenting cell. HIV is now known to infect monocytes and macrophages (M-M) many of which bear the CD4 antigen [13, Cla- pham et al., unpublished observations]. Other viruses that are able to reside at low levels in M-M also appear to incite low levels of NAB, i.e. Visna Maedi (VM)[36] and lactate dehydrogenase virus (LDV)[37], It could be that M-M is able to alter antigen presentation of various membrane epitopes or that M-M represent an immunolo- i gical privileged site for these viruses. It is interesting to note that these other viruses (VM, LDV) are able to inflict severe neurological damage (such as demyelina- tion) on their hosts. Moreover, brain disease now ac- counts for the major morbidity of HIV infected persons, ranging from minor neurological dysfunction to severe pre-senile dementia[38-40]. The reasons for this are not clear although in the case of HIV infection many poten- tially susceptible T4 positive mononuclear cells are present in the brain and some nervous system primary cells also express CD4. A useful therapeutic strategy would be to induce NAB by infecting mice or similar animals. This has now been done by many groups and although monoclonal ABs to both core and envelope proteins have been prepared, I am not aware of any which have significant neutralising ability. Attempts to change the antigen presentation using ISCOM techniques have increased the number of MCABs raised against the envelope proteins but, again, none have been reported as eliciting neutralisation. Clearly, other antigen presentation modification tech- niques should be entertained. Anti-idiotypes Knowing that the T4 antigen is the virus receptor suggests the possibility of raising an anti-virus antibody by making an anti-idiotype. As the virus binds to T4, the T4 could be used to make an anti-T4 AB (by immunising mice); then repeating the technique using the anti-T4 AB should lead to the production of anti-anti-T4 which could conceivably be active against the virus (Fig. 8). This is theoretically an attractive way of raising what would effectively be a neutralising antibody. However, I am unaware of any successful NABs raised with this tech- nique. Recently, Waldmann and his colleagues[41] have reported that anti-mouse T4 given to mice acts as a tolerogenic umbrella for the immune system. In other words mice become tolerant to antigens given under the cover of anti-mouse T4 antibodies. This has some attrac- tive speculative appeal for HIV. Idiotypes against HIV will include anti-T4 ABs, could they therefore allow the neutralising epitope to be seen as self? Speculation aside, the use of anti-idiotypes as surrogate antigens has already been shown to have a role in vaccination against hepatitis B virus[42] and schistosomiasis[43]. The T Cell Response The immune system's other arm of defence after B cells and their antibodies is the T cell system. Unfortunately the T cell system in HIV infection is severely disturbed. T4 + cells are destroyed and even those not known to be infected have impaired function[44], Many retroviruses have a conserved transmembrane protein called P15E[45] which is known to be immunosuppressive in some T cell response assays. Other soluble sustances may be pro- duced by infected cells which interfere with T cell func- tion!^]. The clearance of many viruses is dependent on the activity of virus-specific cytotoxic T lymphocytes (CTL) restricted by Class II molecules of the major histocompatibility complex. Indeed, in some animal model systems, persistent infection occurs if there is an absence of, or decrease in the production of these cells[47]. It will be interesting to see if CTL cells are induced against HIV infected cells and whether or not the natural killer (NK) cells or lymphokine activated killer (LAK) cells have any role. Immunotherapy The T4 lymphocyte effectively acts as the conductor of the immunological orchestra[48], and hence there is probably no more effective way of vandalising the im- mune system than killing T4 positive cells, which is how HIV acts in vitro and in vivo. Therefore therapeutic stratagems designed to replace the body's flagging im- mune defences have been studied, and, although they may have an important role to play in the overall Virus Anti-ldiotype \> Neut. AB Idiotype Receptor Receptor Virus Fig. 8. Anti-idiotypes: Two different presentations of the same theme; antibody to the receptor will itself act as an antigen in its variable region raising an antibody which should also react with the virus. Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 263 treatment plan, it is unlikely that immune restoration alone will succeed while the virus is able to replicate unhindered. The numerous immunological abnormalities described in HIV infection are beyond the scope of this article [reviewed in 49]. Suffice it to mention however that the most severe defect appears to involve cellular immunity. Therapeutic stratagems have therefore focused on the following potential therapies: interferons, thymic replace- ment hormones, lymphokines and cytokines, bone mar- row transplantation, isoprinosine and cimetidine, intra- venous immunoglobulin therapy and plasmapheresis. Interferons are known to have a viral function and the availability of recombinant human interferon has enabled in vitro and in vivo studies in AIDS patients. There are two types of interferons: alpha, produced by leukocytes and fibroblasts and gamma, produced by lymphocytes and monocytes. Studies in vitro showed that alpha interferon suppresses the replication of HIV[50], In vivo studies have unfortunately been disappointing with the exception of patients with Kaposi's sarcoma (KS). As vinblastine also has considerable single agent activity against KS, several centres are now studying combined therapy using regimes containing alpha interferon and vinblastine. Clinical trials with gamma-interferon, which should be theoretically superior to alpha-interferon, were delayed due to the lack of sufficient material. Preliminary studies suggest that gamma-interferon may not be as useful as alpha in the treatment of KS. However numer- ous centres are intensively studying gamma-interferon in AIDS and will report in the near future. Thymic replacement therapies in patients with AIDS are unfortunately both anecdotal and uninspiring. Whereas it is easy to overlook the lack of reported clinical success, it should be noted that numerous different thymic peptides are now available and some, or a combi- nation of them, may be useful in some cases. A recent report that antibodies to thymosin also neutralise HIV demands further investigational]. Interleukin-2 (IL-2) is a lymphokine which has been shown to reconstitute deficient in vitro immune re- sponses]^]. Although IL-2 may improve some immune responses in vivo, no dramatic response has been reported from numerous clinical studies. Moreover, it has been argued that as IL-2 augments the number of T4 + cells it may in fact be adding fuel to the fire by adding further infectable cells. Indeed virus production may be 'hotted up' in vitro by adding fresh T4 + uninfected cells. Nevertheless IL-2 may yet have a role to play in combi- nation with other agents such as reverse transcriptase inhibitors. Marrow transplants and lymphocyte transfusions have been performed in a few cases and do not appear to help the immune status. Again one is adding fresh uninfected cells to an 'infected' in vivo culture. Isoprinosine and cimetidine are both able to improve cellular immunity in vivo with varying degrees of success. Encouraging results with these agents in melanoma, systemic lupus erythematosus and rheumatoid arthritis have led to controlled trials in patients with AIDS and related conditions, which have yet to be reported. Intravenous immunoglobulin therapy may have a role in the management of ill HIV infected patients. It is unlikely that sufficient neutralising antibody would be present to have a specific anti-HIV effect. Early trials in children are said to be encouraging. Anecdotal experience with plasmapheresis does not suggest that this will be a useful therapeutic modality in AIDS. Whereas there may be some cautious ground for optimism using some modality in combination, it should be noted that improvements in in vivo immune function and clinical status remain curiously uncoordinated in the majority of trials and reports reviewed. Vaccines Studies of the epidemiology of HIV infection suggest that the only certain barrier to further spread of the disease is a vaccine. Previous viral epidemics which have inflicted signifi- cant mortality and morbity, e.g. paralytic poliomyelitis and smallpox, have been successfully contained by mass vaccination. Hepatitis B virus (HBV), the causal agent of 'serum' hepatitis and responsible for the high incidence of chronic liver disease, and hepatocellular cancer (one of the most common cancers in some parts of Africa and Asia), has recently been the target of a successful vacci- nation programme using antibodies against the envelope antigen of (HBsAg)[53], The vaccine has been prepared directly from infected persons by cloning the envelope gene and, more recently, by preparing an anti-idiotypic antibody vaccine[42]. The Epstein Barr Virus (EBV) is causally linked with Burkitt's lymphoma in Africa and nasopharyngeal carci- noma in Asia. Recently a vaccine, prepared against the surface antigen (glycoprotein 340), has been shown to protect against EBV induced lymphomas in cottontop tamarins[54]. The only retrovirus for which a successful vaccine has yet been developed is the feline leukaemia virus (FeLV). This was also the first retrovirus to be identified as being exogenously transmitted in animals, when Prof. Jarrett and his colleagues reported the transmissable nature of lymphosarcoma in cats[55]. He was able to isolate a retrovirus (FeLV) and showed that infection may be accompanied by the development of a lymphosarcoma in some cats, or acquired immunodeficiency (manifested by wasting and death from opportunistic infections) in others, while some cats remained asymptomatic[56]. The development of a vaccine was far from straightforward. The first prototype, although inducing protective anti- bodies, did not protect against the development of malig- nant disease and indeed may have worsened the outcome[57]. However, the later use of an inactivated vaccine prepared from a high titre supernatant in such a way as to preserve the envelope glycoproteins, which was then combined with an adjuvant, protected against lab- oratory challenge and natural exposure[58]. This prep- aration is now commercially available. Although the successful development of this retrovirus vaccine is en- couraging, making a vaccine for AIDS is unlikely to be as 264 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 easy because protective neutralising antibodies are not known to be effectively induced in vivo[32] as they are in FeLV infected cats. HIV has now been cloned and many isolates have been extensively characterised[59]. It is clear that there is considerable variation in the genes coding for the enve- lope antigens, and any vaccine would have to depend on conserved regions. Such regions are being sought in numerous different isolates from different parts of the world. In the meantime the envelope gene has been subcloned and inserted into a vaccinia vector which readily induces envelope antibodies to the glycoproteins gp. 110, 120[60,61 ]. Unfortunately these antibodies are not as yet known to have any neutralising or protective function. No doubt trials using subunits of the same protein as well as different proteins alone or in combi- nation are now in progress. Another approach which could achieve the same end is the use of synthetic peptides manufactured from known base pair sequence information. Sequence peptides, how- ever, are not necessarily good antigens, as studies on the tobacco mosaic virus (TMV) have shown[62j. Peptides having the correct amino acid sequence do not necessarily have the correct conformation at the region of binding. In contrast to the relatively stable structure of a protein in solution, small peptides are thought to exist in a multi- plicity of transient conformational states in dynamic equilibrium. The conformation of the binding site may change to improve structural complementary with the peptide ligand. X-ray crystallography studies have re- vealed rotations and translations of aromatic side chains and expansion of the binding cavity by movement of various hypervariable loops[62]. Furthermore, the im- munogenicity of a peptide may be increased by coupling it with the purified protein derivative of tuberculin (PPD) in animals presensitised with BCG[63], Against this background the development of a pro- cedure for the rapid synthesis of a solid support of a large number of peptides by Geysin and colleagues[64] has exciting implications for developing peptides potentially useful in AIDS. Using this technique he has been able to develop a neutralising antibody to a putative discontinu- ous epitope of foot and mouth disease virus[65], Taking as a template a non-neutralising antigenic epitope (VPI), peptides of increasing length were synthesised and as- sayed for antibody binding after addition of each residue, some of which were /3-alamines to allow structural flexi- bility. Finally, a neutralising peptide was eventually obtained. Such a technique could be used against the binding site of HIV and the T4 molecule. Vaccine Evaluation Once a successful vaccine or peptide has been prepared it will be necessary to establish an evaluation programme that will document safety and efficacy whilst minimising the time needed for approval. A primate model has been developed using the chimpanzee which is susceptible to HIV infection [for review of vaccine development see 66], Chimpanzees have already been used successfully to test HIV vaccines[53], A cheaper primate that was infectable and had a shorter life cycle would be an advantage, and one may yet be discovered. Once satisfactory protection is shown in other primates human trials would then follow. Initially, trials will need to investigate immunogenicity safety and protection against infection; it will be necessary to decide whether or not volunteers from the AIDS 'at risk' group or others should be used. Larger scale pilot studies would follow and then mass vaccination?but for whom? Obviously those in 'at risk' groups will need to be given the vaccine but what about the general population? Increasing re- ports of heterosexual transmission in the West[67,68] and the epidemic nature of AIDS-like illnesses in Afri- ca[69,70] could suggest that all sexually active persons be included in the at risk groups. Genetic Approaches to Treatment Following the successful cloning and sequencing of sev- eral isolates much has been learnt about HIV (Fig. 9). Initially, it was thought to be very closely related to HTLV-I in that both are human retroviruses with T cell trophism for T4 + lymphocytes, and both have standard retrovirus genomic structure with genes encoding for core or structural proteins (GAG), reverse transcriptase (POL) and membrane proteins (ENV) without any known oncogenes but with the addition of a gene capable of transactivation (TAT gene) and regulating the rate of virus replications. Homologous sequences between HTLV-I and III for the GAG, POL, ENV and TAT genes have been reported[71]. It is now known that HIV is a considerably more complicated virus than HTLV-I. It has at least two extra genes[72,73] (Fig. 9). These are known as the short open reading (SOR) frame which may regulate the TAT gene and the open reading frame at the 3 prime end of the virus (3'ORF) which may be respon- sible for the cytopathogenicity of the virus. This structure is very similar to that of the Visna-Maedi virus in sheep and HTLV-III is now regarded as being more akin to the lenti viruses than to HTLV-I[72, 73], Recent studies have shown that the TAT gene, which lies between SOR and ENV, is able to mediate activation in a trans configuration of the genes linked to HIV long terminal repeat (LTR) sequences. Biological clones of HIV with the TAT gene deleted do not replicate until the TAT gene is restored or by introduction of the TAT III protein itself[ 74,75]. The gene which may encode the cytopathic potential for HIV (3'ORF) is under similar investigation. How then might these genetic Achilles' heels lead to further therapeutic strategies? The construction of clones encod- ing genes the wrong way round so that they make mirror image or anti-sense RNA has been reported in several systems[76-78]. A recombinant AIDS virus with the TAT gene reversed (or 3'ORF) is obviously an attractive theoretical proposition[79]. But could it be given in vivo? A coupled gene encoding responsiveness to a drug that could control replication in vivo would be a desirable addition (e.g. DHFR gene responsive to methotrex- ate)[80] which would be the minimum control needed to assuage fears of what recombinant AIDS-viruses might Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 265 inflict in vivo. Whereas this approach will be regarded as scientific fiction for some time, it should not obscure the tremendous amount of hard scientific fact that has been accumulated about this virus (viruses) which has allowed the development of a rational approach to therapeutic options summarised here. In spite of the many problems encountered in isolating and trying to understand HIV there are certainly grounds for optimism that we will eventually be able to effectively treat if not to eliminate AIDS and its related conditions. It cannot be over-emphasised how much of what has been done in the way of combating the AIDS problem was only possible because of the strong base of scientific research covering many disciplines such as animal retro- virology, immunology, cell and molecular biology, which were able to be rapidly recruited to identify the causal agent and subsequently attack this disease. Although there is no present cure, it should be remembered that the rate of progress in AIDS research has no historical equal. Addendum Since this paper was prepared, one or possibly two new HIV like viruses have been announced. Montaignier and colleagues report a virus from West African AIDS patients which they call LAV-2, whilst Essex and col- leagues report a virus from healthy Senegalese prostitutes which they call HTLV-4 and which is claimed to be apathogenic. Both these viruses have considerable differ- ences to known strains of HIV and may be more similar to the T lymphotropic viruses. Acknowledgements I would like to thank Professor Robin Weiss, in whose laboratory some of the quoted work was performed, and also Paul Clapham, Mark Marsh, Quentin Sattentau and Peter Beverley with whom we worked on these projects. This article is based on a paper read at the Conference on AIDS held at the Royal College of Physicians in May 1986. References 1. Barre Sinoussi, F., Chermann, T. C., Fey, F. et al. (1983) Science, 220, 868. 2. Gallo, R. C., Salahuddin, G. Z., Popovic, M. et al. (1984) Science, 224, 500. 3. Sarngadharan, M., Popovic, M., Bruch, L., Schupback, J. and Gallo, R. C. (1984) Science, 224, 506. 4. Chiengsong-Popov, R., Weiss, R. A., Dalgleish, A. G. et al. (1984) Lancet, ii, 477. 5. Poeisz, B. J., Ruscetti, F. W., Gazdar, A. F. etal. (1980) Proceedings of the National Academy of Science USA, 77, 7415. 6. Kalyanaraman, U. S., Sarngadharan, M. G., Robert Guroff, M. et al. (1982) Science, 218, 571. 7. Levy, T. A., Hoffmann, A. D., Kramen, S. M., etal. (1984) Science, 225, 840. 8. Coffin, J. C., Haase, A., Levy, J. A. etal. (1986) Nature, 321, 10. 9. Norman, C. (1985) Science, 230, 518. 10. Weiss, R.A., Teich, N., Varmus, H. and Coffin, J. (eds) (1985) RNA Tumour Viruses. New York; Cold Spring Harbor Laboratory. 11. Nagy, K., Clapham, P., Chiengsong-Popov, R. and Weiss, R. A. (1983) International Journal of Cancer, 32, 321. 12. Clapham, P., Nagy, K. and Weiss, R. A. (1984) Proceedings of the National Academy of Science USA 81, 3083. 13. Dalgleish, A. G., Beverley, P. C. L., Clapham, P. et al. (1984) Nature, 312, 763. 14. Maddon, P. J., Littman, D. R., Godfrey, M. etal. (1985) Cell, 42, 93-104. 15. Maddon, P. J., Dalgleish, A. G., Clapham, P. etal. (1986) Cell, (in press). 16. McDougall, J. S., Kennedy, M. S., Sligh, J. M. et al. (1986) Science, 231, 382. 17. Hahn, B., Shaw, G. M., Arya, A. K. etal. (1984) Nature, 312, 166 18. March, M. (1984) Biochemical Journal, 218, 1. 19. Oberg, B. (1983) Pharmacology and Therapeutics, 19, 387. 20. Balzarini, J., Mitsuya, H., De Clerq, E. and Broder, S. (1986) International Journal of Cancer, 37, 451. 21. Mitsuya, H., Popovic, M., Yarchoan, R. etal. (1984) Science, 226, 172. 22. Sandstrom, E. G., Byington, R. E., Kaplan, J. C. and Hirsh, M. S. (1985) Lancet, ii, 1480. HTLV 1,11,111 Genomic structure HTLV I,II LTR GAG POL ENV X-LOR LTR p 15,24,12 9P 45 9P 21 HTLV LTR GAG p 17,24,15 LTR = long terminal repeat POL TAT SOR LTR ENV p 23 3'ORF gp 120 gp 41 Fig. 9. The genetic structure of HTL V-I and HTL V-III (HIV) showing the extra genes (SOR, TA T, ORF 3') of HIV which make the virus more closely related to the lenti viruses. The X or LOR of HTLV-I also has a transcriptional activational (TAT) function. 266 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 23. Sarin, P. S., Taquchi, Y., Sun, D. et al. (1985) Biochemical Pharmacology, 34, 4075. 24. Broder, S., Yarchoan, R., Collins, J. M. et al. (1985) Lancet, ii, 627. 25. Rozenbaum, W., Dormont, D., Spire, B. et al. (1985) Lancet, i, 450. 26. Yarchoan, R., Klecker, R. W., Weinhold, K.J. et al. (1986) Lancet, i, 575. 27. McCormick, J. B., Setchell, J. P., Mitchell, S. W. and Hicks, D. (1984) Lancet, ii, 1367. 28. Blanche, S., Fischer, A., LeDeist, F. et al. (1986) Lancet, i, 863. 29. Pompidou, A., Zagury, D., Gallo, R. C. et al. (1985) Lancet, ii, 1423. 30. Sarin, P. S., Gallo, R. C., Scheer, D. I., Crews, F. and Lippa, A. S. 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(1986) Nature, 320, 449. 42. Kennedy, R. C., Gidberg, J. W., Lanford, R. E. and Dreesman, (1986) Science, 232, 220. 43. Grzych, J. M., Capron, M., Lambert, P. H. et al. (1985) Nature, 316, 74. 44. Murray, H., Rubin, B. Y., Masur, H. and Roberts, R. (1984) New England Journal of Medicine, 310, 883. 45. Cianciolo, G., Copeland, T. D., Oroszlan, S. and Synderman, R. (1985) Science, 229, 453. 46. Ruddle, N. (1986) Immunology Today, 7, 8. 47. Flyer, D. C., Burakoff, S.J. and Faller, D. V. (1983) Nature, 305, 815. 48. Dalgleish, A. G. (1986) Immunology Today, 7, 142. 49. Gottlieb, M., Wolfe, P. R. and Mitsuyasu. (1985) In Advances in Host Defense Mechanisms Vol. 5. (edsj. Gallin and A. S. Fauci, New York: Raven Press. 50. Ho, D. D., Hartshornk, L., Rota, J. R. et al. (1985) Lancet, i, 662. 51. Sarin, P., Sun, D. K., Thornton, A. H., Naylor, P. H. and Goldstein, A. L. (1985) Virology, 232, 1135. 52. Lifson, J. D., Benike, C. J., Mark, D. F. and Koths Engleman, E. G. 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(1984) Proceedings of the National Academy of Science USA, 81, 3998. 65. Geysin, H. M., Barteling, S. J. and Meleon, R. H. (1985) Proceedings of the National Academy of Science USA, 82, 178. 66. Frances, D. P. and Petricciani, J. C. (1985) New England Journal of Medicine, 313, 1586. 67. Redfield, R., Markham, P. D., Salahuddin, S. Z. et al. (1985) Journal of the American Medical Association, 254, 2094. 68. Mortality and Morbidity Weekly Report (1985) 34, 37. 69. Serwadda, D., Mugerwa, R. D., Sewankaribo, N. K. et al. (1985) Lancet, ii, 849. 70. Biggar, R. J. (1986) Lancet, i, 79. 71. Arya, S. K., Gallo, R. C., Hahn, B. H. et al. (1984) Science, 225, 927. 72. Wong-Staal, F. and Gallo, R. C. (1985) Nature, 317, 395. 73. Sonigo, P., Alizon, M., Staskus, K. et al. (1985) Cell, 42, 369. 74. Fisher, A. G., Fernberg, M. B., Josephs, S. F. et al. (1986) Nature, 320, 367. 75. Sodroski,J., Goh, W. C., Rosen, C. et al. (1986) Nature, 321, 412. 76. Izant, J. G. and Weintraub, H. 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Confidentiality and the Use of Medical Records for Research Medical records obey gravitational laws. They accumu- late in heaps and in retrieval systems; they draw upon themselves an overlay of legislation and controls. Hippoc- rates was the first in this field, setting out the confidential basis of medical practice. A recent contender, the Data Protection Act, exhibits only a tangential concern for medicine, responding to quite different social pressures. Hippocrates could scarcely have imagined the modern shortening of communications, or the problems that this would create. In particular, he said nothing on the conflict between the needs for confidentiality and the communication of data for research. May records be used at all for research? May they be released to other doctors; or to non-doctors? Who de- cides? Are they to be available only for medical research, or for non-medical research as well? For health-economic, health-management and health-finance research? Is the consent of the patient always required; must he be informed in advance that his records might be used for research? What is the position when the patient is dead or unavailable or incapable of giving consent? Is a refusal to release information for research and for the health-benefit of mankind as culpable as an agreement to release it, thus infringing the individual's right to privacy? These problems are especially serious for epidemiolog- ical research which requires large-scale access to records. This access is precariously vulnerable to legal and bur- eaucratic measures designed in good faith to supply access to the subject or to protect confidentiality, but not necessarily guided by a technical knowledge of research needs, or a full appreciation of the dependence of im- proved health care upon enquiries of these kinds. The legal systems and processes of different countries generate threats of varying severity. The Hippocratic precept of secrecy is generally accepted, but different legal codes (Napeolonic: common law) and different pro- fessional traditions recognise and accommodate, with unequal success, the necessary exceptions to the rule. A group of research workers from several European coun- tries met under the sponsorship of the EEC to consider these issues, and their report, The Confidentiality of Medi- cal Recotds, is now available (Commission of the Euro- pean Communities, 1984. Report EUR 9471 EN). They tried first to identify global principles, applicable in any country; then to devise a general Code of Practice from which individual countries might derive specific codes for particular legal and regulatory contexts. Several points of general interest emerged. 1. Modern reformulations of the Hippocratic rule, such as the Declaration of Geneva, assert a joint concern for the good of man as an individual and for the corporate benefit of mankind. In a competitive world the two principles sometimes come into conflict. In this field, as in others, the difficult moral choice is not between good and evil, but between two principles of equal merit. 2. Appeals to larger principles (contractual agreements, property rights, and the right to privacy) do not solve the dilemma. The rules of personal contract demand secrecy, but the integrity of the society that sanctions and supports such contracts, demands the broader view. The treatment of medical records as 'property' invokes the same issue. The individual's right to 'privacy' also requires excep- tions in order to protect the society which confers the right. The Council of Europe demanded in 1950 that there be . . 'no interference by a public Authority with the exercise of this right . .' but added '. . except such as is necessary . . in the interests of national security, public safety or the economic well-being of the country, for the prevention of disorder or crime, for the protection of health or morals, or for the protection of the rights and freedom of others'. A chill draught on moral ardour! 3. The EEC group concluded that there were no formal solutions to the dilemma; neither a concern for the individual nor a concern for mankind may hold absolute sway over the other. Any strictly enforced legislation on confidentiality would almost always be harmful in other ways. For this reason they recommended instead a Code of Practice, a set of interpretable rules applicable to day- to-day decisions, but without the direct force of law. 4. Assertions of medical secrecy are often stated in absolute terms, but are followed by a list of open-ended exceptions devoid of subsequent regulatory control. The group questioned the moral force and the practical utility of such leaky absolutes. They preferred a positive state- ment of all legitimate uses (including research) to which medical records might be put, whether at first or second release; and restriction in these terms. This retreat from absolutes breached a taboo. The report did not actually declare that the principle of Hippocrates was false, but recognised that modern con- texts sometimes reveal its pragmatic defects. An open recognition of practical necessities will probably achieve more than will hard legal regulations, not only for research and for the benefit of society, but for the effective protection of confidentiality itself. E. G. Knox 234 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986

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Editorial Who was it who said that travel broadens the mind? Such a fatuous generalisation; it all depends on what you have in mind when you travel. The very ease of long distance travel has tended to make it a trivial pursuit. To our remote forebears every journey was arduous and needed a toughened body and a determined mind. Celia Fiennes was a lady of mettle to ride through 17th century England and produce her extraordinary personal journal. No wonder that Francis Bacon considered in 1595 that 'Travel in the younger is part of education; in the older a part of experience.' So what do we make of our present freedom to visit the world? The hordes of people now sweeping the skies do not apparently increase the amity of nations. A week of fish and chips on the Costa Brava transports the body and leaves the mind at home. Breaking the sound barrier is nothing compared to breaking the barriers of language and culture. We seldom stay long enough in another country to appreciate the problems involved. Today's doctors certainly do travel. In many specialties visiting the people concerned rather than just reading about their results has led to most fruitful international collaboration. Medical students also travel, usually to exotic places for there elective study. Judging from their enthusiastic and perceptive accounts their eyes have been opened to world medicine, a perspective not found in their somewhat self-regarding medical schools. It is good to think that the College aids ten students a year to extend their education in this way. The postgraduate is less fortunate in his travel aims which have to be geared to furthering his home career. So he learns techniques in established centres of excellent but does not broaden his mind to encompass world medical problems. Those that do go to the underde- veloped countries to help solve local problems give great service to the community of their choice but may well find that such experience is detrimental to their career. This reflects badly on their seniors who stand in judgement. It would also be naive to consider that the average international medical congress does anything to foster the concept of medicine as a global profession. It is very pleasant to get away and meet colleagues from New York or even Glasgow at a conference in Rio but it gives no insight into the medical problems of Brazil. The plethora of confer- ences has lead to the wicked whisper that some physicians are found more readily in airport lounges than in their departments. However the ease of international travel has brought the medical profession closer together in many areas of research and personal understanding. Hopefully it could support Sir Gordon Wolsten- holme's concept of world medical action for which he argued most persuasively in his FitzPatrick lecture (J. Roy. Coll. Phycns, 1985, p. 17). Most of the time we are busy defending our own corner and see what we want to see on our journeys. But travel can broaden the well- intentioned mind. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 157

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Book Review Genetic Biochemical Disorders by Philip F. Benson and Anthony H. Fensom. Oxford University Press, 1985. 692 pages. Price ?55. This is a straightforward, very concise compendium on inborn errors of metabolism by two authors who have supervised the Supraregional Laboratory for Genetic Enzyme Defects. I have found it a useful quick reference book, but its limitations should be pointed out. There is no significant overall discussion of the general concepts of inherited disorders and the ways in which the biochemical consequences may be harmful, nor of the interaction between genetic and environmental factors. Neither is it comprehensive. The reader looking for information on the renal tubular acidoses, familial periodic paralysis, pseudohypoparathyroidism, the haemoglobinopathies, diabetes mellitus and cystic fibrosis, to choose six of the conditions I used as test cases, will go away empty- handed. I tried to work out the rationale for what had been included and what had been left out, without much success. However, I obtained rapid and excellent infor- mation on variants of phenylketonuria and glutaric aci- duria?two of the three relevant conditions which came my way in clinical practice during the time this review was gestating. Not surprisingly, it is quite strong on biochemistry, but it makes no serious attempt to deal with the 'new genetics', i.e. knowledge obtained from recom- binant DNA techniques. It is exceedingly well referenced for the conditions it deals with?over 25 per cent of the text is occupied by the references. This book is of value as a lead into many rare conditions which the potential readership of paediatricians, neurologists, geneticists, obstetricians, pathologists, medical biochemists and dieti- cians listed in the preface will occasionally encounter. It makes no attempt to give the very detailed consideration of these disorders to be found in Stanbury et al. (The Metabolic Basis of Inherited Disease) in either the back- ground, diagnosis or treatment areas. However, the reader should be able from the reference list to get on to the right sources rapidly if further details are required. R. D. Cohen 218 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986

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Physical Disability in 1986 and Beyond A REPORT OF THE ROYAL COLLEGE OF PHYSICIANS CONTENTS Page INTRODUCTION 161 BACKGROUND What is Wrong? 162 The Size of the Problem 162 The Principles of Medical Involvement 164 FUTURE EVOLUTION OF DISABILITY SERVICES The Need for Standards of Care and Audit 165 Basic Criteria for a Disability Service 165 Regional Units 166 District Services 166 Research and Development 168 Organisation and Administration 169 District Advisory Machinery 170 Medical Staffing 170 Education of Medical Students and Postgraduates 171 Timetable 171 Audit Function 172 Costs and Resources 172 GENERIC SERVICES Disabled Living Centres 173 Housing, Housing Modifications and Re-Housing 174 The Physically Disabled School Leaver 174 Support Services for Younger Severely Disabled and Handicapped People 175 Driving for the Disabled 176 Sexual Counselling 176 Head Injury Services 177 Visual Impairment 178 Hearing Impairment 179 Communications Aids 179 Wheelchairs 181 Prosthetics and Orthotics 182 Page Urinary Continence Services 183 Stoma Care Services 184 Pressure Sores 185 APPENDICES 1. Definitions used throughout the Report 186 2. Prevalence of Physical Disability 186 3. Evaluation of the Services provided by Mary Marlborough Lodge 186 4. Assessment and Training Facilities for Re-Learning Driving Skills " 187 5. Communication Aids Centres 188 6. List of Demonstration Centres 188 7. Associations for the Disabled 190 SUMMARY 191 REFERENCES 193 Membership of the College Committee on Disability Sir Raymond Hoffenberg, KBE, MD (President) C. B. Wynn Parry, MBE, DM, FRCP (Chairman) R. Langton Hewer, FRCP (Honorary Secretary) A. O. Frank, MRCP (UK) (Assistant Honorary Secretary) C. J. Earl, MD, FRCP J. F. Harrison, FRCP K. S. Holt, MD, FRCP D. J. Lane, DM, FRCP D. L. McLellan, FRCP J. R. A. Mitchell, MD, FRCP M. D. Warren, MD, FRCP, FFCM V. Wright, MD, FRCP TTA. K. Clarke, MRCP (UK) TJ. R. Hodges, MRCP (UK) **P. A. Gardner, FFCM *D. J. Price, FRCGP D. A. Pyke, CBE, MD, FRCP (Registrar) D. G. Williams, MD, FRCP (Assistant Registrar) G. M- G. Tibbs, Hon FRCP (College Secretary) Miss H. K. Irons (Committee Secretary) * representative of the Royal College of General Practitioners ** in consultation with the Faculty of Community Medicine t nominated by the Standing Committee of Members 160 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 INTRODUCTION The past twenty years have seen major changes in the pattern of diseases in the Western World. Acute poliomy- elitis has disappeared, tuberculosis is uncommon, peptic ulcers rarely require surgery, bacterial infections can usually be controlled, and the outlook for acute leukaemia and Hodgkin's disease is much improved. By contrast, many disabling diseases such as rheuma- toid arthritis, stroke, multiple sclerosis, Parkinson's dis- ease and motor neurone disease, remain incurable. Some of these patients endure much suffering and require substantial help from the various support services. Dissat- isfaction with Disability Services in England and Wales has been expressed both by disabled people and by health workers. The present Report is written against this background. The Royal College of Physicians' Rehabilitation Com- mittee was established in 1979. It was renamed the Disability Committee in 1983, thus emphasising that the problem concerns not only those patients who are likely to improve (e.g. after head injury or stroke) but also those whose condition may deteriorate (e.g. rheumatoid arthri- tis and multiple sclerosis). The Committee felt that it should produce a document setting out its views as to the way in which Disability Services in England and Wales might be developed. In approaching its task, the Committee felt that it could not review all aspects of the problem, and that it would be appropriate to concentrate on the medical aspects of physical disability (defined in Appendix 1). The Report considers mainly (but not exclusively) those aspects of disability that are a responsibility of the NHS as opposed to, for instance, Social Services. It concentrates on dis- ability resulting from disorders which are encountered by physicians and does not deal in detail with disability resulting from, for example, surgical, orthopaedic, or psychiatric disorders. The Report analyses particularly the future role of doctors in the establishment and operation of Medical Disability Services. The Committee recognises that there is much overlap with other pro- fessional groups, especially remedial, nursing, #nd social work, as well as with other statutory services including Social Services, Housing, Education and Employment. We also recognise the important contribution of volun- tary societies and of disabled people themselves. We consider that the medical profession has an essen- tial leadership role in the development of Medical Dis- ability Services. This role includes the catalysis of local initiatives and the setting up of services for particular groups of disabled people. We consider it important that the medical profession is seen to have a major commit- ment to the subject of medical disability. Although the Report concentrates on the physical aspects of disability, the Committee is keenly aware of the enormous psychological stresses that are often exper- ienced by disabled people and their families. The ideas put forward in this Report concern certain parts of a large and complex subject. They are not meant to be exclusive, and should be considered within the total context of professional endeavour in this field. It is hoped that the Report will form the basis for constructive discussion and will assist Regional and District Health Authorities to review, organise and evaluate Medical Disability Ser- vices. The Report is divided into four sections. The first, entitled 'Background', deals with the evidence that there are serious shortcomings in the organisation of Disability Services and also discusses epidemiology and terminol- ogy. The second, entitled 'Future Evolution of Disability Services' outlines our recommendations for Regional and District Services and discusses medical manpower and administration. The third section deals with 15 specific areas of disability (e.g. Continence Services, Pressure Sores and Wheelchairs), which require particular atten- tion by District and Regional Health Authorities. The last section includes a summary of the Report's main recommendations and lists some basic audit standards. BACKGROUND What is Wrong? For many years there has been professional and public concern about the care given to disabled people. The response to the recommendations of a number of official and other reports[l-6] has been inadequate and unsus- tained[7,8], A survey carried out throughout Great Brit- ain in 1971 showed that many disabled people who could be helped by advice, equipment, adaptations and services were not getting such help[9]. The Chronically Sick and Disabled Persons Act, 1970, placed an obligation on Local Authorities to inform themselves of the number of disabled people and their needs, and to take steps to meet these needs. Following the activities of the International Year of Disabled People (1981) there has been increased understanding of the needs and feelings of disabled people, who share the same desires, aspirations and rights as other citizens. In addition to the national survey mentioned above[9], there have been many community-based surveys[10] and in-depth studies and personal accounts published of the experiences of disabled peoplefl 1,12]. These have in- cluded accounts of people disabled by rheumatoid arthri- tis[ 13], multiple sclerosis[14-16], paraplegia[17,18], strokesf 19-21], , Parkinsonism[22], spina bifida[23,24], motor neurone disease[25-27], amputations[28,29], can- cer[30-32], myocardial infarction[33,34], ileostomy and colostomy[35,36] and incontinence[37]. Certain themes recur throughout the reports and per- sonal accounts. There are major problems concerning housing, employment, and the various financial allowances. There is unevenness of provision between different Regions and Districts. This was highlighted by Lady Hamilton in her 1984 Harding Award Address. She pointed out that there are, for instance, major Regional differences in medical staffing in rheumatology and neu- rology. The best staffed Region has six times as many rheumatologists per head of population as the worst staffed Region. These reports record a widespread lack of co-ordination between services which results in frag- mented help and advice, omissions or duplications of services, delays in obtaining help, and discontinuity of help, as the disabled person is referred from one service to another. Patients with chronic disorders attending for 'follow-up' complain that they are seen by inexperienced junior doctors who are not familiar with the particular problems experienced by the patient. A frequent com- plaint is the inadequate information given to the disabled person about the nature and expected course of the underlying condition; about the treatment and the plan of management of the ensuing disabilities, and about the opportunities, services and help that are available. Given sufficient information, a disabled person can choose certain courses of action and thus retain autonomy. Many disabled people are concerned about the additional work and restrictions imposed on the spouses, relatives and friends looking after them at home. The carers often give up their jobs, children's contacts and activities become restricted, social and leisure activities are reduced, extra costs are incurred, and disturbance at night leads to physical and mental fatigue. The picture is not entirely black, and there have been important initiatives. These include the activities of vol- untary organisations of all sizes, ranging from the large national charities to small local groups who together offer a considerable range of facilities. Various community- based resources, including the Home Help, Direct Meals, and Community Nursing Services, make it easier for severely disabled people to live in their own homes. The Local Authorities finance adaptations to existing dwell- ings, and specialised housing has been developed in some areas. Several agencies provide residential care for se- verely disabled younger people. Disabled Living Centres have been established in some areas of the country? where expert advice is available regarding personal cloth- ing and equipment for disabled people. Some Districts operate a Continence and/or a Stoma Care Service. These various services are provided by a variety of agencies, including Health, Local Authority, the private sector, and voluntary services. The result is a patchy distribution of services, with some areas being very badly served. It is clear that Health Authorities can make major contributions to improving the quality of life for disabled people. The aim is to enable people with disability to have access to the various medical services they need, so that there is the minimum disruption of their lives and preferred activities. This will involve reviewing local services, identifying and remedying deficiencies, estab- lishing collaboration with resources outside the Health Service, and educating disabled people in safeguarding their health and avoiding the medical complications of their condition. The Size of the Problem Estimates of the numbers of people with disability in the population will vary according to the criteria used in defining disability and its severity, and the intensity of case-finding. Broadly speaking, in England and Wales, approximately 10 per cent of the population are physical- ly disabled (excluding sensory and mental disorders); 20- 30 per cent of these (i.e. 2-3 per cent of the total population) will be severely or very severely disabled. The Health District with a population of 250,000 is therefore likely to contain about 25,000 disabled people, of whom approximately 6,250 will be severely or very severely disabled. About 10 per cent of all disabled persons are aged under 45 years; 30 per cent are between that age and 64 years, and 60 per cent are 65 years or older. Overall, more women are disabled than men, but at ages up to 65, the prevalence rates of disability are slightly higher in males than in females. Table 1 gives estimated numbers of people with various disabilities. Table 2 deals with selected diseases and types of impairment (for definitions, see Appendix 1). In an average Health District there will be about 1,810 people with a wheelchair, about 11,000 persons with regular 162 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 Table 1. Estimated numbers of disabled people and of those who are severely or very severely disabled or handicapped in various categories in a District with a population of 250,000 people reflecting the national age distribution. Category Estimated number in category Per 10,000 Per 250,000 Per cent population population severely or very e.g. typical group e.g. typical severely disabled practice Health District or handicapped Estimated number severely or very severely disabled or handicapped in District All physically 'disabled' people National Sample Survey [9] Local Authority. Surveys [10] Lambeth Survey [38] Impaired Hearing Min. 35 dB HL, at 0.5, 1, 2 & 4 kHz in better ear [39] Impaired Vision Less than 6/18 with Snellen with glasses [40] Regular Urinary Incontinence [41] (Persons aged 15 yrs or more) Use of Wheelchairs (See page 68) 670 adults 557 1,150 adults 1,000 adults 52 adults 440 72 16,750 adults 13,925 28,750 25,000 adults 1,300 adults 11,000 1,810 20 30 10 (66-95dB HL) 32 (6/60 or less) 3,350 adults 4,180 4,170 2,500 adults 408 adults Table 2. Estimated number of persons with major physical disabling conditions and of those who are severely or very severely disabled or handicapped thereby in a district with a population of 250,000 people reflecting the national age distribution. Estimated number of severely or very severely disabled or handicapped in District Based on Harris Survey[9]* Disabling condition Osteoarthritis Rheumatoid arthritis Ischaemic heart disease Other heart disease Respiratory conditions (excluding cancer of lung) Stroke (survivors) Parkinsonism Multiple Sclerosis Motor Neurone Disease Muscular dystrophy Epilepsy Paraplegia Colostomies Injuries Head Injuries Amputations [42] [43] [42] [43] [44] [44] [44] [44] [44] [44] [45] [46] [46] Estimated prevalence of disease/condition (Various sources) Per 10,000 population Per 250,000 population 2,900 1,280 250 100 c.700 c.800 55 20 8 1 1 50 16 72,500 32,000 6,250 2,500 17,500 20,000 1,375 500 200 15 15 1,250 400 Major congenital malformations About 2,500 people per 'District' are treated as in-patients in hospital each year. About 675 people per 'District' are treated as in- patients in hospital each year. About 30 people per 'District' are referred annually for the first time to a Limb Centre. Incidence is about 2 per cent of all live births. 860 all forms and unspecified arthritis 60 110 115 340 55 80 not known 35 40 (head injuries excluded) *The Harris Survey deals mainly with physical disability. urinary incontinence, and 25,000 adults with significant deafness. The principal causes of severe physical disabil- ity are neurological disease and arthritis. In the average Health District there will be 500 people with Parkinson- ism, of whom 55 will be severely or very severely disabled. There will be at least 200 patients with multiple sclerosis and there could be up to 6,000 with rheumatoid arthritis. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 153 The- epidemiology of physical disability is discussed at greater length in Appendix 2 which deals with the important differences between impairment, disability, and handicap. The Principles of Medical Involvement Historically, rehabilitation of the physically disabled de- veloped from the speciality of Physical Medicine and Rehabilitation. This arose largely from the residential Service Rehabilitation Units in World War II. Specialists in physical medicine were concerned with management of chronic disability and with the diagnosis and management of the rheumatic diseases. In time, the specialty merged with that of rheumatology and became known as rheumatology and rehabilitation. With the expansion of rheumatology in recent years, to become a sub-specialty of medicine in its own right, its proponents no longer feel that their work should necessarily be concerned with the management and rehabilitation of non-rheumatological disorders. This applies particularly to disability resulting from neurological disease in which many rheumatologists have not been trained. However, many Districts welcome a consultant who can not only care for patients with rheumatic disorders in the widest sense (including backache, soft tissue rheumatism, degen- erative joint disease, and inflammatory arthritis), but also provide a more general rehabilitation service for chron- ically disabled people. England and Wales are almost alone amongst western countries in having no medical specialty of physical medicine, or its equivalent. Only a handful of consultants have a full-time commitment to rehabilitation. In addi- tion, there are a small number of consultants who have dual accreditation?usually in rheumatology and re- habilitation. Some Health Districts do not have any designated sessions in rehabilitation. It seems probable that one of the principal reasons for the poor state of Medical Disability Services in England and Wales is the fact that there are very few doctors with any formal professional commitment to the subject. Few have the experience, time, or responsibility for formulating, pre- senting, and arguing the case for resources. Planned investment in the area has been small at both Regional and District levels. In the UK there is a well-developed geriatric service which not only provides for the frequently complicated medical needs of the elderly, but is also concerned with their social problems. In many ways it is a Medical Disability Service for older people. A similar service exists for children in many parts of the country. However, no such service exists for the large number of disabled people aged between 16 and 65 years, who have, to some extent, become a 'deprived population' with few specific facilities (e.g. Day Centres) and a paucity of consultants with specific expertise in the management of their disability problems. The Working Party on Rehabilitation Medicine of the Royal College of Physicians[47] was firmly of the opinion that 'Rehabilitation is an integral part of total patient care, and is therefore the concern of all clinicians' and considered that clinicians, whatever their specialty, should extend their role and assume at least limited responsibility for the medical aspects of the rehabilitation of all patients under their care. However, virtually all clinicians are fully committed and time has to be found for them to develop this aspect of medicine. Certainly there does not seem to be much evidence of major advances in this particular direction since the Working Party Report of 1978, and the implications of the recom- mendations have not, as yet, been explored. This country, through the NHS, is therefore engaged in an important, if unplanned, experiment?'Is it poss- ible to set up an effective care service for the physically disabled without a substantial specialty of rehabilitation, or its equivalent?' The view of the medical profession at the moment appears to be that we should try to do this, and the remainder of the Report is written on this assumption. Terminology (See Appendix 1) The term 'Rehabilitation' has been used extensively in the past. Unfortunately, the term lacks any agreed defi- nition (although a large number have been attempted) and is widely misunderstood. For example, some people consider that the term should be confined to the manage- ment of sequelae of a 'once and for all' insult such as head injury, or stroke. Others consider that it should include progressive disorders such as multiple sclerosis and rheu- matoid arthritis. Historically, rehabilitation has been linked with rheumatology. This link has now, to a large extent, been severed. The term "Physical Medicine" is applied in place of Rehabilitation in some countries. The term Physiatry is used in North America and the term Rehabilitation Medicine in Australia. The terminology used in this Report reflects the present situation: 1. Services for disabled people are referred to as Disability Services. 2. Existing consultant posts in rehabilitation or rehabili- tation medicine are referred to as posts in rehabilitation. 3. The term 'Disability Medicine' is used in this docu- ment to cover the application of medical and of general health care services for physically disabled people. The term is also used in reference to new consultant sessions that are devoted specifically to the management of disabil- ity and the co-ordination of Health Care Services for physically disabled people. Consultants The Royal College of Physicians has published reports on the 'Management of Disabling Chest Diseases'[48] and on the 'Management of Coronary Heart Disease'[49]. A Working Party is currently considering the subject of neurological disability. Rheumatological disability is also the subject of a Working Party Report, to be published shortly. By publishing these documents, the College hopes shortly to be in a position to advise on manpower and training requirements for each of these specialties? with particular reference to the management of disability. 164 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 Whatever the details of the final proposal?a substantial increase in the number of consultant sessions devoted to disability and its management is likely to be rec- ommended. This may well involve an increase in the number of doctors in certain specialties?e.g. neurology, with some sessions devoted to disability medicine. Some physical disability falls primarily within the province of surgeons rather than physicians. For example, orthopae- dic surgeons are involved with many aspects of disability. General Practice The 1978 College Report on Rehabilitation Medicine[47] recognised the important role of the general practitioner in the recognition and management of disability. It commented as follows: 'The great majority of patients, whether suffering from chronic or temporary physical disability, are living in the community. The general practitioner, therefore, has a lynch-pin function of identifying the need for Disability Services. The general practitioner is likely to be most effective in helping the disabled patients in his practice if he is working as a member of a Primary Health Care Team. The Team needs to have access to, and collabora- tion with, remedial therapists working in the com- munity'. Community Medicine Community physicians are concerned with the promotion of health, the prevention of disease and disability, the assessment of the community's health needs and with the provision of services to that community and to special groups within it. They are especially involved with epidemiology, Health Service planning, and in the joint planning of services with Local Authorities and voluntary organisations in respect of child health, young disabled people, and frail elderly people. They provide the medical advice to the Social Services, Education, Housing and other departments of the Local Authorities, and have a collaborative link with the General Practitioner Services. Community physicians have an important contribution to make in developing integrated planning of services, and a concern that the needs of disabled people are brought to the attention of the Health Authorities and, as far as possible, are met. Occupational Medicine Occupational physicians have a major responsibility to prevent disability resulting from accidents or occupation- al disease. Within the individual workplace, they can advise on the employment of disabled people. The Man- power Services Commission is responsible for employ- ment policy in England and Wales, which includes providing services to facilitate the employment of disabled people. One of the resources available is the Employment Medical Advisory Service, which employs trained occu- pational physicians to help assess people's suitability for employment or training, as well as providing medical advice for the Employment Rehabilitation Centres, and the Disablement Resettlement Officers, who are respon- sible for assessment and placement services. FUTURE EVOLUTION OF DISABILITY SERVICES The Need for the Setting Up of Standards of Care and Audit Before the quality of services for the management of disability can be judged, standards of care have to be established. This Report lists some of the services which need to be provided. Many of these services will be provided by each District Health Authority, some by one District on behalf of other Districts, and some by other agencies. In whichever way these services are provided, they should be readily available to all disabled people who require them. Subsequent sections of this Report describe essential components of the services listed and suggest simple minimum standards of care. These suggestions can form the standards against which the provision and performance of the services can be reviewed. Such re- views should be carried out periodically in every District and by each Regional Health Authority. It is particularly important to listen to the views of disabled people, and of their spouses or others caring for them at home, about the provision and use of services. As the services required are so diverse and are provided by so many authorities, it is too easy for gaps and unnecessary overlaps to occur. Any review of the services should seek reports from the various voluntary organisations representing particular groups of disabled people. Basic Criteria for a Disability Service The remainder of this report outlines our suggestions as to how Disability Services in England and Wales should be planned in the future. In making our recommenda- tions, we have been mindful of the following factors: 1. The urgent need to establish an effective Medical Disability Service. 2. The importance of taking into account the views of disabled people and their families. 3. Proposals must be cost-efficient, using existing facilities where possible. 4. The Service should be based upon the principle that the management of disability is an integral part of total patient care and is the responsibility of all clinicians. 5. Certain consultants should have designated responsi- bility and commitments for services such as Continence, Stoma Care, the District Head Injury Recovery Service, and Pressure Sores. 6. There should be a system of internal and external checks and audit. These should help the service to Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 165 develop in the light of experience and of changing needs. Plans should be flexible enough to allow for local con- ditions, whilst at the same time ensuring that a basic minimum pattern of provision for physically disabled people is achieved. 7. Regional and District plans should include a timetable for the development of adequate services, with provision for review if targets are not achieved. 8. A simple permanent administrative structure should be set up at both District and Regional level. Regional Units We recommend that each Region should have at least one Unit which would be concerned with certain specific aspects of disability. Functions 1. The assessment of severely physically disabled people. Some severely disabled patients have multiple problems which require considerable expertise and knowledge re- lating to a wide variety of techniques and equipment. For instance, a patient with Duchenne muscular dystrophy may have as many as 15 different problems, including difficulty with breathing, difficulty with sitting comfort- ably because of a severe scoliosis, pain (associated with skeletal deformity), severe immobility, difficulty with sleeping (partly due to discomfort) and a wide range of impaired self-care activities. Such a patient may require a specially built wheelchair, specialised seating, a moulded back support, a special bed, and a hoist. In addition, the relatives and carers will need to be trained in the best ways of handling the patient. The majority of hospital physiotherapy and occupational therapy departments are not equipped to undertake this type of assessment. A unit catering for patients with severe and multiple physical disabilities and handicap is Mary Marlborough Lodge, Oxford, established in 1960. The activities of the Unit have recently been reviewed and evaluated (see Appendix 3). This evaluation shows that the Oxford Region itself generates a substantial number of patients and that there is a substantial demand for the type of services offered from far beyond Oxfordshire. It appears clear from this evaluation and from the experience of members of the Committee, that facilities of this type should be widely available throughout the country. We therefore recommend that each Region should establish a Unit whose functions would include: a) The assessment of the severely physically disabled person?many of whom have multiple handicaps. b) The provision of appliances, aids and equipment (including Possum) not readily available from other centres and some of which may need to be modified or adapted in the Unit workshops. c) The training of the disabled person so that he achieves his maximum potential. 2. The Regional Unit should provide facilities for ortho- tics (e.g. splints), prosthetics (e.g. artificial limbs), and difficult wheelchair problems. Some of these functions are currently provided by the Artificial Limb and Appliance Centres (ALAC's), and it would seem sensible to incor- porate these into the Regional Units. This concept was introduced by the ALAC Review[50], The Unit might well incorporate a Regional Communication Aids Centre (see page 179). 3. The Unit could include a Disabled Living Centre (see page 173) where a wide variety of equipment should be available for inspection and trial by physically disabled people, their relatives, and professional workers. 4. It might be possible for the Unit to encompass the management of certain specific disorders?for example, a Regional Spinal Injuries facility and/or a Stroke Unit. It would provide an important service for its own Health District. 5. The Unit would act as a focus for teaching and training of professional staff. 6. A major function of the Unit would involve research. The development and evaluation of the various types of equipment for disabled people could, and should, take place in the Unit. The Centres might well become a focus for the design and modification of wheelchairs and other equipment. Siting and Staffing These Regional Units should be sited in a major centre and would ideally be linked with a university and a medical school. The Unit should have facilities for in- patients and also engineering workshops. There would be a staff of trained therapists. It is essential to avoid isolation and in our view the Unit should usually be situated in the grounds of a District General Hospital (DGH) to give ready access to a wide variety of medical specialist skills, and allow for medical 'on call' cover, and ensure that a close relationship develops with the staff of the DGH. Rotation of staff in training, both medical and non-medical, should be arranged. Hostel accommodation for relatives and for less disabled patients living at a distance from the Centre, should be available. We recommend that there should be, at the Regional Unit, the equivalent of at least two full-time consultants in disability medicine. The possibility of appointing consultants with dual accreditation who are still practis- ing in another specialty, e.g. rheumatology, neurology, geriatrics or orthopaedics, should be considered. We consider that these Regional Units are absolutely essential for the establishment of proper Disability Ser- vices in England and Wales. The precise way in which they are established will clearly depend upon local cir- cumstances, including existing facilities. District Services What are the main requirements for Medical Disability Services within a Health District? We have compiled a list, which, although not entirely comprehensive, should form the basis for review and audit. In making our suggestions we are well aware that there is overlap with many other organisations, both statutory and non-statu- tory..These include Social Services, Education, and the Local Authority. It is clearly important that the relevant staff, including the district nurses, in each Health District should be 166 Journal of the Royal College of Physicians of London Vol. 20 No. 3 1 July 1986 adequately trained in the management of disability. The domiciliary occupational therapists and physiotherapists are trained to assess the disabled person in his own home. This service is particularly important. Generic Services The Committee has outlined brief criteria for the estab- lishment of services in 15 particular areas which are discussed in Section III of the Report. We suggest that all Health Districts should give consideration to these areas but in some instances it may be appropriate for certain facilities to be shared with adjacent Health Districts. Aids and Equipment Centres. Housing, Housing Modifications and Re-Housing. The Physically Disabled School Leaver. Support Services for Younger Severely Handicapped People. Driving for the Disabled. Sexual Counselling. Head Injury Services. Visual Impairment. Hearing Impairment. Communication Aids. Wheelchairs. Prosthetics and Orthotics. Urinary Incontinence. Stoma Care Service. Pressure Sore Service. Information about Services for Disabled People within the Health District Each Health District should maintain an up-to-date data base of facilities locally available for disabled people. This could be accessed using a Ceefax-type system if television screens were provided in health centres and elsewhere. This data base should be used to produce a booklet, to be updated annually, of facilities that are available for disabled people locally. These lists should include facili- ties provided not only by the Health Service, but also by Social Services, voluntary bodies, and other organisa- tions. This information is needed by disabled people themselves, and also by doctors and other Health Service professionals, teachers, social workers, and others. The lists should include the names and addresses and tele- phone numbers of local charities and organisations for the disabled, and advice on how to obtain information about matters such as wheelchair provision, sexual counselling and leisure facilities for disabled people. A list of some of the national organisations and chari- ties concerned with facilities for disabled people is in- cluded in Appendix 7 of this Report. More detailed information can be found in the Directory for the Disabled (1985) and the Disability Rights Handbook. Medical Staff Consultants with Designated Sessions in Disability Medicine The precise organisation of Disability Services within the Health District will also depend upon local circum- stances. A few Health Districts already have a consultant whose main commitment is to Disability Medicine. How- ever, the majority do not do so. We make our recommen- dations on the assumption that it is generally agreed that individual specialists should supervise the management of their own disabled patients. It is realised, however, that this does not always happen at present. In our view, there should be a number of designated disability sessions in each Health District. We suggest that, in addition to the care of his own patients, the consultant would undertake some, or all, of the following:- 1. Giving advice to consultant colleagues about disability problems relating to patients under their care. 2. Looking after in-patient facilities for physically dis- abled people, especially the Young Disabled Unit where one exists, but also planned short-stay, crisis admission, holiday relief and terminal care beds. 3. Catalysing the District Health Authority in the pro- vision of Disability Services. This may involve member- ship of the District Disability Committee. 4. Being involved in running a number of services including, for example, continence, splint making, wheel- chair and stroke disability. In addition, there should be a commitment to the local Disabled Living Centre. We regard it as essential that there should be clear-cut areas of responsibility. 5. Operating a Head Injury Recovery Service. At present, patients with head injury tend to get admitted under a number of different consultants in various speci- alities. We suggest that one consultant in each Health District should be responsible for implementing the Dis- trict policy on the management of head injury (see page 177). 6. The consultant(s) would have responsibility for the training of undergraduates, doctors, nursing and para- medical staff. 7. As mentioned below, there are important require- ments for research. We suggest that there should, initially, be 10-11 disability sessions per week (the equivalent of one full-time post) in a Health District and these might be held by two or more consultants. These consultants, together with the com- munity physician mentioned below, would be responsible for the medical input concerned with General Disability Services, and would, in addition, be responsible for ensuring that Disability Services in their own particular discipline were developed. We have suggested some general guidelines. We wish to avoid rigid rules, but we consider that the principle of a substantial number of designated disability sessions held in each Health District is absolutely essential. These sessions could be held by consultants from a wide number of disciplines, including general medicine, rheumatology, geriatric medicine, neurology, and orthopaedic surgery. Community Physician There should be a community physician with designated responsibility for the development of District Disability Services. The precise nature and distribution of the community physician's responsibilities would depend Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 167 upon the medical staffing structure within the Health District. The responsibilities might include:- 1. Membership of the District and Regional Medical Disability Advisory Committees. 2. The collection of epidemiological data relating, for example, to patients suffering with pressure sores, incon- tinence, head injury, and severe physical dependency. 3. Maintaining a list of severely disabled people within the Health District who are living at home but are 'at risk'. 4. Monitoring the inappropriate use of beds within the Health District. For example, it may be important to identify patients who are occupying hospital beds for 'social' reasons, or because a long-stay bed cannot be found. 5. Ensuring that there is an effective District policy for housing and housing alterations for disabled people. The person concerned might be responsible for drawing up a list of priority cases. This work would involve close liaison with other statutory bodies, notably Housing and Social Services. 6. Ensuring that the plan for disabled school leavers is drawn up and implemented (see page 174). 7. Ensuring that a five year plan for Disability Services is drawn up by the Health District and updated regularly. 8. Compiling annual reports on Disability Services for the managers and for the District and Regional Disability Committees, with particular emphasis on cost and effec- tiveness. 9. Being responsible for running the data base relating to services for, disabled people and for compiling a booklet on these services, which would be updated annually. We see the community physician as having a most important function in collecting and analysing data, identifying trends, and acting as a co-ordinator for certain important clinical groups. We envisage that the com- munity physician and consultant(s) in medical disability would work closely together. General Practitioners General practitioners have a most important role. The list of 10,000 people cared for by a group of four or five principals will include up to 1,000 who are physically disabled; 200 of these will be severely or very severely disabled. To function effectively as the primary medical adviser to disabled people, the general practitioner under- takes the following:- 1. Defines his patients' problems in physical, psychologi- cal and social terms. Problem-orientated records can be helpful. 2. Helps the patient in the management of everyday maladies to which the disabled population are at least as prone as the rest of society; the management will often be modified by the disability. 3. Together with the district nurse and health visitor, members of the Primary Health Care Team, he provides information about a wide range of locally available public and voluntary sources of assistance, advice and support. 4. Helps the disabled person to live with his disability and his family to support him in doing so. 5. Refers to the social workers, remedial therapists and other agencies, including voluntary societies working in the community. He will therefore need to be aware of the provisions of such services from the National Health Service, Local Authority, and the voluntary services in his District. 6. Refers to appropriate consultants, including those with particular expertise in disability. He would also make appropriate use of the specific District Disability Services (e.g. Continence, Stoma Care, etc.) Research and Development Disability involves problems that cause much stress and unhappiness. The costs, both to individuals and to the State, are very considerable. Many treatment and man- agement regimes have never been scientifically evaluated and the task of drawing up criteria for 'model' Disability Services is seriously hampered by lack of epidemiological and operational data. There is clearly a need for a substantial investment in research. Recent Developments Developments during the last few years have included the following: 1. Scientific journals now contain a small but increasing number of refereed papers relating to disability. 2. The Society for Research in Rehabilitation (SRR) was started six years ago. The Society is multi-professional, drawn from a wide variety of disciplines, including medicine (less than 50 per cent of the Membership are doctors), the remedial professions, nursing, social work, psychology, physiology, and engineering. The object of SRR is to provide a forum for the presentation of scientific papers relating to causes, prevention, effects and management of disability. 3. Demonstration Centres. Twenty-seven Demonstration Centres have been estab- lished in England and Wales (see Appendix 6) and these have provided a valuable focus for training and the development of services. 4. Academic Departments. There are now two Academic Departments of Rehabili- tation in the UK (Edinburgh and Southampton). Future Research There is an urgent need for the drawing up of validated audit criteria on which model services could eventually be based. The establishment of agreed criteria will require considerable experimentation. The research areas to be covered are very large, and the following list gives some examples:- 1. Epidemiology. There is a need for epidemiological data relating to disability in a number of areas?e.g. head injury and multiple sclerosis. We need to know the numbers of people and the costs involved. Community physicians are well placed to initiate and participate in this type of research. 2. The development of reliable measures of outcome 168 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 which can be used for clinical audit and research pur- poses. 3. Research into the natural history and physiology of recovery. 4. Social implications of disability. 5. Evaluation of equipment, e.g. splints, wheelchairs, etc. 6. Evaluation of rehabilitation techniques, e.g. assess- ment of the effectiveness of various types of therapy (new and old). 7. Evaluation of different ways of providing care, e.g. home versus hospital for stroke patients. There is also a need to examine the different ways of improving collabo- ration between professional staff and between members of different disciplines. Implications of Research Needs More academic units are needed to undertake research into various aspects of disability. Such units would prob- ably need to be attached to major hospitals where there is a steady flow of patients. The proposed Regional Disabil- ity Units (see page 166) should have an important function in this regard. Not only would they undertake research projects, but they would also be concerned with the training of staff in research methodology. The import- ance of enthusiastic medical leadership in this field seems clear. The Arthritis and Rheumatism Council Research Unit in Manchester has provided valuable data on the epide- miology of rheumatic diseases. We consider that more of these units may be needed and commend particularly the possibility of establishing research units concerned with the epidemiology and management of neurological dis- ability. Organisation and Administration We think it unlikely that Disability Services at Regional and District level will be properly established until a clear-cut administrative structure is set up. This would involve committees at both Regional and District levels. These committees would, amongst other functions, be concerned with providing an internal audit system for Disability Services. In making our recommendations, we have been mindful of four particular points:- 1. The need to avoid unnecessary bureaucracy. The number of committees should be kept to a minimum and the membership should be kept as low as is reasonable. 2. The lack of published experience. It is known that various District advisory bodies already exist. These operate under a number of different names, including the District Disability Committee, the Principal User Com- mittee, and the Health Care Planning Team for Disabil- ity. To our knowledge, there have been no published accounts of the workings of these bodies. 3. The fact that a large number of professional bodies, and individuals, are concerned with providing services. Within the NHS there are doctors (working in the hospital and in general practice), nurses and therapists. Many groups are not part of the NHS, including Social Services, the Employment Resettlement Service, some occupational therapists, the Artificial Limb and Appli- ance Centres, the Department of Housing, and the Department of Education. All these bodies will need, at some point, to be involved with various aspects of District Disability Services. 4. The wish of disabled people themselves to be involved with discussions relating to the operation of Disability Services. It will not be easy to satisfy all these require- ments. Any administrative plans will necessarily be ex- perimental and subject to modification in the light of experience. Each Region and District will need to develop its own structure. As far as the committee membership is con- cerned, a number of theoretical options exist:- 1. A membership consisting of doctors only. 2. A multi-professional membership?composed of NHS employees only (e.g. doctors, therapists, and nurses). 3. The membership could be both multi-professional and multi-organisational?including representatives of some or all of the various bodies itemised above?e.g. Social Services, Housing, etc. Our suggestion is that Regional Committees should be multi-professional, but confined to NHS employees. Dis- trict Committees would probably be multi-professional and multi-organisational. The lack of co-terminous ad- ministrative boundaries for, for example, the NHS and Social Services, is likely to be a significant problem and a matter which will need to be discussed locally. Regional Disability Medicine Subcommittee It is suggested that each Regional Health Authority should have a Regional Disability Medicine Subcommit- tee. The Subcommittee would have the following func- tions:- 1. Being responsible for reviewing supra-District facili- ties, including the Regional Disability Unit(s). 2. Producing, and updating annually, short and long- term plans for Regional and supra-District Disability Services. Realistic targets for the establishment of Re- gional Disability facilities should be set and the Commit- tee would be responsible for monitoring these. 3. Reviewing Disability Services in constituent Health Districts. The Regional Disability Committee would receive annual reports from each District Disability Com- mittee. The Committee would also expect to receive copies of the short and long-term plans for each Health District. 4. The Regional Disability Committee would produce its own annual report for the Regional Manager; this would review the current situation in constituent Health Dis- tricts, and at Regional level. It is suggested that the membership of this Committee might be multi-professional. There would be at least one representative from each Health District within the Re- gion. The person concerned would be a member of the relevant District Disability Committee, and might be its Chairman. At least one of the full-time consultants in disability medicine based on the Regional Unit, would be a member. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 169 District Advisory Machinery The District Health Authority will require well thought- out advice and recommendations on a wide variety of issues. We suggest that each DHA should have a small Advisory Disability Committee which would certainly be multi-disciplinary, and would probably be multi-organi- sational. It would thus include not only doctors, but also a social worker and a representative of the nursing and remedial professions. The Committee would need to represent both hospital and community interests. The District Advisory Disability Committee would draw up an annual report for the District Manager, and this would be available for the Regional Disability Com- mittee and for the Regional Manager. It would also draw up short and long-term plans for the development of Disability Services within the Health District. It is important that medical staff locally should develop a mechanism for the discussion and formulation of its views. This might be done by a small subcommittee of the medical staff, which would report to the main Medical Staff Committee. The committee would include consult- ants with designated sessions in Disability Medicine and also the community physician with responsibility for the development of Disability Services. This committee would be concerned primarily with the medical aspects of disability (e.g organisation of stroke care within the DGH). At least one member of the Medical Disability Subcommittee would also be a member of the District Advisory Disability Committee. The suggested administrative structure is necessarily experimental. We would strongly encourage Health Dis- tricts to publish their experience with various types of committee structure. A national survey of the matter might be worthwhile. Hopefully, within a short time, the basis for a nationally applicable administrative structure will have been established. Medical Staffing This section deals with the medical staffing implications of the recommendations in this Report. Consultant Staff Consultants in Disability Medicine working mainly at the Regional Centre We have recommended the setting up of Regional Dis- ability Units and that each Unit should be staffed by the equivalent of two full-time consultants, whose principal commitment would be to Disability Medicine. If all the consultants were to be full-time, then 30-35 full-time appointments would probably need to be made. How- ever, if a substantial proportion of the appointees con- tinue practising in another field (e.g. geriatric medicine or neurology) then the number required would be great- er?in order to make up the equivalent of two full-time posts. There is clearly scope for considerable flexibility. It should be noted that there are at present only a handful of posts with a major disability/rehabilitation component, I and it is clear that in some cases it will be necessary to create new posts. , Consultants with dual responsibility and accreditation We recommend that there should be about 10 disability sessions held in each Health District. We envisage that in the majority of Health Districts, the sessions would be divided amongst 2-3 consultants in different specialties. It is possible that some Health Districts will be able to identify 'spare' sessions where consultants feel that they can take on additional responsibilities. However, there will need to be a significant increase in the number of consultant posts, many of which will involve dual ac- creditation (e.g. neurology and disability medicine). Training of existing consultants in disability skills Some existing consultants should be asked to take on designated disability sessions. It is hoped that where appropriate, the RHA will allow the doctors concerned to have a substantial period of study leave (perhaps 3-6 months spread over two years) in order to allow him/her to acquire the requisite skills. Full use should be made of the Demonstration Centres (see Appendix 6) and special- ist units. The precise content of the training programme required will depend upon the experience of the consult- ant and the particular needs of the Health District. i Academic Posts We have already discussed (page 168) the importance of research into a wide range of problems involving disabil- ity. We recommend that there should be an increase in the. number of academic appointments which concentrate on Disability Medicine. Senior Registrars Full-time Posts It is, at the moment, unclear as to how many senior registrar posts will be required in order to achieve the target of 30-35 full-time consultants in Disability Medi- cine/Rehabilitation. The number needed will become clear once Regions have drawn up their plans. In the short term, it will be necessary to train a number of doctors at senior registrar level, so that eventually these consultant posts can be filled. We envisage that some existing senior registrars in, say, neurology or geriatrics, may wish to move 'sideways' into Disability Medicine. Some of the doctors may wish to consider continuing practising in their primary specialty, whilst allocating the major part of their time to Disability Medicine. Once the posts are filled, then the number of replacements required annually will be small. The posts can be suitable for part- timers who have domestic responsibilities, but who are of high' calibre and are otherwise suitably qualified. It is worth repeating that the short-term aim is to have in post, within five years, 30-35 consultants working mainly in Regional Centres whose principal (although not necessar- 170 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 ily exclusive) commitment will be to Disability Medicine. The wide range of responsibilities listed on page 166 indicates that considerable flexibility in training and ultimate responsibility is both inevitable and desirable. % We wish to emphasise the importance that we place on the consultant posts in Disability Medicine. There will be considerable clinical and organisational responsibility, and in addition the Regional Units will have an import- ant research function (see page 168). It is essential that ? { high quality candidates be recruited. Dual Training and Accreditation A substantial number of posts involving dual training and accreditation should be set up?particularly in neurology, but also in general medicine, geriatrics and rheumato- logy. The relevant SAC's should be asked to draw up training standards as a matter of urgency. In some instances, there may be proleptic consultant appoint- ments?the appointee being seconded to appropriate centres for training in Disability Medicine. > Clinical Assistants and Hospital General Practitioner Sessions Continuity of care is an essential principle in the manage- ment of all chronic disorders. We strongly support the proposition that patients with serious disabling diseases should be dealt with by doctors who are trained and who know the patient concerned. Unsupervised follow-up by a succession of different junior doctors is not good clinical practice and is generally unacceptable. Clinical assistants and hospital general practitioners working in out-patient departments could provide very useful help in the run- ning of Disability Services. This suggestion should be tried and evaluated. Education of Medical Students and Postgraduates Any discussion of education and training starts with the assumption that the management of disability is the responsibility of all clinical doctors. If this premise is accepted, then it follows that the subject should be taught routinely. We consider that in the education of under- graduates and postgraduates the management of disease and its consequences should receive similar emphasis as diagnosis and treatment. Some practical ways in which this might be implemented include the following:- 1. Disability should be routinely included when a 'case' is discussed?whether it be on a routine ward round, a clinical meeting, or a grand round. 2. Examinations should routinely contain questions re- lating to disability. 3. Disability management should be included in voca- tional training schemes for general practitioners. 4. Disability and its implications and management should be discussed in medical textbooks. Training schedules should include visits to the Re- gional Disability Centre, a Hospice, a Spinal Injuries Centre, an ALAC, and one or more Demonstration Centres. The possibility of attaching undergraduates to a family, in which there is a disabled person, for the whole or part of their clinical course, should be considered. Training should reflect the emphasis being put on the management of disabled people in the community rather than in institutions. Timetable We are keenly aware of the poor state of Disability Services in many parts of England and Wales, and that the recommendations of previous reports (e.g. the Reid Report on epilepsy[51] and the Tunbridge Report (1972)[4] have been largely ignored. We think it import- ant that action on Disability Services be taken in the very near future, and for this reason we are suggesting a timetable and a mechanism for ensuring that the Medical Disability Service is actually set up. In making our suggestions, we have tried to be realistic and it is fully appreciated that the recommendations cannot be imple- mented immediately. Suggested Timetable 1. July 1986?publication of this Report. 2. End of 1986?the Report should have been read and digested by relevant organisations and authorities. 3. 1986-1987?We would hope that during these years Regional and District Medical Advisory Disability ma- chinery should have been established. By the end of this time there will be in existence a five-year plan for Regional and District Disability Services and the siting for Regional Disability Units should have been identified. The number of senior registrar training posts required for future service needs will have been agreed, and the number of new training posts approved by the relevant specialist advisory committees of the JCHMT. 4. 1988?In all Health Districts, sessions in Disability Medicine will have been designated, with the responsibil- ities for the services outlined in this Report. A sufficient number of senior registrar training posts approved in Disability (Rehabilitation) Medicine (many of which are likely to involve dual approval with another specialty) will have been established to train the number of senior registrars required to fill those consultant posts which are to contain designated Disability Medicine sessions. 5. Early 1990''s?Sessions in Disability Medicine should by now have been established and filled in all Health Districts, covering responsibility for the services outlined in this Report. A major review of Disability Services in England and Wales should be taken in the early 1990's to ascertain whether the targets itemised above have been met. If there has been no substantial improvement in Medical Disability Services by the early 1990's, and if no improve- ment appears likely within the foreseeable future, then the option of establishing a much larger specialty of Disability Medicine such as exists in other countries, should be considered. However, this would almost cer- tainly be much more expensive than the plan suggested here. It would probably involve the appointment of at Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 171 least one full-time consultant in disability medicine/ rehabilitation in each Health District. Audit Function We have attempted in this Report to draw up some professional standards for Medical Disability Services. We have suggested some audit criteria in certain specific areas (e.g. management of incontinence). It is obviously important to ensure that the relevant services are actually established, and the question arises as to how this is to be achieved. Much of the responsibility for the provision of services will fall on Regional and District Managers. However, they will undoubtedly be under pressure from many other directions, and in times of financial stringency may find it difficult to implement the suggestions outlined in this Report. We think it likely that some form of external 'Watchdog' mechanism will be required to stimulate Managers and Health Authorities to make sure that Disability Services are actually established. It may be these checks should be made by some independent organ- isation which is not funded by the NHS. A number of possible organisations exist, including the local Com- munity Health Councils, the Health Advisory Service, and The Consumer Association (which has published the Drug and Therapeutics Bulletin for many years). It is envisaged that the independent organisation con- cerned would have access to annual disability reports produced by District and Regional Health Authorities. In addition, they should be in a position to undertake their own checks?e.g. how many Health Districts within the Region have a trained and designated senior nurse to run the Continence Service? The precise way in which the performance of Disability Services is monitored will require further discussion. We hope that the monitoring function can be undertaken by existing organisations. We certainly think it highly desir- able that a regular review should be undertaken, and published. We hope that the basic audit standards that have been suggested in this Report will prove useful as a basis for the review. It may be asked why such a special system of review and audit is required for Disability. We would answer this question by pointing out that no high quality medical service has ever been established without a substantial core of doctors committed to the topic (e.g. geriatrics, renal failure, spinal injury, mental handicap, etc.). As indicated earlier in the Report?we are attempting to set up an effective Medical Disability Service with very few doctors committed whole-time to the subject. For this reason, and because of the long history of inaction, we think that the system of audit and checks that we have suggested is justified. Costs and Resources We recognise that additional expenditure will be involved in many Regions and Districts if the basic standards of provision of services and help for people with severe disabilities, set out in this Report, are to be achieved. The cost of providing good basic services must, however, be set against the enormous hidden costs of not providing them. In many Districts, these concealed costs are being borne by disabled people themselves or their carers, in terms of misery, deprivation, loss of access to facilities enjoyed by the rest of the population, and loss of choice and autonomy. There are, in addition, direct costs that fall on their families if they feel obliged to provide facilities which should be made available to them through an adequate Disability Service. We have not carried out a survey to ascertain the level of present provision. There is no doubt that some Dis- tricts have good services and some District and Regional units are pioneers and leaders in the provision of certain facilities. However, there is evidence, set out at the beginning of this Report, that there is scope for consider- able improvement. Without detailed knowledge of ser- vices currently being provided, it is not possible to identify what resources are required to implement our recommendations. For example, the recommendation that each Region should have at least one Regional Centre concerned with the assessment of very severely disabled people, the development of equipment and other forms of help, and research and training, may require little action from two or three Regions, some expansion of an existing Centre or Unit for some Regions, and major developments in others. Similarly, at District level, the recommendations concerning consultant sessions in Dis- ability Medicine, or involvement in a Continence Clinic, may require no more than revising the contract of a consultant who is already carrying out the function. In some instances, however, additional consultant sessions will be required. Again, the method of funding will have to be discussed locally. For example?if there is to be a Disabled Living Centre in each Region?'joint' funding money may be available. Similarly, where equipment is not available through the NHS, private companies might loan samples of such equipment for trial. Voluntary bodies may be able to raise money for such equipment. We are well aware that many disabled people require, and benefit from, 'acute' services and from many techno- logical advances?e.g. joint replacement and kidney transplants. It is clear, therefore, that although there may be some need to transfer resources from the acute to the chronic sector, this process needs to be done with con- siderable circumspection. A balance has to be sought, and this will be helped, the Committee believes, if the present trend for all specialties to be involved in the management of disability arising from diseases within their purview, is further developed, and is backed up by explicit District and Regional policies. Additional expenditure will undoubtedly be required, particularly for the establishment of Regional Centres. Three areas are currently given priority for funding by the NHS?mental illness, mental handicap, and the care of the elderly. We suggest that physical disability should be a fourth such area. Our" views on costs may be summarised as follows:- 1. There is clear evidence of major defects in the pro- vision of medical services for patients with physical disability (see page 162). 172 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 2. We note the extraordinarily low level of current investment in medical disability?considering the extent and size of the problem. We have noted previously that virtually all other developed countries have substantial specialties of physical medicine or rehabilitation medicine incorporating considerable numbers of specialists whose main professional responsibility is the management of Medical Disability. 3. Physical disability is expensive, however it is man- aged. It is obviously important to ensure that money is spent effectively (e.g. money spent on the prevention and early treatment of pressure sores may avoid lengthy and expensive stays in hospital). 4. The Committee recommends that physical disability should be recognised by the DHSS as an area for top priority funding. GENERIC SERVICES The term Generic Services is used in respect of those services which are likely to be used by a variety of disabled patients, but are not necessarily the responsi- bility of a particular specialty. We have identified fifteen specific areas. It is recommended that Health Districts should have a policy on each of these topics. We have outlined some brief guidelines, and we hope that these will be helpful to Health Authorities as they draw up and check their plans for these particular areas. The policy guidelines have been written on the following principles: 1. There should be agreed professional standards of care and provision. 2. A system of audit should be established. The audit criteria should be unambiguous and be based on (1). 3. Clear-cut areas of responsibility should be defined (e.g. there should be a named consultant in charge of the District Continence Service). 4. Each Health District should keep records of certain specific problems (e.g. the number of significant pressure sores occurring in the District during the year). 5. As far as possible, the costs of each generic service should be identified and the details published in the Annual Report of the Health District. The object of this section is emphatically not to produce a mini-textbook of Disability Medicine. The purpose is to demonstrate that it should be possible to set, and achieve, realistic standards of care in a number of important areas. Disabled Living Centres (DLCs) (Previously called Aids and Equipment Centres) The provision of aids and appliances is one of the most important activities associated with a District Disability Service. Aids need to be appropriate both in their func- tion in the timing of supply. This requires assessment facilities and an adequate supply procedure. Although most, if not all, occupational therapy departments, both in the NHS and in Local Authority Services, do provide assessment facilities, supply is often very limited and this may make the assessment irrelevant. There is obviously no point in recommending an aid if it is not likely to be provided reasonably quickly. Many Local Authorities only provide aids associated with a limited range of activities such as toileting, and there are often large gaps in what is available. Even when an activity is covered? the range of products offered may well be limited. About a dozen DLC's have been opened in this country. Some Regions (e.g. the South West) do not have a single Centre. The Centres are usually large rooms (the size of one or two standard hospital wards) in which a wide range of equipment is on permanent display. To the best of our knowledge, no formal evaluation has been published but experience indicates that they are much used by both patients and staff. Examples of the kind of equipment displayed include various types of bed, chairs, walking aids, and non-statutory electric wheelchairs. Some Centres include some of the less sophisticated Possum equipment and British Telecom usually have a permanent display. Ideally, all significantly disabled people should live within easy reach of a Disabled Living Centre. Initially there should be at least one Centre in each Region. Later, satellite Centres should be established in each reasonably sized town. We strongly recommend that adjacent Health Districts should combine their efforts so that there is a reasonable scatter of Disabled Living Centres throughout the country. Rural areas might need to be covered by a mobile unit. The Disabled Living Centres would have two principal functions:- 1. To provide a permanent standing exhibition of a comprehensive range of aids and equipment with a supporting information service. 2. To act as an educational centre for staff, volunteers and patients. Requirements for Disabled Living Centres 1. To carry as large and representative as possible a selection of aids and equipment. 2. To ensure that skilled professional advice (e.g. from nurses, occupational therapists, and physiotherapists) is available to disabled persons, their relatives and profes- sionals visiting the Centre. 3. To provide adequate space for assessment, with priva- cy, of the client with the equipment. 4. To provide information on a wide variety of problems arising out of disability. 5. To act as a teaching centre for all classes of people dealing with disability, including such groups as archi- tects and school teachers. 6. To gather information about the usage of aids and equipment and feed back information to manufacturers and other interested parties, including other Disabled Living Centres. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 173 Conditions which need to be met when setting up Disabled Living Centres 1. They must be properly funded with contributions from both NHS and Local Authority Services, even where charitable funding is, or was, responsible for the establishment of the Centre. This activity is well suited for joint funding. 2. Whoever is appointed to be in charge of the Centre would need to have a wide experience of disability and its management. It might be appropriate to appoint a thera- pist with good managerial skills. Health Authorities might like to consider the possibility of having a doctor with designated sessions in the Centre. 3. The therapist appointments should be part of the local NHS or local Authority manpower establishments to ensure a proper career structure for the therapist. 4. The Centre could be situated in the grounds of a hospital, but this need not necessarily be the case and some successful Centres have been established elsewhere. An advantage of a hospital site is that staff can be easily rotated through the Centre. The Centre needs to be housed in adequate premises with good access and ample car parking space. There must be sufficient floor space to allow the display of aids and equipment, and for assess- ment. 5. A library and information service, including appropri- ate audio-visual teaching aids must be available. Ulti- mately, Centres need to be linked together and to be able to provide information for a computerised data base on aids, equipment and other aspects of disability. 6. Where it is appropriate that the aid or appliance is provided from public funds, these should be rapidly supplied and each Health District must establish with the appropriate Local Authority or Authorities joint aid stores which contain stocks of essential items such as commodes, which can be delivered to the client within 24 hours of being ordered. Referral to the Centre should be encouraged from any source, including self referral by disabled people. Housing, Housing modifications and Re-housing The provision of residential accommodation is not pri- marily an NHS responsibility. However, it is clearly essential that, when a disabled patient (e.g. after an amputation or following a stroke) is fit for discharge from hospital?appropriate accommodation should be avail- able. Our experience is that a substantial proportion of hospital beds are currently being occupied inappropriate- ly by patients who are waiting either for re-housing or for housing modifications. As in other areas, the problem involves the need to provide a humane and caring service that is also related to economics. It seems likely that a more effective and efficient service could be provided at little extra cost.[52] During the last few years there have been important developments in the housing field, including the setting up of a considerable amount of warden-supervised ac- commodation. However, important problems remain, and these are exacerbated by the complexity of the administrative system. Many different organisations are involved, including the Housing Department, Social Services and the NHS. In many instances, the adminis- trative boundaries do not coincide. Other problems in- clude the small stock of appropriate housing for the disabled, the fact that new houses are still being con- structed without a downstairs toilet, and long and inap- propriate delays in effecting housing modifications, such as the installation of stair-rails and the widening of doors for wheelchairs. We think it important that each Health District should ensure that proper liaison exists between the hospital- based services (including the occupational therapy de- partment), Social Services, the Housing Department, and the Voluntary Housing Associations. Some mechan- ism must be established which would allow housing modifications to proceed without prolonged committee wrangling. Recommendations The problems are complex and clearly cannot all be solved by the NHS. However, the NHS can, and should, make an important contribution. We suggest the following:- 1. The Health Authority, Social Services and the Hous- ing Authority should be represented on a joint committee (for example, we propose the District Disability Commit- tee?see page 170), which would be concerned with all aspects of housing modifications for the disabled. Others could be co-opted as appropriate, including representa- tives of voluntary bodies and of disabled people them- selves. 2. There should be a community physician with specific responsibility for housing matters (see page 168). He/she would have specific responsibility for allocating medical priorities for housing (this would be done after consul- tation with the appropriate clinician) and for other hous- ing matters. He/she would probably be a member of the local Committee (see above) concerned with housing modifications for the disabled, and would be responsible for keeping records of the numbers of people with out- standing housing needs. The Physically Disabled School Leaver The problem of the disabled school leaver has been recognised for many years, but little action has been taken. The following quotation, taken from a Lancet annOtation[53], commented: Handicapped people need sequential care. Yet doc- tors based in hospitals tend to see their illnesses as episodic; instead of taking a personal grip on follow- up, they often leave the patients to organise return visits. In general, the pre-school leaver and school- aged person gets adequate continued care, but not so the school leaver and the young adult. When these people pass from the care of the Paediatric Hospital and Paediatric Community Health Ser- vice, often there is no organisation waiting to take 174 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 over. Handicapped school leavers and young adults need follow-up services comparable to those that they had before they left school. A recent important study was undertaken by a Work- ing Party set up by the Regional Medical Committee of the S.E. Thames Regional Health Authority[54] which set out to investigate the medical needs of the physically disabled school leaver. It found very little published information on the subject. It surveyed all the Regional Health Authorities in England, Scotland and Wales, and found that the majority of Regional Health Authorities made no specific provision for, nor were investigating, this group of patients. It also found in its catchment area that:- 1. There were inadequate routine medical examinations for the disabled child, leading to lack of understanding of his future needs. 2. There was lack of liaison between the School Medical Services and those services which would be responsible for the care of the disabled child when he or she left school; this included the District General Hospital and the Primary Care Team. There was no adequate arrange- ment ensuring that the disabled child was referred to the appropriate discipline for ongoing adult medical care. The parents commented that there was lack of communi- cation between them and the medical and caring services concerning the facilities that were available, such as appliances, wheelchairs, and finance. 3. Orthotic appliances and wheelchairs were frequently unsatisfactory. Recommendations Our recommendations are based partly on the findings of the S.E. Thames Working Party which suggested that a pilot study should be set up to assess the practical implications of its recommendations, and this we support. 1. Every Health District should have a written policy on the subject of the physically disabled school leaver. 2. Each District Health Authority should have a District Handicap Team for children. This team may be based in a Child Development Centre or in an out-patient depart- ment. The leadership of this multi-disciplinary team may be a consultant paediatrician with special experience in complex handicap, and/or paediatric neurology, but may be a community paediatrician. 3. Early in the year before leaving school?the physically disabled child should be the subject of a case conference at which there is medical (representing both the paediatric and adult services), educational, employment and Social Services representation. Whenever possible, parents should be encouraged to attend such conferences. The careers adviser and the DRO would also be involved. 4. At the final school medical examination of physically disabled school leavers there should be a full clinical examination and all the various disability problems would be reviewed. Hopefully?this exercise would be the cul- mination of a programme which began when the various disabilities were first recognised. If necessary, there should be referral to an appropriate consultant or Assess- ment Centre where the future needs of the disabled school leaver could be further explored. 5. An accurate Register of disabled school leavers in each Health District should be compiled, with a senior medical officer, perhaps the community physician, made respon- sible for organising and assessing the ongoing care of the individual disabled school leaver. It is suggested that each child should remain on the Register for three years. There should be liaison with the various services, medi- cal, social, educational and employment. 6. The paediatric team at the District Hospital level should develop a transfer procedure that would ensure continuity of care for disabled school leavers who will require ongoing adult medical care. 7. Appliances and wheelchairs should be checked at regular intervals by a designated person. Support Services for Younger Severely Disabled and Handicapped People Every district contains an important group of severely disabled people below retirement age. Cerebral palsy is the principal cause of the disabilities that date from birth. Of those that are acquired, the principal causes are rheumatoid arthritis, multiple sclerosis, stroke, and injur- ies of the brain and spinal cord. A Royal College of Physicians' Report (about to be published) will give details of the epidemiology and discuss many aspects of the support and care which these people require[55]. In both public and voluntary sectors, there has been a tendency, until quite recently, to concentrate on the provision of residential care. It is now recognised that many people with severe disabilities not only live in the community, but prefer to do so, provided that adequate facilities exist. Improved community services have in- creased disabled people's living options, but much re- mains to be done[56], A balance has to be maintained between the desire of many younger people not to be identified with the 'elderly' and needless duplication of facilities caused by the rigid segregation into two age- group categories. If younger disabled people are to live in their own homes, then certain criteria need to be met:- 1. The house must be suitable. Necessary requirements may include fittings and space for wheelchair living, and for storage of special equipment, wide door-frames, ready accessibility to shops, post offices and bank, and special provisions to ensure safety. 2. The support services must be adequate, and when, as is usual, responsibility falls heavily on one or two carers, these people must not be subjected to unmanageable workloads. Provision of 'respite care' facilities is often crucial, as are day centres, residential homes, and a variety of hospital-based services. 3. Helping a disabled person to find an occupation and/or leisure activity is often highly desirable, and is frequently essential. Day centres and special workshops are a partial solution, but access to activities in which able-bodied people participate may be of even greater importance. 4. Changes in the underlying illness and/or disability may require reassessment of the subject's needs, e.g. a Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 flare-up of multiple sclerosis may suddenly lead to incon- tinence and inability to walk. Efficient assessment ser- vices must exist in the Health District. 5. Realistic contingency plans should be prepared in the event of crises such as the development of intercurrent illness by disabled people or their principal carers. Recommendations 1. The Health District should keep an up-to-date list of the severely disabled people among its population (al- though it is acknowledged that the methodology for keeping such lists is yet to be properly developed). We suggest that this task could be undertaken either by one of the designated consultants in Disability Medicine, or by the designated community physician. 2. Support services for the young physically disabled would be a responsibility of the District Disability Com- mittee. This Committee would be expected to produce an annual report for the District Manager. The report would include matters itemised below (3-6). 3. The stock of houses suitable for disabled people would be reviewed annually. A similar exercise would be con- ducted for houses under construction or planned. 4. There should exist, somewhere within or near to the Health District, some permanent residential accommoda- tion for the most severely physically disabled patients. The adequacy, or otherwise, of this would be reviewed annually. 5. The residential accommodation could include pro- vision for intermittent planned short-stay, and for coping with occasional crises. Periods of short-stay can often be combined with reassessment of existing problems and active intervention, if appropriate. Some carers are reluc- tant to allow their dependants to go into residential homes or hospitals, because they fear that the care will be less good than that provided at home. For these reasons, it is essential that the staff involved are present in sufficient numbers. There must be access to the various skills represented in a multi-disciplinary team (particularly including remedial therapists). 6. A Day Centre for younger disabled patients should be available. Driving for the Disabled Car driving is an essential constituent of independence for many people. The loss of the ability to drive a car can be one of the most devastating results of illness and injury. Additionally, the ability to drive a car is often the key factor in finding and keeping employment. It is not always recognised that many patients with very severe disability are still able to drive suitably adapted vehicles. Thus, some tetraplegics and most paraplegics can drive. Some stroke patients can also drive. Problems that virtually preclude driving include severe athetosis, uncontrolled epilepsy, and hemianopia. There have recently been considerable advances in technology which are enabling an increasing number of disabled people to re-start driving. The majority of Health Districts do not provide specific assessment and training facilities for re-learning driving skills. However, a variety of options are available and these are listed in Appendix 3. We recommend that each District Health Authority should review the local facilities for the assessment and re- training of patients for driving. We regard it as essential that each severely disabled patient in whom there is the slightest possibility of re-starting driving should be able to be assessed without undue difficulty. Sexual Counselling In these days when the media seem to assume that sexual athleticism is a part of normal personality?it is particu- larly important that the physically disabled should not be, or feel, at a total disadvantage. Doctors need to recognise that the vast majority of people?however badly disabled, have sexual needs[57]. Sexual dysfunction may occur in disabled people for a considerable number of different reasons. Particular problems are likely to be experienced by patients who have a urinary or supra-pubic catheter, colostomy, mas- tectomy, or severe facial disfigurement due to burns. The doctor is frequently in a position to offer helpful advice. Examples include:- 1. The treatment of depression, which is very common amongst disabled people, and is an important cause of impotence. 2. A knowledge of the effects of drugs may be helpful? particularly those that have an effect on potency. 3. Genetic counselling may be helpful, as some patients have an unspoken but unwarranted fear that they may pass on their disease (e.g. multiple sclerosis) to a child. 4. Many patients are anxious about the effect of sexual intercourse on their disease?this is particularly liable to occur in patients who have suffered a myocardial infarc- tion or a stroke. Medical 'permission' to have sex can be important. 5. Analgesics, given before intercourse, may help patients with an inflammatory arthropathy. Counselling about positions, appropriately placed cushions and pil- lows, may be helpful in relieving discomfort. 6. Orthopaedic operations may be helpful in improving mobility (e.g. hip replacement in a patient with severe osteo-arthritis). Some severely disabled patients are not capable of under- taking full sexual intercourse and may need advice on other ways of achieving sexual gratification. Recommendations 1. Counselling advice should be available by someone who is knowledgeable both about sexuality and physical disability. Sometimes advice can be given by the general practitioner, or the hospital consultant. In other in- stances, more detailed help may be required, and this can sometimes be provided by a psychiatrist or psychologist who has developed an expertise in the subject. SPOD (Sex and Personal Relationships of the Disabled) is a voluntary organisation which provides information sheets and is sometimes able to provide counselling. 176 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 2. Patients who are being looked after in long-term residential accommodation should be provided with pri- vacy and the opportunity for sexual contact, if this seems appropriate. (This provision is frequently not met in Units for the Younger Physically Disabled.) 3. The management of sexual problems in the physically disabled should be included in both undergraduate and postgraduate educational curricula. Head Injury Services In our experience, head injury services are frequently not well organised and there is considerable scope for im- provement. This is occurring despite the obvious heavy economic cost, both to the State, and for individuals. These costs are incurred as a result of a number of factors, including the use of a considerable number of hospital beds, heavy use of staff time, and the consequences of unemployment. There is evidence that some patients are inappropriately placed. For instance, eight patients with head injury were found to have been in the acute wards of a London teaching hospital for up to two and a half years. Six of these were said to have potential for rehabilitation, but apparently had nowhere else to go[58]. The majority of Health Districts do not appear to have developed specific facilities for the management of dis- abled head injured patients. A similar position exists for the immediate post-traumatic period, although this mat- ter is not strictly within the remit of this Report. In some hospitals, a neurosurgical or neurological opinion cannot easily be obtained. Head injured patients are frequently scattered among many different wards, thus making it difficult for the staff to acquire a reasonable level of expertise. Research in these circumstances is usually not possible, and the MRC Working Group[59] suggested that Assessment and Therapeutic Units should be estab- lished, where patients from several Districts could attend during the early months after the acute brain damage. There seems to be little evidence that Health Districts have acted on this suggestion, although a successful experiment, involving the admission of head injured patients to one unit, has recently been conducted at the Edinburgh Royal Infirmary[60]. There is some evidence that severe post-traumatic behaviour disorder can be lastingly improved by beha- vioural modification techniques[61]. The present position relating to head injury Disability Services has been summarised in two recent articles by Gloag[62]. Epidemiology Field[63] estimated that there are about 7,500 major head injuries annually in England and Wales (34 per Health District of 250,000 people). About eight patients per Health District will be left with a severe permanent disability. The MRC Group on Stroke and Head In- jury[59] estimated that 250 persons with head injury per 100,000 population (625 per Health District) are ad- mitted to hospital annually. This figure corresponds reasonably well with the figure of 675 given in Table 2. The prevalence of serious head injury disability is prob- ably about 150 per 100,000 population (375 per Health District). Males outnumber females by about two to one. About 50 per cent of those admitted to hospital are under the age of 20 years. Road traffic accidents account for 33-37 per cent of head injured patients admitted to hospital[63]. The data relating to head injury disabilities are, in general, not of high quality and many are out of date. The problem is compounded by the changing patterns of injury resulting from a variety of factors, including seat- belt legislation. Head injury is an excellent example of a topic where up-to-date epidemiological information is required. The Nature of the Deficits Closed head injury produces a number of different, and overlapping, deficits. These may be roughly characterised as follows:- 1. Cognitive disorders. Patients may experience prob- lems with learning, language, and memory. In addition, there may be difficulties with concentration and atten- tion. These patients are frequently described as being 'poorly motivated'. 2. Emotional difficulties. Irritability is common occur- ring in 63-71 per cent of cases, in a recent study by McKinley et al. [64] Mood swings and severe depression also occur. 3. Behavioural disorders. These include irrational, anti- social and disinhibited behaviour. A few patients become violent. 4. A proportion of patients have associated 'physical defects' including hemiplegia, speech disorders and epi- lepsy. Some have multiple fractures. The profound effect of change in personality and mood on the relatives has become recognised[65]. Families tend to feel lonely, isolated and under stress for many years. In addition?there are obvious financial and economic con- sequences. Many of these problems do not readily fall within the province of conventional psychiatry. Nonetheless, psychi- atrists can have an important role to play. Neuropsycho- logists are trained in the assessment and management of many of the problems, but unfortunately very few are available, and most Health Districts do not have the benefit of their services. Some patients with mild/moderate head injuries appear to recover quickly. However, some have intellectual and behavioural disorders which are not always recognised. These patients are in danger of losing their jobs if they return to work too early. A case can be made out for ensuring that they have at least one routine neuropsycho- logical assessment. Basic Criteria for Head Injury Services within an Average Health District 1. Every Health District should have a written policy for the management of head injury?both in the acute and the recovery phase. This should be updated regularly. 2. Statistics should be kept and reviewed regularly. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 177 These would include the number of cases, severity, bed occupancy, and some measure of outcome. An estimate of head injury costs to the Health District should be made annually. We suggest that this information should be available in the annual Report of each Health District. 3. There should be a named consultant in each Health District who would be in charge of the Head Injury Recovery Service. He would have allocated sessional time for this work. It might also be appropriate to identify a consultant who would 'run' the acute head injury service. In some instances this job could be undertaken by the same consultant. Consultants from a variety of disciplines could be involved in the Recovery Service?including neurology, neurosurgery, psychiatry, and general medi- cine. 4. Patients in the acute stage (the first 1-2 weeks) require intensive nursing and are probably best cared for where there are other similar patients (e.g. those who are suffering the effects of an acute stroke). 5. Patients with significant head injury in the recovery phase (3-30 weeks) should be managed on a ward where the staff are fully trained. The Health District would probably not generate sufficient head injured cases to justify a specific ward dedicated to head injury. We suggest that these patients might be 'mixed' with patients who have suffered a stroke and other forms of allied neurological disability (e.g. multiple sclerosis). Patients with other disorders could be included in the rehabili- tation ward?depending on the particular circumstances of the hospital. 6. Special facilities will probably be required for severe behavioural and emotional problems. The District Psy- chiatric Service should be actively involved with this group. Specific provision should exist for the manage- ment of noisy and aggressive patients. 7. Follow-up. There should be a system to ensure the effective follow-up of all patients with a significant head injury. A register should be kept of such patients. A clinical psychologist (preferably a neuropsychologist) would be the appropriate person to supervise the long- term care of patients with severe residual cognitive problems. 8. Employment. There should be facilities for the assess- ment and re-training of head injured patients. 9. Day care. Many patients with severe residual disability impose an enormous strain on their families. Some form of day care facilities for this younger group of patients is required. We do not think that it would be suitable for the younger patients to be managed in a geriatric day hospital. Staff We consider it essential that there should be a named consultant in charge of the running and development of the Head Injury Recovery Service. We also recommend that a psychologist should be appointed, and he/she would work closely with the consultant. Other staff will also need to be recruited and trained. This operation would include social workers, remedial therapists, and nursing staff. Other Comments Although the scale of the problems posed by head injury can be predicted from published surveys, there is insuffi- cient evidence to identify the features that would consti- tute a model service. The sporadic placement of isolated patients in wards such as general surgical and general orthopaedic wards is widely regarded as inappropriate and has been a very considerable barrier to the conduct of clinical research in this field. The alternatives of a general rehabilitation ward in the District Hospital, or a District head injury ward, or a Supra-District (or Regional) Head Injury Unit have not yet been evaluated. There is an urgent need for research into the optimum organisation of the in-patient care of head injury rehabilitation and also into the techniques of cognitive and behavioural therapy employed in such units. It is essential that current Head Injury Services are evaluated and that a detailed system of audit is written into the operational policy of all head injury units. Many patients are helped by Headway, a voluntary organisation concerned with the support of head injury victims and their families. Referral to Headway should be made in all appropriate cases. Visual Impairment We fully appreciate that the medical responsibility for problems of vision and hearing rests primarily with clinical departments of ophthalmology and otorhinolar- yngology. But, as many patients with impaired limb function also have these problems, we thought it appro- priate to include short sections on visual impairment and defective hearing. Visual impairment is defined as corrected vision of lower than 6/18. The prevalence of visual handicap was found to be 520 per 100,000 population[66]. An average Health District of 250,000 would thus generate about 1,300 visually impaired people. Five per cent occur under the age of 16; 24 per cent in persons of working age, and the remainder in elderly and old people. Major causes are cataract, macular degeneration, diabetic retinopathy, glaucoma and retinal detachment. Clearly, each Health District will require a detection service for preventable and treatable causes of blindness, such as glaucoma, cataract, and diabetic retinopathy[67]. This would involve the appropriate training of opticians and general practitioners. It is assumed, also, that each District will have ophthalmic services for the treatment of ocular disorders, for example, cataract. In setting up a District Low Vision Service a close link will need to be maintained with the Social Services Department and with the various voluntary bodies. The suggested basic components include the following: 1. Each Health District should have a written policy. 2. There should be a consultant ophthalmologist with designated responsibility and sessions for the manage- ment of visual impairment. This consultant would be expected to act as a catalyst for the setting up and operation of the District Low Vision Service. 178 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 3. There would be an optician with designated sessions for the management of visual impairment. 4. A Low Vision Clinic, to which there would be open access, including by self-referral. The Clinic would pro- vide an assessment and follow-up service for patients with visual handicap (both total and partial blindness), as well as other visual problems including hemianopia and diplo- pia. The Clinic staff would be expected to undertake home assessments and to keep in regular touch with the patients. They would give advice on simple measures to overcome visual problems, including those involving housing, good lighting and the use of contrast. The staff would be knowledgeable about the various types of magnifiers and telescopic lenses. Training in various compensatory techniques, including eccentric fixation for patients with macular degeneration, should be available. A supply of equipment should be available for display and trial by patients. 5. There should be a domiciliary service?so that elderly and immobile patients can receive advice in their own homes. 6. There should be a static display of equipment for the visually handicapped. Hearing Impairment Taking an average hearing level of 35 dB or more over the range 500-4000 Hz in the better hearing ear as significant impairment, the prevalence of such impair- ment is around 10 per cent in the adult population of the UK[39], This figure rises to 75 per cent in those over 70 years old. Significant sensorineural hearing impairment in the newborn is found in approximately one case per 1000 live births. From these figures it would appear that hearing impairment is one of the most widespread of all physical disabilities having a marked effect on the ability to communicate socially and in the work place. In most Health Districts, the Hearing Impairment Service will be organised by the local ENT Department. The following are some suggested criteria for the setting up and running of District Services: 1. There should be a written District policy for the management of hearing impairment. 2. There should be a named consultant with designated responsibility for hearing assessment and the provision of services for hearing impairment. 3. A Hearing Assessment Clinic should be held regularly within the Health District. Ease of access is important, bearing in mind that much hearing impairment occurs in elderly people. 4. There should be a fixed site Clinic. This could, if appropriate, be combined with other Disability Services such as those concerned with visual impairment. The Clinic would have several sound-proofed rooms for as- sessment. There would be a static display of equipment for the hearing impaired ('environmental aids'), for example visual doorbells, television listening devices and telephone amplifiers. 5. Clearly defined links should be established with the Social Services Department which is empowered to pro- vide environmental aids. 6. Specific services should be available for the assessment and management of hearing deficit in small (pre-school) children. This will require an appropriately trained au- diological scientist with access to the necessary equip- ment. 7. The Hearing Assessment Clinic should have facilities for the management of tinnitus. 8. Domiciliary Services. Many deaf people are living in residential homes for the elderly. Others are too disabled to easily attend clinics. There should, therefore, be a domciliary service for the assessment of hearing impair- ment and the provision of aids. 9. Each Health District should have a hearing therapist who would provide support and after-care for deaf people (for example, running classes and visiting people in their homes). The duties of the hearing therapist would include teaching lip-reading and sign language, and giving advice on environmental aids. The therapist would also be concerned with the education of institutional (old people's homes) and hospital staff in ways of communicating with deaf people. Communication Aids In each Health District there are a substantial number of patients who are unable to communicate in the normal way. Examples of communication disorders include: cleft palate, laryngectomy, bulbar involvement in motor neur- one disease, and writer's cramp. Deafness is considered elsewhere. Many patients can be helped by electronic, or other devices termed 'communication aids'. Space-age technology has had a major influence in this area, and a large number of devices are available in a rapidly chang- ing field. A 1972 figure[68] of 1200 persons with impaired speech in a population of 250,000 (the size of the average Health District) is now thought to be an underestimate as a current review[69] suggests that the average Health Dis- trict contains 800 persons with severe communication disorders with a further 1600 with less severe but signifi- cant problems. Table 3. Medical diagnoses of 193 patients referred for, and recommended aids, at the Frenchay Communication Aids Centre in 1984/5. Number % Progressive Neurological Disease? Motor Neurone Disease, Parkinson's Disease and Multiple Sclerosis 68 35 Stroke 29 15 Cerebral palsy 29 15 Head injury 23 12 Miscellaneous (Including Laryngectomy and Glossectomy) 44 23 Communication aids are of particular use to patients whose language function is intact, but who, for some reason, cannot speak and/or write. They are not usually of use to patients with dysphasia, where there is a disturbance of linguistic ability. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 179 The main communication systems in use are: 1. Sign and letter systems?e.g. Deaf Alphabet, Maka- ton, and Amarind. 2. Symbol systems?e.g. Bliss Symbolics (the patient points to a symbol to represent an expression). 3. Low technology aids to communication?e.g. pointing boards, pictures and word charts. 4. Medium technology aids?e.g. Canon Communicator and the Cambridge Lightwriter. 5. High technology aids for communication such as speech synthesisers and computers. It is clearly important that patients should not be supplied with equipment which is inappropriate. Each patient must be individually assessed and this will involve an analysis of the precise type of communication defect, physical, visual and cognitive abilities, as well as his educational background and the prognosis of the under- lying disease. The following are the suggested criteria for an adequate Communication Aids Service. Recommendations Assessment It should be possible for all patients to be assessed by a speech therapist, and sometimes by other professional staff, including an occupational therapist, teacher, and sometimes an engineer. Equipment 1. A wide range of equipment should be available for trial purposes. 2. The patient must be able to acquire the requisite equipment quickly. This is particularly important for patients with rapidly progressive disorders such as motor neurone disease. 3. Each patient and his family should be properly in- structed in the use of the equipment. 4. Most patients require prolonged follow-up to ensure that their equipment is functioning properly and is the most suitable and up-to-date device. Different aids may be needed as the patient's environment or condition changes. Hospitals Sign, letter, and hospital picture boards should be avail- able in wards and Intensive Care Units where there are patients with major communication difficulties?for example, after a tracheostomy. Assessment of each situ- ation by a speech therapist is desirable. Regional and District Services Ideally, all patients should be within a reasonable dis- tance of a Centre that can provide a Communication Aids Service. We recommend that each District should have the ability to undertake simple assessments. More com- plicated needs would be dealt with at a Regional Centre. Some Health Districts should consider establishing a mobile Communication Aids Service for patients in iso- lated rural areas. Regional Unit The Regional Unit should be situated in the speech therapy department in a major hospital. It would ideally have links with the university, occupational therapy, and an engineering department. It should be staffed by two full-time speech therapists, and there should be some occupational therapy sessions and appropriate clerical help. Each Centre would have the capacity to assess patients with a wide variety of communication disorders, and have available a wide range of communication aids to be tried out by each patient. In addition, the Centre would hold a limited number of aids available for imme- diate loan (whilst the equipment was being ordered from the appropriate firm). Because many patients have to travel a substantial distance?we recommend that there should be three or four residential places (some of which could be in hostels) so that patients could attend the Communication Aids Centre over a number of days. The Regional Communi- cation Aids Centre would have an important educational function and run courses for professional staff. Services in Individual Health Districts There should be a small Communication Aids Centre, offering specific expertise, somewhere within each Health District. In certain areas it might be possible for this facility to be shared between Health Districts. This limited Communication Aids facility would be contained within a speech therapy department. One of the speech therapists would be expected to have a sessional commit- ment to the subject, and there would need to be appropri- ate cover for sickness and leave. A small amount of equipment would be held?including the more commonly used communication aids. The District Communication Aids Centre should have a close link with the Regional Centre. At both Regional and District levels, the Com- munication Aids Centre could be combined with a Dis- abled Living Centre (see page 173). Funding The setting up of a Communication Aids Service will inevitably involve some expense. It is likely that some additional staff will be required. Equipment for demon- stration purposes will need to be provided. We also think it highly desirable that each Communication Aids Centre should hold a 'bank' of the more commonly used aids. These could be loaned out to patients and recalled when no longer required. Some of the cheaper aids could be purchased by patients themselves. Aids may be funded for individual patients by Social Services, Manpower Services Commission, or the Edu- catidn Department. More frequently the patient would qualify for an aid, on consultant prescription, from the NHS. Each Health District will have to ensure that the necessary funds for these aids are available. A list of 180 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 Communication Aids Centres in England and Wales is given in Appendix 5. Wheelchairs The provision of wheelchairs is the responsibility of the Artificial Limb and Appliance Service (ALAC), which is directly responsible to the DHSS. In Scotland, this service has been incorporated into the Health Boards. An enquiry into the future of the ALAC Service has recently been published[50]. Wheelchairs are provided for people of all ages and sizes, and for widely disparate patterns of disease and disability. Data collected during 1973-1976 suggest that about two thirds of users of wheelchairs are above retirement age; 5 per cent are in paid employment; 5 per cent of wheelchairs are privately acquired, and one person in five will have two or more wheelchairs, with about 20 per cent requiring non-standard chairs[70]. Figures derived from the Scottish Home and Health Departmental] indicate that the number of chairs per 1,000 population increased from 1.2 in 1960 to 4.0 in 1970. Recently the Report on ALAC Services in Eng- land[50] found that 362,000 people have a wheelchair. Most elderly use a chair once a day; 15 per cent were totally reliant on the chair, using it on average for 64 hours a week. If these latter figures are accepted, the average group practice (with a list of 10,000) will have 72 persons with a wheelchair and there will be 1,810 persons with a wheelchair in each Health District with 250,000 people. Audit Fenwick[70] found that 9 per cent of his sample were 'not very satisfied'. Moreover, the longer a chair was used the more dissatisfied the user. Delay in the provision of wheelchairs was unsatisfactory for some people, 22 per cent waited for more than eight weeks. The Association for Spina Bifida and Hydrocephalus told the recent ALAC Review Committee that nine out of 10 of all young people with spina bifida are in wheelchairs which are unsuitable, needing adjustment or repair. A representative from Mary Marlborough Lodge told the Review Committee that 10 per cent of severely disabled people have wheelchairs which are unsafe or completely unsuitable. A recent survey in Leeds[72] showed that 77 per cent of hospital wheelchairs were defective; 57 per cent had tyres which were soft or flat, and 61 per cent had defective brakes. Similar results were found by Young et al. [73], Needs of Wheelchair Users Wheelchairs are required to fulfil a number of functions, which include mobility within the home, within the immediate vicinity of the house including the garden, and also for longer distances, including travelling to and from shops and public houses. Many patients need to be able to travel in a car, and so will require a chair which can fit into the boot. Comfort is important; some patients are likely to spend a large proportion of the whole day sitting in their chair. A number of patients have particular problems, such as: 1. Gross trunk instability?necessitating side supports. 2. Scoliosis, requiring a moulded cushion. 3. Hemiplegics, with only one functional arm and leg, have difficulty propelling the chair themselves. 4. Incontinence. Common Problems Experience indicates that problems with the Wheelchair Service include: 1. Slow provision. 2. Lack of instruction in usage and maintenance. 3. Difficulty with obtaining non-standard wheelchairs; it can take many months to get an appropriate chair. 4. Some chairs are unsuitable for the needs of the patient. 5. Maintenance of wheelchairs in hospitals seems to be particularly bad. Common problems include sagging seats and backs, worn brakes and unsuitable cushions. 6. Non-NHS chairs. There is at the moment, in most areas of the country, no way of obtaining an unbiased assessment for a non-NHS chair. What should be done by Health Districts? The Wheelchair Service is currently under review but we feel that some comments are desirable. We suggest that Health Districts might consider the following actions: 1. Set up a factual review of wheelchairs within the Health District. Information would need to be collected relating to the numbers of chairs, and the diseases encountered. It might be helpful to undertake an 'in depth' assessment of a sample of wheelchair users? examining such matters as: a) How well the various mobility needs are met?e.g. getting to the shops. b) General suitability for the patient's needs, e.g. foot supports, reclining back-rest, etc. c) How many wheelchairs each patient has, and whether this number appears to be appropriate. d) State of maintenance of the chairs. 2. Within the Health District there could be a Wheelchair Clinic attended by a doctor and an occupational thera- pist. This Clinic should cater particularly for patients with severe deformities who are likely to require special chairs. Advice on non-NHS chairs should also be given at such a Clinic. 3. Each Health District should ensure that chairs are maintained, and arrange for all wheelchairs to be re- viewed at regular intervals?at least twice a year. Within each hospital there should be a nominated person with responsibility for the maintenance of hospital wheel- chairs. The Health District should consider setting up a small workshop where all but major repairs could be effected. 4. Health Districts should make some provision for advice to be given on non-Statutory chairs?particularly electric chairs for outdoor use. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 181 Children Standard wheelchairs do not always fit the patient proper- ly. Special chairs and modifications are needed in some cases. Chairs need to be changed frequently?because of the varying requirements of the growing and developing child. The wheelchairs are needed for use at home and at school, and the problems arising from transporting chairs between home and school should be remembered. The possibility of holding an occasional Paediatric Wheelchair Clinic should be considered. Prosthetics and Orthotics The term 'prosthesis' is applied to equipment which replaces a lost part (e.g. an artificial limb). The term 'orthosis' is applied to equipment which can be attached to the body (e.g. a splint or collar). Amputations and Prosthetics The ALAC (Artificial Limb and Appliance Centres) Review Committee[50] reported that in 1984 there were 51,130 (285 per Health District) lower limb amputees in England and Wales. There were 11,813 (60 per Health District) upper limb amputees in England and Wales. There were approximately 5,000 (28 per Health District) new amputees each year. The vast majority of patients had lost limbs as a result of peripheral vascular disease and 78 per cent of new patients were over the age of 60. The vast bulk of patients are thus in the older age group, and they present with multiple problems, which include cardio-respiratory disease, arthritis, and some- times the effect of a stroke. Ideally, these patients need the services of a multi-disciplinary team for the assessment and management of multifarious disability problems. The loss of the limb is only one facet of their overall problems. At present, patients with amputations attend one of the DHSS Artificial Limb and Appliance Centres (ALAC) for fitting of the limb. There they are seen by a medical officer, employed by the DHSS, who acts as an interface between the surgeon at the hospital and the prosthetist at ALAC. This service was originally set up in 1945 to provide limbs for otherwise healthy war veterans, whose total number was in the order of 45,000. The Service now has to deal with a much larger number of older patients. Unfortunately, the training of ALAC medical officers has not always kept pace with recent advances, and this criticism has been voiced by the medical officers them- selves, amongst others. There is also widespread criticism of the delays in the provision of limbs, and the long waiting time the patients have to suffer at the ALACs. Another important aspect is that there seems to be evidence that British manufacturers have not caught up with the technical developments in artificial limbs that have occurred in the USA and in Europe. Also, while most ALACs are supplied by two or more firms providing prostheses under contract to the DHSS, there are several Centres where no choice is available as only one firm is represented. Thus, there is considerable evidence that the services for patients who have sustained the loss of a limb are not, in general, satisfactory. It seems clear that the ALAC system requires modernisation. A Working Party was set up by the Secretary of State to look into the present ALAC Services and make recommendations, and this reported in January, 1986. The Report recommends the establishment of Regional Centres where primary ampu- tations would be undertaken wherever possible. It also envisages that the ALAC facilities would be incorporated into a Regional Disability Centre where a whole range of disability problems could be catered for (including those of mobility, communication, continence and special senses). Prosthetists would work as part of the team at the hospital and a much wider range of artificial limbs would be available. In this way, hopefully, the present physical isolation of ALAC's would be overcome, and the Service would be largely incorporated into the overall disability facilities of the Region. These recommendations are very much in keeping with our own view, which we set out on Page 166. Orthotics Background The number of orthotic devices (orthoses) is large. The commonest are special footwear, spinal supports, lower limb splints and abdominal appliances, e.g. trusses. Less commonly prescribed orthoses include elastic stockings, collars, breast prostheses and wigs. Costs The costs are apparently unknown, but must be very considerable. The British Orthopaedic Association (BOA) Engineering Subcommittee[74] estimated in 1978 that two million orthoses are prescribed commercially each year. The DHSS does not produce any consumption figures and Districts do not usually keep detailed figures. Private contractors supply 97 per cent of orthoses; only 2.5 per cent are supplied by the very few hospital workshops in existence. Dissatisfaction with Orthotic Services Criticisms include: 1. Many orthoses are old-fashioned, ugly and ill-fitting. 2. The supply of orthoses is often slow and erratic? particularly when the device has to be specially made. 3. Lack of competition. Most Health Authorities deal with only one, or possibly two, commercial firms for the supply of equipment. They rely on the orthotist employed by the firms for advice as to the most suitable equipment. This orthotist thus becomes partly a salesman and partly a professional. Clearly, his main allegiance is likely to be to the company who employs him. So it is difficult for the patient to obtain independent advice regarding the most suitable orthosis. 4. There is no incentive for contractors to undertake research and development?hence the fact that many devices are clearly out-dated. 182 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 Short-Term Recommendations Ideally, the whole Service needs to be re-organised. In the short-term, however, it will be necessary to work with the system as it exists, however imperfect. Only prescribers (and patients) can make sufficient demands on the sytem to ensure that the correct equipment is supplied on time. This implies particularly that the prescriber (i.e. the doctor) is properly informed and educated as to what should be available and provided. Longer-Term Action 1. The majority of orthoses will be prescribed at District level and therefore it is clear that Districts themselves should employ some orthotists. This will mean substan- tially increasing the salary of orthotists so that the NHS can compete on equal terms with the private contractors. Some arrangement with private contractors will have to be made and proper audit arranged. 2. There should be a proper career structure for orthotists and prosthetists within the NHS. This will involve the development of training facilities. Action in this area is urgently required. 3. There should be Regional (and probably sub-Re- gional) Orthotic Centres with appropriately equipped workshops and equipment stores as an integral part of the Regional Disability Centre. At each major Centre there should be a display of the principal orthotic devices. 4. The Regional Centres would act as a major focus for staff training and for research (see below). Health Dis- tricts at a distance from the Centre might need to combine in the establishment of smaller satellite Centres which would be linked organisationally with the main Centre. 5. A consultant in disability medicine would be in charge of the Regional Orthotics and Prosthetics Service. He should be supported by other Health Service profession- als, including physiotherapists, occupational therapists, and orthotists. 6. Each Region and District should publish records of the number and costs of orthoses supplied each year. 7. The DHSS should sponsor research into the develop- ment of new and improved orthoses, using modern materials and modular systems. The Regional Disability Centres, with their university links, would be the ideal sites for such research. Urinary Continence Service Incontinence is defined as a condition in which involun- tary loss of urine is a social or hygienic problem and is objectively demonstrable. Thomas et al. [41] estimated that about 11,000 people (2,000 men and 9,000 women) could be anticipated to experience some degree of urinary incontinence in a Health District of 250,000. Of these, 1,000 would be under supervised care, but 10,000 would not be receiving any services. Incontinence increases with age. Common causes include prostatic disease in men, weakness of the pelvic floor in women, multiple sclerosis and mental subnormality. The cost of incontinence, both to individuals and the community, is high. Exton-Smith et al. [75] showed that incontinence accounted for 25 per cent of nursing time on a geriatric ward. Frost and Sullivan[76] in 1979 estimated that the current UK market for incontinence pads and appliances was in the order of 12 million pounds. Inconti- nence is often a reason for patients not being accepted into residential accommodation. General Principles for the Operation of a District Continence Service 1. Every Health District should operate a Continence Service. There should be a written District policy. 2. The Continence Service should be the responsibility of a designated consultant clinician with a particular interest and appropriate training in the subject. He would have one or more designated sessions. The consultant would frequently be a urologist, but in some cases could come from another discipline, such as gynaecology or geriat- rics. 3. Each Health District should employ a full-time nursing sister as a continence adviser (see below). This person, together with the consultant, would together be respon- sible for running the District Continence Service. 4. The District Continence Service should be centred on a permanent site. This would be manned during working hours, and telephone enquiries would be welcomed. An automatic telephone answering service could be in oper- ation at other times. 5. There should be a regular Continence Clinic in the Health District?held as often as necessary?perhaps weekly. This Clinic would have open access and patients would be able to refer themselves, or could be referred by any caring agency. The Clinic should be able to advise on all aspects of incontinence and it should be the focus of clinical assessment. 6. Each Health District should have a supply of basic equipment, including catheters, pads, and incontinence garments. These would usually be held at the permanent site. 7. There should be a permanent display of incontinence equipment?at the permanent site. This would include catheters and protective garments. Links would need to be forged with the local Disabled Living Centre, which could also have a static display, if this were felt to be appropriate. 8. There should be a plentiful supply of literature cover- ing common topics such as the prevention and manage- ment of incontinence, and catheter care. This literature should be widely available?in the Continence Clinic and elsewhere. 9. There should be training and educational facilities for professional staff?nurses, doctors, medical students, and others. These facilities are probably best centred at the District base. 10. Urological Assessment. Facilities must be available for the expert assessment of bladder problems, usually by a urologist. It should be possible to get urodynamic studies undertaken without difficulty, in order to measure pressure changes in the bladder and urethra during the Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 183 passage of urine, and urinary flow rates. We envisage that the urodynamic facilities would be sited in the District Urological Centre, and they might need to be shared between two or more Health Districts. Current evidence is that about six patients per week will require a urodynamic investigation[77], 11. Surgery. Facilities for urological and gynaecological surgery will be available in most Health Districts as part of the routine health service. Facilities for the implanta- tion of artificial sphincters should be available in a limited number of Centres, as implantation is a very specialised technique. Staffing Medical As mentioned above?we are suggesting that there should be a consultant in each Health District with designated sessions in the management of incontinence. He would be responsible for: 1. Organising and running the Service (in conjunction with the nursing sister). 2. Producing, and updating at regular intervals, plans for the District Continence Service. 3. Running a regular Continence Clinic in the District Continence Centre. Consultant time would need to be available for urodyna- mic studies. Clinical Assistant We suggest that the consultant input could be augmented by one or two clinical assistant sessions per week? depending on local needs. Nursing The nursing involvement will require a proper structure. There is now an Association of Continence Advisers with a particular responsibility for Continence Services. A high standard of training is now recognised as being necessary and the English National Board have estab- lished a Continence course to promote this (ENB Conti- nence Course 941). It is suggested that each Health District would employ a full-time nursing sister (Grade 1) or nursing officer, as a continence adviser. He/she would supervise the hospital and community care of incontinent patients. The conti- nence adviser would work in close collaboration with the responsible medical staff (particularly the consultant) and would require support from resource nurses who have also undertaken some specialist training. A close link should be established with the Stoma Service in the Health District. Other Staff The help of a secretary and a medical physics technician would be required (the latter to help with the running of the urodynamic assessment facilities). Stoma Care Service The term 'stoma' in the present context, is applied to any artificial external opening into one of the abdominal organs. For practical purposes, the principal stomas are ileostomy and colostomy for a bowel diversion, and urinary conduit. Other forms of stoma include gastros- tomy, jejunostomy, pharyngostomy, and suprapubic uri- nary catheters. The number of permanent ileostomies for colitis is falling. [78] There is a male-female ratio of 1:1.2. The number of permanent colostomies for rectal cancer has remained constant?5,510 operations in 1968 to 5,635 operations in 1980, with a male-female ratio of 1.5:1. Thirty per cent of all stomas are constructed in emerg- ency situations?ileostomies for acute fulminant ulcer- ative colitis and a variety of stomas for intestinal obstruction, trauma, and other causes. Prevalence data are sparse. Devlin[45] estimated that there are about 100,000 patients in England and Wales with a permanent colostomy (i.e. approximately 4-5 per general practitioner and 400 per average Health District). The comparable figures for permanent ileostomy is prob- ably about a tenth of this figure. The number of urinary conduits per Health District is not known. Rubin[79] estimated that the average cost of equip- ment for colostomy patients was ?496. This works out at about ?200,000 annually for each Health District (assum- ing 400 patients with a colostomy per Health District). There will be a smaller sum for patients with other types of stoma. In addition, there are substantial staffing costs (mainly nursing and medical). Present Pattern of Stoma Care Most stoma care in the United Kingdom is hospital- based. It has grown up in a haphazard manner, often with one surgeon showing a specific interest in the problem, and perhaps having a clinical assistant to help him run a Stoma Clinic with dedicated nurse involve- ment. Stoma nurses are generally hospital-based, though extension of their activities into the community is increas- ing. Since the early 1970's?Stoma Nurse Training Centres have provided the ENBCC 216 Clinical Course in Stoma Care Nursing for registered general nurses, usually lasting eight weeks, and including the physical, physiological, psychological and social aspects of stoma care. Some Centres provide a shorter (eight day) course on principles of stoma care (ENBCC 980); this course is available for all qualified nurses. The improvement in stoma care in the last 8-10 years has largely been the result of endeavours to train nurses to give them a greater facility for counselling and to provide them with reasonable hospital premises. There appears to be a deficiency in the service?principally in the lack of continuity that often occurs between the hospital, where the stoma is created, and the community, where it has to be rrianaged. The small number of stomas in the average general practice means that few general practitioners have any direct knowledge of stoma care and are not usually in a position to provide detailed advice. 184 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 The voluntary organisations, the Ileostomy Associ- ation, the Colostomy Welfare Group, and the Ileal Conduit Association, have provided much support. Other Background Information There is widespread recognition of the enormous psycho- logical consequences of the establishment of a stoma. Patients require continuing advice about a number of problems, including types of equipment, irrigation of the bowel, avoidance of leakage, skin protection, avoidance of odour, diet, clothing, alcohol intake, and taking of medication; employment, foreign travel, sexual activity and pregnancy. A number of complications can occur, and these need to be dealt with effectively. These compli- cations include leakage, sore skin and contact dermatitis, herniation around the stoma, prolapse of the stoma, depression and impotence. Particular problems are likely to be encountered by patients who have visual problems, defective arm function (e.g. after a stroke), and where there is intellectual deterioration. Considerable expense is involved in the running of a Stoma Service. Appliances are expensive and should be used effectively. Suggested Criteria for the Operation of a District Stoma Care Service Our recommendations are very similar to those which we have made in relation to the District Continence Service. Indeed, we consider that there is some scope for fusing the two Services. Certainly, we think that it should be possible for the two services to use the same building and probably the same secretarial staff. The overall objective is that all stoma patients should have pre- and post-operative counselling, informed and sympathetic medical and nursing care, and support. The general practitioner should have an important role. He is usually the first person to whom the patient turns when problems arise[80]. 1. Every Health District should operate a Stoma Care Service. There should be a written District policy. 2. There should be a consultant with designated responsi- bility for the running of the Stoma Care Service. The consultant will need to give enthusiastic and informed leadership. He will also need to develop links with other departments, including psychiatry and dermatology. The consultant input might need to be augmented by one or two clinical assistant sessions per week. 3. There should be a full-time stoma care nurse, with the grade of sister. She, together with the consultant, would be responsible for the operation of the District Stoma Care Service. There is probably need for a part-time staff nurse to provide back-up. 4. The Stoma Care Service should have a permanent Centre within the Health District (possibly shared with the District Continence Centre). 5. It will probably be desirable to run a regular Stoma Clinic?this would be the responsibility of the designated consultant and the nurse. 6. Within the Stoma Centre there should be a room which is comfortable, so that the medical staff can sit and counsel patients and their relatives about stoma care. There is also need for a room where clinical examinations can be undertaken, and this room would require sluice facilities so that patients can be taught how to change appliances and, for instance, irrigate a colostomy. 7. All patients undergoing elective colostomy or ileostomy should receive pre-operative counselling. They should be put in touch with patients in whom the operation has been satisfactorily completed. In this way, confidence may be gained. The Stoma Centre should hold a supply of basic equipment and have a permanent display (as discussed in relation to the Continence Service), and also a supply of literature for lay and professional staff. The Centre would be used for training and teaching. Careful records should be kept of the incidence, prevalence, and type of stomas within the Health District, and this information should be published in the annual Report of the Health Authority. There should be a record of equipment used, and of the costs of running the Service. Pressure Sores Pressure sores are life-threatening, unpleasant, socially undesirable and expensive. It was estimated in 1973 that hospitals were treating some 60,000 sores annually at a cost of around 60 million pounds[81], A survey in Glasgow found that 8.6 per cent of patients in hospital or community care had tissue damage, from superficial skin effects to necrosis and cavitation[82]. A review of four published hospital surveys found the prevalence of press- ure sores to range from 3 to 8.8 per cent[83]. Thus it appears that at least 5 per cent of patients in general hospitals will have one or more sores. A survey of all patients in the Bath Health District showed a prevalence of sores in hospital patients of 6.17 per cent compared with 1.27 per cent for patients in the community[84]. Pressure sores are an increasing problem with age so that the number of patients at risk will inevitably increase. Suggested Criteria for Operation of a District Service The current evidence indicates that pressure sores are common, frequently preventable and probably are cost- ing each Health District hundreds of thousands of pounds each year. On both humanitarian and economic grounds we recommend that every Health District should have a properly organised and audited Pressure Sore Prevention and Treatment Service set up with the following outline criteria? 1. There should be a written District policy for the prevention and management of pressure sores. 2. There should be a designated member of the medical staff in the District General Hospital who should be knowledgeable about medical aspects of pressure sore prevention and treatment. 3. There would be a designated senior member of the nursing staff who would have responsibility for running the District Pressure Sore Service (in conjunction with the designated member of medical staff). This person should be properly trained and informed on all aspects of Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 185 pressure sore prevention and management, and would be available to advise and train hospital and community staff. He/she should know about the various types of weight dispersal cushions and beds. 4. Training. District and ward nurses would be expected to have training in pressure sore prevention and manage- ment; this would be one of the responsibilities of the designated nurse. 5. A regular survey of the incidence and prevalence of pressure sores, both in the hospital and in the com- munity, should be undertaken. The annual cost (particu- larly of admission to hospital) to the Health District should be calculated and reported in the District annual Report. 6. Patients at risk of developing pressure sores should be identified routinely by means of a pressure sore prediction system, e.g. Norton[85]. There is an argument to be made for some form of enquiry whenever a major pressure sore occurs. The subject of pressure sore preven- tion has been discussed by Scales[86], 7. Plastic surgery help should be available when required. 8. There should be a readily available supply of beds, mattresses, and weight dispersal cushions. The most commonly available equipment should be available for demonstration and trial. APPENDICES 1. Definitions Used Throughout The Report Medical Disability Services?This term is used in the Report in relation to NHS Services that are required in order to prevent or minimise disability resulting from the disorders under discussion. Rehabilitation?The term 'Rehabilitation' has been used widely for many years and has proved to be virtually incapable of definition. We have not found it possible to entirely avoid using this term. However we broadly agree with the 'Mair Report'[5] which stated: Rehabilitation is a concept whose meaning varies from the precise to the vague, according to individ- ual taste, practice and experience. In the past, it was frequently taken to mean the application of physical methods of treatment aimed at restoring local function and general fitness after disease or injury. In recent times, a much broader meaning has been given to the word, which now implies the whole complicated process of the restoration of individuals rendered unfit from any cause to a degree of social and economic independence, within the limits imposed by any residual restriction of function. For the purposes of this report, the follow- ing simple definition was adopted: Rehabilitation implies the restoration of patients to their fullest physical, mental and social capability. 2. Prevalence of Physical Disability Estimates of the prevalence of physical disability and of the numbers of disabled people in the population vary according to the criteria used. In an effort to standardise definitions, the World Health Organisation has intro- duced a Manual of Classification?the International Classification of Impairments, Disabilities and Handi- caps (ICIDH)[87], This classification, based on the work of Wood[88], distinguishes between impairment, disabil- ity and handicap as different dimensions of the conse- quences of disease. Impairment is defined as any loss or abnormality of psychological, physiological or anatomical structure or function; disability as any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner or within the range considered normal for a human being; and handicap as a disadvantage for a given individual, resulting from an impairment or a disability that limits or prevents the fulfilment of a role that is normal (depending on age, sex, and social and cultural factors) for that individual. The following example illus- trates the differences between these three definitions: A building labourer of 40 undergoes a below-knee amputation as a result of an accident. The term 'impair- ment' refers to loss of part of the leg. The disability refers to his inability to walk quickly or to climb ladders. The handicap refers to the fact that he can no longer under- take his previous work because of his inability to climb ladders. To date, no results have been published of a survey of a large, defined population which identified impaired, dis- abled and handicapped people using the definitions and criteria of the ICIDH. It was necessary, therefore, to estimate numbers using data from surveys which used different definitions (Table 1). 3. Evaluation of the Service Provided by Mary Marlborough Lodge (Based on a Report to the Oxford Regional Health Authority; January, 1985, by G. M. Cochrane and G. I. Hughes). Mary Marlborough Lodge (MML) was established in 1960 as a Disabled Living Research Unit by the National Fund for Research into Poliomyelitis and other Crippling Diseases. In 1964 it was absorbed into the National Health Service. The Unit was under the direction of Dr. Philip Nichols from 1964 until his death in 1979. Dr. George Cochrane was appointed Medical Director in 1980. The principal function of the Unit is the assessment of severely disabled persons, and the provision of appropri- ate equipment, which is not readily available in other Centres. A wide variety of skills are available, and there is a comprehensive Workshop. 186 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 A study was undertaken of all new in-patients and out- patients attending MML during the three month period September to December 1983. In this period 81 new patients were seen and 42 (52 per cent) came from outside the Oxford Regional Health Authority. Patients were referred from as far away as Cumbria and Cornwall. Extrapolation of the figures for one year gives 325 new referrals in a year. Further examination of these figures shows: 1. The Oxford Regional Health Authority itself generated a substantial number of patients during this study period?equivalent to 156 annually. 2. Each year 168 patients will have come from beyond the Oxford Regional Health Authority catchment area. This indicates that the need is not being met by the other Regions. What Diseases are Involved? Details of the five principal diseases are given in Table 4. Table 4. Medical diagnoses of 81 patients seen at MML over a three month period. Diagnosis Number % Cerebral palsy 19 24 Amputees 10 12 Multiple sclerosis 7 10 12 Motor neurone disease 9 11 Spina bifida 7 9 Miscellaneous 26 32 Miscellaneous disorders (none of which comprise more than 5 per cent of the total) included stroke, muscular dystrophy, skeletal conditions (e.g. osteoarthritis) and spinal cord injury. Principal Problems Many patients were referred with a mixture of problems; 33 per cent of patients presented with five or more difficulties. Table 5 gives details of some of the main problems. Recommendations Made and Advice Given In all 412 recommendations were made?the median number for a single patient being five (range 1-13). Table 6 gives details of some of the recommendations. Particular Skills Available at MML The staff are fully trained in the understanding and management of the problems of patients with multiple handicap. Particular skills include: 1. The making and fitting of orthoses. 2. Customised seating. 3. Wheelchairs?advising on special types, alterations, and controls. Table 5. Patients' problems at MML (% of total). Problem % Wheelchairs and seating 58 Pain/weakness/joint contracture 44 Difficulty with transferring 36 Activities of daily living 30 Mobility 26 Psychological 19 Housing 16 Communication/speech 6 Table 6. Recommendations made at MML. Recommendation Number Wheelchair/seating 79 Medical 66 Transfer aids 51 Orthoses 27 Exercises, including limb training for amputees 26 Small aids 26 Mobile arm supports 7 4. Special items of equipment for personal care and recreation. 5. Moulded thermoplastic trunk supports. 6. Design and mounting of special switches for patients with absent or defective limb control. 7. Mobile arm supports for patients with severe proximal arm weakness. 8. Gardening for the severely disabled. Audit An audit was conducted of the patients who had attended MML. At follow-up after three months, 90 per cent of patients remained satisfied with the help that they had received. More than 80 per cent of the principal pro- fessional carers were satisfied with the service, infor- mation, and recommendations made. 4. Assessment and Training Facilities For Re-learning Driving Skills Assessment of the possibilities for driving must be carried out by an expert in this field whose recommendation as to suitability to drive will be accepted by the Licencing Authorities. Assessments can be provided by some branches of the British School of Motoring. If there is no local school prepared to offer help, enquiries should be made to the British School of Motoring, Disabled Drivers Section, 81/87 Hartfells Road, Wimbledon, London SW19. Assessment and driving instruction courses, and advice on conversion, are given at the Banstead Place Mobility Centre, Park Road, Banstead, Surrey, SM73 3LE, who specialise in the difficult case. Enquiries for driving test and licencing should be addressed to the Medical Officer, the Medical Advisory Branch, Depart- ment of Transport, Oldway Centre, Orchard Street, Swansea. To claim exemption from Road Fund Tax on Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 187 account of disability, enquiries should be addressed to the DHSS, Department DSB, 7a Warbreck Hill, Blackpool. The introduction of Mobility Allowance has marked a considerable advance for disabled patients who cannot use public transport. The criteria are strict and laid down in Leaflet L1211/April 1983. They comprise inability or virtual inability to walk or to make the exertion needed to walk, creating a serious risk to life or health. The allowance is ?20 per week, and this may be spent in any way preferred. Application is made on this form obtained from the local DHSS Offices and forwarded to the Mobility Allowance Unit, Norcross, Blackpool, FY5 3TA, to arrange a medical assessment. If an award of Mobility Allowance has been made, clients are eligible for the Motability Scheme. The Motability Scheme offers leasing or hire purchase of a vehicle, or purchase out- right. Leasing can be a most effective method, for a small car can be leased for seven years for a down payment of as little as ?13.00 and the Mobility Allowance assigned to Motability. There is an annual insurance premium of ?80. All servicing costs and repairs are paid by Motabi- lity, except the first four new tyres and with a mileage ceiling of 10,000 miles a year. Outright purchase is possible on low interest rates, but adaptations duty and comprehensive insurance must be paid. VAT exemption, however, is allowed on adaptations at competitive rates. There is a Disabled Drivers' Insurance Association ad- dress; 292 Hayle Lane, Edgware, Middlesex. It is well worth joining the Disabled Drivers Association, which offers benefits and advice. Its address is: Ash well Thorpe Hall, Ashwell Thorpe, Norwich. Motability's address is: Boundary House, 91/93 Charterhouse Street, London EC1. Orange Badge Scheme Most people in receipt of Mobility Allowance will qualify for the Orange Badge, which allows special parking. This is issued by the Social Services Department. Application should be accompanied by a medical report. The system has been much abused, and the issue of the badge is strictly controlled. 5. Communication Aids Centres BRISTOL Assistive Communication Aids Centre, Speech Therapy Department, Frenchay Hospital, Bristol BS16 1LE. Tel. 0272-565656 Ext. 2140. LONDON Communication Aids Centre, (Speech Therapy) Charing Cross Hospital, Fulham Palace Road, London W6. Tel. 01-7482040. NEWCASTLE Communication Aids Centre, Royal Victoria Infirmary, Queen Victoria Road, Newcastle-upon-Tyne. Tel. 0632-325131 Ext. 455. SANDWELL Communication Aids Centre, Sandwell Health Authority, Boulton Road, West Bromwich, West Midlands B70 6NN. Tel. 021-553 0908. WALES Communication Aids Centre, Rookwood Hospital, Fairwater Road, ? Llandaff, Cardiff. Tel. 0222-566281. LONDON Communication Aids Centre, Wolfson Centre, Mecklenburgh Square, London WC1N 2AT. ' Tel. 01-8377618. 6. List of Demonstration Centres CENTRE 1. Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ. 2. Crawley District General Hospital, West Ham Drive, Crawley, Sussex RH11 7DH and Horsham Hospital, Hurst Road, Horsham, Sussex. 3. Derbyshire Royal Infirmary, London Road, Derby DEI 2QY. and Derwent Hospital, Derby, Kings Lodge Younger Disabled Unit. CONSULTANT IN CHARGE Dr J. R. Jenner Dr J. A. Hicklin Dr A. Martin Dr R. Bailey Dr C. F. Murray Leslie SPECIALITY General Rehabilitation Rheumatology General Rehabilitation Geriatric Rehabilitation Geriatric Rehabilitation Rheumatology & Rehabilitation Orthotics & Disability Research Rehabilitation Engineering & Disabled Driving Centre 188 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 4. Devonshire Royal Hospital, Buxton, Derbyshire. Young Disabled Unit, Withington Hospital, West Didsbury, Manchester M20 8LR. Wythenshaw Hospital, Southmoor Road, Manchester M23 7LT. 5. Garston Manor Medical Rehabilitation Centre, Garston, Watford, Herts. WD2 7JX. 6. Guy's Hospital, St. Thomas Street, London SE1 9RT. 7. Medical Rehabilitation Unit, RAF Headley Court, Leatherhead, Surrey. 8. Kings College Hospital, Denmark Hill, London SE5. 9. The London Hospital, Whitechapel, London El IBB. 10. Mary Marlborough Lodge, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD. 11. Medical Rehabilitation Centre, 152 Camden Road, London NW1 9HL. 12. Middlesbrough General Hospital, Ayresome Green Lane, Middlesbrough, Cleveland TS5 5AZ. 13. Norfolk & Norwich Hospital, St. Stephens Road, Norwich NR1 3SR. Mundesley Hospital, Mundesley, Norfolk. St. Michael's Hospital, Aylsham, Norfolk. 14. Pinderfields General Hospital, Aberford Road, Wakefield, Yorks WF1 4DG. 15. Robert Jones & Agnes Hunt, Orthopaedic Hospital, Oswestry, Salop SY10 7 AG. 16. Royal East Sussex Hospital, Cambridge Road, Hastings, Sussex. 17. Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath, Avon BA1 1RL. 18. Regional Rehabilitation Unit, Salisbury General Hospital, Odstock Branch, Salisbury, Wilts. SP2 OBJ. 19. Westminster Hospital, Dean Ryle Street, London SW1 2AP. 20. The Wolfson Medical Rehabilitation Centre, Atkinson Morley's Hospital, Copse Hill, Wimbledon, London SW20. 21. Fazakerley Hospital, Longmoor Lane, Liverpool L9 7AL. 22. Royal National Orthopaedic Hospital, 234 Great Portland Street, London SIN 6AD. Stanmore Branch, Brockley Hill, Stanmore, Middx. HA7 4LP. Dr E. P. Copp Dr P. H. Merry Dr H. N. Misra Dr A. P. H. Randle Dr R. Grahame Group Captain A. F. T redre Dr E. B. D. Hamilton Mr B. Roper Dr G. M. Cochrane Dr F. R. Middleton Dr J. Fordham Dr W. G. Wenley Dr. J. R. Burrows Dr N. Cardoe Dr A. A. Burt Prof. B. T. O'Connor Mr S. C. Gallennaugh Dr A. K. Clarke Dr R. M. Ellis Prof. D. A. Brewerton Dr D. G. Jenkins Dr E. Williams Dr C. B. Wynn Parry Rheumatic Disease: Rehabilitation of Severe Locomotor Disorders Arthritis, Stroke and Geriatric Rehabilitation General Rehabilitation Rehabilitation after Trauma Residential Rehabilitation Rheumatology Rehabilitation of Locomotor Disorders Orthopaedic Rehabilitation Rehabilitation of Hand and Head Injuries Rheumatology and General Rehabilitation Rheumatology: Joint Replacement Surgery and Orthopaedic Rehabilitation The Severely Disabled: Daily Livine?Rehabilitation Research Unit Day Rehabilitation Centre Rheumatology: Rehabilitation of Locomotor Disorders Rehabilitation Rheumatology Sub-Regional Service Neurology Orthopaedic Rehabilitation Rheumatology Orthopaedic Surgery Joint Replacement Surgery and associated problems of rehabilitation Rheumatology General Rehabilitation Rheumatology and Rehabilitation Neurological Rehabilitation Rheumatology and Rehabilitation; Neurology Pain Rheumatological Rehabilitation Orthopaedic Rehabilitation Neurological Rehabilitation Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 w 6. List of Demonstration Centres (continued) CENTRE 23. Royal Devon & Exeter Hospital, Heavitree, Exeter, Devon. 24. Humberside National Demonstration Centre in Medical Rehabilitation of the Elderly, Kingston General Hospital, Beverley Road, Hull HU3 1UR. 25. Northwick Park Hospital, Watford Road, Harrow, Middx. HA1 3UJ. 26. Newmarket General Hospital, Exning Road, Newmarket, Suffolk CB8 7JG. 27. Rehabilitation Unit of Western District of Leeds, plus Younger Disabled Unit, plus William Merritt Aids Centre. Correspondence to: Leeds General Infirmary, Great George Street, Leeds LSI 3EX. Tel. 0532-4322799. 28. Queen Mary's Hospital, Roehampton, London SW15 5PN. 29. Rookwood Hospital, Fairwater Road, Llandaff, Cardiff CF5 2YN. CONSULTANT IN CHARGE Dr J. S. Watkins Dr J. McV Loudon Dr A. Frank Dr B. Hazleman Dr M. Anne Chamberlain Dr I. H. M. Gurwen Dr J. C. Chawla SPECIALITY Geriatric Medicine and Rehabilitation in the Elderly Geriatric Medicine Childhood and Adult Rheumatic Disorders. Provision of a Service to the Health District including Domiciliary and Coronary Rehabilitation Rehabilitation of Rheumatic Diseases Rheumatology and Rehabilitation Rheumatology and Rehabilitation Neurological Rehabilitation Neurosurgical Rehabilitation 7. Some Useful Addresses from the Disability Rights Handbook British Sports Association for the Disabled: Hayward House, Barnard Crescent, Aylesbury, Bucks. HP21 8PP. Tel. 0296-27889. DEMAND (Design and Manufacture for Disability): 99 Leman Street, London El 8EY. Tel. 01-488 9869. Disabled Drivers Association: Ashwellthorpe Hall, Ashwellthorpe, Norwich NR6 1EX. Tel. 050-841 449. Disability Alliance: 25 Denmark Street, London WC2H 8NJ. Disabled Living Foundation: 380-384 Harrow Road, London W9 2HU. Tel. 01-289 6111. Disablement Income Group: Attlee House, 28 Commercial Street, London El 6LR. Leonard Cheshire Foundation: 26-29 Maunsel Street, London SW1P 2QN. Tel. 01-828 1822. Motability: Boundary House, 91-93 Charterhouse Street, London EC1 M6BT. Tel. 01-253 1211. National Bureau for Handicapped Students: 40 Brunswick Square, London WC1N 1AZ. Tel. 01-278 3450/3459. PHAB: Tavistock House North (2nd Floor), Tavistock Square, London WC1H 9HX. Tel. 01-388 1693. John Grooms Association for the Disabled: 10 Gloucester Drive, Finsbury Park, London N4 2LP. Tel. 01-802 7272. Radar: 25 Mortimer Street, London WIN 8AB. Tel. 01-637 5400. REMAP (Rehabilitation Engineering Movement Advisory Panels): 25 Mortimer Street, London WIN 8AB. Tel. 01-637 5400. Riding for the Disabled Association: Avenue 'R', National Agricultural Centre, Kenilworth, Warks. Tel. 0203-56107. Royal National Institute for the Blind: 224 Great Portland Street, London WIN 6AA. Tel. 01-388 1266. Royal National Institute for the Deaf: 105 Gower Street, London WC1E 6AH. Tel. 01-387 8033. SPOD (Sexual and Personal Relationships of the Disabled): 286 Camden Road, London N7 OBJ. Tel. 01-607 8851/2. Winged Fellowship Trust Holidays for Disabled People: Angel House, Pentonville Road, London N1 9XD. Tel. 01-833 2594. Note: The Disability Rights Handbook is published each November, and has a comprehensive list of organisations, including those for particular conditions. It is available from the Disability Alliance. 190 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 SUMMARY This Report puts forward a plan for the management of physical disability. It recognises that the subject is admin- istratively complex and that many different organisa- tions, including Social Services, are involved. The Report concentrates upon the role of the NHS in general, and upon the position of physicians in particular. The Report starts by reviewing some of the evidence that services for the physically disabled are in many respects deficient. The evidence includes accounts given by disabled people themselves, the fact that many patients are 'followed-up' by inexperienced junior hospital staff, and the lack of agreed standards of provision in many areas (see Section 3) such as pressure sores, incontinence, wheelchairs, and the care of head injured patients. Dis- abled people between the ages of 15 and 65 are identified as requiring particular attention (Paediatric and Geriatric Services probably cater reasonably well for the young and the old). The 'size' of the problem of physical disability is examined. For instance, the average Health District (of 250,000 persons) will contain 25,000 physically disabled people, of whom 6,250 will be severely, or very severely disabled; and 1,800 will have a wheelchair; 40 per cent of disabled people are under the age of 65. The Working Party on Rehabilitation Medicine of the Royal College of Physicians (1978) was of the opinion that rehabilitation is an integral part of total patient care, and is therefore the concern of all clinicians. The implica- tion of this view is that Medical Disability Services should be developed without a major specialty of Rehabilitation or its equivalent, such as exists in most western countries. The Report explores the practical implications of this principle in the light of evidence discussed above. Research (Page 168) There is a need for a major expansion of research. Priority areas include epidemiology (particularly of head injury), the physiology of recovery, and the evaluation of equipment, rehabilitation techniques, and different ways of providing care. We recommend particularly the setting up of units capable of investigating the many problems of neurological disability. Regional Disability Units should be important Centres of research. Regional Services (Page 166) Some Services will need to be organised at Regional level, some at District level, and, in other situations, two or three Health Districts may combine in the setting up of services. The principles involved are intended to be firm enough to provide a minimum standard of care, but sufficiently flexible to allow for local circumstances. We recommend the setting up of a Regional Disability Unit in each Region in England and one in Wales. We agree with the ALAC Review Committee that it would be sensible to incorporate the functions of the ALACs into the Regional Disability Units. Each Unit would form close links with Health Districts in its Region, and would form an important focus for the development of Regional Disability Services. The Units would have research and training functions and would be attached to a major District General Hospital with, ideally, links with the medical school and/or university. Each Unit would in- clude on its staff the equivalent of two full-time consult- ants in Disability Medicine. The functions that we envisage for the Unit are as follows: 1. The assessment of severely disabled patients?es- pecially those with multiple problems. 2. Orthotics, Prosthetics and difficult Wheelchair prob- lems. Appropriate workshops would be provided. 3. The Unit could include a Disabled Living Centre, where a wide variety of equipment is available for inspection and trial. 4. The Regional Communication Aids Centre could be included. 5. The Unit might incorporate the management of certain specific clinical disorders, such as spinal injury and/or stroke disability. District Services (Page 166) 1. Information. Health Districts should maintain an up-to- date data base of facilities for the physically disabled locally. A booklet should be produced annually. 2. Generic services. Certain specific services (e.g. a District Continence Service) should be provided and minimum standards should be attained and maintained. 3. Domiciliary Services. Each Health District should ensure that there are adequate numbers of therapists and district nurses who are properly trained in the management of disability. These community workers should collaborate closely with general practitioners. 4. Medical Staffing. (a) Consultants. We recommend that in each Health District there should be 10-11 disability sessions held by two or more consultants practising in a variety of special- ities (e.g. general medicine or neurology). Each consult- ant would have certain specific designated responsibilities. (b) Community Physicians. We see an important role for a community physician who would be involved in collecting and analysing data and acting as a co-ordinator for certain clinical groups (particularly the disabled school leaver). We envisage that the community physician and consultants with Medical Disability sessions would work closely together. (c) General practitioners. The GP has a vital co-ordinating and supportive function. This role is particularly import- ant if the principle of maintaining disabled people in the community, rather than in residential care, is to be implemented. He should be able to 'plug in' easily to the wide variety of Disability Services provided within and outside the District. Generic Services (Page 173) The term Generic Services is used in respect of those services which are likely to be used by a variety of disabled patients, which are not obviously the responsi- Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 191 bility of a particular specialty. We have identified 15 specific areas: 1. Disabled Living Centres. 2. Housing, Housing Modifications and Re-Housing. 3. The Physically Disabled School Leaver. 4. Support Services for Younger Severely Disabled and Handicapped People. 5. Driving for the Disabled. 6. Sexual Counselling. 7. Head Injury Services. 8. Visual Impairment. 9. Hearing Impairment. 10. Communication Aids. 11. Wheelchairs. 12. Prosthetics and Orthotics. 13. Urinary Continence Service. 14. Stoma Care Service. 15. Pressure Sores. For each of the 15 areas we have suggested some basic professional standards which can be used as a basis for audit. We anticipate that the establishment of these Services will make it easier for doctors to care effectively for disabled patients under their care. Some of the principles underlying these Generic Services include the following: 1. There should be a written agreed District policy. 2. There should be a series of simple audit criteria. 3. Areas of defined responsibility should be identified (e.g. a Consultant in charge of the District Continence Service). 4. For certain services (e.g. Continence and Stoma Care) there should be a permanent District site where clinics are held, equipment is available for trial and inspection, and where advice can be obtained and training given. 5. A plentiful supply of literature should be available for patients, relatives and professional staff. 6. Domiciliary facilities should be available for house- bound patients relating to, for example, visual and hearing impairment. 7. Certain basic records and statistics should be kept (e.g. the number of pressure sores, and patients with a signifi- cant head injury occurring within the Health District). Medical Staffing (Page 170) The Committee makes its recommendations on the prin- ciple that each doctor is responsible for dealing effectively with the disability problems of patients under his care. Nonetheless, it is felt that certain defined consultant sessions in Disability Medicine should be established: 1. Consultant Posts a) Posts with Disability as the principal component. We recommend that each Region should have two full-time, or equivalent, consultants practising in disability medi- cine. Their main work would be at Regional Disability Units. b) Each Health District should have 10-11 consultant disabiity sessions which would be held by two or more consultants from a variety of specialties. We anticipate that these consultants would seek dual accreditation (e.g. neurology and disability medicine). c) In each Health District there would be a community physician with specific responsibility for certain aspects of Disability Services. 3. Training A certain number of 'one-off senior registrar training posts will need to be created in order to achieve a target of 30-35 full-time consultants in disability medicine within five years. Once these consultant posts have been filled, then there will need to be a smaller number of permanent senior registrar posts. A substantial number of posts involving dual training are required (e.g. general medicine and disability). The SAC's are asked to draw up training schedules as a matter of urgency. Undergraduate and Postgraduate Education (Page 171) The management of disability should be an integral part of all undergraduate and postgraduate training pro- grammes. The practical implications of these recommen- dations include ensuring that examinations include questions relating to disability, and the inclusion of the subject in vocational training schemes for general prac- titioners, and in medical textbooks. Organisation and Administration (Page 169) We consider that there should be a formal Committee structure at both Regional and District levels. Annual reports would be drawn up by Disability Committees, and these would be submitted to District and Regional managers. The Committees would also be expected to draw up short- and long-term plans. Timetable (Page 171) WE suggest a five-year timetable. At the end of this time the principal recommendations in this Report should have been implemented. A major review of Disability Services should be undertaken in the early 1990's. Audit (Page 172) This document contains a number of audit standards by which the quality of Disability Services can be judged. 'Internal' audit would be conducted by District and Regional managers. 'External' audit would probably need to be undertaken by some outside body not funded by the NHS. Costs and Resources (Page 172) Because existing patterns of care vary from Region to Region, no attempt has been made to 'cost' the proposals outlined in this document. We make the following points: 1. The current level of investment in Medical Disability Services is low. 2. It is, essential to ensure that money is effectively spent (e.g. prevention and early treatment of pressure sores may be cheaper than lengthy stays in hospital). 3. Physical disability should be recognised by the DHSS as an area for top priority funding. 192 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 REFERENCES 1. British Medical Association (1954) The Rehabilitation and Resettlement of Disabled Persons. London. BMA. 2. Report of the Committee of Enquiry on the Rehabilitation, Train- ing and Resettlement of Disabled Persons (1957) Cmnd. 169 London. HMSO. 3. British Medical Association (1968) Aids for the Disabled. London. BMA. 4. DHSS. Central Health Services Council (1972) Rehabilitation Lon- don. HMSO. 5. SHHD. Scottish Health Services Council (1972) Medical Rehabili- tation. Edinburgh. HMSO. 6. National Fund for Research into Crippling Diseases (1976) Integrat- ing the Disabled. Horsham. NFRCD. 7. Disability Studies Unit (1977) Look Back at 'Tunbridge'; a Review of the DHSS Report. Arundel. Disability Studies Unit. 8. Royal Commission on the National Health Service (1979) Report. Cmnd. 7615. London. HMSO. 9. Harris, A. I. (1971) Handicapped and Impaired in Great Britain. London. HMSO. 10. Knight, R. and Warren, M. D. (1978) Physically Disabled People living at Home. DHSS Report on Health and Social Subjects 13. London. HMSO. 11. Sainsbury, S. (1970) Registered as Disabled. Occasional Papers on Social Administration 35. London. G. Bell and Sons. 12. Blaxter, M. (1976) The Meaning of Disability. London. Heinemann. 13. Locker, D. (1983) Disability and Disadvantage. The Consequences of Chronic Illness. London. Tavistock Publications. 14. Johnson, G. S. and Johnson, R. H. (1977) Social Service Support for MS Patients in West Scotland. Lancet 1, 31. 15. Elian, M. and Dean, G. (1983) Need for and use of Social and Health Services by MS Patients living at Home in England. Lancet, 1, 1091. 16. Milward, S. (1984) Practical Help in Multiple Sclerosis. British Medical Journal, 289, 1141. 17. Johnson, R. H. and Johnson, G. S. (1972) Differences in Opportu- nities for the Disabled in England and Scotland: a Survey of Paraplegics in Scotland. British Medical Journal, 1, 779. 18. Coe, R. G. (1982) 22 Years a Paraplegic. Lancet, 1, 789. 19. Mackay, A. and Nias, B. C..(1979) Strokes in the Young and Middle-aged. Journal of the Royal College of Physicians, 13, 106. 20. Brocklehurst, J. C., Morris, P., Andrews, K., Richards, B. and Laycock, P. (1981) Social Effects of Stroke. Social Science Medicine, 15A, 35. 21. Holbrook, M. (1982) Stroke; Social and Emotional Outcome. Journal of the Royal College of Physicians, 16, 100. 22. Sacks, O. (1983) Awakenings. 2nd edn. London. Picador. 23. Evans, K., Hickman, V. and Carter, C. O. (1974) Handicap and Social Status of Adults with Spina Bifida. British Journal of Preventive and Social Medicine, 28, 85. 24. Castree, B. J. and Walker, J. H. (1981) The Young Adult with Spina Bifida. British Medical Journal, 283, 1040. 25. Newrick, P. G. and Langton Hewer, R. (1984) Motor Neurone Disease. Can we do better? British Medical Journal, 289, 539. 26. Carus, R. (1980) Motor Neurone Disease. A Demeaning Illness. British Medical Journal, 1, 455. 27. Pollard, D. (1984) Personal View: Motor Neurone Disease. British Medical Journal, 288, 481. 28. Chilvers, A. S. and Browse, N. L. (1971) The Social Fate of the Amputee. Lancet, 2, 1192. 29. Van de Ven, C. M. C. (1981) An Investigation into the Manage- ment of Bilateral Leg Amputees. British Medical Journal, 283, 707. 30. Cartwright, A., Hockey, L. and Anderson, J. L. (1973) Life Before Death. London. Routledge and Kegan Paul. 31. Oakley, A. (1979) Living in the Present. British Medical Journal 1, 861. 32. Skinner, B. (1984) How to participate in your own Health: A Cancer Patient's View. Lancet, 2, 971. 33. Mayou, R., Foster, A. and Williamson, B. (1978) The Psychologi- cal and Social Effects of Myocardial Infarction on Wives. British Medical Journal, 1, 699. 34. Naismight, L. D., Robinson, J. F., Shaw, G. B. and Macintyre, M. M. J. (1979) Psychological Rehabilitation after Myocardial Infarction, British Medical Journal, 1, 439. 35. Kennedy, H. J., Lee, E. C. G., Claridge, G. and Truelove, S. C. (1982) The Health of Subjects Living with a Permanent Ileostomy. Quarterly Journal of Medicine, 51, 341. 36. Burnham, W. R., Lennard-Jones, J. E. and Brooke, B. N. (1977) Sexual Problems among Married Ileostomists. Gut, 18, 673. 37. Dobson, P. (1974) Management of Incontinence in the Home. London. Disabled Living Foundation. 38. Patrick, D. L., Darby, S. C., Green, S. et al. (1981) Screening for Disability in the Inner City. Journal of Epidemiology and Community Health, 35, 65. 39. Haggard, M., Gatehouse, S. and Davis, A. (1981) The High Prevalance of Hearing Disorders and its Implications for Services in the UK. British Journal of Audiology, 15, 241. 40. Cullinan, T. R. (1978) Visually Disabled People at Home. Health Trends, 10, 90. 41. Thomas, T. M., Playmat, K. R., Blannin, J. and Meade, T. W. (1980) Prevalance of Urinary Incontinence. British Medical Journal, 281, 1243. 42. Kelsey, J. L. (1982) Epidemiology of Musculoskeletal Disorders. Oxford. Oxford University Press. 43. Wood, P. H. N. (ed) (1977) The Challenge of Arthritis and Rheumatism. London. British League against Rheumatism. 44. Rose, R. C. (ed) (1980) ClinicalNeuroepidemiology. Tunbridge Wells. Pitman Medical. 45. Devlin, H. B. (1985) Stoma Care Today. The Medicine Publishing Foundation. 46. DHSS. (1984) On the State of the Public Health for the Year 1983. London. HMSO. 47. Royal College of Physicians (1978) Report of the Working Party on Rehabilitation. London. RCP. 48. Royal College of Physicians. (1981) Disabling Chest Disease. Journal of the Royal College of Physicians, 15, 69. 49. Royal College of Physicians (1975) Care of the Patient with Coronary Heart Disease. Journal of the Royal College of Physicians 10, 5, 50. DHSS (1986) Review of Artificial Limb and Appliance Centre Services. London. DHSS. 51. DHSS. Welsh Office. Advisory Committee on the Health and Welfare of Handicapped Persons. (1969) People with Epilepsy. London. HMSO. 52. Goldsmith, S. Towards a Housing Policy for Disabled People, Central Council for the Disabled. 53. Annotation (1976) The Handicapped School Leaver. Lancet, 1, 77. 54. S. E. Thames Regional Health Authority (1984) The Medical Needs of the Physically Disabled School Leaver. 55. Royal College of Physicians (1986) Use of Residential Home and Hospital Units for Younger Disabled Adults (in preparation). 56. Prince of Wales Advisory Group on Disability (1985) Living Options. 57. Greengross, W. (1981) Sex and Physical Disability. British Medical Journal, 283, 1089. 58. Gloag, D. (1985) Services for People with Head Injury. British Medical Journal, 291, 557. 59. Report of an MRC Coordinating Group (1982) Research Aspects of Rehabilitation after Acute Brain Damage in Adults. Lancet, 2, 1034. 60. Miller, J. D. andjones, P. A. (1985) The Work of a Regional Head Injury Service. Lancet, 1, 1141. 61. Eames, P. and Wood, R. (1985) Rehabilitation after severe Brain Injury. Journal of Neurology, Neurosurgery and Psychiatry, 48, 613. 62. Gloag, D. (1985) Rehabilitation after Head Injury. British Medical Journal, 290, 834 & 913. 63. Field, J. H. (1976) Epidemiology of Head Injuries in England and Wales. London. HMSO. 64. McKinlay, W. W., Brooks, D. N., Bond, M. R. et al. (1981) The Short Term Outcome of Severe Blunt Head Injury. Journal of Neurology, Neurosurgery and Psychiatry, 44, 527. 65. Oddy, M. and Humphrey, M. (1980) Social Recovery during the Year following Head Injury. Journal of Neurology, Neurosurgery and Psychiatry, 43, 798. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 193 66. Cullinan, T. R. (1977) The Epidemiology of Visual Disability. Canter- bury. University of Kent. 67. Burns Cox, C. J. and Dean Hart, J. C. (1985) Screening of Diabetics for Retinopathy by Ophthalmic Opticians. British Medical Journal, 290, 1052. 68. DES (1972) Speech Therapy Services, London. HMSO. 69. Enderby, P. M. and Phillip, R. (1986) The Incidence and Preva- lence of Speech and Language Disorders, (in press) 70. Fenwick, D. (1977) Wheelchairs and their users. London. HMSO. 71. Working Group of the Prosthetics and Orthotics Committee (1983) The Wheelchair Service in Scotland. Edinburgh HMSO. 72. Wright, V. Personal communication. 73. Young, J. B., Belfield, P. W., Mascie-Taylor, B. H. and Mulley, G. P. (1985) The Neglected Hospital Wheelchair. British Medical Journal, 291, 74. Report by the British Orthopaedic Workshops (1972) Orthopaedic Hospital Workshops Survey. 75. Exton-Smith, A. N., Norton, D. and McLaren, R. (1962) An Investigation of Geriatric Nursing Problems in Hospital. London. National Corporation for the Care of Old People. 76. Frost and Sullivan (1979) Urinary Incontinence in Europe. New York. Frost and Sullivan. 77. Feneley, R. C. L. Personal communication. 78. OPCS (1980) Report on Hospital Inpatient Enquiry; 1969-80. London. HMSO. 79. Rubin, G. Personal communication. 80. Mitchell, A. (1980) Patient's View on Stoma Care. Community Nursing, 38. 81. Editorial (1973) Lancet, 2, 309. 82. Jordan, M. A. and Clark, M. O. (1977) Incidence of Pressure Sores in the Patient Community of the Greater Glasgow Health Board Area. Univer- sity of Strathclyde Bioengineering Unit and Greater Glasgow Health Board. 83. David, J. (1981) The Size of the Problem of Pressure Sores. Care, Science and Practice, 1, 10. 84. Clarke, A. K. and Dixon, A. (1975) Unpublished observations. 85. Norton, D., McLaren, R. and Exton-Smith, A. N. (1975) An Investigation of Geriatric Nursing Problems in Hospital. Edinburgh. Churchill Livingstone. 86. Scales, J. T. (1982) Pressure Sore Prevention. Care, Science and Practice, 1, 2. 87. World Health Organisation (1980) International Classification of Im- pairments, Disabilities and Handicaps. Geneva. WHO. 88. Wood, P. H. N., and Badley (1978). An Epidemiological Appraisal of Disablement. In Bennett, A. E. (ed) Recent Advances in Community Medicine 1. Edinburgh. Churchill Livingstone.

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Corrigendum Dr P. G. F. Nixon has pointed out that in the article on 'Incidence and management of arterial injuries from left heart catheterisation' in the last issue of the Journal (Vol. 20, p. 126) the authors misquote (their reference 9) a publication by Dr H. Ikram and Dr P. G. F. Nixon. The original letter in the Lancet by Drs Ikram and Nixon referred to the introduction of a needle into the brachial artery but not to left heart catheterisation.

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Metabolic Basis of Adverse Drug Reactions B.K. PARK, BSc, PhD, Wellcome Senior Lecturer, Department of Pharmacology and Therapeutics, University of Liverpool The rate of elimination of a lipophilic drug is governed largely by its rate of metabolism. Therefore, the ability of an individual to metabolise a particular drug will be an important determinant of the efficacy (intensity of effect), the duration of effect and the toxicity of that drug. Metabolism is usually associated with an increase in water-solubility of the drug, which in turn leads to an increase in the rate of either biliary or urinary excretion. The chemical changes involved usually result in a loss or diminution of pharmacological activity. Metabolism may therefore be considered a detoxification process. How- ever, in certain circumstances, normal metabolic pro- cesses (biotransformations) may produce a toxic metabolite. Of particular importance in this context is the formation of chemically reactive metabolites which are responsible for various forms of drug toxicity. Figure 1 shows that both the rate and route of drug metabolism are important determinants of drug toxicity, so it is necessary to identify factors that may contribute to inter-individual variation in drug metabolism and to characterise metabolites which have toxicological activity. Inter-individual Variation in Drug Metabolism Drug metabolism reactions observed in man consist of phase I reactions (oxidation, reduction and hydrolysis) and phase II conjugation (Table 1). The enzyme systems responsible for these biotransformations appear to have the ability to metabolise an unlimited number of diverse organic compounds, including drugs. It is thought that one of the reasons for the versatility of the drug-metabo- lising enzyme system is that the enzymes exist in multiple forms which represent different gene productsfl]. Table 1. Drug metabolism reactions observed in man. Phase I Phase II Oxidation Acetylation Reduction Glucuronidation Sulphation Hydrolysis Glutathione conjugation Amino acid conjugation N,S,0, ? methylation Population studies have shown that there are large differences between individuals in their capacity to meta- bolise drugs and other lipophilic xenobiotics. This inter- individual variability is due to a number of factors, centred on the genetic constitution of the individual and including an array of host factors, such as age, environ- mental considerations, disease and drugs, which interact dynamically with each other[2]. All of these factors may, in theory, partly determine the susceptibility of an indi- vidual to drug toxicity. Genetic Variation Given that the main purpose of drug metabolism is to convert lipophilic substances into more water-soluble metabolites and thereby prevent toxicity through accu- mulation, it is important to recognise individuals who have a genetically determined inability to perform a particular biotransformation. Genetic polymorphisms arise because of the occurrence of mutant alleles in the population which can influence either the structure or the amount of enzyme synthesised. t The two classical examples of polymorphic drug me- tabolism reactions are acetylation of various drugs and hydrolysis of succinylcholine. More recently, it has be- come apparent that certain drug oxidation reactions exhibit polymorphism. Succinylcholine produces skeletal muscle relaxation of short duration because of its very rapid degradation, by plasma cholinesterase, to succinylmonocholine which is inactive. About one in 3,000 individuals is extremely sensitive to succinylcholine, responding to it by prolonged paralysis, because of an atypical plasma cholinesterase which hydrolyses the drug at a considerably reduced rate[3]. The disposition and toxicity of many aromatic amine and hydrazine compounds are partly determined by the rate and extent of their N-acetylation. Thus, the capacity Fig. l. The relationship between drug metabolism and drug toxicity. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 195 of individuals to N-acetylate such drugs as isoniazid, hydralazine, procainamide, dapsone, sulphadimidine, phenelzine and sulphapyridine is genetically determined. Quantitative assessments of the rate and extent of acetyla- tion yield bimodal frequency distributions which separate 'fast' and 'slow' acetylators; 52 per cent of the population are slow acetylators[4]. Drug acetylation is controlled by two autosomal alleles at a single gene locus, the trait for fast acetylation being dominant and that for slow, reces- sive^]. The clinical implications of acetylator status illustrate the influence of phenotype on adverse drug reactions. Differences in acetylator status have marked effects on the pharmacological and toxicological profiles of a number of important drugs (Table 2). The neurotoxicities which Table 2. Adverse reactions associated with slow acetylator status. Susceptible Drug Toxic effect phenotype Isoniazid Peripheral neuritis Slow SLE syndrome Slow Hepatitis Rapid/Slow Hydralazine SLE syndrome Slow Procainamide SLE syndrome Slow Salicylazo- Cyanosis and sulphapyridine haemolysis Slow Arylamines Bladder cancer Slow result from isoniazid, hydralazine- and procainamide- induced systemic lupus erythematosus and sulphasala- zine-induced toxicity, illustrate the significance of acetylator status in clinical medicine[6], These toxicities are dose-dependent and therefore more common among slow acetylators, who usually have higher serum concen- trations of the drug at any time after ingestion, than do rapid acetylators. Other disorders for which acetylator status has been claimed to be a predisposing factor include isoniazid- induced hepatitis[7,8], arylamine-associated bladder cancer[9] and haemolysis induced by sulphones and sulphonamides in glucose-6-phosphate deficiency[10,11]. Analysis of the relationship between the metabolism and toxicity of some of these compounds is complicated by the fact that a metabolite is thought to be responsible for the toxicity. Acetylator phenotype may partly determine whether or not an individual is susceptible to drug interactions. For example, Kutt et al. [12] observed phenytoin intoxication in approximately 10 per cent of epileptics who took the drug together with isoniazid. All the patients were slow acetylators and intoxication could be avoided by simply reducing the dose of phenytoin. Although there seems to be common agreement that acetylator status is an important determinant of an individual's susceptibility to the toxicity of certain drugs, the value of acetylator phenotype as a predictor of drug toxicity remains an open question[13,14]. However, the distinction made between the two phenotypes is only semi-quantitative and thus may not be a sufficiently powerful method to identify those individuals most at risk. Until recently pharmacogenetic polymorphisms in drug oxidation were considered rare, despite the fact that the majority of lipophilic drugs are metabolised by the hepatic cytochrome P-450 enzymes, a family of enzymes with distinct but overlapping substrate specificity. A number of monogenically controlled polymorphic drug oxidation reactions have now been discovered. The prin- ciple biotransformations that have been investigated are debrisoquine 4-hydroxylation and sparteine oxidation; independent polymorphisms have been reported for tol- butamide hydroxylation[15], mephenytoin hydroxyla- tion[16] and nifedipine oxidation[17]. The formation of the major metabolite of debrisoquine, 4-hydroxydebrisoquine, displays polymorphism in the British population. Two distinct phenotypes, 'extensive metabolisers' and 'poor metabolisers', are recognisable; the 'poor metaboliser' phenotype frequency is an auto- somal Mendelian recessive character and has a frequency of 8.9 per cent[18]. Poor metabolisers have grossly im- paired metabolism and excrete little or no metabolite. Since the original report that debrisoquine hydroxyla- tion in man exhibits genetic polymorphism, there has been much interest in other drug biotransformations which co-segregate with the defect in debrisoquine 4- hydroxylase activity and, perhaps more importantly, whether poor metabolisers are more susceptible to ad- verse drug reactions (Table 3). Table 3. Adverse reactions associated with impaired debriso- quine oxidation. Drug Adverse reaction Metoprolol Excessive /3-blockade[21,22] Nortriptyline Confusional state[35,36] Phenacetin Methaemoglobinaemia[32] Phenformin Lactic acidosis[28,29] Perhexiline Neuropathy and hepatotoxicity[25] A number of reports have linked adverse reactions to lipophilic /3-adrenoceptor blockers with impaired ability to hydroxylate debrisoquine[19,20], Lennard et al. [21,22] found that plasma metoprolol concentrations and areas under the plasma concentration-time curve were greater in poor metabolisers than in normal metabolisers. A significant correlation was found between debrisoquine metabolic ratio, metoprolol elimination half-life and per- centage reduction in exercise-induced tachycardia (24 hours) which was taken as a measure of /3-blockade. However, Clark et al. [23] found in hypersensitive subjects no relationship between adverse reactions necessitating metoprolol withdrawal, and oxidation status. It^has been tentatively suggested that patients due to receive lipophilic /3-blockers should first have their drug oxidation status determined. Jack and Kendall[24] have questioned the need for this and suggested that subjects at risk can be detected by measuring pulse rate. Neverthe- 196 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 less, measurement of oxidation status may be of value iri (a) investigating the mechanism of the adverse reaction, (b) detecting individuals potentially at risk from the conventional doses of /3-adrenoceptor blockers and (c) recognising drugs subject to wide inter-individual vari- ation in metabolism within the population. The anti-anginal drug perhexiline is associated with a number of adverse reactions, the most important of which are peripheral neuropathy and hepatotoxicity. The drug is amphiphilic and thus forms stable, non-degradable complexes with phospholipids which accumulate in cer- tain cells and thereby produce cytotoxicity. Shah et al. [25] have suggested that determination of debrisoquine oxidation status may be of predictive value in determining perhexiline dosage and in controlling the neurotoxicity of this drug, the incidence of which appears to be related to individual half-life[26]. The metabolism of perhexiline is associated with that of debrisoquine and poor oxidisers of perhexiline are also poor metabolisers of debrisoquine[27]. Shah et al. [25] compared a group of patients who had perhexiline-induced neuropathy with a control group who had no serious adverse effects on long- term treatment. The percentage of poor metabolisers of debrisoquine in the group who had suffered peripheral neuropathy was about 50 per cent, whereas the propor- tion of poor metabolisers in the control group was similar to that expected in a normal, healthy population. The oral hypoglycaemic agent phenformin has been withdrawn from use in many countries because of its association with lactic acidosis. The oxidation of phenfor- min is thought to be linked with debrisoquine 4-hydroxy- lation and it has been suggested that phenformin toxicity might have arisen because of poor metabolism[28]. There is no direct clinical evidence to support this hypothesis, although it has been shown that volunteers, phenotyped as debrisoquine poor metabolisers, given phenformin had significantly higher blood lactate concentrations than corresponding extensive metaboliser phenotypes[29]. The analgesic phenacetin is associated with a risk of renal toxicity and was therefore virtually prohibited in the UK in 1980. It is converted into paracetamol in the liver by oxidative de-ethylation. In poor metabolisers of debri- soquine, the rate of formation of paracetamol is slower than in extensive metabolisers[30] and phenacetin pro- duces methaemoglobin in poor metabolisers but not in extensive metabolisers[31]. It has been suggested that, in the poor metaboliser, more of the drug is converted into a toxic metabolite, 2-hydroxyphenetidine, via an alterna- tive metabolic pathway (de-acetylation and aromatic 2- hydroxylation) not controlled by the same gene locus responsible for de-ethylation[32]. The metabolism of tricyclic antidepressants is related to that of sparteine and dibrisoquine[33,34]. Indeed, it has been suggested that it is possible to predict steady-state plasma concentrations from an individual's debrisoquine metabolic ratio[35]. The poor metaboliser appears to be at greater risk to nortryptyline-induced vertigo, dizziness and confusional state[36] but the clinical significance of this observation has not been defined. Thus it can be seen that where metabolism is strongly influenced by a major gene effect, there may be pro- nounced differences in drug response, and toxicity may ensue through drug accumulation. Adverse effects are generally more frequent in the poor metaboliser, but encainide provides an example of the extensive metabo- liser possibly being more predisposed, as the metabolites of the drug are pharmacologically active[37]. In no instance has the determination of phenotype provided an absolute test for drug toxicity. Indeed, it would have been naive to suppose that it would. Never- theless, such information should be useful for detecting individuals potentially at risk and in the evaluation of the relationship between the metabolism and toxicity of new drugs. Modulation of Drug Metabolism Numerous factors may alter the capacity of an individual to metabolise drugs[l,2] and thereby increase the risk of toxicity because of either drug accumulation or enhanced rate of formation of a toxic metabolite. In practice, the most important considerations are age, enzyme induction and enzyme inhibition. Age The incidence of adverse drug reactions in elderly patients is approximately twice that found in younger patients. Numerous factors such as multiple disease states and multi-drug therapy contribute to this difference. There is, however, an expanding literature of clinical studies in man which clearly indicate that metabolism of some drugs is impaired with older age[38]. Therefore the elderly may be more susceptible to adverse drug re- actions, especially from drugs with long half-lives. This point is illustrated by the experience with the anti- inflammatory drug benoxaprofen (Opren), which was withdrawn because of adverse effects which were more severe and frequent in elderly patients[39-41]. The agent was designed with a longer half-life than other non-steroidal anti-inflammatory drugs, so that it could be administered once daily, while maintaining a therapeutic response. However, the rate of metabolism showed a profound dependence on age, the half-life in elderly patients being approximately four times longer than in younger patients[42]. The fatal hepatic and renal cytotoxicity of benoxaprofen appears to have been related to the excessive accumulation of the drug. After paracetamol overdose, children experience rela- tively mild liver involvement, despite paracetamol serum concentrations that would be associated with life-threat- ening hepatotoxicity in adults. Paracetamol toxicity is due to formation of a toxic reactive metabolite. The lower incidence of severe toxicity in children may be related to a greater ability to metabolise paracetamol via non-toxic pathways[43]. Enzyme Inhibition and Enzyme Induction The clinical implications of induction and inhibition of drug metabolism have been reviewed elsewhere[44]. Drug interactions which occur as a result of enzyme Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 197 induction or inhibition are usually produced by drugs prescribed in doses of 100 mg or more daily. Interactions involving such changes in enzyme activity are usually of importance only for drugs with a narrow therapeutic index such as anticonvulsants, anticoagulants, anti- arrhythmics and oral contraceptives (Table 4). With these Table 4. Clinical importance of enzyme induction and enzyme inhibition. Enzyme Inducers Enzyme Inhibitors Substrates Anti-arrhythmics Anticoagulants Anticonvulsants Oral contraceptives Tolbutamide Carbamazepine Phenobarbitone Phenytoin Rifampicin Cimetidine Erythromycin Isoniazid Sulphaphenazole drugs, a relatively small alteration in elimination rate may be associated with a change from a therapeutic to a toxic response. For example, co-administration of the H2-antagonist cimetidine increased warfarin plasma steady-state con- centration and prolonged prothrombin time to a danger- ous level[45], More recent work[46] has shown that cimetidine stereoselectively inhibits the metabolism of R- warfarin. Phenobarbitone, on the other hand, stimulates the metabolism of warfarin. Concurrent administration of phenobarbitone and warfarin produces a change in steady-state plasma warfarin and anticoagulant effect within six days[47]. However, after withdrawal of pheno- barbitone, drug metabolism returns to normal and this may lead to fatal haemorrhage during continued anti- coagulant therapy[48]. New drugs thought to be either enzyme inhibitors or enzyme inducing agents may be screened using model drug substratesfl]. The time-course of enzyme induction may be monitored by simply measuring changes in the disposition of an endogenous compound, 6 /3-hydroxy- cortisol. Theoretically, enzyme induction could lead to a selec- tive increase in toxic metabolite formation. Although such a mechanism has been demonstrated for carcinogens and hepatotoxins in sensitive animal test systems[49,50], there is nO direct evidence for it in man. Furthermore, White et al. [51] did not find an increased rate of cancer in patients on long-term anticonvulsant therapy, as might have been expected if there was enhanced activation of aromatic hydrocarbons. Animal studies have shown that toxicity may be reduced by inhibition of paracetamol and isoniazid reactive metabolite formation with cimetidine, but this has not been achieved in man[52,53]. Toxic Metabolites For most drugs metabolism represents a clearance mech- anism. However, in certain circumstances, a normal biotransformation may lead to the formation of a toxic metabolite (Fig.2). Chemically reactive metabolites are particularly important in this respect because their cova- lent interaction with biopolymers in vivo might induce tumorogenicity, cytotoxicity and hypersensitivity[54]. In the process of the chemical induction of a tumour, binding of that chemical or one of its metabolites to a biological macromolecule seems to be the initial step. Good correlations between carcinogenicity and covalent binding to DNA as target macromolecule rather than RNA or protein have been observed[55,56] The liver is the major site of drug metabolism and a number of drugs, including paracetamol (overdose), ison- iazid and halothane, are thought to produce hepatotoxi- city by generating chemically reactive metabolites which react indiscriminately with vital cellular macromolecules (reviewed by Timbrell[57]). The relationship between the toxicity and metabolism of paracetamol has been investi- gated extensively in both man and experimental ani- mals[49,58,59]. Paracetamol is largely metabolised via glucuronidation and sulphation which account for approximately 50 per cent and 25 per cent of the drug, respectively. In addition, about 10 per cent of the drug is oxidised to a chemically reactive metabolite N-acetylbenzoquinone imine, which is normally detoxified immediately by con- jugation with glutathione. However, after an overdose (10-20g) the sulphation and glutathione pathways become saturated, allowing the chemically reactive metabolite to arylate essential cell structures[60]. The severity of para- cetamol-induced cellular necrosis varies in proportion to the amount of arylation. Administration of N-acetyl- cysteine may afford protection by providing more glu- tathione for detoxification of the reactive metabolite[61]. Work on ipomeanol-induced lung disease in animals provides further convincing evidence for the role of metabolic activation in chemical-induced tissue in- jury[50]. In particular, formation of chemically reactive metabolites in tissues other than liver, may produce organ-selective toxicity. Our current understanding of drug hypersensitivity (allergy) is based on the assumption that drugs form haptens in vivo. This concept derives from classical Fig. 2. The role of chemically reactive metabolites in drug toxicity. 198 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 immunochemical studies[62,63] which showed that low molecular weight compounds (e.g. drugs) must be linked by a covalent bond to a macromolecular carrier in order to elicit an immune response (Fig. 3). Evidence that drugs produce hypersensitivity in man, by acting as haptens, came from several groups working on penicillin allergy[64-66]. Antibodies directed against antigenic determinants derived from penicillin can be detected in the majority of patients treated with penicillin. The sensitising capacity of penicillin can be explained by the inherent chemical reactivity of the /3-lactam nu- cleus. However, the question of whether the ultimate immunogen is formed in vivo from autologous proteins or is in fact an impurity from the manufacturing process has not been resolved[67]. Most drugs do not possess direct protein reactivity, and it is assumed that haptens are formed from chemically reactive metabolites (Fig. 3). Although this is an attrac- tive hypothesis, there is no direct experimental evidence to confirm it. A number of drugs with suspected immuno- logical adverse effects, such as practolol, procainamide, chlorpromazine, sulphonamides, ethynyloestradiol, halo- thane and hydralazine readily form 'reactive metabolites' in in vitro drug-metabolising systems[68]. It is therefore possible that such metabolites might form effective (im- munogenic) haptenated protein conjugates in certain individuals, especially those with deficient detoxification mechanisms (e.g. glutathione conjugation). Conclusion Individuals show remarkable variation in their ability and capacity to metabolise drugs. Drug toxicity may occur because of excessive accumulation of the parent drug or formation of a toxic (reactive) metabolite. To avoid adverse reactions, it is important to understand factors that affect dosage requirements and thus identify, within the population, individuals susceptible to dose-dependent drug toxicities. Drug toxicity may be a function of the route rather than the rate of drug metabolism. In such circumstances, toxicity will be partly dependent on the balance between activation and deactivation pathways. At present it is not possible to assess an individual's capacity for generating such toxic metabolites. However, chemical studies of the in vitro and in vivo metabolism can provide some insight into the potential toxicity of a particular drug. A cknowledgements I should like to thank Professor A. M. Breckenridge for many helpful discussions. This article is based on a paper read at the College Regional Conference in Liverpool in September 1985. References 1. Park, B. K. (1982) British Journal of Clinical Pharmacology, 14, 631. 2. Vesell, E. S. (1984) Clinical Pharmacology and Therapeutics, 35, 1. 3. Kalow, W. (1962) In Pharmacogenetics: Heredity and the Response to Drugs. Philadelphia: Saunders. 4. Price Evans, D. A. and White, T. A. (1964) Journal of Laboratory and Clinical Medicine, 63, 394. 5. Price Evans, D. A. (1968) In Recent Advances in Medicine, 15th edn. (ed D. N. Baron, N. Compston and A. M. Dawson) London: Churchill. 6. Weber, W. W. (1985) In Drug Metabolism, p.5. (ed G. Siest) Oxford: Pergamon. 7. Mitchell, J. R., Thorgeirsson, U. P., Black, M. et al. (1975) Clinical Pharmacology and Therapeutics, 18, 70. 8. Dickinson, D. S., Bailey, W. C., Hirschowitz, D. I., Soong, S. J., Eidus, L. and Hodgkin, M. M. (1981) Journal of Clinical Gastroenter- ology, 3, 271. 9. Price Evans, D. A., Eze, L. C. and Whibley, E.J. (1983) Journal of Medical Genetics, 20, 330. 10. Van Hees, P. A., Van Elferen, L. W., Van Rossum, J. H. and Tongeren,J. N. (1979) American Journal of Gastroenterology, 70, 501. 11. Woolhouse, N. M. and Atu-Taylor, L. C. (1982) Clinical Pharma- cology and Therapeutics, 31, 377. 12. Kutt, H., Brennan, R., Dehijia, H. and Verebely, K. (1970) American Review of Respiratory Disease, 101, 377. Fig. 3. The relationship between drug metabolism and drug hypersensitivity: the hapten hypothesis. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 jgg 13. Lunde, P. K. M., Frislid, K. and Hansteen, V. (1977) Clinical Pharmacokinetics, 2, 182. 14. Clark, D. W. J. (1985) Drugs, 29, 342. 15. 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(1983) British Journal of Clinical Pharmacology, 16, 157. 33. Bertilsson, L., Eichelbaum, M., Mellstrom, B., Sawe, J., Schulz, H.-U. and Sjoqvist, F. (1980) Life Sciences, 27, 1673. 34. Eichelbaum, M. (1982) Clinical Pharmacokinetics, 7, 1. 35. Bertilsson, L. and Aberg-Wistedt, A. (1983) British Journal of Clinical Pharmacology, 15, 388. 36. Bertilsson, L., Mellstrom, M., Sjoqvist, F., Martensson, B. and Asberg, M. (1981) Lancet, 1, 561. 37. Wang, T., Roden, D. M., Wolfenden, M. T., Woosley, R. L., Wood, A.J.J, and Wilkinson, G. R. (1984)Journal of Pharmacology and Experimental Therapeutics, 228, 605. 38. Vestal, R. E. and Wood, A.J.J. (1980) Clinical Pharmacokinetics, 5, 309. 39. Anonymous (1982) British Medical Journal, 284, 459. 40. Del Favero, A. (1984) In Meylers Side Effects of Drugs, p. 167. (ed M. N. G. Dukes.) New York: Elsevier. 41. Halsey, J. P. and Cardoe, N. (1982) British Medical Journal, 284, 1365. 42. Handy, R. C., Murnane, B., Perera, N., Woodcock, K. and Koch, I. M. (1982) European Journal of Rheumatology, 5, 69. 43. Lieh-Lai, M. W., Sarnaik, A. P., Newton, J. F. et al. (1984) Journal of Pediatrics, 105, 125. 44. Park, B. K. and Breckenridge, A. M. (1981) Clinical Pharmacokine- tics, 6, 1. 45. Serlin, M.J., Sibeon, R. G., Mossman, S. et al. (1979) Lancet, 2, 317. 46. Choonara, I. A., Cholerton, S., Haynes, B. P., Breckenridge, A. M. and Park, B. K. (1986) British Journal of Clinical Pharmacology, in press. 47. Breckenridge, A. M. and Orme, M. L'E. (1971) Annals of the New York Academy of Sciences, 179, 421. 48. MacDonald, M. G. and Robinson, D. S. (1968) Journal of the American Medical Association, 204, 97. 49. Gillette, J. R. (1981) Archives of Internal Medicine, 141, 375. 50. Boyd, M. R. (1980) CRC Critical Reviews in Toxicology, p. 103. 51. White, S. J., McLean, A. E. M. and Howland, C. (1979) Lancet, 2, 458. 52. Ruud, G. D., Donn, K. H. and Grisham, J. W. (1981) Research Communications in Chemical Pathology and Pharmacology, 32, 369. 53. 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;? I Mayerne and his Successors: some Huguenot Physicians under the Stuarts RANDOLPH VIGNE, MA President, The Huguenot Society of London Calvinism today has for many a connotation of intolerant narrowness and rigidity of thought, yet in the late 15th and early 16th centuries Calvinists, or Huguenots, were the most intellectually advanced and inventive com- munity in France. After 1629, with the breaking of Huguenot power, they were forced on to the defensive as their community and faith were increasingly threatened and perhaps the most productive element left France, either in that early period or in the years around 1685 when 250,000 fled abroad at the Revocation of the Edict of Nantes, 50,000 of them to Britain. The successful careers of many of these Huguenot refugees have been recalled in 1985, the tercentenary year: their contribution to medicine should also not be overlooked. There were great names like the Chamber- lens, Ent, Primrose, the Hameys, Martineaus and many lesser men whose careers are also representative or of special interest. Sir Theodore Turquet de Mayerne of the first category, the Colladons, father and son, and Pierre Silvestre of the second, have in common their service as physicians to the Stuarts, from James I to William III, and their connection with the Royal College of Phys- icians, of whom all were Fellows or Licentiates, though only one of them learned his medicine in Britain. Theodore de Mayerne was born in 1573 in Geneva where his family had sought refuge the year before. With an MD from the great Huguenot university of Montpel- lier, he established himself in Paris in medical practice and in teaching, becoming a follower of two leading neo- Paracelsians, Du Chesne (Quercetanus) and Ribit de la Riviere, both Huguenots. In 1600, through their influ- ence, he became physician-in-ordinary to the Huguenot- turned-Catholic King Henri IV, a position he retained even when the Paris medical faculty, determinedly Galen- ist and bitterly hostile to his chemical remedies, banned him from teaching. Like his two fellow Paracelsians, he was used by the King as a political agent in promoting a pro-Protestant foreign policy and, after the assassination of Henri IV, he was, in 1611, brought to England by James I, to whose court he had already been invited in 1606, after a glowing testimonial from an English noble- man he had cured in Paris. James had appointed him physician to the Queen and as such he was made a DM of Oxford University. Mayerne's medical practice at the courts of James I and Charles I brought him great wealth and also lasting fame, due to the survival of his vast collection of detailed case notes on his English and, by correspondence, French patients. In the British Library and the Royal College of Physicians (which published his Opera in 1703) are to be found what the medical historian Aikin called in the 18th century 'the medical annals of the Court of England'. These records display the meticulous pains he took in clinical observation, which were as much the reason for his success and continuing influence, as were his chemical remedies, involving the use of calomel, iron, mercury and even antimony. His early years in England were marred by the death of the brilliantly promising 18-year-old Henry, Prince of Wales, whom he was accused of poisoning, and by a similarly false implication in the death in the Tower of Sir John Overbury. His account of Prince Henry's illness is the first written record of a case of typhoid fever, and a model of its kind. He retained the King's confidence, despite James's scornful dismissal of medicine, which Mayerne recorded in his lengthy memoir on the King's health. James made use of Mayerne's valuable Huguenot connexions and he was on a visit to France in 1625 when a stroke caused the King's death amid an unpleasant wrangle among the doctors, including William Harvey, and courtiers around him. Mayerne returned as Charles's physician and treated him, his Queen, Henrietta Maria (daughter of his old master, Henri IV) and all her children, as he did Charles's sister Elizabeth of Bohemia, the 'Winter Queen' and her family in England and abroad for 30 years to come. For Henrietta Maria Mayerne produced a wide range of cosmetics, for which he has been criticised, but Mayerne was a dedicated chemist and his interests in- cluded the making of colouring matter for paints and enamelling (he introduced the great enamellist Petitot to Charles's court). His chemical remedies included the taking of 'steel', in powdered form, for 'the spleen' or melancholy, pre- scribed for one of Elizabeth of Bohemia's ladies, as well as for Dorothy Osborne, who called it 'a drench that would poison a horse . . .'tis worse than dying by the half!' Mayerne was socially ambitious, making himself the Baron D'Aubonne by the purchase of an estate in Swit- zerland, advancing one of his daughters, Louise, as an 222 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 attendant on Elizabeth of Bohemia, and affiancing another, Elizabeth, to the young Earl of Huntingdon who died of smallpox on the eve of the wedding. She mar- ried?unhappily, wrote Dorothy Osborne?a French no- bleman, as did her sister Adriana, his youngest and only child to survive him. The early deaths of both of his sons were a great grief, again described by Dorothy Osborne, whose family were the Mayernes' neighbours in Chelsea in later years. He had many patients outside the Court, including Oliver Cromwell, then a young MP suffering from 'a periodic throbbing pain lasting three hours' and de- scribed by Mayerne as 'undoubtedly melancholic', and the wife of Bulstrode Whitelocke, whose doctor's letter asking his advice may be the first on record from a 'general practitioner' to a 'consultant'. As a foreigner Mayerne showed less loyalty to Charles than did Harvey, who followed the King to war while Mayerne stayed on in London. When the Commons asked him in 1641 for his views on the necessity of the Queen's proposed, and rightly suspect, visit to Spa, he had equivocated, speaking of her 'inward discontent of mind'. Yet Henrietta Maria continued to rely fully on him: he had delivered her nine children without a miscar- riage and had saved two of them, Prince Charles, heir to the throne and Mary, mother of the future William III, at the point of death. In 1644 she left the embattled King at Oxford, for the relative safety of Exeter for the birth of her last child, Henrietta Anne, later Duchess of Orleans. Mayerne, though 72 and hugely fat, obeyed the King's one-line summons to attend her: 'Mayerne: Pour I'amour de moy alle trouver ma Femme. C.R. ' After the Queen's escape to France, and Charles's execution, he tried to save the delicate 14-year-old Princess Elizabeth, leaving, as al- ways, an exhaustive account of her case. But 'from the death of her father she fell into a great sorrow whereby all the ailments from which she suffered were increased' and she died at Carisbrooke Castle in 1649. Mayerne found time outside his large practice and constant attention on the Queen and her children, to help establish the Apothecaries' Company, drafting its charter, with the support of the College of Physicians to which he had been elected the year before. He also wrote the dedication to James I of the Pharmacopoeia Londinensis in 1618, and was responsible for much of its contents. These included Thomas Muffet's Paracelsian medicines, which he had acquired after Muffet's death. He pub- lished, after many difficulties, Muffet's great work on insects (undeservedly less well-known than his daughter Patience's encounter with a spider famous in every British nursery). Having freed the Apothecaries from the Grocers (thus improving their status) he freed the Distillers from the Apothecaries, in which action he had a personal interest as a patentee for 'strong waters' and for making vinegar 'from cider, perry and buck'. Mayerne's activities sound respectably 'scientific' to modern ears yet he maintained a continuing interest in and secret correspondence with Quercetanus and others on alchemy and was a member of the Fratres Societatis Rosa Crucis, surprising in one who had prevailed against all attempts to persuade him to abjure his Protestantism in France, and who played his part in support of the Huguenot chapel in the Strand at which he worshippped. This contradiction can also be seen in his taste for rich and copious eating (displayed in his posthumously pub- lished cookery book, Archimagirus Anglo-Gallicus, 1658), and love of wine, beside the immense pains he took for the health of his patients and often sound advice on diet. Though not a refugee in the common sense, Mayerne had come here because he could not teach and practise the chemically-based medicine which he and other Hugue- nots were championing against an inflexible system. He flowered under English skies, in a way that religious hostility in France would have made impossible. Both he and the country that took him in were the gainers. He died in 1655, aged 82, after drinking bad wine with friends at a tavern near his old home at Charing Cross, and was buried at St Martin-in-the-Fields, beside his First wife, mother, and five of his children. Mayerne's model case notes, chemically-based drugs, and the institutions he created lived after him, as did his great wealth, but his only family descent was through his daughter Adriana, Marquise de Monpouillan. Her only child married the brother of that prime eccentric, Charles, first Duke of Bolton, leaving a numerous posterity. He left his library to the Royal College of Physicians. In 1631 Mayerne brought to England a young Gene- van Huguenot, Jean Colladon, who became an MD of Cambridge and, after practising briefly at Norwich, Fig. 1. Sir Theodore de Mayerne. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 223 married in France in 1637, Ayme de Frotte, daughter of Mayerne's sister Judith. Colladon, whom Mayerne ad- dressed in letters as 'Mon Enfantfollowed his uncle and patron as a Royal physician?to Charles II, first as Prince of Wales, from 1640, and after the Restoration as King. Like Mayerne he had patients among the King's en- emies, too, attending, with Mayerne, John Pym in his last illness. They both, with others, signed the post mortem report, designed to show that Pym had died not of an 'Herodian visitation', in all its horror, because of his sacrilegious opposition to the King, but of an 'impostume in the bowel'. Colladon also followed Mayerne as unofficial agent for the Republic of Geneva at the Court of St James, retaining, unlike Mayerne, his Genevan nationality until all hope of being officially appointed by the Sindics of Geneva had gone. (The premier sindic was his cousin Esaie Colladon). Both Protector Richard Cromwell and the restored Charles II urged him to take the post but the Sindics, always fearful of offending Louis XIV, refused him politely. In 1655 he had helped transmit the funds? ?38,000?collected throughout England for the Vaudois survivors of'the late massacre in Piedmont' immortalised in Milton's greatest sonnet. While maintaining his Genevan identity, Colladon was playing a major role in the integration of the Huguenot community in Britain. He led the petitioners for the separation of the Church of the Savoy from the mother church in Threadneedle Street which was resolutely Calvinist and non-conformist. When Charles II consent- ed, the new church (a development of Mayerne's Somer- set House chapel in the Strand) followed the Anglican liturgy (in French) and accepted the authority of the Bishop of London. After 1685 other Huguenot congrega- tions followed the Savoy into the Anglican fold, their members' descendants abandoning their old Huguenot churches in the late 18th and early 19th centuries as their refugee past faded. Colladon's professional and other activities are a pale reflection of Mayerne's: a few references in the Verney papers (in one Tom Verney expresses the impious hope that the plague then raging 'might touch my chief creditor Colladon before it yet leaveth'), in Court papers and in a patent document with Samuel Pepys's unstable, improvi- dent Huguenot father-in-law, for curing smoking chim- neys. He became an Honorary Fellow of the Royal College of Physicians in 1664, was knighted the same year and remained, as he appeared on the Savoy petition, physician to the king. He married off one daughter well in Geneva and the other to the son of an elder of the Huguenot church in London. His son-in-law Wickart became a Canon of Windsor and later Dean of Winchester and chaplain to the King. His son, Theodore Colladon, a Mayerne on his mother's side, was already in practice, with his Oxford DM, when Sir John Colladon died suddenly in 1675, leaving a handsome estate to his widow, the daughter of Judith de Frotte, born de Mayerne. Theodore Colladon's career as a society doctor and Royal physician maintained the family reputation and fortune. He was elected an Honorary Fellow of the Royal College of Physicians in 1685 and was 'constituted a Fellow by the charter of James II and was admitted as such at the Comitia Majora Extraordinaria of 12 April 1687', writes Munk. He was knighted by William III in 1700 and married the same year. In 1703 he was present at William's deathbed, with seven other physicians, including the President of the College, Sir Thomas Millington and William's most trusted physician, his compatriot Dr Govart Bidloo, who was closest to the King in his dying moments. Curiously, the broadsheet issued next day omitted the names of both Colladon and Bidloo, possibly to allay any alarm based on the public dislike of William's foreign courtiers and servants. The following year Sir Theodore was appointed phys- ician to the six-year-old Royal Hospital, Chelsea, and looked after the old soldier inmates and a host of out- patients until his death in 1712. Unlike the Huguenot apothecary to the Hospital, Isaac Gamier, who was succeeded by his son in the post, Colladon left only a young widow and ten year old daughter, Ann, later to marry Charles Montagu, MP, a Nottinghamshire land- owner. Their son became the Rt. Hon. Frederick Mon- tagu, a Lord of the Treasury in 1782, and was able to pass on a family fortune and an equally prodigious Tory loyalty to Victorian and Edwardian descendants. Ann Colladon's marriage marks the final integration of the family into English life, but her mother, Susanne Maria, Lady Colladon, played her own part in her long widowhood, as a leading member of the group of Hugue- nots in high places who administered charitable funds for the poor and the afflicted among their growing com- munity. From 1718 the French Hospital, La Providence, shared the burden, helped at the outset by a generous subscription from Lady Colladon. She also maintained the tradition of Royal service that had begun with Mayerne's appointment by Henri IV in 1600, as sous- gouvernante to the five daughters of the Prince of Wales, later George II, at Richmond, after the death of Queen Anne at last removed the Stuarts from the scene. Lady Colladon died in 1753. Pierre Silvestre, the last of the succession of Huguenot Royal physicians, was a post-Revocation refugee, unlike Mayerne and the Colladons who were part of the great Huguenot international with links across Europe but few remaining connections in France. Silvestre's father was an advocate at the parlement of Bordeaux and the family lived at Tonneins on the Garonne, 75 km to the south- east. After qualifying at Montpellier in 1683, he was sent to Paris to walk the wards but the Revocation, two years later, meant the ruin of his career or betrayal of his family's Protestant faith and he was able to make his escape to Amsterdam in the company of some German noblemen. He attracted the attention of the Stadtholder, William of Orange, and became his physician, ac- companying him to England and the Glorious Revolution in 1688. The Duke of Schomberg, William's commander- in-chief in Ireland, commandeered his services as phys- ician, but, aged 80, fell in action in the hour of victory at the Boyne. Silvestre, who was not on the establishment, was cut adrift but, returning to England, was offered by William 224 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 a post with the army in Flanders. He accepted instead the patronage of Ralph, Duke of Montagu, who had been Charles II's ambassador to Louis XIV, and Silvestre became one of the large band of Huguenots who came to serve him in England after the Revocation. He seems to have been both physician and adviser on buildings and paintings, and has even, on no evidence, been suggested as the architect of the very French north front added to Montagu's Boughton House, near Ketter- ing in Northamptonshire, before 1700. 'Dr Sylvestre's Room' is listed in the inventory of the house, made at Duke Ralph's death in 1709. Silvestre acquired a large practice in London, becom- ing a Licentiate of the Royal College of Physicians in 1693, and in 1696, like a number of fellow Huguenot men of learning, a Fellow of the Royal Society. He was also appointed a physician to the King but there is no record of payment, though a pension from his days at the Dutch court had tided him over after his return from Ireland without a post. Montagu put him in charge of his heir, Viscount Monthermar, on the Grand Tour in 1700, and he made use of their time in Italy to send two reports and a collection of 'natural curiosities' (earth, gum, Vesuvius salt, etc.) to the Royal Society. The second and only surviving report describes 'the virtuosi I have seen in Italy and the state of learning there, chiefly as to natural philosophy and physick'. It illuminates Silvestre's own eclectic interests and wide cultivation, as much as it does the scientists he met. His chief interest and skill was anatomy and his greatest excitement was expressed at seeing in Genoa a 'wax carving' of a human body, in natural colour, made by a lecturer and compatriot, Desnoms, so perfect as to be indistinguishable from 'a newly embalmed corpse', which he urged as a marvellous aid to the study of anatomy. Silvestre had become part of the circle of the brilliant wit and man of letters, the exiled Catholic nobleman, St Evremond, who expressed surprise to Montagu that he had come back from Italy, not 'all upon his Architecture and Painting' but with the violin sonatas of Corelli. He did not seem to have suffered as so many Huguenot tutors did, in charge of wild, philistine young milords on the Grand Tour, and in 1706 again travelled with Month- ermer, now married to Marlborough's daughter, in the Low Countries. He reported to Montagu their difficulties in getting to see Mothermer's father-in-law, who was otherwise occupied routing Louis XIV's army at Ramil- lies. Silvestre was naturalised in 1705 and thereafter served on various boards, such as the commissions for naval sick and aged, and for 'Poor French Proselytes'. He peti- tioned with others against the inheritance of estates in France that rightly belonged to refugee heirs, but the resulting bill was withdrawn when it was shown that those receiving remittances from their French estates would suffer. Perhaps his elder brother, who had inherited the estate at Tonneins, had abjured: their mother came to England and outlived her son, as did his younger brother Francis, naturalised in 1707. Madame Susanne Silvestre made Francis's son, Jean-Baptist Zacharie, her heir, provided he did not move to France 'or any country where the Romish religion is predominant'. Perhaps she feared the influence of his mother, who had been taken from her Protestant family and put in a convent, until, at 13, she emerged to marry Francis Silvestre, the hope being that she would be reclaimed. She remained a Catholic but exemplified both Huguenot stubborness and longevity by remaining 'd'une bigoterie extreme' until her death at 93. Silvestre's double role as physician and man of the arts continued with his appointment as literary executor to St Evremond, whose own doctor, Sebastian Le Fevre, MD (of Rouen), LRCP, had looked after him for 40 of his 42 years in exile. Yet in several letters and in some 'Stances irregulieres' dedicated to him, Silvestre's great medical skill, and power to cure by his piercing look, were praised by St Evremond, who called him 'le docteur aux regards salutaires Pierre Des Maizeaux, FRS, who edited St Evremond's complete works for Silvestre, recalled, in later editions, his delightful manner and conversation, his gay, healthy, and laughing countenance, his good taste in music, painting and the 'beaux arts', and his deep knowledge of anatomy, medical practice and chemistry. Silvestre, then living in Frith Street, Soho, among his fellow Huguenots, died in 1718, his estate passing through his mother to his nephew, later Sir John Baptist Silvester, MD (of Leyden), LRCP, FRS, physician to General Wade in the Low Countries, to The London Hospital and the French Hospital, La Providence. He was the father of Sir John Silvester, Bt, FSA, Hon DCL (Oxon), FRS, Recorder of the City of London. The baronetcy, under a second patent, survived only a further generation, through a Carteret nephew. Silvestre's name now lives only in the letters of St Evremond, which project him as embodying some of the characteristic Huguenot virtues he shared with his predecessors, Mayerne and the Colladons, virtues which, with their skills, were the contribution the Huguenots made in return for the asylum given by the British people at their most tolerant. This article is absed on a lecture given at the Royal College of Physicians in December, 1985. Some Printed Sources Agnew, Rev David C. A. (1871) Protestant Exiles from France. Edinburgh. Aikin, John. (1780) Biographical Memoires of Medicine in Great Britain. London. Debus, Allen G. (1968) The English Paracelsians. New York. Debus, Allen G. (1977) The Chemical Philosophy. New York. Ellis, Henry. (1827) Original Letters Illustrative of English History, Series 2, Vol III. London. Gagnebin, Bernard. (1941) 'Un Diplomat Genevois a la Cour d'Angle- terre au XVIIC Siecle,' Le Mois Suisse, Vol. 26. Geneva. Gibson, Thomas. (1933) 'A Sketch of the Career of Theodore Turquet de Mayerne.' Annals of Medical History, Vol. V. New York. Haag, E. and E. (1858) La France Protestante ou Vies des Protestants Francais, Vol. VII. Paris. Hayward, John (ed). (1930), The Letters of St Evremond. London. Keynes, Geoffrey. (1966) The Life of William Harvey. London. Kingsley Hart (ed). (1968) The Letters of Dorothy Osborne to Sir William Temple, 1652-4. London: Folio Society. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 LeFanu, W. R. (1956) 'Huguenot Refugee Doctors in England' Proceedings of the Huguenot Society of London, Vol. XIX. London. Mayerne, Theodore Turquet de. (1703) Opera Medici in quibus continentur epistolae et observationes, pharmacopoeia, variaeque medicamentorum formulae. (Ed. Joseph Browne.) London. Moore, Norman. (1908). The History of the Study of Medicine in the British Isles. London. Munk, W. (1878) The Roll of the Royal College of Physicians of London. London. The Works of Monsieur de St Evremond made English from the French original, with the life of the author by Monsieur des Maizeaux FRS. 2nd ed., 1728. London. Scouloudi, Irene. (1940) 'Sir Theodore Turquet de Mayerne, Royal Physician and Writer.' Proceedings of the Huguenot Society of London, Vol. XVI. London. Trevor-Roper, Hugh. (1985) 'The Paracelsian Movement.' Renaissance Essays. London.

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Medical Disability?A New Look Thirteen years after the publication of the 'Tonbridge Report' on Rehabilitation the majority of its recommen- dations have still not been implemented. Disability Ser- vices in England and Wales remain in a parlous state and only a handful of doctors have any professional commit- ment to the subject. Some people would argue that we have one of the worst Disability Services in Western Europe. The point cannot be proved one way or another, but the potential for improvement is obvious. The publi- cation of an RCP Report on the subject of Medical Disability is therefore to be welcomed. The evidence that Disability Services are in a poor state is reviewed in the College Report. It includes criticisms by disabled people themselves, and the fact that in many cases there are no minimum standards of care. Patients disabled as a result of head injury are an obvious example. There is an almost total lack of high quality epidemiological data, which makes planning difficult, and many Districts have no policy guidelines and no organised Rehabilitation Service. Further examples are given in the recent review of Artificial Limb and Appli- ance Centre Services which highlights major deficiencies in the provision of wheelchairs and of artificial limbs. The picture is, however, not entirely black. Good quality services now exist in some parts of the country for disabled children, the elderly disabled, and for patients with spinal injury. However, disabled people aged be- tween 15 and 65 are not well provided for and the Report identifies this group as representing a particular problem. The need for high quality Disability Services seems self-evident. In the first place?no civilised country should allow its disabled members to suffer unnecessary hardship. In particular, the 'caring professions', which obviously include medicine, should not connive at the existence of services which are substandard, even in the present state of apparent national penury. Secondly, the cost of disability to the State is considerable, and it is clearly desirable that maximum use should be made of the money available. Why have we ended up with such enormous gaps in our Disability Services? The question has no simple answer. One reason is probably that there is no-one 'in charge'. Indeed, it appears to be true that no high quality medical service has ever been established without the full- time commitment of a substantial number of doctors? renal medicine, spinal injury and geriatrics are obvious examples. The Working Party on Rehabilitation of the College (1978) was of the opinion that rehabilitation is the responsibility of all clinicians. The implication is that we do not require a large specialty of rehabilitation, or its equivalent. This new Report explores the implications of this principle and suggests ways in which a high quality service might be established. Reports by themselves never change anything. Cynics will doubtless anticipate that this Report, like others before it, will be quietly shelved after some initial enthusi- astic noises. It is important to ensure that this does not happen. The Report suggests a system of internal audit involving District and Regional Managers, and an exter- nal audit system which would involve outside autono- mous bodies such as the Consumer Association and/or the Community Health Councils. Using the professional audit standards suggested in the Report, these bodies could become effective. Certainly, nothing will be achieved without sustained pressure. How should individual Fellows and Members respond? What is needed is a group of interested and committed doctors in each Health District who are keen to make progress. The first step will be to ensure that the Report is distributed to administrators, social services, remedial therapy departments, and other interested bodies. The second step might be for the group to apply the audit standards suggested in the Report to their own Health District. This, after consultation with colleagues, could form the basis for a Report for the District and Regional Managers. The opportunity to make progress exists. We should now grasp it with both hands. R. Langton Hewer

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Terminal Care: How can we do Better? ERIK WILKES, OBE, FRCR FRCGR FRCPsych Medical Director, St Luke's Nursing Home, Sheffield In any major organisation it is likely that a majority perform their duties satisfactorily yet without distinction, and a minority at each end of the spectrum perform exceptionally well or exceptionally badly. This also ap- plies to terminal care, and a recent surveyfl] has attempt- ed to quantify this quality of performance by interviewing recently bereaved relatives. These may not be conspicu- ously reliable or accurate as witnesses, but their opinions will at least be of interest in their comparative ratings of doctor and nurse. The design of the survey mimicked the national pattern by analysing a sample of two deaths in hospital for each death at home. The relatives in a quarter of cases praised with respect and affection the care given by their GP, although the hospital nurse, closely followed by the hospital doctor, were slightly more often praised, in nearly a third of cases. But the relatives found fault?sometimes with bitter criticism and great resentment?with both GP and hospi- tal too often for our comfort. The GP in 16 per cent of cases did not seem interested, did not explain, did not examine, did not visit except on demand, and the visits were grudging, brief, inadequate and revolved excessively and improperly around the repeat prescription that is so often the symbol and token of second-rate care. Symptom control was often unsatis- factory despite this eagerness to prescribe and move on. When the GP was praised, it was because the doctor seemed to care, to be interested, to respect patient and relative, to visit regularly and also (when they lived in the area) to give them their home telephone number in case of urgent need, to explain things, and to check how well drugs were working before repeating the prescription. The hospitals were criticised for their uncaring ap- proach in a quarter of cases. Doctors or ward sisters were evasive, information had to be pursued too often by the relative, it was not often efficiently conveyed, and too rarely shared adequately among members of the firm so that different doctors were saying rather different things. There was also disquiet, not at elderly relatives dying but becoming, near the end, confused or drowsy strangers as a result of what the relatives saw as pointless or degrading overtreatment. Such complaints point towards the specific problems that need tackling and, since the hospices look after only 5-10 per cent of deaths, despite their expansion to nearly 100 units, this demands training on a large scale for both hospital and community. Training Fortunately, training is well under way. Various ap- proaches are being tried. Edinburgh preclinical students talking with advanced cancer cases, Sheffield students visiting them in their own homes, and the education of Belfast students in this fascinating and important sub- ject[2] are all examples of a general trend. Indeed, the majority of medical schools not only take more interest in the care of the dying than 25 years ago, but have a nearby hospice as a reservoir of patients and teachers who help to set the local standards of terminal care. At postgraduate level the situation is less satisfactory. The demand for a module of hospice training far exceeds the supply. There are comparatively few registrar posts in the hospices and only very few general practice vocational schemes include a hospice module, for all the relevance and value of such an experience. This will need correcting over the next decade and it is good, but not good enough, that some national charities are concerned enough to consider helping with the funding of some such posts. The ritualistic lectures held for family doctors at so many postgraduate centres are usually attended only by those who do not need to be there. A better idea is to invite whole practices, receptionists, doctors and attached nurses, to meetings, perhaps in the local hospice, together with several neighbouring practices, to discuss their management of terminal cases at local level, with videos and a problem-solving approach. This provides some access at least to the doctors in greatest need. Meetings of hospital firms or primary health care teams should discuss regularly the deaths of those under their care, to see how lessons can be learned and standards raised. Postgraduate centres and medical schools should hold occasional clinico-pathological conferences which start with the GP describing the patient before the illness, continue with the hospital doctors describing steps in diagnosis and the acute treatment, then on to the terminal hospice care to end with a discussion on the management of the bereaved relatives' problems. This will accelerate the integration of hospice expertise with traditional re- sources that we must achieve. With ageing relatives, marital breakdown, and looser family ties generally, it is reassuring to see how hard families try to cope with a dying relative. This has been well recognised by the geriatricians[3] but not necessarily by the system; too often an expensive hospital bed is more quickly available to a dying patient than incontinence 216 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 pads, a commode or other simple essentials for home care. Yet home is not always suitable for terminal care and we know that the needs of the relatives require admission of the dying patient more often than the needs of the patient. This makes it clear that the management and support of the family are as central in terminal care as the efficient control of symptoms. There needs to be a more family-centred approach that is not yet well taught in our medical schools nor easily practised in busy hospitals. Basic techniques of family therapy need to be marketed more aggressively to both doctors and nurses, and to be developed among hospices personnel. But this broadening of the professional role inevitably takes the doctor and the nurse beyond the bedside and the laboratory. Despite the admirable clinical symposia re- currently held at such centres as St Christopher's, Lon- don, Michael Sobell House, Oxford and St Colombus', Edinburgh, we need the clinician to understand some- thing of leadership, of team-work, of the functioning of small groups and of the other outside assistance available for patients within the system ranging from social services to the voluntary sector. This is partly why management training for newly-appointed NHS consultants has been so rapidly developed. It should also be available to senior colleagues, who may be unhelpfully set in their ways. We need to remember that most patients seeking the comforts of fringe medicine have previously been dissatisfied with conventional medical care of a less than distinguished quality. Terminal care is thus another area requiring management skills. It is impossible in the care of advanced cancer to ignore the role of the nurse. So far as the patient is concerned, she may well be a more central figure than the physician. Training in the schools of nursing has, as with doctors, greatly improved over the last decade yet is still of variable quality. This may mean that more senior col- leagues are less well trained than their juniors, a phenom- enon not unknown to medicine. The English National Board runs in some 15 centres approved full-time six-week courses on the care of the dying and their family. These improve the confidence and background of already interested and experienced nurses. The course explicitly does not claim to produce specialist nurses yet is routinely misused to that end. We need to plan for an advanced course to take such experience further; pilot courses are already being worked out. Since most major centres now have a hospice within reach, it has been found of the utmost value to arrange temporary exchanges of nursing staff between hospice and acute wards. The hospice staff gets updated, and they learn again to respect their nursing colleagues from the local hospital. This mutual respect is also learned by the visiting hospital nurse and the acute wards become influenced by the detailed nursing care and the regard for the emotional and physical welfare of the patient so characteristic of hospice care. Case conferences on suitable patients should be held for both doctors and nurses, although the enthusiasm of the nurses often makes the occasional doctor appear as a lonely colleague dedicated more to a sponsored lunch than to an interdisciplinary meeting of minds. Attitudes Advanced cancer is a problem that requires teamwork. It involves the needs of the patient, the resources of the family, the therapeutic strategies of the doctor, the bed- side and management skills of the nurse, the emotional and spiritual support from social worker and chaplain, and most important of all, the interplay and fusion of these elements to produce a strategy agreeable to the patient. The patient needs to feel actively concerned in his management rather than a helpless prisoner. This cannot be helped by the fact that nearly a third of dying patients have little idea of their real situation. And basic teamwork is greatly prejudiced when a third of doctors are unwilling to entrust to capable and exper- ienced nursing colleagues honest discussions with the patients about the future. Although lies are rare, evasion is common, but it is not enough to tell the patient the truth and let them get on with it. This is a recent and growing tendency that can be as damaging as uncertain- ty" Prognosis should remain uncertain within limits, for that is the truth of it. Patients should be encouraged to ask for information they want, but not have it forced upon them. Someone dying may, early in the illness, feel the need for less information than is required later on. The young usually need more information than the old, but generalisations are to be mistrusted. Relatives are to be listened to courteously but the plea 'You won't tell him will you, he couldn't stand it' is often to be translated as 'You won't tell him will you? I don't think I can handle it'. Family members may need more time, information and confidence than their patient. This cannot be deliv- ered if communication between hospital and GP is unsa- tisfactory, and family doctors still need to keep an eye on the local obituary column to see when their hospitalised patients have died. Furthermore, a higher priority must be given to im- proving communication between different hospital col- leagues, and who told what and when must be clearly written up in the notes, or juniors will need to play safe, say nothing, and so unwillingly deprive their patients of solace and comfort. But we are at last ceasing to look upon death as our failure. There is more to the art of medicine than the production of a tidal wave of unfilled geriatric need. We are at last beginning to realise that part of the art of medicine is not to prolong life but independence, for as long and as comfortably as possible. Survival at all costs is a false objective: just as a cry for euthanasia is usually a symptom of inadequate support, a brave inclination not to be a nuisance, and inadequate symptom control. Cost-Effectiveness Many junior doctors and nurses are most critical of their own achievements in terminal care; their dissatisfaction is indeed an encouraging feature. However, they have little idea of how to improve the situation and tend to want to transfer too many to hospice care, just as their seniors Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 217 transfer the old and confused but keep the young on active treatment to treat their own needs, despite the superior family counselling experience of the hospice. But it is clear that a massive proliferation of hospices is not the answer. We need hospices for the problem case, to provide extra support in the home, day care, respite care and family support or?since 20 per cent of hospice admissions are social isolates?a new family. Yet most patients will die on the acute ward or at home. The hospices need to be sited near schools of medicine and nursing, in big cities and in retirement areas. They should not be built in market towns where often the best of British medicine is to be found and the community network of support is reasonably intact. Hospices are expensive. A nurse:patient ratio of 1.5:1 means roughly ?500 per patient-week. Home support nurses, each costing ?15,000 a year are much more cost- effective so long as they are able to integrate with the local district nurses and GPs without mistrust or paranoia complicating the provision of an additional resource. Hospice-trained support nurses working similarly in the local hospitals can influence communication and symptom control out of all proportion to their cost: but they need in their turn to be tactful as well as tough, and to be both accepted and supported. Day hospitals for hospice-type patients are growing. They allow relatives to feel more supported, and an eye to be kept on progress without wasting time on unnecessary home visits by the doctor. They provide a stimulus and companionship often more effective than the drugs, a hairdresser more welcome than the health professional, and a variety and diversion that help to keep them going. Such a Day Hospital could look after about 15 patients each day for five days a week for a cost of less than three hospice beds. Yet in our enthusiasm we must remember that the most cost-effective of all is a well-briefed and involved family, a well-trained doctor and a caring nurse and, if need be, a trusted local hospital up the road. This article is based on a paper read at the Conference on Advanced Cancer held at the Royal College of Physicians in December 1985. References 1. Wilkes, E. (1983) Lancet, 1, 950. 2. Irwin, W. G. (1984) British Medical Journal, 289, 1509, 1604. 3. Isaacs, Bernard, Livingstone, Maureen, Neville, Yvonne. (1972) Survival of the Unfittest, London: Routledge & Kegan Paul.

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Reasons for Delay in Permanent Pacemaker Insertion A F MACKINTOSH, MD, mrcp* Consultant Cardiologist R M BOYLE, mrcp Lecturer in Cardiology, Killingbeck Hospital, Leeds International surveys continue to show that the rate of permanent pacemaker insertion is substantially lower in the UK than in the USA, West Germany, France and other countriesfl]. The rate in Britain could be a more accurate reflection of the need, but it is possible that British patients are being denied the benefits of pacemak- er therapy. Patients who should be paced but never are, cannot be identified easily, but those who do receive a pacemaker can be assessed for any delay in instituting pacing and for the reasons underlying that delay. Patients and Methods One hundred and one consecutive first implants by the authors were studied from September 1982 to October 1983. They represent 64 per cent of the first implants at Killingbeck Hospital in that period and a third of all first implants in the Yorkshire region. The information con- cerning each patient was recorded at the time of the pacemaker procedure. The patient and/or the relatives were questioned. In nearly all cases the notes of the referring hospital were available for inspection. Statistical analysis was by the chi squared test. Results Nine patients had no symptoms of a bradycardia prior to pacemaker insertion. The rest of this report is concerned with the remaining 92 patients (54 men, 38 women, aged 32-97 years); 64 patients had predominantly atrioventri- cular block, 27 had predominantly sinoatrial disease, and one showed a mixed picture. The time from the onset of symptoms to permanent pacemaker insertion was more than 10 years in four patients. Two were women, aged 87 and 92 years at the time of implantation, who were known to have atrioven- tricular block. Another was a 62 year old man, with sinoatrial disease, who was being treated for epilepsy. The fourth was an 81 year old woman with initially no clear diagnosis, who was subsequently found to have sinoatrial disease. Nine patients had been waiting for 3- 10 years: a cardiac arrhythmia had been identified in only one. More than six months had elapsed between the onset of symptoms and permanent pacing in 36 patients (39 per cent). Increasing age was not associated with a longer delay, but men were paced quicker than women (Table 1). Table 1. Distribution of patients by sex and time to pacing. Men Women Time to pacing (n = 54) (n = 38) Less than 31 days 27 9 (p<0.02) Less than 6 months 39 17 (p<0.01) There was no significant difference in the delays exper- ienced by patients referred from hospitals in the two Leeds (teaching) districts, or those referred from non- teaching districts (Table 2). Fifteen (56%) patients with Table 2. Duration of symptoms in teaching and non-teaching districts (determined by source of referral). <6 months Total Teaching districts 25 (68%) 37 Other districts 31 (56%) 55 (p>0.1) sinoatrial disease waited longer than six months com- pared with 21 (33%) patients with atrioventricular block, but this difference was not significant. The date of the first medical consultation and the first referral to hospital were recorded. Nine of the 36 patients whose symptoms started more than six months before pacemaker insertion did not initially seek medical advice. Another five were not referred on by their general practitioner. Thirteen were seen at hospital soon after the onset of symptoms, but were not paced at that time. The remaining nine had a combination of delays. Only one of the 13 patients whose delay occurred after attending hospital had ambulatory electrocardiographic monitoring "Correspondence to Dr A F Mackintosh. 220 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 soon after being seen for the first time; it showed a sinus bradycardia. Four of the 92 patients received anticonvul- sant therapy prior to pacing and four had a cerebral CAT scan or an EEG. Comment This study demonstrates that a prolonged period of time may elapse from the onset of symptoms to permanent pacing. Some delay may be appropriate, especially in patients with sinoatrial disease; their arrhythmias do not seem to be associated with excess mortality[2]. Time may be needed for clarification of the diagnosis or adjustment of drug therapy. But delays could be dangerous in patients with atrioventricular block. Without pacing, complete heart block has a one year mortality of almost 50 per cent[3,4]; the risk is not predictable by the character of the symptoms or the nature of the ECG findings[4]. More than six months elapsed in a higher proportion of patients with sinoatrial disease compared to patients with atrioventricular block; but the difference was not signifi- cant. A third of the patients with atrioventricular block waited more than six months. Some of the delays demon- strated in this study may represent not only an unneces- sary persistence of symptoms, but also an avoidable risk to the patient. The results do not confirm some common assumptions. The elderly did not wait significantly longer for pacing than the relatively young, though men did receive a pacemaker more promptly than women. A mistaken diagnosis of epilepsy or a series of neurological investi- gations was rare. Few long delays were solely due to the general practitioner not referring the patient for a special- ist opinion. The majority were caused by the patient not seeking medical aid or by delay once the patient had been seen at the hospital. Rickards has suggested that the low rate of pacemaker implantation in the UK is produced by a shortage of cardiologists[5]. This study does not support that conclu- sion. The delays in the two Leeds teaching districts, with three adult cardiologists in each district, were not signifi- cantly less than the delays in the non-teaching districts which possess a maximum of one physician with an interest in cardiology. In both teaching and non-teaching hospitals, decisions about further assessment of syncope and dizziness will be made by general physicians or by the staff of the accident department. Cardiologists may only be involved at a later stage. Whatever the cause, the overall impression of this study is that the hospital service did not approach these patients with sufficient vigour to find a remedy for syncope, dizziness and a risk of sudden death. References 1. Feruglio, G. A., Rickards, A. F., Steinbach, K, et al. (1983) Pace, 6, A-149. 2. Shaw, D. B., Holman, R. R. and Gowers, J. I. (1980) British Medical Journal, 280, 139. 3. Friedberg, C. K., Donoso, E. and Stein, W. G. (1964) Annals of the New York Academy of Sciences, 111, 835. 4. Johansson, B. W. (1966) Acta Medica Scandinavia, suppl 451, 1. 5. Rickards, A. F. (1984) British Medical Journal, 288, 737.

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Aspergillus Lung Disease I. }. GORDON, MB, MRCP(UK) Medical Registrar, Regional Adult Cardiothoracic Unit, Broadgreen Hospital, Liverpool C. C. EVANS, MD, FRCP Consultant Physician, Regional Adult Cardiothoracic Unit, Broadgreen and Royal Liverpool Hospitals Few general physicians include aspergillus infection in a differential diagnosis of lung disease as they feel that it is too much of a rarity. Thus the diagnosis may be suggested by the bacteriologist from sputum culture, by the radiologist on detecting a mycetoma on the chest radiograph or by a bright registrar on finding an asth- matic with significant eosinophilia. The pathologist can also be included in this list, especially in cases of broncho- centric granulomatosis and at autopsy when the diagnosis of invasive aspergillosis is made more often than in life. In this review we have summarised the main pulmonary diseases caused by aspergillus which could be relevant to the general physician (Table 1). As invasive aspergillosis Table 1. The major forms of aspergillus lung disease. Bronchopulmonary aspergillosis (BPA) Aspergilloma Extrinsic allergic alveolitis (EAA) Bronchocentric granulomatosis Invasive aspergillosis is one of the atypical pneumonias seen in immunosup- pressed patients, the fungus has increased its notoriety recently. History The term 'aspergillus' was coined by Micheli, a botanist and priest, in 1729[ 1 ]. He likened the spore-bearing heads of the fungus to the aspergillum used in religious ceremonies to scatter holy water (Latin: aspergere, to scatter). However, it was over a century later that Sluyter first described human aspergillus disease in 1847 [2]. Although there are 18 groups with 130 different species of aspergillus[3], from the point of view of human disease Aspergillus fumigatus is by far the most important. Other species which may cause disease in debilitated or immunosuppressed patients include/I. niger, A.flavus, A. glaucus and A. terreus. The following discussion therefore refers mainly to infection with A. fumigatus. Distribution and Epidemiology Aspergillus spores are ubiquitous and are the most fre- quently found fungus in the environment. They have been recovered from the Antarctic, Sahara Desert[4] and even from the Skylab spacecraft[5]. They are found in house dust[6], wet paint[7], cracked dialysis bags[7], distilled-water bottles[7], ventilation systems[8], tap water[9], and can even survive in formalin[7]. Numerous studies have shown the presence of spores in the outside environment and also in the home[10-14], with increased concentrations in the winter months. The pathogenicity of the aspergillus species is enhanced by several factors: (a) The spores are light, easily dispersed[15], and also have thick walls; (b) the spores grow most rapidly at 40?C (limits 12-53?C) while the majority of moulds have optimum growth below 28?C[16]; (c) the spores of A. fumigatus are approximately 5 microns[17] which makes them ideal for lodging and growing in the region of the terminal bronchioles. The most important predisposing feature in the host is the presence of underlying disease such as asthma, old tuberculous cavitation, cystic fibrosis and altered immunological status. Thus patients with myeloproliferative disease, lymphoma, carcinoma or on immunosuppressive therapy are especially at risk of inva- sive and disseminated aspergillosis. Aspergillus species may be second only to Candida as a cause of fungal infections in such patients[18]. Atopy to Aspergillus and Saprophytic Colonisation The association between asthma and aspergillus lung disease was first noted in 1925[ 19]. Spores are more often found in the sputum of asthmatic patients and about 25 per cent of asthmatics have a positive immediate skin test reaction without other features of broncholpulmonary aspergillosis (BPA)[ 19-22]. The presence of aspergillus in the respiratory tract in the absence of direct tissue damage is sometimes referred to as saprophytic BPA. In addition to asthma this is "more likely to occur in cystic fibro- sis^,24], bronchiectasis, chronic bronchitis and ciliary Correspondence to Dr I. J. Gordon, Chest Laboratory, Broadgreen Hospital, Thomas Drive, Liverpool L14 3LB. 206 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 dyskinesia syndromes[25], The reasons for this are thought to be the presence of viscid secretions together with bronchospasm and ineffectual sputum clearance but repeated antibiotic and steroid therapy and the presence of malnutrition may also be important[26]. Positive skin tests to aspergillus are more commonly seen in these groups, and up to 58 per cent of patients with cystic fibrosis have been shown to give a positive skin prick test[27], In the absence of other features of BPA, the skin test itself does not warrant any change of management. Allergic Bronchopulmonary Aspergillosis Allergic bronchopulmonary aspergillosis was first de- scribed by Hinson et al. in 1952. They reported eight cases who had asthma, eosinophilia, aspergillus in the sputum and pulmonary infiltrates on the chest radio- graph[28]. At present BPA is probably the commonest cause of pulmonary eosinophilia in the UK[29] but it is not known why only 1 per cent of asthmatic sufferers develop the disease. There have been several reports of increased exposure to aspergillus in patients who sub- sequently developed BPA[19,30,31] but this cannot be shown in the vast majority of cases. One study showed no increase in the spore counts of aspergillus in the homes and external environment of 10 patients with BPA[32] compared to five atopic patients without BPA. Criteria for Diagnosis The criteria for diagnosing BPA are not clearly estab- lished. Many physicians accept the quartet of asthma, eosinophilia, pulmonary infiltrates on the chest radio- graph and a positive immediate and delayed skin test reaction. The presence of raised IgE levels and aspergillus precipitins are probably only confirmatory, as the range of IgE levels in asthma is extremely variable and precipi- tins may be absent in the chronic phase of the disease[33]. Some authorities consider that the presence of proximal bronchiectasis is the only way of making a definite diagnosis[34] although bronchography is not without risk in patients with asthma. At this stage the diagnosis has been made late in the natural history of the disorder. Clinical Findings Asthmatics may develop BPA at any age, although there is said to be a longer period between the onset of asthma and the development of BPA in the younger patient[29]. The usual features of an acute exacerbation are worsen- ing of asthma, malaise and fever, and occasionally expec- toration of plugs of fungal mycelia[35]. Collapse of a lobe or even an entire lung may occur due to impaction of a plug and initially this may suggest a more sinister diag- nosis. Patients with chronic disease who have developed bronchiectasis present with the features of any other form of bronchiectasis. It is for this reason that the diagnosis should be borne in mind when any asthmatic develops increasing amounts of purulent sputum. The bronchiec- tasis in BPA is classically found in the upper lobes and affects the proximal bronchioles; such proximal lesions are unusual, as virtually all other forms of bronchiectasis are distal and more marked in the lower lobes (with the exception of cystic fibrosis). The end result of chronic BPA is pulmonary fibrosis and retraction of the upper lobes, which leads to a mixed obstructive and restrictive pattern on pulmonary function testing. Cor pulmonale may develop in such patients. Laboratory Investigations Eosinophilia is invariably found, although the level will be suppressed by oral steroid therapy. Positive sputum culture only provides corroborative evidence, as it is non- specific and is seen in saprophytic colonisation and even in the sputum of normal individuals[36]. One other drawback is that expectoration of the fungus is often intermittent. However, the finding of fungal hyphae is more significant and suggests active growth of aspergillus in the bronchi. In view of the variability of these findings the report of a positive sputum culture must not be the sole criteria for the diagnosis of BPA. As mentioned previously, positive skin prick tests may be found in asthmatics without BPA and in patients with cystic fibrosis. In BPA the immediate skin test is always positive and a subsequent delayed reaction may occur up to six hours later in patients who have positive precipitins. Intradermal skin tests are more sensitive but may induce an asthmatic attack and should not be routinely used. The last 10 years have produced significant advances in the understanding of the immunology of BPA. Most of the work has been concentrated on the IgE and IgG classes, although antibodies in most classes have been reported[37,38]. Radioimmunodiffusion methods have shown IgG antibodies in nearly all patients with BPA[4], More recently, total and specific serum IgE have been found to be significantly elevated with peak values imme- diately prior to, and during a flare-up of the disease[39- 41]. Oral steroids have been shown to depress the level of total IgE[39]. It has therefore been suggested that IgE levels are of value in monitoring disease activity, although whether predicting an exacerbation leads to a reduced incidence of irreversible disease and better patient wellbe- ing is not known. Aspergillus precipitins are of the IgG class and reflect either active or recent infection. They can be shown to be present in up to two-thirds of patients with BPA in undiluted serum and in 100 per cent if concentrated serum is used[36], but their presence does not necessarily reflect disease activity[42]. Precipitins have been demon- strated in up to 31 per cent of patients with cystic fibrosis [23] and in 7-18 per cent of asthmatics without BPA[43,44], Radiological Changes The radiographic appearances can be divided into acute and chronic changes. Acute changes consist of perihilar infiltrates that may simulate lymphadenopathy, upper zone tram-lining and infiltration, gloved fingerlike pro- jections due to mucus impaction and collapse of a lobe or entire lung[45]. In the chronic phase fibrosis of the upper Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 207 lobes, leading to reduced lung volume and tubular and ring shadows, may be seen[46]. Treatment No therapy has been shown to effectively eradicate aspergillus from the respiratory tract. Antifungals such as nystatin[47], clotrimazole[48] and natamycin[49] have been reported as having some success but are not gener- ally accepted as being useful in treatment. The use of corticosteroids in the management of BPA is well estab- lished[50-52]. They probably reduce the antibody re- sponse to the fungal antigen which is the cause of the constitutional symptoms and pulmonary infiltration. Steroids may inhibit growth of aspergillus and they rapidly reduce the volume of sputum[29], but have not been shown to be directly fungicidal. The usual starting dose is 30-40mg of prednisolone daily and this is reduced according to response. The aim should be to control symptoms and clear pulmonary infiltrates. A regime has been proposed in which serial IgE measurements are used to tailor the prednisolone dose[53]. Inhaled steroids are of little value in controlling and preventing exacerbations of BPA[53,54], possibly because the drug cannot penetrate mucoid plugs to the site of the antigen/antibody reaction. Additional therapy should include inhaled bronchodi- lators, physiotherapy to clear plugs and, if necessary, bronchoscopy to remove viscous plugs which have caused lung collapse. If there is likely to be considerable exposure to aspergillus (e.g. farm workers) attempts should be made to avoid the high concentration of spores found in mouldy hay and compost heaps. Aspergilloma An aspergilloma is a fungal ball developing in a lung cavity which is poorly drained. The term was first used by Deve in 1938[55]. Aspergillomata have been found in patients with BPA[56,57] or may cause BPA[58,59]. The incidence in the general population is estimated at 0.01- 0.02 per cent[60], and although usually solitary they may be bilateral or multiple[61, 62]. Aetiology and Pathogenesis Aspergillomata may form in any preformed cavity but undoubtedly the commonest antecedent disease is pul- monary tuberculosis. They have also been reported to occur in sarcoidosis, bronchial cysts, bronchial carci- noma, lung abscess cavities, pneumoconiosis, ankylosing spondylitis, and bullous emphysema[63]. Approximately 25 per cent of patients with an aspergilloma have a positive history of tuberculosis[64,65] and, surprisingly, aspergillomata are as common in patients with recent disease as in those with longstanding healed cavities[66]. The apical regions of the lung are the most frequently affected, probably because predisposing cavities are more common in this region. The growth of the fungus is usually silent, especially in the early phase. The initial stage is growth of fungal conidiophores on the wall of the cavity, followed by a growing phase in which a ball is formed. The final stage is a resting phase in which the formed aspergilloma may remain quiescent for years. The possible progressions following the resting phase are: persistence associated with clinical features, calcification, degeneration and spontaneous resolution of the cavity, and development of BPA or, rarely, invasive aspergillo- sis[63]. The latter is usually confined to immunocompro- mised patients. Clinical Features Patients with aspergilloma may be entirely asymptomatic and the diagnosis only made from a routine chest radio- graph. They more usually present with haemoptysis as the commonest symptom which may be associated with cough and sputum production. Constitutional symptoms of fever, malaise and weight loss are sometimes seen, especially if there is a concomitant BPA. Physical examin- ation may reveal finger clubbing and reduced percussion note together with bronchial breathing over the cavity. Radiological and Laboratory Investigations The classical radiological finding is of a dense opacity surrounded by a halo of air (Monod's sign)[55,67]. This may be seen on the PA radiograph but is more clearly visualised by tomography. This appearance can also be produced by a lung abscess, haematoma in a cavity, neoplasm and hydatid cyst[68]. Occasionally the aspergil- loma can liquefy and a fluid level may be seen[67]. Since the fungal ball is not fixed in the cavity it may alter position and this can be detected by taking several films with the patient in different positions[69]. Other radio- graphic features are pleural thickening over the cavity and lobar contraction. Bronchography has little to offer in the routine diagnosis of an aspergilloma as there is often no direct bronchial connection. Interestingly, a metabo- lite of aspergillus takes up radio-strontium, and isotope scanning may therefore be useful if the diagnosis is in doubt[70]. As with other forms of aspergillosis, sputum culture is too non-specific to be of any value. Immediate skin prick tests are positive in about 30 per cent of patients[71], whereas precipitins are found in virtually 100 per cent[71,72]. Precipitins may be absent if the fungus is dead, in immunosuppressed individuals[63] or if a fungus other than A. fumigatus is present[73]. Treatment Patients who are asymptomatic need no specific manage- ment but should be reviewed at intervals. The common- est group are those with recurrent haemoptyses who are repeatedly admitted to hospital for observation. Usually the haemoptysis subsides spontaneously but approxi- mately 5 per cent of patients die from this cause. Attempts at medical management have met with only limited su'ccess. These range from nystatin[74], and inhalations of brilliant green[75], to installation of nystatin and amphotericin pastes into the cavity. The latter technique has led to disappearance of the aspergilloma in 50 per cent 208 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 of cases[76], In addition, treatment with natamycin has been attempted with good results[77] and clotrima- zole[78] and amphotericin[61] have been used in the peri- operative period with some success. It is generally agreed that a large single aspergilloma associated with recurrent haemoptysis and chronic sputum production should be excised, providing the general health of the patient is reasonable[79,80]. The operation of choice is lobar resec- tion[81], or, for poor risk patients, cavernostomy[82]. The main post-operative complications are empyema and bronchopleural fistula, and morbidity rates have varied between 7 per cent[83] and 75 per cent[84], The use of radiotherapy and bronchial artery embolisation are now being evaluated. Multiple aspergillomata should be treated conservatively, as the surgery required to remove all the lesions is too extensive. Occasionally patients develop fever, malaise and weight loss, and on some occasions invasive aspergillosis may occur[85]. Although steroids do improve the constitutional features and may be required if there is associated BPA, they also increase the risk of invasive disease[86,87]. If there is any evidence to suggest immunodeficiency (malnutrition, alcoholism, lymphoma, etc.) steroids must be used with extreme caution but preferably avoided. Extrinsic Allergic Alveolitis (EAA) This is a non-specific response to inhaled aspergillus spores and occurs with many other antigens such as avian proteins in bird fancier's lung and thermophyllic actino- mycetes in farmer's lung. Aspergillus spores are es- pecially plentiful in mouldy hay, compost heaps, straw and grain[88] and it is from these sources that this form of aspergillosis is likely to occur. A further source is mouldy barley which contains A. clavatus, the cause of malt worker's lung[89]. It is important to note that the site of the pulmonary response is different in BPA and extrinsic allergic alveolitis. In BPA the major airways are the site of the allergic reaction whereas in EAA the lung parenchy- ma is the primary target. Clinical Features and Investigations Symptoms of cough, fever, chest tightness and headache begin within four hours of exposure to the stimulus and classically they are noted on return to work after the weekend. Physical examination reveals upper zone inspi- ratory crackles and the chest radiograph may show diffuse pulmonary infiltration. Pulmonary function tests show a restrictive pattern. All of these findings are non-specific and are found in other examples of EAA. The diagnosis will be provided by the history and the finding of aspergillus precipitins in the serum. A further useful aid is a delayed response to skin prick testing which is maximal at 4-6 hours. Treatment Treatment consists of avoiding the offending site if it can be identified. If this is not possible a mask should be worn. Oral steroids produce rapid improvement but are not a substitute for avoiding exposure. If the alveolitis is allowed to persist, pulmonary fibrosis and honeycomb lung will inevitably occur. Bronchocentric Granulomatosis This manifestation of aspergillus lung disease was first decribed by Liebow in 1973[90], It is a form of vasculitis and is similar in some respects to Wegener's granuloma- tosis. The exact incidence is unknown. Clinical Features[90] The typical features are productive cough, chest pain, constitutional disturbance and occasionally haemoptysis. In contrast to BPA a background of asthma is not invariable and eosinophilia is not always present. Typical radiographic features are consolidation, pneumonic infil- trates, lobar collapse, and nodular or mass densities which may simulate a tumour. Bronchograms may show segmental bronchial obstruction and bronchiectasis. Pathological examination reveals cheesy material in the lumina of small bronchi and bronchioles, with a foreign body type of giant cell reaction together with granulomas, eosinophilic clumps and fungal hyphae. The diagnosis is usually made following removal of a nodule because of the possibility of a tumour. Lobar resection has produced good results in one series, with a symptom-free interval of up to four years. Oral steroids may produce symptomatic and radiological improvement although there may be a recurrence. Invasive Aspergillosis Invasive aspergillus lung disease has become important in recent years with the increasing use of cytotoxic drugs, and more recently with the advent of the acquired immune deficiency syndrome. Whereas in BPA colonisa- tion is confined to the bronchi, with only limited tissue invasion, in invasive aspergillosis there is extensive in- volvement of the lung parenchyma which can be shown histologically. The condition is almost totally confined to immunosuppressed patients but has been described in a patient with an aspergilloma who received steroid ther- apy[87]. Examples of predisposing diseases include: acute leukaemia, lymphoma, carcinoma, patients on high-dose steroid and cytotoxic therapy, and diabetes mellitus[3]. Neutropenia favours development of invasive dis- ease[92,93] which has been recorded in 70 per cent of patients with neutrophil counts below 0.5 x 109/ litre[94]. In contrast to BPA, other species of aspergillus are frequently pathogenic and these include A. flavus, A. glaucus, and A. niger[94], The pathogenesis of invasive aspergillosis is complex and may involve three mecha- nisms[95]. First, colonisation of the respiratory tract is followed by endobronchial proliferation and bronchial ulceration; this is sometimes referred to as 'aspergillary bronchitis'. Progression may then proceed to membrane formation. Invasion of the lung parenchyma can occur at any stage, producing most commonly a necrotising bron- chopneumonia, lobar pneumonia or haemorrhagic infarc- Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 209 tion[94]. The second mechanism involves colonisation of necrotic lung tissue following pulmonary emboli, bac- terial infection or in pre-existing lung cavities[63]. This results in abscess formation which may be single or multiple. This diagnosis is usually only made at autopsy. Finally, haematogenous spread can occur from such sites as the gastrointestinal tract or intravenous catheter lines[63]. This results in multiple miliary micro-abscesses throughout all organs and is also usually diagnosed at autopsy. Diagnosis The symptoms are usually non-specific and include cough, wheeze, dyspnoea and fever. The chest radio- graph is normal in aspergillary bronchitis but in estab- lished invasive disease there are single or multifocal nodules up to 3cm in diameter. These may undergo infarction or cavitation and the appearances at this stage are of consolidation, which tends to be bilateral[95]. It should be noted that the radiograph may be normal until very late in the disease, at which time treatment is hopeless. Blood cultures and aspergillus precipitins are unhelp- ful[96] and sputum culture is only positive in about 30 per cent of patients[97]. Nasal swabs may be helpful in predicting the development of pulmonary disease[98]. An improved diagnostic yield has been shown using serial immunodiffusion and radioimmunoassay techniques for detecting aspergillus antibody, but this involves twice- weekly blood sampling in individuals thought to be at risk[99]. The ideal method of diagnosis is the detection of aspergillus antigen[100] and this has been documented in a few patients[101]. Unfortunately, the methods required are of unknown sensitivity and are not available to the majority of clinical laboratories. However, it is likely that future hopes for the earlier diagnosis of this form of aspergillosis rest with this method. Bronchoscopy, trans- bronchial biopsy and bronchoalveolar lavage should be performed as soon as possible after the onset of respirat- ory symptoms in any patient at risk of developing asper- gillosis or any atypical infection. This is of vital importance especially if pulmonary infiltrates have ap- peared on X-ray. Once widespread radiological infiltrates are present the disease has already spread extensively. The differential diagnosis of invasive aspergillosis in- cludes Pneumocystis carinii, nocardia, Candida, tubercu- losis and mycoplasma infections as well as the commoner bacterial infections. Treatment The key to treatment of invasive aspergillosis is to start therapy as soon as the above investigations have been done even if there is only a high index of suspicion. Results of sputum culture and histology of bronchial biopsy specimens may be confirmatory but should not be awaited. Patients who are most likely to respond to therapy are those with disease limited to the lung[102] and those who have treatment started within 96 hours of the onset of pulmonary infiltrates[103]. The treatment of choice is intravenous amphotericin B which may be required for up to 12 weeks. To obtain an adequate response a certain degree of host immune-competence is necessary and it is recommended that, as in bacterial infection, severely neutropenic patients receive tranfu- sions of leucocytes from compatible donors[104]. The use of nystatin and 5-flucytosine by aerosol been reported to give better results than amphotericin B alone[105]. 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(1979) American Review of Respiratory Disease, 120, 863. 25. Bardana, E. R. Jr. (1985) In: Aspergillosis, (ed Y. Al-Doury and G. E. Wagner.) Springfield, Illinois: C. C. Thomas. 26. Sandhu, D. K. and Sandhu, R. S. (1973) Mycopathologia et Mycologia Applicata, 49, 77. 27. Warren, C. P. W., Tai, E., Batten, J. C., Hutchcroft, B.J. and Pepys, J. (1975) Clinical Allergy, 5, 1. 28. Hinson, K. F. W., Moon, A. J. and Plummer, N. S. (1952) Thorax, 7, 317. 29. McCarthy, D. S. and Pepys, J. (1971) Clinical Allergy, 1, 261. 30. Austwick, P. K. C. (1963) Recent Progress in Microbiology, 8, 644. 31. Riddell, R. W. and Clayton, Y. M. (1958) British Journal of Tuberculosis, 52, 34. 32. Vernon, D. R. H. and Alan, F. (1980) Clinical Allergy, 10, 217. 33. Malo, J. L., Longbottom, J., Mitchell, J., Hawkins, R. and Pepys, J. (1977) Thorax, 32, 269. 34. Rosenberg, M., Patterson, R., Mintzer, R., Cooper, B. J., Roberts, M. and Harris, K. (1977) Annals of Internal Medicine, 86, 405. 35. Safirstein, B. H., D'Souza, M. F., Simon, G. H-C., Tai, E. and Pepys, J. (1973) American Review of Respiratory Disease, 108, 450. 210 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 36. Pepys, J. (1966) Postgraduate Medical Journal, 42. 698. 37. Hayward, B. J., Augustin, R. and Longbottom, J. L. (1960) Acta Allergologica, 15, (Supplement 7), 87. 38. Forman, S. R., Fink, J. N., Moore, V. L., Wang, J. and Patterson, R. (1978) Journal of Allergy and Clinical Immunology, 62, 131. 39. Imbeau, S. A., Nichols, D., Flaherty, D., Dickie, H. and Reed, C. (1978), ibid., p. 91. 40. Wang, J. L. F., Patterson, R., Rosenberg, M., Roberts, M. and Cooper, B. J. (1978) American Review of Respiratory Disease, 117, 917. 41. Turner, K. J., O'Mahony, J., Wetherall, J. D. and Elder, J. (1972) Clinical Allergy, 2, 361. 42. Rosenberg, M., Patterson, R., Roberts, M. and Wang, J. (1978) American Journal of Medicine, 64, 599. 43. Benatar, S. R., Keen, G. A. and Du Toit Naude, W. (1980) Clinical Allergy, 10, 285. 44. Henderson, A. H., English, M. P. and Vecht, R.J. (1968) Thorax, 23, 513. 45. Mintzer, R. A., Rogers, L. F., Krugli, G. D., Rosenberg, M., Neiman, H. L. and Patterson, R. (1978) Diagnostic Radiology, 127, 301. 46. Malo, J. L., Pepys, J. and Simon, G. (1977) Thorax, 32, 262. 47. Stark, J. E. (1967) Diseases of the Chest, 61, 90. 48. Crompton, G. K. and Milne, L. J. R. (1973) British Journal of Diseases of the Chest, 67, 301. 49. Henderson, A. H. and Pearson, J. E. D. (1968) Thorax, 23, 519. 50. Malo, J. L., Hawkins, R. and Pepys, J. (1977) Thorax, 32, 254. 51. Campbell, M. J. and Clayton, Y. M. (1964) American Review of Respiratory Disease, 89, 186. 52. Golbert, T. M. and Patterson, R. (1970) Annals of Internal Medicine, 72, 395. 53. Wang, J. L. F., Patterson, R., Roberts, M. and Ghory, A. C. (1979) American Review of Respiratory Disease, 120, 87. 54. Turner-Warwick, M. (1973) Clinical Allergy, (Supplement), 3, 53. 55. Deve, F. (1938) Archives medico-chirurgicales de I'appareil respiratoire, 13, 337. 56. Safirstein, B. H. (1973) American Review of Respiratory Disease, 108, 940. 57. McCarthy, D. S., Simon, G. and Hargreave, F. E. (1970) Clinical Radiology, 21, 366. 58. Ein, M. E., Wallace, R.J. and Williams, T. W. (1979) American Review of Respiratory Disease, 119, 811. 59. DuBois, R. M., Newman-Taylor, A. J., Clark, T. J. H. and Cole, P. J. (1979) Clinical Allergy, 9, 313. 60. MacPherson, P. (1965) British Journal of Diseases of the Chest, 59, 148. 61. Saliba, A., Pacini, L. and Beatty, O. A. (1961) British Journal of Diseases of the Chest, 55, 65. 62. Plithal, V., Jedlickova, Z., Viklicky, J. and Tomaneck, A. (1964) Thorax, 19, 104. 63. Orie, N. G. M., DeVries, G. A. and Kiestra, A. (1960) American Review of Respiratory Disease, 82, 649. 64. McCarthy, D. S. and Pepys, J. (1973) Clinical Allergy, 3, 57. 65. British Tuberculosis Association (1968) Tubercole, 49, 1. 66. Bardana, E. J. Jr. (1981) CRC Critical Reviews in Clinical Laboratory Sciences, 13, 85. 67. Goldberg, B. (1962) Clinical Radiology, 13, 106. 68. Pennington, J. E. (1980) Medical Clinics of North America, 64, 475. 69. Irwin, A. (1967) Clinical Radiology, 18, 432. 70. Adiseshan, N. and Oliver, N. A. (1973) American Review of Respiratory Disease, 108,441. 71. Longbottom, J. L., Pepys, J. and Clive, F. T. (1964) Lancet, 1, 588. 72. Avila, R. (1968) Thorax, 23, 144. 73. Editorial (1983) Lancet, 2, 1066. 74. Manning, L. K. and Robertson, L. (1959) British Medical Journal, I, 345. 75. Editorial (1971) British Medical Journal, 2, 124. 76. Krakowka, P., Traczyck, K, Walczak, J, Halweg, H., Elsher, Z. and Pawlicka, L. (1970) Tubercle, 51, 184. 77. Edwards, G. and La Touche, C. J. P. (1964) Lancet, 1, 1349. 78. Evans, E. G. V., Watson, D. A. and Mathews, N. R. (1971) British Medical Journal, 4, 599.' 79. Editorial (1977) Lancet, 1, 635. 80. Laustela, E. (1969) Scandinavian Journal of Respiratory Disease, 50, 309. 81. Henderson, R. D., Deslaurier, J., Ritcey, E. L., Delarue N. C. and Pearson, F. G. (1975) Journal of Thoracic and Cardiovascular Surgery, 70, 1088. 82 Eguchi, S., Endo, S., Sakashita, I., Terashima, M., Asmo, K. and Yanagida, H. (1971) British Journal of Diseases of the Chest, 65, II. 83. Kilman, J. W., Changuroo, A., Andrews, N. C. and Klassin, K. (1969) Journal of Thoracic and Cardiovascular Surgery, 57, 642. 84. Belcher, J. R. and Plummer, N. S. (1960) British Journal of Diseases of the Chest, 54, 335. 85 Degott, C., Potet, F., Werner, P. and Lesobre, R. (1973) Annates de Medecine Interne, 124, 135. 86. Leggat, P. D. and DeKretser, D. M. H. (1968) British Journal of Diseases of the Chest, 62, 147. 87. Gregory, P. H. and Lacey, M. E. (1963) British Mycological Society Transactions, 46, 73. 88. Riddle, H. F. V. and Channel, S. (1968) Thorax, 23, 271. 89. Liebow, A. A. (1973) American Review of Respiratory Disease, 108, 1. 90. Katzenstein, A. L., Liebow, A. A. and Friedman, P. J. (1975) American Review of Respiratory Disease, 111, 497. 91. Anderson, C. J., Craig, S. and Bardana, E. J. (1980) Journal of Allergy and Clinical Immunology, 65, 140. 92. Bujak, J. S., Kwon-Chung, K. J. and Chusid, M. J. (1974) American Journal of Clinical Pathology, 61, 361. 93. Hutter, R. V. P. and Collins, H. S. (1962) Laboratory Investigation, 11, 1035. 94. Young, R. C., Bennett, J. E., Vogel, C. L., Carborne, P. P. and Devita, V. T. (1970) Medicine (Baltimore), 49, 147. 95. Orr, D. P., Myerowitz, R. L. and Dubois, P.J. (1978) Cancer, 41, 2028. 96. Bodey, G. P. {\965) JOurnal of Chronic Disease, 19, 667. 97. Nalesnik, M. A. (1980) Journal of Clinical Microbiology, 2, 370. 98. Aisner, J., Murillo, J., Schimpff, S. C. and Steere, A. C. (1979) Annals of Internal Medicine, 90, 4. 99. Bardana, E. J., Gerber, J. D., Craig, S. and Cianciulli, F. D. (1975) American Review of Respiratory Disease, 112, 799. 100. Shaffer, P. J., Kobayashi, G. S. and Medoff, G. (1979) American Journal of Medicine, 67, 627. 101. Weiner, M. H. (1980) Annals of Internal Medicine, 92, 793. 102. Davies, S. F. and Sarosi, G. A. (1985) Aspergillosis (ed Y. Al-Doory and G. E. Wagner). Springfield, Illinois: Charles C. Thomas. 103. Aisner, J., Schimpff, B. C. and Wiernik, P. H. (1977) Annals of Internal Medicine, 86, 539. 104. Editorial (1977) Lancet, 1, 1294. 105. Sinclair, A. J., Rossof, A. H. and Coltman, C. A. (1978) Cancer, 42, 2019. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986

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Modern Methods of Diagnosis in Liver Disease I. T. GILMORE, md, frcp Consultant Physician, Royal Liverpool Hospital, Liverpool The advances in the diagnosis and assessment of hepatic disease in the last 10 years have been considerable, and have certainly outstripped those in therapy. However, it is reasonable to expect that this increased understanding will contribute to more effective treatment in the next decade. The concept of a universally applicable 'liver function test' is no longer adequate, and the information from an investigation is only as good as the question asked of it. Some investigations are sensitive to early or mild disease without giving information as to the cause, while others are aimed at the underlying aetiology; some aim to give a global estimate of liver function whereas others are to detect complications; finally, some are aimed at the assessment of hepatic architecture, the reversibility of liver damage and the prognosis. Assessment of the Cause of Liver Disease Viral Liver Disease The greatest recent diagnostic advances have been in viral hepatitis. Infective hepatitis type A may now be simply and reliably diagnosed by detection of specific antibodies of the IgM class. Hepatitis B may usually be diagnosed by the presence of the virus outer coat, HBsAg, and it is likely that monoclonal antibodies will provide yet greater sensitivity than the existing radioim- munoassays. In the absence of detectable HBsAg, recent infection will be indicated by the presence of IgM anti- body to the core antigen (HBcAg) of the intact virus or Dane particle. Also, the 'e' antigen in serum, a soluble component of the virus, indicates the presence of virus in the bloodstream and hence potential infectivity. A consequence of these more sensitive serological tests, and in particular the application of molecular hybridisa- tion techniques to detect integrated sequences of hepatitis B DNA within hepatocytes, 'is that many cases of chronic liver disease previously thought to be cryptogenic may be the result of previous hepatitis B exposure. In a recent study[l], 52 of 88 patients with cryptogenic chronic liver disease had HBV DNA sequences detected in the liver, including 17 of 20 patients with primary hepatocellular carcinoma. The diagnosis of non-A, non-B hepatitis remains prob- lematical; there are probably at least three types and no reliable serological test, so in practice it remains a diagnosis of exclusion. However, the delta agent can now be elevated to the status of hepatitis D[2]. This is an incomplete RNA virus which utilises HBsAg to become an infective agent, and is now well described as a cause of hepatitis supervening in patients who are carriers of HBsAg. There are serological tests for anti-delta, and HBsAg carriers who have antibodies to the delta agent have a higher frequency of abnormal liver function tests and of active liver disease[3]. Alcoholic Liver Disease The diagnosis of alcohol as the cause of liver disease depends on a high index of clinical suspicion. Elevation of the serum gamma-glutamyl transpeptidase and the eryth- rocyte mean corpuscular volume are useful laboratory markers of alcohol abuse, being abnormal in 60-90 per cent[4], but it should be noted that these may be abnor- mal in other forms of chronic liver disease and hence have low specificity. To these blood markers may be added the mitochondrial fraction of aspartate aminotransferase, m- AST, which has been recently reported to be reliably elevated in alcoholics with and without liver damage[5]. Metal Storage Diseases The early and accurate diagnosis of haemochromatosis and Wilson's disease is crucial because there are effective treatments to prevent progression of the hepatic damage. Haemochromatosis is an autosomal recessive condition linked to the HLA locus on the short arm of chromosome 6. Relatives of a proband have a very high risk of being affected if they share the same HLA genotype, although the particular HLA haplotype varies from family to family. As a defective gene product has not been identi- fied, we must rely on indicators of increased iron stores to pick up affected relatives. In a recent study of early, asymptomatic cases of haemochromatosis, detected by screening siblings of known patients, serum ferritin was the most reliable single biochemical screening test, pick- ing up 30 of 35 affected, although serum iron and iron saturation did nearly as well[6]. In Wilson's disease, depression of plasma caeruloplasmin remains the most reliable non-invasive indicator, but in high risk subjects this should be supplemented by serum and urine copper estimations and by slit-lamp examination for Kayser- Fleischer rings. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 201 Detection of Mild Liver Disease The search for an exquisitely sensitive test of liver function has been a popular one, as shown by the large number of potential candidates. Plasma bromsulphtha- lein (BSP) retention after an intravenous bolus or infusion has been the most widely used. Its recent relative neglect is due in part to anxiety over occasional adverse reactions to BSP and in part to the lack of any direct clinical utility of such a sensitive test. Indocyanine green clearance produces similar results, is safer, but expensive. The clearance of both is influenced by changes in liver blood flow as well as function. In the last decade the endogenous concentration of bile acids in serum has emerged as the 'state of the art' sensitive liver function test and is also specific for liver disease[7]. However, the gain in sensitivity over the aggregate of conventional biochemical liver function tests is small, so its use is confined to clinical research. Another highly sensitive biochemical marker of liver dysfunction under evaluation is plasma glutathione S-transfer- ase[8,9]. Hepatic imaging methods have been disappointing in the detection of early or mild diffuse parenchymal liver disease. In cirrhosis or fatty liver the ultrasound image may appear unusually 'bright' but this is non-specific. Density of tissue may be accurately quantitated on CAT scan; fatty liver is less dense than usual whereas the liver in haemochromatosis is more dense[10]. These changes may be useful in following the course of haemochromato- sis during treatment. Magnetic resonance imaging is promising because tissue characteristics may be quanti- tated in ways such as spin relaxation times T1 and T2. The T1 may be prolonged in cirrhosis[l 1]. However, there are not yet enough reports on the findings in early disease. Quantitative Assessment of Liver Function While some liver function tests such as serum bile acid concentration and BSP retention become abnormal early in the progression of liver disease, others such as plasma albumin and prothrombin time are well maintained until severe liver dysfunction develops. This is shown sche- matically in Fig. 1. It would be useful to have a test which gives an estimate of functional hepatic mass analogous to the creatinine clearance in nephrology. However, the hepatic clearance of substances with high hepatic extrac- tion depends more on liver blood flow than function[7], so a substance with low extraction and long half-life time must be selected. Unconjugated bilirubin clearance would be suitable in theory, and in fact the plasma bilirubin concentration correlates well with survival in conditions as diverse as fulminant hepatic failure and primary biliary cirrhosis. However, in many instances many other factors such as haemolysis and cholestasis contribute to the plasma concentration. The elimination of galactose has been a popular quantitative liver function test in Scandinavia[12] but has not been widely adopted in the UK or USA. The clearance of the drugs antipyrine and aminopyrine fall progressively with increasing dam- age to the liver and may be useful. A breath test utilising 14C-aminopyrine in which cumulative breath 14C-C02 is measured is a simple test for clinical practice, and the spread of results in patients with differing severity of liver disease is shown in Fig. 2. With a conventional "Tcm sulphurcolloid isotope liver scan, it is possible to get some impression of the efficacy of hepatic uptake of the radioisotope by its density and Normal result t Abnormal result Decreasing liver function Fig. 1. Schematic representation of the possible relationships of liver tests to alterations in liver function. Fig. 2. Cumulative 2 hour excretion of ,4C-C02 after adminis- tration of ,4C-aminopyrine to patients with liver disease of varying severity. (Gilmore, unpublished data.) % 10.01 9.0- O 8.0-1 I (severe) II (moderate) III (mild) Disease severity group 202 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 distribution; in cirrhotic patients there is reduced, patchy uptake with increased amounts of activity in the spleen and bone marrow. It is now possible to quantitate this by a technique known as Single Photon Emission Tomo- graphy (SPET; Table 1). Following intravenous bolus injection of a suitable radiopharmaceutical agent such as I23I-BSP, there is rapid disappearance of activity from plasma and uptake by the liver (Table 2 and Fig. 3). By performing serial axial scans in a mode analogous to the X-ray CT scan, it is possible to make computer recon- structions of horizontal slices through the liver. The activity in each slice can be accurately measured and, by Table 1. Types of radionuclide liver scan. Target: Kupffer cell, e.g. "Tcm sulphurcolloid Hepatocyte, e.g. I2T-BSP, "Tcm-HIDA Mode: Anteroposterior scan Single photon emission tomography Table 2. Hepatic uptake of l23I-BSP assessed by SPET in patients with liver disease of differing severity. (Alstead et al., unpublished data.) Group n % uptake, mean ? SEM I (severe) 19 36.5 +2.02* II (moderate) 21 56.7 + 1.75** III (mild) 20 73.2 + 2.24 *1 v. II, P < 0.002, Mann-Whitney 'U' Test. **II v. Ill, P < 0.002, Mann-Whitney 'U' Test. integration of the slices, the liver volume and activity per unit volume calculated. Such SPET scans can be per- formed with hepatocye and Kupffer cell imaging agents, and we have found that uptake of 123I-BSP relates to disease severity as judged by scoring other multiple parameters (Fig. 3)[ 13,14], Detection of Focal Hepatic Disease This is where the non-invasive hepatic imaging methods come into their own. Ultrasonography is the cheapest and most convenient starting point for the assessment of suspected focal disease, and may detect unsuspected biliary tract pathology by showing dilated intrahepatic bile ducts or gallbladder stones. Metastases down to a size of 1 cm or less may be found, although occasionally metastases from certain primary sites such as the breast may not stand out. Also, diffuse infiltrative lesions may prove more difficult. The outstanding problems with ultrasonography are its dependence on the skill of the radiologist, and the marked inter-observer differences. The clinician cannot interpret the scans himself, whereas CT scans are more open to general discussion. The CT scan is particularly useful for suspected vascular lesions, as intravenous contrast may be administered and the liver imaged dynamically. It is clearly important to exclude a haemangioma before a suspected metastasis is biopsied. For obtaining a tissue diagnosis from small lesions, both ultrasonography and CT scanning are very useful for carefully targeting percutaneous biopsies. Most radiolo- gists find radioisotope scanning less sensitive for picking up small metastases in the liver, but SPET improves the Fig. 3. Plasma disappearance and hepatic uptake of intravenoulsy administered ,23I-BSP[14]. Sp.act Tomographic period Plasma mins Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 203 sensitivity considerably. When there is a single focal defect in the liver and surgical resection is being con- sidered, hepatic arteriography with late films of the portal vein is essential. Histological Assessment Percutaneous liver biopsy remains an essential part of the full assessment of most hepatic diseases, but carries an appreciable morbidity and mortality[15]. Even a mortal- ity rate of one in 5,000 procedures has to be viewed with concern. Although the bleeding time of the liver after biopsy, as viewed through the laparoscope, does not correlate with the usually measured parameters of clot- ting[ 16], it is clinical experience that the major bleeding complications occur in those with disordered haemostasis. There have been various approaches to making the procedure safer in these individuals (Table 3). Laparos- copy is widely used in continental Europe and has the added advantages of allowing direct inspection of the liver, before and after biopsy, and targeting biopsies. However, it is more complex than 'blind' percutaneous Table 3. Attempts at safer liver biopsy. Infusion of clotting factors/platelets Laparoscopic liver biopsy Operative liver biopsy Transjugular liver biopsy Percutaneous 'plugged' biopsy biopsy, and has not found favour in the UK except in focal liver disease. Transjugular liver biopsy is theoreti- cally attractive in those patients with severe coagulopath- , ies; the flexible biopsy needle is passed down a catheter previously inserted into the right jugular vein and posi- tioned in a wedged position in a branch of the hepatic vein. It is then advanced into the liver tissue to secure a sample for histological assessment, and any bleeding should be back into the venous circulation. During the procedure, it is convenient to perform hepatic veno- graphy and hepatic vein wedged pressure measurements in addition, and multiple samples may be taken from the patient without extra discomfort. However, like laparos- copy, the procedure is complex and unlikely to find a routine clinical place except in a few centres[17]. In patients with impaired coagulation it is technically much more straightforward to plug the biopsy site with absorba- ble gelatin sponge after routine percutaneous biopsy. ^ This has proved safe in our experience of 80 cases[18], but clearly much larger numbers are required to evaluate modifications in a technique with a low mortality. It is the destruction of normal architecture by hepatic fibrosis that heralds the onset of cirrhosis and portal hypertension. A serological marker of this fibrogenesis would be helpful, particularly for following patients treated with agents aimed at reversing this destruction when serial liver biopsies are not justified. An encourag- ing approach is the measurement of the n-terminal propeptide of collagen III in serum, and there is a reasonable correlation between serum levels and hepatic fibrosis as judged by morphometry[19]. Fig. 4. Endotoxaemia in normal subjects and in patients with liver disease[23]. 0 = decompensated cirrhosis, no infection; A = biliary obstruction or liver failure with sepsis; ? = other liver disease; A = normal controls. 0.5H c 0.4H 0.3H 0.2- e A 0 s _8_ A A Upper limit Normal controls All patients with liver disease Decompensated cirrhosis without infection Biliary obstruction or liver failure and gram-ve sepsis 204 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 Diagnosis of Complications in Chronic Liver Disease , Portal Hypertension Fibreoptic oesophagoscopy has largely replaced barium contrast studies in the diagnosis of oesophageal varices. It may be quite difficult to judge whether or not small varices are present, particularly in a restless patient, but this is not usually clinically vital, as the risks of variceal haemorrhage relate to their size. Gastric varices may be difficult to see endoscopically, especially in the bleeding patient, but are even more difficult radiologically. Patients with portal hypertension may have a gastritis, and this may be the cause of bleeding rather than the varices. This is probably the result of mucosal congestion, and has been termed 'congestive gastropathy'[20]. ^ Infection Spontaneous bacterial peritonitis is a potentially fatal complication of cirrhosis. It is undesirable to withhold treatment in a febrile, ill patient until the results of bacteriological cultures are available, but it is now clear that the diagnosis is highly likely if the polymorphonu- clear leucocyte count in ascitic fluid is greater than 250/ mm3[21]. Initial reports that the pH of ascites was a quick and reliable indicator of spontaneous bacterial peritoni- tis[22] have not been widely confirmed. Endotoxaemia is common in patients with cirrhosis and >. reflects their impaired reticulo-endothelial function and susceptibility to infection. Assays for circulating endo- toxin are notoriously fickle, but a new quantitative chromogenic modification of the standard limulus assay looks promising[23]. Using this method, most patients with decompensated cirrhosis have endotoxaemia in the absence of overt sepsis (Fig. 4). ! Primary Liver Cancer Alphafetoprotein is the circulating marker of hepatocellu- lar carcinoma (HCC) most widely used, and the positivity rate of 50-80 per cent depends in part on whether an immunodiffusion or radioimmunoassay is used. How- ever, there are other potential markers that may become more widely used. B,2-binding protein is detectable, particularly in the fibrolamellar variant of HCC[24], and serum ferritin[25] and alphafucosidase[26] seem to have similar detection rates to alphafetoprotein. This review is by no means comprehensive and has just touched on some of the numerous approaches to the diagnosis and assessment of liver disease. It has also been biased towards those tests of greatest personal interest. However, I hope it demonstrates that the clinician has availed himself of the very best of scientific advances in the last decade, from magnetic resonance imaging on one hand to molecular genetics on the other. Perhaps in the next decade this will be a springboard for developing more rational and effective therapy. Acknowledgements I wish to thank Dr E. Alstead, Dr A. I. Morris, Dr S. Grimes and Dr M. Critchley for their collaboration in some of the reported studies, and the Mersey Regional Health Authority for financial support. This article is based on a paper read at the College Regional Conference held at Liverpool in September 1985. References 1. Brechot, C., Degos, F., Lugassy, C. et al. (1985) New England Journal of Medicine, 312, 270. 2. Thomas, H. C. (1985) Gut, 26, 1. 3. Arico, S., Aragona, M., Rizzetto, M. et al. (1985) Lancet, 2, 356. 4. Whitehead, T. P., Clarke, C. A. and Whitfield, A. G. W. (1978) Lancet, 1, 978. 5. Nalpas, B., Vassault, A., Le Gillou, A. et al. (1984) Hepatology, 4, 893. 6. Bassett, M. L., Halliday, J. W., Ferris, R. A. and Powell, L. W. (1984) Gastroenterology, 87, 628. 7. Gilmore, I. T. and Hofmann, A. F. (1980) Gastroenterology, 78, 177. 8. Bass, N. M., Kirsch, R. E., Tuff, S A. and Saunders, S.J. (1978) Gastroenterology, 75, 589. 9. Beckett, G. J., Kellett, H. A., Gow, S. M., Hussey, A. J., Hayes, J. D. and Toft, A. D. (1985) British Medical Journal, 291, 427. 10. Fawcitt, R. A., Forbes, W.St C., Isherwood, I., Morris, A. I., Marsh, M. N. and Turnberg, L. A. (1978) Clinical Radiology, 29, 251. 11. Haaga, J. R. (1984) The Radiological Clinics of North America, 22, 879. 12. Tygstrup, N. (1966) Scandinavian Journal of Clinical and Laboratory Investigation, 18, 118. 13. Alstead, E. M., Morris, A. I., Gilmore, I. T., Grime, J. S. and Critchley, M. (1984) Gut, 25, A572. 14. Alstead, E. M., Morris, A. I., Gilmore, I. T., Ware, J., Grime, J. S. and Critchley, M. (1985) Gut, 26, A563. 15. Westaby, D., MacDougall, B. R. and Williams, R. (1980) British Medical Journal, 281, 1331. 16. Ewe, K (1981) Digestive Diseases and Sciences, 26, 388. 17. Bull, H. J., Gilmore, I. T., Bradley, R. D., Marigold, J. H. and Thompson, R. P. H. (1983) Gut, 24, 1057. 18. Tobin, M. V. and Gilmore, I. T. (1985) Gut, 26, A1127. 19. Frei, A., Zimmerman, A. and Weigand, K. (1984) Hepatology, 4, 830. 20. McCormack, T. T., Sims, J., Eyre-Brook, I. et al. (1985) Gut, 26, 1226. 21. Hoefs, J. C-, Canawati, H. N., Sapico, F. L., Hopkins, R. R., Weiner, J. and Montgomerie, J. Z. (1982) Hepatology, 2, 399. 22. Gitlin, N., Staffer, J. L. and Silvestri, R. C. (1982) Hepatology, 2, 408. 23. Alstead, E. M., Khan, F. J., Morris, A. I., Gilmore, I. T. and Ware, J. (1984) Journal of Hepatology, 1, S4. 24. Paradinas, F. J., Melia, W. M., Wilkinson, M. L. et al. (1982) British Medical Journal, 285, 840. 25. Giannoulis, E., Arvanitakis, C., Nikopoulos, A., Doutsos, I. and Tourkantonis, A. (1984) Digestion, 30, 236. 26. Deugnier, Y., David, V., Brissot, P. et al. (1984) Hepatology, 4, 889. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 205

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Book Review Interferons: Their Impact in Biology and Medicine edited by Joyce Taylor-Papadimitriou. Oxford University Press 1985. 148 pages. Price ?20 (hardback), ?10 (paperback). It is just over a quarter of a century since Isaacs and Lindenman described the interferons (IFN)?a group of proteins produced by cells in response to virus infection. This concept was not immediately accepted, some critics even suggesting that the material found should really be called 'misinterpreton'. However, the skilled work of Isaacs and his colleagues has established beyond doubt the importance of IFN. These substances are involved in human immune responses, in growth regulation and differentiation, and may also affect the growth of malig- nant tumours. There has been an exponential increase in the amount of research done in the last few years, much of it due to the more ready availability of a host of interfer- ons, and it is one of the most exciting fields of biology at the present time. Joyce Taylor-Papadimitriou is to be congratulated on reflecting this sense of excitement in her book. Clinicians will, of course, be primarily interested in the role of IFN in viral infections (presented by Scott), and in malignant disease (described by Nethersole and Sikora), but they would be missing one of the most lucid accounts of the human immune system and the role of interferon if they do not read Balkwill's chapter on the regulatory role of IFN in these responses. The early chapters on the genes of the IFN system and their expression are somewhat hard going for those not in the field of molecular biology, but good summaries and conclusions help to pave the way for understanding later chapters. It would be an advantage in a future edition to have an introductory chapter on the different forms of interferon and their derivation, in order to help the general reader. The object of the book is to stimulate thought about IFN and to help with the institution of new trials. The chapters are well referenced, and undoubtedly the book will be of great help to those doing research on IFN. Wisely, no great claims are made for its clinical efficacy in either virus diseases or cancer. The editor stresses that careful, controlled clinical trials will be necessary to find the role of IFNs in therapy. The number of chapter authors working in institutions primarily concerned with cancer research indicates where experimental hopes have been over the last few years. Nethersole and Sikora have provided an excellent brief review of the present position with regard to interferons in malignant disease. There is no doubt that in a limited number of cancers a beneficial effect on tumour growth may be seen, and in one very rare leukaemia, hairy cell leukaemia, it may be that IFN will establish itself as a treatment of choice. As they emphasise, however, it is the insight that may be obtained into tumour cell growth and its regulation that may produce the greatest benefit from the study of the biology of IFN. There is no doubt that in whatever field of medicine one's interest lies, IFN, but more particularly its biology, will be increasingly relevant during the next decade. This book provides a good introduction to the subject and a basis for further reading. J. S. Malpas. 194 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986

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Management of Upper Gastro-intestinal Bleeding in a District General Hospital M. V. MADDEN, FRCS, Registrar* G. H. GRIFFITH, FRCS, Consultant Surgeon. Royal Gwent Hospital, Newport, Gwent Upper gastro-intestinal bleeding is a common and serious problem which accounts for approximately 8 per cent of medical admissions to hospitals in the UK[1], Detailed results of treatment have been reported from several academic units in Britain[2,3,4]. However, most patients with upper gastro-intestinal bleeding are managed in District General Hospitals and we have therefore exam- ined our experience to see if it reflects the spectrum of pathology and the results of treatment found in teaching hospitals. Materials and methods This District General Hospital has 650 beds and serves a population of 320,000 people. We examined emergency ward admission records and Hospital Activity Analysis data for the years 1980 and 1981 to identify patients who fulfilled Morgan's criteria for the diagnosis of upper gastro-intestinal bleeding: the patient's history of vomit- ing blood or clots, or 'coffee grounds' or passage of tarry black stool or blood confirmed by medical or nursing staff[5]. We excluded patients not admitted on the day of referral, to eliminate those referred for elective investi- gation of anaemia or occult gastro-intestinal bleeding. Two patients' records could not be traced. From clinical records we obtained information on drug or alcohol ingestion, incidental medical problems, pre- vious upper gastro-intestinal bleeds and the blood press- ure and haemoglobin level on admission. The initial clinical diagnosis was recorded, as were endoscopic, radiological, operative and autopsy diagnoses; when these conflicted precedence was given to information obtained at autopsy, operation, endoscopy or barium meal in that order. Re-bleeding in hospital, operations performed for bleeding within seven days of admission, operative com- plications and deaths were noted. Results Altogether, 330 patients were admitted of whom 194 were men (59 per cent) and 136 were women (41 per cent). Their age distribution is shown in Table 1. The common- Table 1. Age of patients (% of total) Y ears % <40 14 40-59 27 60-79 44 >80 15 est diagnosis was duodenal ulcer (29 per cent) followed by gastric ulcer (19 per cent) and gastric erosions (14 per cent); other diagnoses were much less common (Table 2) and 16 per cent of patients left hospital or died without a diagnosis being made. Table 2. Final diagnoses % of patients Patients % Deaths who died Duodenal ulcer Gastric ulcer Gastric or duodenal erosions Gastric carcinoma Oesophageal varices Mallory-Weiss tear Oesophagitis Stomal ulcer Other diagnoses No diagnosis made TOTAL 96 29 7 7 63 19 10 16 46 14 1 2 11 3 7 64 9 3 5 56 17 5 0 0 23 7 0 0 5 2 1 20 7 2 2 30 53 16 17 32 330 100 50 Co-incidental medical problems were recorded if they might have complicated medical, surgical or anaesthetic management of bleeding and were present in 36 per cent of patients. Most of these patients had cardiac or respirat- ory disease; liver or renal disease was occasionally identi- fied. Aspirin, non-steroidal anti-inflammatory drugs or corticosteroids were being used at the time of bleeding by 44 per cent of patients, while in 13 per cent the admitting doctor indicated that recent alcohol ingestion might have precipitated bleeding. *Correspondence to Mr M. V. Madden, Surgical Gastro-enterology Clinic, Groote Schuur Hospital, Cape Town, 7925 South Africa. 212 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 Previous upper gastrointestinal bleeds had occurred in 86 patients who had bled either once (64 patients), twice (12), 3 times (3), 4 times (6) or 5 times (1). The death rate in these patients was 14 per cent, very similar to the 16 per cent death rate in patients who had not bled pre- viously. Admission haemoglobin values were obtained for 326 patients: 132 were below 10 g/dL (41 per cent) and 35 of these were below 7 g/dL (11 per cent). Systolic blood pressure was below 100 mm Hg, when first recorded in 37 patients (11 per cent). Blood was transfused in 189 patients (57 per cent) who received a mean of 5.7 units. Endoscopy was performed within 48 hours in 20 per cent and later during the same admission in a further 46 per cent, while a barium meal was performed in 11 per cent. No angiograms were performed to identify sources of bleeding. Histamine receptor antagonists were given to 51 per cent of patients, alkali to 6 per cent and 19 per cent received both. Neither form of treatment was used in 24 per cent. Operations were performed for bleeding within 7 days of admission in 32 patients (10 per cent) (Table 3). Table 3. Indication Results of surgery Operation performed Number Deaths Duodenal ulcer Gastric ulcer Gastric erosions Gastric carcinoma Oesophageal varices Stomal ulcer Aorto-duodenal fistula TOTAL Vagotomy & pyloroplasty with under-running of ulcer 9 2 Pyloroplasty with under-running of ulcer 1 0 Partial gastrectomy 4 2 Partial gastrectomy 8 4 Vagotomy & excision of ulcer 1 1 Vagotomy & pyloroplasty 1 0 Under-running of ulcer 2 0 Vagotomy & pyloroplasty 1 0 Partial gastrectomy 1 1 Laparotomy only 2 2 Vagotomy & under- running of ulcer 1 0 Direct suture of fistula 1 1 32 13 Three patients underwent reoperation: for re-bleeding from a duodenal ulcer, for a subphrenic abscess after gastrectomy with splenectomy for gastric ulcer and for embolectomy following aorto-duodenal fistula repair: all three died. In all, 50 patients died (15 per cent). The causes of death are shown in Table 4. Thirteen deaths followed surgery (operative mortality 41 per cent) and a further 14 were ascribed to continued bleeding in patients who did not have an operation. Deaths were significantly more common in patients aged 60 or over, in women, in Table 4. Causes of death Total of 50 patients Number (%) of patients Number (%) No operation Bleeding 14 (28) Pneumonia 7 (14^ Liver failure 6 (12) Stroke 3 (g^ Carcinomatosis 2 (4) Cardiac failure 1 (2) Limb gangrene 1 (2) Unknown 3 ^ Total 37 (74) Following operation Suture line leak 4 ^ Pneumonia 2 (4) Cardiac failure 2 (4) Bleeding varices 2 (4) Pulmonary embolus 1 (2) Acute renal failure 1 (2) Hypovolaemic cardiac arrest 1 (2) Total 13 (26) Table 5. Factors associated with death Patients dying/Total % dying P (chi2) Age <60 5/136 Age 60 + 45/194 Men 21/194 Women 29/136 No medical problems 19/210 Medical problems 30/120 Hb 10+ 18/194 Hb <10 30/132 Endoscoped 18/217 Not endoscoped 31/113 No re-bleed 44/303 Re-bleed 8/27 4 23 11 21 9 25 9 23 8 27 15 30 <.001 <.01 <.01 <.01 <.01 <.05 patients with incidental medical problems, those with Hb below 10 g/dL, in those who had not undergone endos- copy and in patients who re-bled (Table 5). However, in each of these categories the group with a higher mortality rate also had a higher average age, except for patients undergoing endoscopy whose average age was very simi- lar to those not endoscoped (60.1 vs 61.2 years). Discussion The total of 330 patients admitted during two years confirms that upper gastro-intestinal bleeding is a com- mon cause of emergency admission to a District General Hospital, even assuming that some patients went unde- tected because the study was retrospective. Using admis- sion ward records to cross-check the Hospital Activity Analysis data identified roughly a quarter of the patients Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 traced, so the potential inaccuracy of using HAA data alone must have been reduced substantially. Our patients had a mean age of 60.4 years, confirming that this is largely a disease of the elderly. Allan[3] has pointed out that the average age of patients with upper gastro-intestinal bleeding in the UK has risen steadily, which probably explains why mortality rates have re- mained static over several decades. Unchecked bleeding was the commonest cause of death in our non-operated patients, and was the indication for surgery in all those who died after an operation. These two groups accounted for 54 per cent of all deaths, so a safe and effective way of stopping bleeding in the elderly should make a major difference to overall mortality. It is therefore disappointing that reliable endoscopic and phar- macological methods of controlling bleeding have not yet been found[6]. However, histamine receptor antagonists were given to 70 per cent of our patients and this seems to be a common practice[4] despite the lack of evidence that they improve survival from upper gastro-intestinal bleed- ing. Most of the factors we found to be associated with an increased death rate were predictable ones: age 60 or more, associated medical problems, haemoglobin below 10 g/dL and re-bleeding in hospital. Women died more often than men, probably because they were on average 9.4 years older (66.0 vs 56.6). However, we cannot explain the higher survival rate of patients who under- went gastroscopy. It is unlikely that more precise diag- nosis led to their having better treatment: first, more than two thirds of endoscopic examinations were performed over 48 hours after admission, so it would be surprising if the findings led to life-saving changes in management. Second, referral for endoscopy was strongly influenced by the policy of the consultant physician under whom patients were admitted, so it is possible that enthusiastic use of endoscopy was accompanied by more aggressive and successful treatment. Third, routine early endoscopy has not been shown to influence patient survival[7] although it seems logical that oesophageal varices, in particular, should be treated endoscopically once identi- fied, thus avoiding dangerous surgery in patients with portal hypertension. Our two patients operated on for bleeding varices both died because bleeding was not controlled. Most patients with upper gastro-intestinal bleeding are treated in District General Hospitals, so it may be misleading to deduce national mortality rates from teach- ing hospital data. We have therefore compared three series describing teaching hospitals' experiences with our own, to see if there were differences in the overall death rate, the operation rate and the operative death rate. We also compared the proportion of elderly patients in each series and the causes of bleeding, as these have a major impact on the likely death rate (Tables 6 and 7). Allan[3], Berry[4] and Cotton[2] and their co-workers specify the diagnoses for most or all of their patients, and the proportions of patients with the three commonest causes of bleeding (duodenal ulcer, gastric ulcer and erosions) are similar in all four series. The proportions bleeding from varices, which are uncommon but have a Table 6. Causes of bleeding in this series and series from UK teaching hospitals (%). This series Allan[3] Berry[4] Cotton[2] Duodenal ulcer 29 Gastric ulcer 19 Erosions 14 Gastric, carcinoma 3 Varices 3 Mallory-Weiss 5 Oesophagitis 7 Stomal ulcer 2 Other diagnoses 2 No diagnosis 16 30 23 24 19 23 29 17 14 11 2 2 2 2 3 3 1 10 7 1 3 2 3 9 17 15 Table 7. Death rate, operation rate and operative death rate in this series and in series from UK teaching hospitals. No of % aged 60 Deaths Operat- Operative patients or over (%) ions (%) deaths (%) This 330 59 50 32 13 series (15) (10) (41) Allan[3] 296* 48 25+ 96+ 9 + (9) (32) (9) * * Berry[4] 125 69 6+ 24+ 3 (5) (19) (13) Cotton[2] 206* 45 8+ 54+ 6 + (4) (26) (11) *patients specified as not having bled from the upper gastro-intestinal tract have been removed + lower operation rates and higher death rates when compared to this series (chi2, p<0.1) **lower death rate when compared to this series (Fisher's exact test, P = 0.04) high mortality rate, are almost identical. The patients may therefore be sufficiently similar to allow valid com- parison. Our results show three clear differences from each of the teaching hospital series: our overall patient mortality was higher, the operation rate was lower, and the post-operative death rate was higher. If the patients in each series were indeed comparable, our treatment was less effective, both for patients who had operations and those who did not, and we have tried to work out why this was so. It is disturbing that the commonest cause of death in patients who were not operated on was unchecked bleed- ing: these patients may have bled to death because surgery was used so seldom. Surprisingly, most had not been referred for a surgical opinion. A reluctance to operate may also have led to dangerously delayed oper- ations and contributed to the 41 per cent operative mortality. The high proportion of our patients aged 60 or more does not excuse these poor surgical results: we had fewer elderly patients than in the Oxford study, in which Berry reported a lower death rate and fewer post-operat- ive deaths despite a higher rate of recourse to surgery. Our results are so much worse than those achieved by others who treat apparently similar patients that a change in management seems necessary. Potentially avoidable 214 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 deaths appear to have occurred in two situations: first, the post-operative death rate of 41 per cent was excessive and second, continued bleeding caused 14 of 37 deaths in patients who did not have operations. This suggests that surgical treatment, in the broadest sense, needs improve- ment but also that more operations to stop bleeding should be performed. This might be achieved if patients with haematemesis and melaena were routinely admitted to a surgical ward. Admitting bleeding patients directly to a surgical ward might avoid dangerously delayed operations, and allow many procedures to be performed on elective surgical lists, when consultant surgical and anaesthetic cover is readily available[8]. It should virtually eliminate con- tinued bleeding as a cause of death. On the other hand, over a third of our patients had incidental medical illnesses, usually cardiac or respiratory, which would be less effectively managed in a surgical unit. Furthermore, most patients do not actually need operations and would occupy beds otherwise available for elective surgical procedures. Perhaps this is why only 4 per cent of UK hospitals sampled by Thomas[9] admitted patients with haematemesis and melaena to surgical wards, although Hegarty and colleagues[8] found that this policy worked well in a District General Hospital. Alternatively, Cotton and RussellflO] have suggested that bleeding patients be nursed in an intensive care unit for 72 hours after admission. This should ensure early detection of continued bleeding or re-bleeding, as well as skilled management of associated illnesses during the period of maximum risk, but it would be an expensive way to manage patients who usually turn out not to have needed intensive care after all. A third approach has been used by Hunt et al. [11,12] who have reported a steady improvement in the survival of patients with bleeding peptic ulcer since the establish- ment of a haematemesis and melaena unit, which is run jointly by a gastro-enterologist and a surgeon. This approach would reduce the use of expensive intensive care facilities. It should also allow early endoscopic identification and discharge of low-risk patients (erosions, oesophagitis or normal endoscopy) as well as careful monitoring of patients with oesophageal varices, or peptic ulcers with signs of recent bleeding. We feel that our results might have been better if management had in- volved closer co-operation between medical and surgical teams. A haematemesis and melaena unit, drawing staff from both sources, should lead to better selection of patients for surgery, more appropriate timing of oper- ations, and improved perioperative care as well as earlier discharge of low-risk patients. Because upper gastro- intestinal bleeding is a common, dangerous problem in a District General Hospital it may be worth re-allocating staff and resources which are already used to care for these patients to a special unit. References 1. Johnston, S. J., Jones, P. F., Kyle, J. and Needham C. D. (1973) British Medical Journal, 3, 655. 2. Cotton, P. B., Rosenberg, M. T., Waldram, R. P. L. and Axon, A. T. R. (1973) British Medical Journal, 2, 505. 3. Allan, R. and Dykes, P. (1976) Quarterly Journal oj Medicine, 45, 533. 4. Berry, A. R., Collin, J., Dudley, N. E., Frostick, S. P. and Morris, P. J. (1984) Journal of the Royal College of Surgeons of Edinburgh, 29, 134. 5. Morgan, A. G., McAdam, W. A. F., Walmsley, G. L., et al. (1977) British Medical Journal, 2, 237. 6. Editorial (1984). Lancet, 1, 715. 7. Conn, H. O. (1981) New England Journal of Medicine, 304, 967. 8. Hegarty, M. M., Grime, R. T. and Schofield, P. F. (1973) British Journal of Surgery, 60, 275. 9. Thomas, G. E., Cotton, P. B., Clark, C. G. and Boulos, P. B. (1980). Journal of the Royal Society of Medicine, 73, 90. 10. Cotton, P. B. and Russell, R. C. G. (1977). British Medical Journal, 1, 37. 11. Hunt, P. S., Korman, M. G., Hansky,J. et al. (1979) British Journal of Surgery, 66, 633. 12. Hunt, P. S., Hansky,J., Korman, M. G. et al. (1980) Australian and New Zealand Journal of Surgery, 50, 41. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 215

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Book Review Principles and Practice of Geriatric Medicine ? edited by M. S. J. Pathy. John Wiley and Sons, Chichester, 1985. 1336 pages. Price ?62.50. It has taken me some six months to review this massive book, reinforcing my admiration of the labour which must have been involved in its generation. There are now two major British reference books on geriatric medicine, this one and Brocklehurst's Textbook of Geriatrics and Gerontology. Both are too heavy to carry around or for bedtime reading, so I have dipped into Brocklehurst at work and Pathy at home during the autumn, looking up clinical problems I have encountered and topics I have had to teach. 'Big Brocklehurst', now in its third edition, is already established as a source. Although a handful of its authors are also contributors to the new Pathy tome, I found enough difference between the two books to be glad to have both. Pathy (and his 72 contributors) start with introductory chapters on the basic sociology, biology and psychology of ageing, but the major part of the book is devoted to the practical consideration of clinical problems as they affect the elderly. This is apparent in the emphasis given to neurological disorders (almost 300 pages) compared to, for example, the respiratory system (30 pages) or gastro- intestinal disease (100 pages). The selection of subjects and their respective allocation of space reflects the prob- lems posed by the elderly sick, particularly where their presentation may differ from that seen in younger patients. As is customary in such large textbooks, the arrangement of chapters is based on bodily systems, with additional material on specific topics such as exercise, pharmacology, sleep disorders, anaesthesia and surgery in the elderly. While this traditional approach is probably the most reasonable structure for a reference book, some shorter introductory texts on geriatric medicine have successfully adopted a more integrated, problem-orientat- ed format. Although many of the chapters in Pathy are eminently readable at a sitting, the book as a whole would be difficult to plough through from beginning to end. Towards the end of the book there are chapters on health care delivery in the UK, Japan and the USA. These contributions are of broad interest, and since 20 of the authors come from outside the British Isles the book should appeal to readers in other countries. It is refresh- ing to see a chapter on health problems of older people in the developing world: this is where some two-thirds of the world's population over 65 years of age will live as we go into the next century. We can only hope that Bob Geldof will not retire too early. With over 60 chapters to choose from, it is customary for the reviewer to comment on variable standards, but I will refrain from poaching the curate's egg on this occasion. However, it is fair to say that this book is primarily aimed at clinicians, with enough gerontology included to set the stage for geriatric medicine. The editing and layout are excellent, the index good, and most chapters have a useful selection of references. I hope that Pathy will join Brocklehurst as a standard source in hospital libraries and departments of geriatric medicine. Roger Briggs 226 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986

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Susan Ryland Susan Ryland, Deputy Editor of the Journal, died on 25th March. These words are written soon after her tragically early death when the community of the College is joined with her family in mourning their great loss. Almost twenty years ago Susan came to the College and started work on the Journal when its first issue was launched. From that time onwards the complex organisation of the Journal and College Commentary was in her hands. That it has run so smoothly is entirely due to Susan's intelligence, diligence and sheer hard work. There was the secure feeling that as long as she was there nothing could go far wrong; and nothing did. As befitted a graduate of Trinity College, Dublin, she had a gift for lucid accurate written English which she applied to her meticulous editing. Always wanting to increase her expertise, she learnt to be a skilled sub-editor and could 'page' a journal with elegance. All her work was measured by her own high standards and, being unassuming, she was genuinely surprised by praise. Apart from her heavy editorial responsibilities, she was also Secretary to the Standing Committe of Members. In the last issue of the Journal the Committee thanked Susan for 'her unerring efficiency and unending patience' in her work on 'Training to be a Physician' which she had nursed from conception to the printed page. This was an accurate tribute to the way she always did things. This brief factual account tells little of Susan and of what a pleasure it was to work with her. She had great charm and courtesy. She looked at the world with a clear perceptive eye, had an informed love of art and music, especially opera, disliked pomposity and had compassion for all who suffered. She never put herself forward but had a dry wit. Her friends knew her to be a special person and their lives are diminished by her death. S.M. Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 159

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I j i ( Towards Rational Drug Therapy in Old Age The F. E. Williams Lecture 1985 F. I. CAIRD, DM, FRCP David Cargill Professor of Geriatric Medicine, Southern General Hospital, Glasgow University Department of Geriatric Medicine, Drug therapy can play a major part in the prevention and relief of the sufferings of old age?the end for which F. E. Williams endowed the lecture which bears his name?but is very much a two-edged sword, since injudicious and irrational therapy may do much more harm than good. Rational therapy must aim at efficacy with safety, though these two objectives may at times be incompatible. What help can we get towards rational drug therapy in old age from epidemiology, the study of drug kinetics and dyna- mics, and from official bodies? Information from Epidemiology Epidemiology tells us, as might be expected, that the multiple pathology of the elderly constitutes a standing temptation to polypharmacy, and that they consume more drugs than younger people[l-3]; they are respon- sible for twice the national average drug bill per head[4]. Adverse reactions to drugs (ADRs) increase with age[5- 7] (Fig.l), and some 12 per cent of admissions to geriatric units are occasioned wholly or partly by ADRs[8]. The frequency of ADRs may have fallen over the last 20 years but, at their most recent absolute level, they leave no place for complacency, and they are still at least twice as common in the elderly as in the young (Fig.l). The frequency of ADRs rises with the number of drugs prescribed; in one study it was 100 per cent if 10 or more were given[9], and the trend, though not so striking, is similar in many[10]. ADRs are often attributed to poor patient compliance, but non-compliance most often leads to under-consump- tion of drugs. The blame should be taken by the prescrib- es since multiplicity of drugs has been shown in several studies to be a most important factor in poor compli- ancefll]. To simplify the task for the patient must be a major objective, and should be assisted by deliberate and repeated teaching and monitoring of the patient's drug- taking^]. Proper aids to memory, demonstrated as useful to the patient in question[13], and the proper use of containers[14], should now be a part of standard practice both in hospital, in medical wards as widely as is com- monly now the case in geriatric wards, and in general practice. In the longer term there is doubt of the efficacy of active teaching[15], but at least it can do no harm. In the last analysis, however, it would be most unwise to improve compliance before improving prescribing, since that would mean the disappearance of the patient's last defence against the doctor. Symptomatic postural hypotension in elderly hospital patients is very commonly associated with drug therapy, and not infrequently with multiple potentially causal drugs[16]. It is then of little value to decide as to the precise cause, and in most situations the best thing is to strike out all drugs. Another approach, particularly useful on those occasions when one or more of the individual drugs is essential, is to stop drugs serially and observe the effects closely. This should allow a decision to be made on which drug or drugs is a predominant cause, and will often permit the essential therapy to be continued. Simplicity of prescribing and the use of as few drugs as possible are important principles of rational geriatric clinical pharmacology, which should reduce the frequen- Fig. 1. Relationship between age and frequency of adverse reactions to drugs. <20 30 40 50 60 70 80 + Age (years) ? ? Seidl [5] USA * * Hurwitz [6] UK o o Levy [7] Israel Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 235 cy of adverse reactions and interactions. These principles should only be set aside if absolutely necessary. Gosney and Tallis[17] observed 133 adversely interacting combi- nations of drugs in 6,160 prescriptions for the elderly (2 per cent). Sixty of these 133 were potentially serious, and 67 were avoidable. Clearly, well-established knowledge was not being correctly applied. A computer program to assist in the avoidance of these and other ADRs has been designed[18], and may well prove necessary to reduce the consequences of the imperfections of human memory. Meanwhile, much can be achieved by the simple but arduous process of taking thought. Single drug therapy may also result in unacceptable adverse reactions. The frequency of adverse reactions to flurazepam[19] is low at any age with a small dose, which is ineffective as a hypnotic, becomes more common in the elderly with an intermediate dose and rises to totally unacceptable levels with a dose which is effectively hyp- notic. Here safety and efficacy are clearly incompatible, at least in the elderly, and since there are alternative hypnotics to flurazepam, a rational prescriber would conclude that this drug should not be given to the elderly. In the case of nitrazepam, its depressant effects on the CNS are age-related, and the so-called stimulant effects are not[20]. It must be questioned whether any benzodiazepine should be prescribed for the elderly unless there is an overwhelming requirement. Hypnotics as a whole may be much less necessary for the elderly than has been thought. In my wards they have, for the last two years, been prescribed for fewer than 10 per cent of patients, without complaint from patients or staff. Indeed, one is driven to wonder whether they have not been prescribed more to treat the staff than the patients. Information from Pharmacokinetics and Pharmacodynamics We learn much from pharmacokinetics about the reasons for the elderly reacting adversely both to individual drugs and to certain combinations of them. Drug absorption is little affected by age, and although reductions and delays in absorption have been described for some drugs[21], they are of little clinical importance. One important exception is levodopa with which there is an approximate- ly three-fold increase in absorption in the elderly[22], probably due to age-related reduction of gastric dopamine decarboxylase, and consequent greater availability of levodopa for absorption. This increase in absorption is undoubtedly one of the main reasons for the substantially lower dose of levodopa required for the elderly[23], and for the place of levodopa as one of the commoner causes of ADRs in the elderly[8,24]. In the elderly, decrease in pre-systemic elimination by the liver of lipid soluble drugs with a high hepatic elimination rate, e.g. propranolol, lignocaine and chlor- methiazole[25-27] results in increased bio-availability, which may be a reason for dose reduction in the elderly. Alterations in drug distribution with age[21] are of great interest but not very easy to interpret. Age reduces lean body mass and increases fat mass so that water- soluble drugs are distributed in a smaller volume and fat- soluble drugs in a larger volume[28], This effect is of small magnitude, except with digoxin, when the 30 per cent reduction in its volume of distribution is probably in part related to reduced lean body mass[29,30]. This necessitates a reduction in the loading dose, where a reduced volume of distribution has its greatest effect. Altered volume of distribution has an important effect on the interpretation of changes in the plasma half-life, which cannot be used alone to provide evidence of changes in clearance, the most valid measure of elimina- tion, because clearance is defined as half-life divided by volume of distribution, so that changes in the latter as well as in the former may result in changes in clearance. Properly conducted studies are required, with i.v. as well as oral dosage, to elucidate the facts with certainty. Altered protein binding may perhaps be important, although this is also a confusing subject. Reduced serum albumin, a common finding in sick but not healthy old people[31], is clearly important in this connection since many drugs are bound to albumin, and there is a greater possibility of interaction between drugs, due to greater displacement of one by another in the elderly[32]. The most important single kinetic cause of adverse reactions in the elderly is undoubtedly impaired renal elimination. This affects drugs eliminated predominantly by glomerular filtration (digoxin, phenobarbitone, cime- tidine and procainamide) and those largely eliminated by tubular secretion (penicillin and aminoglycoside anti- biotics). Impairment arises because of the magnitude and regularity of occurrence of reduction in renal function with age, and the sensitivity of the renal circulation to extrarenal disturbances in disease. At all ages the renal clearance of digoxin is related linearly to clearance of creatinine[8]; the small effect of the spironolactone-sensitive renal tubular secretion of digoxin[34] may be ignored in quantitative terms. The mean digoxin clearance of elderly patients who are given the drug[33] is only around 40 ml per minute, with values as low as 10 ml per minute, as against the average normal glomerular filtration rate in the elderly of 80-90 ml per minute[35]. The hepatobiliary clearance of digoxin is also reduced in these patients from the value in young normals of 50-60 ml/min to around 20 ml/min[33,36], but there is little clinical evidence that this is of importance. Any intercurrent factor which produces acute alter- ations in the glomerular filtration rate, such as the onset of congestive heart failure or of dehydration, will reduce digoxin clearance and so increase the risk of toxicity. Conversely, any factor which increases glomerular filtra- tion rate, such as the resolution of those conditions mentioned, will increase digoxin clearance, and render inadequate a previously adequate dose. The only import- ant cause of a persistent increase in glomerular filtration rate above normal at any age is hyperthyroidism[37], which also increases the volume of distribution by a factor of 2-3 times[30], probably by increase in muscle Na-K ATPase[38], of which the volume of distribution may well be a reflection. Digoxin provides an excellent example of the effects of pharmacokinetic knowledge upon rationality of prescrib- 236 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 ing in the elderly. In a study of three loading and one maintenance dose in three groups, each comprising 7-9 elderly patients with normal renal function[39], the load- ing doses were 0.75, 0.5 and 0.25 mg, and the mainten- ance dose 0.25 mg. The time course of the serum concentrations over five days was calculated from the fractional absorption of the drug accepted as unaltered in the elderly[40], estimates of the volume of distribution and hepatobiliary clearance[30,33], and the previously demonstrated equivalence of renal digoxin and creatinine clearances. The agreement between theory and obser- vation is very close. The three loading dose schedules result in therapeutic blood levels on days 1, 2, and 4 respectively, without any level approaching the toxic. The choice of regime can thus depend on a decision on how fast it is thought necessary to digitalise the patient. u By contrast, age-related changes in the kinetics of drugs with predominantly hepatic metabolism are rarely of the same magnitude and regularity, though statistically sig- nificant differences may be demonstrable. Surprisingly, direct measurement in liver biopsy samples has shown few age-related alterations in the concentration of several important drug metabolising enzymes in man[41], and presumably the age-related reduction in liver size and blood flow is more important[42,43]. Age may affect hepatic oxidative more than conjuga- tive metabolic pathways[28], and the delayed production j' and further delayed elimination of active metabolites produced in the liver may operate to prolong drug action. The basic genetically determined differences between individual rates of metabolism of some drugs are pre- served[44]. There may be differential sex effects, women being more affected than men[28], and though in the elderly reduced induction of hepatic enzyme activity has been shown[45], it is much more difficult to demonstrate nutritional and other environmental effects, except those 4 ? of cigarette smoking, particularly when the effects may be due to exposure to noxious agents many years previously. We know too little of the effects of disease in old age on drug kinetics, and specific studies should be carried out. The clearance of Cortisol, which is metabolised by the same hepatic enzyme system as are many drugs, is much increased by the chronic infection of pressure sores, roughly in proportion to their severity; this increase is abolished by healing of the sores[46]. Chronic infection may thus lead to a need for greater drug dosage. Altered pharmacodynamics in the elderly are another area of great interest but, because of the considerable difficulties of study in man, have been less investigated. Almost all that has been studied is the relationship of plasma concentration to drug effect, which has been attributed to reduced receptor number or affinity, or to post-receptor changes. For instance, the heart rate re- sponse to equivalent concentrations of isoprenaline is blunted in the elderly[47,48], and beta-blockers are rela- tively less effective, blood level for blood level[49]. The failure to demonstrate any effect of age on alpha-adrener- ? ? gic function is one of the few examples of direct measure- ment of drug effect in man[50]. The increased effect of some benzodiazepines may also be due to receptor alterations, or to alterations in the balance of neurotransmitters in the elderly brain, al- though the effects of any change in the blood/brain barrier and consequent better penetration of the drug into the brain have not been investigated. One such example is the age-related fall in the plasma concentration of diazepam required to produce abolition of response to voice but not to pain[51], The psychomotor effects of nitrazepam are increased in the elderly at equivalent blood levels[52]. That the effect in both cases may be due to better penetration into the brain is suggested by the fact that, in the elderly mouse, cerebral benzodiazepine receptors are not apparently altered in concentration[53]. The anticoagulant effect of warfarin is increased, owing to increased sensitivity of hepatic synthesis of clotting factors[54]. Difficulties with drug therapy and adverse reactions in the elderly can also be caused by what might be called conditioning factors. For example, in middle age diuretics do not cause substantial potassium depletion, but in old age they often do[55]. This is not due to some peculiarity in the action of the drugs themselves, but to the known reduction in potassium intake that occurs with age[56]. Any drug that increases potassium output in the face of a reduced input must cause potassium depletion. It is often wrongly and dangerously inferrred that because supple- mentary potassium is not required with diuretics in middle age, it is not required at any age. A second conditioning factor is the effect on tempera- ture regulation in the elderly of drugs such as phenothia- zines, which are well up among the causes of hypothermia in old age; old age itself is associated with a high prevalence (up to 40 per cent) of abnormalities of tem- perature regulation[57], A third example is the high frequency of postural hypotension caused by many drugs. This is in part a consequence of the age-related impair- ment of baroreceptor function[58]. The scientific study of drugs in the elderly is at last well under way. There are now striking examples of age- related alterations of drug kinetics and dynamics; there is as yet no very clear set of principles from which useful predictions may be made about drugs not yet studied in the elderly. A blanket recommendation to reduce the doses of all drugs given to the elderly is certainly unwar- ranted, since no change has been demonstrated in the handling of several, such as phenytoin[59] and ateno- lol[60]. Every drug commonly used in the elderly must have its pharmacology specifically elucidated in the eld- erly before we can confidently say that our prescribing is rational. Meanwhile, simple empirical adjustments, such as in drug numbers and in doses, are required, though based perforce on only half knowledge. Clearly, drugs which have already been studied in the elderly are far preferable to those which have not. There is a consider- able, but by no means an insuperable, task ahead in this vital field. Information from Official Bodies The Royal College of Physicians' Reportfll] makes a number of recommendations which are by and large admirable and open to criticism in detail only. These Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 237 recommendations are, in the case of hospital doctors, mainly concerned with the responsibility of senior doctors for proper prescribing, which the report rightly stresses. Too often this important matter is left to juniors, as a mere day-to-day question. A thorough and regular review of drug therapy is rightly suggested (though rather bizar- rely as occurring 'every 10 days', when most of us work to a working week), and particularly when the patient leaves hospital, and is the cornerstone of the proper discharge of this responsibility. The final decision on drug therapy should be combined with the beginning of active teaching of the patient in the days immediately before return home. The report also stresses the responsibility of gen- eral practitioners for the supervision of repeat prescrip- tions, and the limitations of such repeats to a set number. My main criticism is concentrated on the statement that the pharmacology of the elderly is not suggested as a subject for specific study in the undergraduate curricu- lum, when in the long run nothing will advance ration- ality of prescribing in the elderly more surely than that it should be emphasised at the undergraduate level, and that advantage should be taken of the usefulness of the facts described as illustrating principles of clinical phar- macology in one of its most important practical areas. In Glasgow a considerable proportion of our formal lectur- ing time in geriatrics is devoted to this topic, and its importance is stressed at every opportunity during bed- side teaching. The second official body is the Committee on Safety of Medicines. Its criteria with regard to the elderly have recently been altered. The Committee's definitions of what constitutes an 'at risk' drug for the elderly are eminently sensible (Table 1). It is difficult to believe that Table 1. At risk drugs in the elderly (Licensing Authority criteria). 1. Low therapeutic index 2. Clearance likely to be reduced 3. Interactions likely with other drugs commonly used by the elderly 4. Possible kinetic or dynamic effects due to ageing of organs or common disease processes 5. Membership of therapeutic class with a bad record in the elderly any drug will escape its last requirement. The require- ments for drugs not yet marketed differ from those for drugs already marketed. For new drugs likely to be a risk for the elderly there are stringent requirements for testing in old age, and close monitoring. Thus, what has for years been immoral and unethical has suddenly become compulsory. The considerable practical difficulties in such testing (e.g. exclusion factors can easily become so numerous that there are virtually no subjects left to study) should not be allowed to prevent these much-needed investigations. It is to be hoped that new drugs will be specifically tested in patients with the conditions for which they are to be given rather than solely in the fit 'normal elderly', who may well be very different. Much more important quantitatively are the require- ments in respect of drugs already on the market; these are much less stringent, and there is no monitoring pro- cedure. This decision may perhaps be due to the apparent size of the task and the limited resources of the Commit- tee. A very simple study shows these fears to be unfound- ed. The study was carried out in November 1984, thus antedating the DHSS's limited list of drugs for simple conditions, which in any case is largely irrelevant to the question. The results of the study err somewhat in quantitative terms but its principles remain. Those drugs relevant to the elderly (Table 2) were counted in MIMS, Table 2. Drugs relevant to the elderly (data sheet study). Cardioactive drugs (inc. diuretics) CNS-active drugs (inc. analgesics) Anti-arthritic drugs (inc. NSAI) Drugs acting on GI and GU systems with systemic adverse effects (e.g. anticholinergics, carbenoxolone) Selected antibiotics (tetracyclines, aminoglycosides) Anti-diabetic drugs Cytotoxic drugs used by generalists and totalled 35 per cent of 1,084 drugs. The pertinent data sheets in the ABPI's latest data sheet compendium were studied for any mention of the elderly. It was not profitable to decide whether the mention was useful and appropriate or not. Only 27 per cent of drug data sheets mentioned the elderly. However, with drugs most im- portant to the elderly, such as psychotropics in the broadest sense, over half the data sheets already mention the necessity of care with the elderly (Table 3). The Table 3. Drugs relevant to the elderly, preparations, and percentage of preparations in which data sheet mentions the elderly. Drug group Elderly Number of mentioned (% of Drugs Preparations preparations) Digitalis 4 4 Benzodiazepines 18 30 Antidepressants 20 32 Phenothiazines 9 19 Other hypnotics 4 7 Barbiturates 8 21 Analgesics 20 34 Anti-Parkinsonism 12 17 Anti-diabetics 12 29 Other psychotropics 31 46 Other hypotensives 17 24 Diuretics 21 66 NSAI 21 48 Anti-angina 4 19 Anti-arrhythmics 9 13 All other 58 104 Anti-convulsants 8 9 /3-blockers 11 34 Theophylline, etc. 9 23 Anti-histamines 17 51 Sympathomimetics 20 54 100 93 88 74 71 48 48 35 34 33 25 21 19 18 15 14 11 9 9 2 2 238 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 J i. proportion of hypotensive drug data sheets mentioning the elderly is far less. The important thing about this study is that it took one man a week of his spare time, and one might imagine that rather greater resources might have managed it in a month. The problem is therefore ? !> much smaller than has been thought, and there is no reason why a monitoring procedure should not be set up; Table 2 indicates where the drug companies should be instructed to look on their data sheets. v The European Branch of the World Health Organisa- tion has recently taken a major interest in the problems of the elderly, and has made a number of useful practical suggestions with regard to drug therapy. The most important of these is perhaps a monograph to be pub- \ lished soon, which details in very simple terms, and without references, the considerations that are important to drug therapy in general in the elderly and to specific therapeutic situations. These three official bodies have therefore contributed, each in its own way, to rationality in drug therapy in old '<? age. References 1. Stewart, R. B. and Cluff, E. (1971) Johns Hopkins Medical Journal, 129, 319. 2. Moir, D. C. and Dingwell-Fordyce, I. (1980) Journal of Clinical and Experimental Gerontology, 2, 239. 3. Castleden, C. M. and George, C. F. (1984) In Clinical Pharmacology and Drug Treatment oj the Elderly, pp.71-98. (ed K. O'Malley.) Edinburgh and London: Churchill Livingstone. 4. Office of Health Economics (1980) Effects of Prescription Charges OHE Briefing? December, No. 13. 5. Seidl, L. G., Thornton, G. F., Smith, J. W. and Cluff, L. E. (1966) Bulletin of Johns Hopkins Hospital, 119, 299. 6. Hurwitz, N. (1969) British Medical Journal, 1, 536. 7. Levy, M., Kewitz, W., Altwein, W., Hillerbrand, J. and Eliakim, M. (1980) European Journal of Clinical Pharmacology, 17, 73. 8. Williamson, J. and Chopin, J. M. (1980) Age and Ageing, 9, 73. 9. Kellaway, G. S. M. and Macrae, E. (1976) New Zealand Medical Journal, 78, 525. ^ 10. Sue, S. G. (1984) In Drug Treatment in the Elderly, pp.21-42. (ed R. E. Vestal.) Sydney: ADIS Health Science Press. 11. Royal College of Physicians (1984) Journal of the Royal College of Physicians of London, 18, 7. 12. Davidson, J. R. (1974) Nursing Times, Mar.14. 13. Wandless, I. and Davie, J. W. (1977) British MedicalJournal, 1, 359. 14. Davidson, J. R. (1973) Journal of Hospital Pharmacy, 31, 180. 15. Roden, S. M., Harvey, P. G., Mayer, P. P. and Spence, L. I. (1985) Journal of Clinical and Experimental Gerontology, 7, 71. 16. Caird, F. I. (1979) In Drugs and the Elderly, pp. 263-6. (edj. Crooks and I. H. Stevenson.) London: Macmillan. 17. Gosney, M. and Tallis, R. (1984) Lancet, 2, 564. 18. Tallis, R. (1985) In Advanced Geriatric Medicine 5. (ed F. I. Caird and R. Tallis.) Tunbridge Wells: Pitman Medical, in press. 19. Greenblatt, D. J., Allen, M. D. and Shader, R. I. (1977) Clinical Pharmacology and Therapeutics, 21, 355. 20. Greenblatt, D.J. and Allen, M. D. (1978) British Journal of Clinical Pharmacology, 5, 407. 21. Cusack, B., Denham, M. J. and Kelly, J. G. (1984) In Clinical Pharmacology and Drug Treatment of the Elderly, pp. 19-38. (ed K. O'Malley.) Edinburgh and London: Churchill Livingstone. 22- Evans, M. A., Triggs, E. J., Broe, G. A. and Saines, N. (1980) European Journal of Clinical Pharmacology, 17, 215. 23. Broe, G. A. and Caird, F. I. (1973) Medical Journal of Australia, 1, 636. 24. Moore, S. R. and Jones, J. K. (1985) In Geriatric Drug Use: Clinical and Social Perspectives, pp. 70-7. (ed S. R. Moore and T. W. Teal.) Oxford: Pergamon. 25. Castleden, C. M. and George, C. F. (1979) British Journal of Clinical Pharmacology, 7, 49. 26. Nation, R. L., Triggs, E. J. and Selig, M. (1977) British Journal of Clinical Pharmacology, 4, 439. 27. Nation, R. L., Learoyd, B., Barber, J. and Triggs, E. J. (1977) European Journal of Clinical Pharmacology, 10, 407. 28. Greenblatt, D. J., Abernethy, D. R. and Shader, R. I. (1985) In Geriatric Drug Use: Clinical and Social Perspectives, pp. 153-9. (ed S. R. Moore and T. W. Teal.) Oxford: Pergamon. 29. Ewy, G. A., Kapadia, G. G., Yao, L., Lullin, M. and Marcus, F. I. (1969) Circulation, 39, 449. 30. Reid, J., Kennedy, R. D. and Caird, F. I. (1983) Age and Ageing, 12, 29. 31. Hodkinson, M. (1984) In Clinical Biochemistry of the Elderly, pp.24- 34. (ed M. Hodkinson.) Edinburgh and London: Churchill Living- stone. 32. Wallace, S., Whiting, B. and Runcie, J. (1976) British Journal of Clinical Pharmacology, 3, 327. 33. Roberts, M. A. and Caird, F. I. (1976) Age and Ageing, 5, 214. 34. Steiness, E. (1974) Circulation, 50, 103. 35. Rowe, J. W., Andres, R., Tobin, J. D., Norris, A. H. and Shock, N. W. (1976) Journal of Gerontology, 31, 155. 36. Whiting, B., Lawrence, J. R. and Sumner, D. J. (1979) In Drugs and the Elderly, pp.89-101. (ed J. Crooks and I. H. Stevenson.) London: Macmillan. 37. Croxson, I. J. and Ibbertson, D. H. (1975) British Medical Journal, 3, 566. 38. Kjeldsen, K., Norgaard, A., Gotzche, C. O., Thomassen, A. and Clausen, T. (1984) Lancet, 2, 8. 39. Caird, F. I. and Kennedy, R. D. (1977) Age and Ageing, 6, 21. 40. Cusack, B., Kelly, J., Horgan, M., O'Malley, K., Noel, J. and Lavan, J. (1979) Clinical Pharmacology and Therapeutics, 25, 772. 41. Woodhouse, K. W., Mutch, E., Williams, F. M. and James, O. F. W. (1984) Age and Ageing, 13, 328. 42. Calloway, N. O., Foley, C. F. and Lagerbloom, P. (1965) Journal of the American Geriatrics Society, 13, 20. 43. Skaunic, V., Hulek, P. and Martinkova, J. (1978) In Liver and Ageing, pp. 115-30. (ed K. Kitani.) Amsterdam: Elsevier North Holland. 44. Farah, F., Taylor, W., Rawlins, M. D. and James, O. F. W. (1977) British Medical Journal, 2, 155. 45. Salem, S. A. M., Rijjayabun, P., Shepherd, A. N. M. and Stevenson, I. H. (1978) Age and Ageing, 7, 68. 46. Caird, F. I. (1983) Journal of Clinical and Experimental Gerontology, 5, 207. 47. Vestal, R. E., Wood, A. J. J. and Shand, D. G. (1979) Clinical Pharmacology and Therapeutics, 26, 181. 48. Lakatta, E. G. (1979) Federation Proceedings, 38, 163. 49. Feely, J. and Stevenson, I. H. (1979) Journal of Clinical and Experimental Gerontology, 1, 173. 50. Scott, P. J. W. and Reid, J. L. (1982) British Journal of Clinical Pharmacology, 13, 237. 51. Reidenburg, M. M., Levy, M., Warner, H. et al. (1978) Clinical Pharmacology and Therapeutics, 23, 371. 52. Castleden, C. M., George, C. F., Marcer, D. and Hallett, C. (1979) British Medical Journal, 1, 10. 53. Heusner, J. E. and Bosmann, H. B. (1983) Journal of Clinical and Experimental Gerontology, 5, 121. 54. Shepherd, A. N. M., Hewick, D. S., Moreland, T. A. and Stevenson, I. H. (1977) British Journal of Clinical Pharmacology, 4, 315. 55. Judge, T. G. (1968) Gerontologia Clinica, 10, 102. 56. Judge, T. G., Caird, F. I., Leask, R. G. S. and McLeod, C. C. (1974) Age and Ageing, 3, 167. 57. Collins, K. J., Exton-Smith, A. N., James, M. H. and Oliver, D. J. (1980) Age and Ageing, 9, 11. 58. Gribbin, B., Pickering, T. B., Sleight, P. and Peto, R. (1971) Circulation Research, 29, 424. 59. Lambie, D. C. and Caird, F. I. (1977) Age and Ageing, 6, 133. 60. Rubin, P. C., Scott, P.J. W., McLean, K., Pearson, A., Ross, D. and Reid, J. L. (1982) British Journal of Clinical Pharmacology, 13, 235. Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 239

PMC005xxxxxx/PMC5371085.txt

The Prevalence of Diabetes Mellitus in a Typical English Community WENDY GATLING, MB, MRCP(UK), Novo Research Fellow A. C. HOUSTON, MB, MRCP(UK), Medical Officer (Research) R. D. HILL, MB, FRCP, Consultant Physician Poole General Hospital, Longfleet Road, Poole, Dorset Diabetes mellitus is a chronic medical disorder which, although eminently treatable, still has a considerable mortality and morbidity[1,2]. Evidence is now accumu- lating to suggest that well-controlled diabetics suffer fewer complications than poorly controlled diabetics[3,4], It is, therefore, incumbent upon the Health Service to provide adequate management and follow-up. There has recently been considerable interest in the organisation of diabetic care in the UK[5-7], However, to plan effectively, it is important to know the extent of the problem in both quantitative and qualitative terms. This survey identifies the number and type of diabetics in a well-defined population in the Poole area. Method The study population consisted of all the patients regis- tered with 40 general practitioners working from 10 practices in the Poole district. The geographical area covered in the survey was divided into two parts. In part A, a semi-rural area north-west of Poole, all the 28 GPs in the area were included. In part B, an urban area, 12 GPs were included, that is only about 25 per cent of all the GPs in the town of Poole. During an 18 month surveillance period all the known diabetics in the study population were identified from the following sources: (a) a previous diabetic survey[8]; (b) the Poole Diabetic Register, a computerised record of all diabetics, listed by GP; (c) diabetic registers held by the GPs; (d) all the diabetic clinics held in the hospital during the study period, and (e) repeat prescription requests and letters in each practice, collected by the GPs' reception- ists. A card index file of the names of the diabetics was maintained in each surgery. All records were scrutinised to ensure that each patient fulfilled the diagnostic criteria set by the WHO Expert Committeee on Diabetes Melli- tus[9]. If they had been treated continuously with insulin or had had a break of less than one month since diagnosis, or had suffered a documented episode of diabetic ketoaci- dosis, the patients were classified as insulin-dependent. All other patients were classified as non-insulin depen- dent. All diabetics were called for review by one observer (W.G.) as part of another study. When a majority had been seen in each practice, a count was made of the total number of people registered with that practice, using the age/sex register, when available, or the patient record folders. Thus, for each of the 10 practices a point prevalence of diabetes mellitus was determined. These were added together to produce the prevalence for the study population. Results In the study population, 917 diabetics were identified. At the beginning of the study, the Poole Diabetic Register and the previous survey[8] had found 604 (65.8 per cent) diabetics alive and still registered with the 40 GPs. During the surveillance period a further 313 diabetics were identified, 248 (27.1 per cent) from the GPs and 65 (7.1 per cent) from the hospital diabetic clinics. The 40 GPs had 90,660 people registered on their lists; 66,542 in part A, the semi-rural area and 24,118 in part B, the urban area. Thus, the prevalence of known diabetes mellitus in the study population is 1.01 per cent. Table 1 Table 1. Age distribution of patients registered with 40 GPs compared with UK population (1981 Census). Age No. of patients % (yr) registered % UK <5 5,497 6.1 6.1 5?14 12,176 13.4 14.7 15?29 17,961 19.8 22.5 30?44 19,309 21.3 19.5 45?64 20,214 22.3 22.3 65?74 9,204 10.2 9.2 75 and over 6,207 6.8 5.7 Unknown 92 0.1 Total 90,660 100 100 shows the age distribution of the study population and a comparison with that of the UK. There is a small but insignificant excess of over 65-year-olds but otherwise the 248 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 age distribution of the study population is comparable with that of the general population. t The cumulative frequency with respect to age in the diabetic patients is shown in Fig. 1, which clearly demon- strates that more than half the diabetics are aged over 65 years. Table 2 shows the age specific rates for diabetes in Table 2. Age specific rate for diabetes mellitus in the female and male populations. Rate per Age No. of patients No.of 1,000 study (yr) registered diabetics population F M F M F M <5 2,661 2,836 0 1 0 0.4 5?14 5,694 6,482 6 9 1.1 1.4 15?29 9,199 8,762 34 36 3.7 4.1 30?44 9,973 9,336 50 43 5.0 4.6 45?64 10,474 9,740 105 154 10.0 15.8 65?74 5,169 4,035 128 134 24.8 33.2 75 and over 3,973 2,234 115 102 29.0 45.7 Unknown 47 45 Total 47,190 43,470 438 479 the female and male populations respectively. The rates are similar in both sexes in the under 45-year-olds, but in the older age groups the rate is strikingly higher in the male population. The prevalence of diabetes in the female population is 0.93 per cent against 1.1 per cent in the male population. Of the 917 diabetics identified, 222 (24.2 per cent) were classified as insulin dependent and 679 (74 per cent) as non-insulin dependent. There were insufficient data avail- able to classify the remaining 16 (1.8 per cent) diabetics. The. type of treatment known for 901 diabetics was diet alone in 187 (20.4 per cent of the study group), oral hypoglycaemic agents in 358 (39 per cent) and insulin in 356 (38.8 per cent), of whom 222 were classed as insulin dependent and 134 as non-insulin dependent diabetics (NIDDs). The type of diabetes according to age is shown Table 3. Type of diabetes mellitus in relation to age in 901 diabetics in the survey (excluding 16 unclassified diabetics). Insulin dependent Non-insulin dependent Age %in that % in that (yr) No. age group M/'F No. age group M/F <10 6 100 1.0 0 0 10?19 32 100 1.3 0 0 20?29 43 90 1.26 5 10 0.3 30?39 40 71 1.35 16 29 0.6 40?49 30 37 1.0 52 63 1.38 50?59 24 19 1.67 101 81 1.25 60?69 21 11 1.1 175 89 1.33 70?79 18 7 0.8 245 93 0.87 80 and over 8 9 0.6 85 91 0.93 Total 222 679 in Table 3. As expected, the proportion of non-insulin dependent diabetics increases with age. Discussion This survey is unusual in that it was population-based and sought to identify both hospital and GP treated diabetics. Because of the five different sources used, ascertainment of all the known diabetics was probably very high. The fact that over 25 per cent of the diabetics were picked up through the GP surgeries demonstrates that a hospital-based survey would have significantly under-estimated the prevalence of diabetes mellitus. The surveillance, especially in the GP surgeries, relied heavily on reviewing repeat prescriptions for insulin, oral hypo- glycaemic agents and urine testing equipment. A small number of diabetics treated by diet alone, whose requests for urine testing equipment may be infrequent, may have been missed, particularly as some diabetics were found to have stopped testing their urine altogether. However, the GPs' own diabetic registers (available in five out of 10 practices) and other sources mentioned earlier were ex- tremely helpful in identifying these patients. The population under study was defined as all the people registered with 40 GPs. It is well known that GP lists tend to over-estimate the number of patients under their care because records of deaths and removals may not be kept up to date. Recent computerisation of all the records with the local Family Practitioner Committee (FPC) has reduced this problem to a minimum and the counts made at each practice were in close agreement with the FPC numbers for the nearest quarter. However, it is likely that the prevalence of diabetes mellitus is slightly higher than the 1.01 per cent determined. Previous studies on the prevalence of diabetes mellitus in the UK have been either screening surveys[10], hospi- tal-based studiesfll] or small-scale community studies[12,13]. The Edinburgh group[ll] attempted to identify all the diabetics alive on 1st January 1968, using the hospital clinic lists as a starting point. Although all the 263 GPs were contacted, no prolonged surveillance in the surgeries was attempted. They found a prevalence of diabetes mellitus of 0.63 per cent. However, only 13 per Age in years Fig. 1. The cumulative frequency in the 917 diabetics with respect to increasing age. Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 249 cent of their diabetics were aged 65 years and over compared with 52.2 per cent in this survey, suggesting poor ascertainment in the older age groups. In Oxford- shire, Dornan[12] found a prevalence of diabetes mellitus of 0.8 per cent, identifying the diabetics principally by a postal survey. In a large practice in Norfolk (practice list 20,010), Tasker found a prevalence of diabetes mellitus of 1.2 per cent[13]. However, in neither of these two studies are the diagnostic criteria for diabetes defined. The higher prevalence of diabetes in men aged 45 years and over is striking. This may reflect more frequent diagnosis of diabetes during routine employment and insurance medicals which men have more commonly than women. In addition, a higher percentage of male NIDDs (32.1 per cent) were treated by diet alone, compared to 22.3 per cent of female NIDDs. In 1965 Malins reported a change in the sex incidence of newly diagnosed diabetics towards more men being diagnosed[14]. However, the overall male:female ratio of new attenders was still less than 1.0. These figures on the prevalence and type of diabetes mellitus will be useful in planning adequate facilities for the management of diabetic patients. An average District General Hospital in Britain serves a population of 250,000, which will contain approximately 2,530 diabe- tics. If reasonable diabetic care is to be offered to these patients, the district health authority must provide facili- ties for an annual eye and medical examination and twice-yearly blood sugar and HbAl estimations as a minimum. Diabetic problems such as pregnancy, serious retinopathy, nephropathy, painful neuropathy and foot ulcers require specialist attention. In total, this represents a large workload. Health authorities, diabetologists and GPs must make detailed and integrated plans to provide an efficient workable system. Summary A survey was carried out in the Poole area to identify all the known diabetics under the care of 40 general prac- titioners. Surveillance in both hospital and general prac- tice ensured maximal ascertainment. From a study population of 90,660, whose age distribution was similar to that of the UK population, 917 diabetics were identi- fied. The prevalence of diabetes mellitus was 1.01 per cent. The age-specific rate for diabetes mellitus was higher in men over 45 years old than in women. Of the diabetics, 479 (52.2 per cent) were aged 65 years and over; 222 (24.2 per cent) were classified as insulin- dependent diabetics, 679 (74 per cent) as non-insulin dependent and for the remaining 16 (1.8 per cent) insufficient data were available for classification. A cknowledgemen ts Dr Wendy Gatling is a Novo Research Fellow. This research was supported by Wessex Regional Health Authority Research Fund, the British Diabetic Associ- ation and the Bournemouth Lions. Thanks are due to Professor R. J. Jarrett for his help in preparing the manuscript, and to all the 40 general practitioners and their staffs, without whose co-operation the survey would not have been possible. References 1. Deckert, T., Poulsen, J. E. and Larsen, M. (1978) Diabetologia, 14, 363. 2. Fuller, J. H., Elford, J., Goldblatt, P. and Adelstein, A. M. (1983) Diabetologia, 24, 336. 3. Pirart, J. (1978) Diabetes Care, 1, 168, 252. 4. Johnsson, S. (1960) Diabetes, 9, 1. 5. Hill, R. D. (1976) British Medical Journal, 1, 1137. 6. Singh, B. M., Holland, M. R. and Thorn, P. A. (1984) British Medical Journal, 289, 726. 7. Hayes, T. M. and Harries, J. (1984) ibid., p.728. 8. Houston, A. (1982) In Advances in diabetes epidemiology, pp. 199-206. Inserm Symposium No. 22 (ed E. Eschwege.) Amsterdam: Elsevier Biomedical. 9. WHO Expert Committee on Diabetes Mellitus (1980) Second Report. WHO Tech. Rep. Serv., No. 646. 10. Butterfield, W. J. H. (1964) Proceedings of the Royal Society of Medicine, 57, 196. 11. Falconer, D. S., Duncan, L.J. P. and Smith, C. (1971) Annals of Human Genetics, 34, 347. 12. Dornan, C., Fowler, G., Mann, J. I., Markus, A. and Thorogood, M. (1983) Journal of the Royal College of General Practitioners, 33, 151. 13. Tasker, P. R. W. (1984) Practical Diabetes, 1, 21. 14. Malins, J. M., Fitzgerald, M. G. and Wall, M. (1965) Diabetologia, 1, 121. ' 250 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985

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The Influence of Menstrual Status, Body Weight and Hypothalamic Function on Nocturnal Respiration in Women E G. KOPELMAN, MD, MRCP(UK), Lecturer in Metabolism and Endocrinology M. C. P APPS, MB, MRCP(UK), Senior Registrar in Respiratory Medicine T. COPE, SRN, Research Nurse, Department of Respiratory Medicine D. W. EMPEX MB, FRCP, Consultant in Respiratory Medicine The London Hospital, Whitechapel, London A disorder of breathing during sleep with episodes of haemoglobin oxygen desaturation and apnoea has been described in asymptomatic men of all ages and normal weight postmenopausal women; an increase in body weight in either group is associated with a greater fall in oxygen saturation and an increased frequency of ap- noea[l,2]. In contrast, obese women with regular men- strual cycles show a less severe fall in oxygen saturation during sleep and do not show sleep apnoea[3]. It has been proposed that the higher plasma progesterone levels in women with regular menstrual cycles is a protective factor against the development of sleep-disordered breathing[2], but, more recently, it has been suggested that sleep- breathing abnormalities are related to the age rather than the sex of a patient[4], We have recently reported evi- dence that the hypothalamus is also important for the control of nocturnal respiration[3]. We have now investigated the relationship of body weight and central factors to sleep-breathing patterns in asymptomatic normal weight and obese postmenopausal women and six younger women with amenorrhoea and obesity due to a hypothalamic-pituitary disorder, whose only complaint was progressive weight gain. Subjects and Methods Tables 1 and 2 give details of the subjects studied. The obese patients were volunteers who had become obese either as a teenager or during adult life and were attend- ing the Obesity Clinic; the control group of women were volunteers from the hospital staff. All of the subjects had normal thyroid function, were non-smokers and were not taking any form of medication. They had experienced regular menstrual cycles until the time of the menopause which had occurred at least two years prior to study. The patients with hypothalamic-pituitary disorders (Table 2) attended the Endocrine Clinic and were characterised by an insatiable appetite, progressive weight gain and amen- Table 1. Details of women studied. W/H2 weight (kg)/height2 (m); VC: Vital capacity; FEV: forced expiratory volume in one second; PEFR: peak flow rate, expressed as a percentage of predicted normal. Patient no. 1-9 : postmenopausal normal weight women ? no. 10-15: postmenopausal obese women ? no. 16-21: hypothalamic-pituitary disorders. Patient Age Weight no. (yr) (kg) W/H2 VC FEV! PEFR 1 62 67 23 104 98 94 2 50 74 25 94 90 88 3 51 64 22 86 92 95 4 55 67 24 102 96 92 5 65 65 22 111 102 94 6 52 65 24 98 94 98 7 50 65 24 90 88 82 8 55 63 22 85 77 80 9 50 63 24 95 100 89 Mean ? SEM 54 66( ? 1) 23 96 93 90 10 54 96 35 96 93 92 11 60 80 31 107 114 91 12 55 115 46 89 83 91 13 48 96 34 85 92 110 14 53 107 43 80 80 97 15 52 90 32 94 110 96 Mean ? SEM 54 98( ? 6) 37 92 95 96 16 35 104 40 75 75 76 17 44 106 42 84 85 81 18 48 115 44 92 90 104 19 60 106 37 80 85 95 20 30 85 31 95 98 110 21 58 112 44 79 78 81 Mean ? SEM 45 105( ? 4) 40 84 85 91 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 243 Table 2. Details of patients with hypothalamic-pituitary disorders. Patient Age at no. diagnosis Diagnosis Current treatment (daily dosage) 16 17 18 19 20 21 23 Craniopharyngioma treated by hypophysectomy and external radiotherapy 38 Hypopituitary after surgery and external radiotherapy for invasive chromophobe adenoma 48 45 29 57 'Hypothalamic syndrome'?unexplained hyperphagia and somnolence with hyperprolactinaemia. Normal CT cranial scan, menopause at age 45 years Acromegaly treated by external radiotherapy. Subsequent pituitary apoplexy and rapid increase in weight Hypopituitary following 2nd pregnancy with subsequent rapid weight gain Progressive weight gain with daytime somnolence. Normal anterior pituitary function. CT cranial scan suggests a partially empty sella. Menopause at age 46 years Hydrocortisone (30mg), thyroxine (200/ig) and nasal DDAVP (0.2ml) Hydrocortisone (30mg), thyroxine (200/xg) and nasal DDAVP (0.2ml) Nil Hydrocortisone (25mg), thyroxine (150/ig) Hydrocortisone (30mg), thyroxine (200fig) Nil orrhoea; those patients requiring pituitary hormone re- placement treatment were taking physiological doses and no patient was taking an oestrogen preparation. All the subjects were asymptomatic and none had a past history of a respiratory disorder. The hypothalamic-pituitary patients were investigated because of their progressive weight gain; none of them complained of hypersomno- lence, severe snoring or extreme tiredness. It was only after investigation that a history of these complaints was confirmed by their husbands. Pulmonary function was assessed using a Wright peak flow-meter and a Vitalo- graph dry spirometer. Body index was defined as weight (kg) divided by height in metres2 (normal female range 19-24). We considered patients to be obese if their body index exceeded a value of 26. The methods for monitoring respiration during sleep were identical to those we have previously reported[3]. Obese subjects were studied for two nights but it was only possible to study the lean subjects for one. Airflow at the nose and mouth were sensed with a laryngeal micro- phone, movement of the chest and abdomen was assessed with inductance bands (Respitrace) which show the movement of chest and abdomen separately. Apnoea was defined as a pause in airflow for more than 10 seconds; obstructive apnoea was characterised by increased respiratory effort with paradoxical collapse of the chest during inspiration with no airflow due to obstruction at the pharynx or larynx; central apnoea was indicated by the absence of airflow with no abdominal or chest movement and mixed apnoea if there was no movement early in the episode of apnoea and unsuccess- ful movement later in the episode[5]. Haemoglobin oxy- gen saturation (Sa02) was measured with a Hewlett Packard ear lobe oximeter with the patient in the supine position. Sleep was staged with an electroencephalogram (C4Ai), electro-oculogram and submental electromyo- gram using standard methods. Time to sleep (Ts) was defined as the time (in minutes) from the start of the study until the onset of sleep. Time to REM (TREM) was the time from onset of sleep until REM sleep. The number of episodes of waking (W) for periods of longer than one minute was also recorded. One of the investigators remained at the bedside throughout, noting the subjects' behaviour, such as snoring or restlessness, and recording this on the tracing. Timing of the events was also recorded on the tracing and each tracing was reviewed in detail and correlated with the stage of sleep. Statistical analysis was by a Wilcoxon non-parametric test, because the results were not normally distributed, and Spearman rank correlation test. Each subject gave fully informed written consent and the study was approved by the hospital's ethical committee. Results Pulmonary Function Tests (Table 1) All the patients and controls had normal spirometric values?that is, between 75 per cent and 125 per cent of predicted normal. Sleep Study Time awake during the night and times for sleep stages I, II, III/IV, REM and REM latency and the number of arousals (W) during the night are given in Table 3. The mean time spent in the stages was not significantly different between the three groups but only 4 of 9 normal subjects, 2 of 6 obese and none of the hypothalamic- pituitary group showed stage III/IV. There was no significant difference found between the indices of sleep latency (Ts), TREM, number of arousals and percentage time of sleep spent in REM sleep. Two of the patients had numerous apnoeas, one of these (patient 18) had very poor sleep (90 minutes without REM) and 32 arousals, the other (patient 19) slept well but with 12 arousals and only 10 minutes of REM sleep. Apnoea (Table 4) Obstructive apnoea was not seen in the normal weight or obese subjects but three of the hypothalamic-pituitary patients showed this (cases 16, 18, and 19) and in cases 18 244 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 Table 3. Duration of sleep stage and analysis of sleep pattern in the women studied. Wake T: total time awake during night; Ts: time from start of study until onset of sleep; TREM: time from onset of sleep until REM sleep; W: number of episodes of waking > 1 minute during night. Patient no. 1-9: postmenopausal normal weight ? no. 10-15: postmenopausal obese ? no. 16-21: hypothalamic-pituitary disorders. Patient no. Wake T Sleep stage (min) I II III/IV REM Total sleep time (min) REM/(%) total sleep Ts TREM (min) W Mean ? SEM 121 237 111 14 14 153 187 172 127 126 ?25 118 67 111 51 188 129 45 39 24 6+18 98 101 135 259 183 136 87 165 175 149+ 18 6 9 55 11 55 10 8 42 77 22 14 34 35 33 + 8 273 187 254 407 448 287 122 237 232 272 ?34 20 5 3 10 17 8 11 14 15 11 ?2 105 147 25 5 7 12 5 35 10 39 + 17 47 185 260 290 97 215 175 215 45 170 ?29 10 11 12 13 14 15 Mean + SEM 243 246 202 162 142 158 192 + 19 79 48 65 27 21 75 52 ? 10 97 109 117 163 196 172 142 + 17 25 17 11 12 50 32 24.5 ?6 201 174 193 207 271 275 220 + 18 12 9 6 6 18 12 10.5 + 2 94 150 115 15 102 51 8 + 20 85 183 208 175 72 82 134 ?25 16 17 18 19 20 21 Mean ? SEM 56 216 330 149 145 97 165 + 40 45 43 53 79 78 32 55 + 8 273 124 37 159 114 151 143 ?32 33 35 0 10 68 51 33 + 10 351 202 90 248 260 234 231 ?35 9 17 4 26 22 13 + 4 4 17 167 42 21 31 47 + 25 119 134 285 108 230 4 5 32 12 5 3 146 ?42 10 and 19 this was very frequent. In addition, case 19 showed mixed apnoea. The duration of apnoea was variable, patient 19 showing long apnoea (mean duration 24.5 + 12, range 14-60 sec), patient 18 shorter apnoea (mean duration 18.2 + 5, range 11-40 sec) and other patients showing no apnoeas longer than 25 sec. Haemoglobin Oxygen Saturation (Sa02) All measurements were made in the supine position and are given in Table 4. The mean awake saturation did not differ significantly between the three groups. Oxygen saturation fell in all subjects on falling asleep but the mean asleep value was not significantly different between the three groups. In all subjects except patient 18 (in whom there was no REM sleep), the minimum oxygen saturation was seen during REM sleep. The mean mini- mum saturation value did not differ significantly between the normal weight and obese subjects but was significant- ly less in the hypothalamic-pituitary women (P<0.01 versus normals, P< 0.05 versus obese). The lowest values were seen in the two hypothalamic-pituitary women with numerous apnoeas (cases 18 and 19) and case 21 in whom severe desaturation occurred during periodic breathing without apnoea. Time spent asleep with Sa02 less than 95 per cent was similar in the three groups, but the hypothalamic-pitu- itary group spent significantly longer time with Sa02 less than 90 per cent (/><0.01). Two of these women had an oxygen saturation less than 90 per cent for greater than 60 minutes during the night, case 17 without apnoea and case 19 with apnoea. There was no significant correlation in the 18 non- apnoeic women between body index or body weight, and total sleep time, total REM time, time awake or oxygen saturations. The narrow distribution of the patients' ages made it impossible to analyse the effect of age on sleep and nocturnal oxygen saturation. Discussion We have previously reported that premenopausal obese women have periods of oxygen desaturation but not Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 245 Table 4. Haemoglobin oxygen saturation values (%), number and types of apnoea during sleep in the women studied. Apnoea index: no. of episodes of apnoea/hours of sleep. Patient no. 1-9: postmenopausal normal weight ? no. 10-15: postmenopausal obese ? no. 16-21: hypothalamic-pituitary disorders. Time Patient Mean Mean Minimum <95% no. awake asleep asleep (min) Time Total <90% no. of (min) apnoeas Type of apnoea Apnoea central obst. mixed index 1 2 3 4 5 6 7 8 9 Mean + SEM 94 94 98 95 94 95.5 97 96 98 92 93 97 93 92 94 96 94 98 96 + 0.5 94 + 0.7 91 90 94 85 90 90 95 90 97 91 + 1 all all 4 207 all 140 0 185 0 0.4 0.1 10 11 12 13 14 15 Mean + SEM 94 94 97 97 96 96 92 92 95 96 95 94 96 + 0.6 94 + 0.7 82 84 94 93 94 92 9 + 2 all all 11 3 7 176 2 0.3 16 17 18 19 20 21 Mean + SEM 98 94 97 95 95 93 94 90 93 89 92 90 80 81 87 76 85 72 82 all 63 290 216 all 12 62 3 184 9 17 34 0 277 217 0 4 0 0 97 29 0 4 34 0 180 126 0 4 0 0 0 62 0 4 5.5 186 55 0.7 95 ?0.7 91 +0.8 80 ?2.3 apnoeic episodes during sleep[3]. The fall in oxygen saturation seen in these women occurs predominantly during REM sleep and is much less severe than that reported in obese men of comparable weight[l]. We found no abnormality of sleep-breathing patterns in premenopausal women of normal weight, the minimum oxygen saturation recorded in this group during sleep being 95 per cent[3]. We now find that normal weight postmenopausal women show a fall in oxygen saturation when asleep and in 8 of the 9 women studied, the minimum Sa02 measured was less than that seen in the lean premenopausal women. These results are similar to those reported by Block and colleagues[2]. Our obese postmenopausal women similarly show lower oxygen saturation during sleep. An increased amount of fat in the chest wall and abdomen has the predictable mass loading effect on the chest and diaphragm and leads to a reduction in vital capacity, expiratory reserve volume and chest wall compliance[6,7]. This effect is substantially magnified when an obese subject lies flat[8,9], but posture alone does not explain the findings in our patients because all of the subjects, both obese and normal weight, were studied only in the supine position. However, the mean awake and mean asleep oxygen saturation values found in the postmenopausal obese women are both significantly less than the values we previously reported in similarly obese premenopausal women (P<0.01). This finding supports the hypothesis that increasing age is an important deter- minant for the development of abnormal sleep-breathing patterns[4]. Extremely obese subjects show an increased ventilatory response to hypoxia but a decreased response to hyper- capnia and this finding may explain the association of alveolar hypoventilation during sleep at which time cen- tral respiratory drive is decreased[10,12]. Obstructive sleep apnoea syndrome is particularly common in obese men but only a minority of such men develop the obesity- hypoventilation syndrome (OHS) characterised by hypo- ventilation, hypercapnia and hypersomnolence[13,14]. An increase of alveolar ventilation is seen in women during pregnancy and during the luteal phase of the menstrual cycle and this appears to parallel the increase in plasma progesterone concentrations^ 5,16]. Some patients with OHS have been treated successfully with medroxyprogesterone, which probably has a direct stimu- latory effect on the central respiratory centre[17]. The 246 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 ( J ( I differences in nocturnal oxygen saturation found by us between the pre- and postmenopausal women support the concept that plasma progesterone has a protective effect on the maintenance of oxygen saturation during sleep. We have previously proposed a relationship between ' hypothalamic function and respiratory control during sleep[3]. We found that obese premenopausal women with an absent prolactin response to insulin-induced hypoglycaemia, a possible marker of abnormal hypotha- lamic function, showed a significantly greater fall in oxygen saturation during sleep than equally obese pre- menopausal women with a normal prolactin response. In the current study, the six women with proven hypotha- lamic-pituitary disorders had a greater number of ap- noeas and lower oxygen saturation than those older subjects with simple obesity. Insulin tolerance tests were not considered justifiable in the latter group in view of their age. This difference cannot be explained by body weight or body index because these differ little between the two groups. The results from the women with hypo- ^ , thalamic-pituitary obesity show a variety of disorders of sleep-breathing, in particular cases 18 and 19 whose < i sleep-breathing patterns were typical of obstructive sleep apnoea and case 22 whose oxygen saturation fell to 72 per cent during REM sleep without apnoea. We consider that ^ centrally mediated relaxation of the larynx during sleep leading to reversible obstruction may explain the obstruc- tive apnoea seen in our patients. No evidence of an obstructive lesion was found in any patient on direct laryngoscopy; nor was there any narrowing from an increase in adipose tissue distributed around the larynx, which has been suggested as a cause of obstructive apnoea in obese patients[18]. None of these women gave a history of disturbed sleep, daytime somnolence or lethargy to suggest such disturbances and the only reason for investi- gation was the complaint of progressive weight gain dating from the onset of their illness. The husbands of cases 18 and 19 confirmed that the patients snored loudly and were restless during sleep. Despite the heterogeneity i' of the hypothalamic-pituitary group, the finding that their breathing during sleep is more disordered than that of obese women suggests the importance of central factors for nocturnal respiratory control. We conclude that a decrease in oxygen saturation and apnoea occurs in postmenopausal women during sleep irrespective of body weight but is significantly more severe in women who become amenorrhoeic at a younger age as the result of a hypothalamic-pituitary disorder, and subsequently become extremely obese. These findings, when considered with previous reports, suggest that the sex, menstrual status, weight of the patient and hypotha- lamic function, may individually be important factors which influence the control of nocturnal breathing. v [ Summary i We have previously reported that obese women with i , regular menstrual cycles show a fall in haemoglobin oxygen saturation when asleep. It has been suggested that the menstrual cycle, as well as body weight, may influ- ence sleep-breathing patterns: we have investigated this by studying respiration during sleep in nine postmeno- pausal women of normal body weight, six postmenopau- sal women who were obese and six women who had become amenorrhoeic and obese following a hypothalam- ic-pituitary disorder. All of the postmenopausal women showed a decrease in oxygen saturation during sleep, the fall being similar between the lean and obese groups. In comparison, the women with hypothalamic-pituitary dis- orders showed more disturbed sleep-breathing patterns with a significantly greater fall in oxygen saturation (P<0.01 versus lean postmenopausal P<0.05 versus obese postmenopausal). Three of the hypothalamic-pitu- itary women had frequent apnoeic episodes during sleep and one had severe oxygen desaturation unassociated with apnoea. We conclude that a patient's sex, menstrual status, body weight and hypothalamic function are indi- vidually important factors for the control of respiration during sleep. Acknowledgements We thank Dr D. Scott and Dr P. Sheaff, of the Depart- ment of Clinical Neurophysiology, for their help with the study, Dr J. P. Monson, consultant endocrinologist, for permission to study his patients and Miss T. Peterson for secretarial work. References 1. Block, A. J., Boysen, P. G., Wynne, J. W. and Hunt L. A. (1979) New England Journal of Medicine, 300, 513. 2. Block, A. J., Wynne, J. W. and Boysen, P. G. (1980) American Journal of Medicine, 69, 75. 3. Kopelman, P. G., Apps, M. C. P., Cope, T. and Empey, D. W. (1983) British Medical Journal, 287, 859. 4. Cattershall, J. R., Claverley, P. M. A., Flenley, D. C. and Douglas, N. J. (1984) Clinical Science, 67, 34P. 5. Guilleminault, C., Tilkian, A. and Dement, W. C. (1976) Annual Review of Medicine, 27, 465. 6. Naimark, A. and Cherniack, R. M. (1960) Journal of Applied Physiology, 15, 377. 7. Sharpe,J. T., Henry, J. P., Sweany, S. K. et al. (1964) Journal of Applied Physiology, 19, 959. 8. Said, S. I. (1960) Annals of Internal Medicine, 53, 1121. 9. Craig, D. B., Wahba, W. M., Don, H. F. et al. (1971) Journal of Applied Physiology, 31, 717. 10. Kaufman, B. J., Ferguson, M. H. and Cherniack, R. M. (1959) Journal of Clinical Investigation, 38, 500. 11. Burki, N. K. and Baker, R. W. (1984) American Review of Respiratory Disease, 129, 538. 12. Phillipson, E. A. (1978) American Review of Respiratory Disease, 118, 909. 13. Burwell, C. S., Robin, E. D., Whaley, R. D. and Bickelman, A. G. (1956) American Journal of Medicine, 21, 81. 14. Lopata, M. and Onal, E. (1982) American Review of Respiratory Disease, 126, 640. 15. Zwillich, C. W., Natalino, M. R., Sutton, F. D. and Weil, J. V. (1978) Journal of Laboratory and Clinical Medicine, 92, 262. 16. Plass, E. D. and Oberst, F. W. (1938) American Journal of Obstetrics and Gynaecology, 35, 441. 17. Lyons, H. A. and Huang, C. T. (1968) American Journal of Medicine, 44, 881. 18. Guilleminault, C., Van den Hoed, J. and Mitler, M. (1978) In Sleep Apnoea Syndromes, pp. 1-12. (ed C. Guilleminault and W. C. Dement.) New York: Alan R. Liss. Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 247

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Prospects for New Antibiotics: Keeping One Step Ahead DAVID GREENWOOD, DSc, MRCPath Reader in Microbiology, Department of Microbiology and PHLS Laboratory, University Hospital, Queen's Medical Centre, Nottingham L So many antimicrobial agents are now available to the physician that it comes as something of a shock to recall that 50 years ago there were none, save quinine and a handful of other, generally rather toxic, antiprotozoal and anthelminthic agentsfl]. So far as antibacterial agents ? ] were concerned, only the antisyphilitic arsenicals, ars- phenamine (Salvarsan) and neoarsphenamine were avail- able when Domagk's Prontosil (the activity of which was later shown to be due to sulphanilamide) burst on the scene exactly 50 years ago[2]. Since then, the prolifera- tion of antibacterial agents has advanced to the stage where an embarras de richesse exists, whereas expansion of the armamentarium of antiprotozoal, anthelminthic, antifungal and antiviral agents has progressed extremely slowly. /3-Lactam Antibiotics The astonishing proliferation of antibacterial agents is nowhere more evident than within the /3-lactam group. Originally consisting of benzylpenicillin and a few closely related derivatives, and later widened by the development of semi-synthetic compounds and by the discovery and exploitation of the cephalosporins, the group has blos- \ somed to the extent that over 70 different /3-lactam derivatives are now in clinical use worldwide, of which 40 ?> are on the market in the UK (Table 1). Most of these compounds are directly derived from 6-aminopenicillanic acid or 7-aminocephalosporanic acid, but they include some unusual molecular variants. For example, cefoxitin carries a methoxy group on the (S-lactam ring, a feature that confers stability to /3-lactamases; latamoxef also exhibits this feature and additionally has an oxygen atom in place of sulphur in the fused ring structure; and the /3- f ? lactamase inhibitor, clavulanic acid, exhibits a completely * novel structure that also features oxygen in the fused ring. j. Present Progress The most significant recent advance has been the devel- opment of agents that overcome /3-lactamase mediated resistance in coliform bacteria. The earliest of these compounds, cefoxitin and cefuroxime, display striking enzyme stability, but only moderate intrinsic activity. More recently, a group of structurally related cephalo- sporins has appeared in which stability to /3-lactamases is combined with high intrinsic activity against a wide range of bacteria. Three of these cephalosporins, cefotaxime, ceftizoxime and ceftazidime, are available in the UK and two others, ceftriaxone and cefmenoxime, are on the market elsewhere; a structurally unrelated /3-lactam agent, the oxa-cephem, latamoxef, shares similar proper- ties and is generally considered together with this group. The appearance of these highly active compounds undoubtedly represents a useful advance in the treatment of infection, particularly in those patients prone to sys- temic infection with Gram-negative rods. Moreover, these compounds, and in particular cefotaxime and cefti- zoxime, display outstanding activity against the common causes of meningitis, including neonatal meningitis, and this may represent an important area of use. However, the impressively enhanced activity of these antibiotics against Gram-negative bacteria has been achieved at the expense of somewhat reduced antistaphylococcal activity, and none of these agents possesses useful activity against Streptococcus faecalis (Table 2); certain species of entero- bacteria, notably Enterobacter cloacae, readily develop re- sistance^]. Furthermore, only ceftazidime exhibits therapeutically useful anti-pseudomonal activity, and only latamoxef covers adequately for anaerobes of the Bacteroides fragilis group. Thus, all of these agents possess notable gaps in their antibacterial spectrum and, indeed, the amoxycillin/clavulanic acid combination, which em- braces staphylococci, enterococci and anaerobes, covers a broader range of organisms. A few other properties serve to distinguish between the new cephalosporins; cefotaxime is susceptible to hepatic enzymes that may reduce its activity in the body, and latamoxef (as well as cefmenoxime) possesses the methyl- tetrazole side chain which, in several cephalosporins, is associated with hypoprothrombinaemia[4]; ceftriaxone exhibits the unusual property of an extremely long serum half-life (associated with high protein binding) and is preferentially excreted in bile. Future Prospects Judging from the number of new compounds still being described in the literature, the scope for developing new cephalosporins is far from exhausted. However, the most Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 231 L Table 1. /3-lactam agents in clinical use throughout the world azidocillin clometocillin penethamate hydriodide (penethacillin) penimepicycline nafcillin oxacillin dicloxacillin bacampicillin* pivampicillin* talampicillin* metampicillin Benzylpenicilhn and its oral and long-acting derivatives benzylpenicillin* phenoxymethylpenicillin * phenethicillin* penamecillin* propicillin Antistaphylococcal penicillins methicillin* cloxacillin* flucloxacillin* Broad-spectrum penicillins ampicillin* amoxycillin* ciclacillin* amoxycillin/clavulanate* epicillin Antipseudomonal /3-lactam agents carbenicillin* peperacillin* ticarcillin* apalcillin azlocillin* sulbenicillin mezlocillin* carfecillin* Oral cephalosporins cephalexin* cefadroxil* cephradine* cephaloglycin cefaclor* cefatrizine /3-lactamase-susceptible injectable cephalosporins cephalothin* cephamandole* cephaloridine* cephacetrile cephazolin* cefapirin /3-lactamase-stable cephalosporins cefuroxime* ceftizoxime* cefoxitin* ceftriaxone cefotaxime* cefmenoxime ceftazidime* cefotetan * = on the market in the UK; t = strictly an oxa-cephem. procaine penicillin* benzathine penicillin* benethamine penicillin* clemizole penicillin hydrabamine penicillin V diphenicillin (ancillin) mecillinam* pivmecillinam* hetacillin fibracillin penimocycline carindacillin cefoperazone cefsulodin* pivalexin cefroxadine cefazedone ceftezole cefotiam cefmetazole latamoxeff * Table 2. Activity in vitro of new cephalosporins against some common bacterial pathogens, including those commonly in- criminated in bacterial meningitis. R = resistant. Minimum inhibitory concentration (/xg/ml) Organism Cefotaxime Ceftizoxime Ceftazidime Latamoxef Staph, aureus 2 2 4 8 Sir. faecalis R R R R Enterobacteria 0.06 0.03 0.12 0.12 Ps. aeruginosa 16 32 2 16 B. fragilis 16 16 16 4 N. meningitidis 0.01 0.01 0.02 0.01 Str. pneumoniae 0.02 0.02 0.2 0.5 H. influenzae 0.01 0.01 0.06 0.06 intriguing innovations concern (3-lactam agents that exhibit fundamental changes in the central part of the molecule, rather than simple side chain modifications. Four compounds have received particular attention: az- treonam, one of a family of compounds known collec- tively as monobactams, in which the (3-lactam ring is not associated with another fused ring system; imipenem, a carbapenem derivative in which carbon replaces the sulphur of the thiazolidine ring of penicillins; temocillin, a penicillin which (like cefoxitin) carries a methoxy group on the /3-lactam ring; and sulbactam, a penicillanic acid sulphone which, like clavulanic acid, possesses little in- trinsic antibacterial activity, but inhibits most bacterial (3- lactamases. These four compounds exemplify two diametrically opposed approaches to antimicrobial chemotherapy: nar- row-spectrum, targeted therapy (aztreonam, temocillin) and the ultra-broad spectrum, cure-all approach (imi- penem, sulbactam/ampicillin) (Table 3). Imipenem, in- deed, exhibits the broadest antibacterial spectrum of all (3- lactam antibiotics and combines this spectrum with impressive intrinsic activity and /3-lactamase stability. Ironically, however, the compound is rapidly inactivated in the body by a renal dehydropeptidase and has to be administered with a dehydropeptidase inhibitor[5], Quinolones It is perhaps a tribute to the persistence of the pharma- ceutical houses that, after years of research effort that yielded compounds offering little or no improvement over 232 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 Table 3. Comparative activity in vitro of some novel (3-lactam agents. Minimum inhibitory concentration (/ig/ml) Sulbactam/ Organism Aztreonam Temocillin Imipenem ampicillin* Staph, aureus R Str. faecalis R H. influenzae 0.5 Enterobacteria 0.06 Ps. aeruginosa 4.0 B. fragilis R *expressed as ampicillin activity R 0.02 2.0 R 2.0 1.0 0.5 0.06 1.0 4.0 0.12 4.0 R 4.0 R R 0.12 2.0 the parent substance, nalidixic acid, they finally succeed- ed in devising a derivative that displayed greatly im- proved spectrum and intrinsic activity. This compound was norfloxacin, and its discovery has naturally given rise to a family of closely related compounds, at least one of which, ciprofloxacin, offers a further improvement in activity. The new quinolones, and ciprofloxacin in particular, display a spectrum of activity rivalling, or even surpass- ing, that of the new (3-lactam agents (Table 4); they are Table 4. Comparative activity in vitro of nalidixic acid, norflox- acin and ciprofloxacin against selected bacterial pathogens. S/nal = sensitive to nalidixic acid; R/nal = resistant to nalidixic acid; NT = not tested. . : Minimum inhibitory concentration (/ig/ml) Nalidixic Organism acid Norfloxacin Ciprofloxacin Staphylococci 32 1.0 0.5 Streptococci >32 8.0 1.0 Enterobacteria (S/nal) 2.0 0.06 0.02 Enterobacteria (R/nal) 256 0.5 0.25 Ps. aeruginosa 64 0.5 0.25 Bacteroides spp. >32 16 2.0 L. pneumophila NT 0.12 0.06 > M. tuberculosis NT 8.0 1.0 quite well absorbed when administered orally, have a half-life of 3-4 hours, and are excreted in high concentra- tion into the urine. These properties suggest a valuable role for the quinolones in urinary tract infection and norfloxacin is likely to be marketed solely for this indi- cation. Manufacturers of other quinolones have their sights on wider indications, but blood levels are not high (c. 1-4 /tg/ml, depending on the compound and the dose) and this may insufficiently exceed the minimal inhibitory concentration of some organisms, notably staphylococci, streptococci and Pseudomonas aeruginosa to prevent the development of quinolone resistance, which emerges readily. However, on the credit side, these drugs appear to be extremely well distributed in the body and may be concentrated within cells[6], factors that may be crucial in certain infections. Furthermore, parenteral formulations are becoming available which may provide improved blood levels when needed. It is still too early to assess the place of these interesting compounds; meanwhile, their appearance has provoked the drug industry into renewed interest in these sub- stances and yet more derivatives are waiting in the wings. Other New Antibacterial Agents Although a trickle of new aminoglycosides continues to appear (amikacin and netilmicin in the UK, sissomicin and dibekacin elsewhere), none offers substantial advan- tages over gentamicin or tobramycin, except in those units troubled by gentamicin-resistant organisms. Other new derivatives, such as fortimicin B, and various related compounds are under development. Little of note has emerged from the other major antibiotic groups, although macrolides continue to attract some attention. Josamycin, a macrolide described over 20 years ago, is being actively promoted in several countries, but not, as yet, in the UK. Progress in the development of truly novel antibacterial agents has been extremely slow and such compounds as have been described do not appear to represent major advances. Perhaps the most interesting is the new glyco- protein, teicoplanin, a distant relative of vancomycin, with which it shares a similar narrow spectrum; however, teicoplanin appears considerably more active against staphylococci and streptococci[7]. Other novel com- pounds that deserve mention are mupirocin (pseudo- monic acid) and bicozamycin. Mupirocin is an antibiotic obtained from Ps. fluorescens which, like teicoplanin, exhibits a spectrum virtually restricted to Gram-positive cocci. It is extensively metabolised when administered systemically, but may be of value in the topical treatment of staphylococcal and streptococcal skin infections[8] or for the elimination of staphylococci from nasal carriers. In contrast, the spectrum of bicozamycin is confined to enteric Gram-negative bacilli. Even against these organ- isms the activity is fairly feeble, but oral administration leads to sufficient concentrations in the lumen of the gut (the drug is not absorbed) to eliminate enteric pathogens, and satisfactory trials have been reported in the treat- ment^] and prophylaxis[10] of traveller's diarrhoea. Prospects of Non-Antibacterial Agents In stark contrast to the abundance of therapeutically useful antibacterial agents, the choice of chemotherapeu- tic alternatives for non-bacterial infection is severely limited. Antiviral agents in particular are still in their infancy, although the appearance of the anti-herpes drug, acyclovir, has revived hopes of effective antiviral therapy and a number of interesting compounds are under devel- opment^ 1]. Progress in antifungal agents has been largely restrict- ed to the imidazoles. Most of these compounds are suitable only for topical use, but ketoconazole, which is well absorbed when administered orally, has proved useful in systemic mycoses. Recently, attention has turned to triazoles, one of which, itraconazole, seems particularly interesting, as experiments in animals sug- gest that it may be safe and efficacious in aspergil- losis^]. Journal of the Royal College of Physicians of London Vol. 19 No.4 October 1985 233 Prospects for new antiprotozoal agents are rather gloomy. Despite the availability for many years of several excellent anti-malarial agents, the inexorable spread of resistance, notably resistance to chloroquine in Plasmo- dium falciparum, has seriously undermined their useful- ness. Years of endeavour at the Walter Reed Army Institute of Research in Washington has yielded one important new antimalarial, mefloquine, but it is feared that resistance to this drug will also emerge readily[13], A few other novel antimalarials are under study, one of which, qinghaosu (artemisinine) has been used as a herbal remedy in China for centuries[14]. Protozoal diseases such as amoebiasis, giardiasis and trichomoniasis have yielded to 5-nitroimidazoles (metron- idazole and its relatives). Resistance has not yet emerged as a major problem and the therapeutic future of these drugs thus seems secure. Among other important proto- zoal infections of man, leishmaniasis still has to be treated with antimonials and African trypanosomiasis with arsen- icals. However, two drugs, nifurtimox and benznidazole, are now available for the previously untreatable Chagas' disease (South American trypanosomiasis), although both have toxicity problems. Chemotherapy of helminthic infections has benefited from the economic importance of similar diseases in animals and several important anthelminthic agents have found their way into medical use via the veterinary route. Such compounds include the benzimidazoles, thiabenda- zole and mebendazole (the first really broad-spectrum agents for intestinal worms) and praziquantel, a major advance in the treatment of trematode infections, includ- ing schistosomiasis, and also of tapeworm infections. This fruitful search for medical anthelminthics among veterinary products is continuing: another veterinary benzimidazole derivative, albendazole, is showng prom- ise in hydatid disease[15], and a new anthelminthic antibiotic that is active against a wide variety of animal nematodes (and, curiously, arthropods), ivermectin[16], appears to be of value in onchocerciasis and other filarial infections[17]. It is ironic that developments in the treatment of infections that affect hundreds of millions of people throughout the Third World should depend on the eco- nomic importance of animals, but that seems the harsh reality of the market place. Certainly, what is needed on a global scale is not yet another new cephalosporin, but agents active against non-bacterial pathogens. This article is based on a paper read at the Conference on Infectious Diseases held at the Royal College of Physicans in May 1985. References 1. Greenwood, D. (1983) In Antimicrobial Chemotherapy, p.5 (ed D. Greenwood.) London: Bailliere Tindall. 2. Domagk, G. (1935) Deutsche Medizinische Wochenschrift, 61, 250. 3. Sanders, C. C. (1984) Journal of Antimicrobial Chemotherapy, 13, 1. 4. Smith, C. R. and Lipsky, J. J. (1983) Journal of Antimicrobial Chemotherapy, 11, 496. 5. Kahan, F. M., Kropp, H., Sundelof, J. G. and Birnbaum, J. (1983) Journal of Antimicrobial Chemotherapy, 12, (Suppl. D,) 1. 6. Easmon, C. S. F. and Crane, J. P (1985) Journal of Clinical Pathology, 38, 442. 7. Williams, A. H. and Griineberg, R. N. (1984) Journal of Antimicro- bial Chemotherapy, 14, 441. 8. Sutherland, R., Boon, R. J., Griffin, K. E., Masters, P. J., Slocombe, B. and White, A. R. (1985) Antimicrobial Agents and Chemotherapy, 27, 495. 9. Ericsson, C. D., DuPont, H. L., Sullivan, P., Galindo, E., Evans, D. G. and Evans, D. J. (1983) Annals of Internal Medicine, 98, 20. 10. Ericsson, C. D., DuPont, H. L., Galindo, E. et al. (1985) Gastroenterology, 88, 473. 11. De Clercq, E. (1985) In The Scientific Basis of Antimicrobial Chemo- therapy, p. 155. (ed D. Greenwood and F. O'Grady.) Cambridge University Press. 12. Van Cutsem, J., Van Gervan, F., Van de Ven, M., Borgers, M. and Janssen, P. (1984) Antimicrobial Agents and Chemotherapy, 26, 527. 13. Peters, W. (1985) In The Scientific Basis of Antimicrobial Chemotherapy, p.95. (ed D. Greenwood and F. O'Grady.) Cambridge University Press. 14. Bruce-Chwatt, L. J. (1982) British Medical Journal, 284, 767. 15. Morris, D. L. (1983) Journal of Antimicrobial Chemotherapy, 11, 494. 16. Campbell, W. C., Fisher, M. H., Stapley, E. O., Albers-Schon- berg, G. and Jacob, T. A. (1983) Science, 221, 823. 17. Aziz, M. A., Diallo, S., Diop, I. M., Lariviere, M. and Porta, M. (1982) Lancet, 2, 171. 234 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985

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Dr Shephard Thomas Taylor Besides his two important books, described in the next paragraph, the College has all the surviving papers of Dr Shephard Thomas Taylor, 1840-1936. His father was a Norfolk farmer, of Dilham Hall, near Hippisburgh, an early expert on farming machinery and a skilled carver of ivory. y", Dr Taylor kept a diary all his life, in a legible copper- | plate hand. He was apprenticed to Dr F. Bateman of Norwich and worked in the Norfolk and Norwich Hospi- tal, and subsequently went to King's College Hospital in London. In 1927 and 1930 he published the volumes describing his medical education, as The Diary of a Norfolk and Norwich Hospital Student, 1858-1860, and The Diary of a Medical Student, 1860-1864. They are the best descriptions of their subject, profusely illustrated with photographs, and are most amusing. They were complet- ed by his postgraduate period in Berlin in Reminiscences of Berlin during the Franco-Prussian War 1870-71; interest- ing, but written in 'journalese', which he thought proper for books. This is not in the Library, but is in the London Library. He was later on physician to the Norfolk and Norwich, and the Jenny Lind, Hospitals from about 1880 to 1910, and Medical Officer of Health, one of his primary interests: on p.l of the book on his apprenticeship, he describes how the first thing he did when allotted his room was to measure it to see if it came up to standard volume and floor-area (it did not). As a youth he was interested in a great many things, became a highly competent botanist, collected epitaphs in churchyards, got into mischief and never wasted a mo- ment. While at King's, which was then in Portugal Street off the Strand, he had lodgings near King's Cross and occupied himself in 1863 by sketching the iron coal hole lids in the London pavements. He collected 150 different designs seen between his lodgings and the hospital, taking in Portland Place to Gray's Inn Road. This unique collection of Victoriana was eventually brought to the attention of the editor of The Ironmonger in 1929. That journal carried a short account of the work and then published all the drawings in a pamphlet aptly titled Opercula, (London coal-hole Plates, sketched by Aesculapius Junior), a copy of which is in the library. He left a fair copy of all the lectures he gave at the Norfolk Students Society, bound in a volume, written in beautiful handwriting, in the most unfortunate 'literary' English, and other MS volumes of lists of plants, medical cases, etc. When he had published the student diaries in 1930 he destroyed all the originals, except the current volume, probably because they contained notes of the pretty girls he saw (one survives from the age of 18, and another at 85!). The last volume, 1895-1926, is so interesting that it looks as though we lost a heritage as valuable as Parson Woodforde's diary. He was a first-class linguist, and read widely in French, German, Italian, Latin and Greek, with most interesting comments: e.g. Erasmus' Colloquies 'most delightful read- ing, abounding in inimitable wit'; 'but a little coarse here and there, which adds to their attraction, although per- haps I ought not to say so!'. Of Carlyle's Sartor Resartus, almost the most revered book of his day, he observed: 'one of the most tedious and exasperating books I have ever read' (23rd December, 1924); and of Tristram Shandy, which I for one would include in the top ten essential books: 'clever and witty, but tedious reading, being much ado about nothing' (16th September 1924). He played the cither and taught Edith (?a servant) to play it: he also taught Katie, the cook, German. He retired to The Mount, Edgefield, near Holt, added a large area of woods and cleared the brambles and weeds with his own hands at 90. It was characteristic of him that he recorded the exact number of dock plants he dug up and burned each day. The last volume of the dairy gives a clear picture of an impressive old man. When the editor of The Ironmonger went to see him in 1929 he wrote of hearing 'light and rapid footsteps in the hall' and being greeted by 'a small elderly gentleman with an almost imperceptible stoop and a merry twinkle in his eye', adding that he 'had met a man who was infinitely more remarkable than his hobby'. C. E. Newman Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 213

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Editorial It is easy to make a fairy story from the history of medicine with every ending happy and conclusive. The sober truth is that the brightest expectations of a discovery are always dulled by experience. The dawn of bacteriology was bright enough when bacteria were identified as specific causes of disease. With the enemy pinpointed, it only needed a magic bullet to shoot them dead. Years later the bullet of penicillin was hailed as making lust safe for democracy and sounding the death knell of venereology as a specialty. The discovery of animal and insect vectors of human disease was another triumph; kill the vector and the disease disappears. Yet anopheline mosquitos still fly and the snails of the Nile positively flourish with the building of the High Dam at Aswan. We have learnt the hard way that pathogens are not sitting targets. They readily counter initially successful attack and, particularly with viruses, can appear in new pathogenic forms. The disconcerting ability of P. falciparum to render every therapeutic attack null and void is pointed out in these pages by Dr Lucas. He rightly stresses the need for constant surveillance and research if infectious disease is to be continuously controlled throughout the world. In the same way the College's report (in the January issue of the Journal) stressed the present lack of physicians trained in infectous diseases. It is important that the public should be made aware of these matters of public health. A false sense of security engendered by past success may lead to alarming drops in the take-up rates of inoculation programmes. The public's attitude towards infectious diseases does, in a long and complicated run, matter in terms of financial provision for research in the subject and the maintenance of the extensive laboratory facilities required for the swift detection of new threats and the adjustment of remedies for the familiar. It is always difficult to produce a convincing argument for expendi- ture to face a threat. Publicity likes to comment on a disaster and to search out why funds have not been available before. Equally, publicity for an advance in the control of infectious disease can leave the impression that nothing more needs to be done in that particular corner of the field, when all may have to be done afresh. Perhaps it is the huge success of antibiotics that has made us so complacent in our attitude to infections and somewhat cavalier in our prescribing. That complacency may well be enhanced by the word- smiths. 'Hospital gangrene' was, rightly, a fearful term. It certainly made patients and doctors alike acutely aware of the perils of hospital admission. However respectable its etymology, nosocomial is far too bland a term for hospital-based infections. The hospital's contribu- tion to the population of antibiotic-resistant bacteria is well known. But our newest hospitals harbour risks in their kitchens and ubiqui- tous air conditioning. Given the lowered resistance of the patients they house, hospitals give the best of opportunities to opportunist infections. Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 201

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Medical Accountability SIR DOUGLAS BLACK, MD, FRCFj Emeritus Professor of Medicine, University of Manchester, Past President of the Royal College of Physicians j ^ The third in the College's new series of one-day symposia on 'Controversial Issues in Medicine' was held on June 5th under the above title. One speaker, Mrs M. Saunders from the Public Consultation Unit of the GLC, referred to the wider social responsibilities of doctors; and within the title the discussion could certainly have included examples of this, such as Tudor Hart's concept of the 'community general practitioner', making specific use of the opportunity given him by a relatively defined popu- lation within his reach. But in the event, discussion focused on the accountability of the individual doctor to his patient. As usual in such discussions, the large number of episodes in which a reasonable process of care leads gently to a satisfactory outcome was not given much prominence; attention was concentrated on the problem cases in which things go wrong. A bad outcome may of course be inherent in the clinical situation; it may arise from a misreading of the complex uncertainties of disease; it may represent idiosyncracy in the reaction of a patient, or in the performance of a doctor. More seriously, it can * arise, as Dr Gwyn Williams pointed out, from 'sloppy medicine'; this may be the equivalent for the physician of ham-handed technique for the surgeon, whose disasters, when they occur, are more likely to be conspicuous. The initiative for the conference, with support from the King's Fund, had come from the group 'Action for the Victims of Medical Accidents', commonly shortened to AVMA. This group was set up after public interest had been stimulated in 1980 by the showing of the TV drama 'Minor Complications', by Peter Ransley, now President of AVMA, who attended the conference. It was appropri- ate that the first and longest paper should be given by Mr A. Simanowitz of AVMA. He described cases in which it was fairly clear that either the treatment given, or sometimes the withholding of appropriate treatment, had : ? been the main cause of a patient's deterioration in health. It had often proved difficult to extract the information required to obtain redress, and he appealed to doctors to change their present attitude, which he looked on as commonly too secretive, towards one of 'frank disclo- sure'. He was aware that this might carry some cost, both financial and to reputation; but suggested that our profes- sion would gain in moral stature by so doing. He compared the current defence subscriptions paid by doctors with that paid by solicitors in the UK, which he quoted as ?1,200 p.a.?still a small sum in comparison with American rates for doctors. He suggested that greater openness about clear-cut mishaps might actually save us from going further along the American road to very high defence costs; another possibility was a 'no fault' system. In the brisk discussion that followed, Dr P. Harvey suggested a role for the specialist societies, which might set up panels to review treatment given by their colleagues, perhaps those at some distance. Dr G. H. Hall suggested that there might be an excess of masochists and a deficiency of sadists among those doctors likely to attend this kind of conference. The participation of administrators in dealing with complaints was criticised, especially if they tried to prevent discussion between patients or relatives and the responsible doctor; but Mr Wall reminded us of the frequent, and indeed statutory, involvement of the health authority. Miss Katharine Whitehorn asked if there were anything to be learnt from the private sector, where perhaps there was less adminis- tration and more time; but no quantitative answer was forthcoming, though the private sector was not immune from mishap. Dr David Sumner pointed out that the word 'negligence' carried unfortunate overtones for doc- tors, whereas for lawyers it was simply a term of art; and Mr Simanowitz agreed it should be 'de-mystified'. It became clear that in some regions senior doctors were being given the useful responsibility of assisting the Regional Medical Officer to deal with complaints. Next, Dr Peter Reynell gave what I shall describe, in terms of high praise, as a very physicianly paper on the importance, and also the problems, of 'information given to patients'. It was very possible to alarm patients needlessly by forcing information on them which they did not want or need; and on at least one occasion he had been reproached by a widow for doing so. It was worth consulting the spouse of a patient about how much the patient should be told. Referring to the Siddaway case, his own view was that patients should be warned of likely dangers, but not of remote ones (Mr Simanowitz had also referred to this case, declaring his conviction that if the patient had known how the operation would turn out, she would have refused it; it occurred to me that, if the surgeon had had equal foresight, he would not have done it). Because of the great diversity among patients and their illnesses, Dr Reynell did not favour a 'bill of rights' for giving information to patients. Of course the doctor had an ethical (not a legal) obligation to give appropriate information; but 'appropriate' was not necessarily 'com- plete', even if that were practically possible. In summary, what he wanted to see between patient and doctor was 'a system of trust, not a set of rules'. Sir John Walton gave a crystalline account of the mechanisms available to the General Medical Council, in Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 203 dealing with complaints made against doctors, or doctors convicted in the criminal courts. These are also clearly set out in the GMC Blue Book, which has recently under- gone important revision. Questioned as to the part which patients could play in proceedings relating to the conduct of doctors, Sir John stated that formal proceedings had to be initiated with a statutory declaration by the complain- ant; and thereafter they would be called as witnesses, and examined and cross-examined, as in a court of law. Dr A. M. Dawson reminded the meeting that the object of medical activity was to improve the care of patients, and for that they were accountable to themselves and to their colleagues. Litigation was necessary in certain cases, but its contribution to patient care was minimal, and might even be negative if it were to promote unnecessary investigation and defensive medi- cine generally. That all consultants were equal in status created the possibility for genuine peer review; and this should, in his view, be made mandatory, and a condition of accepting a hospital for training purposes. Over the past 30 years, the power of medicine to do good had greatly increased, but so had the possibility of doing harm, whether by ill-judged action or by failure to take the correct action. In discussion, the idea of selecting cases 'with a lesson' was raised; but our President commended considering cases as they arose, since there was no case from which nothing could be learned. In considering the responsibility of doctors towards their nursing colleagues, Miss E. Winder described the changing status and responsibility of nurses. While some retained the traditional attitude of subordination to medi- cal staff, nurses were really entitled to a role in which, while certain aspects of their work were still subject to medical supervision, the area of nursing autonomy, for example in special care units, was increasing. It was very important that nurses should acquire these particular skills while at the same time conserving the basic nursing responsibility of caring for the patient in the full sense of the word. In a spirited intervention, Dr Ian Munro maintained that the duties laid upon us arose from our moral, ethical and professional responsibility, and should not require legal enforcement, nor appearance before the disciplinary mechanisms of the GMC. Dr B. Pentecost described some of the ways in which complaints arising in hospital practice could be handled. The matter could be discussed informally with the patient, though an administrator should be kept in touch with this; if the complaint was not satisfactorily dealt with in this way, it could be made formally in writing to the health authority, and considered by the Regional Medi- cal Officer. There was in the background always the possibility of legal action, but from time to time patients or relatives would affirm convincingly that they did not wish to damage a doctor, but were only concerned to prevent a similar mistake happening to someone else. To meet this case, the Joint Consultants Committee set up a few years ago what has been described as a 'second opinion procedure'. Over the years, this College has been concerned with about 100 such exercises, in which a consultant from another region discusses the case both with the complainant and with the consultant concerned, with the object of reassuring the complainant, and report- ing the result to the RMO. In about half the cases, there has been a fault of communication, which might be in the manner more than in the actual matter. Some doctors clearly evaded discussions with patients or relatives. On the other hand, there were patients with whom communi- cation was difficult, because they themselves were in a difficult situation, as members of 'a sensitised family', e.g. a family with an elderly dependent parent, or a handicapped child. Sir Antony Buck, MP, who had chaired the Select Committee which had recommended additional com- plaints procedures, to which the 'second opinion pro- cedure' was the profession's response, said straightforwardly that what had happened was somewhat different from what he and his committee had had in mind. Certain threads ran through the day's proceedings? the unpredictability of outcomes; the tendency of doctors to be less than forthcoming when asked to criticise their colleagues; the vital importance of communication; and the public and political feeling that, in spite of the various mechanisms for handling complaints, some problems remained. The occasion was educational and not judg- mental; and I felt that good had been done by bringing out the range of attitudes as between doctors, lawyers and pressure groups. Our visitors may have accepted the plea that some bad outcomes are inevitable, and do not imply medical shortcomings; we were made aware of the strength of feeling that we may not yet have done enough to protect the public, and, indeed, our own profession, either from isolated scandalous happenings, or from persistent malpractice. Occasionally in the past I have had an odd feeling that in some quarters the flame of love for the patient was fuelled by hate for the doctor. I did not suffer from a recurrence of that feeling at this conference. We were made soberly aware of a very real problem, not perhaps for the first time; but I came away with the notion that we should be doing more about it than we are. For example, I was shaken to hear that the 'second opinion procedure' may take two to three years to complete?almost as long as litigation. Even if we do no more than speed up a procedure which is within our own hands, we shall have done something useful. 204 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985

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Dr John Radcliffe, Court Physician, and the Death of Queen Anne ALEX SAKULA, MD, FRCP Lately Consultant Physician, Redhill General Hospital, Surrey Dr John Radcliffe's generosity to the University of Oxford has ensured that his name remains perpetuated in such institutions as the Radcliffe Infirmary, the Radcliffe Observatory, the Radcliffe Camera and the Radcliffe Library. In addition, his bequests included the Radcliffe Scholarship and Prize, the Radcliffe Travelling Fellow- . ships as well as important contributions to University College, Oxford, the Royal College of Physicians, Lon- don, and St Bartholomew's Hospital, with all of which he was associated. Such philanthropy was made possible by the fortune which Radcliffe amassed from his highly successful prac- tice as a London consulting physician. Towards the end of his life, his estate was valued at more than ?80,000, a considerable sum in seventeenth century England. Being a medical adviser to royalty must have contributed to Radcliffe's reputation as the leading physician in London society. Yet his relationships with his royal patients were by no means always harmonious and this was especially so with Queen Anne. Doctor John Radcliffe (1652-1714) John Radcliffe (Fig. 1) was born in 1652 in Wakefield, Yorkshire, where his father was Governor of the House of Correction. He went up to University College, Oxford, in the plague year 1665, graduated BA in 1669 and then held a Fellowship at Lincoln College from 1670 to 1677. He read medicine, qualifying BM in 1675 and DM in 1682. From 1675 he practised successfully in Oxford but in 1680 he decided to move to London[l]. Radcliffe settled in Bow Street, Covent Garden (his garden backed on to that of the portraitist, Sir Godfrey Kneller) and soon established himself as one of the , leading physicians in the capital. On the death of Dr Richard Lower (1631-91), famed for his pioneer experi- ments in blood transfusion, Radcliffe took over his prac- tice. In 1687 Radcliffe was elected FRCP but his relations with the College of Physicians were troubled and in 1689 he was expelled because he insisted on writing his direc- tions in Latin, but he was soon readmitted on payment of a fine. He became a Governor of St Bartholomew's Hospital in 1690[2]. Radcliffe was no great scholar and made no important original medical discoveries. His fame lay in his being a sound practical physician, who inspired confidence in his patients, numbered amongst whom were Sir Isaac New- ton, Alexander Pope and Jonathan Swift. They seemed to enjoy his witty conversation and forthright personality. Sir Richard Steele wrote of him in The Tatler[3]\ You are not so ignorant as to be a stranger to the character of Aesculapius as the patron and most suc- cessful of all who profess the Art of Medicine. But as most of his operations are owing to a natural sagacity or impulse, he has very little troubled himself with the Doctrine of Drugs, but has always given Nature more room to help herself than any of her learned assistants, and consequently has done greater wonders than is the power of the Art to perform, for which reason he is half Fig. 1. Dr John Radcliffe. (Oil painting from the studio of Sir Godfrey Kneller, 1712. Courtesy the Treasurer of the Royal College of Physicians of London.) Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 255 deified by the people and has even been courted by all the world. Radcliffe's coffee-house consultations were conducted at the Bull's Head Tavern. One of his typical prescrip- tions is his 'Receipt for a Cough'[4]. Take an ounce of Consarve of Roses An ounce of Sirrup of Clove Gilly Flowers A teaspoon of Venice Treacle A teaspoon of Flower of Brimstone. Take a teaspoon night and morn. Drink a glass of Milk Water after it and keep warm all the time you take it. If consumptive, drink Asses Milk instead of Milk water. The advertisement for 'Doctor Radcliffe's Bitter' read: 'Doctor Radcliffe's Royal Tincture or the General Recti- fier of the Nerves, Head and Stomach. It corrects all irregularities of the Head and Stomach by hard drinking or otherwise'[5], Despite Radcliffe's tendency to be 'perpetually at war with his professional brethren'[6], the profession must have held him in high esteem. Dr Richard Mead (1673- 1754) said that Radcliffe '. . . was deservedly at the head of his profession, on account of his great medical penetra- tion and experience'[7]. Dr James Monro (1680-1752), in his Harveian Ora- tion in 1737, described Radcliffe as 'the Aesculapius of the age'. With his increasing wealth, Radcliffe acquired estates in Buckinghamshire, Yorkshire and Northamptonshire and moved to a fine house in Bloomsbury Square, where his paintings included some by Rembrandt and Rubens. He later purchased a house by the river at Hammersmith and in 1713 a mansion in the village of Carshalton, Surrey, 12 miles from London (Fig. 2). Radcliffe never married, although in 1709, in his fifty- eighth year, he fell in love with a lady much younger than himself. He was lampooned in The Tatler by Sir Richard Steele as 'the mourning Aesculapius . . . the languishing hopeless lover of the divine Hebe, the emblem of youth and beauty'[8]. In 1695, Radcliffe refused the offer of a baronetcy, since he had no one to inherit. A confirmed Jacobite and violent Tory, he was Member of Parliament for Bramber from 1690 to 1695 and for Buckinghamshire from 1713 to 1714. Towards the end of his life, Radcliffe transferred his patients to the younger, brilliant Dr Richard Mead and also handed over to him the Gold-Headed Cane, which was to become the emblem of five other royal physicians. It is now displayed at the Royal College of Physicians of London[9]. Radcliffe and William III (1650-1702) In 1689, William III (Fig. 3) became ill with an acute respiratory complaint. His personal physician was Gott- fried Bidloo (1649-1713), the eminent Leyden surgeon- anatomist, who had been persuaded by William of Orange to accompany him to England in the Glorious Revolution of 1688[ 10]. The efforts of Bidloo and another royal physician, Dr Thomas Laurence, not proving suc- cessful, the King asked that Radcliffe be consulted. A difference of opinion on the diagnosis ensued, Radcliffe maintaining that the King was suffering from 'the dis- tressing symptoms of an asthma, the consequence of the dregs of the smallpox that had fallen on his lungs'fll]. Fig. 2. Carshalton House, Dr John Radcliffe's Surrey resi- dence, now St Philomena's Convent School. Fig. 3. King William III. (Oil painting after Sir Peter Lely, 1677. Courtesy National Portrait Gallery, London). Fortunately, the patient recovered and, for the next 11 years, Radcliffe remained Physician-in-Ordinary to Wil- ,, liam III. A further controversy among the physicians arose in 1699 when Queen Mary II was suddenly taken ill. Her personal physician, Dr Richard Lower and one of Wil- liam Ill's physicians, Dr Walter Harris (1647-1732) diagnosed haemorrhagic smallpox, which was confirmed by Sir Thomas Millington (1628-1703), who was later to become President of the Royal College of Physicians 1696-1703. At the request of William III, Radcliffe was called for consultation. He favoured a diagnosis of mea- sles and openly criticised the treatment which the Queen I had received. The Queen died a few days later, aged 33[12]. It was said of Radcliffe that . .at first sight of the prescriptions, without having entered the chamber of the Royal patient, he exclaimed, with his characteristic rude- ness, that HM was a dead woman, for it was impossible to do any good in her case, where remedies had already been given that were so contrary to the nature of the j distemper'[13]. Gilbert Burnet, Bishop of Salisbury, no doubt activated by religious and political bias, wrote thus of Radcliffe: * ... I will say no more of the physician's part but that it was universally condemned; so that the Queen's death was imputed to the unskilfulness and wilfulness of Dr. Radcliffe, an impious and vicious man, who hated the Queen much, but vertue and religion more. He was a professed Jacobite and was by many thought a very bad physician, but others cried him up in the highest degree imaginable. He was called for; and it appeared but too evidently that his opinion was de- pended on. Other physicians were called when it was too late[14]. Radcliffe, however, maintained that '. . .he was called too late and that no remedies that could then be tried had the least chance of doing her good'[15]. In his dealings with the King, Radcliffe was on occa- sions too forthright. In 1697, he addressed his Royal patient in these blunt terms: Your juices are all vitiated, your whole mass of blood corrupted, and the nutriment for the most part turned to water; but, if your Majesty will forbear making long visits to the Earl of Bradford [where, to tell the truth, the King was wont to drink very hard], I'll engage to make you live three or four years longer; but beyond that time no physic can protect your Majesty's exis- tence[16]. This was certainly plain speaking. But even more so, verging on plain rudeness, was the occasion in 1699 when William III was suffering from cardiac dyspnoea with marked oedema of the lower limbs and Radcliffe said to his monarch: 'Why, truly, I would not have your Majes- ty's two legs for your three Kingdoms'[17], The King never forgave Radcliffe for this remark and would not allow him in his presence again, although he continued to use his prescriptions. Radcliffe and Queen Anne (1665-1714) Anne was born in 1665, the daughter of James, Duke of York (later to be James II) (Fig. 4). At the age of 12, she suffered a mild attack of smallpox. In 1683, aged 18, she married Prince George of Denmark and they lived in The Cockpit at Whitehall Palace (the site of the present 10 Downing Street). In 1686, Radcliffe was appointed Physi- cian-in-ordinary to HRH Princess Anne of Denmark[18- 20], Princess Anne had a most tragic obstetric history. In the course of the 16 years 1684-1700, she endured 17 pregnancies, which terminated in 11 miscarriages, three stillbirths and three live births, of whom two died under the age of 18 months (probably from smallpox) and only one, William, Duke of Gloucester, born in 1689, sur- vived. The explanation of this sad series of events remains a matter for speculation. Syphilis[21], rhesus incompati- bility!^], porphyria[23] and pelvic sepsis (perhaps from infection by Listeria monocytogenes[24]), have all been postulated, but there is no convincing proof of any of these theories. In 1691, Radcliffe attended the two-year-old Duke of Gloucester, diagnosed 'an attack of ague' and the patient recovered. Queen Mary was so delighted that she reward- ed Radcliffe with 1,000 guineas[25]. In 1695, shortly after one of her miscarriages, Princess Anne felt unwell and thought she might be pregnant Fig 4. Queen Anne and William, Duke of Gloucester. (Oil painting by studio of Sir Godfrey Kneller, ca. 1694. Courtesy National Portrait Gallery, London.) Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 257 again. She sent a messenger to Radcliffe to attend her at St James's-. Radcliffe, perhaps too fond of the bottle, was drinking in a tavern with some friends. He told the messenger he would come at once but failed to do so. On the arrival of a second messenger Radcliffe publicly proclaimed that 'Her Highness' Distemper was nothing but the Vapours and that she was in as good a state of health as any Woman breathing could she but give into the belief of it'[26]. Radcliffe was proved to be correct: the Princess was not pregnant. But Anne was furious when she heard of Radcliffe's remarks, dismissed him from her service, appointed Dr William Gibbons (1647-1728) in his place and thereafter bore Radcliffe a grudge. In 1700, the Duke of Gloucester, aged 11, and possibly hydrocephalic, became seriously ill at Windsor. His personal physician, Sir Edward Hannes (1667-1710), together with Dr William Gibbons and Dr Walter Harris, diagnosed scarlet fever. When the case became desperate, Anne, despite her aversion to Radcliffe, allowed him to be consulted. Radcliffe diagnosed smallpox, was openly critical of Hanne's treatment by bleeding and, protesting that he had been called too late, exclaimed: 'Then you have destroyed him and you may finish him, for I will not prescribe'[27], The young prince died six days later. In 1702, on the death of William III, Anne became Queen. She suffered from generalised body pains, la- belled 'the gout', which were so severe that she needed to be carried to her coronation. In 1708, fate dealt a further sad blow: her consort, Prince George of Denmark, an asthmatic and also a sufferer from 'the gout', became acutely ill. Queen Anne's favourite physician, Dr John Arbuthnot (1667-1735) attended him but the patient's condition worsened. As a last resort, Anne overcame her antipathy to Radcliffe and permitted him to be consulted. Yet again, Radcliffe maintained that he had been called too late; six days later, Prince George died, aged 55. Queen Anne's health continued to deteriorate. She was chronically affected by 'the gout' and was attended by her Physicians-in-Ordinary: Dr Thomas Laurence, Dr Mar- tin Lister (1638-1711) and Sir David Hamilton (1663? 1721), with Sir John Shadwell (1670-1747) as Physician Extraordinary. Hamilton became a close friend of the Queen; as a man-midwife, he understood 'women's troubles' and considered the Queen's symptoms to be largely psychosomatic and prescribed Spirit of Milli- pedes[28]. Anne steadfastly refused to allow Radcliffe to attend her, but . .he was consulted in all cases of emergency, and though not admitted as the Queen's physician, he received large sums for his prescrip- tions'^]. Queen Anne's Final Illness At Christmas 1713, the Queen became ill at Windsor, suffering from fever and painful inflammation of the inner portion of the right thigh[30-34]. She was attended by Doctors Laurence, Arbuthnot and Shadwell, Sir Da- vid Hamilton and Sir Hans Sloane (1660-1753). Laur- ence and Shadwell diagnosed 'a violent inflammatory fever' and recommended bleeding. Arbuthnot overruled them with a diagnosis of 'an ague' and prescribed Jesuit's bark. Radcliffe was, of course, not asked to attend the Queen but his analysis of the case is to be found in this letter to a friend[35]. ; j Jan. 5 1714 ... I don't doubt but you have heard an account of her Majesty's illness; and here we are all in the dark as well as the doctors. At first they said it was ague and then they gave the Jesuit's bark. She took but three doses, and that was left off, so that I suppose they found it no ague, or else she would have taken more or none at all. Then it was conjectured to be the gout in her stomach; and now it is thought to be the gout all over excepting the joints. One of the doctors declared, because there was no intermission on the second day, that it was a tertiary postponed. Another, which was Sir David [Hamilton] declared, now, God be thanked, her Majesty would certainly be well; and when he was asked the reason, he told them she had grown deaf, and that was a sign the bark had taken effect: and at that time she had taken two doses, and never took but one afterward. Shadwell was asked how the Queen did, and he said she would do very well, but the pouls was dure, \ which puzzled all the maids of honour. The country was led to believe that the Queen would die; however, she rallied but remained weak and required to be carried from room to room at Windsor. In February 1714 she was well enough to be transported by coach to Kensington Palace. Matters came to a head in the summer of 1714 when the Queen's illness took a more serious turn. In this, the final chapter of Queen Anne's long saga of sickness, she was attended by Doctors Laurence, Shadwell and Ar- buthnot (Physicians-in-Ordinary); Sir Hans Sloane (Physician Extraordinary) and Mr Daniel Malthus (Roy- al Apothecary). Sir Richard Blackmore (1653-1729) and Dr Richard Mead were also consulted, as well as the famous 'eye quack', Sir William Read (d. 1715), Oculist- in-Ordinary to the Queen. On Wednesday, July 28th, Daniel Malthus reported 'Her appetite was quite lost and her spirits sunk'. On Thursday, July 29th, the Queen vomited and the follow- ing day, Friday, July 30th, she suffered two convulsions and for one hour was 'speechless, motionless and miser- able'. The Queen would not herself have desired Rad- cliffe to be called and the Privy Council certainly would not have wished to offend her sensibilities by so doing. The queen's friends, however, felt that Radcliffe might yet help her. Without obtaining anyone's permission, one of the Ladies of the Bedchamber and the Queen's close confidante, Lady Abigail Masham, took it upon herself to send for Radcliffe, who happened to be out of town staying at his country house in Carshalton, and who was himself laid up with an attack of 'the gout'. Radcliffe declined to respond to the call. It was reported later: '. . . the Duke of Ormonde had in all haste sent Mr. Lowman with one of the Queen's coaches to Dr. Ratcliffe (sic) but whether the celebrated Physician thought he could do no good, or expected to be call'd by an express 258 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 J order from Council, he excused himself, upon account of having taken Physic that very day'[36]. On Saturday, July 31st, the Queen's condition wors- ened and on the following morning she 'ate an inordinate quantity of black heart cherries', lay back and died[37]. She was aged 49. A partial autopsy was performed by Dr Thomas Laur- ence in Kensington Palace on August 2nd but the internal organs revealed little that was remarkable. The report was presented to the Privy Council the next day and was signed by Dr Thomas Laurence, Sir David Hamilton, Dr John Arbuthnot, Sir John Shadwell and Sir Hans Sloane[38], i There was no official announcement of the Queen's death. Her illness, which had dragged on since December 1713, had given rise to so many false rumours that 'Queen Anne is dead', that on the day before the Queen's death, Thomas Ford wrote to Jonathan Swift: '. . . I don't doubt but you have heard the Q is dead . . . but at present she is alive and much better than could have been expected'[39], On the day following the Queen's death, Delaune, the Whig head of St John's College, Oxford, ordered prayers for the new monarch 'King George the First' to be said in morning worship. When the chaplain objected that the Queen might not yet be dead, he replied: 'Dead? She is as dead as Julius Caesar'[40], Queen Anne's death occurred in the midst of consider- able political turmoil. Dr John Arbuthnot subsequently wrote to Jonathan Swift: 'My dear mistress' days were numbered, even in my imagination, and could not exceed certain limits, but of that small number a great deal was cut off by the last troublesome scene of the contention among her servants. I believe sleep was never more welcome to a weary traveller than death was to her . . .'[41]. The Last Days of Radcliffe Immediately the news of the death of the Queen became generally known, it was put about in London that Radcliffe had refused orders from the Court that he should attend the dying Queen. Radcliffe refuted this accusation[42]. . . . his duty to her Majesty would oblige him to attend her, had he proper orders for so doing; but he judged as matters at that juncture stood between him and the Queen, who had taken an antipathy against him, that his presence would be of more disservice to her Majesty than use, and that since her Majesty's case was desper- ate and her distemper incurable, he could not at all think it proper to give her any disturbance in her last moments which were so very near at hand; but rather an act of duty and compassion to let her Majesty die as easily as possible. Among the London populace, feelings began to run high; they cried for Radcliffe's blood. 'Give us back the Queen', they chanted. It was even said later of Radcliffe that '. . .he was alike charged with killing Queen Mary, whom he did attend in her dying illness?and Queen Anne, whom he didn't'[43], Not everyone joined in these charges against Radcliffe. The Wentworth Papers contain the following letter[44] to the Earl of Stafford. July 30 1714 My Lord, I am informed that when Dr. Ratcliffe (sic) was sent for to her Majesty in her illness, he announced too morrow would be time enough to wait on her Majesty, but the insolence of this expression makes one scruple the truth of it . . . However, some of Radcliffe's friends did give credence to the story. On 5th August 1714 the matter was raised in Parliament, where Sir John Pakington (1671-1727), an old friend of Radcliffe, moved '. . . that Radcliffe should be summoned to this place to be censured for not waiting upon the Queen when sent for by the Duke of Or- monde'[45], Radcliffe being absent and there being no seconder to the motion, the subject was dropped. Radcliffe was nevertheless very hurt by Sir John Pakington's action. He wrote to a friend on August 7th[46]: ... I could not have thought that so old an acquaint- ance and so good a friend, as Sir John always professed himself, would have made such a motion against me. God knows that my will to do her Majesty any service has ever got the start of my ability, and I have nothing that gives me greater anxiety than the death of that glorious Princess. I must do that justice to the physician that attended her in her illness, from a sight of the method taken for her preservation by Dr. Mead, as to declare that nothing was omitted for her preservation. But the [political] people about her?the plagues of Egypt fall on them?put it out of the power of physic to be any benefit to her. I know the nature of attending Crowned heads to their last moments too well, to be fond of waiting upon them without being sent for by a proper authority. You have heard of pardons signed for physicians before sovereigns demise. However, as ill as I was, I would have went to the Queen in a horse-litter had either her Majesty or those in Commission next to her command- ed me so to do. Writing to Dr Richard Mead, Radcliffe confided that he had received several anonymous violent letters threat- ening him with being torn to pieces, should he ever make his appearance in London. A gang of 13 toughs planned his assassination, but one of them thought better of it and divulged the plot to Radcliffe in the following letter[47]: Doctor, Though I am no Friend of yours, but on the contrary, one that would wish you Destruction in a legal way, for not preventing the Death of our most Excellent Queen, when you had it in your Power to save her; yet I have Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 259 such an Aversion to the taking away Men's Lives unfairly, as to acquaint you, that if you go to meet the Gentlemen you have appointed to dine with, at the Greyhound in Croydon, on Thursday next, you will be most certainly murther'd. I am one of the Persons engag'd in the Conspiracy with Twelve more, who are resolved to sacrifice you to the Ghost of her late Majesty, that cries aloud for your Blood, therefore, neither stir out of Doors on that Day, nor any after, nor think of changing your present abode for your House at Hammersmith, since there, and everywhere else, we shall be in quest of you. I am touch'd with Remorse, and give you this Notice; but take Care of yourself, lest I repent of it, and give proof for so doing, by having it in my Power to destroy you, who am, Your Sworn Enemy, N.G. Radcliffe decided it would be safer not to show his face again in the capital. He remained in Carshalton, where he became depressed and his health declined. Three months after the death of Queen Anne, he suffered an apoplexy while in church, and died on 1st November 1714 aged 62. A contemporary historian said of Radcliffe[48]: He was the most eminent Physician England ever produced. This common Opinion procured him such vast Practice and consequently Riches and puff'd him up to that Degree of Surly Pride that he often disdained to consult with other Physicians; and on many Occa- sions, refused to attend Persons of the Highest Quali- ty .. . nay even the late Duke of Gloucester and her late excellent Majesty Queen Anne on her last Sick- ness, which was justly resented by all the High-Church Party . . . However, his last Will and Testament atoned . . . Radcliffe may well have been the most successful physician of his time, but he was certainly a complex and controversial figure, with a full complement of both admirers and enemies. Religious and political differences contributed to the inter-personal tensions in which he appeared so often to be involved, but it is possible that his fondness for alcohol may have ac- counted at times for his apparently intemperate speech and behaviour. Radcliffe's approach to his royal patients often lacked the sensitivity and tact which one would normal- ly associate with a physician to the court. His maladroit behaviour and conversation may on occasions have resulted from pique, but as far as his role in the final illness and death of Queen Anne is concerned, it would be unfair to accuse him of lese-majeste. References 1. British Biography (1766-72) Vol. 8, p. ^46. Dr John Radcliffe. London: R. Goadby. 2. Dictionary of National Biography (1882) Vol. 16, pp. 572-575. Drjohn Radcliffe. Oxford: University Press. 3. Steele, Sir Richard (1709) The Taller, No. 44. 4. British Library Add. MSS (Ca. 1690) no. 39289, f. 21. Drjohn Radcliffe's 'Receipt for a Cough'. 5. Hone, C. R. (1950) The Life of Dr John Radcliffe, p. 71. London: Faber & Faber. 6. Munk, W. (1878) The Roll of the Royal College of Physicians of London, Vol. 1, p. 457. London: Royal College of Physicians. 7. Ibid, p. 458. 8. Steele, Sir Richard, op. cit., ref. 3 above. (21st July, 28th July and 13th September 1709). 9. McMichael, W. (1968) The Gold-Headed Cane, pp. 1-55. London: Royal College of Physicians. 10. Dictionary of National Biography (1882) Vol. 21, pp. 306-325, William III. Oxford: University Press. 11. McMichael, W., op. cit., ref. 9 above. 10. Strickland, A. and Strickland, E. (1847) Lives of the Queens of England. Mary II: Vol. 10, p. 239: Vol. 11, p. 1. Anne: Vol. 11, p. 341; Vol. 12, p.l. London: H. Colburn. 13. McMichael, W. (1830) Lives of British Physicians. London: J. Murray. 14. Burnet, G. (1724) The History of my Own Time. London: T. Ward. 15. McMichael, W., op. cit., ref. 9 above. 16. Ibid. 17. Pittis, W. (1715) Some Memoirs of the Life of John Radcliffe. London: E. Curll. 18. Dictionary of National Biography (1882) Vol. 1, pp. 441-473. Queen Anne. Oxford: University Press. 19. Green, D. (1970) Queen Anne. London: Collins. 20. Gregg, E. (1980) Queen Anne, p. 100. London: Routledge & Kegan Paul. 21. Stevenson, R. S. (1962) Famous Illnesses in History, pp. 213-227. London: Eyre & Spottiswoode. 22. Anderson, M. (1963) Queen Anne's Children. British Medical Journal, 1, 684. 23. McAlpine, I. and Hunter, R. (1969) George III and the Mad Business, pp. 221-222. London: A. Lane. 24. Saxbe, W. B. (1972) Listeria monocytogenes and Queen Anne. Paediatrics, 49, 97. 25. Green, D., op cit., ref. 19 above, p. 55. 26. British Library Add. MSS. (1695) No. 17677 PP. f.216. L'Hermi- tage to States. 2/12. April 1695. 27. Nias,J. B. (1918) Dr John Radcliffe, pp. 11-31. Oxford: University Press. 28. Roberts, P. (ed) (1975) The Diary of Sir David Hamilton 1709-14. Oxford: University Press. 29. Munk, W., op. cit., ref. 6 above, p. 457. 30. British Library. Sloane MSS (1714) No. 4034. ff. 44 & 46-50. 31. Lavers-Smith, H. (1901) Memoirs of celebrated physicians who flourished in the reign of Queen Anne. No. 1: Dr. John Radcliffe. Guy's Hospital Gazette (New Series), 15, 545. 32. Rae, J. (1913) The Deaths of the Kings of England, p. 127. London: Sherrat & Hughes. 33. Kemble, J. (1933) Idols and Invalids, p. 155. London: Methuen. 34. Yearsley, M. (1935) Le Roi est Mort, p. 136. London: J. Heritage, Unicorn Press. 35. Cumston, C. G. (1911) Some medical gossip pertaining to the last illness of Queen Anne of England. New York Medical Journal, 94, 179. 36. Boyer, Abel (1711) The Political State of Great Britain, Vol. 8, p. 90. London. 37. Nias, J. B., op. cit., ref. 27 above. 38. Public Records Office: Treasury Papers (1716). No. Tl/21. Item 33. (12th March 1716). Autopsy report on Queen Anne. 39. Swift, Jonathan (1935) Letters of Jonathan Swift to Charles Ford, p. 40. (ed D. N. Smith). Oxford: University Press. 40. Historical Manuscripts Commission (1891) Portland Papers, Vol. 7, p. 198. Letter: Dr William Stratford to Edward Lord Harley, 2nd Aug. 1714. London: HMSO. 41. Swift, Jonathan (1911) Letters, (ed Ball.) Vol. 2, p. 92. London. 42. Pittis, W., op. cit., ref. 17 above. 43. Jeaffreson, J. C. (1860)^4 Book about Doctors, Vol. 1, pp. 134-174. 44. Historical Manuscripts Commission (1883) Wentworth Papers (ed J.J. Cartwright) Letters 1705-39. London: Wyman. 45. Ibid. 46. Pittis, W., op.cit., ref. 17 above. 47. Ibid. 48. Boyer, Abel, op. cit., ref. 36 above. 260 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985

PMC005xxxxxx/PMC5371094.txt

Audit Reviewed: Does Feedback on Performance Change Clinical Behaviour? M. W. MITCHELL, BA, Research Officer F. G. R. FOWKES, MB, MRCP(UK), MFCM,* Senior Lecturer in Epidemiology Department of Epidemiology and Community Medicine, University of Wales College of Medicine, Heath Park, Cardiff The purpose of medical audit should be to improve the effectiveness and efficiency of medical care. An audit that v simply identifies poor practice, or has the sole objective of * educating clinicians, may not lead to improvements which are assured only if the detection of inadequate care is followed by a change in clinical practice to correct observed deficiencies. Re-observation of practice may r then be required to establish whether or not the desired improvements have taken place. For an audit to lead directly to improvements in the effectiveness or efficiency of medical care it is necessary to (a) observe the practice; (b) set a standard of practice; (c) compare the observed practice with the standard; (d) implement change, and (e) re-observe practice. These actions form a cycle of auditfl] (Fig.l). Often the cycle is incomplete because no attempt is made to change clinical practice. It is commonly assumed that the information produced by audit will naturally lead to change. In this article we review some past experiences with feedback of information and consider whether the evidence supports the assumption that the provision of information on performance changes clinical behaviour. Information feedback c^n be divided into two broad categories?passive and active. Passive feedback consists of supplying information without any overtly evaluative material or suggestions for improvement. The infor- mation is usually relayed to clinicians in the form of statistics in newsletters or computer printouts. Often the statistics may be ranked according to the levels pertaining to the consultants or junior doctors in receipt of the information. In contrast, active feedback of information includes some judgement of the behaviour being studied. The feedback may be combined with other forms of education such as seminars or the regular review of medical records by clinicians in a firm. Clinical guidelines or protocols may also be provided for clinicians participating in the feedback process. Passive Feedback Many of the trials of passive feedback have taken place in the USA, and most were concerned with the numbers and costs of diagnostic tests ordered. In one study designed to reduce the use of laboratory tests[2], clinicians were divided into several experimental groups. The 'cost edu- cation' group received a series of newsletters on cost containment and a list of charges for commonly used laboratory tests. The 'cost audit' group received passive feedback in the form of a weekly computer printout of tests and charges per patient generated by each clinician. Another group acted as a control. No change of practice was recorded in the 'cost education' or control groups. The 'cost audit' (passive feedback) group surprisingly increased total test use during the intervention period. Although education alone and feedback alone had no effect in reducing the use of diagnostic tests, a group of clinicians receiving both education and feedback showed a significant reduction in test usage. Similar results were obtained in an out-patient clinic in Baltimore[3], Feedback of haematological, biochemical and radiological tests ordered on each patient and the percentage of these tests found to be abnormal produced no effect on the use of tests over a period of one year. Indeed, the number of tests per patient increased from 0.7 to 1.5. "Correspondence to: Dr F. G. R. Fowkes, MRCP(UK), Department of Community Medicine, University of Edinburgh, Usher Institute, War- render Park Road, Edinburgh EH9 1DW. Fig. 1. Cycle of audit. Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 251 Schroeder et al. [4] included rankings of clinicians when feeding back statistics. They examined variations in the costs of laboratory tests and drugs used by internists at a university clinic. Rankings of physicians according to levels of laboratory and drug use were circulated among the clinicians, although each was only able to identify himself or herself on the list. Laboratory and drug charges were reviewed again, the clinicians being un- aware that a repeat audit was taking place. In the first audit, large variations (17-fold) between doctors were reported for laboratory costs and less so for drug use (fourfold). Following distribution of the results of the first audit, there was a 29.2 per cent decrease in laboratory use but a 6.4 per cent increase in expenditure on drugs. The greatest reductions were attributable to the high-cost physicians. At Flinders Medical Centre in Adelaide, Grivell et al. [5] also used rankings of medical specialists and identi- fied them by name. The order used was total diagnostic costs per bed day incurred by the specialists. (This ranking was compiled after the complete failure to change practice by regular feedback to clinicians of their own use of tests.) The ranking information also had no effect on the ordering of tests by the specialists. Passive feedback on aspects of clinical care other than the use of tests has also had only a limited effect on utilisation, for example on the use of drugs[6] and on the process of care for cholecystectomy patients[7]. However, feedback of tonsillectomy rates to surgeons in Vermont[8] was associated with a reduction in operating rates over and above that occurring in the USA as a whole. Thus, with few exceptions, passive feedback has been shown in several studies to have almost no effect on clinical practice. Active Feedback In the commonest form of active feedback, information on the management of patients is provided during regular reviews of medical records by clinicians in a firm. In one trial attempting to modify the use of tests by residents in a hospital in Boston, Martin et al. [11] randomly allocated 24 junior doctors into three groups. The first group reviewed at weekly intervals the medical records of patients in their wards; the second group received a moderate financial incentive if they reduced their use of tests; the third group acted as a control. During the year of the study, the group reviewing medical records showed the greatest decrease in the numbers of laboratory tests ordered (a reduction of 47 per cent). A regular audit of medical records in a Birmingham hospital, however, did not produce a greater reduction in numbers of tests ordered by clinicians participating in the audit than by those in a control group[12]. The author suggested that no substantial change took place because only emergency medical admissions were reviewed, and these patients were unlikely to have had many unneces- sary investigations. Nevertheless the review did lead to changes in other aspects of care, namely an improvement in medical recording, a reduction in drugs prescribed on discharge, and better discharge summaries. An American hospital study[13] tried to reduce the use of a wide range of clinical resources by means of feedback to junior staff during individual tutorials and seminars held in the wards and out-patient clinics of one medical department. Average length of stay was reduced by 21 per cent and the cost per admission in the department rose by only 4.3 per cent per annum compared with an average growth rate of 14.5 per cent in other depart- ments. The number of out-patient laboratory tests de- creased, thus reducing overall patient costs. Change may be forthcoming if feedback is combined with general guidelines or specific protocols outlining recommended modes of practice. Ln a recent study in the UK (Fowkes, unpublished), surgeons and anaesthetists in one hospital were issued with the Royal College of Radiologists' guidelines on the use of pre-operative chest X-rays. Issuing the guidelines had only a minor effect on utilisation, but regular feedback to the clinicians on their own utilisation resulted in a 55 per cent decrease in the use of pre-operative chest X-rays over a period of one year (in comparison with no significant change in a control hospital). In a Canadian study, the College of Physicians and Surgeons of Saskatchewan formulated a list of indications justifying hysterectomy. After hospitals were presented with data on their numbers of 'justified' and 'unjustified' hysterectomies according to the College's protocol, the numbers of 'unjustified' hysterectomies fell mark- edly [ 14]. As with other methods of active feedback, the provision of guidelines or protocols is an educational measure additional to that provided by feedback. Most edu- cational measures combined with feedback do appear to have an impact on practice. Discussion From the results of studies presented in this review, it would appear that simply feeding back information on performance has almost no impact on changing clinical behaviour. However, feedback combined with other edu- cational measures would appear to have some success in changing practice. It is not surprising that the very act of providing clinicians with relevant data does not automatically initi- ate change. Experience of traditional postgraduate educa- tion would suggest that new knowledge by itself impinges very little on clinical behaviour. This has also been demonstrated in studies concerned with the adoption of innovations: only a few key individuals tend to respond to new information with some appropriate action[15]. Most people resist change, being concerned primarily with maintaining current practices. In the case of clinicians the picture is further confused by the large amount of infor- mation with which any individual is constantly presented. As the amount increases, choosing which pieces of infor- mation to ignore and which to act upon becomes.increas- ingly difficult. In addition to the difficulties in overcoming a natural resistance to change, the failure of passive feedback may be due in part to the recipients' perceptions of the 252 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 J information and of the system for supplying it. A survey of consultants' opinions of the Scottish Consultant Re- view of Inpatient Statistics (SCRIPS)[16] showed that 61 per cent thought it was of no value, 44 per cent found it difficult to understand, 46 per cent thought there was too long a delay in the provision of data and 64 per cent were concerned with the extent of errors. However, 82 per cent said that in future they would like to receive routine data of some sort. Thus most consultants were not opposed to the idea of receiving information but they did not approve of the SCRIPS system. The lack of involvement of consultants in the planning and provision of data was probably a major factor contributing to the system's failure. The system was undoubtedly perceived as an external review of clinical practice and was counterpro- ductive in motivating change. The individuals providing feedback may be crucial to success in promoting change. Martin et al. [11] thought that one reason for the success of their weekly chart reviews in reducing the use of diagnostic tests was that the reviews were led by senior clinicians whose views were , respected by junior staff. Eisenberg et al. [17] postulated that one of the reasons they failed to reduce the inappro- priate use of tests for lactate dehydrogenase (LDH) in a hospital was because feedback was provided by junior and not senior staff in the hospital. They thought that house officers would be more likely to respond to figures of authority. Feedback of information must also be directed to the most appropriate person. Grivell et al. [18] sugges- ted that a major reason for the lack of effect of feeding- back data on numbers and costs of tests was because the feedback was presented to senior staff when in fact the junior staff ordered tests. In the UK, one of the most ambitious programmes of information feedback to consultants was conducted by the Information Services Division of the Scottish Health Service in the form of Scottish Consultant Review of Inpatient Statistics (SCRIPS)[9], Statistical information on numbers of discharges, diagnoses, ages of patients, and lengths of stay, was provided regularly to consultants on patients discharged from their wards. This feedback of information had almost no effect on clinical practice and was subsequently withdrawn. In a more recent experiment in Brent Health Dis- trict[ 10] consultants were provided with monthly reports of their use and costs of diagnostic and other services. The information was also presented intermittently to div- isions; this allowed consultants to compare their own firm's performance with that of colleagues. After three years, there was no evidence to suggest that any consult- , ant's pattern of work or expenditure had changed mark- edly. Restuccia[19] conducted a study in which the persons providing feedback undertook different roles. The pur- pose of the feedback was to reduce the number of days in which patients remained inappropriately in hospital. Cli- nicians in four hospitals were provided with different forms of feedback on selected groups of patients. 'Direct' feedback, in which a nursing officer automatically in- formed clinicians that patients were in hospital inappro- priately, resulted in the greatest change in terms of reduced length of stay and decrease in inappropriate days in hospital. 'Judgemental' feedback in which the nursing officer first had to decide whether to inform doctors about inappropriately located patients, also had a positive effect on length of stay. 'Indirect' feedback to medically quali- fied 'advisers', who were then responsible for contacting the clinicians in charge of patients, proved ineffective as the 'advisers' appeared unwilling to confront their clinical colleagues. The success of active feedback is undoubtedly due to the combination of feedback with other educational inter- ventions. The education may not simply provide the logic for change, but may ensure a more personal environment between provider and recipient than is the case with passive feedback. The recipient may feel more involved and responsive to suggestions for change. Awareness of peer pressure may also be greater than that provided by sheets of statistics distributed by colleagues. Although active feedback may be successful in initiat- ing change, sustaining this change over a period of time is a major difficulty. Martin et al. [11] documented a con- tinuing reduction in use of diagnostic tests for four months after stopping their weekly chart reviews, but other studies have not found this to be the case. For example, Rhyne and Gehlbach[20] combined feedback to residents on their use of thyroid function tests with an educational seminar. This reduced use for three months but, with no further feedback, use then returned to pre- intervention levels. The stimulus for change has to be sufficient to sustain change and to overcome the danger of recipients becoming immune to the stimulus. To sustain change over a long period of time, active feedback may have to be accompanied by a variety of educational interventions or some form of financial incentive or sanction[10]. In conclusion, there have been relatively few trials of the effect of feedback on performance in changing clinical behaviour. Active feedback in its variety of forms appears to be moderately successful but the lack of appropriate research design in many studies and the varying enthusi- asm of researchers and participants make it difficult to decide on the most appropriate methods of feedback. Methods used in the future to feed back information on performance should be implemented on an experimental basis and should be carried out for a sufficiently long time to establish that any change is indeed longstanding and not just a short-term response to a new initiative. References 1. Fowkes, F.G.R. (1982) Medical Education, 16, 228. 2. Everett, G., de Blois, S., Chang, P. F. and Holets, T. (1983) Archives of Internal Medicine, 143, 942. 3. Pozen, M. W. and Gloger, H. (1976) Social Science and Medicine, 10, 491. 4. Schroeder, S. A., Kenders, K., Cooper, J. K. and Piemme, T. (1973) Journal of the American Medical Association, 225, 969. 5. Grivell, A. R., Forgie, H. J., Fraser, C. G. and Berry, M. N. (1982) Medical Journal of Australia, 2, 326. 6. Brown, C. R. and Uhl, H. S. M. (1970) Journal of the American Medical Association, 213, 1660. Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 253 L 7. Mitchell, J. H., Hardacre, J. M., Wengel, F.J. and Lohreny, F. N. (1975) Medical Care, 13, 409. 8. Wennberg, J. E., Blowers, L., Parker, R. and Gittelsohn, A. M. (1977) Pediatrics, 59, 821. 9. Heasman, M. A. (1970) Scottish Medical Journal, 15, 386. 10. Wickings, I., Coles, J. M., Flux, R. and Howards, L. (1983) British Medical Journal, 226, 575. 11. Martin, A. R., Wolf, M. A., Thibodeau, A. L., Dzau, V. and Braunwald, E. (1980) New England Journal of Medicine, 303, 1330. 12. Heath, D. A. (1981) Journal of the Royal College of Physicians of London, 15, 197. 13. Lyle, C. B., Bianchi, R. F., Harris, J. H. and Wood, Z. L. (1979) Journal of Medical Education, 54, 856. 14. Dyck, F. J., Murphy, F. A., Murphy, J. K. et al. (1977) New England Journal of Medicine, 296, 1326. 15. Rogers, E. and Shoemaker, F. (1971) Communication of innovations. New York: Free Press. 16. Parkin, D. M., Clarke, J. A. and Heasman, M. A. (1976) Health Bulletin, 5, 273. 17. Eisenberg, J. M., Williams, S. V., Garner, L., Viole, R. and Smits, H. (1977) Medical Care, 15, 915. 18. Grivell, A. R., Forgie, H. J., Fraser, C. G. and Berry, M. N. (1981) Clinical Chemistry, 27, 1717. 19. Restuccia, J. D. (1982) Medical Care, 20, 46. 20. Rhyne, R. L. and Gehlback, S. H. (1979) Journal of Family Practice, 8, 1003.

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Gram-Negative Shock: Approaches to Treatment MARK A. JACOBSON, MD, Fellow in Infectious Diseases LOWELL S. YOUNG, MD, Professor of Medicine Division of Infectious Diseases, Department of Medicine, UCLA School of Medicine and Center for Health Sciences, Los Angeles, California Shock (systolic blood pressure less than 90 mm Hg and signs of tissue hypoperfusion) following Gram-negative rod bacteraemia represents a medical emergency. For some groups of patients the mortality has exceeded 80 per cent despite appropriate antimicrobial therapyfl ,2]. Some physicians might raise the nihilistic view that the high mortality is but a reflection of the underlying disease which in turn has been complicated by the onset of severe hypotension and diminished tissue perfusion. On the other hand, rather salutary developments have occurred in the therapy of bacteraemia due to Gram-negative bacilli[3]. Mortality which, prior to 1970, exceeded 80 per cent in patients with so-called underlying 'rapidly fatal' diseases is now often less than 25 per cent in a number of recent studies of antimicrobial therapy[3-5]. The ability to control the underlying disease processes and the termination of blood-stream infection appear to be associated with a better prognosis. There are four subjects, all controversial, that are at the forefront of any discussion of recent developments in the management of human bacterial shock. The processes discussed here relate only to the shock associated with Gram-negative rod infections. Such a narrow focus is necessary because of the burgeoning microbiological and clinical literature on Gram-positive infections and shock, particularly the well-publicised toxic shock syndrome. Use of Combinations of Antimicrobial Agents Literally hundreds of studies of antimicrobial efficacy have been published in the last 15 years, during which there appears to have been significant overall improve- ment in survival from human Gram-negative rod bacter- aemia. Many of these studies, despite enrolment of large numbers of cancer patients or critically ill individuals, have restricted themselves to the therapy of bacteraemic infections, particularly those complicated by shock. A retrospective study by Anderson et al. [6] demonstrated that the use of the synergistic combinations of antimicro- bials in patients who had developed shock was associated with a significantly better survival rate than that of individuals who were treated with non-synergistic combi- nations of agents. In that study a synergistic combination was most likely a combination of an aminoglycoside, such as gentamicin, with a (3-lactam (a cephalosporin or anti- pseudomonal penicillin). The study involved the individ- ual testing of actual combinations of antibiotics used therapeutically against isolates from the infecting organ- ism of each case studied. Thus a correlation between in vitro synergism and clinical outcome was demonstrated but the information obtained did not directly influence treatment. One of the problems in studies employing retrospective correlations is that the data are seldom if ever available for clinical management of the patient. Indeed, the very definition of in vitro antimicrobial synergism has varied considerably and there is no widely accepted methodology for the performance of such tests. Nonetheless, studies using several accepted criteria have shown that 40-80 per cent of combinations of aminoglycosides with /3-lactam agents result in a synergistic interaction[7]. The use of synergistic combinations therefore becomes the rationale for the empiric use of antimicrobial agents. The results of Anderson's study[6] have not been confirmed or refuted by any subsequent analysis of antimicrobial chemotherapy in patients with shock. The relevance of the nature of antimicrobial therapy to the outcome of the management of shock should be obvious to practising clinicians. The controversial studies about the therapeutic use of steroids as published by Schumer[8] in man or the therapeutic adjunctive use of an antiserum against endotoxin by Ziegler et al. [9] give no detailed analysis of the effect of choice of antimicrobial therapy on outcome. Indeed, the study by Schumer[8] makes it very unlikely that synergistic combinations of antibiotics were ever employed in patients because of the use of such therapeutic approaches as chloramphenicol alone or the combination of clindamycin and gentamicin. Ziegler et al. [9] make no mention of specific antimicrobial therapy except to indicate that the appropriateness of treatment was similar in recipients of control and thera- peutic J-5 antiserum. It is surprising therefore that this highly important aspect of therapy has not been clearly detailed in major studies claiming that other forms of intervention are specifically responsible for a beneficial therapeutic outcome. 214 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 One can easily imagine how more rapidly effective bactericidal therapy could influence the outcome of the ^ management of bacterial shock. Death of organisms might result in enhanced release of endotoxins. This might make the clinical situation even worse, but it can be argued that more rapid killing of the responsible bacteria will terminate the pathogenic process earlier and lead to greater likelihood of survival. In immunocompromised patients likely to have a massive inoculum and high grade i bacteraemia, the rapid killing of organisms must be accepted as a desirable therapeutic goal which is most effectively reached by using synergistic combinations of antimicrobials. Although potent new monotherapeutic agents have been introduced into clinical practice, such as , the newer (3-lactam agents (e.g. cefoperazone[10] or imipenem), the preferred synergistic combination of anti- microbials is an aminoglycoside with a /3-lactam agent (e.g. gentamicin or amikacin with piperacillin or azlocil- lin). I - Corticosteroids The use of steroids in patients with shock due to Gram- A ? negative bacteraemia has been a focus of controversy for over 20 years. Many studies of this use of glucocorticoids have significant methodological problems. Weitzman and Berger reviewed the English language literature in 1974 and analysed 32 human studies for adherence to eight standards of clinical trial designfll]. Only 41 per cent of the studies were prospective, 44 per cent used concurrent controls, 25 per cent were randomised, and 16 per cent were double-blind. Most of the studies lacked consistency in details of steroid administration (e.g. dosage, duration of therapy, use of a single preparation). The best study dealing with Gram-negative bacteraemia was by Klas- tersky et al. [12]. No difference in mortality rates was seen between patients given placebo and those treated with betamethasone, 1 mg/kg/day for three days (equivalent to j - 7 mg/kg/day of methylprednisolone). In 1981, the Federal Drug Administration (FDA) removed septic shock from its list of indications for the use of high-dose methylprednisolone. The controversy has been kept alive by two further major reports. The first[8] involved 172 consecutive - * patients with blood culture-proven septic shock. Higher doses of glucocorticoids were used than by Klastersky et al. [12]. Therapy was started at the time of diagnosis. The mortality rates were significantly different: 10 per cent in the steroid-treated group and 38 per cent in the placebo , " group. This study has been criticised for the following reasons: use of two different steroid preparations (dexa- methasone and methylprednisolone), failure to use a uniform antibiotic protocol, use of chloramphenicol alone during the first phase, lack of data on adjunctive support- ive measures, and unusually low mortality in the steroid treated group. A large body of animal experiments suggests that early use of steroid therapy prevents the occurrence of the septic shock syndrome. A recent prospective controlled unblinded study by Sprung et al. [13] showed that large corticosteroid doses had a significant effect on reversing septic shock. Although mortality was unaffected, septic shock was reversed within 24 hours in 11 of 43 steroid- treated patients but in none of 16 controls (P< 0.05). Patients who received corticosteroids within four hours after onset of shock experienced a significantly higher incidence of shock reversal than those who were treated later, but many patients did not receive steroids until more than 12 hours after onset of shock. Use of large doses of steroids in shock may delay death, but the ultimate mortality may be similar in non-steroid treated subjects. Recovery seems related to ability to improve the underlying disease, and steroids may 'buy time' for the patient with a potentially reversible disorder. There may be a sound physiological basis for empiric use of steroids. High-dose steroids appear to inhibit the release of /3-endorphin as well as adrenocorticotrophic hormone (ACTH) from the pituitary. This may counter endotoxin stimulation of endorphin release and blunt the severity of resultant hypotension. Inhibition of comple- ment-mediated granulocyte aggregation may be another mechanism of action of high-dose steroids in septic shock[14]. Endotoxin activates the complement system, and it has been shown recently that granulocytes aggre- gate when exposed to activated complement, specifically C5a[ 15]. When cultured human umbilical vein endotheli- al cells were exposed to neutrophils activated by C5a, the neutrophils adhered to the endothelial cells and released toxic oxygen species which resulted in endothelial cell damage. Cell damage was inhibited by hydrocortisone. In another study, the plasma level of methylprednisolone achieved by a 30 mg/kg dose completely prevented in vitro complement-mediated granulocyte aggregation[16]. Until further double-blind prospective studies of high- dose methylprednisolone with controlled antibiotics clari- fy the clinical value of steroids in septic shock, we favour restricting administration of a single 30 mg/kg dose of methylprednisolone to the following patients: those who are early in the course of presumed Gram-negative bacteraemia, have suffered hypotension for less than two hours, and have potentially reversible underlying disease. In this clinical setting, Sprung et al. showed a significant superinfection rate attributable to dexamethasone; patients treated with methylprednisolone did not experi- ence such increased adverse effects compared to con- trols[13]. Naloxone Some researchers have proposed that endorphins play a major pathogenic role in septic shock. This has logically led to inquiry about the possible therapeutic effect of naloxone. Earlier research on endorphins focused on their role as opiate analogues that function as pain modulators. Naloxone, a pure opiate antagonist, was shown to block endorphin analgesia. Endorphins, like exogenous opiates, produce hypotension, and naloxone can also block this effect. Faden and Holaday's animal studies suggest that naloxone can reverse hypotension in Gram-negative bac- teraemia[17]. Unanaesthetised rats were given purified Escherichia coll endotoxin. When the mean blood pressure Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 215 dropped to 65 mm Hg, rats received either a placebo or naloxone. Naloxone restored mean pressure in rats that received endotoxin. Naloxone maintained pressure when given as a continuous infusion, and a dose-response relationship was shown with maximal effect at 1 mg/kg. Experiments with levo- and dextrorotatory isomers of naloxone showed that the effect of naloxone on blood pressure after endotoxin administration occurred only with the levo-rotatory form. This stereospecificity sug- gests that the effect of naxolone is opiate-receptor-mediat- ed and not due to some other pharmacological effect of the drug. Increased mean pressure was produced when a small amount of levo-naloxone was injected into the cerebral ventricle. There was no effect when the same amount was given peripherally or when dextro-naloxone was given intraventricularly. Thus, it appears that the effect of naloxone in shock is mediated by central nervous system opiate receptors. Although naloxone increased mean arterial pressure in the rat endotoxin model, it did not significantly change survival. Experiments by these same investigators using the canine endotoxic model suggest that the primary therapeutic effect of naloxone in endotoxic shock is to reverse depression of myocardial contractility[17]. Naloxone, given to pigs two hours after the induction of Esch. coli septic shock, had only tran- sient, relatively minor effects on blood pressure[18]. Perhaps the haemodynamic effect of naloxone occurs only when given early in the course of bacteraemia and not at a later time. There are few human studies of naloxone in septic shock, although several case reports have appeared[19- 21]. Severe septic hypotensive episodes unresponsive to pressors were dramatically reversed when naloxone was administered. Doses used ranged from 0.01 to 0.1 mg/kg. There is one small uncontrolled study[22] in which 13 patients with sustained hypotension, 10 of whom had sepsis as the aetiology, and all of whom had either oliguria or impaired mental status, were given intravenous nalox- one. Pressors, antibiotics, and fluids were continued unchanged. Four of the 13 were hypoadrenal from either Addison's disease or chronic steroid administration. Eight septic patients who were not hypoadrenal had a 45 per cent increase in systolic pressure within minutes of receiving 0.4-1.2 mg of naloxone. This increase lasted about 45 minutes (compared with a half-life for naloxone of about one hour). In two of these patients a second dose resulted in another increase in blood pressure. The hypoadrenal patients had no pressor response to nalox- one. In the light of these data and the apparent safety of naloxone, we believe a trial of naloxone therapy can be justified in cases of septic shock that have been unrespon- sive to appropriate volume replacement and pressors. In this situation, we favour giving a 1 mg bolus and repeating this until hypotension resolves or a maximum dose of 0.1 mg/kg is reached. Once a clinical response occurs a 1 mg/hr maintenance infusion is started. While naloxone appears to have a transient pressor effect in septic shock and causes minimal adverse effects, clinical trials are needed to establish its precise efficacy and the full range of dose response in humans. Therapeutic Antiserum Interest in enhancing the protective effect of host anti- body to bacterial endotoxin was stimulated in part by the report of McCabe et al. which related different host antibody titres to the frequency of shock and fatal out- come in 175 patients with Gram-negative bacter- aemia[23]. When bacteraemia was first diagnosed or suspected, serum antibody titres were measured to three Gram-negative cell-wall antigens: O-specific antigen and two shared cross-reactive antigens (CA and Re). O antigen is determined by the polysaccharide component of the outer membrane and is unique to each bacterial strain. Re antigen is a shared cross-reactive antigen associated with core glycolipid. Mutant Re bacteria lack both the polysaccharide O antigen and the outer core structures and thus have core glycolipid exposed. Hence, antibody to Re antigen is essentially antibody to the core glycolipid common to all Gram-negative bacilli. Shock and death occurred less frequently only in patients with elevated titres of anti-Re antibody. Braude et al., using a mutant form of Esch. coli designated J-5, have entered the therapeutic arena[24], J-5 bacteria lack an enzyme required for incorporation of galactose into cell-wall lipopolysaccharide. This prevents the" attachment of side chains to core glycolipid. The exposed core is presumed to be antigenic. Healthy rabbits vaccinated with killed J-5 Esch. coli developed high levels of antibody to J-5. Antiserum harvested from these vaccinated rabbits protected other rabbits from the toxic effects of injected endotoxin. Bacteraemia neutropenic rabbits given antiserum had markedly improved survival compared with controls given non-immune serum. This group later reported results of a multicentre, double-blind, randomised, prospective trial of J-5 anti- serum in patients with Gram-negative bacteraemia[9]. Human J-5 antiserum was obtained from healthy young men vaccinated with boiled J-5 Esch. coli cells. Control serum was also obtained from each volunteer before vaccination. Patients were enrolled if they appeared septic and had a high probability of Gram-negative infection. Each participant received one unit of control serum or antiserum at the time of enrolment. Among patients with documented Gram-negative infections, the mortality rate was 22 per cent for those who received antiserum and 39 per cent for controls (P = 0.01). In the subgroup with profound shock, the mortality rate was 44 per cent but 77 per cent for controls (P = 0.03). The fact that antiserum was most effective in non- neutropenic patients and in those with profound hypoten- sion supports the hypothesis that antiserum acts by binding to core glycolipid and blocking its access to host mediators of shock. J-5 antiserum and active J-5 immu- nisation have also been shown to be protective against H. influenzae type b infections in mouse studies[25]. Currently, a major problem is availability of anti- endotoxin antibodies. Some commercial preparations of gammaglobulin modified for intravenous use contain augmented levels of such antibodies, but data on their efficacy in man are not yet available[26]. The incidence of Gram-negative bacteraemia is now 216 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 estimated to be 70,000-300,000 cases per year[27,28], so c large amounts of therapeutic antiserum would be needed if it became a major form of treatment for Gram-negative septic shock. From a practical standpoint it may be unrealistic to plan on immunisation and plasma donation filling such requirements. In addition, current fears about the safety of blood products in general may limit patient acceptance. Hence for antiserum to become a practical treatment, in vitro antibody production is needed. Hu- > man monoclonal IgG antibody specific for H. influenzae capsular polysaccharide has been created by fusing hu- man splenic lymphocytes with a mutant human myeloma cell line[29]. These monoclonal antibodies are protective in an animal model of H. influenzae infection. Monoclonal antibodies to Gram-negative lipopolysaccharide have also been developed and appear protective in animal models of infection[30,31]. Perhaps monoclonal antibodies will be the next major therapy to lower mortality in Gram- negative septic shock. This article is based on a paper read by Dr Young at the ?r '? Conference on Infectious Diseases held at the Royal College of ^ Physicians in May 1985. , References 1. Bryant, R. E., Hood, A. F., Hood, C. E. et al. (1971) Archives of _ Internal Medicine, 127, 120. 2. McCabe, W. R. and Jackson, G. G. (1962) Archives of Internal Medicine, 110, 92. 3. Love, L. J., Schimpf, S. C., Schiffer, C. A. et al. (1980) American , Journal of Medicine, 68, 643. ) , 4. Winston, D. J., Barnes, R. C., Ho, W. G. et al. (1984) American '' Journal of Medicine, 77, 442. 5. Pizzo, P. A., Commers, J., Cotton, D. et al. (1984) American Journal of Medicine, 76, 436. 6. Anderson, E. T., Young, L. S., Hewitt, W. L. et al. (1978) Chemotherapy, 24, 45. 7. Weinstein, R. J., Young, L. S. and Hewitt, W. L. (1975) Journal of Laboratory and Clinical Medicine, 86, 853. u I , 8. Schumer, W. (1976) Annals of Surgery, 184, 333. 9. Ziegler, E. J., McCutchan, J. A., Fierer, J. et al. (1982) New England Journal of Medicine, 307, 1225. 10. Boliver, R., Fainstein, V., Elting, L. et al. (1983) Reviews of Infectious Disease, 5, (Suppl), 181. 11. Weitzman, S. and Berger, S. (1974) Annals of Internal Medicine, 81, 36. 12. Klastersky, J., Cappel, R. and Debusscher, L. (1971) New England Journal of Medicine, 284, 1248. 13. Sprung, C. L., Caralis, P. V., Marcial, E. H. et al. (1984) New England Journal of Medicine, 311, 1137. 14. Sheagren, J. N. (1981) New England Journal of Medicine, 305, 456. 15. Jacob, H. S., Craddock, P. R., Hammerschmidt, D. E. el al. (1980) New England Journal of Medicine, 302, 789. 16. Hammerschmidt, D. E., White, J. G., Craddock, P. R. et al. (1979) Journal of Clinical Investigation, 63, 798. 17. Faden, A. I. and Holaday, J. W. (1980) Journal of Infectious Disease, 142, 229. 18. Gahhos, F. N., Chiu, R. C., Hinchey, E.J. et al. (1982) Archives of Surgery, 117, 1053. 19. Swinburn, W. R., Phelan, P. et al. (1982) Lancet, 1, 167. 20. Dirkson, R., Otten, M. H., Wright, D. J. et al. (1980) Lancet, 2, 1360. 21. Tiengo, M. (1980) Lancet, 2, 690. 22. Peters, W. P., Priedman, P. A., Johnson, M. W. et al. (1981) Lancet, 1, 529. 23. McCabe, W. R., Kreger, B. E. and Johns, M. (1972) New England Journal of Medicine, 287, 261. 24. Braude, A. I., Ziegler, E. G., McCutchan, J. A. et al. (1981) American Journal of Medicine, 70, 463. 25. Marks, M. I., Ziegler, E. J., Douglas, H. et al. (1982) Journal of Clinical Investigation, 69, 742. 26. Roby, R. E. and Collins, M. S. (1984) Proceedings of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstr. 94. 27. Wolff, S. M. (1982) New England Journal of Medicine, 307, 1267. 28. Bryan, C. S., Reynolds, K. L. and Brenner, E. R. (1983) Journal of Infectious Disease, 5, 629. 29. Hunter, K. W., Hemming, V. G. and Fischer, G. W. (1982) Lancet, 2, 798. 30. Kim, K. S., Green, D., Cross, A. et al. (1984) Proceedings of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstr. 92. 31. Young, L. S. (1984) American Journal of Medicine, 76, 664.

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Science in Medicine The breathtaking advances in the basic sciences in the last decade have left most clinicians bewildered and with something of a feeling of hopelessness in their inability to catch up with and understand current physiology and biochemistry, let alone immunology and molecular biol- ogy. Nonetheless, every clinician, whatever his field of practice, has seen diagnosis and treatment profoundly altered by the impact of new scientific knowledge on medicine. We are all aware, for example, that the practical application of physics has brought new facilities for imaging, that monoclonal antibodies have been used for specific immunosuppression and as diagnostic agents, and that the techniques of molecular biology have led to the pre-natal diagnosis of inherited disease. No doctor, therefore, can afford to be out of touch with the advances in scientific knowledge which are pertinent to medicine. It could be (and indeed, has been) said that one does not really need to know the scientific principles underlying and governing diagnostic procedures, laboratory tests, and treatment; as long as one can order the appropriate investigation and choose the correct therapy, understand- ing need go no further. Not only is this approach intellectually sterile, it also produces a person blind to the intricacies, sheer excitement and, indeed, aesthetic values of current science. Recognising that there is a need for clinicians to revise what basic science they remember, and also to be intro- duced to new facts and hypotheses, the College'began in 1981 a series of conferences entitled 'Science and Medi- cine'. The second was held in 1983 and the third will take place on 6th-8th November 1985. Their content ranges widely, covering obvious fields such as neurobiology, cell physiology and structure, immunology, the pathogenetic mechanisms of infectious diseases, and less obvious ones such as psychology and electronics. Now and again rather shadowy areas have been explored, such as evolution and the form it is currently taking. A very pleasing and, to be frank, unexpected feature of the two conferences held to date has been the attendance throughout the whole two and a half days of many of the basic scientists invited to deliver a lecture. Their reasons for staying the whole course were the mirror image of those which brought about the conferences; the scientists felt a need to learn about the clinical field in which their own work was being applied. The College feels that it has fulfilled a need for drawing together clinicians and basic scientists, and making each group aware of advances enjoyed by, and problems facing, the other. Such an association can only be fruitful, and we must now consider ways in which the College could be even more instrumental in ensuring that the dialogue continues. D. Gwyn Williams

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The Persistent Challenge of Tropical Parasitic Infections The Milroy Lecture 1984 ADETOKUNBO O. LUCAS, MD, FRCFJ FFCM, Director, Special Programme for Research and Training in Tropical Diseases, World Health Organisation, Geneva, Switzerland Like Dr Leonard Rogers, Milroy Lecturer for 1907, I consider my appointment as being 'due to a desire on the part of this College to recognise the work now being done in the investigation of tropical diseases'[l]. In choosing my subject I have been guided by Milroy's suggestions for the lectureship in which he wrote, 'There is a vast amount of protracted malaise and suffering, disablement, or lessened capacity for industrial work, and often, too, of slow but eventually fatal sickness, in almost every region of the world. . In many parts of the tropics, malaria and other parasit- ic infections remain major causes of disease, death and disability, killing some, maiming others and, in a variety of ways, limiting the scale and scope of human endea- vours and often denying man the full enjoyment of the fruits of his labour and enterprise. Even where the diseases have been eliminated or controlled, they con- tinue to exact a toll by requiring that vigilance be maintained indefinitely to offset the ever-present risk of resurgence or re-invasion. These diseases present prob- lems that confront individuals, communities and govern- ments in the developing countries of the tropics. In the efforts to control these infections, the successes in some places have been as dramatic as were the failures in others. The overall picture is of the persistence of the challenge?with the parasites displaying an arrogant defi- ance to attempts to bring them under control and con- founding optimistic forecasts that they would fade away. The challenge posed by these infections can be examined at three levels: the community, the clinical state and the cells and tissues. Community In extreme cases, the impact of tropical parasitic diseases can be devastatingly obvious, even determining the course of history. There is the familiar example of the role of these diseases in deterring, in fact preventing, Euro- pean settlement in West Africa[2]. River blindness result- ing from infection with Onchocerca volvulus caused the depopulation of large tracts of arable land in Africa[3]. The waxing and waning of epidemics of African sleeping sickness in endemic foci have had a similar devastating effect on many communities in Africa[4], Epidemics of kala-azar in India caused . .a decrease in population of the affected tracts and the falling out of cultivation of much land. . .'[1]. It is more difficult to assess the specific contributions of individual parasitic infections in the typical situation, where the community is afflicted by a variety of parasitic and other infectious diseases, often compounded by mal- nutrition^]. The specific contributions of individual infections can be teased out by using case-control studies and multiple regression analyses. The situation is further complicated by the interactions that occur in cases of concurrent infections as, for example, the peculiar syndrome of chronic typhoid infection in association with Schistosoma mansoni infection[6], Dr Morrow and his colleagues have devised and tested a quantitative method for assessing the health impact of different diseases in less developed countries, based on the concept of the number of useful days of life lost[7]. This single index adds the deleterious effects of different degrees of disability to the losses due to premature death. Morrow's approach and similar ones require a conceptual leap to set up a table of equivalence between deaths and morbidity in clinical cases. One must take this leap in order to be able to compare the impact of diseases like malaria, which is a major cause of death in children in the highly endemic areas, with that of leprosy, which is a chronic disabling disease. In order to determine the full impact of these parasitic infections, it is important to recognise and assess their indirect effects on the community. Dr Molineaux of WHO[8] recently reviewed three methods of estimating the number of deaths caused by malaria in highly en- demic areas: (a) Deaths attributed to malaria. (b) Reduction in death rates on specific anti-malarial control. (c) The distribution of the sickle cell gene. These approaches have yielded estimates that are con- flicting and internally inconsistent. The number of per- sons recognised as dying from the classical manifestations of malaria grossly under-estimates the total mortality due to this infection. Some of the difference is accounted for by the indirect mortality caused by the infection. For Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 205 example, Gigioli[9] noted that, following the eradication of malaria in Guyana (a) the decline in the general mortality greatly exceeded the fall in mortality specifically related to malaria; (b) in infants, there was a marked fall in prematurity, and (c) in adults there was a marked fall in deaths due to chronic nephritis and chronic respiratory disease; the decline continued for some 10 years after the registration of the last death from malaria. Since Gigioli's observations, the syndrome of nephrosis in association with Plasmodium malariae infection has been more clearly defined by studies in Nigeria[10]. Malarial infection is also associated with immunosuppression, but it is not clear to what extent this phenomenon aggravates the morbidity and enhances the mortality of other concur- rent infections. Analysis of the distribution of the sickle cell gene gives the highest estimates of the mortality due to falciparum malaria. If it is assumed that malaria is the only selective factor conferring the advantage to AS heterozygotes, then the high sickling rates of 10-20 per cent in some African populations suggest that as many as 20 per cent of the subjects with normal haemoglobin, AA, die of malaria in childhood. Onchocerciasis provides another example of the need to include indirect effects in estimating the impact of tropical parasitic infections. In a prospective study of adults (30 or more years old) living in an endemic area of onchocerciasis, Prost and Vaugeladefl 1] found that the mortality rate among the blind was four times greater than among non-blind; such excess mortality would not normally be attributed to onchocerciasis but it clearly represents a significant element of the burden of disease. In addition, there is clinico-pathological evidence of renal pathology in association with onchocercal infection but there has been no proper appraisal of the contribution of this renal complication to morbidity and mortality on a community basis. If epidemiologists are having difficulties in assessing the health impact of these diseases, the methodological difficulties in assessing the economic impact are even greater, but social scientists have made brave efforts to tackle this difficult area[12]. It is well recognised that these diseases have their maximum impact in the developing countries of the tropics. This association has misled some to assume that the more significant association is with development rather than with the ecological effects of climate. Some have promulgated the doctrine of spontaneous regression, suggesting that these diseases would fade away, as they did in Europe, under the pressure of social and economic development or in response to broad non-categorical measures such as personal hygiene and environmental sanitation. To overlook or underplay the role of climate is a dangerous over-simplification. After all, there was no onchocerciasis in Oslo, no sleeping sickness in Siberia, and no schistosomiasis in Stockholm. Even though malaria did occur in colder climes, its incidence was miniscule and its impact trivial compared with the intensive transmission in the tropical belt, especially in tropical Africa where it is deeply entrenched. In England, at its worst malaria was estimated to kill 8 persons per million population per annum; compare this with the estimated 10-20 per cent of children in Africa dying of falciparum malaria[13], Not to recognise this enormous difference in scale would be tantamount to equating a raging tornado with a storm in a teacup. Added to the development equation is the fact that man- made lakes, irrigation schemes and similar agro-engin- eering projects tend to extend and intensify the transmission of malaria and schistosomiasis. Clinical State The clinical features of malaria and other parasitic infec- tions have been so well described that this mass of information tends to obscure our deep ignorance of the subtle features of the host/parasite relationship. For some of these infections there is a wide spectrum of clinical manifestations ranging from asymptomatic or mild cases at one end to acute life-threatening illness or chronic crippling disease at the other extreme. What factors determine the position of the individual patient in the clinical gradient? For some helminthic infections the severity of the disease can be correlated with the number of worms in the particular patient. Thus, in hookworm infection, there is a correlation between the load of infection, the intake of dietary iron and the occurrence of anaemia. In a series of elegant studies on schistosomiasis, Cheever and his col- leagues[14] have shown the correlation between the egg count in the tissues, the number of worms recovered at autopsy and the severity of the pathological lesions; but there was still a considerable amount of variation in the severity of the pathological lesions at each level of inten- sity. In Schistosoma haematobium infections, there is a correlation between the load of infection, as measured by the egg count in the urine, and the lesions shown on radiological examination. In Ibadan, Nigeria, our find- ings suggest that in the natural history of this infection there is a crucial stage of reversible obstructive uropathy; but as yet there is no clue to the factors that determine the outcome either in the direction of relief of the obstruction or of irreversible damage[15]. Similar problems are encountered in the filarial infec- tions. In lymphatic filariasis, only a proportion of those infected show lymphoedema. Although some of the im- munological differences between these types of patients are being described, we do not know why some patients develop swollen limbs but others do not. Similarly, in onchocerciasis there is some correlation between the severity of the anterior lesions of the eyes and the intensity of infection as measured by the microfilarial count, but the risk factors associated with the posterior lesions have still to be identified. In 1908, Carlos Chagas made the important discovery of the parasitic infection that bears his name. He found the parasite Trypanosoma cruzi in the blood of a two-year- old girl Berenice[16], In 1961, at the age of 53, Berenice still showed immunological and parasitological evidence of the infection but there was no evidence that she had developed any of the cardiac or gastrointestinal lesions normally associated with this infection. She died in June / 206 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 1981 at the age of 73 with a form of heart disease but probably not Chagas' disease. Whereas Berenice lived in peaceful co-existence with Trypanosoma cruzi for over 70 years, there are countless others infected with the same organism whose damaged hearts and other organs show the battle scars of the confrontation between host and parasite and in whom the infection traces a relentless downward course of chronic disease and disability, lead- ing inexorably to premature death. Why the difference? There are many theories and suppositions as to factors in the parasite, in the host or in some incompatibility in their relationship which determine the nature and the ? ? intensity of the struggle as well as its outcome; in most cases we are still groping in the dark. ?*> Therefore, it is not surprising that the management of :T? patients tends to be based largely on the stereotyped approach of killing the parasites with drugs. The current crude chemotherapeutic approach, with the single-mind- ed aim of killing the parasites, is associated with the twin hazards of the toxic effects of the drugs and the reactions of the host to the decaying mass of the dead parasites. It is conceivable that if and when we know more about these subtle relationships, we could devise treatments which could be more suitably tailored to the needs of individual patients; we could decide whom to treat, when to treat, u what drug to use, not merely to kill the parasites, but, more specifically, to modulate the host/parasite relation- \ ? ship in favour of the host. ^ New techniques bring the hope that light can soon be shed on these dark areas. For example, with the use of i monoclonal antibodies and gene probes, it is now possible to define more precisely the strains and species of the parasites of man. In the case of Chagas' disease, studies are under way to correlate the genetic variations of the parasite with the clinical epidemiological features of the disease. Immunological and genetic studies of the host may also provide useful clues. New imaging techniques and other non-invasive diagnostic methods should make it feasible to study the evolution of the pathological lesions and their response to various types of treatment. With this new information, we would gain a better understand- ing of the clinical challenge and this should lead to a more rational management of infected persons. Cells and Tissues New powerful research tools of various basic biomedical disciplines have led to a major explosion of knowledge of living cells, their membranes and their constituent organ- elles. Parasitology has benefited from these advances. Immunologists, molecular biologists, biochemists and geneticists are expanding our knowledge of the parasites and their relationships to their hosts at the level of cells and tissues. I wish to highlight three important aspects: host/parasite relationships; vaccine development, and new drugs. Host/Parasite Relationships Except for Entamoeba histolytica which is truly carnivo- rous, most parasites do not display specific aggression towards the host. Their activities seem to be directed towards the achievement of the four cardinal require- ments of parasitism: to multiply, to emerge from the host, to find a new host and to infect it. In the course of these events, damage to the host is usually incidental, and is, as often as not, due to the misguided attempts of the host to evict or destroy an inoffensive but persistent guest, or else to inappropriate reactions of the host to the dead or dying parasites, their eggs or other products. It is fascinating to discover the intimate details of the mechanisms by which these organisms adapt to parasitic existence, how they exploit the available resources within the host and how they protect themselves in what is clearly a hostile environment. Take, for example, Plasmo- dium falciparum, whose biology has been intensively studied since its continuous in vitro culture was achievedfl 7], It has devised mechanisms for dealing with the aggressive immune responses of the host. With regard to humoral immunity, the parasite protects itself by several mechanisms, some of which are not fully under- stood. These include antigenic variation and the occur- rence of changes in the antigenic structure of the parasite as it switches from one stage to the other. The overall effect is to present the host with an antigenic 'smoke- screen' obscuring the most significant antigens that could provoke protective immunity. Its sequestration in liver and red cells at crucial stages of its development provides additional routes of escape from the host's immune system. With regard to cellular immunity, the phenomenon described by Udeinya et al. [18] suggests a mechanism by which falciparum avoids destruction by the reticulo- endothelial cells in the spleen and elsewhere. At the stage when the infected red cells are most clearly recognisable as foreign elements and the mature schizont is therefore most susceptible to the scavenging action of the spleen, the parasite extrudes knobs, covered with a histidine-rich protein, that specifically adhere to the endothelial cells of bloodvessels. This sequestration of the mature schizont is one of the mechanisms by which falciparum malaria builds up a level of parasitaemia far higher than that achieved by the freely circulating malarial parasites of other species. Drug Resistance The apparently unlimited capability of falciparum ma- laria to deal with the challenge of anti-malarial drugs is remarkable. The parasite has had thousands or even millions of years to adapt to the immune responses of the host; in fact, this is a prerequisite of successful parasitism. But in the short space of a few years, falciparum malaria has devised metabolic answers to the challenge posed by practically every anti-malarial drug that has been exten- sively used. The parasite has developed resistance to pyrimethamine, proguanil, chloroquine and other 4- aminoquinolines, to combinations of pyrimethamine and long-acting sulphonamides, and even to quinine, which is regarded as a general protoplasmic poison. The success of falciparum malaria may eventually be traced to mecha- Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 207 nisms permitting it to reorganise its genetic material in a flexible manner. One may imagine that its genes are not cast in a solid mould or a rigid template but are construct- ed out of interchangeable elements that can be fitted and refitted as in a Meccano set or in Lego. Vaccine Development Attempts to develop vaccines against malaria and parasit- ic diseases have encountered four major problems. 1. Natural infections do not confer a lasting immunity. 2. Parasites possess a wide variety of mechanisms to evade and/or compromise the host's immune responses. 3. Parasites are large complex organisms as compared with the viruses and bacteria against which successful vaccines have been developed. 4. Problems with in vitro culture and the lack of appropri- ate animal models have made it difficult to manipulate parasites in the laboratory. Natural Infections. With most of these parasites, natural infection confers no immunity or at best an incomplete protection. Even though most parasitic infections do not confer sterilising immunity, subsequent attacks may be clinically less severe; for example, patients recovering from amoebic liver abscess are unlikely to develop this complication when reinfected[19]. Falciparum malaria provides an even more striking example of the way in which repeated attacks of infection modify the severity of the clinical manifestations and the outcome of the illness. In areas of intensive transmission of falciparum malaria (the so-called holo-endemic areas) adult males and non- pregnant women become immune to the severe complica- tions of the infection; in particular they have absolute immunity to cerebral malaria, even though some compli- cations tend to occur during pregnancy. Pre-school chil- dren, pregnant women and foreigners are highly susceptible and tend to develop fulminating, rapidly progressive disease[20]. This immunity from cerebral malaria is lifelong, persis- tent after long absences from the endemic area, and passively transmitted to the fetus, providing protection against cerebral malaria during the first few months of life. The host achieves an accommodation with the parasite?not total victory but a sort of armed truce. The knowledge that the adult male inhabitants of holo- endemic areas can stand up to falciparum malaria was exploited in the deployment of West African soldiers to fight in Burma during the Second World War. Falci- parum malaria provides a convincing case that man is able to mount some degree of protective immunity to parasitic infections. The immunity develops slowly and the protection is not absolute but it is nevertheless clinically and epidemiologically significant. The response to malaria is not typical of all parasitic infections; it is but one example of the many variations of the complex relationships between man and his endo-parasites. Evasion of Host Immunity. Parasites evade host immunity by hiding in safely secluded places in the body of the host, sometimes finding refuge in the most unexpected places, e.g. Leishmania organisms in macrophages; hypnozoites (the dormant phase of P. vivax) in hepatocytes. Some parasites are able to escape from the host de- fences by manipulating their antigens. Each developmen- tal stage of the parasite in man is usually associated with different sets of antigens. This stage specificity keeps the parasite one step ahead of the specific immune response of the host. Antigenic variation is another phenomenon by which some parasites, notably the blood stages of African trypanosomiasis and falciparum malaria, escape the host defences. Schistosome worms adopt antigenic disguise by acquiring a surface coat of host antigens. Host Responsiveness. Parasites undermine or compromise the host's defence mechanisms by various mechanisms. These include immunosuppression, antibody cleavage, complement consumption, the formation of circulating immune complexes, and polyclonal lymphocyte activa- tion. Some of the parasitic infections provoke clinically significant immunopathological effects including anaphy- lactic, cytotoxic and delayed hypersensitivity reactions, as well as lesions associated with immune complexes. It is important to identify the antigenic components of the parasites provoking these undesirable effects so that they are excluded from the candidate vaccines. Size and Complexity of Parasites. Parasites are large and complex organisms. Modern immunological techniques for purifying and characterising antigens, in particular monoclonal antibodies, have provided immunologists with precision tools for dissecting parasite antigens, a means of separating the wheat from the antigenic chaff. In Vivo/In Vitro Culture. For many of these parasites there are no satisfactory animal models. It is also difficult to extrapolate to man the results obtained from model parasites in surrogate hosts. In vitro culture techniques have improved, particularly for the blood stage of falci- parum malaria, Trypanosoma brucei, and some filarial worms[21]. Methods are being devised for the production of the specific antigens in quantities sufficient for laboratory tests, clinical trials, field trials and eventually for oper- ational use. Three main approaches are currently being explored: (a) splicing the parasite gene material into Escherichia coli; (b) determining the sequence of amino acids in the reactive sites of the polypeptide chains and synthesising them, and (c) the use of live carriers, e.g. the vaccinia virus. There is now an atmosphere of cautious optimism about recent steady progress leading to the development of vaccines against some of the major parasitic diseases of man. The most exciting progress has been made in the search for malaria vaccines. Candidate antigens have been identified for three developmental stages of the parasite?sporozoite, merozoite and gamete stages. If the present progress is maintained, clinical trials of a malaria vaccine may start within the next few years, and others are likely to follow[22]. 208 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 Drug Development Until recently, the strategy for the development of anti- parasitic drugs was based on screening natural and synthetic products; more often than not they were dis- covered through fortunate accidents. In the case of herbal remedies, from quinine to Qing-hao-su, we were literally borrowing a leaf from nature, or perhaps a root or a bark. We are now moving into the era of the rational develop- ment of anti-parasitic drugs based on the identification of leads from comparative biochemistry. The study of the metabolic pathways of the parasites is revealing likely targets for therapeutic attack. (a) Trypanosoma brucei, like other haemoflagellates, is highly vulnerable to agents that interfere with polyamine synthesis. This clue led to the screening of specific inhibitors of ornithine decarboxylase and the identifica- ? tion of di-fluoro-methyl ornithine (DFMO) as a likely drug for the treatment of African trypanosomiasis[23], (b) The scavenger pathway utilised by Leishmania organ- isms instead of de novo purine synthesis led to the testing of allopurinol and its riboside for the treatment of Leish- maniasis]^]. (c) Peculiarities of the folate metabolism of the filarial worms may provide a suitable target for chemotherapeu- tic attack in filariasis[25]. These new approaches promise the development of anti-parasitic drugs that are more potent, more selective and specifically targeted by using lysosomotropic agents i\ or suicide substrates, or that can achieve special effects, / e.g. blocking the receptors on host cells, reducing egg production in worms, or disrupting the trigger mechan- ism for antigenic variation. It should then be possible to banish such notorious poisons as arsenic and antimony from the pharmacopoeia of tropical medicine. Conclusions !, We have three ways of responding to the challenge of persistent parasitic disease. r Biological. The biological responses of the host include a variety of immunological defence mechanisms, both hu- moral and cellular. Genetic factors are also important, as in the case of the high prevalence of the sickle cell gene in areas of endemic falciparum malaria; there are other genetic markers, such as glucose-6-phosphate dehydro- genase deficiency, whose relationships to parasitic infec- tions are less well defined. }: Behavioural. Changes occur as part of the adaptation in endemic areas, an extreme reaction being the total aban- donment of areas that are heavily infested with infections such as onchocerciasis or sleeping sickness. * V . Biomedical, or the deliberate fashioning of weapons of offence and defence against the parasite invaders and their vectors. In recent years there has been an intensifi- cation of biomedical research on parasitic diseases and it is hoped that the discoveries will widen the range and effectiveness of our armamentarium of anti-parasitic weapons to include vaccines, drugs with novel properties, powerful diagnostic methods, and innovative vector con- trol measures, including biological control. If these expectations are realised in the coming dec- ades, if the public health services in the endemic countries can be equipped with these new weapons, and if their strategic plans for controlling these diseases can be based on sound epidemiological analyses with inputs from the appropriate social sciences, we can confront the persistent challenge of malaria and other parasitic infections with a reasonable hope of attaining greater success than in the past. References 1. Rogers, L. (1907) British Medical Journal, 1, 427. 2. Schram, R. (1971) History of the Nigerian Health Services. Ibadan: University Press. 3. World Health Organisation (1966) Technical Report Series, No.335. Geneva: WHO. 4. De Morais, A. T., Schneider, C. R. and Wright, W. H. (1962) Tropical Health: A Report on a Study of Needs and Resources, Publication 996. Washington, DC: National Academy of Sciences-National Research Council. 5. Buck, A. A., Anderson, R. I., Sasaki, T. T. and Kawata, K. (1970) Health and Disease in the Chad: Epidemiology, culture, and environment in five villages. Baltimore and London: The Johns Hopkins Press. 6. Neves, J. and Lobo Martins, N. R. L. (1967) Transactions of the Royal Society of Tropical Medicine and Hygiene, 61, 541. 7. Ghana Health Assessment Project Team (1981) International Journal of Epidemiology, 10, 73. 8. Molineaux, L. (1985) Health policy, social policy, and mortality prospects. (ed J. Vallin and A. Lopez) Liege: Ordina Editions. 9. Gigioli, G. (1972) Bulletin of the World Health Organisation, 46, 181. 10. Gilles, H. M. and Hendrickse, R. G. (1963) British Medical Journal, 2, 27. 11. Prost, A. and Vaugelade, J. (1981) Bulletin of the World Health Organisation, 59, 773. 12. Rosenfield, P. L., Golladay, F. and Davidson, R. K. (1984) Social Science and Medicine, 19, 1117. 13. Bruce-Chwatt, L. J. and de Zulueta, J. (1980) The Rise and Fall of Malaria in Europe. Oxford University Press. 14. Cheever, A. W. (1968) American Journal of Tropical Medicine, 17, 38. 15. Lucas, A. O., Akpom, C. A., Cockshott, W. P. and Bohrer, S. P. (1969) Annals of the New York Academy of Science, 160, 629. 16. Lewinsohn, R. (1979) Transactions of the Royal Society of Tropical Medicine and Hygiene, 73, 513. 17. Trager, W. and Jensen, J. B. (1976) Science, 193, 673. 18. Udeinya, I. J., Schmidt, J. A., Aikawa, M., Miller, L. H. and Green, I. (1981) Science, 213, 444. 19. Sepulveda, B. and Martinez-Palomo, A. (1982) Immunology of Parasitic Infections, (ed S. Cohen and K. S. Warren.) Oxford: Blackwell. 20. Gilles, H. M. (1961) West African Medical Journal, 10, 293. 21. Rowe, D. S. and Hirumi, H. (1980) The in vitro Cultivation of Pathogens of tropical Diseases. Basel: Schwabe. 22. Maddox, J. (1984) Nature, 310, 541. 23. Bacchi, C. J., Nathan, H. C., Hunter, S. H., McCann, P. P. and Sjoerdsma, A. (1982) Biochemical Pharmacology, 31, 2833. 24. Berens, R. L., Marr, J. J., Nelson, D.J. and Lafon, S. W. (1980) Biochemical Pharmacology, 29, 2397. 25. Jaffe, J. J., Chrin, L. R. and Smith, R. B. (1980) Journal of Parasitology, 66, 428. Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985

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A Profile of Geriatric Rehabilitation Units KEITH ANDREWS, MD, MRCP(UK), Senior Lecturer J. C. BROCKLEHURST, MD, MSc, FRCR Professor Department of Geriatric Medicine, Clinical Science Building, Hope Hospital, Manchester There are at present about 270 separate departments of geriatric medicine in the UK, each providing a district service. This service includes the admission and manage- ment of elderly people with acute illness, the rehabili- tation of those with disabilities, the use of day hospitals in continuing support within the community, and provision of long-term hospital care when necessary. The actual delivery of these services varies from one unit to another, depending on the nature of the available resources, e.g. whether the beds are in one or more hospitals, and on the style of practice adopted by the consultant. In 21 per cent of departments all the functions (acute, rehabilitation and long-stay) are combined on every ward; in 24 per cent there are separate acute, rehabilitation and long-stay wards; while in 38 per cent the acute and rehabilitation aspects of care are combined in one group of wards but there are separate long-stay wardsfl]. This article pro- vides a profile of the rehabilitation wards of those 24 per cent of geriatric departments in which there are separate rehabilitation wards. A previous study[l] had identified 52 such departments and 36 of these (69 per cent) completed a further questionnaire which gave details of patients admitted and discharged from the rehabilitation wards during a two-week period (14th-27th March 1983) together with information about time spent on these wards by medical staff during the two weeks. Results During the two-week period 387 patients were admitted and 326 discharged from the rehabilitation wards, which is equivalent to 6.6 admissions and 5.9 discharges per consultant geriatrician or 0.28 admissions and 0.23 dis- charges per rehabilitation bed. Admissions Table 1 shows the source of the admissions. Two-thirds were directly from the community and one-fifth by transfer from other specialties. In many cases, those admitted from home or residential homes would have been seen there prior to admission by the consultant or a deputy on a domiciliary assessment visit. Similar num- bers of patients (8-10 per cent) were transferred from orthopaedic wards (principally with fractured neck of femur) as from medical wards (principally stroke Table 1. Source of admission of 387 patients admitted to rehabilitation wards. Source % Home 58 Residential home 6 Private rest home 1 Acute geriatric unit 13 Medical 8 Orthopaedic 10 Surgical 3 Not stated 1 patients). The mean age of patients admitted was 80.5 years. Seven per cent of the males and 5 per cent of the females were aged less than 70 years, and 24 per cent of the males compared with 30 per cent of the females were aged 85 years and over. Altogether 103 patients were male and 284 were female. Discharges The mean age of those discharged was slightly lower for males (76.7 years) than for females (80.6 years), although a greater proportion of males (15 per cent) than females (8 per cent) were under 70 years of age whereas a greater proportion of females (29 per cent) than males (13 per cent) were over 85 years of age. Altogether 58 per cent of admissions and 52 per cent of discharges were of patients aged 80 years and over; 110 patients were male and 216 female, showing a slightly higher proportion of males among those discharged than those admitted. Diagnostic Categories The major diagnostic categories are shown in Table 2. Since it is often difficult to decide on the principal diagnosis in the elderly, Table 2 shows either the first or second diagnosis as listed by the respondents. Stroke was the most common single diagnosis, followed by arthritis, fracture of the femur, and confusion. It is surprising, however, that acute medical conditions ac- counted for 22 per cent of admissions and included an even larger proportion of those who were discharged. In 19 per cent symptoms, rather than diagnoses, were listed. 240 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 Table 2. Diagnosis on admission and discharges to rehabili- tation wards. Diagnosis Admissions Discharges (No. = 387) (No. = 326) % % Stroke 27 20 Other Neurological: 6 8 Parkinsonism 3 5 Myopathy/neuropathy 2 2 Paraplegia 1 1 Acute Medical: 22 28 Cardiac failure 8 9 Respiratory 4 2 Other 10 17 Orthopaedic: 15 7 Fracture femur 11 4 Other fractures 2 1 Amputation 2 2 Psychiatric: 13 4 Dementia/confusion 11 4 Depression 2 <1 Musculoskeletal: 12 11 Osteoarthritis 10 9 Spinal problems 2 2 Peripheral Vascular: 5 4 Peripheral vascular disease 1 2 Skin ulceration 4 2 Other: 2 4 Cancer 1 4 Post-operative 1 <1 Symptoms: 19 9 Debility 5 2 Incontinence 5 1 Balance problems 9 6 k Length of Stay The mean length of stay (Table 3) was related particularly to the places to which the patient was discharged. It was 31 days for those going home, but more than twice that length of time for those going to residential homes and long-term care geriatric units. This table also shows that Table 3. Length of stay related to place of discharge of rehabilitation patients. Residential Private Long- Died Length of Home home rest home stay stay (weeks) 225(69%) 30(9%) 10(3%) 12(3%) 39(12%) % % % % % <4 37 7 20 0 35 -6 27 17 30 20 22 -8 17 24 20 30 11 - 10 9 3 10 10 5 - 14 6 17 0 10 11 - 18 2 14 0 0 8 > 18 3 17 20 30 19 Mean length of stay (days) 31.4 70.8 56.1 81.7 70.2 Mean age (yrs) 78.9 82.5 74.3 83.1 80.1 the 10 patients (3 per cent) discharged to private rest homes were significantly younger than all the others. The readier accessibility of home or private rest homes is shown by the fact that more than 50 per cent of patients going to either of these were discharged in six weeks or less. Follow-up Arrangements No follow-up was arranged for 38 per cent of the dis- charged patients. However, 33 per cent continued as day hospital patients, 20 per cent with review in the out- patient clinic and for 8 per cent relief admissions were arranged. Medical Input A consultant ward round took place at least once a week in all but one unit and twice a week in just over half of the units. The average amount of medical time spent per patient each week (Table 4) amounted to lj hours; this included 15 minutes of consultant time?equivalent to one session a week for a 20-bedded ward. Table 4. Time spent by medical staff on 34 rehabilitation wards. Grade No. of Minutes per bed Equivalent units with (mean) hours for grade 20-bed ward Consultant 33 15 4.9 Senior Registrar 9 18 6.1 Registrar 12 21 6.9 SHO 26 65 21.8 House Officer 4 121 42.0 Other 17 7 2.5 All medical staff 34 96 32.1 Very few pre-registration house officers were involved in rehabilitation wards, although when they were this was a full-time equivalent of 42 hours for a 20-bedded unit. The main day-to-day care was carried out by Senior Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 241 House Officers (in 77 per cent of departments) who spent an average of 22 hours per week on a 20-bedded ward. Discussion About one quarter of the departments of geriatric medi- cine in the UK have wards that are specially designated as rehabilitation wards. These are all departments practising along the traditional lines of progressive patient care with further wards designated for acute admissions and for long-stay care. While this is the general pattern of such units, it is the nature of geriatric provision to be spread over a number of different hospitals and each of these has to be used with some degree of flexibility. Thus there is no absolutely constant pattern of practice. This is clear from the fact that the designated rehabilitation wards in this study received almost two-thirds of their patients direct from the community and only one-third on transfer from other wards, and the principal diagnosis in one-third of these cases was an acute medical condition indicating a need for investigation. These findings suggest that the wards were not functioning as pure rehabilitation wards (providing physical therapy after the acute stage has passed) but rather directly accepting patients whose breakdown had been precipitated by an acute medical episode. Thus many of the patients admitted to rehabili- tation wards required medical treatment and/or investi- gation as well as physical rehabilitation. The principal conditions requiring rehabilitation were, as might be expected, those sub-acute, chronic or com- plex disabilities such as stroke (27 per cent), fracture of the femur (11 per cent) and arthritis (10 per cent). The mean length of stay in rehabilitation wards is enormously variable, ranging from one month for patients admitted from home, to two and a half months for patients transferred from other units. This suggests that transfer from other units was for complex disabilities requiring the full skills of a multi-disciplinary team. Eighty per cent of the workload in these rehabilitation wards was for the age group in the population which is expanding most rapidly (i.e those of 75 years and over) and as many as 11 per cent of females were over the age of 90 years. This has clear implications for priorities in the development of future resources and emphasises the need for an increase in the number of therapists and others working with the elderly[2]. The rehabilitation programme was obviously successful for the majority of patients, since 69 per cent returned home and only 3 per cent required a hospital long-stay ward. Although this might have been due to selection of those with the most potential for discharge, it must be recognised that 12 per cent of patients died on the ward and a further 12 per cent required residential care, either in social service or private rest homes. The length of stay of those transferring to social service residential homes was 71 days?much longer than those going to private rest homes or to their own homes. While this may partly indicate increased disability among those going to resi- dential homes, it is just as likely to indicate a waiting list for that facility. Geriatric medicine, especially the rehabilitation com- ponent, might be expected to require continuous moni- toring. It is therefore of interest that no follow-up was arranged for 32 per cent of those discharged, although about one quarter continued their rehabilitation pro- gramme in the day hospital. Domiciliary rehabilitation services were rarely used. The chronicity and complexity of the patient's management is demonstrated by the fact that 8 per cent were scheduled for further readmission as 'relief' patients?usually to provide support for caring relatives. There is a major medical input into rehabilitation wards, one session of consultant time and 22 hours of SHO time being the the norm. From the variety of patients admitted and the fact that many of them were suffering from acute medical disorders, it would seem that these wards are appropriate for general medical training. This study demonstrated the complexity of geriatric rehabilitation management in an age group which is rapidly expanding in number. Acknowledgements We are grateful to the King's Fund for financial support, and to our colleagues who provided the information on which the study is based. References 1. Brocklehurst, J. C. and Andrews, K. (1985) Age and Ageing, 14, 1. 2. Andrews, K. and Brocklehurst, J. C. (1984) British Medical Journal, 289, 661. 242 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985

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Progress towards a Malaria Vaccine S. COHEN, CBE, MD, FRCPath, FRS Professor of Chemical Pathology, United Medical and Dental Schools, Guy's Hospital, London The failure of conventional prophylactic measures to control malaria in tropical and sub-tropical areas of the developing world has focused attention upon the great benefits that would accrue from the availability of effec- tive malarial vaccines. However, some features of ma- larial immunity, as it develops in its natural hosts including man, have long cast doubts upon the plausibil- ity of such a goal. Thus, in areas of sustained malaria transmission, clinical immunity develops slowly over perhaps a decade of repeated exposure to infection. In addition, the immunity achieved is incomplete in the sense that low levels of parasitaemia are seen intermit- tently in subjects who are clinically immune. Such obser- vations have suggested that malaria parasites may be antigenically diverse so that clinical immunity prevails only after exposure to a wide spectrum of antigenic variants. A high degree of variation within a given plasmodial species could seriously jeopardise attempts to develop malaria vaccines. However, certain features of acquired malarial immun- ity do encourage the hope of vaccine development. For example, immunoglobulin from immune African adults effectively clears parasitaemia from infected infants, in- cluding those resident in geographically remote areas. In addition, specific immunoglobulins can be shown to prevent, in vitro, the entry of sporozoites into liver cells and merozoites into red cells. As anticipated from such observations, both sporozoites and merozoites, appropri- ately inactivated, have provided the basis for stage specific vaccination against various species of experimen- tal malaria, including Plasmodium falciparum, the cause of malignant tertian malaria in man. But the large-scale production and standardisation of such vaccines is not practical. These difficulties have been circumvented by two major recent technological developments which have facilitated the production of vaccines comprising individ- ual antigenic constituents of malaria parasites. These are hybridoma technology for production of monoclonal anti- bodies, and gene cloning which permits the detailed characterisation and in vitro production of specific plas- modial polypeptide antigens with potential for inducing immunity to natural infection. These advances have rev- olutionised prospects for practical vaccine development. The Malaria Cycle More than 100 plasmodial species have been described, which cause malaria in a wide range of vertebrates and exhibit narrowly defined host specificity, only four species being naturally infective for man. Infection is initiated by the bite of a female anopheline mosquito which inoculates saliva containing sporozoites. These motile organisms, 11-12 /un long, are rapidly cleared from the circulation and initiate the tissue stage of primary exo-erythrocytic (ee) development, which in mammalian malarias is con- fined to liver parenchymal cells. Exo-erythrocytic forms become multinucleate and within about 10 days they rupture to liberate 100-30,000 ee merozoites. In some species, including P. vivax in man, ee forms may remain latent for several months before maturation. Blood infec- tion is initiated by merozoite invasion of red cells. This involves a sequence of random adherence to the erythro- cyte, attachment of the apical prominence of the mero- zoite to a specific red cell receptor and induction of endocytosis by the red cell. Intracellular growth proceeds through stages of ring, trophozoite and schizont and terminates with rupture of infected cells at 24-72 hour intervals, liberating 10-30 merozoites which initiate a further cycle of development. The clinical signs and symptoms of malaria are associated exclusively with cyclical blood stage development. After a period of purely asexual multiplication of erythrocytic parasites, a proportion of newly invaded merozoites differentiate into male and female gameto- J cytes. These mature without undergoing cell division over a period of about 10 days. When ingested into the mosquito stomach, the male (microgametocyte) under- goes exflagellation, liberating eight microgametes, and fertilisation occurs. The zygote differentiates in the wall of the mosquito gut and sporozoites finally accumulate in the insect salivary glands to complete the sexual cycle of development. Current attempts at prophylactic vaccine development are concentrated on two separate stages of the parasite, which induce stage-specific immunity. These comprise the sporozoite and the blood-stage mero- zoite. i Sporozoite Vaccines Natural sporozoite infection does not lead to acquired immunity in man or any experimental animal. However, the inoculation of sporozoites attenuated by irradiation does induce effective immunity in experimental rodent and human malarias; this protection is strictly stage specific and without effect upon the blood-stage of infec- tion. Sporozoites for vaccine preparation can be isolated 210 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 I from salivary glands of infected mosquitos by laborious dissection but a practical vaccine based on such material cannot be envisaged. The induction of stage-specific -> clinical immunity by attenuated sporozoites is neverthe- less of considerable interest and has stimulated attempts ' to identify protective sporozoite antigens. Monoclonal antibodies secreted by hybridoma cell lines 'recognise' an immunodominant surface antigen, the y- circumsporozoite (CS) antigen, which occurs in distinct but analogous forms in several species of plasmodia, including the human parasites P. falciparum and P. malariae. The protective nature of the antigen is indicated by the fact that specific monoclonal antibodies directed ,J, against it are able to neutralise sporozoite infectivity both in vitro and in vivo. The molecular structure of CS antigens has been established in two species by cloning the genes which control their synthesis. In the case of P. falciparum, the entire gene was isolated from a genomic DNA library and , shown to encode a protein, of 412 amino acids, which includes an unusual central region consisting of 41 tan- (, dem repeats of a tetrapeptide that constitutes the immun- odominant portion of the molecule. The simian parasite, P. knowlesi, has a CS antigen of analogous structure (Fig. 1) with a central segment of repeat sequences of a dodecapeptide. This peptide has been synthesised and, after attachment to a carrier protein, used to immunise. Although the vaccinated animals produced antibody reac- tive with the CS protein, there are no reports of induced protection against sporozoite challenge, probably because an essential component of immunity against exo-erythro- cytic stages of malaria may be cell-mediated and directed against parasites developing in hepatic parenchymal cells (Fig. 2). Thus most mice rendered B-cell deficient by repeated injection of anti-IgM serum can be successfully vaccinated with irradiated sporozoites; the failure of these immunised animals to produce measurable levels of 11, specific antibody indicates that cell-mediated effector mechanisms have a role in anti-sporozoite immunity. Effective vaccination may therefore require both the CS antigen to induce antibody which limits the number of IK sporozoites entering the liver, and other as yet unidenti- Tied antigen(s) which induce cell-mediated immunity against the developing hepatic forms of the parasite. Blood-Stage Antigens As the clinical manifestations of malaria are associated exclusively with the blood-stage of parasite development, this stage is a prime target for any malaria vaccine. Immunity to blood-stage infection does develop naturally after long and repeated exposure to infection and has been actively induced in experimental malarias by using isolated erythrocytic merozoites as vaccines. The develop- ment of more practical and refined vaccines is compli- C?terminal N?terminal Asn Anchor Charged Sequence Area Area of Degenerate Repeats? INTRAMOLECULAR TANDEM REPEATS 12 (Ala3, Gln3, Gly3, Pro, Asp, Asn) Met Charged Area Signal Sequence Fig. 1. Diagrammatic representation of the amino acid sequence of the P. knowlesi circumsporozoite protein deduced from the nucleotide sequence of the gene controlling its synthesis. The central region consisting of 12 tandemly repeated dodecapeptides constitutes the immunodominant region of the csp protein. Fig. 2. Immunity to the sporozoite stage of malaria infection probably requires induction of both antibody to the csp protein, which limits the number of organisms gaining access to hepatic parenchymal cells, and cell-mediated immunity which destroys intracellular exo-erythrocytic schizonts. L Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 211 cated by the considerable antigenic complexity of the erythrocytic parasite and the apparent absence of any immunodominant surface structure as seen in sporo- zoites. In addition, there is considerable antigenic diversi- ty of blood-stage plasmodia within a given species. The phenomenon of antigenic diversity can be illustrat- ed by the properties of a component found on the surface of schizont infected red cells in several species of malaria. This antigen, recognised by monoclonal antibodies, is synthesised late in the cycle of asexual blood-stage devel- opment as a high molecular weight protein (about 200 kD) and is localised on the surface of schizont infected erythrocytes. At the time of rupture of the parasitised red cell the protein is cleaved to a series of smaller peptides present on the surface of newly released merozoites. The protective role of this antigen is shown by the fact that monoclonal antibodies directed against it inhibit parasite multiplication in vitro and in vivo; in addition, vaccination with the antigen confers significant immunity in rodent malaria. Analysis of the antigen in different isolates of P. falciparum reveals that it contains a region of invariant structure while other portions of the molecule vary in different parasite strains. It is the variable part of the molecule which seems to be expressed on the red cell surface and it is this heterogeneity which seems likely to limit the value of the antigen as a potential vaccine component. Fortunately, other protective antigens of blood-stage parasites appear to have an invariant structure in all isolates of a given species. One such antigen (150 kD molecular weight) appears to be lodged in the membrane of ring-infected red cells during merozoite invasion. Antibodies reactive with this antigen inhibit parasite multiplication in vitro. Part of the gene controlling the synthesis of this antigen has been analysed and found to code for a series of repeat peptides enclosing a non- repeating amino acid sequence. This antigen remains invariant among geographically remote isolates of P. falciparum and therefore has considerable interest as a putative vaccine. However, its stability must be estab- lished by direct testing since another antigen found to be common to several strains of the simian parasite P. knowlesi underwent variation when subject to the immune pressure which followed its use as a vaccine. Apart from the complication of antigenic plasticity among malaria parasites, the development of blood-stage | vaccines may, as suggested above for sporozoites, require the induction not only of anti-merozoite antibody, but also of specific cell-mediated immunity active against intra-erythrocytic parasites (Fig. 3). Specific T-cells reac- tive with plasmodial antigens are known to stimulate macrophages to release such parasiticidal agents as tu- mour necrosis factor and oxygen-derived free radicals I, which can kill parasites developing within red cells. Such agents might be most effective when parasitised cells come in close contact with activated macrophages as would occur in the splenic circulation; this may explain the prime importance of the spleen in malarial immunity. >j The identification of blood-stage plasmodial antigens reactive with T-cells and able to induce cell-mediated effector mechanisms against intracellular blood-stage parasites, may ultimately be mandatory for successful vaccine development. Conclusion . Acquired immunity to malaria is stage and species specific; it depends in part upon antibodies that block sporozoite attachment to hepatocytes or inhibit merozoite invasion of red cells. Additional mechanisms, mediated by T-cells and macrophages, killing intracellular parasites through oxidative and other mechanisms, are involved in the maintenance of immunity. Some forms of experimen- tal vaccination, including the use of irradiated sporozoites * and non-viable extracellular blood-stage merozoites, in- duce effective immunity, but are impractical for mass human vaccination. The isolation of individual plasmo- dial antigens is currently being expedited by the use of I monoclonal antibodies and gene cloning techniques. Sporozoites of all species have a uniform (but unique) circumsporozoite protein which has the properties of a protective antigen. No comparable immunodominant protective antigen has been identified in blood-stage parasites, which are antigenically extremely complex. However, a variety of antigens with protective properties are being delineated; many of them are associated with mature schizonts and some appear in a partially degraded form on the surface of merozoites. This work has led to the cloning of several genes controlling the synthesis of protective polypeptide antigens, and is concentrated on those common to all strains of a given species. Some immunodominant antigenic peptides of these antigens have been synthesised and show promise as components of an ultimately practical and effective vac- cine against the exo-erythrocytic and erythrocytic stages of human malaria. The remaining areas of uncertainty in this endeavour concern the antigenic stability of individ- Fig. 3. Immunity to the blood-stage of malaria requires the presentation of antigens by accessory cells (A) to Tjj cells. These induce B-cells to make antibody which neutralises free merozoites and also activate macrophages (M<\>) to produce oxidative and other products, such as tumour necrosis factor, which kill intra- ervthrocytic parasites. 212 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 I I ual protective antigens when subject to immune pressure ?/ following vaccination and the requirement in any vaccine for T-cell reactive antigenic determinants able to induce cell-mediated immunity active against intracellular para- ) sites. r This article is based on a paper read at the Conference on Infectious Diseases held at the Royal College of Physicians in May 1985. References The following reviews provide the sources of original work quoted. 1. Allison, A. C. and Eugui, E. M. (1983) Annual Review of Immunol- ogy, 1, 361. 2. Cohen, S. (ed) (1982) British Medical Bulletin, 38, 115. 3. Cohen, S. and Cross, G. A. M. (eds) (1984) Towards the Immunologi- cal Control of Human Protozoal Diseases, p.213. London: The Royal Society. 4. Deans, J. A. and Cohen, S. (1983) Annual Review of Microbiology, 37, 25.

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The Protean Manifestations of Legionnaires' Disease M. A. WOODHEAD, MB, MRCP(UK), Research Registrar J. T. MACFARLANE, DM, MRCP(UK), Consultant Physician Department of Thoracic Medicine, City Hospital, Nottingham The nine years following the dramatic discovery of Legionnaires' disease (LD) in 1976 has seen a rapid growth in knowledge about the subject. The explosive outbreak in the Legionnaires in Philadelphia, the ubiqui- tous distribution of the organism in moist environments, its recognition in tourists returning from Mediterranean holidays, the apparent high mortality and the suggestion of a unique clinical picture all helped stimulate interest in the disease. The recent, severe outbreak of LD in Staffordshire, with over 160 people affected and at least 34 deaths, has shown that the disease is capable of presenting, even in Britain, as a major outbreak as well as the more usual sporadic, community-acquired cases that we are used to. Thus doctors everywhere need to be aware of both the common and and the less usual features of the infection. The disease is remarkable for the diverse nature of its clinical features which suggest multi-system involvement. Not uncommonly respiratory symptoms are minimal despite the principal pathological manifestation as pneu- monia. As with any 'new' disease, complications and unusual features are being reported increasingly often. We now know there are at least 10 species of legionella of which one serogroup, of one species, is responsible for the majority of infections, namely, Legionella pneumophila serogroup 1. Infection may occur in epidemic form, in endemic form or as sporadic cases. The disease may be community-acquired or nosocomial (hospital-acquired). LD is not uncommon and may account for up to 15 per cent of all community-acquired pneumonias in both the USA[1] and Britain[2], although there are regional vari- ations^]. This article sets out to describe the typical clinical features of LD and to review the recorded complications of the condition. Although there is relatively little experi- ence with infection caused by the other legionella species, available evidence suggests that the clinical picture is similar whichever organism is involved and by whichever means the disease is spread. For the purpose of this review all forms of the disease will be considered together. Typical Clinical Features (Table 1) Two distinct clinical syndromes are recognised. The best known is the classical pneumonic form of LD. The other Table 1. Features of Legionnaires' disease. System Common Features Unusual Features Respiratory Cough, dyspnoea, chest pain Progressive consolidation Slow X-ray resolution Cardiovascular Relative bradycardia Neurological Musculo- skeletal Renal Gastro- intestinal Drowsiness Confusion Retrograde amnesia Brain stem features Myalgia + weakness Hyponatraemia Uraemia Proteinuria + haematuria Diarrhoea Vomiting Abdominal pain Abnormal LFTs Hypoalbuminaemia Respiratory failure Pneumothorax Cavitation T achyarrhythmias Myocarditis Pericarditis + effusion Endocarditis Guillain-Barre Peripheral neuropathy Meningitis Rhabdomyolysis Arthritis Acute renal failure Pyelonephritis Paralytic ileus Gut perforation Jaundice is the non-pneumonic form"known as Pontiac Fever[4], In addition, asymptomatic seroconversion to legionella has been recorded[5], but its prevalence is not known. Legionella Pneumonia In classical LD the initial, non-specific symptoms of anorexia, malaise, chills, headaches and myalgia usually appear after an incubation period of two to 10 days[6]. Although rhinorrhoea and nasal congestion have been reported[7], symptoms referrable to the upper respiratory tract are uncommon. Cough, which is initially unproduc- tive, appears in the first few days in 80-90 per cent of cases. Sputum production occurs in only 50 per cent and may be mucoid or purulent. Haemoptysis may occur in up to one-third of cases at some time in their illness. Dyspnoea and chest pain, which is often pleuritic, are found in one- to two-thirds of cases. 224 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 ! I J j Frequently it is the non-respiratory features of the 'j ' illness that attract most attention. Gastrointestinal symp- \ , toms are common, with diarrhoea in up to 50 per cent, nausea and vomiting in up to one-third and abdominal pain in about 20 per cent of patients. Diarrhoea, which may be the presenting symptom, is usually watery and not associated with the passage of pus or blood. Involve- ?- > ment of the central nervous system is also common, up to ; , 50 per cent of patients having neurological symptoms. ' Confusion, lethargy and stupor are quite common, hallu- cinations and agitation being recorded occasionally. Later in the illness retrograde amnesia is often apparent. - _ Fever is an almost universal finding. Initial tempera- ture rise is in a stepwise fashion, very high temperatures often being reached. Up to 90 per cent of patients will have a temperature in excess of 38.9?C and up to two- \ . thirds may have temperatures of over 40?C. Despite the high fever tachycardia is only present in about one-third of patients[7]. The relative bradycardia seen in the majority of patients has been suggested to be characteris- tic of, though not specific to, LD. Skin rash, unless related to therapy, is exceptional, but herpes labialis may ^ If occur. Only about 20 per cent of patients will have classical signs of pulmonary consolidation, but nearly all will have focal crepitations and 50 per cent will have rhonchi. The respiratory rate is usually elevated; 42 per cent had ^ . respiratory rates over 25/minute in the 1976 epidemic[6]. A pleural rub is occasionally noted and pleural effusions may occur but are seldom clinically detectable. The abdomen is usually unremarkable and, although localised tenderness may occur in up to 25 per cent, signs of peritonism have only been recorded when there is an adequate alternative explanation such as coincident ap- pendicitis^]. * Pontiac Fever Few outbreaks of Pontiac Fever have been reported. They are usually epidemic and a common source is often identifiable. Usually there is a 95-100 per cent attack rate in exposed individuals. The illness is 'flu'-like, with a short incubation period of 36 hours followed by fever, chills, headache and myalgia.. Diarrhoea, arthralgia, . dyspnoea and dry cough may occur. The chest radio- graph is always normal. The illness is usually self- limiting, lasting about five days. Complications have not been recorded. Why legionella infection produces Pontiac \ Fever in some individuals and pneumonic LD in others is not known. In one common source outbreak both pat- l - terns of illness were found[9], | Laboratory Findings Leucocytosis is common at presentation with 50-75 per / ? cent[6,7,10] of all patients showing a total white cell count t - of over 10,000/^1 and between one quarter and one half over 15,000/^tl. The elevated white cell count is due to a neutrophilia which is usually accompanied by a left shift. Lymphopenia (< 1,000/yu.l) may occur in one half to two- thirds of patients[7,l 1], High ESR occurs frequently, being greater than 60 mm/hour in two-thirds of patients[6]. Platelet counts are usually normal. One half to two-thirds of patients are hyponatraemic (<130 mMol/litre) at presentation. Although in some cases this may be due to the syndrome of inappropriate ADH secretion[7], in the majority hypovolaemia appears to be responsible[12,13]. This may also contribute to the elevation of serum urea and creatinine found in 50 per cent of patients[10], frank renal failure being uncommon. Proteinuria is a common finding and occurs in about half of all patients; haematuria may also occur in 30-50 per cent, although it was not noted in any of 65 patients in one series[7]. Derangement of liver function is also a common find- ing, 50-75 per cent of patients having elevated liver enzyme levels. In addition, hypoalbuminaemia occurs in up to two-thirds[10]. Hypophosphataemia may also be found in up to half of all cases[7]. Sputum, when present, is usually mucoid and contains scanty inflammatory cells. Gram staining is unable to distinguish legionella from normal oropharyngeal com- mensal organisms. Pleural fluid usually shows features of an exudate and may contain large numbers of polymorphonuclear leuco- cytes. Radiology There are no unique radiological features of LD although it does differ in some respects from other pneumonias. Consolidation is evident on the chest X-ray at presen- tation in at least 90 per cent of patients[10]. As with other pneumonias, involvement of the lower lobes is most frequent. Consolidation may be patchy or homogeneous, segmental or lobar. In some cases small well-circum- scribed areas of shadowing may occur, giving a nodular appearance[6]. In two-thirds to three-quarters of cases changes are confined to one lobe, but as many as one- third may develop bilateral changes[6,14]. Unlike other pneumonias radiographic deterioration is common in LD. Progression of X-ray changes may be seen in up to 65 per cent of cases[14,15], occurring over two to five days. Spread may occur within the same lung or to the opposite lung and may continue despite appro- priate antibiotic therapy and clinical evidence of improve- ment in the patient's general condition. Pleural effusions are quite common, occurring in one- to two-thirds of cases[16], more being detected when lateral decubitus X-rays are routinely performed. Typi- cally these are small. In a few patients pleural effusion may precede parenchymal changes by two to seven days. Muder et al. [17] describe a patient, without parenchymal consolidation, but with bilateral pleural effusions from both of which L. micdadei was isolated. Although hilar gland enlargement is often seen at postmortem[18,19], it is seldom detected radiologically. Complete lobar collapse is uncommon[20], but some degree of collapse may be seen in about one-third of patients[15]. Although in one series 75 per cent of patients showed radiographic resolution by two months[16], the hallmark of most series has been the very slow resolution of Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 225 radiographic changes. Radiographic resolution is slower than for all other pneumonias, with 50 per cent of cases still showing abnormalities at three months[15], The series showing relatively rapid resolution of radiographic changes was of a nosocomial population in whom the illness was detected very early, with most patients receiv- ing prompt erythromycin treatment, and may therefore not be representative. In a number of patients complete radiological resolution does not occur, linear streaky opacities remaining in up to one-third and pleural shad- ows in some. Complications Pulmonary Respiratory insufficiency is common, the majority of patients requiring supplemental oxygen[6]. Respiratory failure of sufficient severity to require assisted ventilation occurs in up to 20 per cent of cases. The mortality in these patients is very high. Of the patients ventilated in the Philadelphia epidemic, 68 per cent died[6] and in a study of nosocomial LD 82 per cent of those ventilated died[7]. In our hospital, of 14 patients ventilated for sporadic, community-acquired LD, the mortality was only 36 per cent, suggesting, perhaps, that the prognosis in this group may be better[21]. Pulmonary cavitation is uncommon, being found in only 1-4 per cent of cases in most series[10,15,22], although in one small series from Holland it was recorded in 20 per cent[23]. Pulmonary cavitation is usually found in immuno-compromised patients, but may also occur in the immuno-competent[24,25]. Cavitation occurs within the area of previous consolidation and more commonly affects the upper lobes, although other lobes may be affected[26]. Cavities may be single or multiple, unilater- al or bilateral[26] and may be complicated by pneumo- thorax[27,28]. Treatment may be followed by complete resolution of cavities[29], persisting lung cysts[26], or in a number of cases, progression to pulmonary fibrosis[25]. In one case cavity formation was followed by total destruction of the whole lung[27]. In some cases other pathogens, capable of causing lung necrosis, have been isolated and may have been responsible for the cavitation. However, a number of well documented cases have now been reported in which legionella was the only organism found. Prolonged carriage of both L. pneumophila]?)^] and L. pneumophila with L. micdadei[26] has been noted in patients with cavitary LD, which suggests that prolonged antibiotic treatment may be necessary in such cases. Empyema has been reported in association with legionella infection[31,32], but must be very uncommon. Relapses of LD over days[26] or months[33] have been recorded. The former is presumably due to inadequate antibiotic treatment, but the latter may conceivably be due to recurrent re-infection. Destruction of alveolar spaces and healing by fibrosis are prominent histological features in LD and led to fears that severe LD might cause persisting lung damage. The majority of patients make a complete recovery from the acute illness and although, as already noted, up to one- third may have persisting radiographic abnormalities, there is little evidence to suggest that the changes are functionally significant. A reduction in transfer factor was noted in nearly 50 per cent of a small group of patients studied two years after the Philadelphia outbreak[34]. Some of these patients complained of effort dyspnoea, but whether this was related to the reduced diffusing capacity is not known. Shaw et al. [35] studied two patients ventilated during their acute illness. Ten weeks after the acute episode, lung volumes were normal and transfer factor was only marginally reduced, despite one patient having persisting radiographic changes. Cardiovascular A relative bradycardia is a common early finding in LD. Arrhythmias may also occur and are usually supraven- tricular in origin[7,36,37]. Sudden, unexpected cardiac arrest has been noted in some series[7,21,38], These episodes may be secondary to myocardial damage or may result from involvement of cardioregulatory centres in the brain stem. Myocardial damage is well documented and may be part of the generalised muscle necrosis seen in some patients (see later) or may result from an inflamma- tory myocarditis. Inflammatory infiltrates have been shown in the heart at postmortem[39], and L. pneumo- phila has been demonstrated in myocardium by immuno- fluorescent methods[40]. Gross[41] described an otherwise fit 51-year-old woman with typical pulmonary LD complicated by transient myocardial dysfunction as shown by electrocardiographic changes and the develop- ment of congestive cardiac failure. Cardiac specific cre- atine phosphokinase was elevated and thallium perfusion scanning showed patchy defects in the myocardium. She also had evidence of generalised skeletal muscle damage. Features suggesting myocarditis, in the absence of pneu- monia, have also been described in three children who showed seroconversion to L. pneumophila[^2]. Shock may result from primary myocardial dysfunction or from peripheral vasomotor collapse. It is uncommon in LD and is associated with a poor prognosis. Recurrent epi- sodes of shock, associated with relapses of LD, were described in one patient[26]. A number of cases of pericarditis, in the absence of uraemia, have been described in association with LD. This has been complicated by effusion, which may be sufficiently large to cause tamponade[37,43-45], or may just be an incidental finding at postmortem[46]. One patient, who developed constrictive pericarditis three months after legionella pneumonia, had received medias- tinal irradiation for Hodgkin's disease 17 years be- fore[44]; pericardial fibrosis is a known complication of mediastinal irradiation[47], L. pneumophila has been iso- lated from pericardial fluid[37], but has not been docu- mented within the pericardium itself. Endocarditis has been reported only once[48]. In this case prosthetic aortic and mitral valves were infected in the absence of pneumonia. L. pneumophila was grown from vegetations after removal of the damaged pros- theses. The patient made a complete recovery. Infection of native valves has not been recorded, but one case had 226 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 features very suggestive of endocarditis with persistent symptoms that resolved only after prolonged, parenteral erythromycin therapy[45], This case was also remarkable for the recurrence of pericarditis after seven months. Two cases of arteriovenous fistula infection with L. pneumophila following pneumonia have been de- scribed^], but no other peripheral vascular complica- tions have been reported. Not surprisingly, deep venous thrombosis and pulmonary embolus have been noted ' following LD[50,51], Neurological A mild and reversible encephalopathy occurs in up to 50 per cent of patients with LD. A number of neurological complications involving both central and peripheral ner- vous systems have also been recorded, some of which appear to be irreversible. The brain stem and cerebellum are the most frequently involved parts of the central nervous system. Weir et al. found cerebellar disturbance in 50 per cent of 27 patients with LD compared with only 5 per cent in non-legionella pneumonia[52]. Typical * < features include dysarthria, ataxia, gait disturbance and a " falls, nystagmus and gaze palsies[36,38,51-55]. Legion- ella infection may cause acute reversible cerebellar dis- A turbance in children in the absence of pneumonia. Nigro et al. found serological evidence of legionella infection in j , 25 per cent of children with acute cerebellar ataxia, all of whom showed complete recovery[56]. In adults cerebellar disturbance may persist and be debilitating. One patient with persisting ataxia had evidence of cerebellar atrophy on CAT scan three years after the original infection[52]. Features of encephalomyelitis leading to coma, hemi- paresis or paraparesis have been described in some cases[36,52,57-60]. Although some recovery has oc- curred in these cases many of the changes have been ! permanent. Loss of memory for the acute illnesss is common, but in some cases a permanent defect in short- term memory may result[36,53]. Other central nervous abnormalities recorded include epileptic fits[6,58], in one case in the absence of pneumonia[61], chorea[55], papil- loedema[62] and isolated cranial nerve palsies[54,59,63]. Two distinct forms of peripheral nervous system in- volvement have been described. A typical Guillain-Barre syndrome may occur, with progressive weakness, sensory loss, areflexia and bulbar involvement[64]. In addition, there may be a predominantly motor neuropathy with electrophysiological changes suggestive of an axonal neuropathy[52]. One reported case showed progression from isolated weakness of one limb to almost complete i quadriplegia within 16 hours[65]. Nine months later i K there had been only minimal improvement. Subclinical neuropathy may be common. Weir et al. [52] found evidence of an axonal neuropathy in all six patients studied, none of whom had symptoms of neuropathy. In one case the electrophysiological changes were still present after seven years. Involvement of the peripheral | nervous system may occur in isolation or with central nervous system involvement. The cerebrospinal fluid (CSF) is usually normal unless signs of meningitis[57,66], encephalomyelitis or Guillain- Barre syndrome are present. Only one of 10 lumbar punctures done in the Philadelphia outbreak showed any CSF abnormality[6], As with other causes of Guillain- Barre syndrome the CSF abnormality is an isolated elevation in protein content with no excess of cells. In meningitis, which is very rare in LD, and encephalomye- litis, both lymphocyte and neutrophil leucocytosis in the CSF have been described, in addition to the raised protein content. Legionella organisms or antigen have not been detected in the CSF but both have been demonstrated within the substance of the brain[58,67,68]. The electro-encephalogram is frequently abnormal but the changes reported have been non-specific and compati- ble with toxic damage to the brain[58]. Of 17 CAT scans performed in patients with LD, 12 were normal, three showed non-specific changes, one showed ventricular enlargement[58] and one cerebellar atrophy, as already described. Musculoskeletal Although myalgias and weakness are common symptoms in LD and mild elevations of muscle enzymes are fre- quently seen, there is not a close correlation between symptoms and enzyme levels. A raised serum creatine phosphokinase (CPK) may occur in up to 78 per cent of cases compared to only 24 per cent in other pneumo- nias[69], although there is some evidence that elevated CPK occurs as frequently in other severe pneumo- nias[70]. A number of cases of acute rhabdomyolysis have been described, associated with massive elevation of skeletal muscle-specific CPK (to more than 400,000 iu/litre in one case), myoglobinuria and acute renal failure[71-74]. Rhabdomyolysis in the absence of renal failure may also occur[46]. Myalgia and weakness occurred in the ma- jority of these cases, but muscle tenderness was noted in only one[73]. Pathologically extensive rhabdomyonecro- sis is found with an associated acute inflammatory infil- trate, but no evidence of vasculitis[4Q], The majority of patients developing renal failure had CPK levels of more than 10,000 iu/litre, but in one case the CPK level was only 3,300 iu/litre[71]. The mechanism of rhabdomyolysis in LD is unknown. As legionella organisms have not been found in skeletal muscle, a toxin may be responsible. High fever, a common feature of LD, may precipitate rhabdomyolysis on its own and another frequent accompaniment of LD, hypophosphataemia, may predispose to or be a cause of rhabdomyolysis[75]. Other than arthralgia, joint manifestations are seldom seen in LD, but one case of acute arthropathy associated with LD[76] may have been due to a coincidental onset of rheumatoid arthritis. Renal Frank renal failure, although rare, is a well recognised complication of LD with a significant influence on out- come. No cases of acute renal failure were seen in one Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 227 review of 65 nosocomial cases[7], but in a study of sporadic LD 13 per cent were recorded as requiring dialysis[77], In the Philadelphia outbreak 14 cases (11 per cent) were noted to have renal failure with oliguria or anuria, of whom three required dialysis. The mortality of these 14 patients was 79 per cent[6]. A number of pathophysiological processes may be responsible for renal failure in LD. Acute tubular necrosis is probably the most common cause of the renal fa.il- ure[78-80] and is usually secondary to hypotension. Twelve of the 14 patients described above had hypoten- sion and shock. Nonetheless, renal impairment was noted in six before the hypotensive episode. Acute renal failure associated with features suggesting glomerulonephritis has been recorded[81] and a number of cases of tubulo- interstitial nephritis has been reported[82], in one case associated with disseminated intravascular coagu- lation[80]. Renal failure associated with thrombotic thrombocytopenic purpura has also been reported in LD[83], It is not known whether nephritis develops as a result of direct bacterial invasion of the kidney, as has been demonstrated at postmortem[18], or is the result of a circulating toxin. Rhabdomyolysis and myoglobinuria as a cause of renal failure in LD have already been men- tioned. In patients recovering from acute renal failure associated with LD renal function usually returns to normal, but persisting renal impairment has been report- ed^]. Legionella infection is a not uncommon cause of pneumonia in renal transplant recipients and has been associated with transplant rejection. In one series rejec- tion necessitating transplant nephrectomy occurred in 50 per cent of legionella infections[7]. In addition to demonstration of the organism of LD in the kidney at postmortem one case has been reported with pyelonephritis[85]. However, the exact role of legionella in this episode is not clear, as another organism was also present but the tissues were not cultured. Gastrointestinal Despite the frequency of gastrointestinal symptoms in LD, more serious complications related to this system have seldom been reported. Diarrhoea, so often a pre- senting feature, usually settles in a few days as the pneumonia is treated. Occasionally diarrhoea may persist for several weeks[41] and be associated with histological features of a non-specific proctitis (Woodhead, unpub- lished observations). Colonic involvement is further sug- gested by the occasional reports of paralytic ileus[6,26]. In one case acute peritonitis developed as a result of multiple caecal perforations[86], Immunofluorescent staining of the specimen removed at colectomy showed intact legionellae within the bowel wall. Acute gastric perforation[18] and acute appendicitis[8] have also been associated with LD. One case of perirectal abscess has been reported from which L. pneumophila serogroup 3 and multiple anaerobic organisms were isolated. The patient had pneumonia that was also shown to be due to L. pneumophila serogroup 3[87]. Jaundice is uncommon both in patients with previously normal liver function[36,41,83,88] and in those with chronic liver disease[89], Acute liver failure has not been reported. Legionella organisms have been detected in the liver at postmortem[90] and one case has been described of pyrexia of unknown origin associated with hepatic granulomata (but no pneumonia) and rising antibody titres to L. pneumophila serogroup 1 [91]. Acute pancreatitis associated with legionella pneu- monia has been seen in one case in life[92], but has also been noted at postmortem[18]. The finding of elevated urinary amylase levels in 16 patients in one series suggests that asymptomatic damage may be quite common[93]. Reticulo-endothelial Legionella organisms have been demonstrated in liver, spleen, bone marrow and lymph nodes at postmor- tem^,90], Three-quarters of patients showed splenic enlargement and one quarter of patients showed organ- isms in the spleen[18]. Clinically detectable splenomegaly has not been described. Legionella has also been detected in bone marrow aspirates during life[89]. Pancytopenia has been noted in LD[18,94] and in one case was associated with marked reticular fibrosis in the bone marrow with many free and intracellular organisms[18]. In the Philadelphia outbreak one patient with an isolated leucopenia and two with thrombocytopenia were not- ed^]. Thrombocytopenia has been seen in isolation[51], associated with disseminated intravascular coagu- lation[61,80] and with thrombotic thrombocytopenic pur- pura and renal failure[83]. Autoimmune haemolytic anaemia has been recorded in two cases[6,88], one of which received steroid therapy. Cold agglutinins are not usually found in significant titres[7]. Although lymph node enlargement, both within and outside the thorax, may be common at postmortem, being found in nearly half of the cases studied[18], clinically detectable lymphadenopathy is rare. Miscellaneous Skin rash in LD is rarely recorded. Erythema multiforme has been described in a three-year-old boy with legionella pneumonia[95]. A painful macular erythematous rash, confined to the lower leg, was described in a 46-year-old man with LD[96], In addition, a local erythematous eruption, in one case progressing to pustule formation, was described in the two cases with infected arteriovenous fistulae[49]. Retinal changes have been described in one patient with LD, but these may have been secondary to endocar- ditis[45]. Comment The pathogenesis of the widespread effects of legionella infection is not known. Direct bacterial invasion, circulat- ing toxins, immunologically mediated damage or a com- bination of these are the most likely mechanisms. There is little current evidence for the involvement of an immuno- logical process. A number of toxins, both exotoxins and a 228 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 weak endotoxin, have been associated with legionel- lae[97], but these are unlikely to be sufficiently potent to produce such distant effects. Dissemination of legionella organisms has been demon- strated on a number of occasions. The organisms have been cultured from lung, blood[98,99], brain and liver[68], pleural[17] and pericardial fluids[37], perirectal abscess[87] and an excised prosthetic mitral valve[48]. Routine histological stains have revealed organisms in lung[ 18,40], pleura[32], kidney[32] and brain[58] and, with immunofluorescent staining, lymph nodes, spleen, bone marrow[18,89], colon[86], myocardium[40] and arteriovenous fistulae[49] have also been shown to con- tain legionella organisms. Of commonly affected tissues only skeletal muscle, skin, pancreas and cerebrospinal fluid have so far failed to yield either legionella organisms or antigen. Clearly, direct spread of the organisms may occur, but the high frequency of immunosuppressed patients in the studies so far performed and the rarity of blood culture isolation suggests that dissemination may only occur in exceptional circumstances or as an agonal event. Despite the growth in our knowledge of LD in the last nine years there remains much to be learnt about this fascinating disease. Analysis of information from the Staffordshire outbreak will certainly be of immense inter- est. Acknowledgements We would like to thank Ms P. Heatley and Ms J. Galletti for typing the manuscript. This article is based on a paper read by Dr Macfarlane at the Conference on Infectious Diseases held at the Royal College of Physicians in May 1985. References 1. Yu, V. L., Kroboth, F. J., Shonnard, J,. Brown, A., McDearman, S. and Magnussen, M. (1982) American Journal of Medicine, 73, 357. 2. Macfarlane, J. T., Finch, R. G., Ward, M.J. and Macrae, A. D. (1982) Lancet, 2, 255. 3. 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M., Bird, T. J., Daugirdas, J. T., Fruin, R. C., Shawkey, M. M. and Ing, T. S. (1981) Canadian Medical Association Journal, 125, 1084. Watts, J. C., Hicldin, M. D., Thomason, B. M., Callaway, C. S. and Levine, A. J. (1980) Annals of Internal Medicine, 92, 186. Gump, D. W. (1982) Scandinavian Journal of Infectious Disease, 14, 75. Gordon, V. and Zmyslinski, R. W. (1980) Military Medicine, 145, 345. Nordstrom, K., Kallings, I., Dahnsjo, H. and Clemens, F. (1983) Scandinavian Journal of Infectious Disease, 15, 43. Hajiroussou, V. J. and Joshi, R. C. (1980) British Medical Journal, 280, 366. Andersen, R., Bergan, T., Halvorsen, K., Kalings, I. and Orsta- vik, I. (1981) Acta Paediatrica Scandinavica, 70, 427. Helms, C. M., Johnson, W., Donaldson, M. F. and Corry, R.J. (1981) Journal of the American Medical Association, 245, 1758. Baskerville, A. (1984) In Legionella: Proceedings of the Second Inter- national Symposium, p. 136. (ed C. Thornsberry, A. Balows, J. C. Feeley and W. Jakubowski.) American Society for Microbiology. Edelstein, P. H., Meyer, R. D. and Finegold, S. M. (1979) Lancet, 1, 750. Macrae, A. D., Greaves, P. W. and Platts, P. (1979) British Medical Journal, 2, 1189. I 230 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985

PMC005xxxxxx/PMC5371101.txt

Book Review Microcomputers in Clinical Practice by D. E. Norris, C. E. Stilbeck, A. E. Hayworth and D. M. Torpy. John Wiley and Sons, Chichester, 1985. 159 pages. Price ?7.90. Physicians who feel inadequate when the conversation in the staff lunch room turns to computers can remedy their perceived deficiency, painlessly, by reading this book. In providing an admittedly superficial overview of the appli- cation of computers to medicine, it inevitably deals with ' \ no subject in any depth. It does, however, provide some detailed information about sources of medical software and how to make a customised keyboard designed for an Apple or Pet computer, and there is an optional compan- ion floppy disc containing demonstration programs, a statistical package and data handling programs (cost ?35 and available for use on Apple II or lie and Commodore Pet computers). Peter A. Emerson I t Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 217

PMC005xxxxxx/PMC5371104.txt

Toxic Shock Syndrome ROGER FINCH, MB, MRCPath, FRCP* Consultant and Senior Lecturer in Microbial Diseases MICHAEL WHITBX MB, FRACR FRCPA, Senior Registrar The City Hospital, Nottingham Staphylococcal scarlet fever, recognised in 1927, is char- acterised by toxaemia, a generalised erythematous rash and subsequent desquamation. In 1978 Todd et al.[ 1] described a 'new' disease in children in which fever, myalgia, erythema and desquamation were associated with Staph, aureus infection. They coined the term Toxic Shock Syndrome (TSS). Subsequently this pattern of disease was described in healthy young women in the USA. Extensive controlled epidemiological investigations later identified the association of TSS with menstruation, tampon usage and the presence of Staph, aureus in the genital tract. Epidemiology Since 1979 more than 2,500 cases of TSS have been reported in the USA. Of these, 96 per cent have been females, of whom 95 per cent have been associated with menstruation and tampon use[2]. The number of cases reported since 1980 has declined and this is attributable to a decrease in retrospectively reported cases and possibly to changes in the pattern of tampon manufacture and usage, following the publicity associated with this syn- drome. It is interesting to observe that eight states contributed more than 60 per cent of cases reported in the USA[3], This may also reflect differences in population immunity, prevalence of toxin-producing staphylococci or, more likely, the intensity of interest and surveillance. The prevalence of TSS in the USA far exceeds that in any other country, including Canada. Cases have been recognised in Western Europe and Australasia, but have not yet been reported in developing countries. Up to April 1984, only 88 confirmed or probable cases meeting the definition of the Center for Disease Control (CDC) had been identified in the UK. All but 15 were associated with menstruation. This incidence in the UK is much lower than that in the USA and may reflect a true lower frequency, reduced tampon usage or failure to recognise the syndrome. Non-menstrual cases account for about 13 per cent of those reported in the USA[2,4]. The mean age for menstrual TSS is 22.6 years, 65 per cent of diagnoses being made in women under 25 years, although only 45 per cent of tampon users are in this age group. Non- menstrual TSS patients tend to be slightly older, reflect- ing the greater age distribution of post-partum and post- surgical cases. Racial differences have been recognised in the USA, 96 per cent of menstrual cases occurring in whites, who represent 83 per cent of tampon users[5]. Clinical Features TSS is a multi-system disease with a wide range of symptoms and signs. There is at present no specific laboratory test and diagnosis is based on clinical features. The criteria of the widely accepted definition, formulated by the CDC in 1979[6] and subsequently modified to include orthostatic syncope and patients with staphylo- coccal bacteraemia[3], are summarised in Table 1. Menstrual TSS Prodromal symptoms may occur and include malaise, myalgia, low grade fever, vomiting, diarrhoea and va- ginal discharge. However, in many instances the onset is abrupt, with fever, rigors, myalgia, pharyngitis, conjunc- tivitis, severe hypotension, vomiting, diarrhoea and gen- eralised skin rash[7,8]. Headache and abdominal tenderness may also occur. The findings on the skin and mucous membranes are among the most characteristic of the disease. The rash occurs early and is usually diffuse, erythematous and blanches on pressure. There may be quite marked oedema of the face, limbs and perineum. A petechial rash may also develop in response to thrombocytopenia or disseminated intravascular coagulation. About 5-10 days into the illness, a discreet maculo-papular rash may develop and be mistaken for a drug eruption. Mucosal abnormalities are common, with conjunctivitis, pharyn- gitis, 'strawberry tongue' and vaginal hyperaemia. There may be multiple punctate ulcers of the cervix and vagina. Desquamation occurs in half the patients 1-2 weeks after onset of the illness but may be delayed for up to 21 days. It predominantly affects the palms and soles, especially around the nails, but may be generalised. Delayed loss of nails and hair may also complicate severe disease. Vomiting and effortless watery diarrhoea occur in "Correspondence to: Dr R. G. Finch, FRCP, Department of Microbial Diseases, The City Hospital, Nottingham NG8 2FX. Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 * 219 K. Table 1. Case definition, toxic shock syndrome. (Revised by the Center for Disease Control, 1982.) Fever Rash Desquamation Hypotension Multi-system involvement Gastrointestinal: Muscular: Mucous membrane: Renal: Hepatic: Haematological: CNS: Other conditions should be excluded 2s 38.9?C (102?F) Diffuse macular erythroderma 1?2 weeks after onset of illness Systolic BP <90 mmHg or orthostatic hypotension >15 mmHg or orthostatic dizziness Three or more of the following: vomiting or diarrhoea severe myalgia or t CPK x 2 normal vaginal, oropharyngeal or conjunctival hyperaemia urea or creatinine T x 2 normal or >5 WBC/HPF in urine total bilirubin, AST, ALT T x 2 normal platelets < 100 x 109/litre disorientation or altered consciousness without focal neurology almost 90 per cent of patients at onset. There is genera- lised abdominal tenderness, frequently accompanied by guarding and reduced bowel sounds, but without re- bound tenderness. Although often severe, these symp- toms generally subside within 72 hours. Diffuse myalgia and muscle weakness are common and many patients complain of exquisite skin and muscle tenderness when touched or moved. Arthralgia, sterile joint effusions and low grade synovitis are uncommon. Hypotension and profound shock are cardinal features of TSS and may be associated with electrocardiographic abnormalities such as conduction defects and ischaemic changes. Acute oliguric renal failure may complicate the presence of profound hypovolaemic shock. Pulmonary oedema is common and may be associated with haemop- tysis or the adult respiratory distress syndrome; head- ache, confusion, irritability, aggression, hallucinations and photophobia may be prominent. The CDC definition was restrictive to provide epidemi- ological homogeneity in case-controlled studies. Many patients do not show the full features of this definition. Such cases are in general milder, and often without significant fever, erythema and shock[9,10], Non-Menstrual TSS TSS has complicated a variety of medical and surgical conditions in non-menstrual females, males and children, but is rare under the age of 10 years[2]. The non- menstrual variant shows the same clinical features as the menstrual form and is broadly divided into three categor- ies of staphylococcal infection: (i) associated with abortion or childbirth in which it may complicate both Caesarean and vaginal delivery; (ii) associated with cutaneous or subcutaneous infections including surgical wounds, ab- scesses, cellulitis, fasciitis, burns and secondarily infected herpes zoster, and (iii) a smaller heterogeneous group complicating deep-seated infection such as osteomyelitis, endocarditis, pneumonia and empyema[5]. Laboratory Findings A broad range of laboratory abnormalities is recognised and reflects widespread tissue ischaemia of various organs rather than the direct effect of a toxin. Frequently reported abnormalities include neutrophilia, profound lymphopenia, normochromic normocytic anaemia and thrombocytopenia. Changes in coagulation include pro- longed prothrombin and partial thromboplastin time and may presage disseminated intravascular coagulation[7], Renal involvement is reflected in oliguria, raised serum urea and creatinine, trace proteinuria and sterile pyuria[ll]. Elevated liver enzymes and bilirubin are common although frank jaundice is rare. Electrolyte abnormalities may include hyponatraemia, hypokale- mia, hypophosphataemia and hypocalcaemia which in part may be secondary to raised calcitonin levels[12]. Elevated creatinine phosphokinase concentrations are proportional to skeletal muscle involvement. Cervical and vaginal cultures will yield Staph, aureus in most menstrual cases [10], while in non-menstrual cases a focus of sepsis should be sought. Although no specific diagnostic test for TSS exists, the demonstration of toxin production by isolates together with a characteristic his- tory or progression to desquamation is strong evidence for the diagnosis. The absence of detectable antibody to toxin in the convalescent phase is also consistent with the syndrome[13]. Differential Diagnosis The differential diagnoses vary both with the predomi- nant organ system involved and geographically. The variety of differential diagnoses in the UK is listed in Table 2. Treatment i! The immediate management is directed towards the >' restoration of circulating blood volume and the mainten- ance of adequate tissue perfusion. Electrolyte solutions, colloids or whole blood are appropriate. Large volumes may be required in combination with vasopressor agents. Hypoxaemia should be reversed and may require mech- anical ventilation. The requirements for haemodynamic monitoring, mechanical ventilation, as well as the arrest of bleeding by infusing platelets and fresh frozen plasma can more easily be managed in an intensive care setting. 220 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 Table 2. Differential diagnosis of toxic shock syndrome Exanthematous conditions Drug eruptions Erythema multiforme Streptococcal scarlet fever Leptospirosis Meningococcaemia Toxic epidermal necrolysis Staphylococcal scalded skin syndrome Kawasaki disease Gastrointestinal conditions Infectious gastroenteritis Staphylococcal food poisoning Miscellaneous conditions Septic shock Systemic lupus erythematosus Pelvic inflammatory disease Haemolytic-uraemic syndrome Acute pyelonephritis f1 Tampons should be removed in menstrual cases. The value of antiseptic vaginal douches has not been assessed in a controlled manner. In non-menstrual cases, the focus of infection should be sought and the need for surgical debridement or drainage assessed. Antibiotics are indi- cated to eliminate the source of toxin production and to prevent recurrent disease; their use probably does not reduce the duration of the acute illness[9]. As most ' - staphylococci implicated in TSS produce (3-lacta- mases^ 4], flucloxacillin is an appropriate choice. Dur- ation of treatment has not been established in controlled <. trials, although a course of less than 10 days does not consistently eradicate colonising staphylococci. The place of corticosteroid therapy is not established, although anecdotal reports suggest that early adminis- tration reduces both height and duration of fever, together with the degree and distribution of erythroderma - and subsequent desquamation[15]. Once life-threatening complications are controlled, im- provement is usually rapid, with dissolution of fever within 72 hours, and the rash and myalgia over the course of 5-10 days. Laboratory abnormalities similarly return to normal. Prolonged sequelae are rare, although muscle weakness, myalgia, impaired memory and concentration may persist[ 16]. Mortality ranges from 2-13 per cent, but has shown a progressive fall each year since the description of the syndrome[2]. This may be attributed to a greater number of fatal cases reported retrospectively in the early years, or to the more rapid recognition and treatment of the l <? condition as physicians have.become aware of the syn- drome. Death may result from refractory cardiac arrhyth- mias, adult respiratory distress syndrome, pulmonary f haemorrhage and disseminated intravascular coagu- lation. t v< Recurrent Disease TSS has also been characterised by a tendency to recur. The peak recurrence rate of 65 per cent has fallen[7] with earlier recognition and more aggressive treatment with antibiotics. Most recurrences have occurred within two menstrual periods after the initial attack and are generally less severe[9]. Recurrence in non-menstrual TSS is rare because the focus of infection is more readily recognised. Antibody to the toxin is often absent or in low titre in those with recurrent TSS and may represent a specific immune defect. Pathogenesis and Pathology The pathogenesis of TSS is not entirely understood but reflects the interaction between Staph, aureus, a specific toxin and a non-immune patient. Staphylococcal coloni- sation of the vagina has been demonstrated in over 85 per cent of menstrual TSS cases[10]. In controlled and uncontrolled studies, vaginal colonisation by Staph, aureus among healthy women varies between 0-17 per cent and peaks immediately after the onset of menstruation and post-partum[17]. However, increased adherence of sta- phylococci to vaginal epithelial cells has not been demon- strated in either normal persons or TSS patients [18]. Colonisation appears to be higher in women with contraceptive diaphragms or intrauterine devices, which suggests that fingers may be a source of these organ- isms[17]. In both the USA and UK, strains of Staph, aureus associated with TSS are predominantly ^-lacta- mase producing and belong to phage group I, especially types 29 and 52[ 19]. Such strains appear to be more resistant to inactivation by heavy metals such as arsenic, cadmium and mercury[20], Lysogenic induction of toxin production has not been demonstrated[21]. Staphylococci are biologically extremely active and produce a variety of toxins and virulence factors includ- ing enzymes. The strains originally isolated by Todd et al.[ 1] showed variable production of an epidermal toxin which was subsequently shown to have no aetiological association with TSS[22]. Later two other candidate toxins were described. Bergdoll et al. [23] isolated staphy- lococcal enterotoxin F (SEF) from 91 per cent of 142 strains of Staph, aureus associated with menstrual TSS. Later this 22,500 dalton protein was renamed toxic shock toxin (TST). On further purification it was called toxic shock marker protein (TSMP), as its emetic action in monkeys was not consistently reproducible. Schleivert et al. [24] described another toxin?pyrogenic exotoxin C (PEC)?identified in all 119 strains of Staph, aureus associated with TSS, since it produced a pyrogenic response in rabbits. Further immunochemical character- isation has confirmed that the biologically active moiety of both SEF and PEC is identical and this has now been named toxic shock syndrome toxin-1 (TSST-1)[25], More than 60 per cent of people over 10 years of age and 88 per cent of individuals over 20 years have antibodies to TSST-1[26], Bergdoll et al. [13] postulated an apparently isolated immunodeficiency in TSS patients, as only 15 per cent develop antibodies to TSST-1 in the convalescent phase. This finding has been confirmed in British patients. The association between toxin production and the development of pathogenicity is not well understood. Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 221 t Staph, aureus isolated during the 1950s have been shown to produce TSST-1 and the prevalence of antibodies in a general population in 1960 appears similar to that in 1980[27]. Furthermore, 10-50 per cent of Staph, aureus isolated from the genitalia of healthy females produce TSST-1 which by extrapolation suggests that between 1-5 per cent of females are at risk of developing TSS. However, attack rates in the USA have varied between 5- 17/100,000 women[28], considerably lower than the pre- dicted figure, and therefore other factors must be involved in the development of the disease. Tampons, particularly of the high absorbency variety, have been implicated in several case control studies[29]. Tampons have been shown to stimulate toxin production to varying degrees although they do not enhance staphylococcal growth[30], It has been suggested that tampons absorb substrates from the vagina, which normally inhibit staphylococcal growth[31]. Alternatively, aerobic Gram- negative bacteria may enzymatically degrade the car- boxy-methylcellulose in tampons, resulting in an environment rich in carbohydrates and conducive to staphylococcal growth[32]. Most recently it has been shown that TSST-1 is a potent inducer of interleukin-1 (endogenous pyrogen) and this may explain many of the features of TSS[33], However, it must be remembered that to date TSST-1 has not been identified in the blood or urine of affected patients. In general, the pathological findings reflect tissue is- chaemia secondary to poor perfusion[34]. There is mini- mal evidence of an inflammatory reaction and no evidence of bacterial tissue invasion. Acute tubular necro- sis, pulmonary oedema and haemorrhage and acute fatty infiltration of the liver are all commonly found. A round cell infiltrate, together with congestion and oedema of the myocardium, correlates with clinical evidence of cardiac involvement. The only characteristic lesions seen are microscopic mucosal ulcerations in the cervix and vagina, with tissue separation occurring below the basal layer. These changes have also been described in the oesophagus and bladder and have been attributed to an action of the toxin and not to tampon damage. Skin biopsies have shown desquamation below the basal layer in association with a perivasculitis, but no evidence of immune complex depo- sition. Prevention A number of suggestions for reducing the risks of TSS in susceptible patients has been made. Most are a logical extension of our current knowledge of the epidemiology and pathogenesis of this condition but few have been proven in controlled studies. Avoidance of tampon use would eliminate the risk of menstruation-associated dis- ease but is impractical. Intermittent use might be a compromise although more realistically high absorbency tampons might be avoided, unless absolutely necessary. No information is available on the advantages of more frequent changing of tampons. Vaginal colonisation by staphylococci might be de- creased by the use of applicators rather than fingers for insertion of tampons. While the frequency of recurrence is demonstrably reduced by appropriate antibiotic treat- ment, the potential for re-colonisation with Staph, aureus remains. Thus patients who have recovered from men- strual TSS should ideally be advised to discontinue tampon use, since monitoring of vaginal and cervical cultures for toxin-producing staphylococci is both insensi- tive and impractical. However, it should be remembered that the risk of recurrence is greatest within three months of an initial attack. Education of both tampon users and medical staff to recognise early symptoms and signs remains the cornerstone of management. The Future Our understanding of TSS has advanced greatly in a very short time. Nevertheless, some fundamental questions remain. As yet, no specific diagnostic test is available and research in this direction is urgent. Although not a common condition in the UK, the varied nature of the clinical manifestations of the syndrome means that TSS may present to a broad range of clinicians?general practitioners, surgeons, obstetricians and gynaecologists, intensive care specialists and psychiatrists as well as general physicians. The advice of the CDC to physicians remains true in that a diagnosis of TSS should be considered 'in all patients with appropriate symptoms and signs, regardless of the patients' age, sex, race and menstrual status'. This article is based on a paper read by Dr Finch at the Conference on Infectious Diseases held at the Royal College of Physicians in May 1985. References 1. Todd, J. K., Ressman, M., Kapral, F. et al. (1978) Lancet, 2, 1116. 2. Reingold, A. L. (1985) Morbidity and Mortality Weekly Report, 33, 19. 3. Reingold, A. L., Hargrett, N. T., Shands, K. N. et al. (1982) Annals of Internal Medicine, 96, 875. 4. Reingold, A. L., Dan, B. B., Shands, K. N. et al. (1982) Lancet, 1, 1. 5. Irwin, C. E. and Millstein, S. G. (1982) American Journal of Public Health, 72, 464. 6. Shands, K. N., Schmid, G. P., Dan, B. B. et al. (1980) New England Journal of Medicine, 303, 1436. 7. Chesney, P. J., Davis, J. P., Purdy, W. K. et al. (1981) Journal of the American Medical Association, 246, 761. 8. Fisher, R. F., Goodpasture, H. C., Peterie, J. D. et al. (1981) Annals of Internal Medicine, 94, 156. 9. Davis, J. P., Chesney, P. J. and Ward, P. J. (1980) New England Journal of Medicine, 303, 1429. 10. Shands, K. N., Schmid, G. P., Dan, B. B. et al. (1980) ibid., p. 1436. 11. Chesney, R. W., Chesney, P. J., Davis, J. P. et al. (1981) American Journal of Medicine, 71, 583. 12. Heimburger, D. C. (1981) Southern Medical Journal, 74, 1265. 13. Bergdoll, M. S., Crass, B. A., Reiser, R. F. et al. (1982) Annals of Internal Medicine, 96, 969. 14. De Saxe, M., Wienke, A. A., De Azevedo, J. et al. (1982) Annals of Internal Medicine, 96, 991. 15. Todd, J. K., Ressman, M., Caston, S. A. et al. (1982) Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract 368, p.131. 16. Sahs, A. L., Helms, C. M. and Du Bois, C. (1983) Archives of Neurology, 40, 414. 17. Guinan, M. E., Dan, B. B., Guidotti, A. L. et al. (1982) Annals of Internal Medicine, 96, 944. 222 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 18. Basscris, H. P., Venezio, F. R., Morlock, B. A. et al. (1981) Journal :f of Infectious Diseases, 144, 386. 19. Altemier, W. A., Lewis, S. A., Schleivert, P. M. etal. (1982) Annals of Internal Medicine, 96, 978. 20. Todd, T. K., Franco-Buff, A., Lewellin, D. W. et al. (1984) Infection and Immunity, 45, 339. j 21. Kreiswirth, B. N., Lofdahl, S., Betley, M.J. et al. (1983) Nature, J" 305, 709. 22. Kapral, F. A. (1982) Annals of Internal Medicine, 96, 972. } 23. Bergdoll, M. S., Cross, B. A., Reiser, R. F. etal. (1981) Lancet, 1, i, 1017. 24. Schleivert, P. M., Shands, K. N., Dan, B. B. etal. (1981) Journal of . * Infectious Diseases, 143, 509. 25. Bergdoll, M. S. and Schleivert, P. M. (1984) Lancet, 2, 691. 26. Schleivert, P. M., Osterholm, M. T., Kelly, J. A. et al. (1982) Annals of Internal Medicine, 96, 937. 27. Vergeront, J. M., Stolz, S. J., Cross, B. A. et al. (198"i) Journal of Infectious Diseases, 148, 692. . ( 11 28. Osterholm, M. J. and Forfang, J. R. (1982) Journal of Infectious Diseases, 145, 431. 29. Schlech, W. F., Shands, K. N., Reingold, A. C. etal. (1982)Journal of the American Medical Association, 248, 835. 30. Lee, A. L. and Cross, B. A. (1983) Proceeding of the American Society for Microbiology, Abstract B27, 59. 31. Sanders, C. C., Sanders, W. E. and Fragnant, J. E. (1982) American Journal of Obstetrics and Gynaecology, 142, 977. 32. Tierno, P. M., Hana, B. A. and Davies, M. B. (1983) Lancet, 1, 615. 33. Parsonnet, J., Hickman, R. K., Eardley, D. D. etal. (1985)Journal of Infectious Diseases, 151, 514. 34. Parvis, A. L., Herwaldt, L. A., Blum, D. et al. (1982) Annals of Internal Medicine, 96, 852. 35. Larkin, S. M., Williams, D. N., Osterholm, M. T. et al. (1982) ibid., p.858. 36. Osterholm, M. T., Davis, J. P., Gibson, R. W. etal. (1982)Journal of Infectious Diseases, 145, 431. The Great Plague of 1665 Far from the City of London the Rev. Ralph Josselin sat '? in his vicarage at Earls Colne, Essex, and wrote up his diary for 28th May 1665 . my personal illness aba- k, teth, blessed bee God. The plague gott into our land at Yarmouth and London, 14 dying this weeke.' He was a bit late with the news for the plague had come from The Netherlands via Yarmouth to London in November //' 1664. Indeed in March 1665 there was no Presidential \ election at the College, its business being disrupted by the plague, and Sir Edward Alston continued as President. Things could not have been too bad as on April 15th the King made his first visit to the College, listened to the Lumleian lecturer, George Ent, and knighted him on the < spot. But on May 17th, at the request of the Privy Council, Comitia discussed measures to be taken against the plague. This was not too difficult as the measures recommended were virtually the same as those published by the College in 1625, 1630 and 1636. Plague had stalked the land for many years and there were many statutory and administrative measures to operate whenever an epidemic threatened. The Plague Relief Act of 1604 had empowered local authorities to raise a tax for the relief of distress and to appoint watchers to ensure that those infected or likely to be infected should be kept in their houses. Anyone found abroad with an I * infectious sore was liable to the death penalty as a felon. Very oddly the powers of this Act were not to be exercised in the universities of Cambridge and Oxford (the Act has them in that order), within the precincts of any cathedral church in England or within the colleges of Eton and Winchester. Apart from the watchers, each epidemic saw the ap- pointment of searchers and bearers, all swearing an oath ?v A 5 jjr f >? of office. The searcher was bound to 'diligently viewe and search the Corps of all such persons as dureing theis infectious times shall dye . . He also had to follow definite rules. 'Yee shall decline, and absent yourselves from your familys, and allwaies avoide the societye of people and in your walke shall keepe as far distant from Men as may be allways carrying in your hands a white wand by which the people may know you and shunn and avoide you.' The bearer swore that he would 'beare to the ground and bury the bodies of all such persons as . . . shall die of the pestilence . . . carrying them to buriall alwaies in the nightyme.' He also had to carry a white wand. All this organisation could do nothing against the rapidly increasing epidemic in the City of London. On 12th June 1665, the College, at the request of the Lord Mayor, nominated eight physicians for a plague service in the City. Of these, two were chosen, Nathaniel Hodges and Thomas Witherley, and two volunteered 'upon principles of honour and conscience', Nicholas Davys and Edward Deantry. It appears that at least 24 physicians remained in the City of whom 17 were Fellows of the College or elected later. Five surgeons and seven apothe- caries are also known to have stayed to work. By that autumn five physicians (including Pepys' doctor, Alex- ander Burnett), and three surgeons were dead. The College lost its apothecary, William Johnson, but the four Fellows named above survived. The long hot dry summer turned the City into a charnel house; only the watchers and searchers were on the streets, with the dead carts rumbling through the night. After the June Comitia the College did not reas- semble for nine months. An astrologer showed how the continued on page 254 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 223 continued from page 223 epidemic was due to the planets and added that the plague only attacked 'persons of narrow souls and understand- ings'; 'those of a more refined reason' escaped. Indeed reason, abetted by money, made many flee the City. A good many physicians left urgently for the country where they joined their rich patients. On July 9th Rev. Josselin wrote 'The plague feares the London. They flie before it and the country feares all trade with London . . . The Lord stay his heavy hand.' The Lord did not stay his heavy hand. During August and September there was a period of 30 days when over a thousand died each day in the City. Many churchmen thought the plague was a punishment from God, as shown in a book titled God's Terrible Voice; while 'Theo- logical Queries' contained advice on the ethics of fleeing the plague or visiting the sick, it also advised the taking of tobacco in the morning against the infection. Of more medical importance was the quick reprinting of Dr Francis Herring's book on the plague which he had published in 1628, his advice then being the same as that given officially by the College. By early winter the worst was over in London. The plague still ravaged Essex towns. Josselin recorded this, adding in wonderment 'yett Colne, sinful Colne, is spared'. But it was not until 1st February 1666 that the King returned to Whitehall. He made some modest awards for service during the great plague when he met his Privy Councillors on May 16th. The College was not mentioned and only two physicians, Drs Astell and Inard, neither Fellows of the College, received a piece of in- scribed plate to the value of ?10. The Council was still uncertain as to the cessation of the plague, as it continued to prohibit public burials 'during the time of infection'. Plague of course did return to London that summer of 1666 but was never severe. More was seen in the country. In July Josselin wrote 'A very hot season. Plague rageth at Braintree, Colchester. At London abated . . .' Of course the whole City of London was to change in terms of density of population and plague. On Sunday, 2nd September 1666, the first flames of the Great Fire started to purge the City of infection. The coming of winter as usual brought the plague to a halt in other towns. Wrote Josselin: 'Nov. 25. A very wett morning. The country clear of the plague.'

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Training to be a Physician Every year or so the President of the Bristol medical students' association writes inviting me to set up a stand at a forthcoming careers fair on becoming a clinical pharmacologist. 'Certainly not' is my perpetual reply but I would be pleased to contribute to the hospital medicine exhibit. So there I have stood with others under the banner headline 'So you want to be a physician', beneath which is a disarming list of medical specialties which grows with each fair and an outline training plan which has become so out of date that it is reduced to the status of a sick joke. The questions shower down. 'What are the chances?' 'How long does it take?' 'Is research neces- sary?' 'Should I stay in a teaching hospital?' And we attempt to answer by fact (where it is available), and opinion (where we have any) and to steer a course between a realistic view of career chances on the one hand and not dampening the zeal of those who might well succeed. The Standing Committee of Members of this College has always had matters of training close to its heart. An initiative was taken by its 1983-84 Chairman to set up the projects and produce the articles which are collected together in this issue as 'Training to be a Physician'. This publication has three main aims and is divided into three sections. First, it provides some authoritative articles on the background to training requirements. Second, it presents some data collected by the SCM in four surveys of MRCP diploma holders. The third part is a collection of articles written on each of the sub-specialties of medi- cine. First reactions might question the need for the latter. After all we have the JCHMT handbook and indeed the order of presentation matches it precisely. In fact these articles are quite different from the entries in the handbook. They provide the personal views of doctors within each specialty on the actual requirements for success, given present manpower constraints and the popularity of the specialty. Useful questions such as whether or not an MD is necessary are aired by most authors and some allow themselves to predict future trends for the specialty. It is hoped that the publication will provide some guidance from those in the know, a few facts and some informed opinion and thus complement the already existing material. It must be acknowledged that giving people careers advice is an extremely hazardous activity. I have seen so many who have 'done all the right things' and then become stuck because they appear over-qualified for the next rung of the ladder or missed the boat by virtue of age. In fact my advice to those on the lower rungs is to be careful about paying too much heed to the recommenda- tions of others. After all, with the conflicting interests of NHS staffing and training programmes, no one can clearly predict an individual doctor's likely career course. Unfortunately, many junior doctors believe that some- where in the ivory towers of London someone is control- ling and organising it all. It just is not true. The General Medical Council wants diversification of interests and experience at an early stage, but you will have a hard time explaining to the.appointments committee for a medical registrar job why you spent six months doing obstetrics and gynaecology. This misconception has been reinforced by the enrolment and accreditation system for higher medical training. Once enrolled, four years later you become an accredited specialist. But that does not guar- antee consultant appointment, and what is more, we learn from the Registrar of the College that accreditation is not necessary for such an appointment. The booklet should be judged not as a College policy document (which it certainly is not) but as a genuine attempt by a group of individuals to clarify misunder- standings and set the scene for a career in hospital medicine. It will become out of date within a single career span, so some pinches of salt will be needed. Neverthe- less, it will certainly be available at the next careers fair in my university. C.J. C. Roberts 74 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986

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Semantics of Death Certification STEPHEN LEADBEATTER, MB, Lecturer in Forensic Pathology, University of Wales College of Medicine, Cardiff 4A man's dying is more the survivors' affair than his own'fl]. This opinion applies as well to medical certifica- tion of cause of death as to disposal of property but is not, apparently, an opinion common among the medical profession, many of whom regard death certification as a tedious chore to be delegated to the least qualified member of the clinical team for completion in whatever manner he pleases. Such practice, however, may lead to distress to relatives, inaccurate national statistics and inappropriate use of resources. In an early paper on the accuracy of medical certificates of cause of death Emery[2] drew attention to two possible sources of error: the wording of a certificate, and the degree of correlation between clinical opinion and subse- quent autopsy findings. The second category has been the subject of several papers [3,4] in recent years and has occupied the attention of the Working Party of the Royal College of Physicians and the Royal College of Pathol- ogists concerned with Medical Aspects of Death Certifica- tion^]. However, there is little information about the first category. This Department has become increasingly concerned by the wording of causes of death seen on cremation certificates and requests for autopsies. Subsequent discus- sion with certifying practitioners has revealed little knowl- edge or appreciation of the principles of death certification. This article provides data on the number of causes of death that are poorly worded and discusses the possible consequences of such poor semantics. Current Practice Issue of the medical certificate of cause of death is the statutory obligation of the doctor in attendance upon the deceased during the last illness[6]. Guidance on the completion of this certificate is printed in the book of medical certificate forms[7]. Briefly, the cause of death is recorded in a form recommended by the World Health Organisation, comprising Part I, which is the sequence of conditions leading directly to death, and Part II, which lists other conditions that have contributed to death but are not related to those listed in Part I. However many conditions are listed in Part I the last-mentioned should be the initiating condition of the sequence resulting in death and should be a cause, not a mode, of death, a mode being a clinical state which may result from many, unspecified, causes. The medical certificate of cause of death is then transmitted by the qualified informant to the Registrar of Births and Deaths who must register particulars of the death as prescribed in the Births, Deaths and Marriages Regulations, 1968[8]: these particulars include the cause of death. Unlike the certifying practitioner, who has only a common law obligation to report a death to H.M. Coroner, the Registrar of Births and Deaths has a statutory obligation to report those deaths which fall into categories prescribed in Regulation 51 of the above Regulations[8], H.M. Coroner, after preliminary inquiry, has three courses of action open to him[9]. (a) If he is satisfied that he has no jurisdiction he issues Part A of Form 100 ('Pink Form A') informing the Registrar that no further inquiry is necessary and direct- ing him to register the cause of death as stated by the certifying practitioner. (b) If he is satisfied that he has jurisdiction he may order a postmortem examination, the results of which may indi- cate that the death was due to natural causes and that no inquest is necessary; he then issues Part B of Form 100 ('Pink Form B') directing the Registrar to register the cause of death as stated by the practitioner who per- formed the postmortem examination. (c) If he has jurisdiction and is obliged to hold an inquest, with or without postmortem examination, he will, at the conclusion of the inquest, issue Form 99 ('Coroner's Certificate After Inquest') from which the Registrar registers the cause of death as determined at the inquest. The causes of death registered by these diverse routes are transmitted to the Office of Population Censuses and Surveys where they are coded in accordance with the International Classification of Diseases[10]. The coders, who are clerical officers, follow coding rules laid down by the World Health OrganisationflO], the application of which reveals the best causal sequence from the infor- mation contained in Parts I and II. If a sequence cannot be derived or a certificate indicates that further infor- mation may be available, a request for clarification is sent to the certifying practitioner or, for a death in hospital, the consultant responsible for the care of that patient. In many cases, however, there is no reply to such a requestfl 1]. Materials and Method In a large general hospital the books of Medical Certifi- cates of Cause of Death completed by clinicians are retained in the Death Registration Office; a clerical officer enters other details regarding deaths in a Death Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 129 Register. The counterfoils of death certificates issued by clinicians from 1979 to 1983 inclusive were scrutinised after receiving permission from the hospital adminis- tration. If a cause of death was not completed in the recommended form it was classified as showing one of the following inaccuracies: 1. No cause given. 2. Multiple causes given, sequence not clear. 3. Single cause given, relevant details absent. 4. Single cause given, error in layout. Each cause of death was assigned to only one of these categories. Only when an inaccuracy was obvious from a cause of death as given on a counterfoil was that cause assigned to a category; in those causes of death where there might be debate as to whether a condition was causal rather than contributory, or vice versa, the clinicians' opinions were respected and those causes were not categorised. Exam- ples from each category are given in Table 1. The numbers of causes of death in each category are given in Table 2. When a cause of death was considered to contain an inaccuracy the certificate counterfoil was i scrutinised to determine whether there was an indication that further information might be available at a later date; the Death Register and Autopsy Records were also scrutinised to determine whether an autopsy had been requested and performed. This information is given in Table 3. Details of those counterfoils which contained no ade- quate cause of death were noted and the Register of Deaths Reported to Coroner, held in the Coroner's Court, was consulted to determine whether these deaths had been reported , who had reported them and what course of action had been pursued by H.M. Coroner. This information is recorded in Table 4. Discussion The results indicate that an unacceptably large number of medical certificates of cause of death are imprecise or inaccurately completed and that at the time of completion of many of these certificates the certifying practitioners are in possession of all the information regarding the deaths that is, or will be, available. It would appear, Table 1. Examples of inaccurate death certification. No cause given Multiple causes given?sequence Single cause given?relevant Single cause given?error in not clear detail absent layout la. Cardiac arrest lb. ? lc. ? II ? la. Respiratory failure lb. Cardiac failure lc. ? II ? la. Acute renal failure lb. ? lc. ? II ? la. Renal failure lb. Myeloma lc. Hypertension II Pelvic peritonitis la. Myocardial infarction lb. Polycystic kidneys lc. Duodenal ulcer II Duodenal ulcer la. Bronchopneumonia lb. Parkinson's disease lc. Fracture neck of right femur II Malignant disease la. Carcinomatosis lb. ? lc. ? II ? la. Malignant ascites lb. ? lc. ? II ? la. Carcinoma of lung lb. ? lc. ? II ? la. Lymphangitis carcinomatosis lb. ? lc. ? II Carcinoma of stomach la. lb. lc. II Septicaemia Systemic lupus erythematosus Steroid therapy la. Heart failure lb. C.O.A.D. lc. Acute chest infection II ? la. Intrapulmonary haemorrhage lb. Thrombocytopenia lc. Mycotic septicaemia II la. D.I.C. lb. Bladder Ca. lc. Aortic aneurysm II Prostate Ca. la. Obliterative arteritis lb. ? lc. ? II ? la. G.I. Haemorrhage lb. Marrow depression lc. Cytotoxic therapy II Ca. breast with lung and retinal secondary deposits Table 2. Number of causes of death in eaeh category. Year 1979 1980 1981 1982 1983 No. of counterfoils 300 259 454 542 530 No cause given No. % 52 51 63 52 70 17.3 19.7 13.9 9.6 13.2 Multiple causes Single cause given?sequence given?relevant not clear detail absent No. % No. % 0.3 1.2 1.5 1.1 1.3 15 12 23 23 34 5 4.6 5.1 4.2 6.4 Single cause given?error in layout No. % 12 16 15 31 20 4 6.2 3.3 5.7 3.8 Total No. 80 82 108 112 131 26.7 31.7 23.8 20.7 24.7 130 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Table 3. Action taken when cause of death considered to contain an inaccuracy, a?autopsy performed, b?autopsy requested but not performed, c?counterfoil indicated further information might be available. Multiple causes Total number of imprecise given?sequence not Single cause given? Single cause given? causes in which further Year No cause given clear relevant detail absent error in layout detail potentially available a b c a b c abc abc No. % 1979 12 6 ? ? ? ? 1? ? 1 ? ? 20 25 1980 38 ? ? ? ? ___ 2 ? ? 13 15.9 1981 441 11? ? ? ?? ? ? 11 10.2 1982 81? 1? ? 2? ? ? 1? 13 11.6 1983 66 ? ? 1 ? ? 2? ? 15 11.5 Table 4. Deaths without stated cause. 1979 1980 1981 1982 1983 Death certificate counterfoils on which no cause of death is 52 51 63 52 70 stated Number of deaths without stated cause reported to H.M. Coroner 9 7 12 7 7 by certifying practitioner Number of deaths without stated cause reported to H.M. Coroner 3 2 4 6 3 by Registrar of Births and Deaths H.M. Coroner's course of action: 'Pink Form A' 11 9 15 10 9 'Pink Form B' 1 ? ? ? ? Inquest ? ? 13 1 therefore, that these certificates are so completed because of ignorance of, or failure to apply, the principles of death certification and not because relevant information is lacking. Previous research[12] has shown a national uniformity in death certification practice: there is no reason to believe practice in this hospital differs from that elsewhere. Information contained in medical certificates of cause of death is important in epidemiological research[13] and forms the basis of national mortality statistics which may be concerned in the allocation of resources within the Health Service. It is important that certifying prac- titioners complete causes of death in the recommended form so that data derived therefrom reflect accurately clinical knowledge and opinion. The causes of death discussed in this article might not permit this. The Registrar of Births and Deaths is required by Regulations to report to H.M. Coroner any death 'the cause of which appears to be unknown'[8], The infor- mation upon which the Registrar, a lay person, makes this decision is that laid before him by the qualified informant and, therefore, so far as medical data are concerned, is confined to the cause of death as stated by the certifying practitioner: an immediate and possibly distressing consequence of a medical certificate of cause of death upon which there is no adequate cause of death is that it may be reported to H.M. Coroner. It can be seen from Table 4, however, that such reporting does not occur in the majority of these deaths: there is a failure of what the Brodrick report[14] described as 'the long-stop function' of the Registrar in identifying the unusual death. The explanation of this failure lies in the wording of many causes of death: to the lay person a cause of death given as 'la Respiratory failure, lb Cardiac failure, Ic Acute renal failure, II Liver failure' appears perfectly adequate in that the deceased has obvious reason to be deceased; however, there is no cause given for the failure of the systems. When the Registrar reports a death because it appears to be of unknown cause, H.M. Coroner will make preliminary inquiries but, in law, can only assume juris- diction if the death is 'a violent or unnatural death or a sudden death the cause of which is unknown'[9]. In many of these deaths preliminary inquiry will reveal no violent or unnatural element: H.M. Coroner may then assume jurisdiction only if he has reasonable cause to suspect that the death whose cause is apparently unknown is sudden. In many cases H.M. Coroner's only course of action is to complete Part A of Form 100: an anomaly arises in that the Registrar may, indeed must, report a death whose cause is inadequately or incorrectly stated but, because H.M. Coroner cannot assume jurisdiction after prelimi- nary inquiry, he must register that inadequate or inaccu- rate cause of death. It can be seen from Table 4 that this is the course of action followed in most of those deaths which are actually reported: the conclusion in the Brod- rick report that '. . . the Coroner's primary function, at present, is to help to establish the cause of death . . .'[14] is more idealistic than practicable. It is obvious that certifying practitioners may cause unnecessary distress to relatives and unnecessary work for Registrars, H.M. Coroners, OPCS statisticians and, indeed, themselves through what are basically simple semantic errors. It is interesting to speculate what in- Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 131 crease in precision of death certification would be afford- ed by the implementation of the Brodrick recommenda- tions^ 4] that a practitioner should have a statutory obligation to report to H.M. Coroner a death whose cause he could not certify 'with accuracy and precision' and that failure to comply with this obligation should be punishable by a fine. Failing this, however, the quality of death certification can be improved only by education; such education, in the most important statutory obligation of medical prac- tice, appears perfunctory in many medical schools and no more thorough in postgraduate training. This deficiency must be remedied, not only by formal tuition at under- graduate level, where admittedly the topic appears re- mote, but also by supervision and example during provisional registration and beyond. References 1. Mann, Thomas (1928) The Magic Mountain. London: Martin Seeker. 2. Emery, J. L. (1962) Proceedings of the Royal Society of Medicine, 55, 738. 3. Waldron, H. A. and Vickerstaff, L. (1977) Intimations of quality: antemortem and postmortem diagnosis. London: Nuffield Provincial Hospitals Trust. 4. Cameron, H. M. and McGoogan, E. (1981) Journal of Pathology, 133, 273. 5. The Royal College of Physicians and the Royal College of Pathol- ogists (1982) Journal of the Royal College of Physicians of London, 16, 205. 6. Births and Deaths Registration Act, 1953. London: HMSO. 7. Forms for Medical Certificates of the Cause of Death (1985) London: HMSO 8. The Registration of Births, Deaths and Marriages Regulations, 1968. London: HMSO. 9. Knapman, P. A. and Powers, M. J. (1985) The Law and Practice on Coroners. Chichester: Barry Rose. 10. World Health Organisation (1977) Manual of international statistical classification of diseases, injuries and causes of death, ninth revision. Geneva: WHO. 11. Busuttil, A., Kemp, I. W. and Heasman, M. A. (1981) Health Bulletin, 39, 146. 12. Diehl, A. K. and Gau, D. W. (1982) Journal of Epidemiology and Community Health, 36, 146. 13. Royal College of Physicians of London (1978) British Medical Journal, 2, 1063. 14. Brodrick Committee (1971) Report of the Committee on Death Certifica- tion and Coroners. London: HMSO.

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Premalignant Disease of the Epidermis _ The Parkes Weber Lecture 1985 RONALD MARKS, mb, frcr FRCPath Professor of Dermatology, University of Wales College of Medicine, and Honorary Consultant Dermatologist, University Hospital of Wales, Cardiff Premalignant disease provokes questions and provides social challenges. Its occurrence on the skin gives un- rivalled opportunities for study of the neoplastic process in vivo. In the past 50 years, many of the aetiological factors responsible for pre-neoplastic and neoplastic dis- ease of the epidermis (non-melanoma skin cancer) have been identified and studied extensively. The most import- ant of these is ultraviolet radiation (UVR) but the carcinogenic potential of X-irradiation, chronic heat in- jury, exposure to soot, pitch and other chemical carcino- gens, as well as papilloma virus infection, should.not be forgotten. With this information and with the accessibility of the target tissue, it should be possible to characterise accurately the stimulus-response relationship and deter- mine factors that modulate this relationship. Because the skin is easy to sample it should also be possible to track the biochemical and immunological alterations that take place during the progression from normal to premalignancy and from there to frank malig- nancy. Why do some premalignant lesions remain in status quo for long periods? Why do others regress? What determines their onward progression? Such questions have implications for neoplasia in general and explain the fascination of this group of disorders. Prevalence Non-melanoma skin cancer is essentially a preventable disease yet its frequency in Caucasian populations is increasing to a frightening degree. It has, for example, been computed that in 1985 there will be 0.5 million new patients with non-melanoma skin cancer in the USA. Robin Marks (a friend but not a relative of mine), surveying a small town in Victoria, Australia, found that 56.9 per cent of the adult population had at least one solar keratosis and 2.32 per cent had at least one squamous cell carcinoma[ 1 ]. In another study by the same group it was estimated that at least 1,000 patients with non-melanoma skin cancer presented per week in the State of Victoria[2]. There appears to have been no similar study in the UK and it may be thought that in our comparatively sunless climate it would be a rather unproductive exercise. However, I do not believe this to be the case. Cardiff can hardly be considered to be exceptionally favoured by the climate, yet solar keratoses, squamous cell carcinoma and other forms of skin cancer occupy a not inconsiderable proportion of our clinic practice. In 1984, 4,540 new patients were seen in our clinic, of whom 187 (4.1 per cent) had solar keratoses or Bowen's disease, 29 (0.6 per cent) had squamous cell carcinoma, and 176 (3.9 per cent) had basal cell carcinoma. That is, 8.5 per cent of all new patients had the commoner types of non-melanoma skin cancer. Interestingly, this relatively high prevalence in Cardiff does not seem to be mirrored in all areas. For example, at St John's Hospital for Diseases of the Skin, London, the comparable figures for non-melanoma skin cancer in 1981, 1982 and 1983 were 1.1, 0.9 and 1.2 per cent respectively (Griffiths, personal communication). Of course, it is difficult to draw firm conclusions on the basis of these figures, as referral patterns differ between centres. Nonetheless, the dissimilarity between the inci- dence in the two centres seems so large that there may well be genuine differences in the experience of non- melanoma skin cancer in the two populations served. The differences may well be due to the comparatively large number of individuals of Celtic origin in the South Wales area and the predisposition of this group may not be entirely due to their light complexions. There is some evidence that they have a fault in DNA repair after UVR injury, similar in type but less in degree, to that seen in xeroderma pigmentosum[3,4]. It is of interest in this respect to find a higher 'Celticity index' in patients with malignant melanoma in Massachusetts and Aus- tralia^^]. Clinico-pathological Considerations The keratosis is the archetypal premalignant epidermal lesion. It is often termed solar or actinic keratosis to denote the usual cause. Solar keratoses are usually scaly or warty, pink or gray patches on a light-exposed area of skin. Histologically the keratosis may be identified as an area in the epidermis in which the basal epidermal cells show irregular staining, shape and size, particularly as far as their nuclei are concerned (dysplasia). In addition, the affected epidermis often demonstrates abnormal differen- tiation resulting in individual cell keratinization (dyskera- tosis) or parakeratosis. We have demonstrated that these lesions have a high rate of epidermal cell production, as 116 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 does the epidermis on which these arise[7]. Bowen's disease represents one further step towards frank malig- nancy. Bowen's disease often presents clinically as a psoriasiform scaling plaque but may also be a warty nodule. In this condition the abnormal cells are bizarre in their heterogeneity of size, shape and staining properties and are present throughout the entire thickness of the epidermis. When these lesions become frankly malignant they enlarge and ulcerate. The histological hallmark of the resulting squamous cell carcinoma is dermal invasion by the abnormal epithelial cells. Not all solar keratoses transform to a more 'malignant' phase but there are only scanty data to characterise the frequency with which this occurs. Early estimates suggested that some 20 per cent of keratoses transform to squamous cell carcinoma[8] but the fact that the former lesions are so much more common than the latterfl] suggests that this is not the case. Nonetheless, the dispar- ity in numbers could be a reflection of the different rates of growth of the two sorts of lesion and it could be that all solar keratoses are committed to develop into frankly neoplastic lesions at some point. To determine whether this is the case or whether an additional stimulus is necessary, good long-term studies are required. How- ever, providing a convincing answer will not be easy because of the need to remove and examine lesions to establish the diagnosis. Without good non-invasive diag- nostic techniques it cannot be certain that any lesion followed is indeed a solar keratosis, and if it is excised there is no knowing how it might have behaved. It may be that some solar keratoses regress and I will discuss one possible example of this later. Regression of bronchial metaplasia after stopping smoking has been described[9] and we are currently involved in determin- ing whether regular use of a sunscreen to prevent further damage from ultraviolet radiation can reduce the degree of dysplasia present. The Role of Solar Ultraviolet Irradiation There can be little doubt that solar irradiation is the major stimulus to the development of non-melanoma skin cancer. The evidence has been summarised on several occasions in recent years[10-13] but it is worthwhile reiterating the main points before proceeding to docu- ment our own involvement. The most persuasive evi- dence concerns clinical experience. Black-skinned individuals are protected from the damage caused by ultraviolet by the melanin pigment produced by melano- cytes and subsequently donated to epidermal cells. Non- melanoma skin cancer is extremely uncommon in this group of individuals. The converse is also true in that the lighter the complexion, the higher the incidence of solar keratoses, squamous cell carcinoma and basal cell carci- noma. There is also evidence of a dose-effect relationship as those individuals with outdoor jobs which involve considerable exposure, to the sun are much more likely to develop lesions than those who are mostly indoors. Recently the matter has been highlighted by the wide- spread use of a form of ultraviolet irradiation in the treatment of psoriasis (photochemotherapy with long wave ultraviolet radiation?PUVA). Individuals treated in this way appear to have a much higher prevalence of squamous cell carcinoma[14], Another plank in the argu- ment is that patients with the rare genodermatoses xero- derma pigmentosum, who often die from some form of skin cancer, have a defect in a DNA repair mechanism after damage by UVR[15], As well as the clinical evi- dence cited above, there is strong experimental evidence, mostly deriving from the irradiation of mice with ultra- violet[16]. A Human Model for Photocarcinogenesis Human skin differs markedly from that of small mam- mals in its response to UVR. Because of this we felt that to answer questions relating to solar protection and the wavelength dependency of photocarcinogenesis it would be more useful to study man. We noted reports suggest- ing that enhanced glucose-6-phosphate dehydrogenase (G6PDH) activity was characteristic of premalignant and malignant epithelial lesions; in particular, changes were noted in bronchial mucosal and gastrointestinal lesions and in a model?the hamster cheek pouch[17-19], We wondered whether this activity could form the basis of a marker for premalignant change in human epidermis. Therefore we decided to study the distribution of this pentose shunt enzyme activity as well as citric acid cycle enzyme activities in solar keratoses and squamous cell carcinoma, and exposed but non-involved skin near the lesions (paralesional skin), as well as in normally non- exposed skin. In order to compare the results of our tests in the different samples examined we used a carefully standardised sectioning and incubation technique. We also measured the densities of the formazan reaction products in the tissues by a densitometric method[20] using a scanning and integrating microdensitometer. The results demonstrated a considerable increase in G6PDH activity in the lesions examined throughout the epidermis but particularly in the granular cell layer. Paralesional skin also showed enhanced G6PDH activity in the epider- mis compared with normally non-exposed skin of the buttock. Studies of the succinic dehydrogenase (SDH) activities also presented us with some interesting results. The SDH activity was only slightly decreased overall in the epider- mis but when the various parts of the epidermis were investigated separately for SDH activity the granular layer showed a significant decrease in both lesions and paralesional areas. As the cytochemical changes (increased G6PDH and decreased SDH activities) were also present in exposed but non-involved skin it seemed quite likely that chronic exposure to ultraviolet radiation was responsible. In order to confirm this we irradiated 3 cm2 areas on the buttock skin of five normal healthy volunteer subjects with broad spectrum ultraviolet (290-400 nm) radiation 10 times in a 14 day period. The dose given was sufficient to keep the colour of the areas slightly pink and was one to two 'minimal erythema doses'. At the end of the experiment the treated sites and non-irradiated control sites in the same, normally non-exposed, area were biopsied. The Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 117 biopsies were studied for G6PDH and SDH activities in the same standardised manner as outlined above. The results of this experiment were quite similar to the findings in patients[21]. After irradiation, the SDH ac- tivity dropped to 50 per cent of the control value in the granular cell layer but did not change much overall in the epidermis. The G6PDH activity increased by about 30 per cent overall in the epidermis and was markedly increased in the basal and granular cell layers. These findings suggested to us that we did have the basis of a model for UVR-induced epidermal change of the type associated with neoplasia. The first question that we wanted to ask of the model concerned the relationship between sunburn and the cytochemical alterations discussed. Are individuals who are 'protected' from sunburn by sunscreen agents simi- larly protected from the epidermal damage caused by UVR? As the sun-worship cult gains strength, outdoor activities increase in popularity and holidays in the Mediterranean sun become ever cheaper, it is important to know how to reduce the risk of sun-induced skin cancer. The experiment we designed to obtain this infor- mation was again in normal human volunteer subjects and we studied two sunscreen products?one containing 2.5 per cent isoamyl-p-N.N-dimethylaminobenzoate and the other containing 4 per cent Mexenone[22]. The first is effective at absorbing UV of wavelengths in the medium UV wavelength band (UVB), around 290 nm?the wave- lengths well known to be responsible for causing sun- burn?and the preparation in which it was formulated had a sun protection factor of 7 (i.e. a seven times greater dose of UV is necessary to cause erythema when it is used than when it is not used). The second preparation has a broader absorption spectrum and is weakly absorbent in part of the long wave UV range though it is mainly effective in the UVB band. The protection factor of this preparation was approximately 6. Small areas on the buttocks were irradiated with different doses of UV from fluorescent tubes. Some areas were 'protected' by one or other of the sunscreens and others were not. Irradiation was performed 10 times in a 14 day period and the irradiated sites, and non-irradiated control sites, were biopsied 24 hours after the last irradiation. The biopsies were assayed cytochemically as described previously and, in addition, portions were incubated in tritiated thymi- dine for subsequent autoradiography and epidermal la- belling index determination[23]. Measurements of epidermal and stratum corneum thickness were also made. The preparations were certainly effective in preventing sunburn erythema, but were less effective in preventing the objective consequences of UV exposure on the epider- mis. At the higher doses of UVR (still less than needed to produce erythema) there was a marked increase in G6PDH throughout the epidermis and some decrease in SDH activity. The same was true for the epidermal thickening and increased thymidine autoradiographic labelling index usually noted after UVR stimulation of normal skin in that, despite the absence of clinical 'burning', there were significant UVR induced alter- ations. Although these changes were most prominent with the higher doses?there seemed to be a regular dose-effect relationship?they were also evident with less irradiation. This dissociation between the clinical sunburn effect and the objective responses of the epidermis to UVR is a cause for concern. It suggests that individuals can expose themselves covered in these sunscreens and not burn, but nonetheless sustain significant injury to the skin. One possible explanation for the dissociation between clinical burning and epidermal damage is that the latter is at least in part caused by wavelengths not absorbed out by the sunscreens used. Both sunscreens used absorb maxi- mally in the 290 nm wave band (the 'erythema' wave band) and allow through most of the longer wavelengths of the fluorescent lamps used. Solar radiation certainly contains the longer UVA wavelengths but this form of UV radiation has always appeared much less biologically effective and less attention has been devoted to it in relation to solar neoplasia. Because of the practical im- portance of knowing whether UVA was indeed respon- sible for the changes in our model, we mounted an experiment employing a monochromator to irradiate the skin instead of 'broad spectrum' fluorescent lamps. We chose UVA at approximately 360 nm and used a similar schedule of treatments on volunteer subjects as described previously. The energy employed was sufficient to pro- duce slight tanning at the sites irradiated by the second week of irradiation. The results demonstrated that similar cytochemical and cell kinetic alterations take place after exposure to UVA as take place after irradiation with 290 nm[24]. Manufacturers have now started to include UVA absorbing chemicals in their sunscreen products. Unfor- tunately, in most cases their presence is ineffectual, as they are not as efficient UVA absorbers as the other substances are UVB absorbers. This suggests that dam- aging radiation may still reach skin protected from burn- ing. We do not know the precise relationship of the cytochemical changes described to the development of epidermal neoplasia. Indeed, the relationship may be indirect, their presence only indicating epidermal damage of the type that eventually leads to skin cancer. We believe, nonetheless, that the human model we have described can be used to answer questions concerning the effects of repeated UVR exposure and attempts to mini- mise the damage caused by such radiation. The Antigenic Profile of Non-Melanoma Skin Cancer Solar keratoses are much more common than squamous cell carcinomata. A suppressive effect by host immunolo- gical defences could explain the apparent lack of vigour of keratoses, and researchers have made special efforts to identify antigenic differences between normal and neo- plastic epidermal tissue. The loss of various cell surface markers and other cytological components of normal epidermal differentiation as detected by immunolocalisa- tion procedures has been reported by several groups, including ourselves. Abnormalities in the distribution of the intercellular pemphigus antigen was probably the first such change recorded[25]. Moragas et al. [26] claimed that there was a progressive loss of pemphigus antigen with increasing 118 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 dysplasia. Others have also found that solar keratoses retained this intercellular component, often with reduced intensity of staining, but that squamous cell carcinomas showed a marked reduction in the presence of pemphigus antigen[27]. We demonstrated that short-term incubation of lesions before examination made the demonstration of antigen loss very much more obvious[28]. The antigenic profile of the skin tissues on which neoplastic epidermal lesions rest has also been studied. The bullous pemphi- goid antigen of the basement membrane region is also deficient in squamous cell carcinoma but we found accentuation of staining in the sub-epidermal region due to antibodies raised to procollagen[29]. The latter has led Mitrani and Marks[29] to suggest that the dermal con- nective tissue synthesis plays a central role in the genesis of epidermal neoplasia. Dabelsteen et al. [30] found that oral premalignant lesions demonstrated loss of blood group substances A and B but that benign leukoplakic lesions did not. Other studies have shown that j82 microglobulin is deficient in epidermal cell surfaces in some lesions, particularly basal cell carcinoma[31, 32]. Binding experiments with the lectin concanavallin A reflect the changes registered with pemphigus antibody?which is not surprising as it seems that pemphigus antibody and concanavallin A share binding sites. Beta 2 microglobulin, however, appears differently distributed over the cell surface. Class 2 mixed histocompatibility (MHC) antigens are expressed on all normal epidermal cells but there are relatively few studies of MHC antigen expression in premalignant and malig- nant tissue[33]. Our own studies indicate a not dissimilar picture, as seen with other cell surface markers. There is a patchy loss of these antigens which is more marked the more dysplastic the tissue appears. Clearly this group of cell surface components may be of particular importance, as they appear to be involved in regulating T-lymphocyte responses. Differences in the distribution of keratins between normal and neoplastic epidermal tissue have also been documented. Winter et al. [34], using both polyacryla- mide gel electrophoresis and two-dimensional electro- phoretic methods, have demonstrated that the larger molecular weight-keratin peptides are absent from both experimentally-induced rodent and spontaneously-occur- ring human squamous cell cancers. A not dissimilar finding was that of Klein-Szanto et al. [35] who deter- mined that the keratin fibril organising basic protein (filaggrin) present in the keratohyalin granules of normal epidermis was absent from squamous cell carcinoma but present in keratoacanthomas. Apart from the potential diagnostic significance of these various findings, do they yield any biologically important messages that inform on the nature of the neoplastic process or can be utilised therapeutically? For the most part they appear to indicate faulty epidermal differentiation and faulty membrane synthesis. From the functional standpoint the loss of cell recognition markers and cell contacts at the surface has several implications. It may allow cells to invade and metastasise rather than stay attached to other cells. It could explain the curious phenomenon of carcinoma segregans in which groups of dysplastic epidermal cells appear to grow around other epidermal structures. Failure of recognition by the im- mune system of the abnormal cells as 'self' may also permit an immune response and explain spontaneous regression. Most of the reported studies have detected an alteration that is evident in frankly malignant lesions but only partially expressed in the premalignant lesions examined. They indicate a stepwise progression and not a fundamental alteration. No tumour-specific antigens have yet been detected in solar keratoses or squamous cell carcinoma. Evidence of 'Immune Surveillance' A dense lymphocytic infiltrate beneath a solar keratosis is a commonly observed histological feature and could be interpreted as indicating an immune response to the lesion. In a few lesions the pathological picture simulates lichen planus in that there is basal cell liquefactive degeneration and 'colloid body' formation as well as a heavy infiltrate of lymphocytes sub-epidermally. These lichenoid keratoses may be examples of the immune response succeeding in checking the neoplastic process. We found that 6.1 per cent of 212 solar keratoses examined retrospectively and 10.7 per cent of 28 kera- toses examined prospectively demonstrated the distinctive changes of lichenoid keratosis[36]. Basal cell liquefactive degenerative change occurred without full-blown 'lichen- oid change' in some 27.8 per cent of keratoses. Colloid body formation and apparently apoptotic cells are often seen in keratoses and may represent a similar type of individual cell death. We could not identify a specific pattern of immunoglobulin or complement deposition in lichenoid keratoses, neither could we identify a particular morphological feature with which the phenomenon was associated. Similarly, Tosca et al. [37] could not identify a particular immunological mechanism for the regression of keratoacanthoma. Patients who have had renal transplants and who have been immunosuppressed for several years to prevent rejection of the transplanted kidney have a higher preva- lence of solar keratoses and squamous cell carcinoma than control populations. Although this is clinically evident in the UK, it is more of a problem in sunnier climates where there is already a high prevalence of non-melanoma skin cancer[38, 39]. A likely explanation for this phenomenon is that the normal immune 'check mechanisms' are prevented from acting to suppress UVR-induced neopla- sia and the onward progression of pre-neoplastic lesions. A corollary of this hypothesis is that if solar keratoses could be transplanted to immunologically privileged sites away from immune influences they would transform and become more malignant. In order to test this idea we have transplanted solar keratoses to athymic nude mice and have been successful in maintaining these lesions for periods of up to nine months[40]. We removed solar keratoses from patients, split them in two and examined half by routine histological methods and transplanted the other half. The transplanted tissue seemed to retain most of its own characteristics during its sojourn in the host site, free of the influence of delayed hypersensitivity. The Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 119 cell kinetic characteristics and the overall morphology of the transplanted tissue were similar to those of the original lesion although there was a tendency for the grafted tissue to be thinner than the original lesion from which it derived. It was quite obvious that the grafted lesion retained its human identity. The dysplastic nature of the epidermis was obvious, as was the solar elastotic degenerative change in the dermis. Even more convinc- ing, however, were the antigenic similarities of the grafts to human epidermis. Involucrin is a component of the tough protein membrane just inside the plasma mem- brane of mature human epidermal cells[41]. Antibodies to this substance reacted with the grafted tissue but not with neighbouring mouse epidermis. Similarly, anti- bodies to the mixed histocompatibility complex (anti- HLA, A, B and C) reacted patchily with the original lesions and with the grafted lesions early on, but not at all with older grafts. Interestingly, we have found that there is an analogy with this state of affairs in cultured epider- mal cells. After the first days of a subculture the HLA positivity is lost?to be regained for a short time immedi- ately after subculturing, but then lost again as the culture ages (Thomas, Dykes and Marks, in preparation). We were surprised that there was so little change overall in the grafted lesions even after periods of nearly nine months. Not a single transplanted keratosis became frankly malignant. We have no complete explanation for this lack of progression but two possibilities should be considered. The first is that the athymic mouse does retain some capacity for mounting an immunological reaction and that this is sufficient to keep the lesions in check. The second possibility is that solar keratoses require further UVR stimulation for any frankly neoplas- tic change to occur. The epidermal dendritic Langerhans cell, for so long an annoying puzzle to dermatologists, anatomists and electron-microscopists, has now been identified as a sort of macrophage. It has the function of presenting antigen to T-lymphocytes and is of central importance in the development of delayed hypersensitivity. In recent years it has been found that irradiation of the skin with UV causes the Langerhans cells to disappear[42] and inhibits the development of delayed hypersensitivity. Whether this is of importance in allowing the development of neoplastic epidermal cells in chronically sun damaged skin is uncertain but clearly it is a possibility. Other work by Margaret Kripke[43] may also be important. When UVR-induced tumours in mice are transplanted to other irradiated mice the tumours are not rejected even though other types of tumour are. It has been suggested that the UVR induces a specific immune tolerance to tumours caused by UVR by inducing suppressor T cells that interfere with the rejection of the tumours. It will be evident from the above that the events leading up to the establishment of a premalignant lesion after long-continued sun exposure and the subsequent further development of a squamous cell carcinoma in some cases are extremely complex. There can be little doubt that the immune system is involved in several ways but the relative contribution of each mechanism to the process is as yet uncertain. Measurement of the Degree of Epidermal Dysplasia Methods have been devised for measuring dysplastic change in bronchial mucosa[9] and have assisted in detecting an improvement after stopping smoking. If we possessed a 'dysplasia index' it would be much easier to assess the effects of drugs and prophylactic measures than with the present subjective qualitative methods. We have used two ways of deriving such a dysplasia index[44]. The first is in reality a semi-quantitative method which em- ploys 10 cm visual analogue scales. A mark is made on a 10 cm line indicating the severity of the epidermal change, the left hand end of the line representing no dysplasia, the right hand end representing the severest possible dysplastic change. The accuracy of this pro- cedure is totally dependent on the experience and consis- tency of the observer, but in our hands can be shown to be reproducible. ,< The second method that we have devised utilises image analysis techniques. Nuclear area and its variability, cell size, epidermal thickness and irregularity, the degree of parakeratosis and the number of dyskeratotic cells are all assessed. The values are weighted arbitrarily and a dysplastic index is obtained with a complex formula. Unfortunately, this method is extremely time-consuming, as at present it takes four man hours per sample. We believe that some modification of one or other of these assessment techniques will be helpful in exploring dose- effect relationships as far as epidermal neoplasia is con- cerned. The Social Significance In countries such as the USA, Australia and South Africa, non-melanoma skin cancer is now a major public health problem. Although the various lesions induced by chronic sun exposure do not often kill, they cause con- siderable morbidity. Campaigns have been mounted through the various popular media in those countries to make the public more aware of the danger of sunbathing and we must hope that these will be successful. Our problem in the UK is smaller but rapidly growing in size because of the increased opportunities for travel and the growing emphasis on outdoor activities. It would be prudent to alert the British public to the potential hazards now. References 1. Marks, R., Ponsford, M. W., Selwood, T. S., Goodman, G. and Mason, G. (1983) Medical Journal of Australia, 24, 619. 2. Ponsford, M. W., Goodman, G. and Marks, R. (1983) Australian Journal of Dermatology, 24, 79. 3. Abo-Darub, J. M., MacKie, R. and Pitts, J. D. (1983) Journal of Investigative Dermatology, 80, 241. 4. Abo-Darub, J. M., MacKie, R. and Pitts, J. D. (1983) Bioscience Reports, 3, 293. 5. Lane Brown, M. M. and Melia, D. F. (1973) In Pigment Cell, Vol. I, pp. 229-235. Basel: Karger. 6. Lane Brown, M. M., Sharpe, C. A. B., Macmillan, D. S. and McGovern, V.J. (1971) Medical Journal of Australia, 1, 852. 7. Pearse, A. D. and Marks, R. (1977) British Journal of Dermatology, 96, 45. 120 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 J 8. Montgomery, H. and Dorffel, J. (1932) Archiv fur Dermatologie und Syphilis, 166, 286. 9. Bertram, J. F. and Rogers, A. W. (1981) British Medical Journal, 283, 1567. 10. Van der Leun, J. C. (1984) Photochemistry and Photobiology, 39, 861. 11 ? Epstein, J. H. (1983) Journal of the American Academy of Dermatology, 9, 487. 12. Zayoun, S., Ali, L. A., Shaib,J. and Kurban, A. (1985) Journal of the American Academy of Dermatology, 12, 522. 13. Holman, C. D. J., Armstrong, B. K., Evans, P. R. et al. (1984) British Journal of Dermatology, 110, 129. 14. Stern, R. S., Laird, N., Melski, J., Parrish, J. A., Fitzpatrick, T. B. and Bleich, H. L. (1984) New England Journal of Medicine, 310, 1156. 15. Kraemer, K. H. (1980) In Clinical Dermatology, Vol. 4 (ed. D. J. Demis, R. L. Dobson and J. McGuire.) New York: Harper & Row. 16. Blum, H. F. (1959) Carcinogenesis by ultraviolet light. Princeton, New Jersey: University Press. 17. Ibrahim, K. S., Husain, O. A. N., Bitensky, L. and Chayen., J. (1983) Journal of Clinical Pathology, 36, 133. 18. Bannasch, P., Benner, U., Hacker, H.J. et al. (1981) Histochemical Journal, 13, 799. 19. Evans, A. W. (1980) British Journal of Oral Surgery, 18, 3. 20. Pearse, A. D. and Marks, R. (1978) Histochemical Journal, 10, 621. 21. Pearse, A. D. and Marks, R. (1978) Bulletin du Cancer, 65, 351. 22. Pearse, A. D. and Marks, R. (1983) Journal of Investigative Derma- tology, 80, 191. 23. Shahrad, P. and Marks, R. (1976) British Journal of Dermatology, 94, 7. 24. Pearse, A. D. and Marks, R. (1985) British Journal of Dermatology, (abstract), 113, 772. 25. Muller, H. K. and Sutherland, R. C. (1971) Nature, 230, 384. 26. Moragas, J. M. de, Winkelmann, R. K. andjordon, R. E. (1970) Cancer, 25, 1399. 27. Tosca, A., Varelzidis, A., Nicolis, G., Hadzis, J., Stratigos, J. and Capetanakis, J. (1980) Cancer, 45, 2284. 28. Marks, R., Pearse, A. D., Holt, P.J. A., Mitrani, E. and Nuki, G. (1978) Les Colloques de I'INSERM, 80, 247. 29. Mitrani, E. and Marks, R. (1982) Archives of Dermatological Research, 274, 21. 30. Dabelsteen, E., Roed-Petersen, B. and Pindborg, J. J. (\975)Acta pathologica et microbiologica Scandinavica, Sect. A, 83, 292. 31. Mahrle, G., Patyk, H. and Boiling, R. (1982) Archives of Dermatolo- gical Research, 274, 85. 32. Turbitt, M. and MacKie, R. M. (1981) British Journal of Derma- tology, 104, 507. 33. Parmiani, G., Carbone, G., Invernizzi, G. et al. (1979) Immunogen- etics, 9, 1. 34. Winter, H., Schweizer, J. and Goerttler, K. (1983) Archives of Dermatological Research, 275, 27. 35. Klein-Szanto, A.J. P., Barr, R. J., Reiners, J. J. and Mamrack, M. D. (1984) Archives of Pathology and Laboratory Medicine, 108, 888. 36. Tan, C. Y. and Marks, R. (1982)Journal of Investigative Dermatology, 79, 365. 37. Tosca, A., Varelzidis, A., Avgerinou, J., Hatzis, J., Perissios, A. and Nicolis, G. (1980) Archives of Dermatological Research, 268, 149. 38. Hardie, I. R., Strong, R. W., Hartley, L. C. J., Woodruff, P. W. H. and Clunie, G.J. A. (1980) Surgery, 87, 177. 39. Koranda, F. C., Dehmel, E. M., Kahn, G. and Penn, I. (1974) Journal of the American Medical Association, 229, 419. 40. Thomas, S. E., Pearse, A. D. and Marks, R. (1985) European Journal of Cancer and Clinical Oncology, 21, 1093. 41. Rice, R. H. and Green, H. (1979) Cell, 18, 681. 42. Aberer, W., Schuler, G., Stingl, G. et al. (1981) Journal of Investigative Dermatology, 76, 202. 43. Kripke, M. L. (1981) Advances in Cancer Research, 34, 69. 44. Pearse, A. D., Barton, S. and Marks, R. (1985) British Journal of Dermatology, (abstract), 113, 786.

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A Note on Dr Frank Buckland Fellows may have noticed a blue plaque let into the wall at the east end of the College garden, recording the fact that Dr Frank Buckland, Medical Naturalist, lived in a house on this site from 1863 to 1880. Buckland, whose given names were Francis Trevelyan, was born in 1826, the son of William Buckland, a Canon of Christ Church, Oxford, who later became Dean of Westminster. William was also a distinguished geologist and naturalist, and in addition a considerable eccentric. He once expressed a wish to eat his way through the whole of the animal kingdom, but had some difficulty with the bluebottle and the mole. Frank qualified in medicine from St George's Hospital, but his only medical practice was a period as Assistant Surgeon to the 2nd Life Guards. The rest of his life was devoted to the study of natural history. His special interest was pisciculture, and in 1867 he was appointed Inspector of Salmon Fisheries. His numerous publi- cations included Curiosities of Natural History and books on pisciculture and fishing. In 1863 he came to live in Albany Street. My father, Arthur Clement Cooke, then aged 11, lived nearby. Like many small boys he was interested in natural history, and used to go fishing in the Regent's Park canal. There he collected some specimens of the 10-spined stickleback, a rare species. My grandfather suggested to Arthur that he should show them to Frank Buckland down the road. This he did, and the schoolboy and the eminent naturalist became firm friends. Frank was not so eccentric as his father, but delighted in keeping numerous pets of most unusual species, which were allowed to roam freely in the house. It must have been a splendid place for a small boy to visit. Needless to say my father retained a keen interest in natural history until his death at 93. When I was a boy we went to the London Zoo almost every Sunday morning. I too am fascinated by medicine and the other biological sciences, and my son is a professional zoologist, all of which I attribute in some degree to Frank Buckland. As I walk past the plaque, I have a pleasant awareness of the continuity of history. Alexander Cooke Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 145

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Increased Longevity In Man (SIR CYRIL CLARKE, kbe, md, frcr frs Director, (Royal College of Physicians Research Unit ' It is well known that in the UK the proportion of pensioners to the rest of the population is rapidly rising and in this article I propose to discuss the old and the very old, i.e. those over 85 years and especially centenarians. The reason for my interest is that I believe it is not sufficiently realised that the old can give important epidemiological data about what accelerates or retards ageing and death. Table 1 shows the nearly ninefold increase in centenar- ians in 30 years and this must have mainly environmental Table 1. The number of centenarians in England and Wales, 1951-81. These estimates are taken from the censuses in 1951 and 1961 and the DHSS estimates of centenarian pensioners in 1971 and 1981. (Courtesy Mr A. R. Thatcher, Registrar General, OPCS.) Year 1951 1961 1971 1981 Number of centenarians 271 479 1,240 2,410 causes. It could not possibly be due solely to the increase in population size, nor could the genetic structure of the population have altered appreciably in this time. So we should look for environmental factors, of which there are plenty?antibiotics and other drugs, various caring as- pects of the NHS, hybridity, the Clean Air Acts, health education, the 'urge to live', central heating, diet and all the rest. All this is well known, but how do these factors rate at different ages on the way to the century? One clue comes from examining the sex ratio, shown in Table 2. What is Table 2. The sex ratio, England and Wales 1981. (Courtesy Mr A. R. Thatcher, Registrar General, OPCS.) Age group Female % 25-34 49.6 35-44 49.6 45-54 50.0 55-64 52.0 65-74 56.3 75-84 65.5 85-94 76.7 95-99 84.4 100+ 87.8 so interesting is that women 'take over' only at about retiring age; they do this to such an extent that by the time the century is reached only about 15 per cent of these very old people are males. This could be because there is some biological basis for increased longevity in women, but it seems much more likely that it is the males who die differentially from about the age of retirement onwards. The survival of the older women is exactly the opposite of what would be expected on the Darwinian theory of selection in favour of biological fitness, since this becomes zero in women after the age of 50?because they then cannot hand on their genes, whereas men can up to any age. So there must be causes working against men in older age groups and these are highly likely to be environmental factors, for example diseases. It would be most interesting to see if these sex ratios are currently different in the different social classes, and to know the position 20 years ago and what is happening in other countries. Some readers may know the answers to these queries, which could indicate changing pressures on the sex ratio. In passing, if there is now a scourge of coronary heart disease deaths in males between 40 and 55 one might expect the sex ratio to be affected, but this is not the case, so I am uncertain how sensitive a marker it is. However, I obtained some useful information from two actuaries. They pointed out that 105 boys are born to 100 girls but because the mortality in children and young adults is higher in boys than in girls the sex ratio at age 25-34 is near unity (49.6). This might be because males are biologically inferior to females, but, if so, I do not understand why the sex ratio between 34 and 54 remains at unity; one would have thought the females should 'nose' ahead during this time, whereas they only start doing so between ages 55 and 64. A more likely expla- nation is that trauma is responsible for an increased death rate in boys and young adults and that between 34 and 54 males are developing but not dying from atheroma to a greater extent than women. After the age of 55 men start dying differentially, probably, from cardiovascular dis- ease, and women 'take over' the sex ratio to an increasing extent in each decade. Table 3 gives information about two cohorts, one between 1876 and 1945 and the other between 1961 and 1980. It will be seen that there is a marked reduction in mortality and surprisingly this is greatest in the younger age groups. So when considering factors prolonging life we have to take the age group into account as well as the sex ratio in that group. The fact that each decade is receiving a contribution from the one before means that there is a cumulative effect such that there are bound to be more centenarians, and we need not look for a specific cause at or around the 122 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 v Table 3. Death rates per 1,000. (Courtesy Mr A. R. Thatcher, Registrar General, OPCS.) Age 1876-1945 1961-80 Reduction % 85 + 264.5 211.5 20 75-84 127.4 90.2 29 65-74 56.9 37.7 34 55-64 26.1 15.1 42 45-54 13.26 5.70 57 35-44 8.00 1.94 76 25-34 4.85 0.82 83 century (apart perhaps from 'urge' in the 99-year-olds). The causes of survival will be building up but will be different in the different decades. The current trend of increased longevity is described by what the Americans call 'rectangularisation' of the population, as shown in Fig.l. In the Stone Age, for example, only about 12 per cent of the population reached the age of 50, whereas in 1971 the percentage was over 90. As a nation, therefore, we are living longer, in spite of cigarettes, drink, drugs, the dreaded coronary artery disease and lung cancer. Have we reached the limit of age? Probably not. The Japanese have reported a definite example of a man living to 116. Likely Environmental Factors favouring Survival Antibiotics and Other Drugs These are available equally to both sexes at all ages and may be the principal cause in the reduction of mortality in the younger age groups where the sex ratio is normal as mdicated by the decline in tuberculosis and many other types of infection. But at retirement age and after, antibiotics will still be as effective in men as in women, and therefore it is probably not infections which are killing off the men differentially at 65 years or more. The NHS and its Facilities These will tend to prolong life after coronary thrombosis and strokes, and there is also the improved treatment of hypertension. The facilities, and the drugs, are available to both sexes, but I surmise that it is the cardiovascular diseases which kill off more men than women in the older age groups, probably because of male life-style in retire- ment. Similarly, more men die of cancer, mainly because of the large number of lung cancer cases (the result of cigarette smoking) than women. So in the older age groups this cancer will favour the higher survival rate in females, at least at the present. Health Education This again is available to both sexes but after retirement men tend to adopt an unhealthy life-style. They run to fat because of excessive calorie intake and smoke and drink more than women. Furthermore, they are less active both mentally and physically?everything is in the bag, so to speak?whereas most women go on as before, cleaning the house, cooking the meals, shopping, washing, etc. There is no retirement for women, so they live longer; this is my view. Support, showing how women, compared with men, have kept cardiovascular disease at bay in the past 80 years, comes from the USA[1], Hybridity This is more speculative but it is a likely factor in the Japanese, where cousin marriages used to be common. A century ago one tended to marry the girl next door but with the coming of the internal combustion engine men became more venturesome and travelled further for their mates ? so there would be less inbreeding and .more hybridity and therefore possibly more hardiness. In ani- mals it holds, for a mule, which is a cross between a mare and a jack donkey, lives longer than either of its parents. The Clean Air Acts These were very important. Pollution (i.e. sulphur diox- ide and soot) will have affected men in their working life more than women, often without killing them until later. Lawther et al. [2] gave bronchitics pocket diaries for the daily recording of their health, with very simple coding, and showed that worsening was highly correlated with smoke and sulphur dioxide levels. With the Clean Air Acts these findings became of historical interest only. The story of the Peppered Moth correlates well with the medical findings. In 1849 the first black mutant appeared in the Manchester region and by the end of the century 93 per cent of the population was melanic, camouflaged by the soot and sulphur dioxide, the latter being toxic to the Fig. 1. 'Rectangularisation': approximate survival curves. (Courtesy Mr A. R. Thatcher, Registrar General, OPCS.) Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 123 pale coloured lichens. In my home at West Kirby on the Wirral I have trapped the moth for 25 years and the proportion of the melanic form has dropped from 93 per cent to 61 per cent (Fig.2). The probable reason is the implementation of the Clean Air Acts in the 1960s and the moth is a good example of evolution in reverse[3]. Central heating This is the same for both sexes and will not affect the sex ratio in old age, though it will certainly tend to keep old people in general alive longer. 'Urge' The urge to reach the century in the very old may be strong, particularly in a cricket-loving country, just as conversely the bereavement syndrome, or the witch- doctor's curse, may turn faces to the wall. Competitive urge certainly seems to have physical effects?beating the four-minute mile is a good example. On the other hand, racehorses bred for speed run no quicker than they did 50 years ago. Reverting to longevity, the decline in belief in an after-life may have increased the urge to keep alive in this one. Eating and Weight Reduction Diet is the modern craze and as regards longevity it receives support from animals. Rats live longer on a low calorie regime, and exercise, if begun in early life, also ( ) increases their lifespan. But rats are not men, and what about the higher animals? I wrote to two experts at the London Zoo and asked whether their mammals were living longer than 20 years ago; both said 'yes'. The longevity improved once the keepers stopped the animals from having the public's picnic scraps. What better indictment of human diet could you have? Interestingly, life appears to be equally prolonged for male and female mammals. Male animals, of course, have no retirement age. That really is the core of my argument. In man it is notoriously difficult to get reliable information on diet; no one can remember what they had for breakfast yesterday, but with golden weddings now ten a penny (provided couples stick together) it might be possible to get useful information between couples who know each other ex- tremely well. The Familial Component in Longevity There is a general feeling among both laymen and doctors that a large component of longevity lies in one's genes, and a number of papers[4-6] have been written on this theme, mainly from the Johns Hopkins Medical School. These may be summarised by the statement that there are not specific genes for longevity but rather the absence of those that make for premature death, e.g. the sickling trait. Furthermore, all the papers emphasise the cultural factors in longevity, and although they do find that long- lived people tend to have long-lived relatives they are all somewhat equivocal as to the reason. No one, as far as I know, has carried out the proper survey to test the genetic hypothesis for polygenic inheritance. What should be done is to take male centenarians (the rarer sex) and look at their brothers and sisters and then do the same with women. Polygenic inheritance would be indicated if the males had longer-lived sibs than the females. It is the same type of work that C. O. Carter[7] did with hyper- trophic pyloric stenosis. All the surveys that I have seen go vertically, and these are complicated by the fact that in looking at the age of the offspring of a centenarian there is his or her spouse to consider, which is confusing. The sibs have the same mother and father. To try and clarify some of these points the RCP Research Unit is beginning an investigation with both the Royal Holloway and Bedford New College Sociology Unit and the Liverpool Institute for Ageing. First, what sort of people are the very old? Are they mostly mentally feeble, stone deaf and just waiting for the end? Some are, and they need to be in institutions, but a great many are not, particularly if they can be looked after at home. My namesakes and their colleagues in Leicester[8] emphasise this particularly, and Dr John Harrison, on behalf of the College, has investigated residential care for people with severe physical disabil- ities. He is all for de-institutionalisation if possible, and he has an excellent quotation from Gerben Dejong which I have modified slightly: 'The dignity of risk is what the movement for independent living is all about. Without the possibility of failure, the disabled person lacks the true independence that is the mark of one's humanity?the right to choose for good or evil'. Year Total 50 Percentage Carbonaria 60 70 80 90 100 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 283 226 426 840 994 982 478 304 398 480 610 848 207 276 318 313 269 446 490 335 631 637 407 122 689 Fig. 2. Percentage of carbonaria moths 1959-84 at Caldy and West Kirby. (Courtesy Biological Journal of the Linne- an Society.) 124 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 In conclusion, I do not think that with the present environmental evidence we need to concern ourselves with the inheritance of longevity, except for the single gene diseases. There is so much that can be put right by paying attention to the environment. So away with testing people for those terrible apolipoproteins and let us concentrate on major factors such as diet, exercise, obesity and hypertension. If we do I think by the end of the century part of the College motto, 'life is short', will no longer be appropriate. Acknowledgments I am grateful to Professor George du Boulay and Dr Leonard Goodwin for their helpful comments about the longevity in animals at the London Zoo. This article is based on a paper read at the College Regional Conference in Liverpool in September 1985. References 1. Tyler, B. (1985) New England Journal of Medicine, 313, 957. 2. Lawther, P. J., Waller, R. E. and Henderson, Maureen (1970) Thorax, 25, 172. 3.. Clarke, C. A., Mani, G. S. and Wynne, Goronwy (1985) Biological Journal of the Linnean Society, 26, 189. 4. Hawkins, Margaret R., Murphy, Edmond A. and Abbey, Helen (1965) Bulletin of the Johns Hopkins Hospital, 117, 24. 5. Abbott, Margaret H., Murphy, Edmond A., Boiling, David R. and Abbey, Helen (1974) The Johns Hopkins Medical Journal, 134, 1. 6. Abbott, Margaret H., Abbey, Helen, Boiling, David R. and Murphy, Edmond A. (1978) American Journal of Medical Genetics, 2, 105. 7. Carter, C. O. (1961) British Medical Bulletin, 17, 251. 8. Clarke, M., Clarke, Susan, Odell, Aileen and Jagger, Carol (1984) Health Trends, 16, 3.

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Book Review Rheumatological Medicine edited by P. A. Dieppe, M. Doherty, D. G. MacFarlane and P. J. Maddison. Chur- chill Livingstone, Edinburgh, London, Melbourne and New York, 1985. 522 pages. Price ?40. Nineteen eighty-five is proving to be the year for rheuma- tological publications. Hard on the heels of new editions of the two North American tomes ('Hollander' and 'Kelley') and with a further edition of the standard British work ('Copeman') due out soon, comes this new, medi- um-sized textbook. The authors state their aims to be that of filling the gap between the major reference works and texts written for students, and also that of setting rheumatology in the context of general medicine. I believe they have succeed- ed in both objectives. The text is divided into six sections, of which I thought the first (on the structure and function of joints, immuno- pathology and epidemiology) was quite outstanding. It provides a reasonably comprehensive account of highly technical topics in a simple, clear and succinct style which is a refreshing change from the heavy approach in the larger textbooks. The second section deals systematically with the major rheumatic diseases. This is practical throughout, and has the ring of experienced clinicians writing with authority. Section three covers rheumatology and general medicine. This is perhaps a less satisfactory mix. Systems such as the skin are discussed in terms of how rheumatic diseases affect them. It does, however, include a useful problem- orientated approach to features such as headache and depression. The fourth section deals with diseases of bone and of collagen, and also provides an excellent account of 'soft tissue rheumatism', including a highly practical approach to the vague aches for which no pathological diagnosis is available. Section five is a useful guide to history-taking, physical examination and laboratory investigations; the account of regional examination being notable for the outstanding quality of the illustrations. Section six is an equally satisfactory review of therapy. There is a large number of illustrations and, apart from a few X-rays, these are all line drawings. Most of these have been prepared with meticulous care and, together with many well-planned tables, greatly add to the ease of following the text, and indeed to the pleasure of reading these well-printed pages. However, the authors might perhaps have been slightly less rigid about excluding all clinical photographs. Both nail-fold arteritic lesions (Fig- ure 4.1) and keratoderma (Figure 5.14) reproduce well in photographs, while the artist's efforts here do not do justice to these important signs. When the book is reprinted it will no doubt be possible to restore the 'triangular ligament' (Figure 9.16) to the correct side of the wrist. A more serious error is that the subjects in the second half of the book are indexed as appearing two pages further on than their actual position in the text. Despite these criticisms this is an excellent book and a useful addition to the available texts. It would be a sound investment for any rheumatology trainee, and a good reference work for undergraduates. H. L. F. Currey Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 115

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Louis Daniel Beauperthuy: Pioneer in Yellow Fever and Leprosy Research ALEX SAKULA, MD, FRCP* Emeritus Consultant Physician, Redhill General Hospital, Surrey Louis Daniel Beauperthuy's achievements in tropical medicine have for long been recognised by South Ameri- can and French medical historians, but in the English- speaking world his name is virtually unknown. This article attempts to remedy the apparent British neglect of a great pioneer of tropical medicine. Beauperthuy (Fig. 1) was born on 26th August 1807 in Sainte-Rose, Guadeloupe, a French island possession in the Caribbean, where his father, Pierre Daniel Beau- perthuy (1785-1861), who derived from an old French family in the Perigord, practised as a physician. His mother, also French, was Marie Laurence Desbonnes Belasse (1783-1859) and Louis Daniel was the second of their six childrenfl], Beauperthuy was educated in France and studied medicine at l'Ecole de Medecine, Paris, where the Dean of the Faculty was Mathieu Orfila (1787-1853) and his teachers included Frangois Magendie (1787-1855). He attended courses in botany and entomology and devel- oped a passionate interest in natural history. He was fascinated by the marvels revealed by the microscope and, as an extra-curricular activity, attended the course held by Alfred Donne (1801-78). During his vacations, while a student, he returned to the Caribbean where tropical diseases (yellow fever, in particular) were rife. It was then that the seed of the idea of the transmission by insects (especially mosquitoes) of human diseases began to germinate in his mind. In 1837, he qualified MD Paris, with a thesis entitled 'De la Climatologie'[2] in which he developed 'la theorie insectile'. Following qualification, the Musee d'Histoire Natur- elle, Paris, appointed him in 1837 as 'naturaliste voya- geur' and during the next four years he explored the basin of the Orinoco, carried out researches on snakes and earthquakes and also made important anthropological observations, sending specimens back to the Paris mu- seum. In 1841, during one of his expeditions off Venezuela, he stopped in the city of Cumana (situated some 300 kilometres east of Caracas) and there he met a Venezu- elan lady, Ignacia Sanchez Mayz, whom he married in 1842; three children were later born to them. He now made the important decision not to return to France but to remain in Cumana. In 1844 he obtained the further qualification MD Caracas and settled in medical practice in Gumana, with the intention of devoting his life to research into tropical disease (Fig. 2). He remained in Cumana until the last few months of his life, when he took charge of a leprosy hospital in British Guiana and it was there, at Bartica, that he died suddenly, following a stroke, on 3rd September 1871, aged 64. His grave lies in the Officers' Cemetery of the British Guiana penal settlement on the River Mazur- uni[3] (Fig. 3). *Private correspondence to: Pilgrims Corner, Pilgrims Way, Reigate, Surrey RH2 9LG. 1. Louis Daniel Beauperthuy. (Oil painting by G. Da Villadda, in Faculty of Medicine, Rome, Italy. Courtesy Editions Hervas, Paris.) 146 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Cholera Beauperthuy was a medical student when the cholera epidemic of 1832 hit Paris and he was able to witness the ravages of this disease. Inl853, he was in Cumana when a major earthquake seriously damaged that city, a sequel of which were epidemics of yellow fever, smallpox and cholera. Beauperthuy was nominated 'Medecin Sani- y taire', and became responsible for controlling the epidem- ic. Examining the excreta of the cholera victims, he detected the motile vibrios which he described in 1855[4]. This was 28 years before Robert Koch definitively isolat- ed the causative organism of cholera. Yellow Fever In the 15 years 1838-53, Beauperthuy had ample oppor- tunity of studying the manifestations of yellow fever during outbreaks in Guadeloupe, Caracas, Barcelona (Venezuela), Cumana and Guiana. He was impressed by both the manner in which the disease related to the rainy season as well as by its relative scarcity in the forests, and he noted a reduction of infection when anti-mosquito precautions were taken, e.g. the use of smoke and nets. He came to the conclusion that the mosquito must be the vector by which the infecting agent of yellow fever was transmitted, although he conceived that the infecting agent was particulate decomposing organic matter rather than a living micro-organism. He became convinced that it was the striped-legged mosquito ('le moustique a pattes rayee de blanc'), Stegomyia fasciata (now known as Aed.es aegypti) which was the variety of mosquito responsible for the spread of yellow fever[5], Beauperthuy published his findings in a local journal Gaceta Oficial de Cumana on 23rd May 1854[6], but an obscure Venezuelan journal did not circulate widely in those days. He followed this up with a report in 1856 to Marie Jean Pierre Flourens (1794-1867), Secretary of the Academie des Sciences, Paris, entitled 'Recherches sur la cause du cholera asiatique, sur celle du typhus icteroide et des fievres des marecages'[7], 'Typhus icteroide' was yellow fever and 'fievres des marecages' was marsh fever or malaria. To consider Beauperthuy's theory that 'le moustique inocule la fievre jaune', the Academie des Sciences set up a special committee of three eminent physicians: Etienne Serres (1786-1868), Gabriel Andral (1797-1876) and Jean Baptiste Boussingault (1801-87) which gave a favourable report and Beauperthuy's paper was presented to a meeting of the Academie on 14th April ? 1856 and published later that year in the Comptes Rendus de VAcademie des Sciences[Q], Beauperthuy's discovery was subsequently republished in L'Abeille Medicale (1856)[9], in the Escuela Medica (Caracas, 1875)[ 10] and in 1891 in the collected Travaux Scientifiques which were published posthumously, edited by his brother, Pierre Daniel Beau- perthuy^ 1], It is important to see Beauperthuy's ideas in the light of his times, the publication by Louis Pasteur (1822-95) of his germ theory of disease not appearing until the 1860s. It is true that Josiah Clark Nott (1807-73) of Mobile, Alabama, had in 1848 proposed that yellow fever was caused by 'animalcula', but he used this term to describe what we would now call micro-organisms[12]. Unfortu- nately, his 'animalcula' came to be miscontrued as 'insects' and it was thus that the priority for the discovery of the association of the mosquito with the spread of yellow'fever has been erroneously ascribed to Nott[13]. Beauperthuy was certainly well in advance of Carlos Juan Finlay (1833-1915) to whom the discovery of the role of the mosquito in yellow fever has also been attributed. Finlay, the son of a Scottish physician who married a Frenchwoman and emigrated to Cuba, studied medicine in the USA, qualifying MD Philadelphia, and then returned to practise in Havana. It was not until 1881, twenty-five years after Beauperthuy, that he pre- sented his famous paper on the role of the mosquito in yellow fever. When the USA occupied Cuba in the Spanish-Ameri- can War (1898) an American Army Commission on Yellow Fever in Havana, consisting of Walter Reed (1851-1902), James Carroll (1854-1907), Jesse William Lazear (1866-1900) and Aristide Agramonte (1868-1911), was set up and its report was published in 1901, almost half a century after Beauperthuy had made his original crucial observations on the association of yellow fever with the mosquito, knowledge which was later put to dramatic and successful use by William Cranford Gorgas (1854-1920) in his control of yellow fever in Havana and during the construction of the Panama Canal[14], Beauperthuy, Yellow Fever and Sir William Osier Sir William Osier (1849-1919) was aware of the import- ance of Beauperthuy's contribution to the unravelling of the mystery of yellow fever. In his "An Address on the Nation and the Tropics' delivered at the London School 2. Map showing area of Beauperthuy's activities. Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 147 of Tropical Medicine in 1909, Osier presented the follow- ing version of the yellow fever story: For centuries there has been a popular belief in the transmission of disease through mosquitoes and flies, and in the middle of the nineteenth century that remarkable clinician and anthropologist, Nott of Mo- bile, suggested the association between the mosquito and yellow fever and malaria. A more scientific pres- entation of the question was made by the French physician Beauperthuy, an enthusiastic student of the epidemics in the Spanish Main. But the first clear demonstration of a mosquito-borne disease was made by Manson (in 1877) in the case of filariasis. . . This lecture was published in The Lancet (1909)[ 15] which in a later issue (1910)[ 16] contained a letter from Juan Gutteras, Director of Public Health, Cuba, protest- ing at Osier's omission of Carlos Finlay, to which the Editor responded: It is probable that the theories of Beauperthuy had already been rife amongst the medical men in the West Indies and on the mainland. Beauperthuy and Finlay will stand bracketed together. . . It is open to everyone to examine the respective writings of both Beau- perthuy and Finlay. Both were original thinkers and both came to the same conclusion, but Beauperthuy formulated his opinions earlier;' Finlay coming later expressed his views more clearly and in a way more in conformity with modern thinking. This editorial comment was followed by the following letter to the Editor: Sir, The omission of Dr Finlay's name was a pure inadvertance for which I am very sorry. His work, of course, on the subject, has been all important. I am, Sir, yours faithfully, Wm. Osier. Malaria During his researches into tropical diseases, Beauperthuy addressed himself also to the problem of malaria and by 1854 considered that, as in yellow fever, the mosquito (but a different variety from the striped-legged Stego- myia) was the vector responsible for transmitting this disease. As early as 1868 he was recommending the use of mosquito nets as an anti-malarial measure[17]. In this context, it is important to remember that Beauperthuy's observations were long in advance of the demonstration by Sir Patrick Manson (1844-1922) of the role of the mosquito in filariasis sanguinis hominis in 1877; also of Alphonse Laveran (1845-1922) who first revealed the cycle of Plasmodium malariae in 1880; of Albert King (1841-1914) who in 1882 favoured the transmission of malaria by mosquitoes; and of Sir Ronald Ross (1857-1932) who in 1897 finally provided the scien- tific proof that was needed. Leprosy In 1867, Beauperthuy was placed in charge of the local lepers in Cumana, which provided an opportunity for him to make a more careful study of the disease. Lepers had first been seen in Cumana in 1730 and, as elsewhere throughout the world, they were considered to be incur- able and treated as pariahs. Beauperthuy's observations, however, convinced him that the disease was treatable and could be controlled. He disposed of the theory that leprosy was hereditary and concluded that the disease was contagious, a living agent being responsible for the infection and its transmission. Shortly afterwards, in 1871, the Norwegian, Gerhard Armauer Hansen (1841- 1912) first demonstrated the leprosy bacillus. Beauperthuy considered that lepers should be treated in special isolation hospitals, where their resistance to infection could be enhanced by improved hygiene and nutrition. His medicinal treatment was by internal reme- dies, e.g. mercury bichloride; as external applications he favoured cashew-nut oil (Thuile d'acajou'), and the cautery or silver nitrate. On this regime, he was able to demonstrate beneficial responses which, if not complete cures, were at least considerably palliative. The news of Beauperthuy's success with his lepers reached Robert Bakewell, the acting medical superinten- dent of the leper asylum in the neighbouring British colony of Trinidad. Bakewell sent some of his patients to Cumana and also spent three months in Cumana in 1868, following which he provided Governor Gordon of Trini- dad with a favourable report[18,19]. In 1869, Governor Gordon forwarded Bakewell's report to the Secretary of 3. Postage stamp issued in Venezuela in 1971, to commemorate the centenary of the death of Beauperthuy. 148 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 State for the Colonies, Lord Buckingham, who in turn sent it to the Royal College of Physicians. The Royal College of Physicians had for some time been taking an interest in leprosy in the West Indies and in 1863 had constituted a Leprosy Committee, composed of five Fellows: Arthur Farre (1811-87), George Rees (1813-89), Edward Greenhow (1814-88), Sir William Gull (1816-90) and Gavin Milroy (1805-86). This com- mittee reported in 1867 that leprosy was 'a constitutional cachexy', was not contagious and therefore special isola- tion facilities for treatment were not recommended. This, in fact, remained the official position of the Royal College of Physicians until, at the Leprosy Conference held in Berlin in 1897, it was convinced that leprosy was a contagious disease[20]. On receipt of Bakewell's report in 1869, the Royal College of Physicians suggested the appointment of 'a competent and disinterested person to enquire into the exact evidence of results of Dr Beauperthuy's treat- ments'. It was not until Bakewell forwarded a second report in 1870 that the College decided to judge Beau- l perthuy's claims. Meanwhile, it had become Beauperthuy's ambition to pursue his leprosy researches in a hospital adequately isolated and especially equipped for the purpose. The authorities in Venezuela would not provide the necessary funds. Beauperthuy and Bakewell had become friends and eventually, through Bakewell's contacts in London, the British government was persuaded to sanction the creation of a leper hospital in British Guiana and Beau- perthuy was placed in charge for a period of two years. There was already in British Guiana a leper asylum at Mahaica, 50 km from Georgetown. This was visited by Beauperthuy, who found the cases too advanced and conditions too crowded for his purpose. Governor Scott of British Guiana finally assigned the beautiful little island of Kaow, situated in the river Mazuruni off Bartica, which lay at the confluence of the rivers Mazuruni, Cuyuni and Essequibo. The island was well drained and free of mosquitoes and the hospital, for 60 patients, was built in pavilion style, one patient per hut. This hospi- tal?basic and simple?was the first of its kind in the world to be built exclusively for the study of leprosy. Beauperthuy arrived in British Guiana in February 1871 and lived in a house at Bartica Grove on the mainland, opposite the island of Kaow. He immediately set to work, being joined in July 1871 by Gavin Milroy, but sadly, two months later, Beauperthuy suffered a stroke and died on 3rd September 1871. , The leper hospital at Kaow was later abandoned. Beauperthuy, Leprosy and Milroy Following Beauperthuy's death, Milroy continued on his travels in the West Indies, visiting Jamaica, Barbados, Antigua and Trinidad, investigating leprosy but also studying other tropical diseases, especially yaws in Jamai- ca. On his return to England, his Report on Leprosy and Yaws in the West Indies (1873)[21 ] contained this vivid > comment on his visit to the leprosy asylum at Mahaica: On leaving the building I could not but feel that the case of the leper at the present time is much like that of the poor lunatic at the close of the last century: a hopeless outcast, regarded as a burden and possibly a danger, to be immured and kept apart with only food sufficient for his subsistence. It was this attitude towards the leper which Beau- perthuy had set out to revolutionise. In his report, Milroy described Beauperthuy's views on the nature and treat- ment of leprosy but concluded that Beauperthuy's treat- ment did not achieve a cure although it did possibly alleviate the leprosy lesions. The Royal College of Physicians set up a special committee to consider Milroy's report, consisting of three fellows with experience of leprosy in India: John Jackson (1804-87), William Tilbury Fox (1836-79) and Sir Joseph Fayrer (1824-1907). They concluded that, to date, no cure for leprosy had been discovered and that Beauperth- uy's treatment was not founded on any new principle, differing from others only in detail. However, they went on to say: Great credit is. due to Dr Beauperthuy for re-exciting the flagging attention of the medical profession to the possibility of alleviating the condition of leprosy, es- pecially by improved hygiene and diet and the use of medicinal tonics. Their report was accepted by the Royal College of Physicians and a Lancet leader, commenting on this verdict, said that the Royal College of Physicians had 'given the profession what was much needed?viz. a distinct and authoritative decision on the valu,e of the Beauperthuy plan of treating the leprous'[22]. The archives of the Royal College of Physicians contain a translated note (which appeared in The Creole News- paper, Georgetown, 22nd April 1874) by Dr G. F. van Coppenaal, accompanying a letter forwarded to the Colo- nial Secretary, Lord Kimberley, in which the writer castigates Milroy for a too hasty and erroneous assess- ment of Beauperthuy's treatment of lepers[23]. Beauperthuy's methods were later tried out around the world (Europe, India, South America) with varying degrees of success. Finale Louis Daniel Beauperthuy was undoubtedly one of that great band of pioneer medical scientists who, in the second half of the nineteenth century, addressed them- selves to unravelling the secrets of tropical disease. His doctrine of insect-borne diseases and especially his discovery of the association of the Stegomyia mosquito with the spread of yellow fever were fundamental obser- vations on which later investigators could build up more scientifically our knowledge of the nature and control of these diseases. In the case of leprosy, Beauperthuy may not have discovered a specific cure for the disease, but the enlight- ened fresh approach he brought to bear on the attitude towards and the handling of lepers provided inspiration for other leprosy workers around the world and also offered fresh hope to the millions of sufferers from that dread disease. Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 149 Acknowledgements I should like to express my appreciation of Madame Rosario Beauperthuy de Benedetti, whose Ecrits de Beau- parthuy (1985) provides testimony to her efforts, during the past 25 years, to establish appropriate recognition of her illustrious ancestor. References 1. De Benedetti, Rosario Beauperthuy (1985) Ecrits sur Beauperthuy, Paris: Hervas. 2. Beauperthuy, L. D. (1837) De la Climatologie. MD Thesis. Paris: Rignoux. 3. Wood, C. A. (1922) Annals of Medical History, 4, 166. 4. Beauperthuy, L. D. (1855) Gaceta Ojicialde Cumana, No. 79, p.350. 5. Tanon, L. (1958) Histoire de la Medecine, Numero special, pp. 37- 43. 6. Beauperthuy, L. D. (1854) Gaceta Oficial de Cumana, No. 57, 23rd May 1854. 7. Beauperthuy, L. D. (1856) Communication a M. Flourens, Paris. Cumana, 18th January 1856. (Archives of Academie des Sciences, Paris.) 8. Beauperthuy, L. D. (1856) Comptes Rendus des Seances de I'Academie des Sciences, Paris, 42, 692. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19 20, 21 22 23 V Beauperthuy, L. D. (1856) LAbeille Medicale, 13, 117. Beauperthuy, L. D. (1875) Escuela Medica (Caracas), No. 10, pp. 139-142. v Beauperthuy, L. D. (1891) Travaux Scientifiques de Louis Daniel Beauperthuy. Bordeaux: J. Gonzalez Font. Singer, C. and Underwood, E. A. (1962) A Short History of Medicine, 2nd ed. Oxford: Clarendon. Ackerknecht, E. (1965) The History and Geography of the most important Diseases, p.58. New York: Hafner. Scott, H. H. (1939) A History of Tropical Medicine (based on FitzPatrick Lectures, 1937-38), p.356. London: Arnold. ' Osier, W. (1909) Lancet, 2, 1402. Guiteras,J. (1910) Lancet,, 1, 1715. Beauperthuy, L. D. (1868) Letter to Madame Luisa Oriach de Monagas, Cumana, 5th May 1868. Bakewell, R. H. (1870) Medical Times & Gazette, 21st May 1870, p.550. Bakewell, R. H. (1871) Medical Times & Gazette, 25th Feb 1871, p.233. Cooke, A. M. (1972) A History of the Royal College of Physicians, Vol.3, p.828. Oxford: Clarendon. Milroy, G. (1873) Report on Leprosy and Yaws in the West Indies. London: HMSO. Editorial (1873) Lancet, 2, 339. Van Coppenaal, G. F. (1874) The Creole Newspaper, 22nd April 1874. (Archives of Royal College of Physicians, London.) Before the Computer In the era of computer medicine even we, the elderly innumerate, know that a byte means information, not mastication. We are trying to love the data base locked away on floppy disk. Did Francis Clifton foresee this when in 1731 he published his 'Tabular Observations Recommended as the Plainest and Surest Way of Practis- ing and Improving Physic'? He argued that 'Physic is only improvable by observation' and added that his 'experiment is attended with no manner of inconvenience or hazard to the patient'. He created a simple table in which the left-hand column was for recording the age, sex, and occupation of the patient with a comment on the patient's constitution and 'way of life as to eating, drinking and exercise.' The middle column was for morbid phenomena, dated by the day of disease and the calendar date. Then followed a column for remedies and a final right-hand column headed Eventus which translates smoothly to outcome. ? Dr Clifton had a short career, ending in mysterious disaster. The son of a merchant of Great Yarmouth, he obtained his MD in the University of Leiden in 1724. He was known for his love and knowledge of the classics and published a Latin edition of the works of Hippocrates. He was so keen on the father of Western medicine that he wrote a paper attempting to show that Hippocrates had anticipated Newton's work on gravity and published proposals for the printing by subscription of 'All the works of Hippocrates in Latin and Greek, digested in a new and regular manner'. No one subscribed and the project flopped. Clifton's classical learning earned him the friendship of Sir Hans Sloane who helped him to the Fellowship of the Royal Society in 1727 and in setting him up in a fashionable London practice. Cambridge University awarded him an honorary MD in 1728 and the College elected him a Fellow a year later. He gave the Gulstonian Lecture and was appointed physician to the Prince of Wales. Then suddenly and inexplicably all went wrong for Clifton. Leaving his house in Hanover Square, his rich patients and his influential friends, he set sail in 1734 for Kingston, Jamaica. There he made a start on writing an account of the diseases found in the island but some family disaster seems to have overwhelmed him. On 3rd May 1736 he wrote to Sloane: 'My misfortunes come so fast upon me and my brother's provocations were so frequently repeated that I was hurried in a manner to death about them'. Indeed he was, for within a few weeks of writing the letter he died. 150 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986

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?A is Editorial For long journeys swiftly accomplished jet travel is splendid. But the splendour lasts only from take-off to landing. Getting to and from the runway is a tedious complicated process full of unexplained delays and enough to exasperate a snail. It is all much like the practice of medicine in hospital. Once with the patient the physician can now accomplish so much. Working directly on behalf of the patient is the object of many years of training and the core of the physician's professional commitment. But how difficult it is to achieve that modest ambition. Time is frittered away on irrelevancies. A brief mention of notes and specimens lost, appointments fouled up and plans upset is enough to trigger off an anxiety state in any hospital doctor, each one nursing a personal file of such minor horror stories. As for communication between all sorts of colleagues within and without the hospital, one might do better with alert pigeons. This picture of a world that does so much good against the odds is sad and sour, but, in many places, true. Any patient can give a graphic account of how he has been affected and so can any member of staff. The frustrations and irritations are shared. However, critics have claimed that hospitals are organised solely for the convenience of consultants, and hospital managers, waving the banner of economy, have been known to ask consultants to 'generate less clinical activity'. It looks like a no win situation for doctor and patient alike. After all, the ultimate economy is to close a hospital and sack the staff. These personal complaints seem trivial when set against the huge and international problems of financing health care and the tensions inherent in deciding clinical priorities. What does matter is that our National Health Service is the biggest employer of labour in the country and that the practice of medicine is all about people. Every little breakdown in day-to-day hospital work means personal irri- tation that is usually expended by everyone blaming everyone else. The complex web of human relationships is a vital factor in the efficiency of a hospital and it is unlikely that every patient will be treated as a person unless every member of the staff is treated in the same way. The concept of health care regulated solely by market forces is fatally flawed because it omits human values from its equations. It is precisely that value of each individual's contribution to the care of the sick that must be seen to be recognised by others. When that is lacking the morale of a hospital suffers and grievances are nurtured by sectional interests. Good work for the patient does need mutual respect for the roles of all concerned. So management for clinicians is more than distributing an inadequate budget; it concerns the well- being of all colleagues and an acknowledgement of their worth. Physicians, with the skills of personal relationships that they should have for their patients, should be equally good in dealing with colleagues of all ranks. Meanwhile the Government needs to remem- ber that virtue is not its own reward and that cash builds morale. Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 73

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( >? Incidence and Management of Arterial Injuries from Left Heart Catheterisation S. G. CHIVERTON, BM, Senior House Officer r~ JOHN A. MURIE, MD, FRCS, Clinical Reader in Surgery t Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, Oxford A widely varying incidence of peripheral arterial injury following left heart catheterisation has been reported, although many studies were performed in the 1960s, well before the present day dramatic increase in reconstructive coronary artery surgery[l-4]. The number of patients being investigated by retrograde arterial techniques has increased correspondingly and these patients are investi- gated in an increasing number of medical centres by an increasing number of cardiologists. The potential for iatrogenic arterial injury is now greater than ever before. This study describes a contemporary experience of peripheral arterial trauma following cardiac catheterisa- tion in a centre performing more than 500 such examina- tions annually. The frequency of significant vessel injury and the nature of such injury is described, along with the outcome of corrective vascular surgical intervention. Method Vascular injuries requiring surgical treatment following cardiac catheterisation over a five year period (1.1.80 to 31.12.84) were reviewed. Case records and operation notes were scrutinised to identify possible mechanisms of injury, operative findings and surgical techniques em- ployed for vascular repair. During the study period 2,760 patients underwent left heart catheterisation in the John Radcliffe Hospital, Oxford. Cardiac catheterisation was usually performed percutaneously via the right common femoral artery using a Seldinger technique. The artery was punctured with a 16 gauge Pott's needle (Beckton-Dickinson, New Jersey, USA) and a 0.965 mm Teflon-coated guidewire introduced, over which cardiac and coronary catheters were inserted. The catheter most frequently employed was the No. 8 Fr Cordis pigtail catheter (Cordis, Ux- bridge, UK). A Cordis catheter sheath that eliminates the need for repeated insertion of the guidewire has recently come into common usage. Exercise testing (straight leg raising) with catheters in situ was used for investigation of Correspondence to John A. Murie, Esq., MD, FRCS, Clinical Reader in Surgery, Nuffield Department of Surgery, John Radcliffe Hospital, Headington, Oxford OX3 9DU. mitral stenosis. At the conclusion of the procedure hae- mostasis was effected by firm pressure over the puncture site for 10 minutes. The majority of patients were given 5,000 units of heparin intravenously during the pro- cedure and this was not reversed. In the 5.7 per cent of patients who had significant occlusive vascular disease of the aorto-iliac segment, left heart catheterisation was performed via the brachial artery. The brachial artery, usually on the right side, was exposed through a short transverse incision at the antecu- bital fossa and a small longitudinal puncture arteriotomy made in the vessel. After final withdrawal of the catheters this arteriotomy was closed either with a purse-string suture or, more usually, with a few interrupted sutures. The hand was inspected for signs of ischaemia at the end of the procedure. Results From 2,760 cardiac catheterisation studies performed during the five year period, nine instances of arterial trauma requiring surgical intervention were identified. Catheterisation was followed, therefore, by significant arterial injury in 0.33 per cent of cases. Clinical details of the three patients with injury to the femoral artery are shown in Table 1. In two instances a local thrombosis with distal limb ischaemia occurred. Although Fogarty catheter thrombectomy was possible in one patient, in the other an axillo-femoral graft was necessary to bypass the damaged segment of common femoral/external iliac vessels. The third patient under- went Fogarty catheter extraction of a small plastic intro- ducer sheath which had become detached in the external iliac artery. All complications were associated with the common femoral or external iliac arteries; no significant puncture trauma was noted in either the superficial femoral or profunda femoris vessels. All complications were diagnosed at the time of cardiac catheterisation or immediately thereafter and all were successfully treated by surgical intervention. No late complications of trans- femoral catheterisation were identified. Table 2 shows the clinical details of the six patients with 126 Journal of the Royal College of Physicians of London Vol. 20 No. 2 .April 1986 Table 1. Complications involving the femoral artery. Sex Age Indication Complication Time of diagnosis Surgery Outcome M M 73 53 50 constrictive pericarditis ischaemic heart disease ischaemic heart disease thrombosis thrombosis introducer sheath free in arterial circulation immediate immediate immediate thrombectomy and simple arterial suture axillo-femoral graft extraction with Fogarty catheter: Dacron patch good distal pulses graft thrombectomy at 8 days: anticoagulation: good graft function good distal pulses Table 2. Complications involving the brachial artery. Sex M M M F F F Age Indication Complication Time of diagnosis Surgery Outcome 30 53 73 31 33 63 aortic valve disease ischaemic heart disease ischaemic heart disease coarctation of aorta aortic valve disease mitral valve disease thrombosis thrombosis thrombosis thrombosis thrombosis haematoma immediate immediate immediate immediate immediate 24h thrombectomy and simple arterial suture thrombectomy and simple arterial suture vein graft vein patch vein patch evacuation of haematoma stenosis: vein graft: late aneurysm good distal pulses good distal pulses good distal pulses good distal pulses no further complication brachial artery trauma. In five cases local thrombosis with distal limb ischaemia occurred. All were diagnosed at or soon after catheterisation. Simple thrombectomy with arterial suture was performed in two patients, one of whom developed a local stenosis one month later which was corrected with a saphenous vein graft. One year after its insertion this graft had become aneurysmal and might need later surgical correction, but no other problem had occurred in the limb. The remaining three instances of thrombosis were treated by Fogarty catheter thrombec- tomy followed by either a saphenous vein graft (on one occasion) or by a vein patch graft (on two occasions). In four of the five patients described, the surgeon noted a raised intimal flap on the posterior wall of the brachial artery and it was assumed that such a lesion was involved in the thrombotic episode. At the time of thrombus extraction the raised intimal flap was sutured flush with the undisturbed vessel intima. All surgical procedures resulted in good distal limb perfusion. The final patient in Table 2 presented 24 hours after left heart catheterisation with an expanding haematoma. This was evacuated and no arterial repair was considered necessary. The integrity of the vascular supply to the limb was not in doubt and no false aneurysm has resulted. Discussion The reported incidence of peripheral arterial injury fol- lowing transfemoral left heart catheterisation varies from almost nil to over 12 per cent[l-3]. The most recent series, however, suggest that the current incidence is very low. Hessel et al. in 1981 described 83,000 peripheral angiograms performed via the femoral artery with an incidence of arterial injury of only 0.47 per cent[4] while Davis et al. in 1979 and McMillan and Murie in 1984 reported an incidence of approximately 0.3 per cent following left heart catheterisation by this route[5,6]. The incidence of femoral artery trauma requiring surgical intervention in the present study was only 0.11 per cent. Studies performed in the 1960s suggested that periph- eral vascular complications, principally femoral thromb- osis, are more likely in patients with cardiac valve diseasefl]. Both aortic incompetence[7] and mitral steno- sis[8] have been implicated. Perhaps the current low incidence of femoral artery complications is due to a relative decrease in recent years in those patients with valve defects undergoing left heart catheterisation. Car- diac catheterisation for the assessment of ischaemic heart disease, on the other hand, has increased. Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 127 Despite the suggestion that anticoagulation may be associated with a four-fold increase in peripheral arterial complications[7], no significant bleeding, haematoma or false aneurysm related to the femoral artery was encoun- tered in the present study. This differs from the report of McMillan and Murie in which false aneurysm was the single most common lesion in the femoral vessel[6]. However, many of their patients underwent left heart catheterisation while fully anticoagulated with warfarin on a long-term basis. This is not comparable to tempor- ary heparinisation of the patient as commonly employed in the present series. Despite an early report of only one complication from 388 transbrachial studies by Ikram and Nixon[9], con- temporary data suggest a much greater incidence, prob- ably nearer 5 per cent[5,10]. Certainly Brenner and Couchfll], in a rare prospective study, demonstrated that 28 per cent of patients developed a diminished or absent radial pulse after cardiac catheterisation via the brachial artery. In the present study the incidence of brachial artery injury requiring formal surgical correction was 3.8 per cent. Furthermore, most major brachial artery trauma was manifested by thrombosis and distal limb ischaemia rather than bleeding, haematoma or false aneurysm. This agrees with data from other centres[5,10]. Longitudinal arteriotomies were made in the brachial artery in the present series. Such wounds cannot be sutured directly without narrowing the vessel. Stenosis incurred from this technique may be responsible for some thrombotic episodes and, on theoretical grounds at least, a transverse arteriotomy with interrupted suture closure would be preferable. Cannulation of the brachial artery is more hazardous than that of the femoral. However, it should be remem- bered that the brachial tends, sometimes, to be used when the aorto-iliac segment is thought to be significantly diseased, possibly increasing the risk of the transfemoral approach. It must be appreciated, however, that the vast majority of peripheral arteriograms are performed via the femoral atery with retrograde introduction of a catheter often through a highly diseased aorto-iliac segment. Indeed, such studies are frequently performed to delin- eate the extent of aorto-iliac disease itself. Even in these severely atheromatous vessels the complications due to catheter passage tend to be minimal, although obstruc- tion may require the examination to be abandoned[4]. Most complications affect the actual site of puncture of the femoral artery, where atheroma is rarely gross even in the presence of serious changes in the iliac vessels. Although no direct evidence exists that cannulation of a diseased iliac artery is less hazardous than that of a normal brachial artery, this may be the case and merits future investigation. This study has shown that left heart catheterisation by the transfemoral approach is attended by very few serious complications from the vascular standpoint. The trans- brachial route appears markedly more hazardous and should be avoided if possible. Nevertheless, vascular surgical correction of any injury incurred at the time of catheterisation is likely to be successful, although the operation itself may not always be simple and should be undertaken only by a vascular surgeon. References 1. Lang, E. K. (1963) Radiology, 81, 257. 2. Kottke, B. A., Fairbairn, J. F. and Davis, G. D. (1964) Circulation, 30, 843. 3. Hautz, G. and Amplatz, K. (1968) Surgery, 63, 594. 4. Hessel, S. J., Adams, D. F. and Abrams, H. L. (1981) Radiology, 138, 273. 5. Davis, K., Kennedy, J. W., Kemp, H. G. et al. (1979) Circulation, 59, 1105. 6. McMillan, I. and Murie, J. A. (1984) British Journal of Surgery, 71, 832. 7. Mortensen, J. D. (1967) Circulation, 35, 1118. 8. Kloster, F. E., Bristow, J. D. and Griswold, H. E. (1970) American Heart Journal, 79, 175. 9. Ikram, H. and Nixon, P. G. (1964) British Medical Journal, 2, 1072. 10. Kitzmiller, J. W., Hertzer, N. R. and Beven, E. G. (1982) Archives of Surgery, 117, 1066. 11. Brenner, B. J. and Couch, N. P. (1973) American Journal of Surgery, 125,521.

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Book Review Practical Geriatric Medicine edited by A. N. Exton-Smith and M. E. Weksler. Churchill Livingstone, Edinburgh, 1985. 475 pages. Price ?34. Doctors in all branches of medicine (save those in paedi- atrics and obstetrics) now have to deal with an increasing number of elderly patients and this trend will continue for the rest of the century. It thus behoves all practising physicians to have some knowledge and skill in dealing with the elderly and differentiating disease from dotage if medical resources are to be used efficiently. This book aims to fill the gaps in the knowledge of 'Primary care physicians' (and hopefully surgeons) who may have had little formal training in geriatric medicine and for whom a major comprehensive textbook of gerontology would be inappropriate. The book is planned to be a practical geriatric vade mecum with a problem-orientated approach. The multi-author text suffers from the advantages and disadvantages of being mid-Atlantic (29 authors from the Americas, 32 from the UK and Ireland and one from the Antipodes). For example, American enthusiasm provided chapters on 'Sleep disorders' and 'Gonadal function and sexual potency in aging men'. However, 15 pages are devoted to the former subject, compared with eight pages on 'Transient ischaemic attacks and stroke' and only six pages on the 'Acutely confused patient', and few British patients would have access to 'well-trained sleep special- ists', polysomnographs or facilities for measuring penile blood pressure. The chapters on 'Diabetes' and 'Renal disease' give all blood glucose and serum creatinine values in mg/dl. The book is divided into three parts. The first is a general introduction to the assessment of the elderly patient and outlines some of the functional changes that accompany the ageing process. There is a useful chapter on 'The evaluation of the elderly patient for surgery' and others deal with such problems as 'Cancer' and 'Infec- tion' in its protean manifestations. The main part of the book deals with specific systems such as 'Special sense organs and communication', 'Res- piratory system' and 'Endocrine disorders'. Chapters within each section deal with selected common problems encountered in the elderly, for example 'Parkinsonism', 'Falls' and 'Hearing disorders'. The most useful parts of these chapters are those describing how illness in the aged differs from that seen in younger patients. Some infor- mation seems superfluous; all physicians will know the typical clinical presentation of myocardial infarction and the accompanying cardiac enzyme changes but it is helpful to have details of the atypical presentations of this condition in older patients. The chapter on 'Small bowel and pancreas' gives very practical advice as to likely causes of malabsorption in the elderly and the most expedient way of confirming the diagnosis. There is much useful guidance in these chapters but some of the advice is rather dated; few doctors would recommend subcutane- ous insulin injection for diabetic coma. The final part of the book deals with such topics as rehabilitation (not mentioned in the chapter on stroke) and public policy for the elderly. There is much of interest here but I wonder if the general reader (non-geriatrician) would delve deeply. The core of this book contains much helpful guidance for the non-geriatrician on the care of his or her elderly patients, which would hopefully speed their return to the community and independent living. G. M. Wood Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 125

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Sharing Knowledge and Experience of Disability R. S. STEVENS, md, frcp Formerly Medical Administrator, Kent Postgraduate Medical Centre at Canterbury M. D. WARREN, md, frcp* Formerly Professorial Fellow, School of Continuing Education, University of Kent at Canterbury The uneven development of rehabilitation services in the UK is a cause of continuing concernfl]. Major difficulties arise from the disjointed provision of services[2], the tunnel vision of members of the professions concerned [3], inadequate explanation and discussion with the dis- abled person and failure to involve him or her in the decisions taken about treatment, and the management of disability [4,5]. The Open University's course 'The Handicapped Person in the Community' is a major attempt to broaden knowledge and understanding be- tween different professional groups and disabled people and their families, to suggest a more questioning attitude towards the roles of 'adviser' and 'helper', and to intro- duce alternative approaches to the solution of problems faced by disabled people. We report a current local effort, jointly organised by the School of Continuing Education of the University of Kent at Canterbury and the Kent Postgraduate Medical Centre, which was intended to bring together doctors, remedial therapists, nurses, social workers, managers, voluntary workers, disabled people and their carers so that they could share both their knowledge and experience. Planning the Seminars It was accepted that each group would tend to have their own perceptions of problems and solutions, and would have different levels of knowledge about the aetiology, pathology, natural history and treatment of the under- lying diseases and disorders, "and of help, aids and services available to ameliorate some of the effects of the disabilities. It was hoped that the proposed seminars would focus on local needs and services against the background of the most up-to-date knowledge and of experience gained in other places. These considerations set the guidelines for the planning of each seminar and identified the intended audience. The main doubt about the plan was the feasibility of presenting knowledge of sufficient interest to the pro- fessional about his or her own subject, while keeping the Correspondence and requests for reprints to Dr M. D. Warren, 2 Bridge Down, Bridge, Canterbury CT4 5AZ. attention and understanding of those who had little previous knowledge of the subject. Each programme included invited contributions from doctors, physiothera- pists, occupational therapists, social workers, and patients, or officers or members of organisations repre- senting their interests. Some of the speakers on each occasion were 'national' leaders in their subject, and some were from the local services. Most of the seminars have taken the form of a whole- day meeting (10 a.m. to 4.30 p.m.) on a weekday, usually a Friday. Three of the meetings have used one or more evenings for sessions in addition to taking up a morning or a whole day. The essential component in the organisation of the seminars is the contribution made by the planner of each seminar. The School, on the advice of the medical administrator and the clinical tutor (now only the clinical tutor, since the post of medical administrator was abol- ished as part of service economies), invited one person to advise on the construction of the programme and to brief the chairmen and speakers. This help has been enthusias- tically and expertly given. Detailed organisation and the extensive distribution of publicity (including a mention in the local newspaper) were carried out by the organising secretary at the School and the medical administrator at the Centre. Topics The topics discussed included groups of diseases, specific diseases, terminal care, and problems related to medical, nursing and social work practice such as ethics, coping with stress, and communicating bad news (Table 1). The presentation of these last three subjects followed a some- what different format to that of the others. Plans are under way for seminars on cancer, AIDS, diabetes and strokes. The applications for attendance at the seminar on 'The confused elderly patient' so exceeded the capacity of the lecture room that arrangements were subsequently made to replicate the meeting with some different speakers on each occasion at other postgraduate medical centres in Kent. Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 133 i Table 1. Topics discussed at seminars Seminar j No. Date Subject and Planner Duration 1 Mar 1982 Ethical problems in the Health Service Dr M. S. Harvey 2 evenings, 1 morning 2 Apr 1982 Parkinsonism Dr M. Hildick-Smith whole day 3 Oct 1982 Hospice care Dr S. R. Kirkham whole day 4 Feb 1983 Communicating bad news Dr C.J. Allison 1 evening, 1 whole day 5 Apr 1983 Arthritis Dr J. Sewell whole day 6 Oct 1983 Hospice?sharing the care Dr S. R. Kirkham whole day 7 Feb 1984 Coping with stress Dr M. S. Harvey 1 evening, 1 morning * 8 Apr 1984 The confused elderly patient Dr R. S Stevens whole day 9 Oct 1984 Asthma Dr A. J. Johnson whole day 10 May 1985 Multiple sclerosis Dr C. I. Roberts whole day Attendance The seminars were held at the Kent Postgraduate Medi- cal Centre at Canterbury which has a lecture room seating 100 people and is well-equipped with audiovisual aids. Coffee, lunch and tea were provided in the Centre. The seminars attracted audiences of 54 to 108 people from the different interests expected (Table 2). It is noticeable that apparently few patients attended, al- though some patients (or disabled persons) were present as members of the voluntary bodies. A disappointingly small number of general practitioners attended the semi- nars on Parkinsonism, coping with stress, the confused Table 2. Attendance at seminars. 1 Subject Nos. (see Table 1) 4 5* 6 7 10 Doctors (GPs in brackets) 22(17) 19(6) 16(8) Nurses 14 24 22 Therapists and aides 23 2 Matron/Staff, Nursing, Residential and Retirement homes 2 2 Community Care organisers, Health Visitors and Day Centre staff 1 6 6 Social Workers and Care Assistants 1 11 Probation Officers Members of voluntary bodies 2 10 DHA or CHC 4 4 Teachers and research workers 1 1 Church workers 4 Patients 2 Chiropodists and Opticians Other, including Counsellors 5 Total 54 102 13 1 25 2 2 2 93 15(8) 12 3 21 5 6 3 3 71 15(10) 15(8) 6 22 18 13 13 17 2 1 3 6 94 19 1 5 72 15(5) 10 4 9 61 31(4) 29(14) 11 18 23 5 16 5 1 2 5 99 3 76 10(6) 10 20 ? 7 29 10 108 'Coincided with Update Workshop on Joint Disease elderly patient, and multiple sclerosis. No remedial thera- pists attended the seminars on ethical problems, hospice (sharing the care), or the confused elderly patient. Five of the seminars attracted more applicants than could be coped with (the maximum figure was set at 100). The numbers have remained high throughout the series, and some people have attended more than one of the semi- nars. Evaluation The high attendance at the seminars is one measure of success, and by and large the seminars have attracted the 134 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 mixture of professionals and others that was the aim. A reasonable proportion of each audience was of doctors, although some meetings attracted only a few GPs, despite the avoidance of the words 'rehabilitation' or 'chronic' in the titles of the seminarsfl]. One reason for the sparse attendance of GPs was that each seminar occupied the major part of a working day. This was the most con- venient arrangement for the other intended participants, but timing is obviously a difficulty in organising multi- disiplinary meetings. However, it should be noted that larger numbers of GPs attended the seminars on arthritis ? and asthma, which were arranged in the same way as some of the seminars they had poorly supported. Each participant was asked to complete a short ques- tionnaire about the arrangements, structure, content and conduct of the seminar. Only a few completed question- naires were returned and most of these made favourable comments such as 'all subjects valuable', 'lively useful v - discussion', 'liked the combined professional/client ap- proach', 'lot of new knowledge presented', 'very useful refresher', 'well planned and well chaired', 'please repeat for more people', 'encouraging to hear about so much research', and perhaps the final accolade, 'two days would have been better' Not all the comments were favourable. One domestic problem was the inadequacy of toilets for the ladies, who were in the majority at each seminar. There were criti- cisms of a few of the speakers and contributions and many useful suggestions about topics which could have been included. Only a very few people complained that the content of the talks was either too technical or too elementary although some people did find this was so on occasions and accepted that within limits it was inevitable at such seminars if so many experts from different backgrounds were to be attracted. Some participants would have preferred more small group discussion. This was considered from time to time by the organisers, but the construction of the groups, the identification and > briefing of group-conveners and the time taken up in reporting back were considered to weigh against this suggestion. However, it is a feature at the 'follow-up' local seminars now being carried out on the topic of the confused elderly patient. The main question, whether the seminars have im- proved the care of disabled people in the health districts in Kent and surrounding areas, cannot be answered direct- ly. As with all educational activities, it is assumed that increased understanding and self-confidence, awareness of other peoples' perspectives on familiar problems, meeting colleagues on 'neutral' ground and putting faces to voices and signatures are all means of improving services. The seminars have certainly been widely ap- preciated and have introduced well-attended and lively meetings at the Postgraduate Medical Centre. Acknowledgements We are grateful to the planners of the seminars listed in Table 2, to Dr Stuart Field and Dr Ian Roberts (succes- sive clinical tutors at the Kent Postgraduate Medical Centre), to Mrs Joan Thomason (organising secretary, health and social service courses, School of Continuing Education) and Mrs Margaret Allen (administrator of the Postgraduate Medical Centre) for their considerable help in organising the seminars, and to Mrs Shirley Wood- ward for typing this report. References 1. Gloag, D. (1985) British Medical Journal, 290, 1333. 2. Blaxter, M. (1979) Report of the Royal Commission on the National Health Service. Cmnd 7615. London: HMSO. 3. Brechin, A. and Liddiard, P. (1981) Look at it this way. New perspectives in rehabilitation. Sevenoaks: Hodder and Stoughton in association with the Open University Press. 4. Warren, M.D. (1985) International Journal of Rehabilitation Research, 8, 3. 5. The Prince of Wales' Advisory Group on Disability (1985) Living options. Guidelines for those planning services for people with severe physical disabilities. London: Prince of Wales' Advisory Group on Disability.

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Book Review Searching the medical literature?a guide to printed and on-line sources by J. Welch and T. A. King. Chapman & Hall, London, 1985. 154 pages. Price ?15. There are over 10,000 medical journals now published and the number is increasing continuously. Keeping up to date with medical developments even in one's own specialty is becoming extremely difficult. The ten or so journals taken regularly pile up on the desk and it is an effort to scan the titles, let alone read the articles. It is against this background that the invitation comes to give a lecture or write a review about recent develop- ments in your chosen field. The memory, that imperfect repository of facts, can recall vague details such as the Lancet had a useful leader last year or the JRCP (or was it the BMJ?) had a useful article in '82 (or was it '83?). But there's always the nagging feeling that out there in the mass of literature there is an article crucial to the endeavour. To assist the profession to search the literature system- atically there have been for many years indexing and abstracting services. Print sources for searching the peri- odical literature have been available since the 1870s. In recent years these have been supplemented by on-line data bases which at first could only be accessed by professional librarians but are now available to be interro- gated by anybody with a home computer and a modem. This book is subtitled 'a guide to printed and on-line sources' and it is the first book written by information scientists for the general medical reader. Although the section on print sources is useful, there will be little in it that is new to those who are regular users of Index Medicus and Excerpta Medica. The chapter concerned with on-line sources, however, will be a revelation to most readers, who are introduced to the services provided by hosts such as Dialog, DIMDI and Data-Star. Drug information services are the subject of a separate chapter and there are further sections on sources of statistical information, the reference literature and sources of advice for medical communicators. The authors have used refreshingly little jargon in discussing the technology, the data-base overviews show a similar clarity and the search examples illustrate well the techniques involved. The overall coverage is comprehen- sive and the book should prove an extremely useful reference tool. But useful to whom? Medical librarians will certainly find it a succinct and well-organised first point of reference, and as background reading for the medical profession the book may well clarify some issues. But the lack of objective evaluation of the services and of guidance about preferred sources will limit its use for the doctor who is only an occasional searcher of the medical literature. A. M. S. Mason 132 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986

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Education in Peripheral Hospitals: Missed Opportunities? J. H. ROSS, MC, MD, FRCP Retired Physician, Hereford The hospitals considered in this review are those district hospitals with heavy commitments in general clinical subjects, where the senior staff can only specialise to a lirnited degree, where the 'on-call' duties for any individ- ual are frequent, and which are distant from the regional centres. There are, for example, nine such districts in the West Midlands, with 31 general physicians and 27 gen- eral surgeons (not more than four of each in each district) serving 32 per cent of the population of the region (about 5 million). These figures do not include those smaller districts near teaching centres in which senior staff work at the centre and the local district hospital, where teach- ing of students is arranged formally and from which it is easy to attend central teaching sessions. It is acknowledged that the younger consultants on the periphery are nowadays of high calibre. They have often deliberately chosen to work away from large cities and have not applied for appointment at teaching hospitals or regional centres; many of them are possibly better teach- ers than their colleagues working and specialising in the centres. What opportunities have they, and should they have, for continuing their own education, looking after that of their junior staffs, and for accepting and helping medical students? Senior Staff The 'Terms and Conditions of Service of Hospital Medi- cal and Dental Staff (England and Wales)' define study leave as 'for postgraduate purposes approved by the employing authority, and includes study (usually but not exclusively or necessarily on a course), research, teach- ing, examining or taking examinations, visiting clinics and attending professional conferences'. All these valu- able activities are to be carried out 'with pay and expenses, within a maximum of thirty days (including off duty days falling within the period of leave) in any period of three years. . .' Employing authorities have in the past been generous and have made it possible for consultants to study for longer periods and in alternative ways, but I have known study leave, requested for a week to complete the writing of a paper, refused although this could surely have come under the heading of 'research' and I doubt if study leave has often been granted to allow consultants to teach junior staff or students within their own hospitals. The present position is not satisfactory, but unfortunately a simple decision to increase the duration of study leave would not help much, as the major limiting factor is the increased > work imposed on colleagues by the absence of one member of a department of three or four; six weeks' annual holiday already results in three months of 'one-in- > two' on-call for the senior staff in a department of three. Physicians may be able to ask their geriatrician colleagues to help in such circumstances, but surgeons, obstetricians and gynaecologists have an inescapable extra burden now that locum cover is less frequently provided. However, it would seem to be widely accepted that a day's absence at a meeting or teaching centre does not require the granting of study leave: no application for absence is made, and therefore statistics about consult- ants' study habits have little meaning. Occasional days spent informally in a specialist unit, with opportunities for discussion and individual attention, can be much more rewarding than attendance at formal courses, meet- ings or conferences, as can the hours spent in a library \ stimulated by a proposed case presentation, publication or teaching session. Time for attendance at regional centres, perhaps a day fortnightly, and time for teaching junior staff and stu- dents should be allowed for in the job descriptions and contracts of consultants in peripheral hospitals. However, this would require extra staff and so would cost money to provide them. : The welcome development of postgraduate centres in district hospitals in the last 25 years has probably ben- efited consultants less than general practitioners and junior medical staff. One often goes out of loyalty to hear one's colleagues or their visitors speak on subjects of little relevance to one's own interests. Perhaps the most ben- eficial activities for consultants in these centres are prep- aration for teaching sessions or lectures and increased contact with general practitioners. Visits by specialists and experts from regional centres are excellent, but are most valuable without the large audiences which every- one usually hopes will gather; the visitors should address small, specifically interested groups with plenty of time I for discussion and exchange of ideas. The visitors must be warned that the small size of the audience is an indication , of interest rather than lack of it. Regional associations or clubs, for example thoracic, urological and endocrine, should have at least one of their meetings each year at a peripheral hospital, the arrange- ments being made by a local consultant. l 136 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Junior Staff Senior Registrars There used to be no place for senior registrars in these hospitals. This was at a time when, throughout their appointment, they were expected to be learning tech- niques in their chosen specialty and to be actively en- gaged in research. Now that periods of general training are recommended for accreditation, at least for phys- icians, by the Joint Committee on Higher Medical Train- ing, both the senior registrars and the local consultants would benefit from more rotation schemes involving peripheral hospitals. The former would really meet gen- eral medicine and take responsibility for its practice i . .for the population as a whole, small district general hospitals are more important than the large teaching hospitals')[l], and the latter would gain specialised infor- h mation and increase their opportunities to be absent for learning and teaching. Unfortunately, the family life of senior registrars often limits their moving far and most rotation schemes make use of larger district hospitals in the cities in which the teaching hospitals are situated; these have larger consultant staffs and the general medical responsibilities of the senior registrars are reduced. Registrars and Senior House Officers This is the staff group which can benefit most from a peripheral hospital where there is enthusiasm to teach. There is little to be said which is not already well known. It is important that junior staff should participate in their v education; presentation of cases following detailed prep- aration using a readily accessible and well stocked library is the most useful activity. The opportunity to learn and carry out practical procedures is often more available peripherally but there must be consultant supervision. Time for further education should be included in job descriptions. The clinical tutor should have the responsibility for seeing that all the hospital departments are providing adequate teaching for their juniors, outside as well as within his postgraduate medical centre. , Teaching for the MRCP and FRCS, given not only by physicians and surgeons, but also by pathologists, oph- thalmologists, radiologists and others, is of course essen- tial but all too often the clinicians have to cancel or fail to arrange their sessions. These should be arranged well ' \ ahead and adhered to. Bedside teaching should be in- itiated by a junior who has seen the patient in advance and discussion groups are also most valuable if initiated by a juniorHwho has prepared a lecturette on the subject. Most regions have centrally arranged day courses for postgraduate degrees but attendance from the periphery can be difficult, especially in the winter, and the optimum duration for a course is probably one week. Pre-Registration House Officers ? Most house physicians and surgeons enjoy presenting cases at their departmental meetings and some occasion- ally attend MRCP or FRCS sessions, but otherwise attendance at postgraduate centres for lectures and meet- ings tends to be food-orientated during lunchtime. This is not surprising after years of formal education. Pre- registration education and experience should for the most part take place at the bedside, in the operating theatres and, morbid though it sounds, in the post-mortem de- partment. Medical Students If, as stated above, there are many good consultant teachers in the periphery and if clinical practice there is nearly related to what most students aspire to, then many opportunities for good undergraduate education are now being missed. Present arrangements are very variable. The postgrad- uate tutor at some teaching hospitals vets a selection of peripheral hospitals and then makes formal arrangements for final year student attendance for about four weeks. The students are attached to medical or surgical firms and spend most of their time in the wards helping to admit patients and following their progress. Attendance at clinics, where pressure of work on the staff makes short- cuts inevitable, is carefully arranged so that the students can see an experienced doctor dealing with awkward problems. These are the ideal arrangements except that contact with consultants is often confined to 'business' rounds when much time is spent in discussing adminis- trative arrangements for the patients. Some of this is no doubt good for the students but the consultant should have time to meet the students at regular intervals entirely for educational purposes and outside the consult- ant's routine clinical work. Most student arrangements are in fact more haphazard than this. Intermittent attachments are arranged by the regional teaching centre. These may only be for 'lame ducks' who can be rewarding to help. First year students may be sent; they get far less benefit from the volume of patients displayed to them and the informal teaching than do final year students. The period of attachment may be only for two weeks or less, which is inadequate and often treated as a holiday. Arrangements made by the students themselves during their elective periods may be successful and more may be learned than during trips to exotic foreign countries. One teaching centre surprisingly used to encourage its students to find their own attachments during their first year, having only completed an introductory course; possibly the students did learn as much as they would have done in their first firms at their teaching hospital but the peripheral teachers could not spare the time for the detailed supervision needed at that stage of medical education. Medical students should play a part when the firm to which they are attached is dealing with emergencies. The drama of emergency admissions and procedures can be a more potent form of education than any number of lectures and demonstrations; few of us forget the details of patients whom we first clerked or had to help in some way at unsociable hours. Journal of the Royal College of Physicians of London Vol. 20 No.' 2 April 1986 137 Nurses The teaching of nurses by consultant staff, especially at the bedside, has diminished in recent years. Possibly this is related to limited funds in nursing schools; consultants are expensive. In addition nursing tutors may believe that nurses should be taught by nurses and not doctors. It is sad, however, when carrying out a procedure which one has done in an orthodox way for many years, to be told by an assisting student nurse that one's method is not that taught in the nursing school which was probably demon- strated there on a video display provided by a drug firm. The teaching and demonstration of clinical activities should be done by clinicians, and most consultants would be happy to help, given time. Their salaries should include an allowance for this without individual lecture fees being necessary, and there should be a contractual obligation to do this work, which would certainly be appreciated by the students. Postgraduate training for ??< I trained nurses has been neglected in most hospitals, and could also be improved by consultant participation. Conclusion Educational opportunities for all staff are being neglected in peripheral district hospitals. There should be improve- [ ment if all consultant appointments allowed time for j teaching and learning sessions. The district clinical tutor should supervise postgraduate education in all depart- ments. Acknowledgements I am grateful to Dr Henry Connor for comments, and to , Mrs Belle Rhodes for secretarial work. I Reference 1. Hampton, J.R. (1985) Hospital Update, 2, 161. J Bold Words 'I would beg any educated person to consider what are the conditions in which alone animal life can thrive; to learn, by personal inspection, how far these conditions are realized for the masses of our population; and to form for himself a conscientious judgement as to the need for great, if even almost, revolutionary reforms'. This pas- sion is unexpected in the annual statistical report of a Medical Officer of Health. The writer, John Simon, was an unusual medical officer and the first to be appointed by the City of London in 1843. Simon, bred and educated in England, was more French than English; both his grandfathers and his mother were French. He started his medical career as a surgeon, being distinguished in comparative anatomy. There was no formal training in public health in those days. Apart from collecting statistics he was all for seeing for himself and then using figures to buttress the argu- ments derived from personal observation. He never ceased to try to impress the administrative bodies to whom he was responsible and they must have been influenced by the power of his words. In his report of 1850 he called the City of London 'this pestilential heaping of human beings' and 'this uncon- trolled evil'. The filth and squalor that he had seen but his masters kept away from created 'mortality enough to mask the results of all your sanitary progress'. He went on to say that it was his duty 'to tell you where disease ravages the people under your charge' and of the injury that these conditions inflicted on the community. Simon knew at first hand what environmental disaster could do to people, apart from specific disease risks. He wrote: 'Side by side with pestilence there stalks a deadlier presence; blighting the moral existence of a rising popu- lation; rendering their hearts hopeless, their acts ruffianly and incestuous; and scattering, while society averts her eyes, the retributive seeds of increase for crime, turbu- lence and pauperism'. Simon was well aware that the interpretation of epide- miological statistics is not easy and that apparently beneficial alterations in environment can have unexpect- ed results. He and others were concerned by the finding that death rates in the higher areas around the source of the river Thames were around 17 per 1,000 per year whereas in the low marshy areas, both on the north and south banks of the Thames east of London the death rates were about 24 per 1,000. It seemed obvious that drainage of the marshes would eliminate many diseases, particu- larly malaria, that had been a scourge of the marsh people for centuries. So the marshes were drained and turned into fertile land which became the vegetable garden for London. The Londoners got better food, the farmers got richer and all things should have been bright and healthy. But the infant mortality rate did not drop as firmly anticipated; it rose. Simon went back to see what had happened. 'It was generally thought' he wrote later, 'that the infants no longer received any injury from the soil, climate or malarious influences but that a more fatal enemy had been introduced by the employment of the mothers in the fields. On this agricultural employment of women there follows identically the same results as have already been traced to result from the employment of women in manufacture'. The women, working for very low wages on the newly fertile ground, had to leave their children with whoever would take them. These minders fed the children on a mush of sugar, bread and water. To keep the children quiet opium was frequently used. A new social evil had come from an apparent improvement of environment. 138 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986

PMC005xxxxxx/PMC5371121.txt

Training to be a Physician COMPILED BY THE STANDING COMMITTEE OF MEMBERS OF THE ROYAL COLLEGE OF PHYSICIANS j CONTENTS Foreword Page 75 Introduction 76 The Standing Committee of Members 76 Acknowledgements 76 1. Preparing for Consultancy The College's Role in Postgraduate Education 77 The Role of the Regional Adviser 78 Consultant Appointments Committees 79 Applying for Consultant Appointments 79 General Professional Training 80 Higher Professional Training 82 Part-time Training 84 Should a Doctor learn to Manage? 85 2. Difficult Choices: Inferences from Original Surveys Survey Method 86 Keeping up to date in (General Internal) Medicine 87 Research post-MRCP 89 Career Planning with the MRCP(UK) 95 Benefits and Problems of Training Abroad 98 Page 3. Individual Specialties Accident and Emergency Medicine 100 Cardiology 101 Clinical Genetics 102 Clinical Immunology/Allergy 102 Clinical Pharmacology 103 Communicable and Tropical Diseases 104 Community Medicine 104 Dermatology 105 Endocrinology and Diabetes 106 Gastroenterology 106 General (Internal) Medicine 107 Genito-urinary Medicine 107 Geriatrics 108 Haematology 108 Intensive Care 109 Medical Oncology 109 Neurology and Clinical Neurophysiology 110 Nuclear Medicine 111 Occupational Medicine 111 Paediatrics 112 Rehabilitation Medicine 113 Renal Medicine 113 Respiratory Medicine 113 Rheumatology 114 FOREWORD The Royal College of Physicians of London was founded in 1518 through a charter given to Thomas Linacre by Henry VIII. The King, and the six physicians who petitioned him to establish the College, were motivated by the need to regulate the standard of medicine as practised in London. The maintenance of high standards of medical practice ? no longer confined to London ? remains the College's main concern. In part, this booklet explains how the College achieves this objective. Through the examination for Membership, which it now shares with the two Scottish Colleges, selection is made of those thought worthy to proceed to 'Higher Medical Training', to become specialists trained in general (internal) medi- cine or one of its branches. This booklet was designed by the College's Standing Committee of Members to offer guidance to those wishing to embark on such training. In a characteristically thoughtful way, the Committee has gone well beyond this narrow brief and has included sections, for instance, that deal with research and the all- important need to keep up to date in general medicine. The extraordinary advance of medical science has introduced complexities into clinical practice that lead inevitably to specialisation. Necessary as this might be in some circumstances, many of us share the concern ex- pressed by Sir William Osier in 1919 about 'the inevitable tendency to a narrow and perverted vision, in which the life of the ant-hill is mistaken for the world at large'. Balance must be sought between the acquisition of broad- based general medical knowlege and experience and the high degree of expertise and sophistication derived from specialisation. At the same time, the pace of scientific advance is such that physicians find it increasingly diffi- cult to keep up with new developments. The use of recombinant DNA technology or nuclear magnetic reso- nance, for instance, will soon transform clinical practice and demand increasing effort and application. What this booklet does not say is that to be a successful physician you will have to work very hard throughout your pro- fessional life. To those of you who accept this challenge I offer the assurance that you will find it overwhelmingly satisfying. Raymond Hoffenberg President, Royal College of Physicians Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 75 INTRODUCTION At the beginning of his term as Chairman of the Standing Committee of Members, my predecessor, Dr Martin Muers, proposed that, each year, the Committee should take a major interest in a specific topic as well as dealing with its usual business relating to College affairs. It was decided to survey the Membership in an attempt to quantify some of the folklore relating to training for physicians after the Membership examination. The mid- dle section of this booklet is an attempt to describe these results and quantify some of the benefits and problems associated with postgraduate education, spending time abroad, and a period of full-time research. The final survey in this section attempts to describe some character- istics of 'high-flyers', identify those who are likely to get into difficulty in their careers and suggest some options that might be considered in career planning. The first section complements this by some clear definitions of the process and requirements for training and has been written mainly by College Officers. In the final section we have asked individuals in the sub- specialties of medicine to provide pen pictures of each sub-specialty with an emphasis on training requirements and long-term job prospects. The booklet contains many personal views and opin- ions and was designed and edited by members of the Standing Committee of Members to whom I am person- ally indebted and grateful for their hard work. It should not be interpreted as being in any sense an official College document. It is aimed at physicians who have attained the Membership, and we hope that it will prove useful to them in planning a career in medicine. Formal require- ments in medicine and its sub-specialties are clearly laid out in the handbook of the Joint Committee on High Medical Training and the latest edition should be con- sulted, bearing in mind that the JCHMT encourages considerable flexibility in training programmes. John H. Tripp Chairman (1984-85), Standing Committee of Members THE STANDING COMMITTEE OF MEMBERS The Standing Committee of Members (SCM) is the forum within the College for representation of the views of younger physicians. Its 20 members are elected by postal ballot of the Collegiate Membership. Usually, the committee has approximately equal numbers of regis- trars, senior registrars and consultants. The five longest- serving members retire each year and of the new members two must be less than 33 years of age and two must work outside London. The committee meets every three months to discuss all matters which affect the interests of Members. Recently we have considered the problems of part-time training, and proposals for changing general professional and higher specialist training. We have commented on many of the guidelines on consultant appointments which are sent to Regional Advisers. It has also been possible to suggest amendments to College publications at draft stage. Often the SCM has expressed concern over aspects of medical training and career structure to the College Council and action has been taken as a result. The President, Registrar, Treasurer, Assistant Regis- trar, Linacre Fellow, Hans Sloane Fellow and College Secretary sit on the SCM and four members of the SCM sit on the College Council. The views of the committee are therefore very readily passed on to the decision- making bodies. Members are informed of our activities by an article written by an SCM member in the quarterly College Commentary. Two Members, one from the general Membership and usually one from the SCM, are elected to each of the College specialty committees, where they sit as full committee members. This provides an important method of communicating developments in the specialties. Each year the SCM arranges an open General Meeting of Members to present reports of its activities and to give Members an opportunity to raise issues for discussion. Thereby a chain of representation exists for anyone who has attained the MRCP diploma. Clive Roberts Chairman (1985-1986) Standing Committee of Members Acknowledgements We thank the College Officers and staff for their individ- ual contributions and the underwriting of this publi- cation. We are especially grateful to Miss Susan Ryland for the unerring efficiency and unending patience with which she has effectively co-ordinated this report. We gratefully acknowledge the help of many others who have advised on the contents of scripts. Our thanks to Dr David Smith, and his student, Hugh Andrew, for the statistical analysis of the data in the middle section of the book. We thank also Mr Chris Ryman and his staff at the College for achieving a very good response rate for the surveys, while preserving confidentiality, and the computer data clerks at the University of Exeter computer unit for successfully de- coding the questionnaires. Tawfique Daneshmend, David Honeybourne, Martin Muers, Andrew Peacock, Clive Roberts and John Tripp 76 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 I 1. PREPARING FOR CONSULTANCY The College's Role in Postgraduate Education In its approach to education the College aims to provide up-to-date information and views; it does not arrange courses designed for the examinations for postgraduate .^ diplomas. The bulk of the educational programme is naturally clinical, with an emphasis on the basic scientific and clinical aspects, but ethical and administrative topics are not neglected. The College's educational activities may be described . . as follows. 'Teach-ins' Selected topics, e.g. the treatment of heart failure, infec- tions in immunocompromised hosts, are dealt with in detail. Each Teach-in is arranged by an expert in the field , who assembles a panel of expert speakers who not only deliver their views but form a brains trust for the audience's questions. The Teach-ins are perhaps the most didactic of the College's teaching activities, and although not overtly planned as such, the closest it comes to teaching specifically for the Membership examination. An obvious disadvantage of the Teach-ins was that they were held only in London. Conscious of this, the College has started to hold Teach-ins outside London. Conferences The purpose of conferences is to present advances in medicine with an emphasis on clinical and basic sciences. J There are three main types of conference. Free Ranging. Two conferences are held each year, one in London, known as the Advanced Medicine Conference, and another in the provinces. Both cover many unrelated topics. Conferences addressing Specific Subjects. Over a period of anything from one to three days a topic is explored and discussed in detail. The subjects of these conferences range from those with wide general appeal, e.g. infec- tions, hypertension, diabetes mellitus, to those of interest to a smaller number of doctors, e.g. sports medicine. One , of these, held every autumn, is a two-day paediatric conference on either a single or multiple child health topics. As well as conventional medical subjects, the College also tries to examine clinical matters in other dimensions, e.g. diseases in ethnic minorities. Within this group of conferences one should be singled out for special mention. This is the biennial conference \ entitled 'Science and Medicine,' at which basic scientists eminent in their field present the most recent advances in their disciplines to an audience of clinicians. The purpose of this meeting is to inform clinicians of the new thoughts and findings in the basic sciences which are or will be influencing their clinical practice. \ One-Day Meetings. More recently, the College has begun to hold one-day meetings, under the general heading of 'Issues in Medicine', that are designed to explore subjects which are controversial or about which there is indecision in the profession. These meetings are not to forge a consensus, but are quite simply to stimulate debate. Both clinical and ethical subjects have been explored, e.g. 'Salt and Hypertension' and 'Priorities in Medical Care'. Lectures Each year the College presents 16 to 18 formal lectures, most of which are endowed. Until recently all but one were held in London but now three or four are held in the regions. The broad subject matter is stipulated in the endowment of some of these lectures, and their actual content usually reflects the special interest and experience of the invited lecturer. The College therefore has only partial control over the subject matter of these lectures, and although they usually accompany the conferences held throughout the year, they are an adjunct to, rather than an integral part of, the College's educational pro- gramme. Nonetheless, they present a rich and varied pool of information and reviews. The Journal of the Royal College of Physicians This quarterly Journal presents a wide-ranging review of medicine for all types of physician. It publishes much material derived from College conferences and lectures. Miscellaneous Educational Activities Some educational activities are not included above. The College holds courses in French with a medical bent ? a one-week residential course in France and a series of weekly lessons held at the College. The possibility of teaching outside London and of including other lan- guages is being examined. The College administers a number of scholarships for travelling and for undertaking research work for a period of two to three years. Although there are no formal curricula for the exami- nations of the College, there are occasional meetings at which those interested ? either teachers or candidates ? are informed of the style of the examinations and the criteria by which candidates are judged. Lastly, mindful of the problems posed to certain doc- tors by the examination for Membership, there is a counselling service for those who are considered on the basis of their performance to need advice, and this, of course, is also available to those who seek help. In all, the College makes available a continual and varied diet of educational material which it attempts to keep topical and comprehensive and which in fact a physician of any age should Find helpful and stimulating. D. Gwyn Williams Assistant Registrar, Royal College of Physicians Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 77 The Role of the Regional Adviser Regional Adviser posts were made in response to the effective organisation of the National Health Service on a regional basis in 1969. As the work gradually increased, deputies were appointed so that now almost all the regions have an Adviser and a deputy. These Advisers are appointed to the regions in England, Wales and Northern Ireland and there are also Advisers overseas. There are no such posts in Scotland, which has Royal Colleges in Edinburgh and Glasgow. The usual method of appointment is for the Fellows in each region to elect the deputy Adviser, who succeeds the Adviser after 2-3 years. Meetings of Regional Advisers The Advisers and the deputies meet quarterly at the College on the morning of Comitia. The meeting is chaired by the President; the Registrar and the Treasurer attend. The Censors and Council of the College are represented. Any Regional Adviser can add to the agenda any subject that he feels should be discussed. The func- tion of the meeting is advisory only, though its influence is considerable. Liaison with Fellows and Members in the Region In order to represent the views of the local physicians, Advisers must keep in close contact with them. In a large region this can be difficult, so the responsibilities within the region are often geographically divided between the two Advisers, one of whom will often come from a non- teaching district. The Regional Adviser can be consulted by any Member or Fellow in the region. Membership of Regional Specialist Sub-committees The Advisers are ex officio members of the Regional Specialist Sub-committees, which usually meet twice a year. The place of the meeting often changes, giving opportunities for visiting each hospital and district. Al- though the Advisers are full members of each of the committees, their main responsibilities are to listen to problems which concern the College and to try and interpret College regulations and views. The Advisers have direct access to the Regional Medical Officers and officers of the Regional Authority. With the recent reor- ganisation, Advisers' opinions on regional problems are sought increasingly often. Consultant Appointments The College is concerned with the appointment of con- sultants in medical specialties and names one of the members of the appointments committee, who is known as the College Representative. Before advertisement, the job description must be approved by the Regional Ad- viser. It is his responsibility to assess all aspects of the proposed job, particularly the facilities available and junior staff support. Senior Registrar Appointments In recent years the Advisers have also become involved in the appointment of senior registrars in medical special- ties. There is no formal representation of the College on these statutory committees but most regions ask the Regional Advisers to nominate a representative. The Regional Adviser may himself be the representative, but, more frequently, particularly if the subject is outside his own sub-specialty, he will nominate another Fellow with- in the region to represent the College. Nominations for Fellowships and Distinction Awards New Fellows are nominated annually, the closing date being December 1st. Soon afterwards the Advisers re- ceive the list of nominations for their region. They make enquiries among the Fellows to determine the support for these nominations and then transmit their findings to the College. The Advisers are not involved in the final decisions. The College has the role of proposing its Fellows and Members for Distinction Awards and one of the Advisers attends the College 'C' Awards Committee. They take soundings in the region before the meeting of the commit- tee. They do not attend the higher Awards Committee but may suggest names. Professional Training The Advisers are involved in the assessment of posts for recognition for general professional training. They are thus concerned in the approval of senior house officer posts and of most registrar posts, which must be so approved before advertisement. The Advisers maintain a list of recognised posts and have to make sure that reassessment by a visit takes place when recognition is about to lapse, usually after approxi- mately five years. In liaison with the Postgraduate Dean the Advisers monitor the recommendations of the visiting team, the visit being organised by the relevant clinical tutor and local clinicians. The Advisers are not responsible for approval of posts for higher medical training, which is organised directly by the College, though they may be members of a visiting team. Other Activities The Advisers are ex officio members of the Regional Postgraduate Committee and as such may serve on its sub-committees. They are frequently concerned with training facilities for junior staff. They may be asked by the College to counsel candidates who have difficulty in obtaining the MRCP and give advice on career pros- pects. The Regional Advisers are at times also involved in the collection 6f information. This has included the on-take commitment of general physicians, the organisation of ethical committees and the establishment of registrar posts. 78 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Conclusion The creation of the post of Regional Adviser was intended to establish a College presence outside London. The fact that the work and responsibilities have gradually in- creased shows that the move has been successful. Fellows and Members of the College, other members of the medical profession and Health Service administrators have become increasingly aware of the function and responsibility of the Royal College of Physicians. F. D. Rosenthal Regional Adviser Consultant Appointments Committees Appointment of a consultant in the National Health Service has to follow a set procedure; the appointment must be advertised, an advisory appointments committee must be convened, an interview held and a person selected to be recommended to the Regional Health Authority. Before a post can be advertised, several steps have to be taken. The District Health Authority decides the nature of the appointment it would like to see made. Whether it is a new post or a replacement, there may be conflicting views on its character and on details of the job descrip- tion. Local medical opinion is likely to be predominant in making the decisions, but the administration will also have its say. When the Authority has decided what it wants, the job description is submitted to the Regional Adviser of the College. By an agreement between the Department of Health and the Colleges, consultant appointments are not advertised before his approval is given. The Regional Adviser may take what advice he likes concerning a proposed appointment. If it is not in his own field of interest he will probably consult officers of the regional specialty committee and/or the chairman or secretary of the College committee. He may ask that certain aspects of the job description be changed or even disallow the appointment altogether, although this is fortunately rare. College committees in the various specialties have drawn up guidelines to help Regional Advisers assess the suitability of an appointment, giving general guidance as to the facilities and resources required for a consultant appointment in that specialty. These guidelines have been scrutinised by the Council of the College to make sure that they are in general harmony with each other and that, while insisting on essential requirements, they do not demand so much that the post becomes impossibly expensive. When its description has been approved, the job is advertised in the medical press. A Consultant Advisory Appointment Committee (AAC) for that job is set up. Its composition is determined by statute and includes two representatives from the District Authority, usually doc- tors from the hospital where the appointment is to be made, and at least one colleague from the same specialty, a teaching hospital representative and a College represen- tative. The College representative, who must come from outside the NHS region concerned, is almost invariably a Fellow of the College, usually fairly senior. He or she is selected from a file held in the College of all Fellows who have been graded on election to the Fellowship and at intervals thereafter by the appropriate Regional Adviser and his deputy and by the chairman and secretary of the relevant College committee. Most Fellows are regarded as suitable to represent the College at consultant AACs but some may be less so, perhaps because, of the limited nature of their interests. The College tries to ensure that a wide variety of Fellows represent it at these important committees. Methods of short-listing vary; the College representa- tives should be fully involved in this process. The com- monest method is for each member of the committee to mark the candidates and then four or five are invited for interview. The College representative is a full member of the AAC, with neither more nor less power than the others. He is charged by the College with seeing that the selected candidate is adequately trained for the appointment but this does not mean that the candidate must be accredited; indeed, we specifically ask our representatives to be flexible on this point. If a candidate is appropriate for the appointment but lacks some limited aspect of training, for example proficiency in a technique, the AAC may rec- ommend that he undertakes further training for a period of a few weeks or months before taking up his appoint- ment. The recommendation of the committee is usually announced to the candidates at the end of the meeting. The College representative is free to question appli- cants on all aspects of their application, not merely the adequacy or otherwise of their specialist experience. He is asked by the College to emphasise its interest in encour- aging research and to bring out the candidates' research contributions. He has a vote in the committee's decision, but he does not have a veto. If he is disturbed about a selection he may report to the College and even, exceptionally, ask the College to take up his objections with the Regional Health Authority. The number and quality of applicants for consultant appointments varies greatly. Some specialties are less attractive than others and may attract few and poor applications and occasionally for this reason no appoint- ment is made. In other specialties the pressure is intense and 10-20 high-class applications may be received. David Pyke Registrar, Royal College of Physicians Applying for Consultant Appointments Members often raise questions about the 'fairness' of Advisory Appointments Committees for NHS consultant posts and it was felt appropriate to include a personal view on a sensible approach to the ordeal of applying for a permanent job. The job description for a consultant post will usually Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 79 have been carefully drawn up to suit the present needs of the department concerned and is strongly influenced by the other members of that department and other senior hospital staff. It is likely that others outside the district consultant body will also have influenced the fine print so that statements such as 'a special interest would be an advantage' require further informal investigation. The department might have very clear ideas as to what that special interest should be but have been prevented from making the job description too specific. Similarly, the job description may have been designed so that it suited a candidate known to other members of the department, though again this may have been modified or not be immediately obvious. Careful, even probing enquiries may be needed to establish how your prospective col- leagues envisage your pattern of work and interests, both so that this discovery is not made at a wasted interview and to guard against being appointed to a job that is not as you had expected it to be. A visit to the district will enable these enquiries to be tactfully made and is an important initial mutual assessment between applicant and potential colleagues. An application, even if on the printed form, should always be accompanied by a clear statement of why you want the job, what you hope to contribute to the hospital, and to stress the appropriateness of your qualifications and experience. Weighting of your curriculum vitae is entirely appropriate ? all of your training will not be equally applicable to the rest of your professional life; for example, research experience would be given a quite different emphasis in applications for a teaching hospital and a DGH post. Word processors are invaluable! During the period after applying, probably most ap- propriately after being short-listed, it is important to allow your future colleagues the opportunity of getting to know you, at least superficially, and vice versa. The appointment of a close colleague is one of the most important professional decisions of a lifetime and has been likened to marriage without the possibility of div- orce. It is not in the interests of either party to appoint an incompatible colleague and while no member of the committee has a veto (see p.79), a statement by the department representative that he (or his colleagues) would find it difficult to work with a particular candidate would be a high hurdle to jump at the interview. In this context the question of favouring a local or known candidate can be put in perspective. 'The devil you know' is a powerful and applicable argument, having an influ- ence on the outcome which is often appropriate. In spite of this it is rare for an advisory appointments committee's decision to be a foregone conclusion, particularly if the job has attracted a good field. It is unwise to withdraw because you know there is a strong local candidate; in the first place, all is not always as it appears from outside the district; secondly, strong support in favour of a candidate from an individual member of the committee who knows him or her (and will have declared this) is unlikely to have a dramatic effect on the outcome. If after your enquiries you decide that you really want the post and appear to be appropriately qualified, it is clearly necessary to examine your own strengths and weaknesses (particularly those which you have inappro- priately included or omitted from your application). You will need to be prepared to defend (or alternatively acknowledge and explain) the latter, hopefully with suggestions as to how they might be remedied before taking up the appointment. At the interview it is rarely the curriculum vitae which decides the recommendation of the committee. Honesty and openness are important ? probing questions are usually probing for a good reason, and it is unusual for the committee to be deceived. Personality is, as already mentioned, an important consideration, but you will not be marked down for an expected degree of nervousness. Clear statements as to your aims and ambitions in the new post are valuable ? most committees will wish to feel that you know where you are going, hopefully with due attention to the needs and aspirations of your future colleagues. Given that more than one candidate with appropriate qualifications and experience appears at the interview, factors other than those on the application form will probably decide the outcome. To complain 'I was much better qualified for the job' (than the person appointed) is to a great extent irrelevant; if the appointed candidate was less well qualified on his curriculum vitae it is necessary to examine what other qualities he had that you perhaps lacked at that interview. It is rare for the recommendation of an AAC to be unfair and more usual for apparent unfairness to be due to the committee having given weight to less obvious attributes of the candidates. The role of the College's representatives on the Advisory Appointments Commit- tees is outlined in page 79. John H. Tripp General Professional Training In order to understand the concept of general professional training it is necessary to consider how the present pattern of postgraduate medical education has evolved. Until 1953 there was no obligation for recently quali- fied doctors to undertake any further training before being admitted to the Medical Register maintained by the General Medical Council. It was on the recommendation of the Goodenough Committee on Medical Schools, which reported in 1944[1], that the pre-registration year of internship was introduced. Under the Medical Act of 1950 it was made compulsory for every doctor after passing his qualifying examination to spend a period as a resident in an approved hospital before becoming eligible to proceed to full registration. This provision came into force on 1st January 1953. In 1964 the Royal College of Physicians published a Report on Training for Consult- ants^] which suggested that after becoming fully regis- tered, those aspiring to a consultant career in a medical specialty shpuld spend a further three years in general professional training and four years in the specialty to be followed. The report of the Royal Commission on Medical 80 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Education (the Todd Report, 1968)[3] recommended that the pre-registration year should be followed by a struc- tured programme of postgraduate training. The following pattern was proposed: 1. An intern year, corresponding broadly to the present pre-registration year, during which the medical graduate would begin to take responsibility for the management of patients, would acquire a sound grasp of general clinical method and would gain confidence, judgement and understanding under proper guidance in conditions ap- proved by a university. , 2. General professional training, lasting about three years and embracing the present senior house officer and registrar grades in the hospital service, in which the young doctor would be given systematic and varied experience in the general field wherein he hoped to make his career. 3. After successful completion of general professional training, further professional training would continue either on a less intensive basis, merging into the normal responsibilities of a professional career, or as a period of a few years' intensive advanced training ? varying in length in different specialties or branches of medicine ? which would be designed to bring the most able hospital doctors more quickly than others to the point where they might reasonably expect to be considered for consultant appointments. 4. Continuing education and training for all doctors in career posts, varying in time, method and intensity, with the object of keeping them abreast of developments in their own branch of medicine and in medicine generally. > - In general these proposals have been adopted and those applying for enrolment for specialist training are required to show that they have spent three years in posts con- sidered suitable for general professional training, during which time they will have passed the MRCP examin- ation. However, there have been many problems con- cerned with this period of general professional training, particularly with regard to its content and quality, the educational facilities in different hospitals and increasing difficulty experienced by trainees in obtaining a suitable series of posts. Content of the General Professional Training Period > The requirements considered to be desirable for general professional training were defined in the First Report of the Joint Committee on Higher Medical Training[4]: General professional training will ordinarily occupy a ? > period of three years after registration. Such training will be obtained in posts approved for this purpose providing general medical care, with or without 'special experience and training' in certain specialties. A proportion of this time may be spent in general practice under conditions approved for training pur- poses. Rigidity in training programmes will be avoid- ed, subject to the suggested restrictions on time to be spent in certain types of posts. Trainees may rotate, possibly part time, through other specialties related to medicine such as clinical pathology, psychiatry and paediatrics, during general professional training. The candidate who has completed general professional training should be 'pluripotential' in the sense that his training by its nature has not committed him to continuing in a special branch of medicine. This definition offers scope for a broad choice of educational opportunity but difficulties have arisen be- cause of the limited availability of SHO posts in the more popular subjects and the tendency of some specialties to encourage too early an entry to the specialty by their recruits. An additional factor has been the advent of vocational training schemes for general practice which incorporate many posts in the popular specialties and so limit the availablitity of these posts for others. Approval of Posts All junior hospital posts require educational approval if they are to be filled by doctors in training. Since the standards required for general professional training by the Royal College of Physicians and for vocational train- ing for general practice by the Royal College of General Practitioners are so similar, a system of joint approval by both Colleges has been established, hospital visits being carried out by teams with representatives from each College. The Linacre Fellow has a special responsibility for the approval of posts for general professional training and through the Training Office of the College, he works closely with Regional Advisers to ensure that posts are inspected or reviewed at the appropriate time. Hospitals are required to submit individual specialty forms in respect of newly established posts and in respect of any established posts being re-structured or due for review. The visiting team normally consists of two physicians nominated by the Royal College of Physicians, one of whom is chairman, and a representative of the Royal College of General Practitioners. The Regional Adviser of the Royal College of Physicians makes the detailed arrangements for the visits and is able to provide valuable information about local conditions. During visits the team will meet the consultants for a general discussion about the work of the hospital and will enquire about the educational facilities and training programmes. Specific questions will be asked about the laboratory and radiology services available, and the Postgraduate Centre and medical library will be visited. The SHOs and registrars will then be interviewed indi- vidually and confidentially, when their clinical duties and weekly teaching activities will be discussed. It is import- ant for them to understand that it is the posts that are being assessed and not themselves. The visiting team will wish to be assured that trainees are only asked to accept responsibility appropriate for their experience, that their work is adequately supervised and that they have access to advice from senior staff whenever necessary. Enquiries may also be made about the ways in which the work of the unit concerned is reviewed and assessed and whether any form of regular audit is undertaken. The reports of visiting teams are submitted by the Linacre Fellow to a sub-committee of the College Com- mittee on General (Internal) Medicine which confirms Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 81 the recommendations. Final approval of posts for general professional training is granted by Comitia. Specialist Posts Difficulties have arisen in the past over the approval for general professional training of SHO or registrar posts in specialist departments. This has applied to posts in departments of cardiology, dermatology and genito-uri- nary medicine and also to certain paediatric posts. How- ever, it is recognised that experience in specialist departments may be beneficial and it is now agreed that it is on the educational value of the post that its suitability for approval for general professional training should be judged. It is recognised that although approval is jointly granted by the RCP and the RCGP, some specialist posts may not be suitable for vocational training for general practice but entirely suitable for those aspiring to a hospital career. MRCP(UK) Examination All those wishing for a career in hospital medicine require the MRCP which must be obtained before entering higher professional training as a senior registrar or honor- ary senior registrar. Candidates for Part 1 of the examination must have completed 18 months' training since qualification. No posts are specifically approved for the MRCP but candi- dates must have spent 12 months in posts involving the care of acutely ill medical patients, either adults or children, and are required to submit evidence that they have done so. The immediate objective for individuals completing the pre-registration year and contemplating a career in a medical specialty must therefore be a series of good posts at SHO level, whether arranged individually or as a rotation, providing experience which will prepare them for this examination. Career Advice During this period of general professional training they should identify the specialty which they ultimately wish to follow. Postgraduate Deans and Clinical Tutors are con- sidered the official sources of career advice and should have appropriate information available in their offices. Consultants should always be willing and usually able to advise their juniors but in practice it seems that most doctors in training seek information from their immediate seniors on the training ladder. The serious imbalance between numbers of training posts and career posts will eventually be corrected, and an increase in the number of consultants has long been agreed to be necessary. The present situation makes it imperative for young doctors planning a career in hospital medicine to take full advantage of the posts available for general professional training, to remain 'pluripotential' for as long as possible and to take advantage of opportunities which may present for higher professional training, though not necessarily in the specialty of their first choice. References 1. Report of the Interdepartmental Committee on Medical Schools (The Gooden- ough Committee) (1944) London: HMSO. 2. Royal College of Physicians (1964). Report on Training for Consultants. 3. Report of the Royal Commission on Medical Education, 1965-68 (1968) London: HMSO. 4. First Report of the Joint Committee on Higher Medical Training, October 1972. John Lister Linacre Fellow, Royal College of Physicians Higher Professional Training Training for a specialty in most branches of British medicine has always been arduous and the ultimate objective of obtaining a consultant post has often been difficult to achieve, though in some specialties it is more difficult than in others. In some respects this difficulty is a measure of the high standard and competitive nature of specialist practice in Britain; in other respects it is a manifestation of an unsatisfactory career structure which in recent years has been characterised by a serious imbalance between the number of training posts and career posts. In most but not all specialties this imbalance at senior registrar level has been corrected, the number of senior registrar posts being closely related to the anticipated vacancies at consultant level. However, there are still nearly three times as many registrars as would be required to fill the vacancies anticipated in the senior registrar grade. The need to correct this imbalance was emphasised in the Short Reportfl] which recommended a reduction in the number of registrars and an increase in the number of consultants with a shift from a consultant 'led' to a consultant 'provided' hospital service. Although there has been a natural concern on the part of consultants that this may lead to major changes in their work pattern, the profession has agreed in principle to the proposals, provided no reduction in junior staff takes place without a compensatory increase in consultant staff. Progress in this matter has been disappointingly slow and any registrar aspiring to a specialist career would be wise at least to ascertain the career prospects in the specialty which he - hopes to follow before making any irrevocable commit- ments. Joint Committee on Higher Medical Training (JCHMT) All those aspiring to a career in a medical specialty must obtain an appointment as a senior registrar or honorary senior registrar in a post approved by the JCHMT. This committee was set up in 1970 as the result of consultations between the three Royal Colleges of Phys- icians of Edinburgh, Ireland and London, the Royal College of ^Physicians and Surgeons of Glasgow and members of the Association of Professorial Heads of Academic Departments of Medicine and Paediatrics. Prior to this, individual Colleges had published training 82 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 programmes in various specialties but it was agreed that policies on all matters relating to higher training in the medical specialties could be more satisfactorily deter- mined by a joint committee on which all the Colleges, the university departments and the specialist associations were represented. The JCHMT now plays an active part in co-ordinating higher training in all the medical specialties and publishes a training handbook[2] which may be obtained from the Training Office of the Royal College of Physicians of London. This handbook provides valuable information about the training requirements for each specialty, the composition of the committee and the names and address- es of all the Postgraduate Deans in the UK. It points out that the responsibilities of the committee are 'to formulate guidelines for training in medical specialties, to approve posts and training programmes which are suitable for higher medical training and to grant certificates of ac- creditation to those who have completed higher medical training'. Specialist Advisory Committee (SAC) It was agreed at an early stage to establish Specialist Advisory Committees within the parent committee, which would determine the training programmes for individual specialties. There are now 19 such SACs with normally six members each, three being nominated by the JCHMT on recommendation by the four Royal Colleges, the other three being nominated by the appro- priate specialist association. However, there are vari- ations in the composition of certain SACs, which are indicated in the Training Handbook. Every effort is made to ensure that the membership of SACs is well balanced, with adequate representation of universities and academic departments, regional phys- icians and younger consultants. Some regard for geo- graphical 'spread' is also desirable. The tenure of membership of SACs is normally four years and each committee elects its own chairman. The inspection and re-inspection of senior registrar posts are carried out by visiting teams set up by the appropriate SAC. The normal period of approval for established NHS senior registrar and university lecturer posts is five years. In the case of certain research posts, educational approval will be granted on an ad hominem basis for the tenure of the incumbent concerned. Enrolment On appointment to a senior registrar post, trainees should apply for enrolment for higher training in the specialty or specialties concerned. Eligibility for enrolment will de- pend on the required period of general training having been completed, and any period of post-Membership training considered suitable for retrospective recognition towards higher training will be indicated by the SAC. The maximum period of retrospective recognition that may be granted is 24 months for single specialty accredit- ation and 12 months in each subject for dual accredit- ation. Enrolment forms may be obtained from Postgraduate Deans and from the JCHMT office in the College. Accreditation Trainees should apply for accreditation towards the end of their four-year training programme with any period of retrospective recognition being taken into account. The forms should be signed by the Postgraduate Dean and submitted to the JCHMT office. The granting of accreditation signifies that the trainee has completed satisfactorily the prescribed period of ' higher training in the specialty or specialties concerned. However, it is the AAC which determines the suitability of a candidate for appointment to a specific consultant post and accreditation is not considered an obligatory requirement. At the same time it is likely that the majority of successful applicants will be accredited in the specialty concerned. Overseas Experience The value of overseas experience is recognised by the JCHMT, but a minimum of two years' training in approved posts in the UK is required of applicants for accreditation. Furthermore, it is not always possible to offer prospective recognition of a proposed period of overseas training. Trainees are advised to seek the advice of the JCHMT about such periods of training well in advance of departure and may also be required to supply documentation of training acquired overseas when apply- ing for enrolment or accreditation. Research Experience The JCHMT recognises that participation in research activities forms an important part of training. In the case of single specialty accreditation, up to two years of relevant research, not necessarily involving clinical re- sponsibilities for patients, is accreditable. Flexibility The objective of the JCHMT is to improve and maintain standards of training. Considerable thought and care have been taken by SACs to ensure that the training programmes are both comprehensive and relevant to the specialty. The need to pursue a policy of flexibility in considering the training of individuals seeking accredit- ation is well recognised and SACs are constantly remind- ed of the need to avoid practising rigidity while preaching flexibility. Career Guidance It is hoped that senior registrars will establish good working and personal relationships with their supervising consultants who will normally be their main source of advice. They should be able to advise on matters relating to the publication of scientific papers and the preparation of theses and, when the time comes, should be willing to Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 83 advise their senior registrars on their applications for consultant posts. Advice on the preparation of their curricula vitae and on interviewing technique may be helpful at this stage. Each region has a Senior Registrar Training Commit- tee which oversees the progress of senior registrars in the region. The Postgraduate Dean and the College Regional Adviser are both members of this committee and al- though reluctant to interfere between senior registrars and their consultant, they will be available for advice if necessary. Finally, although it is not the function of the JCHMT to offer career advice, the Linacre Fellow, who acts as Medical Co-ordinator for the JCHMT, will be glad to respond to any specific queries concerning training pro- grammes and matters relating to accreditation. References 1. Social Services Committee (1980-81) Fourth Report: Medical Education. London: HMSO. 2. Joint Committee on Higher Medical Training (1984) Training Handbook. John Lister Linacre Fellow, Royal College of Physicians Part-Time Training Training for a career in hospital medicine is long and arduous, and occupies the years when most women wish to have their children. Some will continue to work full- time with short absences on maternity leave, but others prefer to spend at least a little time at home with small children and wish to find part-time work which will continue their training in medicine. What is Part-Time Training? A full-time medical post is one with 10 standard Units of Medical Time (UMTs) each week, a standard UMT being a four-hour session between 9 a.m. and 5 p.m. on a weekday. A part-time post is one with fewer than 10 standard UMTs, even when the on-call commitment brings the total week to 40, 60 or even 80 hours. There is a common assumption that all part-time posts are half- time, but the part-time label applies equally to posts of eight or nine standard UMTs. Part-time posts may be approved for postgraduate training in medical specialties, but must normally be half- time or more. It is unrealistic to plan a career in hospital medicine while intending to spend many years working less than half-time. Clinical Assistant Posts Part-time training posts are seldom advertised. Part-time posts seen in journals are usually clinical assistant posts, which offer service commitments but no particular train- ing component. Such posts have the added disadvantage of being insecure, as there is no long-term contract, and they may be terminated by health authorities for financial saving or other reasons at short notice. Such posts may therefore offer sessions with a continuing clinical commit- ment to fill a gap when no other medical work is available, but seldom contribute to training. Supernumerary Posts In 1969 the Department of Health published a circular, HM(69)6, encouraging Regional Health Authorities to set up special posts for doctors prevented by domestic commitments from undertaking full-time work. Such posts were to be supernumerary and personal, ending when the appointed doctor resigned. The use of this scheme for different specialties varied greatly, but the Committees on General Professional Training and High- er Medical Training did not exclude these posts from approval for training, provided adequate experience was obtained. Posts had to provide all the experience which was required in a full-time post, including emergency and on-call work, but this could be spread over a longer period, such as five years for a senior registrar post. Regional uptake of these posts varied greatly, some regions, such as Oxford, allocating a specific budget to part-time training, some Regional Health Authorities funding fewer posts and some with scarcely any posts. The problem of obtaining funding of posts has increased ? with greater financial constraints on health authorities. At senior registrar level there was the added problem of manpower planning. A supernumerary post could offer adequate training and could be funded, but if the special- ty was already over-subscribed there would be poor prospects for a consultant post at the end of the training. The extra post would further increase the number of senior registrars in that specialty looking for a career post. In 1979 the Department of Health introduced another scheme, PM(79)3, under which potential senior registrars would apply centrally and would be interviewed to con- sider whether they should be permitted to enter the grade. If the chosen specialty was already over-subscribed, a part-time post was unlikely to be approved. Competition was intended to be no harder but no easier than for full- time posts. Those who were successful could then go to the region of their choice with their manpower approval. Their posts still had to be set up and approved education- ally, and there was no guarantee of finance being avail- \ able simply because manpower approval had been given. Some doctors discovered to their cost that manpower approval, educational approval, and funding were still not enough; the region had a right to veto an appointment even when all three had been obtained. This has hap- pened more than once in one region. x Part-time posts are not usually set up where there are already many junior staff in training, therefore the supernumerary doctor may find little of her time spent in teaching hospitals. The responsibilities of the post have to be newly defined as the doctor enters it, which may cause problems. Despite these obstacles, some doctors have succeeded i in completing some of their training part-time and sub- 84 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 sequently obtaining a consultant post. This usually ap- plies to those who have completed some years full-time after registration and for whom part-time work filled a hiatus between two periods of full-time work. Part-Time Consultant Posts For those who wish to continue to work part-time, consultant posts are seldom advertised at fewer than eight sessions. Some posts are advertised for which doctors unable to work full-time for personal reasons are invited to apply. This may improve the opportunities available, but very few such posts are at present awarded to doctors who wish to work part-time. Split Posts The present PM(79)3 scheme for supernumerary posts is thought unlikely to continue in the future. An alternative is the use of split posts. The British Medical Association offers a bureau to enable a doctor seeking part-time training in a particular specialty to meet another with an interest in the same specialty so that they may apply together for a full-time post which is then split between them. This scheme has the advantage of the posts being long established so that responsibilities are clearly defined and not seen as detracting from other doctors' experience. The two doctors may apply for posts at any hospital, including teaching hospitals. There is a rapid decision, with the usual application, short-list and interview. If rejection follows, other jobs may be applied for rapidly, which may be in the same area or even the same hospital. With supernumerary posts the separate stages may take months and if rejection follows it may not be possible to arrange any such part-time post in the same region. There are some disadvantages to split posts; the two doctors may not be well matched, and one may handicap the other's applications. Exceptional co-operation be- tween the two doctors is necessary because a careful handover system is required. Needs of the two may narrow the geographical area in which posts may be sought. If either wishes to increase the number of sessions before returning to full-time work this is unlikely to be permitted. The greatest problems must be the difficulty in finding a doctor at the same stage of training in the same specialty, and convincing appointments committees that two can do the job as well as one, and better than other applicants. Choice of Sub-Specialty The doctor who wishes to complete some training part- time will always be at some disadvantage in future applications for posts. It is sensible to study future trends in staffing in different sub-specialties and avoid those in which training grades are already providing too many accredited senior registrars. Often the sub-specialties already under-subscribed, such as genito-urinary medi- cine and geriatrics, also have a less demanding emerg- ency commitment which may allow an earlier return to lull-time work. Training in internal medicine and the MRCP are an excellent background for some other specialties, such as radiology and pathology,^ in which part-time work may be easier to obtain and full-time work includes less emergency duty. For those determined to follow a career in the most competitive sub-specialties such as cardiology, endocrin- ology, gastroenterology, respiratory medicine or neurol- ogy, the decision to work less than full-time should not be taken lightly. Doctors should discuss with those in the sub- specialty the prospects for continuing in it after complet- ing such a post, and should place even greater emphasis on research and publications and the appropriate higher degree. The MRCP and accreditation alone will not guarantee a consultant post against fierce competition. For those who succeed in walking the tightrope of part- time training, and in subsequently obtaining a career post, there are obvious rewards. Being more intimately involved with one's own children when young and seeing them every day is the most obvious. It may be possible to continue an outside interest which otherwise would be lost in the round of work at home and work in hospital. The degree of commitment to the chosen career can be no less for part-timers, and the arrangements for child care must be just as detailed. Part-time training may be an alterna- tive, but to be successful it cannot be a soft option. JEANETTE MEADWAY Should a Doctor learn to Manage? Over the last 10 years there have been dramatic changes in the way the National Health Service is organised and run. In 1974 hospital management committees respon- sible for running hospitals were replaced by health au- thorities responsible for providing health services to a defined geographical population. To a doctor's tradition- al one-to-one relationship with patients was added an explicit responsibility to a community, a defined popu- lation who might have need of his skills. New management techniques have been introduced to attempt to allocate resources more equitably (a formula for resource allocation), to plan more effectively (the NHS planning system) and to make authorities more accountable for their performance (the development of performance indicators and the introduction of account- ability reviews). All this has been happening against a background of a diminution in the amount of money available for growth in services. Throughout the 1960s 3- 4 per cent more money each year was given to the NHS. The situation has been very different in the 1980s, when growth has been near zero. Introduction of the Griffiths' management structure will further alter NHS adminis- tration in this decade. As a result of these changes hospital doctors can no longer, as they often did 10 years ago, ignore administrative responsibility. Running the 'Firm' With increasing demands from patients and dwindling or static resources, consultants have had to become much Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 85 more concerned with making the best use of what beds, clinics and theatre sessions are available to them. Clinical policies have had to be altered, for example the increasing use of day care. The ordering of investigations and drugs has had to be critically reviewed. All these activities will become increasingly important when physicians take on the responsibility for managing clinical budgets which will cover all the capital and revenue consequences of their work. The ability to evaluate clinical policies and the outcome of care is all part of good postgraduate medical education, but organisational skills are not yet part of either the undergraduate or postgraduate curriculum. Running a Department In addition to their responsibilities for direct patient care, an increasing number of physicians run services, such as a pulmonary function laboratory, ECG department or nuclear medicine department, that are used by their colleagues. The manager of a service needs to know about budgeting, personnel policies, industrial relations pro- cedures and other administrative matters. Most clinicians with these responsibilities have gained the requisite skills in the job. The increasing complexity and importance of the managerial function has led the Colleges of Radiology and Pathology to organise seminars on management for their members. Although most services run by physicians are smaller in scope and consume considerably less revenue and capital than pathology and radiology depart- ments, the time may have come for physicians to adopt a more formal approach to acquiring management skills. Involvement in Management in the District Since 1974 clinical doctors have had a major role to play in the management of a District Health Authority. The arrangements were slightly modified as a result of the 1982 reorganisation and major changes occurred in 1985 as a result of the implementation of the Griffiths Report, which recommended a change from consensus to line management throughout the NHS. Each District Health Authority has as a member at least one consultant nominated by the Regional Health Authority. The consultant on a District Health Authority ;. is there as a 'wise man and true'; he does not have the formal role of representing his colleagues and he brings to the authority a knowledge of clinical practice. The appointment of District General Managers, which started in 1984, will diminish the very powerful role that j was played by the consultant member of a district man- agement team. However, a few doctors have been ap- pointed general managers; they come mainly from pathology and radiology but include some clinicians. It is unlikely that many practising physicians will be attracted to this new role or indeed to the post of unit general manager in a large acute unit. The new management arrangements require an input of advice from doctors and there will continue to be a medical representative structure through which consult- 1 ants, on behalf of their peers, negotiate with district and unit managers. Consultants in each district will work out the arrangements that best serve their purpose but it is essential that every committee or group is set up with a clear purpose and that the relationship to other parts of the management structure is explicit. \ Conclusion No consultant can now avoid being involved in adminis- tration or management. The degree of involvement can vary and some doctors will expend a considerable amount of time and energy dealing with these aspects of Health Service life. To be an effective manager requires learning how to manage. Although much can be picked up by doing the job, it is worth while considering participating in one of the many courses now run for clinicians on management matters. Details can be obtained from the Chief Executive of the NHS Training Authority, St Bartholomew's Court, 18 Christmas Street, Bristol BS1 5BT. Alastair Mason 2. DIFFICULT CHOICES: INFERENCES FROM ORIGINAL SURVEYS Survey Method The need for 'hard data' for aspiring physicians, together with qualitative guidance, was the reason for the Stand- ing Committee of Members undertaking this booklet. The areas chosen for investigation were those of interest to individual members. For each of the first three surveys the groups of Members that were likely to provide the most useful data for the particular survey were identified by year of acquisition of MRCP or MRCP(UK) and are described in each chapter. Members were then randomly selected from the records held on the College computer and sent the appropriate survey form. No Member was sent more than one of these first three surveys, but all were, in addition, sent the survey concerned with training abroad , because we expected the positive response rate to be low. Members with permanent addresses abroad or who had qualified abroad and were not practising in this country were excluded (though in the event a number were inadvertently included). Reply-paid envelopes with an identifying number were provided and on receipt the respondent was recorded as having replied and the ques- tionnaires were encoded with a unique (consecutive) number which bore no relation to the identifying num- f ber. This provided complete confidentiality but allowed identification of non-respondents before examination of the responses. Non-respondents were sent a reminder by the Presi- dent when the daily returns had dropped to less than ten 86 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 and this produced a further response. Some were sent back unopened by the Post Office as 'unknown at this address' and where possible these were re-addressed. Response rates given in the following chapters are overall rates, so that rates for those who actually received the questionnaire are higher by an overall figure of 14 per cent. Responses which were narrative in nature were en- coded by a team drawn from the Standing Committee of Members and the data were then analysed by the Depart- ment of Mathematical Statistics at the University of Exeter, using the SPSS package for survey analysis. The same basic personal information and information about MRCP, research and higher degrees was asked for on three of the questionnaires. There is thus some overlap of data between the surveys, particularly in relation to research. Keeping up to date in General Internal Medicine The ease with which doctors keep up to date in general medicine or paediatrics may depend upon the nature of their work and the degree of specialisation, and for those in hospital practice, the size and type of hospital in which they work. Because there was no clear consensus in the Standing Committee of Members as to the means avail- able and their effectiveness in helping doctors keep up to date in general medicine, we decided to include a survey on the subject. The questionnaire was divided into two parts. The first part asked for general demographic data and the second part asked about the ways in which doctors keep up to date in general internal medicine. The questionnaire was sent to a random sample of approximately 50 doctors who obtained the MRCP diplo- ma during each of the years 1968-83; 401 (54 per cent) out of a possible 744 replied. Our comments are made in the light of this response rate and for that reason we shall present the data without attempting any statistical analy- sis. We have drawn some conclusions, but realise that we may be dealing with a biased sample of the population surveyed. Demography Sixty-nine (17 per cent) of the sample were female, 90 per cent were born between 1940 and 1960, and a similar proportion qualified between 1965 and 1980. We ob- tained a better response rate from those passing the MRCP more recently. We have divided the sample into specialties (Table 1) by asking what constituted the major proportion of a doctor's time. Therefore if general phys- icians with a special interest spent the major part of their time in general internal medicine they were categorised under general medicine. However, if a specialty such as cardiology or neurology was the major component, we have included the doctor under 'medical specialties.' Haematologists are included with pathologists under 'other medical specialties' even though they have an increasing clinical commitment. 'Surgically related spe- Table 1. The proportion of specialties which form the major part of the doctor's work. 'Medical specialties' includes neurology, cardiology and renal medicine, etc. where this is the major or exclusive specialty. Haematology and microbiology are included under pathology. Specialty No. ' % General internal medicine 145 36 Paediatrics 51 12.7 General practice 39 9.6 Geriatric medicine 30 7.5 Medical specialties 55 13.7 Non-medical specialties (including pathology and radiology) 31 8 Anaesthetics and surgical related specialties 20 5 Psychiatry 113 Other 19 4.5 dairies' includes obstetricians, surgeons and those work- ing in accident and emergency departments. Of the 58 (14 per cent) not working in the hospital service, the majority (39) were in general practice but others were working in community medicine, occupation- al health and the pharmaceutical industry. There were 51 paediatricians either based in hospital or in the com- munity but we have not separated out this or other specialties. Figure 1(a) depicts the proportion of hospital grades in the sample. There was a higher number of consultants than would be predicted from the sampling frame. The proportion of different hospitals is shown in Fig. 1(b). The number of attempts to pass MRCP are depicted in Fig. 2. Although we have not related this to a future career in hospital medicine, the proportion of those working towards, or obtaining, a higher degree was greater in those requiring less than three attempts at Part 2. An MD or PhD was obtained by 73 men (22 per cent) and four (6 per cent) women. Of the sample 47 per cent had done research work appropriate for a higher degree; 45 per cent of these had completed this work but only 19 per cent of the sample had been awarded a degree. Ways of Keeping up to Date Meetings We asked for a graded response (very useful, useful, not very useful, waste of time, unavailable) to questions about different types of meeting, and specifically those meetings which were of use for general internal medicine and therefore outside the specialist interest of the individ- ual. Departmental meetings were considered useful or very useful by 70 per cent across all grades, but are valued by fewer who work in smaller District General Hospitals. Local hospital meetings were useful to 75 per cent of all grades equally in all types of hospital. Regional presentations, formal postgraduate lectures and single local meetings were less useful (to just over 50 per cent) and were appreciated most in large district Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 87 Page 88 general rather than teaching hospitals. Nationally organ- ised meetings either covering general topics or special interest were useful to more of the senior doctors. Inter- national congresses, drug company symposia, local audit meetings and journal clubs were suggested as additional useful meetings by 10 per cent of the sample. In response to a specific question about audit later in the question- naire, 70 per cent (the majority being junior hospital staff) thought that audit would be a useful form of postgraduate education. Reading Matter We asked for information about textbooks and various journals under the same format as for meetings. Textbooks were still useful to over 65 per cent of the sample; regular reviews in journal form were more useful (75 per cent) than in book form (56 per cent). Regular instructional magazines (e.g. Medicine) were useful to 66 per cent overall, including many no longer in training grades. Light medical reading and pharmaceutical litera- ture were of little use. The British Medical Journal, Lancet and New England Journal oj Medicine were of use to over 70 per cent; the latter two being more popular with hospital doctors and those in specialties requiring MRCP. The Quarterly Jour- nal of Medicine and the Journal of the Royal College of Physicians were of use to less than 30 per cent of respon- dents. Archives of Disease in Childhood was useful to over 90 per cent of paediatricians who also listed the Journal of Paediatrics and Paediatrics as additional journals. Under this heading Drug and Therapeutics Bulletin and Prescriber's Journal were also mentioned by those finding other journals useful. The most frequently used meetings and forms of study are shown in Table 2. This question was answered by over 90 per cent of the sample who were allowed up to three preferences. Fig. 1(a). Different hospital grades of doctor as a percentage of the whole sample (n = 401). The category 'Other Grades' includes some doctors in non-career posts in the hospital service, general practitioners and others working outside hospitals. Fig. 1(b). Type of hospital in which 76 per cent of the sample were working. The category of District General Hospital can be divided further into those with more than six general physicians (13 per cent), four or five general physicians (15 per cent) and three or less (7 per cent). Fig. 2. Number of attempts at passing MRCP. D = Parti. H - Part 2. Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Table 2. The ten most used forms of study. The proportion of paediatricians using Archives of Disease in Childhood was greater than 85 per cent. Ninety per cent responded to this section. Journal or Meeting No. % British Medical Journal 235 59 Lancet 137 34 Regular review journal 98 24 New England Journal of Medicine 97 24 Local hospital presentation 70 17 Textbooks and monographs 70 17 Regular instructional magazines 66 16 Other journals 51 13 Department presentations 41 10 Archives of Disease in Childhood 36 9 Table 3. The forms of study (meetings and journals) that doctors would like to see improved. Only 147 (37 per cent) replied to this section. Form of Study or Journal No. British Medical Journal 58 Journal oj the Royal College of Physicians 50 Regional presentations 48 Formal lectures 41 Material from pharmaceutical companies 45 Local hospital presentations 37 One off local meetings 30 Nationally organised meetings 30 Lancet 25 Department presentations 25 Regular review journals 25 Only 37 per cent replied to the question on areas for improvement in postgraduate general medical education (Table 3) and again they were given up to three prefer- ences. In reply to more specific questions 54 per cent (the majority being hospital junior staff) felt that the appoint- ment of a local postgraduate tutor would help. Seventy- one per cent were in favour of medical audit and 55 per cent felt that regional meetings organised by the College were, or would be, helpful. With an eye to future technology we asked about videos and computer-based teaching programmes: 53 per cent had access to videos; 37 per cent were keen to receive edited recordings of lectures or meetings but only half of these would be prepared to pay for this service. There was less interest in computers. Comments We invited general comments on the topic of postgradu- ate education. Sixty-six per cent were satisfied with their local postgraduate library and only 6 per cent expressed dissatisfaction. The major difficulties that doctors en- countered were in the lack of time available to keep up to date (particularly in the case of women doctors) and the difficulty in attending meetings (particularly those held in London). Several doctors, predominantly senior regis- trars in teaching hospitals, felt that the obligatory time spent in their special interest or specialty prevented them from keeping up to date adequately in general medicine. Conclusions The response rate of 54 per cent is similar to that obtained in the other surveys. The disproportionate number of consultants and low number of registrar respondents suggests that we may have a skewed distribution, as the proportions were unexpected for the sample which we surveyed. The responses to the ways in which people study and which meetings they find useful are more predictable. Clearly, most doctors look to a combination of textbooks, review articles, regular instructional magazines and the medical weeklies as their major source of written infor- mation, and this must have implications for the way in which educational material is presented in the future. There is a paradox in that while the British Medical Journal remains popular, it is thought by many to be in need of improvement. It is salutary that this also applied to the Journal of the Royal College of Physicians, perhaps reflecting the small number who found it useful. The more modern forms of teaching and study need to become cheaper before they are used more widely. The appointment of local postgraduate tutors in medi- cine was supported by just over 50 per cent of respondents and clearly such an appointee may be helpful in organis- ing more local meetings including medical audit, local hospital presentations and local or regional meetings. Such activities may be especially useful to doctors work- ing in the smaller district hospitals. David Carmichael, Pamela Tomlin, Peter Todd and Martin Muers Research post-MRCP Research experience is commonly sought by doctors once the hurdle of the MRCP examination has been crossed. It may take the form of full-time work, often for a higher degree, or part time release during clinical training. Many have argued that in addition to obtaining new knowledge, research improves clinical practice by teach- ing analytical skills so that new or existing medical developments are assessed critically. In view of the competitive nature of many of the general medical specialties, young physicians are fre- quently advised to undertake research so as to improve their career prospects. Some consider it mandatory for progress. However, very little is known about the scale, nature and value of research carried out after the Mem- bership examination or of the experiences and attitudes of doctors. If training is to be improved and appropriate advice given about the role and place of research, better information is required. The aim of this questionnaire was to develop guidance to improve the research component of post-MRCP train- ing. Specific objectives included the following: (a) to investigate the level of research activity undertaken post- MRCP; (b) to determine the nature and degree of problems encountered and attitudes towards the value of research for career development, and (c) to compare the Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 89 results between those likely to advise on research, to have completed research and to be undertaking research. This report summarises the main findings; a more detailed account is in preparation. Methods A sample of 596 doctors obtaining Membership of the Royal College of Physicians in 1972, 1973, 1976, 1977, 1980 and 1981 was randomly selected from the Royal College of Physicians' computerised register. Doctors obtaining the Membership in 1978 or earlier were only included if they had either a current UK address or qualified in a British medical school. Those attaining MRCP after 1979 were only included if they had both a current UK address and qualified at a British medical school. This procedure was followed in an at- tempt to exclude those not practising medicine in the UK. In all, 337 satisfactorily completed questionnaires were available for analysis, 56 per cent of the total sent. Results Characteristics of Respondents The median age of those replying to the questionnaire was 35 years, with the majority (87 per cent) aged between 30 and 40 years. The most frequent years of qualification were 1970, 1974 and 1978; 76 per cent of those returning the questionnaire were male. Table 4 Table 4. Frequency of attempts to pass the MRCP examination (n = 333). No. of MRCP Part 1 MRCP Part 2 attempts Respondents % Respondents % 1 73 57.5 2 19 24 3 6 14 4 2 3 5 1 6 0.5 shows the numbers of attempts required by the group to pass the MRCP Parts 1 and 2 examinations. The ma- jority passed these examinations at the first attempt but, as might be expected, more candidates had trouble with the Part 2 than the Part 1 examination. Research Experience Obtained Higher Degree. Of those completing the questionnaire, 48 per cent (160) claimed to have done research work appropriate for a higher degree, 85 per cent of whom were male. Overall, 54 per cent of the male and 43 per cent of the female respondents said they had worked for a higher degree. At the time the questionnaire was distrib- uted 18 per cent (59) had obtained an MD degree, 4 per cent (12) a PhD, and 4 per cent (14) an MSc. An MD or MSc was usually obtained following the MRCP qualifica- tion but half of the PhDs were obtained before MRCP. Figure 3 shows the distribution of ages at which research for the higher degree started in 159 respondents; / 88 per cent began work between the ages of 26 and 34 although a few began when they were older than 40. Approximately half of those working for higher degrees spent more than two years doing the necessary research. As a rough guide, research activities for a higher degree began four to six years after qualifying as a doctor and terminated six to nine years after qualification. There was a wide distribution of ages at which the degrees were awarded, with a tendency for an MD to be gained at a greater age than a PhD or MSc (Fig. 4). The total periods of time taken to obtain MD and PhD degrees (from the beginning of research to award of the degree) are shown in Fig. 5. Whereas most candidates finished :J the MD degree work within four years, 37 per cent took five or more years. Information was also obtained on the length of time taken to write up the research work. The vast majority of MD and PhD degrees were written up within two years. Doctors undertaking work towards a higher degree were more likely to have made fewer attempts to obtain MRCP. There was, however, no relationship to age at qualification Table 5 shows the percentage of doctors undertaking research for. a higher degree by the year in which they qualified. There was a tendency for more of those qualify- Age starting research (years) Fig. 3. Cumulative frequency distribution of age at which work for a higher degree started. 90 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 ing after 1968 to carry out research but the trend was not clear. It must be emphasised that figures for the most recent cohort sampled (those obtaining MRCP in 1980 Table 5. Percentage undertaking research for a higher degree by date of qualification. Doing research for a higher degree Date of qualification % No. 1968 or before 33 49 1969-71 62 76 1972-3 43 53 1974-6 55 73 After 1977 42 80 and 1981) are probably not yet complete, as some in this group are still likely to embark on a higher degree. Major Research Activities since MRCP. Although only 48 per cent had worked for a higher degree, 85 per cent of those completing the questionnaire said they had under- taken some form of research work after the Membership examination (90 per cent of men and 67 per cent of women). No relationship emerged between research ac- tivities and the number of attempts required to pass the MRCP examination. The amount of time spent in research work is shown in Table 6. Half had done no full- time research but a fifth had spent more than 500 days in full-time work. Altogether one-third of researchers had" spent more than 500 days in total in research work post- MRCP. 5 -i MSc/other (n = 24) >42 5 -i PhD (n = 12) 10 5 H MD (n = 59) 20 25 30 35 Age (years) 40 45 Fig. 4. Distribution of age at which higher degree attained. 15"! 10 H 5 H 0 -J LjLU ? MD (n = 59) EH PhD (n = 12) ? 1 234 56789 10 Years Fig. 5. Distribution of total time spent in obtaining a higher degree. ? = MD. H PhD. Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 91 Table 6. Time spent undertaking research post-MRCP. All research Full-time research No. % No. % Nil 12 4 136 47 < 100 days 77 27 20 7 100-500 days 105 36 71 25 > 500 days 97 33 61 21 Total 291 100 288 100 One question sought to investigate whether data which had been collected had ever been presented at a meeting, written up or published. Table 7 presents the results for Table 7. Outcome of major research activities started 2-3 years previously by 211 physicians. No. % Data collection complete* 187 86 Research written up 163 77 Findings presented out of house 148 70 Results published 148 69 *Of those completing data collection; 76% had published the results 85% had written up the results 74% had presented the results major research activities commenced between two and three years previously (211 doctors). More than a quarter of research work had not seen the light of day and was neither presented at a meeting, nor written up nor published. Another objective index of achievement, and certainly the reward desired by most doctors, is the number of publications that have been obtained. Fig. 6 shows that 38 per cent of respondents had not published 1 at least one paper as first author and 41 per cent had not published at least one paper as other author. ,i. An increasingly important aspect of research in times of financial stringency is the need to raise resources. Of those undertaking research 89 per cent (249) had some form of financial support. Recipients received grants from pharmaceutical firms (42 per cent), research bodies (40 per cent), health charities (29 per cent), NHS (27 per ( cent) and other sources (19 per cent). Of those questioned 71 per cent said that they intended to do research in the future. j Problems Encountered In Undertaking a Higher Degree. Only 138 (43 per cent) of i. physicians had registered for an MD degree. Of these, 43 per cent had obtained it but 18 per cent had abandoned it. ?< The final number of failures might be even higher, as some of those at present working for an MD or writing it up may yet fail to obtain the degree. This may be contrasted with the smaller number of PhD and MSc candidates, none of whom had failed or felt likely to fail to complete their studies and gain the degree. Those 25 doctors who had failed or were failing to obtain an MD degree were invited to list the problems that they had encountered. These are shown in Table 8. Table 8. Major problems encountered by 25 physicians in doing an MD degree. No. Lack of resources (40%): Inadequate financial support 2 Lack of necessary equipment 1 Too few patients 1 Insufficient time to finish 6 Lack of assistance (36%): Poor supervision 4 No support from seniors 2 Methodological problems 2 Problems with planning 1 Lack of thesis (44%): Results lost in computer 1 No time to write up work 3 Lost interest in the work 1 Unnecessary due to career advancement 4 Thesis failed by examiners 3 The most common reasons for failure were lack of resources and finance, inadequate supervision and help from seniors, and problems at the writing-up stage. Only three candidates (12 per cent) had been failed by examin- ers. Very few of those doing PhD or MSc degrees listed any problems and seemed much more contented with their research experience than the MD candidates. In Undertaking Research. Half the doctors involved in research initiated and undertook the research themselves Fig. 6. Number of publications as first and 'other' author. ? = Papers written as first author. I = Papers written as other author. 50 -i 40 H ? Papers written as first author n = 337 ? Papers written as other author n = 337 30 H 20 -\ 10 H JZl 0 -1 01 2345678 >9 Number of Publications 92 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Table 9. Attitudes of 291 physicians undertaking research post-MRCP regarding adequacy of support. Time Support of Support of Personal Funding Supervision Allocated seniors employers earnings More than adequate (%) 10 ^ ^ ^ A J ^ 50 43 54 56 47 < Adequate (%) 53 o Less than adequate (%) 28 27 Very inadequate (%) 9 13 19 8 19 22 and a third participated as a key member of a research team. The views of all doctors undertaking research of any kind post-MRCP were sought regarding the adequa- cy of funding, supervision, time allocated, support of seniors and employers, and earnings. Dissatisfaction was expressed by more than a third in all these areas (Table 9). Many doctors found it hard to ignore patients' needs - and ward commitments and give the time required for research work. Overall, 36 per cent were dissatisfied with their experi- ence of research and 39 per cent wished they had acted differently in regard to research work. The most common unfulfilled wishes were to have done research earlier in one's career, to have sought a period of full-time re- search, and to have found a team already active in research where help and advice would be readily avail- able. In several cases, the wish to have had some experi- ence overseas was also mentioned. Views on the Role of Research The views of those surveyed on the benefits of doing research are shown in Table 10; 42 per cent thought Table 10. Views of 337 physicians on value of research experience in their specialties. Definitely Probably No % % % Necessary for career progression 35 23 42 Makes one a 'good' doctor 13 18 69 Is highly regarded by consultant appointments committees 42 38 20 research was not necessary for career progression in their specialty and only 31 per cent thought such experience was definitely or probably necessary to be a 'good' doctor. Those who had done or were doing an MD and those who had spent more than 100 days in full-time research were more likely to consider research experience made one a 'good' doctor compared to those who had done less research. This view did not apply to those who had undertaken more than 100 days of part-time re- search. Eighty per cent thought that consultant appoint- ments committees regarded research experience as being important. Table 11. Views on the necessity of research for career advancement by year of qualification. Definitely Probably Not Year of necessary necessary necessary qualification % % % Before 1968 22 28 50 1969-71 30 23 47 1972-3 27 29 44 1974-6 40 25 35 1977 and after 49 14 37 Table 11 presents the views on the importance of research for career progression among doctors by year of qualification. A clear trend emerges. Increased import- ance is placed on research by those qualifying more recently. Those spending more time in full-time research were twice as likely to consider that research experience was important for career advancement than those with less experience. Seventy-nine per cent thought that research had helped their careers and only 6 per cent thought it had been a hinderance, so that from a practical point of view as a criterion for promotion, research was thought to be wholly beneficial. This applied to the group with higher degrees as well as those without. However, those who had obtained a higher degree shortly after qualification were more likely to consider that this had helped their career. Twenty-four per cent thought that their relative lack of research experience had hindered their career progress. It was not surprising to find that those not registered for an MD thought research was unnecessary for progress and those working for and having achieved an MD thought it was necessary. However, those who had abandoned or were likely to abandon their research projects seemed to have few regrets and mostly thought that an MD was not necessary (Table 12). Table 12. Views on necessity of research experience for career progression according to MD status. Not Working Awarded Abandoned registered at present MD MD (n = 182) (n = 54) (n = 59) (n = 25) % % % % Necessary 21 57 71 12 Probably necessary 25 22 13 32 Unnecessary 54 22 16 56 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 93 Page 94 Discussion Research after passing the Membership examination forms an important part in the training of physicians and yet the experiences of doctors are very mixed. The vast majority (85 per cent) attempted some form of research, (90 per cent of men and 67 per cent of women). A third spent more than 500 days in research work and half carried out work suitable for a higher degree. Despite this major personal investment there is considerable dissatis- faction with research experience and often poor perform- ance. For example, 40 per cent of physicians had not published at least one paper as first author or other author. A quarter had neither published nor presented the results of research work they had done. At least one in five MDs are abandoned. One-third of those obtaining an MD take more than five years to complete it. More than a third of doctors are dissatisfied with their experience of research and wished they had acted differently. Shortage of funding and time, poor support from seniors and employers, inadequate supervi- sion and lack of earnings are common complaints. The majority (80 per cent) of physicians consider that research experience is highly regarded by consultant appointments committies and helps their careers. However, two-thirds do not think it makes them a good doctor. Better advice is clearly needed if physicians in training are to find re- search work interesting, enjoyable, productive and pro- fessionally rewarding. Based on the findings in this study we suggest the following are considered by those contem- plating research post-MRCP. Are you appropriately motivated? Physicians should consider carefully why they want to do research. Most doctors seem to have a rather pragmatic view of research as being useful for one's promotion but not actually necessary for medical practice. This seems a recipe for disaster. If research is merely to aid their career progression it is likely that many will fail to deliver due to changing circumstances. The result will be a poor experi- ence of limited benefit. Are you sufficiently dedicated? Physicians should be prepared for long-term investment in research, particularly if an MD degree is sought. Very few MD submissions are actually failed by examiners. The vast majority drop out because of lack of resources and assistance. Perseverance is essential and the support of others is vital for success. Are you prepared for funding problems? Research work is not well paid, and funded inadequately in more than a third of cases. It is unlikely that the situation will improve in the future. This is all the more reason to consider carefully your personal priorities and how much time you can afford to invest in research work. This will dictate the form of research possible and which higher degree, if any, you should* attempt. h Have you considered an MSc or PhD? 1 In comparison to an MD, the fewer physicians who undertake an MSc or PhD are not only more successful but appear to enjoy the experience more. This may reflect the fact that these higher degrees are supervised and can be achieved in a shorter time. 1 / Can you find a conducive working environment? Inadequate supervision and support of seniors and em- ployers is reported by more than a third of researchers. Finding the right department is essential. Unless you are incredibly skilled and motivated research cannot be done just anywhere. Conflicts will certainly arise if there are excessive patient demands on your time. A good and caring supervisor is very important. Ni, Can you find a full-time research job early in your training? Doing research full-time not only speeds up the process, but it appears to be more efficient and effective. Earlier research experience is recommended by many. Perhaps the sooner one finds a research post the better after passing the Membership. Have you chosen a research area which will help you? "i\ It is regrettable that so much research never sees the light of day and is not considered to be valuable in improving one's ability as a doctor. This must surely reflect both the choice of research and the manner in which it is carried out. Research above all should teach new skills, e.g. critical appraisal, study design, data collection and processing, interviewing, computing, analysis, time management, writing and presentation. Most doctors will not be pro- fessional researchers, and research experience during training should be seen as a learning experience rather than the quest for new knowledge at any cost. Clear targets should perhaps be set at the start of a research project, e.g. to submit a paper within 18 months of starting research. Have you discussed your proposals with an outside adviser? It is all too easy to be swayed by an enthusiastic senior, team or by your own perceptions. There are sometimes vested interests, e.g. to continue the research programme of the department, which may not be in your best interests. The view of an outside adviser could be particu- larly helpful here. The Postgraduate Dean, Clinical Tu- tor, College Adviser or a previous consultant could give you an objective view on your ideas and point out any unrealistic expectations. It is always a good idea to discuss your research protocol as widely as possible with clini- ' cians, other researchers, and very importantly a statis- tician, so as, to avoid unnecessary problems in the analytical and writing-up stages. Gordon M. Wood and John C Catford 94 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Career Planning with the MRCP(UK) The purpose of this survey was to provide useful guidance for the aspiring doctor with a recently acquired MRCP(UK) by describing the characteristics of those who achieve their career ambitions and comparing them with those who do not. It is of course accepted that many people change their ambitions because they develop an interest in a different specialty or branch of medicine rather than failing to achieve their original aim. Never- theless, throughout this chapter the concept of a career 'aim' will be used. Questionnaires were sent to 951 members who had received the MRCP by examination between 1966 and 1975. This period was chosen so that most would by now be in career posts (as indeed they proved to be, with only 32 remaining in training grades). Of those sampled 575 eventually replied. Members were asked personal data ? (age, sex, marital status, etc), their experience of the MRCP (number of attempts, over what period, etc) and whether they had obtained a higher degree. The second part of the questionnaire asked about career aspirations at certain stages of their training: (a) at registration; (b) at the time of sitting Part 1 MRCP or MRCP(UK); (c) at the time of attaining Part 2, and (d) at the start of the senior registrar job. Information was requested about their current post, main specialty and special interests. This was provided by all respondents. Of the respondents 32 were unable to give their career aspirations at the time of registration but only nine were unable to do so at the time of beginning MRCP. In a third section information was requested about posts that the Member had done in an attempt to keep career options open (e.g. an obstetric job with general practice in mind). Only 100 members had done such jobs at SHO level and of these approximately one- third were in obstetrics and one-sixth in paediatrics. At senior registrar level only 71 had done such posts, mostly in sub-specialties of adult medicine. In the final section Members were asked if they could identify and describe any defects in their career planning. Demography This sample is presumed to be reasonably representative of those obtaining the Membership between 1966 and 1975, there being a 60 per cent overall response rate. The majority were aged 35-49 years, 81 (14 per cent) were women and they were slightly younger than the men (40 per cent aged less than 39 compared to 25 per cent of men), had obtained their qualifying degree at an earlier age (47 per cent aged less than 23 compared to 23 per cent men) and had more often obtained Part 2 MRCP before the age of 28 (42 per cent versus 36 per cent). Only 7 per cent of the sample had not been married but of the 436 who had been married 158 (36 per cent) were separated or divorced. At the time of obtaining the diploma 57 per cent had been married three or more years, 24 per cent five or more years and 20 per cent were not married until two or more years after the examination. The remainder mar- ried at about the time they were sitting the MRCP (22 per cent). Two hundred and forty-one (47 per cent) had had children by the time they took the examination. Women were less likely to have become consultants (57 per cent compared to 65 per cent for men) and much less likely to hold academic appointments (4 per cent compared to 11 per cent). A similar number of men and women were overseas or in non-hospital posts. Nine of 11 individuals who were still not in permanent posts were women; of these 8 had been married and 5 of these were divorced. Marital status did not otherwise appear to have signifi- cant associations with career status. Diploma In common with previous surveys by the College we found that the majority took Part 1 only once (76 per cent). A slightly larger number required more than one attempt at Part 2, only 56 per cent obtaining it at the first attempt. No less than 43 per cent stated that they passed both parts at the first sitting. Twenty per cent obtained Part 2 in the same calendar year that they sat Part 1 for the first time and 72 per cent had obtained both parts by the end of the next calendar year. Sex and marital status had no significant effects on these results. Career Posts All but 32 people had career posts, although a slightly larger number did not regard their present appointments as permanent; 330 were consultants in the NHS, 57 held academic appointments of senior lecturer or professor and 34 held consultant or similar academic appointments overseas. Of the NHS consultants 29 were practising solely in a sub-specialty, 122 as general physicians, 172 in allied branches of medicine, 32 in non-medical hospital specialties and 8 in specialties where it was difficult to regard the MRCP as being of direct professional value. Of those practising in allied branches of medicine the largest group were paediatricians (66). Higher Degrees and Research Only 127 individuals (22 per cent) had completed a higher degree (108 an MD, 14 a PhD and 10 both) although 294 (51 per cent) claimed to have completed appropriate research for a higher degree and 3 had work still in progress. The characteristics of those doing re- search or obtaining higher degrees are broadly similar. Table 13 shows that they are less likely to be women, more likely to be or have been married and may have a child aged less than three at the time of completing MRCP. They are also likely to have been successful at the examination at an earlier age, taking fewer attempts. There did not appear to be a significant change over the ten-year period in the number of individuals doing full- time research or obtaining higher degrees. Achievement of Career Aims One simple but crude way of looking at career paths is to compare the career aim with that actually achieved. For Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 95 Table 13. Social and demographic factors, full-time research and higher degrees. All figures given as per cent. Period of full-time research Higher degree undertaken obtained Men Women Single Married Married and divorced/ separated Age completed MRCP: <27 >30 MRCP in single attempts MRCP in more than 4 attempts in total Children: None or < 3 years at MRCP 3 or more years old at MRCP MRCP: 1965-68 1969-72 1973-75 NS not significant * p<0.05 ** p<0.01 ***p<0. 001 54 38 ** 31 52 57 * 65 **< 39 56 40 * * 56 44 NS 55 53 NS 47 23 15 NS 18 23 NS 22 51 *** 16 25 12 * * 25 12 * 22 22 NS 25 this purpose we made certain generalisations which we believed to be appropriate although limited in their applicability to individuals. We arbitrarily divided the posts according to the following definitions. Academic. Academic posts and full-time sub-specialists practising full-time in one of the main-line medical specialties regarded as highly competitive, e.g. cardiol- ogy, renal medicine. Physicians. Consultant physicians with or without a special interest. Branches. Consultants in branches of medicine other than general medicine in which MRCP is mandatory, e.g. paediatrics, geriatrics, dermatology. , ?- Non-Physicians. Consultants in specialties in which MRCP is an advantage but not necessary, e.g. radiology, ^ obstetrics, anaesthetics, psychiatry. Non-Hospital. Physicians practising outside hospitals in general practice, community health, pharmaceutical in- dustry. Sub-Consultant. Hospital doctors practising below the grade of consultant. Doctors in training are included in other appropriate categories. Overseas. Doctors overseas have generally been considered separately. The aim was to put posts in approximate order of competitive difficulty accepting that there are many exceptions. It is generally agreed that competition in most ij of the 'branches' including paediatrics is less fierce than in general physician posts, though not in all cases. In the non-hospital group the MRCP is often done because of individual enthusiasm rather than career requirements or advantage (for example general practitioners). Table 14 shows the career aims of the group at the time of completing the MRCP compared to their present posts. The data can be examined in a number of ways: e.g. of the 238 whose aim at the time of completing MRCP was a consultant physician post, 122 have ended up in such a post although 37 have become academics and 34 are in other branches of medicine; 33 have gone into non- hospital medicine including general practice (see below). The vast majority of current physicians (122) started their post-MRCP career with that aim though 10 were then t aiming for academic appointments and 7 considered , J careers in non-hospital medicine their first choice at that time. In addition, 27 of these are practising permanently overseas as physicians. In contrast, of the 86 'academics' only 34 were aiming originally at such an appointment and of those practising in branches of medicine (168) only 110 (and some of the 18 academics) were planning this career at the completion j of MRCP. , An alternative way of looking at the situation is to examine their specialty interests and Table 15 shows the Table 14. Comparison of aims at time of passing MRCP and current appointments. Stated aim at time of completion of MRCP Present appointment Consultants Consultant Non- Consultant in other non- hospital Academics physicians branches physicians doctors Overseas Unknown (n = 67) (n = 238) (n = 154) (n = 37) (n = 64) (n = 3) (n = 12) Academic (n = 86) 34 29 18 1 3 ? 1 Consultant physician (n = 122) 10 102 4 0 5 0 1 Consultants in other branches (n = 168) 6 34 110 4 6 0 1 Non-physician consultants (n = 40) 1 6 5 24 20 0 2 Non-hospital doctors (n = 90) 5 31 8 ' 3 41 0 2 Overseas or sub-consultants (n = 51) 5 24 8 5 5 2 2 Unknown (n = 18) 6 9 1 0 0 0 2 96 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Table 15. Number of physicians in different specialties with comparison of number remaining in the specialty of their choice at the time of completing MRCP and research experience and higher degree. Specialty/interests (career posts only) No. Achieving aim at MRCP % No. Spent period in full- Obtained a time research higher degree Physicians: Academic 35 48 NHS (includes full-time specialists) 153 60 General practitioners 69 77 Paediatricians 66 80 Rheumatologists 30 75 Geriatricians 28 63 Dermatologists 20 80 Psychiatrists 15 65 Haematologists 12 92 Clinical pharmacologists 9 ? Miscellaneous branches where MRCP is necessary 27 60 Miscellaneous branches where MRCP is an advantage 50 73 Miscellaneous branches where MRCP is no apparent advantage 13 ? Overseas practice 42 ? 23/48 127/215 40/52 60/75 9/12 5/8 16/21 11/17 11/14 2/2 12/20 24/33 4/8 2/3 82 77 15 33 40 32 40 40 55 100 60 46 62 41 54 39 0 12 7 14 20 27 0 56 15 18 0 17 respondents grouped according to their job description. Physicians in all specialties practising overseas are in a separate group. For general physicians those holding university appointments are separated as 'academics' but those with a full-time special interest are included with consultant physicians. In other groups academics and consultants are included together. After general phys- icians it is perhaps surprising to find that the next largest group is general practitioners, with paediatricians a close third. The second column of Table 15 shows the percent- age (and numbers) eventually achieving the aim they had at the time they completed their MRCP. There are 181 individuals who are not in posts which were their aim when they completed MRCP. Full information is avail- able on 80 who were planning at that time to be general physicians (with or without a special interest) and these are by far the largest group. Of these 80, 18 went into geriatrics, 13 each into general practice and rheumato- logy and 5 into clinical pharmacology; 15 went into a number of other sub-specialties including paediatrics and dermatology; 2 into psychiatry and 14 into sub-specialties in which MRCP is either not a standard requirement or not an obvious advantage. Taking academic and NHS consultants together, 57 per cent (150/263) of those aiming for a career in general medicine at the completion of their MRCP obtain career posts in general medicine and associated sub-specialties. There is also, however, a significant accretion (38) to the eventual number of career posts (188) from individuals who were planning careers in other branches of medicine at the time of completing MRCP and these represent one- fifth of all career posts in general medicine. In paediatrics this accretion is 9 per cent (6 of 66) while in general practice (42 per cent), rheumatology (70 per cent) and geriatrics (82 per cent) it is much higher, with most of the accretion coming from individuals previously aiming for careers in general medicine. Similar results are seen for other branches of medicine where MRCP is necessary (55 per cent), where it is an advantage (52 per cent), and where it is no apparent advantage (69 per cent, note n= 13). Accretions in the smaller sub-specialties of der- matology (20 per cent), psychiatry (27 per cent), haema- tology (8 per cent), or clinical pharmacology (78 per cent) show a pattern similar to that of general medicine and paediatrics, with a low accretion rate apart from clinical pharmacology; but numbers are small and conclusions must be guarded. Only two of the 42 with career posts overseas were planning to go overseas at the time of completion of MRCP so that the accretion rate in this group is 95 per cent. Reasons for Change Very few respondents completed this section of the questionnaire, which asked for reasons why they had changed career paths. Dividing the reasons given very broadly into the three following groups the following data were obtained: Good Reasons. Described as desirable, e.g. preferred new career. Bad Reasons. Described as disap- pointing, e.g. no jobs available in previous career or lack of necessary experience, etc. Social Reasons. Social, finan- cial and other linked reasons. Overall, the good and bad reasons almost exactly balanced, suggesting that in nearly half the cases where the career plan had changed this was seen as desirable and indicated a preference (whether this was the result of rationalisation or not). The social and financial factors were significant in only about one-fifth of all the reasons given. Looking at the large group whose aim was to become consultant physicians but who changed to a branch specialty, or even left hospital medicine, reasons in the 'bad' group outnumber those in the good group by 2:1, while for those now in non-hospital medicine as a whole who changed careers, good just outnumber bad. Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 97 Similarly, those who were aiming for academic posts at completion of MRCP but did not achieve them, give twice as many bad as good reasons and those aiming for branches of medicine give equal numbers of good reasons for their changes of career. Social factors appear of relatively little importance. Dissatisfaction with Career Ladder Respondents were asked if they could identify any defects in their careers which might be responsible for their not achieving the career path which they would have liked. Reasons given were divided into the following categories: (a) blaming the training programme; (b) blaming other people, e.g. seniors/advisers; (c) lack ofjob opportunities; (d) health or social reasons; (e) bad planning; (f) appor- tioning blame to oneself. One hundred and twenty-eight stated that there had been a defect in their training and 115 identified a reason. Of these nearly all (99) blamed 'the system' in one way or another (training 30; people 40; no jobs 29). Remarkably few blamed themselves (2), bad planning (7) or health or social reasons (7). Experience of MRCP Members who are at present in academic or full-time specialist appointments as general physicians were more likely to obtain the MRCP at a younger age so that the ratio of this group passing the examination at 27 or less compared to 30 or more was 2.5:1, for NHS consultant physicians 1.2:1 and for non-hospital practitioners 0.7:1. Cause and effect is not established. Similarly, they are likely to pass the examination after fewer attempts, though this waiS- not statistically significant. Research and Degrees As expected, academics and full-time sub-specialists were much more likely to have done full-time research (88 per cent) than NHS consultants (55 per cent); the percentage of overseas academics (54 per cent) and consultants (42 per cent) was lower than that of their UK counterparts. The same picture is true for higher degrees (53 per cent of academics and 22 per cent of consultants having higher degrees and 39 per cent and 16 per cent respectively of overseas academics and consultants). Non-hospital phys- icians were much less likely to have done research (25 per cent) or have higher degrees (6.2 per cent). It is noticeable that those who aimed initially for careers in branches of medicine other than main-stream consultant physician or paediatrician, etc.; and are now in such posts are much more likely to have done research and obtained higher degrees than those who made a decision to go into one of these branches of medicine at a later date. Of 244 people aiming to be consultant general phys- icians at the time of completing the MRCP, 66 got a higher degree and, of these, 56 (85 per cent) ended up in consultant or academic physician appointments, with a further 4 in branches of medicine and 2 overseas. Of the 178 who did not get higher degrees 92 (52 per cent) are in consultant or academic physician appointments, 30 (17 per cent) in branches of medicine, 21 (12 per cent) overseas and 30 (17 per cent) in non-hospital medicine. Conclusions At the time of completion of MRCP by examination, only about 50 per cent of Members are planning a career in academic or NHS general medicine and of these only 57 per cent achieve this ambition. The 'success' rate is much higher in those who also do a higher degree (85 per cent) than those who do not (52 per cent). However, only a minority (39 per cent) of NHS consultant physicians obtain higher degrees at all. The second most frequent career aim at the time of completing MRCP (n = 75) is hospital paediatrics and this was achieved by 80 per cent of individuals. The other large group is general practice (n = 52) where a similar proportion (77 per cent) do become principals in general practice. The other special- ties with significant numbers can be broadly divided into those where a decision appears usually to have been made by the time of completion of MRCP (dermatology, psychiatry and haematology) and those with a high accretion rate after MRCP (rheumatology, geriatrics, clinical pharmacology and the three pooled groups where MRCP was judged essential, an advantage or no appar- ent advantage). Nearly all (95 per cent) of those with career posts overseas made their decision after completing MRCP. Those in academic posts were characterised by being male, taking fewer attempts to obtain the MRCP at an earlier age and to have done higher degrees and full-time research. Many of those who changed career paths did so for what we characterised as 'good' reasons, i.e. from their own preference. Those changing from career aims as general physicians to branches of medicine twice as often gave 'bad' reasons suggesting that the change had not been of their own choosing, while those initially aiming for and achieving career posts in the branches of medicine were similar to those in general medicine. A large number of those changing career paths felt that there had been a defect in their training though nearly all blamed either the system or senior colleagues and a tiny minority blamed themselves. John H. Tripp Benefits and Problems of Training Abroad Most doctors in training will have considered spending some time working abroad. They will be familiar with the rumour that, on the one hand, the BTA ('Been to America') qualification is important for career advance- ment, and on the other that re-entry to the UK career ladder verges on the impossible. This background led the Standing Committee of Members to survey College Members to clarify the benefits and problems of working abroad for three or more months. 98 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Method The survey questionnaire is available from the College and the author. It was sent with each of the other three surveys described in this section. This questionnaire was therefore sent to 744 doctors randomly selected from those obtaining MRCP between 1968 and 1983; 596 obtaining MRCP in 1972, 1973, 1976, 1977, 1980 and 1981, and 951 obtaining MRCP between 1966 and 1975. Results The overall response rate was 55 per cent. Some question- naires had been sent to College Members living in their own native country abroad, or who had emigrated from Britain. These were excluded, leaving 1,192 valid replies which were analysed. Most respondents failed to fill in details of their own post and specialty, presumably because they had already done so on the accompanying questionnaire. Unfortu- nately, once the two questionnaires were separated this ^ information became irretrievable. A total sample of 410 Members who had been abroad for a period of training was identified and some useful conclusions can be drawn from the answers they gave. Of the respondents 34 per cent had been abroad for more than three months. The most popular countries were USA (33 per cent), Canada (10 per cent), Australia (5 per cent) and South Africa (5 per cent). Seventeen per cent had been to countries within black Africa and of those Nigeria was the most popular (4 per cent). Nine per cent had visited countries in mainland Europe and of these the most popular was France (3 per cent). The majority (55 per cent) had been to teaching hospitals similar in standard to those in the UK but 12 per cent had visited small teaching hospitals and 20 per cent non-teaching hospitals. Thirteen per cent had been in- volved in various pursuits from working in full-time research posts in universities to mountain rescue, ship's surgeon and the flying doctor service. Sixty-one per cent left for their period of training abroad at registrar or senior registrar level and a further 4 per cent were research fellows or lecturers; 20 per cent were senior house officers and 4 per cent were consult- ants. The median time abroad was 18 months, and the greatest number of people were away for 12-15 months (28 per cent); 12 per cent had been abroad for two years. In only 16 per cent was the period abroad a planned , attachment, but 44 per cent said that they had been guaranteed a job on their return to Britain; 31 per cent said that the period abroad was planned at the time of appointment to a UK post; 84 per cent claimed to have arranged the visit themselves. Nineteen per cent found difficulty in gaining employ- ment on returning to Britain, 20 per cent claimed to have lost seniority, and 34 per cent had lost financially. Many different organisations had been used to provide advice and financial assistance. The following organisa- v tions were mentioned frequently as providing finance: Wellcome Foundation, universities, Medical Research Council, church organisations and related charities, phar- maceutical companies. Thirteen people had obtained scholarships for the purpose of travel abroad, but many obviously relied on funding from the country being visited. For advice many people stated that their own consultant or personal friends had been most useful. Language problems were experienced by 20 per cent, and 17 per cent said that they had had difficulty integrat- ing with local practice and consequent problems at work. Other problems concerned cultural and political differ- ences of one type or another (18 people). Discrimination against women was mentioned in particular. Poor facili- ties (16 people) and unfamiliar standards of practice (7 people) caused problems, and four found themselves working with colleagues whom they judged as incompe- tent. Four complained that the work was too hard and ten had experienced various administrative problems or problems with accommodation. Seventy-eight per cent said that they had gained experi- ence which would not have been available in Britain and of these 88 per cent believed that that experience had been useful on return. Fifty-two per cent felt that they had not contributed usefully to the development of facilities abroad. Only 28 per cent had gone abroad primarily for the purpose of research but 57 per cent had produced publi- cations from the work abroad and 15 per cent had achieved a higher degree from research. One hundred and twelve people said that their time abroad was not recognised by JCHMT and in 93 cases it had been. However, it is not clear how many of the former actually requested such recognition and a large number had not applied. Only 2 per cent said that their visit had not been time well spent. People stated a large number of advantages to training abroad. Apart from gaining clinical experience people believed that they had somehow fulfilled them- selves by going abroad and had developed a better understanding of world problems (36 people). A number of people were not ashamed to admit that fun and sunshine were important aspects of the trip. Some felt they had gained by meeting people in their own field of interest (14 people). For many, research facilities and teaching experience had been made available by their trip (24 people). Seven people stated that they valued the experience of seeing medicine run as a financial concern. Twenty-five people complained that there had been a failure to recognise the experience abroad as valuable on return to the UK and 13 mentioned frank prejudice against them. In nine instances the trip abroad had apparently caused personal problems and four felt that their children's education had been disrupted. Three had felt lonely and ignored abroad and four that loss of contact with the UK was a worrying problem. Four felt that they should have received more advice before em- barking on their trip. The present grade of 332 respondents was available. Some comparison between those who had and who had not been abroad was therefore possible (Table 16). Of those presently graded consultant 43 per cent who had been abroad did so at senior registrar level and 29 per Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 99 Table 16. Comparisons of grade in those who had and who had not undergone some training abroad. Percentage of total who had not had Present Grade trained abroad trained abroad (n = 226) (n =106) Academic consultants 5 10 NHS consultants 32 45 General practitioners 12 9 Senior registrars and lecturers 30 15 Registrars 13 10 Others 8 11 Percentage of the grade who had not had trained abroad trained abroad No Academic consultants 50 50 22 NHS consultants 60 40 121 General practitioners 75 25 35 Senior registrars 81 19 83 Registrars 73 27 40 Others 65 35 31 cent at registrar level. Canada and the USA were the countries visited by 61 per cent of those who had become consultants. Of the consultants 45 per cent had spent 12- 18 months away but 20 per cent had been away for 18-24 months. Conclusions The survey identified a large group of doctors in a range of specialties and grades who had worked temporarily abroad. The proportion (34 per cent) was unexpectedly high. This figure does not appear to have been artificially inflated by doctors holding the MRCP but not working in the medical specialties, as 55 per cent of those who had been away were either academic or NHS consultants and a further 23 per cent were in hospital training posts. The data suggest that at present 40-50 per cent of newly appointed consultants have worked abroad. The majority of these have done so during their years as registrar or senior registrar, most having visited Canada or the USA. The majority had been away for more than one year and most had found a fruitful research project which had led to publication, even if that was not the main reason for going. It seems that a trainee following this type of programme is unlikely to damage his career. One clear conclusion is that, despite a number of problems, very few people regretted their spell abroad. Practically all had gained valuable experience. There was a substantial risk of financial loss, including loss of seniority on return. Nevertheless, it is encouraging that the JCHMT recognised the period abroad in a substan- tial proportion of cases. Some people obviously do have problems gaining employment in the UK on return and the prejudice against them which some expressed may indeed have been due to an inappropriate or lengthy period away from the main stream of medicine. The effect of the removal on family life is important to consider before making the upheaval. It had had a detrimental effect on some children's education, and separation or changed environment had caused some marital problems. A number of people had experienced unhappiness at their place of work, mostly related to cultural or political differences but sometimes to inhospitality or incompe- tence of colleagues. Some found themselves isolated and lonely. It is obviously important to look carefully at the local situation which one is planning to enter to ensure that there are no potential problems. The overwhelming implication of this survey is that training abroad is valuable and to be encouraged. It is fruitful in terms of research and experience but social and financial safeguards are sometimes neglected, with harm- ful results. Bona fide training will be credited to one's career. Clive Roberts 3. INDIVIDUAL SPECIALTIES Accident and Emergency (A & E) Medicine The specialty is now 14 years old and still developing. The majority of consultants are full-time and come from a variety of backgrounds. .Of the 170 full-time consultants in post it must be said that the majority hold the FRCS. However, a significant proportion hold the MRCP and often half the patients seen have medical problems. The growth of the specialty has been restricted by the lack of suitably trained applicants but with the recent expansion of the senior registrar grade, consultant expansion is beginning again. It is anticipated that consultant growth will continue for the foreseeable future, as many depart- ments do not have an A & E consultant and very few indeed have more than one. The Casualty Surgeons' Association is the professional body which represents and co-ordinates the specialty and the Emergency Medicine Research Society provides a forum for the discussion of research topics. An A & E consultant is responsible for all the patients who present to the A & E department. Resuscitation of the acutely ill and injured takes priority and is seen by most as the particular forte of this specialty. Management of cardiac arrest and the multiple injured patient are the two areas in which the A & E doctor has a great deal to contribute. Most A & E consultants develop a special interest, often based on their previous backgrounds, e.g. hand surgery, if surgically trained, or poisonings if 100 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 medically trained. There are a small number of paediatri- cally trained A & E consultants who work in paediatric A & E departments. A feature of A & E medicine is that the working day is usually unstructured and the variety is enormous. 'All human life is here' and you can move from sophisticated resuscitation for a severe cardiac prob- lem to the treatment of alcoholism or a child with a cut knee. The requirements are a broad background in both medical and surgical disciplines and the ability to keep cool in a crisis. Casualty departments are informal, and relationships between various specialists and disciplines are undefined. It is essential to be able to co-operate with nursing and ambulance staff on an equal level. Most A & E departments are staffed by senior house officers and sometimes, it must be said, in inadequate numbers. The DHSS considers registrar posts in A & E orthopaedics as posts in A & E. The fact is that these are orthopaedic training posts and there are only a handful of pure A & E registrar posts. The specialty is negotiating with the DHSS to rectify this anomaly and an expansion of the registrar grade is planned. This will eventually * allow entry to the specialty at the registrar level. In many departments for the foreseeable future a consultant will be the first in line on call after the SHO. What this entails in terms of emergency call-out depends upon what other facilities and local arrangements are available at the hospital concerned. Many A & E consultants become involved in out-of-hospital rescue work and the higher training of ambulancemen. Entry for training in A & E medicine is at present at senior registrar level and there are about 65 posts avail- able. No further expansion of the senior registrar grade is planned for the immediate future. Candidates must have the FFA, FRCS or MRCP and a broadly-based back- ground. Many candidates have done a registrar job in A & E medicine. Once appointed senior registrar, the training programme is tailored to ensure that those areas not covered by previous experience are made up. Most senior registrars therefore spend some time in paediatrics and intensive care as well as in psychiatry and general practice. If their training has been predominantly medi- cal, they spend at least six months in general and orthopaedic surgery, and if predominantly surgical, vice versa. It is now possible to take the second part of the FRCS Edinburgh in A & E medicine and surgery. Candidates are eligible to sit this examination if they have been qualified for four years, have either Part 1 of the Membership, or the primary Fellowship or the primary FFA of any of the Colleges and have completed 12 months A & E, 12 months' acute general medicine and 12 months' general surgery. Senior registrars may spend some time abroad during their training and the JCHMT will recognise appropriate experience. Accident and Emergency Medicine is expanding and is now an established specialty. In the past it was thought that A & E departments should be staffed by one phys- ician and one surgeon; now the feeling is they should be staffed by two specialists in A & E medicine. Career prospects are good. Anthony Redmond Cardiology Consultant posts in this specialty are of two main types: general physicians with an interest in cardiology, and pure cardiologists based at regional cardiac centres. Car- diology has changed with the introduction of echocardio- graphy, exercise testing and coronary artery bypass grafting. Coronary angioplasty and intra-coronary thrombolysis are being evaluated. Non-invasive diagnos- tic methods, best performed in District General Hospi- tals, have increased the work of the physician with an interest in cardiology. There are slightly more physicians with an interest in cardiology than pure cardiologists. Anticipated retire- ments are equally divided between the two, averaging six a year up to 1995. As in other specialties, those who have completed four years as senior registrar far exceed the predicted number of consultant vacancies. Expansion, if any, is most likely to occur in the post of physician with an interest in cardiology. In short, present career pros- pects in cardiology are dismal, with fierce competition for the vacancies that arise. Your best chance of becoming a consultant in cardiol- ogy lies in deciding early in your career, making your intentions known to your referees and aiming for posts at well-established centres. General medical experience at SHO and registrar level is essential. Specialisation tends to begin at registrar level. A period of research, of a standard worthy of an MD or PhD, is becoming a requirement for senior registrar appointments. Great care is required in selecting a research post. Well-established departments of cardiology are the best bet. You should be wary of single-drug projects sponsored by pharmaceutical firms. The MRC and British Heart Foundation support research projects in good departments. There is now a single higher training programme at senior registrar level. Two years should be spent in a clinical post as senior registrar in a cardiac centre, including one year in a centre with cardiac surgery. The specialist training should include clinical experience in general cardiology, training in cardiac catheterisation and angiography, echocardiography, ambulatory moni- toring, cardiac pacemaking, exercise stress testing, acute cardiac care, and nuclear cardiology. One year at senior registrar level should be spent in general medicine and a further year in a related sub-specialty, e.g. hypertension, epidemiology, cardiac rehabilitation, clinical pharmacol- ogy or cardiovascular research. Paediatric cardiology remains a small sub-specialty limited to regional centres. An invariable requirement is paediatric experience in SHO or registrar grades, includ- ing six months' neonatal paediatrics, six months in general paediatrics and one year in adult or paediatric cardiology. Again, a prerequisite for senior registrar appointments is a doctorate. Senior registrar training includes some adult cardiology and general paediatrics. The College has a specialist advisory committee in cardiology and also a joint cardiology committee (in collaboration with the Royal College of Surgeons of England). The College continues to press for an improve- ment in services for the diagnosis and treatment of heart Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 101 disease. The British Cardiac Society is the main forum for scientific debate. It has also concerned itself with the problem of inadequate resources and funding for cardi- ology, in particular the bottleneck in the career structure that has resulted in a large number of senior registrars marking time. Lawrence Bryson Clinical Genetics Clinical genetics is a new and expanding specialty and few regions at present have adequate clinical genetic services. It has been recommended that in a region there should be two full-time clinical geneticists per 2-3 million population[l] and ideally these should be based in a Regional Genetic Centre where there are appropriate supporting staff and associated genetic laboratory ser- vices. Genetic clinics are held in the Regional Centres and in 'satellite' clinics in association with local clinicians. Most clinical geneticists do not have beds but can admit by arrangement with consultant colleagues. Genetic conditions can affect all age groups and all body systems and a broad clinical background is essential. Day-to-day work is varied and includes diagnosis of genetic conditions, genetic counselling, ward referrals, acting as an 'information resource' on genetic matters for colleagues, liaison with genetic laboratories and clinical colleagues in investigations and clinical interpretation of results and in prenatal diagnosis of fetal defects. More recently, clinical geneticists have been involved in clinical application of recombinant DNA technology and in re- search in this exciting field. Teaching of undergraduates, postgraduates and associated professional groups is an important aspect of their work. Entry to the specialty is usually at senior registrar level and there are six NHS-funded senior registrar posts in the UK and a small number of ad hominem SR equivalent posts funded by limited-duration research money. Before entering the specialty the trainee should have post- registration general professional training, to include ideally both paediatrics and general medicine, leading to the MRCP. An SHO job in obstetrics has been seen as an advantage by some. A year should have been spent in the study of basic genetics, either as a postgraduate or during undergraduate training in the form of an intercalated BSc. Those SRs without this basic genetic qualification will be seconded during higher specialist training. As senior registrar the trainee should gain knowledge of dysmorphology, biochemical and population genetics, cytogenetics, DNA technology, the genetics of disorders of different body systems and genetic counselling tech- niques. Encouragement is given for research projects leading to an MD degree. It is recommended that there should be one consultant clinical geneticist per million population and, though this target is far from being achieved, the NHS appears to be moving slowly towards it. If these hopes are realised, career prospects should be reasonably good in the medium term. Career prospects should be good if those regions without clinical genetic services fund new posts and those with existing services expand to recommended levels. Trainees for other spe- cialties may wish to acquire training in genetics, and dual accreditation may be possible in some cases. The Clinical Genetics Society, which consists of physicians, scientists and other professional groups working in the field, meets twice yearly and contributions and attendance by younger members are encouraged. References 1. Clinical Genetics Society (1983) Bulletin of the Eugenics Society, Suppl. 5 Dian Donnai Clinical Immunology/Allergy All physicians use the results of immunological investi- gations in the management of their patients but clinical immunology has become sufficiently complex to require specially trained consultant immunologists both in the laboratory and in clinical care. Clinical immunology as a separate specialty is proving slow to develop within the NHS. There are said to be nearly 50 consultants in immunopathology in the British Isles but many hold honorary contracts, often with limited service commit- ments. Many doctors currently practising in this field do so from an academic base with a major research interest. Departments of laboratory immunology have developed in some major hospitals primarily to provide immuno- diagnostic services. Thus it is not surprising that in recent years there has been considerable discussion about how clinical immunology should be developed. Most experts agree that specialist immunology services are not needed in every district hospital but that they should be estab- lished on a sub-regional basis in major medical centres serving populations of 1-2 million persons. The first need is for an even distribution throughout the country of laboratory-based immunologists providing full immuno- diagnostic services. These consultant immunologists almost always see referrals on the wards and do out- patient sessions but the appointment of a specialist phys- ician in clinical immunology/allergy becomes necessary when the workload increases. If money were to be made available for the proper development of this specialty, at least 25 new consultant posts should appear within the next few years. The appearance of the acquired immuno- deficiency syndrome as a major clinical problem makes this more urgent. Collaboration with colleagues in the management of patients is a major attraction of this specialty. Many members of established medical specialties fear the intru- sion of yet another expert in the care of their patients. This fear is not necessary; the shared care of immunologi- cal problems can be most rewarding for all concerned, not least the patient. The consultant immunologist is in- volved ir> the broad spread of medicine without needing to pretend that he is expert in every aspect. This collabora- tion should involve consultation on the wards and often means the development of combined out-patient clinics 102 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 with specialties that see a large number of immunological problems. However, this does not mean that the clinical immunologist never has prime responsibility for a patient's care; for some patients with immunodeficiencies or certain multi-system immunological disorders it is natural for the clinical immunologist to become the main specialist overseeing the management of their illness. This is particularly the case when special treatments like plasma exchange are involved. A further major attraction of this specialty is that the clinical immunologist also works within the laboratory. As the close colleague of the laboratory-based immunol- ogist, he is involved in the planning and interpretation of investigations, and seeing patients' problems through from the bedside to the laboratory bench. This requires comprehensive experience in the laboratory during train- ing. Clinical immunology also offers many research opportunities. At present, training for this discipline is not easy. Clear guidelines for the training of the laboratory specialist are already available, and new guidelines for training the physician in clinical immunology/allergy are currently being considered by the JCHMT. Meanwhile, physicians aspiring to this specialty need as basic training at least two years in posts approved for general medicine, which should also provide some experience of immunological disease. Considerable benefit will be gained from a period in a research post, when knowledge of basic immunology can be consolidated and research skills developed. After this comes the move to higher medical training in an approved post as a senior registrar, which is a little less certain at present. Any young doctor embarking on the early part of training for clinical immunology/allergy will not prejudice his chances in other specialties in which immunology is important. By the time such a doctor is ready for his senior registrar post, the future of clinical immunology will be clearer and posts for specialist train- ing will have been established. Timothy Wallington Clinical Pharmacology Clinical pharmacology is one of the more recently recog- nised sub-specialties in medicine, but has previously existed in one guise or another (materia medica, thera- peutics). It differs from the established sub-specialties in not being 'organ-based', having no clear service commit- ment to offer and, at present, flourishing largely within an academic environment. These factors may have ham- pered its development. In the 1970s the concept of a consultant in clinical pharmacology in every District General Hospital was Popular. However, plans for an expansion of the sub- specialty were shelved by the subsequent adverse econ- omic climate. Clinical pharmacologists in training were rarely considered for appointment to consultant posts, as they could not offer any special service to a clearly defined group of patients. The writing was on the wall and many rapidly re-trained in another sub-specialty. A number have been appointed as physicians with an interest in diabetes, cardiology, or geriatrics. Some have found a niche in acute poisoning. While there has been some expansion of clinical pharmacology posts in medical schools, there are a mere handful of posts in the NHS. The present problem is that many a young doctor finds the subject appealing and is attracted to the idea of becoming a consultant clinical pharmacologist. Academic units need good, enthusiastic, young doctors who will teach and also perform research. There is no shortage of excellent applicants for research or lecturer posts in clinical pharmacology. But after a suitable time in such posts the goal of becoming a consultant clinical pharma- cologist has often not been realised. Many have then entered the pharmaceutical industry ? a decision very few regret. In the latest review (1983) of manpower in clinical pharmacology there were six NHS consultant clinical pharmacologists and 15 NHS consultant physicians with an interest in the subject. However, it is difficult to believe that all the latter were appointed as clinical pharmacologists. In the medical schools there were 54 honorary consultants, though it was not clear how many were also practising general medicine. There were eight senior registrar jobs in the sub-specialty and 32 honorary posts (lecturers and researchers). While only 10 of these were in their fourth or fifth year, only four or five consultants were within five years of retirement. The equations just do not balance. The College is still lobby- ing for the expansion of clinical pharmacology in the NHS. However, despite the acknowledged need for greater influence by clinical pharmacologists on all as- pects of drugs and therapeutics, the chances of a rapid improvement in the situation seem slim. After training in general medicine at SHO and regis- trar level, the aspirant should obtain a senior registrar post in general medicine with clinical pharmacology in a recognised unit. These days it is probably wise to select a particular organ or system for intensive study, as this increases the options when applying for consultant posts. During the senior registrar appointment a knowledge of methods of investigation of drug action in man should be acquired, in addition to pharmacokinetics, clinical trial methodology, statistics and the clinical management of acute poisoning. Most are best learned by doing one's own clinical trial(s) or research project(s). Clinical phar- macologists must be good communicators, so it is import- ant to acquire high standards of lecturing ability, research presentation and scientific writing. An MD or PhD is an essential qualification which is obtained during the senior registrar appointment, but the trend is towards complet- ing the work for these while in a research post at registrar level. When sufficient publications have appeared you will be eligible for membership of the clinical section of the British Pharmacological Society. This provides the principal forum for presentation of scientific research and professional advancement of the sub-specialty. Once trained, the clinical pharmacologist should be a physician, first and foremost. In addition, he should help develop rational drug prescribing policies within his hospital or health authority and be a catalyst for research Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 103 projects and clinical trials. He may take on special responsibility for certain disorders, e.g. hypertension, epilepsy or acute poisoning. Some may also provide a service to other physicians and general practitioners on difficult therapeutic problems, such as drug adverse effects, drug interactions, and the rationalisation of com- plicated regimens. A drug information service is now increasingly provided by hospital pharmacists. Despite the poor prospects, there are many avenues for those who are clinical pharmacologists at heart. Very few senior registrar posts exist for those who are committed to clinical pharmacology alone. Many senior registrar posts in general medicine with another sub-specialty as a primary interest have a period attached to a clinical pharmacology unit. This is perhaps the best approach, for I have serious doubts about the value of an accreditation certificate in clinical pharmacology alone. Other posts offer triple accreditation, i.e. general medicine, clinical pharmacology and one other (cardiology, gastroenterol- ogy, or endocrinology). From these you may apply for consultant jobs in the sub-specialty, other than clinical pharmacology, appropriate to your training. Once ap- pointed consultant you may then develop your interest in clinical pharmacology. For those who set their sights on an academic career, there may be slightly better pros- pects, but remember that present incumbents of chairs of clinical pharmacology have a remarkably youthful air. Clive Roberts Communicable and Tropical Diseases The specialty of communicable diseases has reached a crisis of manpower and status. From a position of pre- eminence at the start of the twentieth century, when Britain led the world in the management of the classical infectious diseases, the specialty has dwindled to 44 consultants in communicable diseases and eight consult- ants in tropical medicine serving the needs of the entire country. Training is very similar in both fields and many jobs overlap, so they are here considered together. Most of the rural isolation hospitals have been closed and though the remaining Infectious Diseases Units are desig- nated as regional units, they rarely function as such. As a result of this contraction of the specialty, district hospital accommodation for patients with suspected or confirmed communicable disease is non-existent, while the majority of districts do not have direct access to the expertise and advice of a specialist in communicable diseases. This parlous state of affairs differs markedly from that in other western countries, in particular North America and Scandinavia, where every major hospital has the advan- tage of a specialist in communicable diseases. The last decade has revealed new problems of infec- tion; Legionnaires' disease; Campylobacter gastroenter- itis; Cryptosporidium enteritis; staphylococcal toxic shock syndrome; new viruses such as parovirus, and the devas- tating effects of HTLV-3 infection and acquired immuno- deficiency syndrome; increasing numbers of imported tropical infections; multiple resistance of bacteria to commonly used antibiotics. These new problems indicate the way contemporary infection cuts across the wide field of medicine, which makes a career in communicable diseases attractive. The form and direction of training in a specialty as diverse as communicable diseases will inevitably define the ultimate structure of the specialty. To achieve an equitable distribution of manpower, training must be co- ordinated centrally and the existing mechanism of the Specialist Advisory Committee (SAC) of the JCHMT is ideally placed to oversee this. What training options are open to the young doctor wishing to pursue this career? First, he must have a soundly based training in general medicine to registrar level and have attained the MRCP(UK). An approved senior registrar post, or its academic equivalent, in a recognised Infectious Diseases Unit or academic depart- ment is then essential. From such a post, and with guidance from the SAC, it is important for the trainee to receive training, either directly or by secondment, at home or abroad (and here the USA has much to com- mend it), in one of several sub-specialties such as epide- miology, clinical immunology and tropical medicine. Those wishing to specialise in tropical medicine will spend a substantial part of their higher medical training in a tropical or sub-tropical country. A period of experi- ence in medical microbiology as part of an MSc or MD project is to be encouraged and would allow a valuable insight into the logistics of laboratory medicine and the interpretation of the investigations performed there. I do not suggest that the clinical microbiologist will no longer have a role in the care of infected patients, but propose to promote the concept of a team approach to clinical infection. Communicable and tropical diseases present a great challenge. The field is as wide as that of a textbook of general medicine which continues to have new chapters added to it annually. Stuart Glover Community Medicine Community medicine is concerned with the promotion of health and the prevention of disease within whole com- munities. It includes assessment of the health needs of communities and the planning, delivery and evaluation of services. Community medicine complements clinical medicine, which concerns the health of individuals, by focusing on the health of populations. Epidemiology is the science fundamental to the practice of community medicine, and the skills which must be acquired are population control of communicable and non-communicable diseases, stat- istics, computing, health economics, nutrition, social and public policy, organisational theory, behavioural science, health education, communication and management. Community medicine is a new and developing special- ty founded in 1974 from the interrelated interests of public health (Medical Officer of Health departments), 104 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 social medicine (university departments) and medical administration (hospital boards). Every health authority has a department of community medicine headed by a District Medical Officer (or Chief Administrative Medi- cal Officer in Wales and Scotland). Community phys- icians also work in Regional Health Authorities, Medical Research Council units, government health departments, universities, armed forces, the pharmaceutical industry and other private sector organisations. Career prospects are good because of the effect of a cohort of older doctors and premature retirements follow- ing reorganisations of the Health Service since 1974. In 1984 there were 542 NHS-equivalent consultant posts and 223 training posts, making it the tenth largest specialty in Britain out of a total of 54. Within the general medical specialties only general medicine (1,141) and paediatrics (573) had greater numbers of consultants. The provision of community health services normally falls within the responsibilities of the District Medical Officer. These can include physiotherapy, speech ther- apy, chiropody and dietetics, as well as clinical medical services such as pre-school and school health, occupation- al health, and family planning services. Community health doctors who carry out these clinical duties are known as Clinical Medical Officers and Senior Clinical Medical Officers. Their training needs are different to those of community physicians and the development of an appropriate career structure has been the subject of much discussion in recent years. Training for a career in community medicine has many similarities to that for other specialties but there are some important differences. First, because the basic sciences of the specialty have a small place in undergraduate teach- ing, it is necessary to provide a special academic input through whole-time study for one year, or part-time over a longer period. In England and Wales this is undertaken either by attending a Master of Science (Community Medicine) course at the London School of Hygiene and Tropical Medicine or Manchester University, or a part- time course organised by two groups of university depart- ments of community medicine (Northern Consortium or Midlands and South West Consortium). Second, service training in community medicine pro- vides experience in a number of topics which relate to clinical medicine but do not feature to any great extent in junior hospital posts or general practice vocational train- ing. Examples would be epidemiological studies, plan- ning and evaluation of particular services, infectious disease control, health education and health promotion. This affects the timing of the specialist qualification, the examination for Membership of the Faculty of Com- munity Medicine. The MFCM Part 1 tests the candi- date's knowledge and understanding of the basic sciences and should be completed before entry to higher specialist training. The MFCM Part 2 tests the candidate's ability to apply these basic skills to community medicine prob- lems and is usually completed during the holding of a senior registrar post. Third, in community medicine there is a single train- *ng grade covering both registrar and senior registrar posts. This means that, once appointed, the doctor would normally stay with the same health authority for the five years of training. However, rotations with neighbouring health authorities and short-term attachments to special- ist units can be arranged. Many doctors entering community medicine already have the MRCP. Although it is not a prerequisite, appointments committees are likely to look favourably on those applicants with higher degrees and diplomas. Training requirements can sometimes be varied. Pre- vious experience is taken into account and those entering community medicine after many years of clinical medi- cine could expect a shorter period of training. For those already in a career post, a specific training programme with provision for protection of salary can be arranged. Those wishing to consider a career in community medicine are encouraged to obtain a copy of the booklet Community Medicine; training, examination regulations and syllabus from the Faculty of Community Medicine, Royal College of Physicians, and to meet the Faculty Adviser for their region, whose name can also be obtained from the Faculty of Community Medicine. John Catford Dermatology The specialty in Britain consists of 220 consultants, six professors and about 120 trainees ? registrars, senior registrars and academic equivalents. Currently, every advertised dermatology registrar post attracts 15-20 well- qualified applicants, i.e. with at least three years' post- registration general professional training and MRCP. Teaching centres typically have two or three consultants, one or two senior registrars and one registrar; any senior house officers are usually part of general practice training or a general medical rotation scheme. There are now increasing numbers of married women training part-time in dermatology. In District General Hospitals there is one consultant per 250,000 population; with rare exceptions, staff below this level are either general practitioner assis- tants or rotating general practice or general medicine trainees. The specialty is expanding by an average of four new consultant posts a year. Dermatology has adopted the same basic training as other medical specialties ? a minimum of three years' post-registration general medical posts and the MRCP, before entering dermatology at registrar level. It is rec- ommended that a total of four years is spent in registrar and senior registrar posts before applying for accredit- ation. Further clinical training is likely to be needed before a consultant post is obtained. Research in the specialty has made considerable pro- gress in the last 20 years; much can be undertaken with very little technological back-up. Disease processes and their treatment can be followed from beginning to end, and tissue is easily obtained with little inconvenience to the patient. In addition, treatments known to be toxic when administered systemically can often be applied topically with impunity. Many important biological prin- ciples in fields such as cell kinetics, immunology and Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 105 mediation of inflammatory reactions have been clarified by dermatology research workers. There can be few specialties in medicine with as much variety in everyday practice as dermatology; in any clinic one may go from examining warts to investigating and treating systemic disease to removing a tumour. The majority of dermatologists still treat all the non-acute general medical problems diagnosed in their department. Most topical therapy is now based on antagonising known pathogenic mechanisms. In practice, much of the work involves the management of eczemas, psoriasis, leg ulcers and a wide variety of benign, pre-malignant and malig- nant diseases. Dermatology is thus an interesting specialty for those who are physicians by inclination but who also wish to continue to exercise their surgical skills. Rodney Dawber Endrocrinology and Diabetes Endocrine disorders are uncommon, so there are few pure endocrinologists except in large referral centres. The majority of physicians with this special interest look after patients with diabetes as well and work in District General Hospitals as general physicians. A consultant might expect to spend about 40 per cent of his time on general (internal) medicine, 40-50 per cent on diabetic services and 10-20 per cent on endocrine diseases. The services provided countrywide for endocrinology are at present about right, and have been complemented by the establishment of the supraregional assay service (SAS) for hormone measurements. Services for diabetics, however, are under-developed and it has been recommended that for each 100,000 of the population there should be one consultant physician specialising in diabetes. The British Diabetic Association is actively pressing for the establish- ment of new consultant posts, particularly in health districts with no such specialist. The British Endocrine Society is the forum for scientific presentations in this field. The majority of patients referred for an endocrine opinion will have thyroid disease (around 80 per cent). The remaining 20 per cent of patients cover the range of glandular disorders, but reproductive problems are in- creasing. Collaboration between physicians and gynaecologists is growing and it is expected that joint clinics will be set up in many hospitals. Diabetic services are no longer limited to the clinic and are expanding to educate patients more effectively and to help general practitioners manage diabetic patients in their own prac- tices. With the knowledge that retinopathy is largely preventable and treatable has come the need to screen large numbers of patients and refer them on at an early stage for ophthalmic assessment. Good liaison with other specialists is essential for adequate management of other long-term complications of the disease. Pure endocrinologists in referral centres usually work with a senior registrar or registrar, and an SHO; there are often research staff as well. Close working relation- ships will be established with general and neurological surgeons, radiotherapists and paediatricians. Diabetolo- gists in large hospitals may have a consultant colleague with the same interests and will probably have similar staffing to the pure endocrinologist but, in addition, on account of the larger case-load, there may be one or more clinical assistants. In District General Hospitals there is seldom more than one consultant to deal with all endo- crine and diabetic problems. He will usually work with an SHO and possibly a registrar and clinical assistant as well as a diabetes liaison nurse. By virtue of the fact that so much of the work of a diabetic clinic is basic general medicine and in such large amounts, a doctor wishing to specialise in this field should, more than most, have a good general grounding. Two to three years in busy general hospital practice is worthwhile, during which the MRCP would normally be obtained and the grade of registrar achieved. At this stage, it is conventional to 'go into research,' usually for two years, and do the groundwork for an MD thesis. This is 'expected' and as a result it would now be a brave aspirant who decided not to follow the path. There is no doubt that endocrinology and diabetes mellitus lend themselves to research nor that a spell in a laboratory teaches a realistic approach to the limitations of hormonal and other assays. The first real hurdle comes in looking for a senior registrar post. There are at least four times as many hopefuls as jobs available at this level. Once into a senior registrarship, consultancy is usually achieved, although it may take a further six or more years and several applica- tions to achieve the goal. To specialise in endocrinology and diabetes is enjoy- able. There is the pleasure of looking after large numbers of different clinical problems. This is why the specialty is likely to remain popular, creating bottlenecks both at senior registrar and to a lesser extent at consultant level. The latter may be eased if new posts in diabetes are created, but the former seems certain to continue. Peter Daggett Gastroenterology The majority of gastroenterologists in the UK are ap- pointed as consultant physicians with an interest in the specialty; a major commitment to general medicine and involvement in general medical on-take rotas are usually expected. Nevertheless, the growing demand for special- ist opinions and diagnostic and therapeutic endoscopies means that most physician/gastroenterologists spend an increasing proportion of their time with gastrointestinal problems. Already there are specialist centres for hepatol- ogy and gastrointestinal physiology, and the physician wholly committed to gastroenterology may become more common. While it is suggested that there should be a gastroent,erologist for every 150,000 population, that is unlikely to become a national reality. Private practice is likely to flourish, particularly since there is payment for procedures as well as consultations. 106 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 A newly appointed gastroenterologist should be profi- cient at endoscopy and its therapeutic aspects, including colonoscopic polypectomy and probably endoscopic sphincterotomy. He will probably supervise enteral and parenteral feeding and will be able to manage acute and chronic liver disease, including bleeding oesophageal varices. Local circumstances govern the division of work- load between physicians and surgeons but close collabora- tion is important, particularly in gastrointestinal bleeding and inflammatory bowel disease. Junior staff support for gastroenterologists is similar to that for other physicians, although contraction of the registrar grade (to improve overall career prospects) would change this. Where funding can be obtained, GP clinical assistants may help with the potentially huge diagnostic endoscopy workload. The trainee gastroenterologist will spend about two years as an SHO in specialties which need not include i* > gastroenterology. Part 1 and if possible Part 2 MRCP should be obtained. A registrar post with an interest in gastroenterology is then appropriate and a rotation with one year in a District General Hospital and one year in a teaching centre is ideal. Next, about two years should be spent in a research unit working towards an MD or PhD thesis; a number of papers should be published and attempts made to remain clinically involved while re- membering that the prime purpose of this period is research rather than further practical experience. Despite a completed thesis, attainment of a senior registrar or lecturer post remains the major obstacle since there are about four times as many suitably qualified candidates as there are SR posts available. The unsuccessful have the opportunity of transferring to radiology or geriatric medi- cine but these opportunities are unlikely to last indefinite- Jy- The SR normally spends one or two years at a district hospital and two or more years in a teaching hospital gastroenterology unit. Even then there is no certainty of a consultant post because many appointments are recent and there will be few retirement vacancies for some years. The current expansion rate of the consultant grade will not absorb the large number of well-trained SRs looking for consultancies; only a significant expansion at consult- ant level will lead to an improvement in career prospects. Alastair Forbes and Anthony Mee General (Internal) Medicine General medicine is rarely practised in isolation but almost always in association with another medical inter- est. However, training for the general component of most physicians' work should be carefully planned. Many specialists are required to take part in on-take rotas and to deal with out-patient referrals of a mixed nature. To be an effective consultant receiving emergency cases wide experience must have been obtained during training years. Indeed, appointment as a consultant may depend % on a candidate's ability to demonstrate convincingly his capability in this situation. It is, therefore, advisable during the course of one's training to get experience in many different specialties. Two to three years should be spent at SHO level in different posts, which is most easily organised in an established rotation. MRCP should be taken during this time. At registrar level it is advanta- geous to rotate between different specialties and between district and teaching hospitals. Many established ro- tations exist. It is very unusual to find a senior registrar post in general medicine alone; most combine a specialty with general medicine or include a rotation of specialty experi- ence in a teaching hospital and general medicine with or without specialty experience in a district hospital. During one's time as a registrar it is necessary to decide on a specialty interest even if the general aspect of a phys- ician's work is the part one finds most attractive. Experi- ence in research is essential for a career in general medicine. It can be gained during the course of a senior registrar appointment, but the field is now so competitive that it is advisable to obtain some research experience in one's chosen specialty between registrar and senior regis- trar posts. The career ladder of general medicine is by no means guaranteed. There is a shortage of 'good' medical SHO posts and rotations since they are also in demand fcom prospective GPs, radiologists, haematologists, etc. At SHO level it is easy to branch out to other fields of medicine, but at registrar level, especially after a period of research, it is more difficult to do so. It is therefore important to take advice about the likelihood of one's ascending the ladder before becoming a registrar. Having passed the MRCP it is relatively easy to get a registrar post but there are far too many registrars for the number of senior registrar posts and in turn too many senior registrars for the number of likely consultant posts avail- able in the next few years. The recommended duration of senior registrarships is four years but most will spend much longer in these posts. Although there is no security of tenure, it is rare for contracts not to be renewed as long as efforts to secure a consultancy are being made. The future of the concept of general medicine is uncertain. On the one hand, most acknowledge that the practice of modern medicine requires that patients be seen by the appropriate expert. On the other, many specialist groups are advising their trainees to ensure that they are accreditable in general medicine to improve their chances of obtaining a consultant post. Edwina Brown Genito-Urinary Medicine This specialty in the UK is long established, well organ- ised and respected worldwide. Departments of genito- urinary medicine see 600,000 new patients annually, a threefold rise in 15 years. There are about 230 clinics, most of which are in the precincts of district general or teaching hospitals. There are about 110 consultants in the specialty and they are supported by clinical assistants, doctors in the training grades, nursing staff and health Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 107 advisers-contact tracers. GU medicine is a growth spe- cialty and the current prospects for doctors who have trained appropriately are excellent. Patients present with a wide variety of clinical con- ditions and also personal, social and psychiatric prob- lems. However, the majority of conditions are curable, an unusual situation relative to other medical specialties, resulting in a high degree of job satisfaction. GU medi- cine is largely an out-patient specialty but most depart- ments have access to in-patient facilities, as well as close links with many other hospital departments. Most patients attend direct without first seeking advice from their own doctor. The spectrum of diseases spread by sexual activity has continued to increase, with hepatitis and more recently AIDS providing new epidemiological problems and interest. Although the concept of consultant physicians with an interest in GU disease has been discussed, such a concept would not seem to be feasible, so the doctor going into GU medicine must be prepared to leave behind the excitement of acute medicine and ward work. In addition to normal teaching duties doctors in this specialty have a resonsibility for health education of young people, and requests for help in this respect from various organisa- tions are increasing. To enter the specialty a higher diploma is necessary ? preferably the MRCP but many doctors holding the MRCOG are attracted to the specialty and are eligible. Those with the MRCP must have had experience in gynaecology and those with the MRCOG in general medicine. During the four years of higher medical train- ing, experience of dermatology and microbiology are desirable. The large numbers of patients attending clinics and the close links with microbiological departments provide excellent scope for clinical, epidemiological and microbiological research. Annual courses in sexually transmitted diseases are held in London and Liverpool. The Medical Society for the Study of Venereal Disease meets six times a year when lectures and original scientific papers are presented. The society publishes its own journal ? Genitourinary Medicine, formerly The British Journal of Venereal Diseases. The good prospects and the different but satisfying work pattern have attracted many well-qualified doctors to full- or part-time consultancies in the specialty. Few regret their choice of career. Ian Weller Geriatric Medicine Geriatric medicine originated from a handful of British pioneers, dealing mainly with the chronic sick and dis- abled, at the inception of the NHS. The specialty grew under the influence of demographic and social changes so that during the 1970s the number of consultants in geriatric medicine rose by 50 per cent and there are now some 500 consultants in the UK, many of whom are overseas graduates. During recent years there has been a shift in emphasis towards more acute care; the majority of consultant posts are still wholly in geriatric medicine, but > about a quarter are now combined posts as a general physician with special responsibility for the elderly. Re- search and teaching in geriatric medicine have been encouraged by the establishment of academic depart- ments in many British medical schools, and there are currently 14 university chairs in the subject. In addition to providing general medical care to ill elderly patients, the geriatrician supervises rehabilitation and long-stay services for the elderly. Geriatrics remains i a very wide field of 'general medicine,' with considerable scope for planning, administrative expertise and liaison with other disciplines both inside and outside the NHS. Most geriatricians are responsible for more beds than their colleagues in other specialties, and often work with relatively few junior staff. In some services the geriatric department is run separately from general medicine, while in others the two are integrated. In either case, good relationships with other specialties and a satisfactory division of responsibility for the elderly are essential; this applies to orthopaedic surgery as well as medicine, and is particularly important with regard to psychiatric illness in the elderly, since many health districts have no formal psychogeriatric service. The first step towards a career in geriatric medicine is wide experience in general medicine, including some sub- specialties (e.g. neurology, cardiology, rheumatology and rehabilitation). Time spent in fields such as general practice or psychiatry will not be wasted, and it is wise to have had some experience in a substantive geriatric post before committing oneself to a senior registrar appoint- ment. At that stage, a decision must be made whether to aim for dual accreditation with general (internal) medi- cine or in geriatric medicine only: at present, prospects for either career post are excellent. Clinical experience and a commitment to care of the elderly outweigh research experience, higher degrees or publications, at least for the time being. However, recruitment to the specialty is improving and there is a trend for well- qualified physicians to switch to geriatric medicine when their paths are blocked during training for other special- ties. Thus it may be advisable to be able to offer either additional general medical expertise (in the form of dual accreditation) or additional geriatric expertise (in the form of a special interest backed up by research) as the specialty of geriatric medicine becomes more competitive. The proportion of frail elderly in the population con- tinues to rise, with serious implications for health services in general. Geriatric medicine offers a broad based, much needed and satisfying career, the patlcin of practice varying greatly from place to place. It is vital to watch developments in these evolving patterns and to adopt a flexible strategy during training. Roger Briggs i Haematology Recent advances in the diagnosis and management of haematological diseases have improved the attraction of a career in haematology and encouraged stiff competition. 108 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Opportunities are perhaps better than in other medical specialties, as haematology is an expanding field. Some pathology jobs may be re-allocated to haematology and future expansion of the consultant grade by 10 per cent per year in the next five years is expected. ;? . District General Hospitals provide 70 per cent of consultant posts in haematology. These are often single- handed, and the consultant is expected to be able to perform and supervise laboratory work, to provide a service for the rest of the hospital, to have clinical commitment to out-patients and, in most cases, a small number of in-patients. There is sub-specialisation in the regional centres, e.g. haematological oncology, coagu- lation. In formulating an adequate training programme, it is important to realise that it is necessary to be competent clinically-and in the laboratory. At present, before obtaining a senior registrar job, and increasingly often a registrar post, the candidate is ex- _ pected to have the MRCP in addition to general pro- fessional training. It is desirable, but not essential, to gain some laboratory experience during this period. MRCP gives exemption from MRCPath Part 1. To enrol for MRCPath Part 2, three years of approved higher medical training are required before the written examination and five years before the practical. It is also necessary to have research experience, and even a further degree, e.g. MD or PhD. General physicians with an interest in haemato- logy are a dying breed, and MRCPath Part 2 is essential for a consultant haematologist post. Some experience of paediatric haematology should be incorporated in the senior registrar training scheme, though to sub-specialise in this branch requires general paediatric training. There are few posts for paediatric haematologists, and expansion is unlikely. Consultant posts in blood transfusion are becoming more popular and require at least two years' experience in an approved blood transfusion centre and two years of general haematology experience. Opportunities for part-time training in haematology do exist, and, depending on the co-operation of the depart- ment, may be easier to arrange than in other medical specialties. However, there are likely to be few part-time consultant posts available, and there is still a reluctance to accept part-time training as equivalent to full-time. Sound advice is to delay part-time training for as long as possible. As in other branches of medicine, personality is an important facet. Haematologists have responsibility to their laboratory staff and other consultant medical staff as well as their patients. It is worthwhile gaining some insight into the managerial role and committee work of consultants during training. Angela Robinson Intensive Care This is an emerging specialty with few consultant posts devoted purely to intensive care. However, it is generally agreed that it is desirable to have physicians experienced in managing patients with multi-system organ failure. Most hospitals now have an intensive care (or intensive therapy) unit. They are usually run by anaesthetists with nominal cover provided by a physician with an interest in cardiology or nephrology. In certain units, the physicians may carry the executive responsibility. Intensive care of patients requires facilities for mechan- ical ventilation, acute peritoneal or haemodialysis, hae- mofiltration, temporary cardiac pacing and invasive haemodynamic monitoring, apart from continuous moni- toring of the ECG, EEG or intracranial pressure and total parenteral nutrition. If an 'intensivist' is to make a real contribution to patient care he must have received train- ing in these techniques. The institution and management of such therapy require a firm grounding in clinical medicine with a special emphasis on cardiovascular and renal physiology and pathology. By its very nature intensive care medicine is a costly specialty both in terms of staff and equipment (thus often described as 'expensive care'). The type of patient re- ferred often depends on the facilities provided by other specialties in a particular hospital. Although intensive care medicine can be very satisfying when a moribund patient is restored to health, the mortality for many conditions requiring such care remains very high. The 'intensivist' must therefore come to accept that a high proportion of his patients will not survive. A recent survey by the College of 168 intensive care units found anaesthetists in administrative charge, while patient care remained with the admitting team or was shared with an anaesthetist in nine out of ten admissions. Only 14 of 1,031 consultant physicians specified intensive care as a primary or secondary interest, and for only five of these was it documented in their contract. At the present time there is no clear training structure for this specialty in Britain and the College has not published guidelines regarding accreditation. The present view of the Intercollegiate Committee on Intensive Care is that the influence of physicians should increase in intensive care units. This committee has suggested that senior registrars already accredited in internal medicine and another specialty may wish to gain additional ac- creditation in intensive care. However, there are as yet no posts designated or approved for such training. For those determined to pursue a career in intensive care medicine, a period in anaesthetics is a must and so probably is a spell abroad (USA or Scandinavia) where the specialty is well established. Dennis Edwards Medical Oncology Cancer medicine is an evolving specialty. In the last two decades, the range and application of cytotoxic drugs has increased considerably, as has the need for special exper- tise in their use; in addition to assessment of their efficacy in particular tumours, there are the problems of the management of adverse effects and support of the whole Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 109 patient with cancer. Physicians have become increasingly involved in aspects of the management of malignant disease other than its medical complications. A sound understanding of the work of related specialties such as surgery, radiotherapy and histopathology is essential. There are at present fewer than 50 consultants in the specialty, and only 14 are funded by the NHS. Though most are full-time medical oncologists working in a major centre, the proportion of physicians with an interest in medical oncology is increasing from the present level of about 30 per cent. The need for more consultant posts is clearly recognised, but overall growth of the specialty has been slow, with only three new consultant posts a year. There is an Association of Cancer Physicians, and a committee advises the College. A cancer physician typically spends most of his time treating patients with chemosensitive tumours such as lymphoma, breast, testis, ovary and small cell carcinoma of the bronchus. In addition there are a few rarer tumours in which chemotherapy is important, and a medical oncologist may also have an interest in a tumour for which chemotherapy is being developed. Oncologists increasingly work as part of a team, and multidisciplinary clinics (with surgeons, haematologists, or chest phys- icians) may form an important part of this work. Thus an attraction of the specialty is that it cuts across traditional specialty boundaries. Some oncologists have developed a particular interest in cell or molecular biology, or clinical pharmacology, while others have concentrated on organ- ising local or multicentre trials. A strong research back- ground is advisable in view of the rapid pace of change in this field. In a teaching hospital, the medical oncologist is usually part of an academic department. In a District General Hospital, the oncologist may be part of the division of medicine or work with radiotherapists in a department of clinical oncology. The supporting junior staff may be on a medical or surgical rotation, trainees in radiotherapy, or clinical research fellows. Entry to the specialty is advised only after solid general medical experience at SHO and registrar level. This should be followed by a registrar post with some experience in oncology and then a period of research. An MD or PhD is essential. Time spent in a related discipline such as pathology, haematology or endocrinology can often be valuable, and the accredit- ation requirements are flexible to allow for this, but the crucial training is that in general medicine. If possible, accreditation should be sought in both general medicine and medical oncology, and most of the 20 or so SR posts are in regional or teaching centres. Paediatric oncology is an even smaller specialty, and trainees would normally progress through major academic centres. Medical oncology is a small but exciting new specialty. There is strong competition for consultant posts because of the large number of candidates of high calibre and the small number of new jobs or vacancies. For those who do not find a suitable niche in oncology, the drug industry or another medical specialty are possibilities. The less aca- demically inclined may find a switch to radiotherapy after MRCP increases their opportunities for obtaining posts which may arise over the next five years or so, but the changing nature of clinical practice in oncology must lead to new posts in cancer medicine in the near future. Cancer now affects one in four of the population, and i physicians need to play a much greater role in its management. John Green Neurology and Clinical Neurophysiology Neurology is a small specialty with a long and prestigious history, and has always been highly popular and competi- tive. The training structure and prospects have remained fairly stable and predictable, and it has been spared the severe manpower problems of many specialties. There are approximately 150 consultant neurologists, with no immediate likelihood of expansion; choice of jobs is, at all stages, necessarily very limited. There remains a handful of 'physicians with an interest,' but they are a dying breed; all new consultant appointments are of full-time clinical neurologists. In addition, there are a small num- ber of pure clinical neurophysiologists, mainly based at large centres, but in many hospitals neurophysiology still falls within the responsibility of the neurologist. Neurology appeals to people who particularly enjoy 'bedside' diagnostic medicine and a large amount of patient contact; basic clinical skills remain of paramount importance. Neurology is mostly out-patient work, and the majority of patients are managed without recourse to specialised investigations. However, there have been enormous technological advances in the last decade and neurologists now need to be conversant with a wide range of investigative techniques. With the growing need for expensive hardware there is an increasing tendency for neurologists to be based at a regional centre, usually attached to a teaching hospital. This will house neuro- radiology, neurophysiology, neuropathology, and neuro- psychology, together with in-patient facilities for neurology and neurosurgery. Liaison with ophthalmol- ogy, ENT and, of course, general medicine is close. As well as having sessions at the centre the neurologist will usually visit one or two regional hospitals each week to see out-patients and ward referrals. Junior staff in training are largely based at such centres, where a group of four to six consultants might have, for instance, one senior registrar, two registrars and two SHOs. Pre-registration posts are unusual in neurology. In some areas facilities are not centralised and a single neurologist may be based at one large hospital and have some specialist facilities elsewhere. The vast majority of neurologists do not sub- specialise although, as neurology encompasses such a wide spectrum of disease and with the growing appli- cation of basic medical science, there is ample scope for special interests. General professional training may include one year in clinical neurology, neurosurgery, psychiatry, or research in related., basic science subjects. Higher professional training is spent in an approved neurological centre with an additional recommended year in psychiatry, neurosur- gery, applied neurophysiology or basic neurological sci- 110 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 ence. The usual course is to spend three to five years as a medical SHO and registrar while obtaining the MRCP, then, as an entree into a specialist centre, many aspiring neurologists become an SHO before going on to be a neurology registrar, the latter for approximately two years. Competition is fierce throughout, and particularly for senior registrar posts. However, the number of senior registrar and consultant posts is fairly well matched, so that obtaining a senior registrar appointment almost guarantees a consultant post elsewhere within four years. In order to get a senior registrar post it is almost essential 'l to have an MD (or equivalent thesis degree), and this means at least two years of full-time research, usually after a neurology registrar appointment. Thus, it is extremely unusual to become a consultant neurologist in less than 10-12 years after registration. The importance of keeping early career options open by making the general professional phase of training as broad-based as * - possible cannot be over-emphasised. Alternative career avenues beyond the stage of neurology registrar are very limited. Clinical neurophysiology is a smaller but expanding specialty with a shortage of adequately trained applicants to fill senior registrar and consultant posts. The develop- ment and clinical application of such techniques as evoked potential studies, ambulatory EEG and specia- lised muscle recording methods are resulting in expansion of the number of consultant posts. Newly appointed consultants have a varied training which usually includes periods in general medicine, clinical neurology, and as a senior registrar in clinical neurophysiology; they usually possess the MRCP and a higher research degree, e.g. MD in a basic science. Senior registrar posts are limited to large regional neurology units. John Hodges Nuclear Medicine Nuclear medicine is almost totally a diagnostic specialty and attracts doctors with a scientific outlook and an interest in the pathophysiology of disease. The doctor " 4 whose natural bent is towards the continuing care of the patient and the development of good doctor-patient rela- tionships would probably be unfulfilled by a career in i nuclear medicine. However, a number of posts exist in which the consult- ant is for part of his time a clinician with full clinical responsibility for patients, and for the rest has oversight of a nuclear medicine diagnostic service. Thus it is possible to be a physician with a 'special interest' in nuclear medicine. Because a large proportion of the results of nuclear medicine investigations are presented as images, there is a similarity to diagnostic radiology and in many hospitals a radiologist provides the nuclear medi- cine diagnostic service. So in parallel with physicians with a 'special interest' in nuclear medicine there is a growing number of radiologists with a similar 'special interest.' ? This is an exciting branch of medicine for the doctor who wishes to be involved in new developments and to interact closely with clinical specialties. Nuclear medicine uses as its essential 'tool' pharmaceuticals labelled with radioactive atoms, and the development of these 'radio- pharmaceuticals' is a major activity both of the pharma- ceutical industry and of research organisations. So the range of applications of nuclear medicine continues to expand. A physician wishing to become a consultant in nuclear medicine will require some special training in basic sciences in addition to the usual programme for accredit- ation. This practical and theoretical training in basic physics, instrumentation, radiochemistry, radiophar- macy, and radiation dosimetry and protection may be obtained by attending a block or day-release course or by obtaining an MSc (Nuclear Medicine). Unfortunately, it is difficult to assess job prospects. A handful of new consultant jobs has been established in the last four years so that there are now about 27 consultant and five senior registrar posts in nuclear medicine. The apparently favourable consultant to SR ratio has to be interpreted with care, as the majority of nuclear medicine consultants are relatively young, so further expansion of the specialty remains speculative. One of the demanding aspects of the subject is its diversity. The nuclear medicine consultant has to keep up to date with a much wider field of medicine than do many of his clinical colleagues. His advice may be sought on a complex renal problem, then on a cardiological, an oncological, or an endocrine problem, all in the space of a few hours. A nuclear medicine consultant may wish to concentrate on particular areas. For example, he may carry out research on bone diseases and the use of radioactive tracers in their diagnosis and follow-up; another may be attracted to cardiological work, and so on. He will, however, remain responsible for providing the general diagnostic service for which he was employed. Edward Williams Occupational Medicine Occupational medicine is a new and expanding specialty which is concerned with the effect of work on health and health on work, and has a major preventive as well as treatment role. There is now extensive legislation relating to health and safety at work and this has encouraged the wider provision of occupational health and safety ser- vices. Professional representation is through the Society of Occupational Medicine which currently has more than 1,700 members, of whom about 900 work full-time. The Faculty of Occupational Medicine was established in 1978 and now has 1,400 Fellows, Members and Associ- ates. The age distribution within the Faculty is heavily skewed towards the 55-65 year old range, so there will be many job opportunities in the next 15 years. The primary role is to advise management, trade unions and workers on all health matters, with the aim of preventing ill-health and promoting good health. It is a Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 111 clinical and preventive discipline which requires a de- tailed knowledge of occupational diseases and expertise in health assessment, rehabilitation and resettlement, occu- pational toxicology, environmental assessment and con- trol, the application of epidemiological and statistical techniques, and much enthusiasm. As industries evolve, new processes may create new hazards, and perhaps new occupational diseases, so there is always a challenge. The problems of different industries ? e.g. aviation, chemical, mining, steel, National Health Service, retail ? lead to much sub-specialisation. As well as the experi- ence described, the occupational physician also needs to acquire administrative and communication skills, as one day he or she may have to justify the departmental budget to the tough financial scrutiny of industrial line manage- ment, and on another speak at a mass meeting of workers concerned about an unfamiliar hazard and then justify the recommendations made. The specialty is unusual in that most posts are outside the NHS, though more are now being created in it. Facilities vary, depending on the nature of the indus- try, but normally include provision for the treatment of illness and injury at work, for critical health evaluation and often physiotherapy or rehabilitation services. A trained occupational physician will be experienced in industrial chest radiology, pulmonary function assess- ment, audiometry, toxicology, skin and allergy testing, and many will develop other skills. While large industries frequently have well-established occupational health services, the majority of physicians may work alone or with perhaps one colleague and a team of occupational health nurses and part-time GPs. The effective provision of occupational health care involves teamwork with other related disciplines such as occupa- tional hygienists, nurses and safety practitioners. Epide- miology and research are fundamental to the role: identification of an occupationally-related health hazard often involves assessment of the health of the group as well as of the individual. Entry to the specialty is normally after the completion of general professional training, and the MRCP(UK), though desirable, is not mandatory; currently 60 training posts are approved. Attendance at an academic course is possible on a full-time, day or block release, or distance- learning basis, and while not essential, is strongly rec- ommended. Most employers are willing to fund training. Associateship of the Faculty is gained by examination, and Membership is awarded after satisfactory completion of training. Once trained, the occupational physician has many career options, and considerable mobility is poss- ible at senior levels. Ewan MacDonald Paediatrics Paediatricians are now the second largest group of phys- icians (after general physicians) who enter higher pro- fessional training via the MRCP; they are represented professionally by the British Paediatric Association as well as by the College. It is a relatively young and growing specialty with an interest in the care of children both inside and outside hospitals. A recent recommendation that Senior Clinical Medical Officers in Child Health should, in due course, be replaced by consultant paedi- atricians in community child health will result in a further major increase in the size of the specialty. As in most specialties, job prospects are hard to predict, but, at present, the number of senior registrars is about right or even low, allowing for the new community posts, the main hurdle being from registrar to senior registrar appointment. Most paediatricians in the country remain generalists, working in acute medicine with in-patients (95 per cent emergency admissions), out-patients, in the maternity unit with the newborn and often also in the community. Until recently many were single-handed in a district, but this is now rare and in an increasing number of districts paediatricians are developing a sub-specialty. A few, mostly in teaching centres, are full-time sub-specialists in neonatology, cardiology, oncology, neurology and handi- cap, nephrology, endocrinology, gastroenterology and respiratory medicine. Most job descriptions require can- didates to have had recent experience in working with the newborn, and this is now the most common sub-specialty (perhaps soon to be overtaken by community child health). Compared to departments of adult medicine, most units are very informal, with no bed allocation, shared wards and junior staff, absence of white coats and often considerable camaraderie. Paediatricians are at present the busiest consultants, in terms of hours of work and call-out rates, but the rewards in terms of benefit to patients are considerable. Ability to work with parents and an understanding of psychology are skills that differ from those required in general medicine and bring their own rewards. Junior staff at SHO level (there are almost no house physician posts) are on the whole good, being recruited both from career paediatricians and general practitioner training schemes, though again the posts are busy and sometimes stressful. A large number of medical, nursing and ancillary staff work directly with paediatricians, including community doctors, paediatric nurses, special care nurses, physiotherapists, occupational therapists, speech therapists, psychologists, social workers, teachers and nursery nurses, so that skills in teamwork and leadership are important. Training requirements are clearly laid down, but are fairly flexible in practice. Time spent in full-time research is undoubtedly valuable, often providing training in a sub-specialty as well as in re- search, and will be valued at appointments committees at senior registrar and consultant level. Higher degrees are not essential and the Diploma in Child Health is not necessary for a career in paediatrics. Time spent in general practice or abroad is valuable, as is a period in related specialties such as general medicine, obstetrics or community medicine. At the final hurdle of a consultant appointments com- mittee the professional members of the committee will be at least as interested in the human skills of personal 112 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 relationships with parents and colleagues demonstrated by the candidate, as in his academic prowess. Peter Todd and John Tripp Rehabilitation Medicine The lack of specialist care for young disabled people is a notable defect of today's Health Service. In 1972 the Tonbridge Reportfi] recommended that there should be a consultant in rehabilitation in every district and, al- though this is unlikely to become a reality in the near future, there is a growing appreciation of the need for specialists in this field and this is slowly being reflected in advertisements for consultant posts. It is not envisaged that more than a small minority will practise exclusively in rehabilitation medicine (RM). Nine out of ten will have another discipline which may be anything from orthopaedic surgery to neurology. There are at present only 18 senior registrar posts approved for training in RM and the majority are linked to rheumatology (14 of 18). Approval may be given for individual posts, however, and it should be possible to acquire the relevant experience and training at any Demonstration Centres in Rehabilitation. In view of the predominance of neurological disease among the severely handicapped, some experience in this field will be par- ticularly relevant and may in due course become a requirement. There can be few areas of medicine in which there is such scope for research projects of direct and practical relevance to patient care. The full potential of new materials and technology has yet to be realised in the treatment of disabled people and there are many estab- lished rehabilitation techniques which would benefit from rigorous scientific evaluation. The Society for Research in Rehabilitation holds regular meetings at which such work can be presented, and the recently formed Medical Disability Society holds scientific meetings as well as representing the political interests of those training and practising in this field. The consultant practising in RM will have to work closely with colleagues of all disciplines as well as with the many other professionals in the health and social services. Useful qualities to possess would be tact, unlimited patience and political and managerial skills. The constant fight for extra resources and facilities for disabled people is a time-consuming but important part of the job. Reference 1. Sub-committee of the Standing Medical Advisory Committee (1972) Rehabilitation. London: HMSO. Thomas Price Renal Medicine Renal medicine is a relatively new specialty, so there will be virtually no retirements in the near future. It is, however, still an expanding specialty and many regions have plans to increase their dialysis facilities. At present, there appear to be 3-5 new renal medicine consultant posts a year. There has also been a similar number of new consultant general physician posts with an interest in renal medicine at district hospitals with no renal unit. General medicine is an integral part of renal medicine because renal problems occur in so many situations and dialysis and transplant patients have general medical problems. It is therefore essential to get general medical experience at SHO level; experience in intensive care at this stage would also be useful. One's first exposure to renal medicine usually occurs at SHO level. At registrar level it is advisable to do a rotation with some general medicine as well as renal medicine. The other option is to do a general medical registrar rotation followed by re- search experience in renal medicine. In either circum- stance it is advisable to obtain research experience at this stage, since senior registrar posts are very competitive. It is very important to look carefully at senior registrar posts because many are in specialist renal units that give no general medicine experience. The main specialist skills obtained during training are the care of dialysis and transplant patients, the ability to insert acute dialysis catheters, do renal biopsies and understand fluid and electrolyte problems. Many aspects of renal medicine, such as transplantation and the under- standing of glomerulonephritis, need an understanding of immunology. Much of nephrological practice occurs acutely, and junior staff usually find themselves busier than their colleagues in other specialties. The acute care of dialysis patients is also largely done by junior doctors with the result that there is a disproportionately large number of SHOs for the size of the specialty. There is a lot of scope for clinical research so it is important not to be diverted into a 'dead-end' research post, since they are more plentiful than senior registrar posts. As pointed out earlier, however, renal medicine is an expanding special- ty so the career prospects are slightly better than in some other specialties. Edwina Brown Respiratory Medicine Respiratory medicine has recently changed radically in terms of work patterns and staffing, so that now it represents a most satisfying field of practice both for the general physician with an interest in the specialty at the District General Hospital and for the thoracic specialist at a referral centre. Most of the consultant posts are of the 'general phys- ician with an interest in respiratory medicine' type based at District General Hospitals. Of the 339 consultants now in post 20 per cent are 'pure' chest physicians and tend to work in the teaching hospitals. The Royal College of Physicians and the British Thoracic Society recommend that there should be one consultant with a substantial commitment to respiratory medicine per 150,000 popu- lation, and at least one in each DGH[1], Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 113 Thoracic medicine offers a wide spectrum of disease. The physician has to be proficient not only in the assessment and management of acute emergencies, in- cluding patients in intensive therapy units, but also in the support and management of patients with chronic or terminal disease. Currently, less than 5 per cent of beds are occupied by tuberculous patients and the majority of the in-patients have obstructive air flow disease, allergic disorders, chest pains, neoplasia, pleural disease, acute infections, and the respiratory presentations of systemic disease. Although smoking-associated diseases will continue to dominate the workload into the 21st century, it is likely that the presentation and management of disease will be substantially altered by improved knowledge of genetic and other factors causing susceptibility, and because of new imaging techniques. A large number of patients are certain to benefit from the present explosion of knowledge about the biochemistry and tissue physiology of asthma, and many young patients with rarer diseases may benefit from heart/lung transplantation. Because of the intense competition for senior registrar posts, the intending thoracic physician would, after ob- taining the Membership, be well advised to obtain experi- ence as a registrar both in general and respiratory medicine before proceeding, most probably, to a research post leading to a higher degree. At the senior registrar level he/she would spend two years in general medicine and two years in respiratory medicine to complete train- ing and obtain dual accreditation. An approved training post would offer experience among other things in chest radiology, including scanning and brochography, fi- breoptic brochoscopy including lung biopsy, respiratory intensive care, respiratory physiology and training in the immunological and allergic aspects of respiratory disease. What are the job prospects in respiratory medicine really like? The most reliable figures are those obtained in 1984 by the British Thoracic Society[2]; for England and Wales there were 403 consultant posts in 1979, and 64 less (339) in 1984. There will probably be 11-14 retirements a year up to 1988, and about 10 a year thereafter. This number would require about 40 senior registrars to fill 10 jobs a year. In 1970 there were 52 senior registrars (including honorary posts), and in 1984 there were 86. Hence in five years' time there may potentially be about 40 time-expired senior registrars. Figures for the current number of research registrars and their prospects of obtaining a senior registrar post are published[3]. They show that about 70 research registrars may be competing for up to 14 senior registrar posts a year. Clearly, many of these doctors may have to re-train in a different field unless there is a substantial expansion of consultant posts in this specialty, and no reduction in senior registrar appointments. In summary, current job prospects in respiratory medi- cine are rapidly approaching those of the other major specialties in adult medicine, such as gastroenterology ind cardiology. The intending thoracic physician should ilways bear these figures in mind when considering his ;areer choice. References 1. British Journal of Diseases of the Chest (1984) 78, 303. 2. Citron, K. M., Byfield, S. P., Darbyshire, J. H. and Nunn, A.J. (1984) Communication at the British Thoracic Society summer meeting in Brighton, July. 3. Moore-Gillon, J., Peacock, A., Johnstone, I. and Woodcock, A. (1984) British Medical Journal, 289, 1080. i David Honeybourne and Martin Muers Rheumatology Despite publicity about the poor opportunities for those wishing to train in rheumatology, there is little evidence to suggest that the situation in this specialty is dramatical- ly worse than in other fields. It is true that the expansion of the senior registrar (SR) grade that occurred in the seventies has now gone into reverse and that competition < for posts at both consultant and SR level is fierce. t Nonetheless, the expected number of consultant vacan- cies predicted on the basis of retirements (8-10 p.a.) was . comfortably exceeded in 1984 and new posts continue to be advertised in parts of the country where previously few existed, for example the West Midlands. The British Society for Rheumatology is monitoring manpower levels closely and it is hoped that the future number of SR posts will be limited to about 50. This should approximately balance the expected number of retirement vacancies and new posts each year, and should lead to a decrease in the present array of time-expired SRs. There is every sign that the rheumatological rat-race will remain intensely competitive for the foreseeable future and those contemplating applying for a place in the starting stalls will need to have had a solid grounding in general medicine and would be wise to have spent sufficient time in a research post to achieve a higher degree before looking for a senior registrar post. Many of the large rheumatology departments will have a special research interest and will be able to advise on the funding and supervision of work in their field. Contrary to the impression that might be gained from a glance at the rheumatological journals, not all such research is immun- ological and there are particularly fascinating develop- ments in biomechanics, orthopaedics, biochemistry and metabolism, which are relevant to the rheumatic diseases. The majority of recent advertisements for consultant posts have been in rheumatology alone. There is a continuing demand, however, for those with experience in rehabilitation medicine and some districts need a general physician with an interest in rheumatology. It pays, therefore, to choose a senior registrar post with care; not all offer dual training with either general medicine or rehabilitation, which is certainly desirable when competition is keen. Although publications are an important component of a curriculum vitae, teaching skills are also valued and most districts will welcome some indication that a candi- date has k/iowledge or experience of administration. Junior staff are represented on all the various sub- committees of the BSR. Despite the recommendation of the Royal College of 114 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 Physicians that there should be one rheumatologist to a population of 150,000, the rheumatologist in the average District General Hospital is likely to be single-handed and may not be well supported by junior staff. Much of the work, however, is done in out-patients where, in some districts, there may be clinical assistants to share the load. Within the hospital the rheumatologist will need to work closely with colleagues in other disciplines and other professions. Many patients with rheumatic diseases have disabling conditions that last a lifetime. To maintain their health and well-being for many years requires good organisation and team-work. Thomas Price

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Pulmonary Eosinophilia DUNCAN M. GEDDES, MD, FRCP Consultant Physician, Brompton and London Chest Hospitals Pulmonary eosinophilia occurs in a wide range of circum- stances and many different classifications have been suggested[l-4]. Recent studies of eosinophil function have shed much light on the role of this leucocyte in disease and the pathogenesis of the pulmonary eosinophi- I lias is therefore easier to understand. l' * Definitions The classical definition of pulmonary eosinophilia is the combination of chest X-ray shadowing with a peripheral blood eosinophilia; both parts of this definition need defining. The normal blood eosinophil count increases during the night and falls in the early morning, is increased in the presence of atopy which affects up to a third of the population, and is influenced by a wide range of drugs and, in particular, is reduced by corticosteroids. A peripheral blood eosinophilia of > 400/mm3 is usually considered abnormal but a single lower count does not exclude an eosinophilic disorder. Most patients with pulmonary eosinophilia have repeatedly high counts ranging from 1,000-50,000/mm3 but there is consider- able day-to-day variability. There are two difficulties in using chest X-ray shadow- ing as a part of the definition. In the first place a considerable eosinophilic infiltrate can exist before it can be seen on a chest radiograph[5], This is usually proved by lung biopsy but recently broncho-alveolar lavage has become popular and is the simplest way of confirming an eosinophilic infiltrate[6], The second problem involves the histological nature of the radiographic shadowing. It is probably best to restrict the diagnosis of pulmonary eosinophilia (PE) to those conditions in which there is a predominance of eosinophils in the pulmonary infiltrate, thus excluding a wide range of miscellaneous lung dis- orders that happen to have an associated eosinophilia from time to time, for example, neoplasms, infections, etc. In clinical practice broncho-alveolar lavage or lung biopsy are seldom necessary as the clinical patterns are so characteristic. A simple diagnostic and aetiological classification of the pulmonary eosinophilias is given in Table 1. Eosinophil Properties and Functions[7-9] The eosinophil has two main functions: cytotoxic and anti-inflammatory. Its contents, surface receptors and tissue distribution appear to be adapted to control these two functions, both of which are normally beneficial to the host. However, the cytotoxic proteins that are nor- Table 1. Diagnostic and aetiological classification of the pul- monary eosinophilias. True Pulmonary Eosinophilia Definition: Blood eosinophil count > 400/mm3 Eosinophilic lung infiltrate (lavage/biopsy only rarely needed) Causes: Fungi Drugs Parasites Unknown causes: Cryptogenic?vasculitis?granuloma spectrum Hyper-eosinophilic syndrome Secondary Pulmonary Eosinophilia Definition: Blood eosinophil count > 400/mm3 Chest radiographic shadowing without eosinophilic infiltrate Causes: Infections: Pneumonia Neoplasm: Hodgkin's. Bronchial carcinoma Miscellaneous: Sarcoidosis, etc mally directed against parasites also have the capacity to damage host tissues and when this happens the eosinophil has a role in the pathogenesis of disease. Eosinophil Contents The eosinophil is a polymorphonuclear leucocyte contain- ing about 200 granules/cell which stain with acid dyes (e.g. eosin). There are probably three sub-populations of these membrane-bound granules which contain a range of different proteins. The largest granules have a crystalline core about half of which is made up of major basic protein (MBP), molecular weight about 10,000 which contains numerous arginine residues and has an isoelectric point over 10. This, together with eosinophil cationic protein (ECP), is cytotoxic to a range of different tissues but particularly to intact helminths. Other contents of the granules include the anti-inflammatory enzymes hist- aminase, acid phosphatase, phospholipase D, arylsulpha- tase B, eosinophil peroxidase and some lysosomal hydrolases. These are all capable of degrading various inflammatory mediators and so modulating immune re- actions, especially those involving mast cell degranula- tion. Surface Receptors Eosinophil cell surface receptors have been demonstrated for various complement components and especially C3b Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 139 as well as for IgG and IgE. These receptors influence the degranulation of the cell in association with various inflammatory events. In particular, when helminths are coated with specific antibodies the latter can then link with eosinophil surface receptors which promote local degranulation. There are also oestrogen and glucocorti- coid receptors whose role is less certain. Tissue Distribution Eosinophils develop in the bone marrow, circulate briefly in the peripheral blood and then distribute to the tissues. For each blood eosinophil there are 100 in the bone marrow and a further 100 in the tissues. The normal tissues with a high population of eosinophils are those in contact with the outside environment, namely, skin, gut and lungs. The eosinophil is thus ideally placed to patrol the frontiers against parasites and also to damp down any uncontrolled immunological fires. The attraction of eosinophils from the blood to tissues secondary to parasite entry or inflammatory reactions depends on a complex interplay of inflammatory and chemotactic factors. Diapedesis from the capillaries is aided by various mediators and vasoactive amines which open intercellular junctions. Thereafter the eosinophil is attracted by products of mast cells and basophils (eosino- phil chemotactic factor A, histamine and various lipid derived factors) as well as by products of other cells (lymphokines, prostaglandins) and some serum factors (complement, IgE). Various parasite extracts are also chemo-attractants. A number of factors influence the production and distribution of eosinophils. Lymphocyte-derived products stimulate the development of eosinophils and their release from the bone marrow while glucocorticoids inhibit eosin- ophil chemotaxis as well as enhancing margination and tissue destruction. The peripheral blood eosinophil count is increased by exercise and beta-adrenergic blockade and reduced by stress, menstruation and glucocorticoids. The influence of these on tissue infiltration and distribution is less well studied. Eosinophil Function in Disease There appear to be three main functions of eosinophils in disease (Fig. 1). Helminthotoxic. Eosinophils can kill trichinella, schisto- somes and their eggs, fasciola, filaria and other parasites in vitro. The process is probably initiated by binding of IgG, C3b and IgE to the parasite, with consequent degranulation of eosinophils. The chief killer proteins are MBP and ECP. Modulation of Immediate Hypersensitivity. Many mast cell mediators are inactivated by eosinophil enzymes. The precise function of the eosinophil as an anti-inflammatory cell in immediate hypersensitivity and other forms of immunological reactions is, however, not yet clear. Tissue Damage. This may occur in any disease in which there is an eosinophilic infiltrate and is chiefly due to the cytotoxic proteins MBP and ECP. The balance between host benefit and damage is obviously a fine one which is likely to depend upon the number of eosinophils and how long they are present. Transient eosinophilic reactions around parasites are probably wholly beneficial, while chronic infiltrates secondary to drug, vasculitic disorders or the hyper-eosinophilic syndrome can cause permanent damage. Fig. 1. Eosinophil chemotaxis and function. Histaminase Phospholipase D Arylsulphatase B etc Anti-mediators modulate mast cell dependent reactions 140 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 The Pulmonary Eosinophilias (PE) Fungal Allergy[ 10,11] Almost all fungal pulmonary eosinophilia is caused by Aspergillus fumigatus. A few cases are caused by Candida, penicillium, stemphylium, geotrichum, culvularia and drechsleria[12] and it is likely that other fungi will be implicated in the future but these causes are all very rare. Diagnosis can be suspected from the clinical pattern and confirmed by skin prick test and serum precipitating antibodies,to the fungus. Aspergillus may also be found in the sputum but this is not essential for diagnosis. Fungi and especially aspergillus favour places that are warm, wet and dark. The bronchial tree is thus well suited for colonisation. The probable sequence of events is immediate hypersensitivity with eosinophilia causing asthma and tissue inflammation which itself allows deeper penetration of fungal antigen. Eosinophils are attracted into the lung in relation to the affected airway, and fleeting segmental infiltrates are seen on the radiograph. The antigenic penetration results in precipitating anti- body formation and immune complex deposition around the affected airways. The resulting inflammation may increase airflow obstruction, promote mucous plugging and eventually damage the airway. Since proximal air- ways are usually involved, the eventual result is proximal segmental bronchiectasis. Sometimes a more generalised pattern of airway damage results in fixed airflow obstruc- tion together with a generalised thickening of the bron- chial wall. A number of different clinical patterns can therefore be seen. Simple asthma without pulmonary infiltrates but with an eosinophilia and evidence of aspergillus allergy. These patients respond well to standard asthma therapy. Fleeting segmental eosinophilic pneumonias. The radiogra- phic shadowing flits from one part of the lung to another, usually altering over a few days. There is fever, a high serum IgE and a moderately high eosinophil count (typically 1,000-3,000/mm3). Systemic corticosteroids clear the radiograph and the fever within a few days but chronic steroid treatment may be needed to prevent progressive pulmonary damage from repeated episodes. Mucoid impaction. Low-grade fever, malaise and fixed breathlessness are more common than asthma or pneu- monic illness in this form. The radiograph shows mucus impacted in a part of the bronchial tree with a typical gloved finger or rabbit's ear appearance. However, more severe mucus plugging can result in the collapse of a lobe, or even a whole lung. Corticosteroids may resolve the impaction but bronchoscopic clearance is often needed. Failure of resolution of mucus impaction causes some cases of bronchocentric granulomatosis. Chronic airway damage. Airflow obstruction becomes pro- gressively fixed as more damage occurs. The radiograph shows proximal segmental bronchiectasis or more genera- lised fibrotic shadowing, especially in the upper zones. Recurrent infections eventually dominate the clinical picture. Figure 2 summarises eosinophilic function in this dis- ease. The inflammatory reaction is based on fungal colonisation of the airways. The dominant clinical and radiographic features are therefore due to airway disease with asthma and segmental infiltrates or mucus impac- tion. Chronic tissue damage occurs in the airways either as proximal segmental bronchiectasis or fixed airway obstruction. Drugs and Toxins[\3,\^\ Almost any drug in any pharmacological group can cause pulmonary eosinophilia. Although antibiotics such as nitrofurantoin^5] and sulphonamides are perhaps best known and reports of PE with non-steroidal anti-inflam- matory drugs are common, this probably reflects how often the drugs are used rather than a special liability to the adverse effect. The Spanish toxic oil syndrome is perhaps the best example of a pulmonary eosinophilia due to an ingested toxin. The pathogenesis of drug-induced PE has seldom been studied, so the mechanisms can only be guessed at. Almost always the drug reaches the lungs via the blood, so the reaction must be based in the pulmonary blood- vessels rather than the airways. A wide range of drugs (usually basic lipophilic amines) are known to accumulate in the pulmonary circulation[16] and this may be the initial event. Probably the drug or a metabolite attaches to the vascular endothelium or modifies it and an allergic reaction is then centred on that blood-vessel. There, is commonly an associated rash, presumably due to an equivalent reaction in the capillaries of the skin. The pattern of the drug reaction in the lungs is highly variable, partly due to the size of the blood-vessel on which the reaction is based and partly to whether the reaction is focal or diffuse. For example, a reaction based on a few segmental pulmonary arteries resembles a pneumonia or pulmonary infarct while one based on many capillaries resembles a diffuse pneumonitis. If the Aspergillus etc Fleeting infiltrates Segmental lobar Mucus plug Collapse Asthma Fever Proximal bronchiectasis Fibrosis-upper zone Fig. 2. Pulmonary eosinophilia caused by fungi. Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 141 drug is continued and the inflammatory reaction becomes chronic, permanent damage occurs, with progressive interstitial fibrosis, especially at the lung bases. There are three main clinical patterns. Pneumonic. Fever, malaise, breathlessness and sometimes chest pain develop acutely within a few days of starting a drug. The white count is elevated, with an eosinophilia of 1,000-5,000/mm3, and the radiograph shows alveolar infiltrates sometimes in a single lobe but more usually with a patchy distribution. Transient pulmonary infiltra- tions without symptoms are sometimes seen and may well be a minor drug reaction analogous to a transient rash. The illness and radiographic changes improve rapidly on stopping the drug and recur if it is restarted. Pulmonary Vasculitis. The clinical picture is similar to the pneumonic form although pleuritic pain and pleural effusions may suggest pulmonary infarction. These reac- tions are somewhat more severe and take longer to resolve than the simple pneumonic form. Corticosteroids are sometimes given to speed resolution. Fibrosing Alveolitis. The best known example is nitrofur- antoin lung. There may be low-grade fever and malaise with a slight eosinophilia but usually progressive breath- lessness is the only symptom. The radiograph shows diffuse lower zone fibrosis. The amount of resolution which occurs after stopping the drug depends upon how long the reaction has lasted. Some degree of permanent damage is quite usual and corticosteroids may be given to ensure maximum resolution. Figure 3 summarises these patterns. The inflammatory reaction is based on blood-vessels producing a pneumonic or vasculitic pattern; prolonged inflammation causes diffuse fibrosis. Parasitic Pulmonary Eosinophiha\2,17] Many different helminth infestations can cause PE. These include nematodes, such as ascaris, strongyloides, ankylostoma and filaria, and flat worms such as paragoni- mus and schistosoma. The details of each life-cycle make exciting reading and are beyond the scope of this article. Nevertheless, they all have one event in common, namely the arrival of the parasite in the lungs, usually via the blood, and its passage into the alveoli and then to the airways. As the parasite migrates through the lungs, eosinophilic attack results in eosinophilic pulmonary infiltrates. The pul- monary vessels are often damaged while the parasite is moving into the lungs or when it is being killed, so haemoptysis is common. Furthermore, a number of dying parasites may set up a vigorous allergic reaction with consequent mediator release and asthma. Chronic damage is probably rare but diffuse fibrosis can follow microfilarial infection, pulmonary hypertension can fol- low obliteration of much of the pulmonary circulation by schistosomes, and paragonimiasis can cause lung cysts and local fibrosis. Clinical patterns are difficult to classify due to the large number of different parasites and the fact that multiple infestations are common. Fleeting Infiltrates. Transient alveolar shadowing on the radiograph represents an eosinophilic reaction to the pulmonary migration of nematodes, and associated cough, transient haemoptysis, anaemia and weight loss are common. Spontaneous resolution of the infiltrate is usual. Peripheral eosinophil counts may be as high as 50,000/mm3 and the serum IgE is usually very high. Asthma. This form of parasitic pulmonary eosinophilia is usually caused by microfilariasis due to Wucheria bancrofti and has become known as tropical pulmonary eosinophi- lia. Donohugh's[18] diagnostic criteria are (a) residence in the tropics; (b) asthma; (c) eosinophil count > 2,000/ mm3; (d) positive filarial complement fixation test, and (e) response to diethylcarbamazine. This approach remains useful for precise diagnosis since both asthma and filarial infestation are common and may co-exist by chance. The chest radiograph usually shows micronodular shadows although rare patterns in- clude cavities, pleural effusions and large pneumonic shadows. Chronic disease causes basal pulmonary fibrosis or persisting asthma. Figure 4 summarises the disorders. Pulmonary eosino- philia due to parasites is caused by their passage through the lungs with transient shadowing and haemoptysis. Tropical pulmonary eosinophilia is the particular associ- ation of asthma and micronodular shadowing caused by microfilariasis. Chronic damage leads to lung fibrosis (microfilaria) or pulmonary hypertension (schistosoma). Cryptogenic Vasculitis?Granuloma Spectrum The pulmonary eosinophilias of unknown cause present a spectrum of disorders that vary from the localised 'crypto- genic pulmonary eosinophilia' to a generalised disease with vasculitis and granulomata. In pathological terms three features are present in variable degrees: eosinophilic infiltrate, granuloma formation and vasculitis. Descrip- tions of these diseases have depended on the relative Infiltrates Non segmental Fibrosis ? lower zone Vasculitis Fig. 3. Pulmonary eosinophilia caused by drugs. 142 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 amounts of each pathological change, the type of blood- vessel involved and the organs which have been predomi- nantly affected. As a result there are a number of quite confusing classifications. The largest single source of confusion stems from two early descriptions of pulmonary eosinophilia with systemic vasculitis. An American paper in 1951 by Churg and Strauss[19] reported 'allergic granulomatosis, allergic angiitis and periarteritis nodosa' and this became known as the Churg-Strauss syndrome, while a UK paper[20] in 1957 described polyarteritis nodosa as having two forms, one with and one without lung involvement and granulomata. As a result, UK texts have continued to link pulmonary eosinophilia and poly- arteritis nodosa, while American classifications include the Churg-Strauss syndrome and reserve the diagnosis of * polyarteritis nodosa for a necrotising vasculitis of small and medium sized muscular arteries in which lung in- volvement and granulomata do not occur. The Ameri- cans have now won the classification dispute, as shown in Table 2. The way in which the pulmonary eosinophilias link up with the systemic vasculitides is shown in Fig 5. Table 2. Classification of the vasculitides[21] Systemic necrotising vascu Hypersensitivity vasculitis Giant cell arteritis Granulomatosis: Polyarteritis nodosa Allergic granulomatosis Overlap syndrome Serum sickness Henoch-Schonlein purpura Essential mixed cryoglobulin- aemia with vasculitis Vasculitis with primary dis- eases, e.g. malignancy Temporal Takayashu's disease Wegener's Lymphomatoid The pathogenesis of these conditions is unclear. A number of immunological mechanisms, including im- mune complex and cell-mediated inflammation, can be implicated. These all have the capacity to attract eosino- phils and macrophages and so set up vascular damage with variable eosinophilic infiltrate and granuloma for- mation, but the antigen that starts the immune reaction is usually unknown. The association of allergic granuloma- tosis with asthma, and often with demonstrable extrinsic allergens, suggests that an external agent which becomes associated with blood-vessels or airways may sometimes be the target, but some unmasked or altered host antigen is an equal candidate. The association of polyarteritis nodosa with hepatitis antigen or drugs and the persistent vasculitis of the Spanish toxic oil syndrome provide good examples of external trigger agents, but these conditions are rare. The dominant site of the immune reaction is in the blood-vessels, although airways can also be involved, particularly when the histology is predominantly granulo- matous. There are two clinical patterns of this disorder. Cryptogenic Pulmonary Eosinophilia[22\. Fever, weight loss and low-grade respiratory symptoms are associated with a very characteristic chest radiograph. There is widespread alveolar shadowing peripherally and in the upper zones. The blood eosinophil count is usually greater than 2,000/ mm3 but is occasionally normal, when broncho-alveolar lavage or biopsy show a predominantly eosinophilic infiltrate. The response to steroids is rapid, with resolu- tion of the fever and radiographic shadowing, and there is subsequent weight gain. Steroid dosage should be re- duced slowly, as recurrences are quite common, but most patients are entirely well with no therapy in 1-2 years. Multi-system disease is not usually apparent clinically although a few patients progress into the second pattern. Asthma is present in a significant proportion of patients but is not universal. Lung biopsy shows an interstitial eosinophilic infiltrate with only occasional areas of vascu- litis. Allergic Angiitis and Granulomatosis[19,20,23], Asthma is almost always present and may precede the multi-system disease by many years. Fever, weight loss, radiographic shadowing and multi-system disease are usually present at the onset but thereafter the clinical course is highly variable. The chest radiographic changes include tran- sient pneumonic infiltrates, nodules which may be mas- sive and show cavitation; pericardial or pleural effusions only rarely occur and diffuse interstitial changes have also been reported. There is a blood eosinophilia at some stage and the ESR is usually raised. Lung biopsy shows a vasculitis involving small arteries and veins and a perivas- cular eosinophilic infiltrate and extravascular granulo- mata. The lungs may not be the best place to look for allergic granulomas, liver, spleen or skin often being better. Any other organ may be involved, but the skin, central nervous system and heart are particularly affected while renal disease is rare. There is usually a good response to steroids but when these fail azathioprine or cyclophospha- mide are effective. The original appreciable mortality has been reduced by cytotoxic drug therapy. A few patients still die from cardiac failure or infectious complications (Segmental Infiltrates Non segmental Cough ? blood Breathless ? asthma Fever Pulmonary BP t Fibrosis Fig. 4. Pulmonary eosinophilia caused by parasites. Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 143 and permanent neurological deficits are quite frequent in survivors. Other patterns of disease have been reported under such titles as eosinophilic pneumonitis, eosinophilic non- necrotising angiitis, bronchocentric granulomatosis or necrotising alveolitis. Churg and Strauss[24] have rec- ommended that all these should be considered part of the spectrum of a single disease rather than separate entities. Hyper-eosinophilic Syndrome[25] This rare condition is quite distinct from the cryptogenic pulmonary eosinophilias. The eosinophilic infiltrate oc- curs without any evidence of an inflammatory or allergic initiating event, there is no vasculitis and no granulomata are seen. It is therefore unclear why the eosinophils have infiltrated the tissues and whether they have any ben- eficial role. It is almost as if there is uncontrolled produc- tion of eosinophils which therefore accumulate. Although the clinical course may be prolonged before symptoms develop, tissue damage eventually occurs, notably in the heart and central nervous system. Few, if any, progress to a frank eosinophilia leukaemia. Men are affected nine times as often as women, usually in the 20-50 age range, and the disease has a worldwide distribution. It has two clinical patterns. Pulmonary Eosinophilia. There are few symptoms, al- though there is occasionally an associated angio-oedema and a raised IgE. Allergy is not otherwise seen. The blood eosinophil count is as high as 50-100,000/mm3. The chest radiograph shows a non-specific diffuse infiltration. There is usually a response to corticosteroids with a reduction in the blood eosinophil count and the pulmon- ary infiltrate. The prognosis is good unless the heart becomes involved. Predominant Cardiac or Central Nervous System Involvement. The eosinophils in the heart cause a restrictive and obliterative cardiomyopathy while diffuse brain infil- tration causes intellectual impairment and more local deposits may cause focal abnormalities. There is often complicating thrombo-embolic disease of large and medi- um bloodvessels. Hydroxyurea and vincristine have been suggested as logical therapy to reduce the bone marrow production of eosinophils. This article is based on a paper read at the College Regional Conference at Liverpool in September 1985. References 1. Crofton, J. W., Livingstone, J. L., Oswald, N. C. and Roberts, A. T. U. (1952) Thorax, 7, 1. 2. Liebow, A. A. and Carrington, C. B. (1969) Medicine, 48, 251. Bronchopulmonary eosinophilia Necrotising granulomatosis Bronchocentric granulomatosis type 1 Drugs Fungi Parasites Asthma etc Bronchocentric granulomatosis type 2 Wegener's^ Necrotising \ Sarcoid . Granuloma Eosinophilia Necrotising vasculitis Fig. 5. The connection between the pulmonary eosinophilias and the systemic vasculitides. 144 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 3. 4. 5. 6. 7, 8 9, 10 11 12 13 Patterson, R., Irons, J. S., Kelly, J. F. et al. (1974) Journal ofAllergy and Clinical Immunology, 53, 245. Schatz, M., Wasserman, S. and Patterson, R. (1982) Archives of Internal Medicine, 142, 1515. ? Dejaegher, P., Dervaux, L., Dubois, P. et al. (1983) Chest, 84, 637. Dejaegher, P. and Demedts, M. (1984) American Review of Respirat- ory Disease, 129, 631. Weller, P. F. and Goetzl, E. J. (1980) American Journal of Pathology, 100, 793. Middleton, E., Reed, C. and Ellis, E. (eds) (1983) Allergy: Principles and Practice, pp. 701-56. St. Louis: Mosby. Weller, P. F. (1984) Journal of Allergy and Clinical Immunology, 73, 1. Hinson, K. F. W., Moon, A. J. and Plummer, N. S. (1952) Thorax, 7, 317. Safirstein, B. H., D'Souza, M. F. and Simon, G. (1973) American Review of Respiratory Disease, 108, 450. Lahoute, C., Tonnel, A. B., Fournier, E. et al. (1983) Poumon Coeur, 39, 87. Cole, P. (1977) Drugs, 13, 422. Toxic Epidemic Syndrome Study Group (1982) Lancet, 2, 697. 15. i6; 17. 18. 19. 20. 21, 22. 23 24. 25 Sovijarvi, A. R. A., Lemola, M., Stenius, B. et al. (1977) Scandinavian Journal of Respiratory Disease, 58, 41. Brandenberger Brown, E. A. (1974) Drug Metabolism Reviews, 3, 33. Frazer, R. C. and Pare, J. A. P. (1978) Diagnosis of disease of the chest, Vol II, pp. 860-80. Philadelphia: Saunders. Donohugh, D. L. (1963) New England Journal of Medicine, 269, 1357. Churg, J. and Strauss, L. (1951) American Journal of Pathology, 27, 277. Rose, G. A. and Spencer, H. (1957) Quarterly Journal of Medicine, 26, 43. Fauci, A. S., Haynes, B. F. and Katz, P. (1978) Annals of Internal Medicine, 89, 660. Carrington, C. B., Addington, W. W., Goff, A. M. et al. (1969) New England Journal of Medicine, 280, 787. Chumley, L. C., Harrison, E. G. and DeRemee, R. A. (1977) Proceedings. Mayo Clinic, 52, 477. Churg, J. and Strauss, L. (1981) New England Journal of Medicine, 304, 611. Leading article (1983) Lancet, 1, 1417.

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Editorial With alarming regularity patients and relatives recount their distress- ing experiences in hospital. Left in ignorance of what is happening or bemused by conflicting statements, they are the victims of psychologi- cal negligence. Of course it should not happen. No hospital should ever present as a production line manned by uninterested shift- workers. Seldom is the individual callous but what is absent is the corporate demonstration of concern by the many people caring for the one patient. Care has to be shown to be both continuous and coherent. This is a difficult matter with a staffing structure that builds-in ill-defined split responsibilities and short periods of 'duty'. The patient is the constant feature in a shifting world of professional visits. He may have to relay information from one professional to another because they have failed to brief each other. For the patient, anyone who is ignorant of his condition appears not to care. Alas, the ignorance can be very real, for the core of the problem lies in the failure of constant communication between those responsible for care. Now is the time for an examination of conscience. Have we not all at some time failed to make intentions clear to house physician and registrar, or listened to someone's account but not to the patient? These omissions are the seeds from which grow the major psychologi- cal disasters for a patient, bereft of knowledge and comfort. More by individual example than by coherent team effort disasters are rare. Patients in their gratitude forgive many anxieties that we unwittingly cause and are benign critics of our performance. There is happy administrative talk of health care teams. The question is how to make the care obvious and effective and what qualities of team spirit are neccessary to achieve this. It is a pity that much high-level discussion is confined to who should be captain. Too little thought is given to the integration of team effort for a single purpose. We are all so used to the idea of a personal one-to-one relationship with our patient that we do not take kindly to shared responsibilities or delegation of care to create a united effort. The daily grind of hospital work blunts our appreciation of the fact that for the patient every experience is fearful, unpleasant and demeaning, unless we can soften the blows. Doctors are beginning to realise that they are not necessarily the good communicators that they thought they were. Some now advo- cate a high priority for the teaching and supervision of doctor/patient communication in undergraduate and post-qualification training. The idea could well be extended to communication between profes- sionals. At one level this means the proper transmission of infor- mation from the person going off duty to the one coming on. Nurses have a routine for this; junior doctors do not. The other level is the pooling of information between different types of professional, includ- ing nurses, laboratory workers and all grades of medical staff. Strengthening personal communication in hospitals needs that scarce resource of time. Once found, it will be well spent. Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986

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The Gentle Queen A. G. W. WHITFIELD, cbe, md, frcp Emeritus Professor of Medicine, University of Birmingham Assistant Director, Research Unit of the Royal College of Physicians Princess Adelaide of Saxe-Meiningen must have had some reservations about leaving the tiny duchy in central Germany, where she had been born and had lived happily for all her 26 years, to come to England to marry Prince ^ William Henry, Duke of Clarence, the third son of ^ George III. She had never seen him but knew that he was more than twice her age, heavily in debt and had had ten ? - illegitimate children by Mrs Dorothea Jordan, the ac- tress. Moreover, she must have known that she was by no means the first with whom he had contemplated, and even proposed, marriage, since his separation from Mrs Jordan and her subsequent death. She would have been further discouraged had she heard Canning's speech in the House of Commons in support of her own and the Duke's Civil List allowance in which he said, 'Into this alliance His Royal Highness entered, not for his own private desire and gratification, but because it was pressed on him for the purpose of providing for the succession to the throne'. However, when she and her mother arrived at Gril- lon's Hotel in London on the evening of 4th July 1818, she was doubtless comforted by the kind and warm welcome afforded to them by the Prince Regent, the Duke of Clarence and the Earl of Munster, the Duke's eldest illegitimate son, and from such inauspicious begin- nings she made a great success of her marriage. Though not beautiful she spoke excellent English and was calm, sensible and very kind. She and her husband became genuinely devoted to each other, the ten Fitzclarence offspring had a real home at Bushey Park and a good > mother', and thanks to financial prudence the debts were discharged. Captain Lord Frederick Fitzclarence, the third of the illegitimate sons, told Creevey that the Duchess of Clarence was 'the best and most charming woman in the world'. In addition she brought about a marked improvement in the Duke's personality and behaviour; in 1831 Earl Grey told Creevey that 'her influence over him as to his manners has been very great and highly beneficial'. The Duchess of Clarence only failed in what was i expected and hoped of her in that she did not produce an heir to the throne. Her first baby, Charlotte Augusta Louisa, died within a few hours of birth. Her second daughter, Elizabeth Georgina Adelaide, was born six weeks prematurely on 10th December 1820 at St James's Palace; at first she thrived but on 5th March 1821 died 'in a convulsive fit'; 'the cause of her death was an entangle- ment of the bowels'. Later in the same year a twin pregnancy ended in miscarriage; so, despite the skill and care of Sir Henry Halford, Sir William Knighton and Sir Andrew Halliday, it had to be accepted that she was unlikely to have a successful pregnancy. When George IV died on 26th June 1830 and the Duke of Clarence acceded to the throne, Queen Adelaide did much to guide and control her husband and to give dignity, charm and respectability to the Court. With such a wide difference in the ages of the King and Queen it is not surprising that malicious gossip linked the name of Fig. 1. Sir Henry Halford, Bart. (From the portrait by Sir Thomas Lawrence. By kind permission of the Harveian Librarian of the Royal College of Physicians.) Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 63 the Queen with others, particularly Earl Howe, her Chamberlain, and David Davies, sometimes spelt Davis, her domestic physician, but there can be no doubt that Queen Adelaide was the most virtuous and faithful of wives. David Davies, who is said to have practised homeopathy, was assistant to one of Queen Adelaide's previous physicians, obtained the Membership of the Royal College of Surgeons in 1815 and was granted an MD Lambeth by the Archbishop of Canterbury in 1836. He was created a Knight of the Guelphic Order (KCH) by Queen Victoria shortly after her accession for his services as King William's and Queen Adelaide's domes- tic physician for many years. In 1819 the Queen had had pleurisy and there was a further attack in 1833. The following year she developed a cough which was to persist for the remaining 15 years of her life. She also complained of oppression on her chest which was relieved to some extent by a long holiday in Meiningen. On her return, however, her friend Miss Clitherow wrote, 'She is most miserably thin and has a sad, wearing cough', and in 1835 Lady Cowper in a letter to Princess Lieven said, 'I must say she looks very ill'. Though her household medical man was David Davies her physician was Halford. He was nearly 70 and The Lancet wrote, 'He is all tact and nothing else. He is ignorant of the modern discoveries in pathology and never employs the modern instruments of diagnosis; he has never written a line that is worthy of perusal on any scientific subject'. He certainly never learned to use a stethoscope and was described by Lord Grey as 'the damnedest conceited fellow in the world'. Queen Ad- elaide, though aware of his excellent manners, had no faith in his abilities. In 1836, therefore, Dr W. F. Chambers, the fashionable St George's physician, was asked to see her at Windsor and three weeks later he was gazetted her Physician in Ordinary. Whether he knew the nature of the Queen's illness is uncertain but she had great faith in him, so great that when King William himself fell ill in 1837 she manipulated affairs so that, to Halford's great annoyance, Chambers saw the King before he did despite the fact that he was the King's first physician. Chambers was immediately appointed Phys- ician in Ordinary to William IV who conferred upon him a knighthood of the Guelphic Order (KCH), Chambers accepting the commandership but declining the knight- hood. The Queen's symptoms persisted and though she remained very active there were occasions when she was not well enough to fulfil her engagements. However, she never left the bedside of King William during his last illness. He had suffered from seasonal asthma for most of his life but died on 20th June 1837 from cardiac failure due to aortic stenosis and probably heart block, for Greville recorded that 'his pulse was down to 30'. After his death Queen Adelaide returned to Bushey Park, which had been her home from her marriage until her husband acceded to the throne in 1830, and Marlborough House was given to her as a town residence. She gave to Halford a silver vase inscribed 'To Sir Henry Halford Bart. GCH. A grateful acknowledgment of his attendance upon his late Majesty King William IV during his last illness. A R'. Thereafter, however, Chambers and not Halford was her first physician. The first winter of her widowhood she spent at St Leonard's but there was no improvement in her cough as her physicians had hoped and they were so concerned about her condition that they advised that she should spend the next winter abroad and suggested Madeira. The Queen Dowager, however, was reluctant to go to Madeira as it was not British but she agreed to go to Malta. Queen Victoria put the frigate HMS Hastings (Captain Francis Loch, RN) at her disposal and she sailed from Kingstairs on 3rd October 1838, Sir David Davies being in attendance. Lieutenant-General Sir Henry Bou- verie was the Governor of Malta at the time and she was made most welcome, staying at Sant Anton Palace until April 1839, the rest and warm dry climate appearing to produce considerable improvement in her condition. The Queen Dowager was a deeply religious woman and as there was no Anglican church on the island she gave ?10,000 as a thanksgiving to build St Paul's Cathedral. The square in which it stands was known as Adelaide Square until Dom Mintoff became Prime Minister when he changed its name to Independence Square. The next winter she stayed in London and, despite a Fig. 2. Dr W. F. Chambers. (From an engraving in the Royal College of Physicians.) 64 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 yJL haemoptysis, attended Queen Victoria's wedding. In 1840 she took a three-year lease of Sudbury Hall in Derbyshire from Lord Vernon, spending December 1840 and January and the first week of February 1841 there and returning to London in time to attend the Princess Royal's christening. While at Sudbury her fellow wor- shippers at the little church close to the Hall noticed her cough, and the Queen Dowager's sister, the Duchess of Saxe-Weimar, told the Duchesse of Dino, Talleyrand's niece and secretary, 'The Queen Dowager has lost the use of one of her lungs and that the other was very delicate'. She returned to Sudbury in September but had a profuse haemoptysis early in November. Chambers was sum- moned from London and stayed for three weeks. It was feared that she would die and she wrote out instructions for her funeral. I die in all humility knowing well that we are all alike before the throne of God, and I request therefore that my mortal remains be conveyed to the grave without any pomp or state. They are to be moved to St George's Chapel, Windsor, where I request to have as private and quiet a funeral as possible. I particularly desire not to be laid out in state, and the funeral to take place by daylight, no procession, the coffin to be carried by sailors, to the chapel. All those of my friends and relatives to a limited number, who wish to attend to do so . . . I die in peace and wish to be carried to the fount in peece, and free from the vanities and pomp of this world. I request not to be disected nor embalmed and desire to give as little trouble as possible. I shall die in peace with the world and full of gratitude for all the kindness that ? was ever shown to me and in full reliance to the mercy of our Saviour Jesus Christ in whose hands I commit my Soul. Miraculously, however, she recovered and was able to return to Marlborough House on 21st January 1842 but had to remain indoors until the spring. A further hae- moptysis, however, occurred later that year. There are but few traces of the Queen Dowager's tenancy of Sudbury Hall nearly a century and a half ago. A remote inn a few miles away is named the Queen Adelaide and while the Meynell and South Staffordshire hounds meet there from time to time custom does not warrant twice-daily opening of the bar! At Sudbury Hall, now the property of the National Trust, the Queen's bedroom is beautifully preserved and contains a print of her and her instructions for her funeral signed and dated November 1841. The Queen Dowager faced her illness with remarkable courage and lack of complaint. She was full of kindness and nothing prevented her from travelling all over the country to visit her friends or returning to Meiningen to see her family and her old home. Whether or not Chambers was influenced by the inconvenience of his prolonged detention at Sudbury is uncertain but he advised her that she should spend the next winter in Hampshire where he himself had a house?Hordlecliffe, near Lymington. The Queen Dowager, therefore, rented Canford House from Lord de Mauley and travelled there by train in September 1842. After she had been there for a few weeks she had a cold which provoked an exacerba- tion of her chest symptoms and led to her return to Marlborough House in January 1843. She was clearly deteriorating and in the summer of 1843 was unfit to attend the marriage of Princess Augusta of Cambridge. Her next winter home was Witley Court, near Worces- ter, which she rented from Lord Dudley and Ward. She spent the winters of 1843-44 and 1844-45 there but these sojourns in one country house after another were of course powerless to halt the inexorable advance of her tuberculosis and she would probably have been wiser to stay at Bushey Park and Marlborough House. In the summer of 1844 and again in 1846 she bravely made the journey to Meiningen without apparent harm and on her return in 1846 took a three-year lease of Cassiobury, near Watford, from the Earl of Essex, but she was ill there and the house proved unsatisfactory, so for the winter of 1847 she went to Madeira. She embarked at Portsmouth in HMS Howe (Captain Sir John Stirling, RN) on October 9th, sailing two days later. Sir David Davies accompanied her and she stayed at Funchal until April the following year but without any benefit to her health. On her return from Madeira she took a three-year lease of Bentley Priory, near Stanmore, from the Marquis of Abercorn and this was her home for the rest of her life apart from visits to Bushey Park and brief periods at Woking and Tunbridge Wells. It was widely appreciated that she could not recover and Queen Victoria and Prince Albert stayed with her for two days at Bentley Priory and visited her there on other occasions, as did the Duchess of Kent, the Duchess of Cambridge, Earl Howe, Prince George of Cambridge and many of the countless others to whom she had given friendship and kindness. In 1848 Chambers suffered a stroke which caused some dysphasia. He retired from practice and went to live at Hordlecliffe where he survived until 1855. It appears that his disability during the last phase of his life was partly due to anxiety. He was asked to see the Queen Dowager but begged to decline as he felt the responsiblity would have been more than he could bear. Richard Bright replaced him. Chambers had a career of great success and distinction, having an enormous practice and being Phys- ician in Ordinary to Queen Victoria and the Duchess of Kent as well as to King William and Queen Adelaide. Though he was a Fellow of the College for 36 years, a Censor, a Councillor and an Elect, he took no prominent part in College affairs, did not engage in research and published no original work. Sir David Davies does not appear to have ever held the College Licence. He died at Lucca in Italy on 2nd April 1865 at the age of 73 and was buried at Biarritz. During the last weeks of her life the Queen Dowager was confined to bed at Bentley Priory and Bright and Davies issued bulletins at frequent intervals, often twice a day. These were inevitably repetitive. She died from a haemoptysis on 2nd December 1849 and was buried in accordance with her wishes written in her own hand at Sudbury Hall eight years earlier. She was generous in death as in life, leaving 100 legatees, the most touching being Queen Victoria, to whom she bequeathed the Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 65 statue by Scoular of her infant daugher, Princess Eliza- beth of Clarence, which is now at Windsor. Had she survived, Princess Elizabeth and not Victoria would, of course, have been Queen. Queen Adelaide was loved and admired by all who knew her for her kindness, generosity, ?friendship and courage, and for all that she did for her adopted country and its monarchy. She is often spoken of as the gentle queen, which is a fitting title but only embraces one of her many attributes. Bibliography British Medical Journal 1865. Sir James Clark's Diaries. Directory of Welsh Biography. Roger Fulford (1973) Royal Dukes. London: Collins. Mary Hopkirk (1946) Queen Adelaide. London: John Murray J Tresham Lever (1957) The Letters of Lady Palmerston. London: John Murray. i. List of Fellows and Members of the Royal College of Surgeons 1845. Sir Henry Luke (1949) An Account and an Appreciation of Malta. London: Harrap. Sir Herbert Maxwell (1904) The Creevey Papers. London: John Murray. William Macmichael (1857) Lives of British Physicians. London: William Tegg. Medical Directory 1866. Medical Register 1845, 1859. Medical Times and Gazette 1865. Munk's Roll. j William Munk (1895) The Life of Sir Henry Halford Bart. London: Longmans. Royal Archives, Queen Victoria's Journal. Lord Sudley (1943) The Lieven Palmerston Correspondence 1828-56. Lon- don: John Murray. The Times 1818, 1837, 1838, 1840, 1841, 1847, 1849. George Whitfield (1983) Beloved Sir fames. Birmingham University. Philip Ziegler (1971) King William IV. London: Collins.

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General Internal Medicine Opinion in the 1970s,gave little support to Mayo's old claim that one well-trained physician would do better work for a thousand people than 10 specialists. It was considered that the mantle of the general physician had fallen on general practitioners, A & E consultants, geri- atricians and even professors of clinical medicine. The growth of relative specialties, fuelled by new technology, had made serious inroads into the traditional province of general medicine and there was a large question-mark over its future. As a result of anxieties expressed from various quarters, the College set up, in 1979, a working party to assess the position and future prospects of the general physician, with particular reference to patient care, medical education and the economic use of re- sources. After five meetings it was resolved, in 1982, that a College committee devoted to the specialty should be established, and one of its first tasks was to undertake a fact-finding exercise, with the help of Regional Advisers, to determine the current role of the general physician. The results of this enquiry have just been published. Involvement in the acute emergency take was accepted as the hallmark of the general physician and replies were received from 1,031 individuals in 185 districts. In both teaching and non-teaching hospitals the majority regard- ed themselves as general physicians with an interest, although 17 per cent claimed to be pure general phys- icians. Of those general physicians with an interest, four- fifths spent more than 40 per cent of their time in general medicine and this figure was remarkably constant over the whole range of special interests. All 20 specialties recognised by the College were represented, with the majority involved in gastroenterology, respiratory dis- ease, cardiology and diabetes; 20 per cent had more than one specialty interest and no less than 36 per cent had interests not included in their original contracts. The majority of physicians worked in more than one hospital, with an acute on-call commitment averaging, in non- teaching hospitals, one in 4.7 days and in teaching hospitals one in 6.8 days. Average admissions per take per day varied from 8.9 in the non-teaching to 4.8 in the teaching hospitals. In a climate of increasing specialisa- tion the routine transfer of patients to other units was expected to be high but, in fact, only 17 per cent of consultants routinely transferred specific patients to other departments or other hospitals. Details of firm structure predictably showed a greater number of senior registrars in teaching hospitals, with more registrars and senior house officers in the non-teaching hospitals. In the intensive care facilities of 178 districts unit administration fell to anaesthetists in 66 per cent but continuing patient care remained with the physician or was shared between the physician and the anaesthetist in 88 per cent, suggesting a satisfactory compromise rather than competition between anaesthesia and medicine. These figures suggest that the general physician, usually with an interest, remains directly responsible for both immediate and continuing care for the major part of acute medicine. Of particular interest is the large number of consultants who developed either interests not included in their contracts or more than one interest. This under- lines the frequently expressed view that flexibility should be maintained in both training and career structures to enable changes in direction, and also for new specialties, to be developed in association with general medicine rather than in isolation. The difference in consultant acute workload between the teaching and the non-teach- ing hospitals must have implications for training in the undergraduate, pre-registration and post-registration periods and reinforces the view that all District General Hospitals should, in fact, develop a greater teaching commitment. The general physician with an interest will continue to provide the basis for acute medical services and the average District General Hospital will require at least five such consultants. If the physician is to remain generally based, his acute experience will be diluted if his on-take commitment falls significantly below one in five. Special interests covering most of the major specialties will be required. This may call for the development of new interests, involvement with more than one and the shar- ing of specialty expertise across adjacent districts or with geriatrician colleagues. Involvement of geriatricians in specialty provision could encourage the College's desire for integration. The development of technology-based new specialties should be viewed with caution and possi- bly assisted by sub-consultant labour substitution. Train- ing for general medicine should be broad-based and flexible, with greater exposure to the acute take, es- pecially at District General Hospitals: we would argue that two years rather than one should be the requirement for accreditation. Serious thought needs also to be given to those areas to which other specialties now lay claim, such as intensive care, haematology and oncology. In each case the clinical component must be identified and quantified and the role and lines of communication specified to aid the development of interdisciplinary training programmes. There is no doubt that the general physician has responded to the need for change and will remain an essential component of hospital staffing. 1^- RjC. King C. |Davidson Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986

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Incidence, Mortality and Prevention of Infective Endocarditis SIR RICHARD &AYLISS, kcvo, md, frcp SIR CYRIL CLARKE, kbe, md, frcp frs CELIA M. OAKLEY md, frcp W. SOMERVILLE, md, frcp A. G. W. WHITFIELD, cbe, md, frcp SUSAN E. J. YOUNG, mb, mrcp(uk) Royal College of Physicians Research Unit Since 1933 the number of deaths in England and Wales, certified as due to infective endocarditis (IE), has fallen by about four-fifths[l ,2]. In the pre-antibiotic era the incidence of the disease was the same as the number of deaths because IE was then uniformly fatal. Since cura- tive treatment became available, reported series from the UK[3-11] and from abroad[12-14], have shown consider- able differences in mortality and, as the disease is not notifiable, the incidence is unknown. Oakley[15] has suggested that it is probably in excess of 1,500 new cases annually in the UK but Smith et al. [9] report it to be only 16 per million of the population each year in South-East Scotland, which is about two-thirds of Oakley's estimate. Certainly IE is still the cause of over 200 deaths each year in England and Wales[2] and of a severe and dangerous illness in those who recover. The purpose of this article is to consider the findings in a recent study of 582 episodes of IE by the British Cardiac Society and the Royal College of Physicians Research Unit and to examine such other relevant evidence as is available in order to ascertain the current incidence of and mortality from the disease and to identify any possible measures by which they might be reduced. Method The Survey All members of the British Cardiac Society were asked, verbally and by letter, to complete a proforma in respect of each patient with IE under their care in 1981 and 1982 and to persuade the physicians in their hospital to partici- pate in the investigation. A similar request was made to all Fellows and Members of the College through its Regional Advisers. Microbiologists reporting cases to the Communicable Disease Surveillance Centre were asked to encourage the clinician in charge to submit a proforma in respect of any such patients about whom details had not already been supplied. The survey was given wide and repeated publicity in the British Heart Journal, the British Medical Journal and The Lancet; cardiologists and physicians were reminded of the project on all suitable occasions. The proforma asked for the patient's full name, age, sex and hospital number, the name of the consultant in charge and the hospital where the patient was treated, the causal organism and the outcome. It also required details of any dental, surgical or investigative procedure, injury or other circumstances that might have caused the illness, and the nature of any pre-existing cardiac abnormality and whether or not its presence was known to the patient or his or her doctor or dentist prior to the illness. Any areas of uncertainty were clarified by further correspondence or other contact. Ofjicial Statistics The Registrar-General's and Office of Population Cen- suses and Surveys' (OPCS) Annual Mortality Statistics for England and Wales were used to obtain the total population and the number, age and sex of those certified as dying from IE during each of the 50 years 1933-83. Other Reported Series All major series of cases of IE reported during the past half-century were studied to obtain evidence regarding total incidence of the disease and changing trends in its mortality, pathogenesis and microbiology. Results From the Survey Proformas in respect of 582 episodes of IE occurring in 577 patients were received, five patients having a second episode within the two-year period. The age range was Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 15 2-87 (mean age 51.4 years); 32 patients were under 20 and all but six of them had congenital heart disease; 163 were over 65 years of age. There was a male preponder- ance (ratio 2:1). In all, 137 had pre-existing rheumatic heart disease, 108 congenital heart disease and 145 other cardiac abnormalities, chiefly mitral valve prolapse and calcific aortic valve disease. Of these 390 patients, 97 had had valve replacement and 38 had suffered previous attacks of IE; 183 patients were not thought to have had any previous cardiac abnormality. The aortic valve was the site most frequently affected (148 patients) and after that the mitral valve (122 patients) and congenital heart lesions (54 patients). In 27 patients both aortic and mitral valves were involved. The portal of entry of the causal organism, where known, is summarised in Table 1. Streptococci were Table 1. Portal of entry for causal organism. No. Possibly dental 108 Gastrointestinal tract 24 Genito-urinary tract 25 Respiratory tract 17 Skin 16 i.v. drug abusers 9 Fractures 4 Pregnancy and parturition 3 Nosocomial infections resulting from procedures involving access to the bloodstream 27 No portal of entry apparent 349 Total 582 responsible in 367 patients, staphylococci in 116, a Gram- negative bacterium in 15 and Coxiella burnetii in 9. Blood cultures were negative in 53 patients and in the remainder IE was caused by a varity of organisms. Factors rendering patients especially susceptible to IE are shown in Table 2. Table 3 shows the age, mortality and infecting organism in the 84 patients with prosthetic valve endocarditis. Table 2. Factors causing increased risk of IE. No. Prosthetic valves 84 Other cardiac surgery 13 Previous IE 38* i.v. drug abusers 9 Diabetes mellitus 8 Alcoholism 4 Immunosuppression 9 Renal failure and haemodialysis 8 * Includes 9 of the 84 who had undergone valve replacement Of the 577 patients, 83 (14.4 per cent) died, of whom 32 were female. The mean age of those dying (59.3 years) was greater than those who recovered (50.0 years). Of those with staphylococcal infections, 31 per cent died, as Table 3. Age, mortality and infecting organism in 84 patients with prosthetic valve endocarditis. Early* Late endocarditis endocarditis Number 11 73 Mean age (yr) 46.9 52.2 Mortality 45% 23.8% Previous IE ? 11 Organisms!: Staphylococci: Coagulase positive ? 15 Coagulase negative 8 10 Viridans streptococci 1 16 Bowel organisms ? 8 Cultures negative 1 10 Negative cultures Coxiella burnetii ? 5 Other organisms 3 10 Valves: Mitral 3 26 Aortic 5 28 Mitral and aortic 5 10 Other ? 9 *Within 8 weeks of insertion of prosthetic valve fThree patients' blood grew two organisms compared with 12 per cent in whom bowel organisms were responsible and 6 per cent who succumbed to other streptococcal infections. Emergency valve replacement was required in 36 patients. The diagnosis of IE was not made until oper- ation in 4 patients and autopsy in 5. From Official Mortality Statistics The total population of England and Wales and the mortality from IE each year over the period 1933-83 as reported in the Registrar-General's and OPCS Annual Mortality Statistics is shown in Fig. 1, the age of those dying in Fig. 2 and their sex in Fig. 3. From Other Reported Series Table 4 shows the period covered by other major reported series, the number of patients included, the sex ratio, mortality and causal organism. It also includes the pro- portion considered to have had previously normal hearts and the number with prosthetic valves. Discussion It was hoped that the joint survey by the British Cardiac Society and the Royal College of Physicians Research Unit would provide information regarding the incidence of the disease, but notification fell very far short of expectations and it was clear that ascertainment was low. The total number of proformas received was only slightly in excess of the known mortality; none was received from the Republic of Ireland and none from a number of large hospitals in the UK, while patients reported to the Communicable Disease Surveillance Centre included 16 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 many for whom no proformas were forthcoming. More- over, the low mortality in the 577 patients (14.4 per cent) suggested under-reporting. If the mortality among those suffering IE was accurate- ly known it would be simple to calculate the incidence from the total population figures. Thus if Hayward's[7] and Oakley's[15] estimate of 30 per cent was correct, an incidence of 1,116 cases in England and Wales in 1983 could be assumed, leaving only the undiagnosed and incorrectly certified deaths excluded. However, Table 4 shows a wide range of mortality (19-46 per cent) in the other reported series [3-14], Some of this discrepancy is explained by the evolution of treatment over the years, particularly in antibiotic therapy and emergency valve replacement, and some reflects the special interest and expertise of the authors. However, it also indicates that none of the series can be accepted as a representative sample. Smith et al. [9], whose series is probably less biased and nearer total ascertainment than any other, suggest an annual incidence of 16 per million of the population but their mortality was 46 per cent. The only way, therefore, to ascertain the incidence of the disease would be to have it made notifiable. This again would exclude undiagnosed cases and there would inevitably be some diagnosed cases which were not notified. It is also doubtful whether the information obtained would be of sufficient value to justify the work and expense entailed in collecting it. The number of undiagnosed cases may be substantial, for it is a disease notoriously difficult to recognise, as is shown by patients undiagnosed until operation or autopsy in this and other series[9,10,15]. Moreover, the traditional purpose of notification, which never gives reliable absolute numbers, is to enable local public health doctors to take early action to prevent spread of disease. Another possible source of information about incidence is the Hospital In-Patient Enquiry. This, however, relates only to a 10 per cent sample of in-patients in National Health Service hospitals and is therefore unlikely to provide accurate data. There is no valid evidence as to whether the incidence is increasing, decreasing or remaining static[7,12,13,15]. The number of cases reported by Public Health Labora- tory Service and hospital microbiologists to the Commu- nicable Disease Surveillance Centre showed an increase from 298 in 1975 to 488 in 1980 but this probably reflects improved reporting rather than higher incidence. The mortality from IE, however, has fallen dramatical- ly since curative treatment became possible, despite an increase in the total population of England and Wales of over nine million during the past half-century (Fig. 1). In 1933 there were 1,256 such deaths in England and Wales and mortality remained at, or slightly below, this level until antibiotics became available some ten years later, Fig. 1. Annual deaths from infective endocarditis and population change, England and Wales, 1933-83. Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 17 Fig. 2. Annual deaths from infective endocarditis by age group, England and Wales, 1933-83. Fig. 3. Annual deaths from infective endocarditis by sex, England and Wales, 1933-83. 18 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 Table 4. Published series of patients with IE Authors Years covered No. of patients Cates and Christie[3] 1945-9 Lerner and Weinstein[12] 1939-59 Cherubin and Neu[13] 1938-67 Hughes and Gauld[4] 1945-64 Shinebourne et al. [5] 1956-65 Hayward[7] 1956-72 Gray[8] 1955-75 Smith et al. [9] 1969-72 Schnurr et al. [10] 1973-6 Pelletier and Petersdorf[14] 1963-72 Moulsdale et al. [11] 1970-9 Lowes et al.[6] 1965-75 Bayliss et al. (present 1981-82 series) (93 (582 M/F ratio Mortality % Streptococcal % Staphylococcal % No. with Prosthetic previously valve normal heart 442 100 655 68 93 N.S. 110 78 70 125 88 episodes) 60 577 episodes) 1/1 2/1 1/1 8/9 2/1 N.S. N.S. 22/17 3/2 96/29 53/35 1.5/1 2/1 44.1 37 19 N.S. 31 31 24 46 34 37 36 20 14.4 94 56 61 59 55 N.S. 53 49 60 32 67 68 63 2 23 14 9 9 N.S. 5 31 27 39 25 9 20 none N.S. none none 1 N.S. 6 13 5 16 20 2 97 0 39 181 18 19 N.S. 5 19 31 35 24 18 183 when deaths from IE were rapidly reduced to 498 in 1948 and 339 in 1953. They remained at about that level for a decade until the benefits of emergency valve replacement became evident and the number of deaths fell to 282 in 1968, but for the past decade they have fluctuated between 189 (1979) and 249 (1974)[1,2]. This failure to reduce further the number of deaths is due to the relatively new phenomenon of IE in i.v.-drug abusers (Tables 1 and 2[8,10,11-15,16-18]), in those with pros- thetic valves (Tables 2, 3 and 4[8-l 1,14,16,19,20]) and the increased number of old people in the population who develop IE on previously normal heart valves and have a poorer chance of survival than younger subjects (Fig. 2(4,5,8-14,16]). The benefits of emergency valve replacement are not wholly attributable to rescuing those in danger from heart failure but also encompass the eradication of a deeply entrenched nidus of infection and protection of the kid- neys from embolic and other damage. Apart from antibiotic therapy and valve replacement, the better dental state of the population and antibiotic prophylaxis to cover dental and surgical procedures and investigations have doubtless helped to reduce mortality, and the diminution in rheumatic heart disease has greatly reduced one group at special risk. The age and sex of those dying from IE have changed significantly during the past 50 years[l,2]. In the pre- antibiotic era about 20 per cent of the deaths occurred in patients under 20 years of age, but during the past 25 years the number has been above 5 per cent in only one year and in 1983 only one of the 225 deaths was in this age group. On the other hand, deaths in the 'over 65s' have risen from about 8 per cent 50 years ago to one half of the total during the past decade (Fig. 2). Before antibiotics there were more female than male deaths but since treatment became available the reverse has been the case (Fig. 3). The diminution in rheumatic heart disease, more common in the female, and the increase, especially in the male, of congenital bicuspid aortic valves and their sequel, calcific aortic valve disease, doubtless explain much of this change[4,5,8-14,16]. The Registrar-Gener- al's and OPCS Mortality Statistics do not show such a high male preponderance as that reported by some authors[5,12,14], another indication that they are de- scribing selected groups. Prosthetic v^lve endocarditis carries a high mortality, 45 per cent in early cases and 23.8 per cent in late cases in this series in which 84 of the 577 patients (15 per cent) had this type of endocarditis (Table 3). The Communicable Disease Surveillance Centre found a lower frequency of endocarditis in those with prosthetic valves (128 cases (5.3 per cent) in 2,432 episodes) but this may reflect failure to mention such a valve on the laboratory forms[20]. Wilson et al. [21] reported a higher mortality (86 per cent in early and 40 per cent in late cases) and 0.98 per cent of the 4,706 who had prosthetic valves inserted at the Mayo Clinic developed prosthetic valve endocarditis during the period 1963-74. Masur and Johnson[19] described 48 cases at the New York Hospital-Cornell Medical Centre during the period 1962-78 during which 1,282 patients had prosthetic valves implanted. The mortality rate in early cases was 75 per cent and in late 66 per cent. All writers have reported an increased proportion of staphy- lococcal infections, - particularly in early cases[8- 11,14,20,22] and due to Coxiella burnetii in those occur- ring later. In this series 33 of 84 cases were caused by staphylococci. Of the 33, all the early cases and 10 of the 25 later cases were caused by coagulase negative species, which accords with the findings of Masur and John- son[19] and the Communicable Disease Surveillance Centre[20], There is a considerable population at especial risk of IE (Table 2). Prosthetic valve implantation is the major hazard but other writers have found a similar susceptibil- ity in those who have had a previous attack of IE[13,14,23-25], in i.v.-drug abusers[8,10-15,16,24], diabetics[5,10,11,13,24,25], those suffering from malig- nancy^, 11-13,15,25] or leukaemia[ll,13], alcohol- ics^, 10,24,25], the immunosuppressed[15,23-25] and those on renal dialysis[8,14,24], Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 19 Table 1 shows the portal of entry of the causal organism in the 582 episodes of IE included in the British Cardiac Society/Royal College of Physicians Research Unit sur- vey. In 349 no portal of entry was apparent, while in the remaining 233 a variety of explanations appeared likely; 108 were possibly dental in origin, while 109 arose from the gastrointestinal tract, the genito-urinary tract, the respiratory tract, or the skin, or from nosocomial infec- tion resulting from procedures involving access to the blood-stream. Smaller numbers were attributable to nar- cotic addiction, fractures and pregnancy or parturition. Other writers have reported similar findings[5,9,11- 15,16,23-27], The success of efforts to reduce the incidence of and mortality from IE is greatly prejudiced by the fact that in three-fifths of the patients there is no hint as to how the causal organism gained access to the blood-stream. Since Horder's[28] classic paper three-quarters of a century ago, dental sepsis and dental procedures have been thought frequently responsible. Cates and Christie[3] thought the teeth were the culprit in nearly one-quarter of their 442 patients and it has long been considered neces- sary to give antibiotic prophylaxis to anyone with known rheumatic or congenital heart disease to cover any dental procedure they may undergo. This has not proved as satisfactory as was hoped. Thousands and thousands of dental procedures are carried out every day under widely differing circumstances and the fact that the patient has a cardiac lesion may be easily forgotten or not known, or the antibiotic may be incorrectly administered or cor- rectly administered and ineffectual[25,29]. Recent re- ports^,6,10,13,14,30] have indicated that a dental source for the infection is less frequent than hitherto and the British Cardiac Society/Royal College of Physicians Re- search Unit survey[25] showed only 11.7 per cent of 544 episodes of IE possibly due to dental procedures and 7.1 per cent possibly due to dental sepsis but of these patients 42.5 per cent were not known to have any pre-existing heart disease. They recommended prophylactic antibiotic cover for all those with known cardiac disease as suggested by the British Society for Antimicrobial Chemotherapy[31], but stressed the importance of en- couraging people to seek better routine dental care. It is even more unrealistic to hope to prevent episodes of IE of gastrointestinal, genito-urinary, respiratory or dermal origin or those associated with fractures, preg- nancy and parturition. Cases so caused are very few, especially when considered in the light of the enormous number of surgical and investigative procedures carried out on the gastrointestinal, genito-urinary and respirat- ory tracts, the common infections, tumours and other lesions in these organs and the very frequent breaches of the skin surface which most people experience, all of which could act as the portal of entry. Added to these difficulties is the increasingly recog- nised fact that in about one-third of cases of IE the infection appears to attack previously normal hearts. The scope for effective prophylaxis is therefore limited but the susceptibility of those with rheumatic or congenital cardi- ac abnormalities, calcific aortic stenosis, prosthetic valves, previous other cardiac surgery, previous attacks of IE, who are immunosuppressed or on dialysis, who are diabetics or addicted to drugs or alcohol, should be kept constantly in mind and for these groups antibiotic pro- phylaxis, as suggested by the British Society for Antimi- crobial Chemotherapy, should be considered whenever they are at risk. Acknowledgements We are greatly indebted to Fellows and Members of the College and to members of the British Cardiac Society for their co-operation and help in this project. References 1. Registrar-General's Statistical Review of England and Wales 1933- -? 73. 2. Office of Population Censuses and Surveys (1984) Mortality Statistics 1974-83, England and Wales. London: HMSO. 3. Cates, J. E. and Christie, R. V. (1951) Quarterly Journal of Medicine, 20, 93. 4. Hughes, P. and Gauld, W. R. (1966) Quarterly Journal of Medicine, 35, 511. 5. Shinebourne, E. A., Cripps, C. M., Hayward, G. W. and Shooter, R. A. (1969) British Heart Journal, 31, 536. 6. Lowes, J. A., Hamer, J., Williams, G., Houang, E., Tabaqchali, S., Shaw, E. W., Hill, I. M. and Rees, G. M. (1980) Lancet, 1, 133. 7 Hayward, G. W. (1973) British Medical Journal, 2, 706, 764. 8. Gray, I. R. (1975) Quarterly Journal of Medicine, 44, 449. 9. Smith, R. H., Radford, D. J., Clark, R. A. and Julian, D. G. (1976) Thorax, 31, 373. 10. Schnurr, L. P., Ball, A. P., Geddes, A. M., Gray, J. and McGhie, D. (1977) Quarterly Journal of Medicine, 46, 499. 11. Moulsdale, M. T., Eykyn, S. J. and Phillips, I. (1980) Quarterly Journal of Medicine, 49, 315. 12. Lerner, P. I. and Weinstein, L. (1966) New England Journal of Medicine, 274, 199, 259, 323, 388. 13. Cherubin, C. E. and Neu, H. C. (1971) American Journal of Medicine, 51, 83. 14. Pelletier, L. L. and Petersdorf, R. G. (1977) Medicine (Baltimore), 56, 287. 15. Oakley, C. M. (1980) British Journal of Hospital Medicine, 24, 232. 16. Petersdorf, R. G. and Goldman, P. L. (1979) Journal of Chronic Diseases, 32, 287. 17. Oram, S. (1981) Clinical Heart Disease. London: Heinemann. 18. Anonymous (1981) British Medical Journal, 282, 677. 19. Masur, H. and Johnson, W. D. (1980) Journal of Thoracic and Cardiovascular Surgery, 80, 31. 20. Communicable Disease Surveillance Centre, PHLS, unpublished. 21. Wilson, W. R., Jaumin, P. M., Danielson, S. K., Giuliani, E. R., Washington, T. A. and Geraci, T. E. (1975) Annals of Internal Medicine, 82, 751. 22. Oakley, C. M. (1982) British Medical Journal, 284, 995. 23. Gray, I. R. (1981) Journal of the Royal College of Physicians, 15, 173. 24. Bayliss, R. I. S., Clarke, C. A., Oakley, C. M., Somerville, W., Whitfield, A. G. W. and Young, S. E. J. (1983) British Heart Journal, 50, 513. 4 25. Bayliss, R. I. S., Clarke, C. A., Oakley, C. M., Somerville, W. and Whitfield, A. G. W. (1983) British Heart Journal, 50, 506. 26. Bayliss, R. I. S., Clarke, C. A., Oakley, C. M., Somerville, W., Whitfield, A. G. W. and Young, S. E. J. (1984) British Heart Journal, 51, 339. 27. Klein, R. S., Recco, R. A., Catalano, M. T., Edberg, S. C., a Casey, J. I. and Steigbigel, N.H. (1977) New England Journal of Medicine, 297, 800. 28. Horder, T. J. (1909) Quarterly Journal of Medicine, 2, 289. 29. Durack, D. T. and Littler, W. A. (1974) Lancet, 2, 846. 30. Pogrel, M. A. and Welsby, P. D. (1975) British Dental Journal, 139, 12. 31. Working Party of the British Society for Antimicrobial Chemo- therapy (1982) Lancet, 2, 1323. 20 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986

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Modern Methods of Diagnosis of Muscle Diseases R. H. T. EDWARDS, MB, FRCP* Professor of Medicine R. D. GRIFFITHS, MB, MRCP, Senior Lecturer, Department of Medicine M. HAYWARD, MD, FRCR Consultant Neurophysiologist, Department of Neurological Science T. HELLIWELL, MB, MRCPath, Senior Lecturer, Department of Pathology University of Liverpool, Royal Liverpool Hospital Muscle diseases are generally considered to be rare and therefore the province of the specialist. Yet there is no single specialty in medicine which sees all muscle dis- eases. At present patients with diseases or complaints referable to skeletal muscle find their way into the clinics not only of general physicians and neurologists but also those of rheumatologists, paediatricians, psychiatrists and orthopaedic surgeons. This is no surprise because skeletal muscle represents about 40 per cent (less in the diseases of muscle which result in wasting) of the body cell mass. Muscle does therefore reflect disorders in a variety of other body systems. The more a search is made for manifestations of disordered structure or function of muscle the more are changes found in diseases which are not at first sight classified as muscle diseases. Thus there are well-recognised changes of muscle structure or func- tion in endocrine disorders whether or not there is weakness[l]. Patients with psychogenic weakness or fa- tigue of the kind which has variously been termed 'effort syndrome', neurasthenia, Da Costa's syndrome or vaso- regulatory asthenia[2] may also have altered muscle mitochondrial function[3] which can result in excessive intracellular acidosis[4]. Skeletal muscle is not only the biological machine on which much of life and movement depends but it is also the tissue capable of the greatest range of alteration in its overall metabolic rate and most obviously related to the generation (and absorption) of mechanical forces. Not surprisingly, the factors that precipitate or aggravate muscle symptoms are those which pertain to energy exchanges or mechanical force. The 'machine' cannot be considered in isolation from its sophisticated control mechanisms, be they neural or metabolic. Because mus- cle is also the largest pool of protein in the body, those factors such as insulin, the sex hormones, prostaglandins ?r amino acids which influence protein metabolism in general also have an influence on size, structure or function of muscle. As yet the diseases of muscle in general and the inherited, progressive ones in particular (the dystrophies) tend to be named in 'syndrome' or descriptive terms, for example 'facioscapulohumeral muscular dystrophy' (FSH) with little knowledge of the underlying mechanism or explanation of the distribution of the pathological process except that the inheritance is clear (dominant in the case of FSH, see Fig. 1) and important for genetic counselling. New genetic studies will, it is hoped, help to explain why there is a high mutation rate in some muscular dystrophies (i.e. why so many patients have no family history) and confirm whether patients with the same clinical appearances have indeed got the same genetically determined disease. The inverse of this is whether there is a significant environmental influence on the course and distribution of the pathological processes, as suggested in the 'mechanical' hypothesis, to explain the largely proximal distribution of weakness in most myopathies[5]. Clearly the identification of the genetic defect in the dystrophies will have its most immediate and useful role in carrier detection and antenatal diagnosis[6]. With this background it is our purpose to present new developments in several fields that help in the diagnosis of muscle diseases. Some of these have been reviewed before[7] but this is a new appraisal of practical and cost- effective techniques we use in a clinical practice involving the diagnosis and management of paediatric and adult patients with muscle diseases. Needle Biopsy This technique is simple, harmless, rapid, and repeat- able. It is, in our opinion, now the ethical alternative to open biopsy for the diagnosis of muscle diseases. Coupled with histochemistry and electron microscopy it is a power- ful and cost-effective method of examining muscle for morphological and biochemical abnormalities with which there has now been years of experience[8]. The residual indications for open muscle biopsy are (a) motor point Correspondence to: Professor R. H. T. Edwards, FRCP. Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 49 biopsy for end-plate studies in myasthenia gravis, (b) the search for affected arteries in polyarteritis nodosa, (c) to obtain large samples of muscle for pharmacological inves- tigation in suspected malignant hyperthermia or to obtain samples for isolation of muscle mitochondrial]. Even here, recent developments in the needle biopsy technique make it possible to obtain adequate samples for such in vitro studies (Professor A. Stadthouders, Nijmegen, per- sonal communication[10]). The most common criticisms levelled against needle biopsy are of poor orientation of cross-sections and over-contraction of sarcomere struc- ture, and of not being sufficiently representative in heterogeneous (especially focal inflammatory) pathologi- cal conditions of muscle. These criticisms can now be countered in practice by orientating the specimen under a dissecting microscope before freezing and allowing the specimen for electron microscopy to 'relax' for some minutes before fixation. The problem of being represen- tative applies equally to an open biospy which is small in size in comparison with that of the muscle as a whole and which is usually more superficially located than a needle biopsy. This criticism can be countered by taking more than one needle biopsy through the same 4mm skin incision from widely separated superficial and deep sites in the muscle in those patients in whom a focal pathology is suspected. If this relatively atraumatic approach is unsuccessful in yielding the information sought, there are still left the options of repeating needle biopsies at a future date from another muscle or reverting to open biopsy from the same or some other muscle. In general the needle biopsy technique is sufficient to provide material for diagnosis and research and it is so valuable a diagnostic tool that it could (should) be carried out on all patients who are referred for diagnostic electro- physiology for suspected neuromuscular disease. Needle biopsy of muscle and histological techniques are aimed at defining the state of the contractile machine. Conventional histological procedures demonstrate that muscle cells respond to damage in only a limited number of ways: atrophy or damage, adaptation to chronic mechanical stress by hypertrophy or splitting, and by invasion (by inflammatory cells) or replacement with fat and fibrous tissues. Further information on the function of individual muscle fibres is obtained using frozen tissues and a variety of staining procedures in order to identify the activities of individual enzymes. In normal human muscle three different fibre types can be identified on the basis of their staining in the myosin ATPase reaction after pre-incubation at different pHs. Fibres in a given motor unit are all of one type and normal muscle consists of a mosaic of the different fibre types. In conditions resulting in denervation and reinnervation of muscle the mosaic pattern is lost and groups of fibres of one type are found. Distinction between fibre types is also important in the recognition of disorders that predominantly affect a par- ticular fibre type, e.g. congenital fibre type dispropor- tion, where the diagnosis is made solely on the presence of small type 1 fibres, and the large range of disorders showing selective atrophy of type 2 fibres, e.g. steroid, hypothyroid and alcoholic myopathies. Other enzyme stains which are part of the routine armament of the muscle pathologist include stains for oxidative enzymes which are useful for displaying the disordered internal architecture of the fibres seen in many diseases of muscle. An example is shown in Fig. 2 where pale areas in many fibres enabled a diagnosis of 'central core disease' to be made. Of recent interest is the identification of a variety of metabolic myopathies in which abnormal enzyme activities can be identified histochemically or biochemi- cally. The accumulation of substrates may give diagnostic clues, e.g. in type 2 glycogenosis (lysosomal acid maltase deficiency) there is increased muscle glycogen and in carnitine palmitoyltransferase deficiency there is in- creased lipid. Histochemical methods can also be used to assess the activities of specific enzymes. The best known example is that of McArdle's disease (type V glycogeno- sis) where the absence of myophosphorylase activity can be readily identified histochemically. Phosphofructokin- ase deficiency, which presents clinically in a similar way to McArdle's disease, can also be shown in biopsy specimens. Mitochondrial myopathies are conditions in which increased numbers of morphologically abnormal mitochondria are found in muscle fibres. This is best appreciated using electron microscopy but histologically a Muscle Clinic. I?Affected male. ? ? Unaffected male. ??Affected female. O?Unaffected female. 50 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 characteristic appearance of 'ragged red' fibres is seen on trichrome staining. Many different clinicopathological entities have been described which have this appearance on biopsy and, although they are presumed to be associ- ated with disordered oxidative metabolism, in only a few cases have specific enzyme defects been identified, e.g. cytochrome C oxidase deficiency[11]. Myoadenylate dea- minase (MAD) is another muscle enzyme whose de- ficiency may be of clinical significance. MAD deficiency was initially identified by routine screening of muscle biopsies[12] by workers who have suggested that de- ficiency may occur in up to 6 per cent of unselected biopsies. This has been disputed and experience in the UK[8,13] shows it to be far less common (<0.1 per cent), and indeed low levels can be found in other disorders, including Duchenne dystrophy. Clinically MAD-defi- cient patients suffer from mild exertional cramps but it is not clear to what extent these symptoms are related to the enzyme deficiency. Obviously there is great scope in the future for unravelling these metabolic myopathies and it may well prove practical to demonstrate them histologi- cally as well as biochemically. The recent revolution in general pathology following the introduction of immunohistological techniques and monoclonal antibodies has so far found limited appli- cation to muscle pathology. Its most significant appli- cation has been in elucidating the role of immune complexes and leucocytes in the polymyositis/dermato- myositis complex?immunoglobulins, complement and the various subclasses of T lymphocytes can now all be readily identified in cryostat sections[14,15]. Immunolo- gical methods for other components of muscle fibres, e.g. myoglobin, actin, myosin, and intermediate filaments are of limited diagnostic use except for the identification of the muscle origin of the various types of rhabdomyosar- coma. The main intermediate filament of muscle, des- min, is involved in forming the inclusion bodies of nemaline myopathy and is also increased in amount in regenerating cells[ 16]. Electron microscopy (EM) has a limited role in the diagnosis of muscle disorders. The ultrastructural changes seen tend to be non-specific and common to many human muscle disorders. The main use of EM is to confirm light microscopic findings of, for example, in- clusion bodies or abnormal mitochondria. Measurement of Muscle Function The determination of the force of maximum voluntary contractions or those elicited by electrical stimulation at different stimulation frequencies is now seen as valuable in the assessment of possible drug effects on muscle or to follow the time course of disease. Measurements with a hand-held 'myometer' can be a useful adjunct to a physiotherapist's charting of muscle strengthfl 7,18]. Ser- ial force measurements can be a useful guide to muscle breakdown and repair in conditions such as polymyosi- tis)^]. Electrical stimulation of muscle by an accessible motor nerve or percutaneously via large pad electrodes that stimulate the intramuscular nerves allows precise determination of the forces generated at different fre- quencies and the relaxation rate[20]. The maximum relaxation rate, determined as the first differential of the force signal, is a particularly useful measurement because it correlates closely with metabolism (determined as the heat production in the adductor pollicis)[21] both with ischaemia at rest and with fatiguing muscular activity. It is of great interest that these tests of muscle function vary with age, sex and nutritional status of the muscle[22,23] possibly due to effects of nutrition on the regulation of intracellular calcium concentration. Better known are the effects of endocrine disorders on muscle strength and relaxation rate[24], Ischaemic exercise of forearm mus- cles followed by venous blood sampling for lactate and ammonia can be a valuable screening test for distinguish- ing a glycolytic defect (producing no lactate) from myo- adenylate deaminase deficiency (producing no ammonia) with exercise[25], Electrophysiology Conventional electrophysiology contributes evidence based largely on recordings of action potentials that can help to establish whether the muscle wasting or weakness is primarily 'neuropathic' or 'myopathic'. Repetitive nerve stimulation is also a valuable test in the diagnosis of myasthenia gravis. New techniques involving computer analysis of the electrical recordings are now providing the opportunity to analyse the function of individual motor units. jrtSfcrVS Fig. 2. Needle biopsy of skeletal muscle showing features of 'central core disease' in a 16year old male with wasted muscles since birth (NADH + TR x 375). Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 51 Electromyographic techniques play an important part in the diagnosis of neuromuscular diseases and an in- creasing role in the understanding of the physiology of normal and abnormal muscle. With the introduction of special types of recording electrodes many new analytical techniques have been developed. The core of a single- fibre electrode (Fig. 3a) is 25 /zm in diameter, comparable to the diameter of a normal muscle fibre, and the electrode records selectively a very small number of fibres. This electrode is widely used to study 'jitter' of pairs of potentials (Fig. 4), a sensitive index of the stability of neuromuscular transmission[26J. Neuromus- cular transmission is disturbed in regenerating poten- tials^?] as well as in myasthenia gravis. A finding of abnormally low jitter occurs when muscle fibres are split[28]. By counting the frequency with which linked pairs of muscle fibres are recorded on random insertion into the muscle, the fibre density is measured, an index of the fine morphology of the muscle, increased in dystro- phies as well as in denervation[29]. The macro-electrode (Fig. 3b) is an adaptation of the original single-fibre electrode in which the proximal part of the shaft is insulated and the distal part left exposed. A single fibre potential recorded from the core is used to trigger an averager and the macro-potential is then averaged be- tween the exposed tip of the shaft and a remote surface electrode. The macro-potential is an indicator of the cross-sectional area of the motor unit[30]. The concentric needle electrode (Fig. 3c) has a core of 150 nm diameter and records motor unit potentials (MUP) from up to 12 of the closest fibres of an active motor unit[31]. This electrode remains the standard tool for diagnostic electromyography. Microprocessors are starting to make automatic measurement of MUP a reality in the clinical service department, bringing in- creased objectivity to the assessment of MUP[32]. In addition, computer modelling of MUP has given new understanding of the origin of the MUP and the conduc- tion of the potentials through the complex ionic environ- ment of the muscle[33,34]. The interpretation of MUP is expanding from the empirical associations of parameters with primary muscle disease or chronic denervation, established by the pioneers of the subject[35,36], to include the interpretation of those parameters in terms of the geometry of the electrical generators. The interpretation of interference patterns, the com- plex activity recorded in a muscle at stronger contraction effort when multiple MUPs are superimposed, requires automated methods of signal analysis in time or frequen- cy domains[37,38]. Methods of analysis which were developed with specifically designed hardware are now being implemented in general purpose microprocessors, making them much more readily available for diagnostic use. Analytical methods which deconvolute the interfer- ence pattern into its constituent potentials give additonal insight into the functioning of muscle but require very considerable computing power and are confined to a few research laboratories[39]. Magnetic Resonance Spectroscopy in the Study of Myopathy This is a new technique which offers much in the understanding of muscle energy metabolism and chemi- cal content. A typical 31P MR spectrum of normal muscle (Fig. 5) shows the key energy metabolites of phosphocrea- tine (PCr), adenosine triphosphate (ATP) and inorganic phosphate (Pi). It is now possible to study non-invasively this high-energy phosphate metabolism along with the intracellular pH of muscle. This has come about with the advent of wide-bore magnets and the application of high resolution magnetic resonance spectroscopy (MRS) using surface coils. In principle MRS is a method of obtaining information about the behaviour and content of nuclei in differing chemical environments through interrogation with weak radio-frequency pulses. Pioneering studies of topical 31P MRS in human muscle metabolism have come from C)xford[40-42), Philadelphia [43,44], and London[45,46], A recent re- view[47] discusses this new technology. The first clinical application of 31P MRS[48] was in a patient with McArdle's syndrome (myophosphorylase deficiency) in which lactic acid accumulation during ischaemic exercise is prevented by the failure of glycogenolysis. It was possible to show non-invasively the lack of an acid shift in the intracellular pH which normally occurs with lactic acid accumulation during ischaemic exercise. Phospho- fructokinase (PFK) deficiency is a more rare glycolytic defect which presents with a similar clinical picture as Fig. 3. Electrodes used for recording from muscle, a?single fibre electrode; b?macro-electrode; c?concentric needle elec- trode. Fig. 4. Pair of single fibres showing jitter. 52 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 myophosphorylase deficiency. The MRS findings are strikingly characteristic, with a steady accumulation of a 3lP sugar phosphate resonance during exercise, consistent with the level of the block in the glycolytic pathway. This MRS finding initially reported[45] and confirmed[44] in 1982 is illustrated in yet another patient (Fig. 6). The ability to repeat the measurements non-invasively enables changes with exercise to be followed (Fig. 7). By studying the kinetics of the metabolite changes it is possible to differentiate PFK deficiency from phosphoglyceratekin- ase deficiency[49]. Patients with mitochondrial myopathies have been studied[41,47,50]. At rest various abnormalities could be demonstrated of reduced PCr, high Pi, high calculated ADP, and in some abnormal intracellular pH. The kinetics of PCr metabolism, best seen in two patients with NADH-CoQ reductase deficiency[40] and in a defect in Pyruvate oxidation[51], show excessive PCr utilisation with exercise and slowed oxidative recovery. Excessive intracellular acidosis on exercise has been demonstrated by MRS in a patient with a post-viral fatigue syn- drome^]. The question whether a reduced energy state exists in Fig. 5. Typical 3,P MR spectrum of normal muscle showing the key energy metabolites of phosphocreatine (PCr), inorganic phosphate (Pi), and the three resonances of the phosphates of adenosine triphosphate (A TP). In the lower spectrum from the calf muscles a noticeable signal (PDi) is seen arising from the phosphodiesters. Sugar phosphate 2 *rtw(ui' 22.95 6.25 -/ & 'V^v'Vv Rest 0 min I i i I i i I i I 10 0 -10-20 PPM Fig. 6. Changes in energy metabolites with exercise in phospho- fructokinase deficiency. A large resonance in the phosphomones- ter region of the spectrum, left of the Pi signal, can be seen and represents the accumulation of the sugar phosphates before the enzyme block. Fig. 7. The energy metabolite changes in a similar study to Fig. 6, shown plotted as fractions of the total mobile phosphorus signal. With exercise there is a fall in PCr and rise in Pi but, due to the trapping of phosphate in glycolytic intermediates, the rise in Pi is small with a large accumulation of sugar phosphates. The absence of lactic acid production is shown by the normal intracellular pH. The slowed metabolite recovery following exercise is seen. Time min Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 53 dystrophic muscle has been studied by MRS, at rest and with exercise in boys with Duchenne muscular dystro- phy[52]. The considerable problems of tissue standardisa- tion, which complicate conventional analysis due to fat and fibrous tissue derangement of the muscle, have been addressed by a combination of 'H, 31P MRS and mor- phometry of needle biopsies. The ATP content was not reduced in the dystrophic muscle, and was not altered in a double-blind controlled trial of allopurinol. A lower PCr and higher Pi content was found indicative of a reduced phosphorylation potential, yet in a disease characterised by a massive leak of the enzyme creatine kinase no defect of intracellular activity of this enzyme could be demon- strated, with a normal oxidative PCr recovery. Proton 'H MRS offers exciting possibilities now that techniques to suppress the dominant water resonance have been developed[53]. The combination with 31P MRS[54] allows lactate measurement to be added to the phosphate metabolite information. The study of urinary organic acids with 'H and the measurement of carnitine and acyl-carnitines following carnitine infusion[55] open up the possibility of studying the disorders of fat metabo- lism in muscle, which so far by 31P MRS have proved difficult[56]. The ,3C techniques[57], along with 13C labelled glucose infusions[58], open up a large field of study, particularly that of glycolytic metabolism. As whole-body spectrometers (as in Oxford and shortly in Liverpool) become available, the study of a myopathy in relationship to other organ/system involvement will be a practical but expensive research and possibly diagnostic opportunity. Imaging of Skeletal Muscle It is obvious that a wasted muscle is weak but it is not so clear whether the muscle, whatever its size, can develop the force expected of it. What then is the force expected? It is proportional to the total cross-sectional area of the actomyosin interactions, which is only approximately proportional to the cross-section of the muscle as a whole. Since it is not possible to determine this from surface measurements (despite attempts to allow for the thickness of subcutaneous fat) there is interest in the use of modern imaging techniques, ultrasound (US)[59-61], X-ray com- puterised tomography (CT)[62] and magnetic resonance imaging (MRI)[63]. Each has its advantages and limita- tions but all can not only give an accurate measurement of the cross-section of the muscle but also an indication of the composition of the muscle (i.e. whether it has been replaced with fat or fibrous tissue as typically occurs in muscular dystrophy[62,64,65]). Radio-nucleide (e.g. 99m pyrophosphate) uptake in skeletal muscle is also a means of imaging muscle damage as in inflammatory myopathy[65] and following mechanical damage to muscle [66]. Conclusions Several techniques are now becoming available to visua- lise the structure, electrical properties, contractile capa- bilities and metabolism in human muscle. As diagnostic tools not one of them is uniquely sufficient but in combination they promise rational explanations for the disorders of muscle structure or function that are current- ly known in descriptive terms as syndromes. However, these new opportunities for studying muscle also yield more descriptive pathological and biochemical diagnoses (e.g. 'central core disease' or 'mitochondrial myopathy') which require further analysis. Accurate (or in practice 'as accurate as possible') diagnosis is necessary in this class of disease in which there are important differences in prognosis and inheri- tance. The new genetics, with the possibility of soon identifying the abnormal gene in the muscular dystro- phies, offer an important theoretical and practical tool to determine the precise genetic diagnosis both antenatally and for a patient as well as for genetic counselling. It should also help to resolve the question as to whether patients with apparently similar clinical appearances have indeed the same muscle disease. Variation in severity could be due to environmental (diet or exercise) influ- ences which might then be explored with possible thera- peutic benefit. The field of interest in clinical muscle science is advancing rapidly, with several developments in basic science and technology, and it is therefore with guarded optimism that we and others look to a more promising therapeutic future for this class of diseases for which there is currently little or no effective treatment. Acknowledgements The research which has established many of the new techniques developed by Professor Edwards' team has been generously supported by the Wellcome Trust and the Muscular Dystrophy Group of Great Britain. Gener- ous support from the Mersey Regional Health Authority in the form of research grants is also gratefully acknowl- edged. This article is based on a paper read at the College Regional Conference held at Liverpool in September 1985. References 1. Edwards, R. H. T., Khaleeli, A. A. and Mills, K. R. (1983) Seminars in Neurology, 3, 294. 2. Newham, D. and Edwards, R. H. T. (1979) Physiotherapy, 65, 52. 3. Mills, K. R. and Edwards, R. H. T. (1983)Journal of the Neurological Sciences, 58, 73. 4. Arnold, D. L., Bore, P. J., Radda, G. K., Styles, P. and Taylor, D. J. (1984) Lancet, 1, 1367. 5. Edwards, R. H. T., Newham, D. J., Jones, D. A. and Chapman S. J. (1984) Lancet, 1, 548. 6. Pearson, P. C. (1985) In Proceedings of the 23rd Symposium of the Society for the study of inborn errors of metabolism. 7. Edwards, R. H. T. (1984) Muscle and Nerve, 1, 599. 8. Edwards, R. H. T., Round, J. M. and Jones, D. A. (1983) Muscle and Nerve, 6, 676. 9. Morgan-Hughes, J. A. (1982) In Recent advances in clinical neurology (ed W. B. Matthews and G. H. Glaser) pp. 1-46. Edinburgh: Churchill Livingstone. 10. Gohil, K., Jones, D. A. and Edwards, R. H. T. (1981) Clinical Physiology, 1, 195. 11. DiMauro, S., Mendell, J. R., Sahenk, Z. et al. (1980) Neurology (N.Y.), 30, 795. 54 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 12. Fishbein, W. N., Armbrustmecher, V. M. and Griffin, J. L. (1978) Science, 200, 545. 13. Hudgson, P. (1983) Recent Advances in Rheumatology, 3, 117. 14. Isenberg, D. A. (1983) Quarterly Journal of Medicine, L.II, 297. 15. Oxenhandler, R. and Hart, M. N. (1983) Human Pathology, 14, 326. 1?- Thornell, L-E, Eriksson, A. and Edstrom, L. (1983) Cell and Muscle Motility, 4, 85. 17. Edwards, R. H. T. and McDonnell, M. (1974) Lancet, 2, 757. 18. Scott, O. M., Hyde, S. A., Goddard, C. and Dubowitz, V. (1982) Muscle and Nerve, 5, 291. 19. Edwards, R. H. T., Wiles, C. M., Round, J. M., Jackson, M.J. and Young, A. (1979) Muscle and Nerve, 2, 223. 20. Edwards, R. H. T., Young, A., Hosking, G. P. and Jones, D. A. (1977) Clinical Science and Molecular Medicine, 52, 283. 21. Wiles, C. M. and Edwards, R. H. T. (1982) Clinical Physiology, 2, 485. 22. Lopes, J., Russel, McL. D., Whitwell, J. and Jeejeebhoy, K. N. (1982) American Journal of Clinical Nutrition, 36, 606. 23. Lenmarken, C., Bergman, T., Larsson, J. and Larson, L-E. (1985) Clinical Physiology, 5, 243. 24. Edwards, R. H. T., Khaleeli, A. A. and Mills, K. R. (1983) Seminars in Neurology, 3, 294. 25. Sinkeler, S. P. T., Daanen, H., Wevers, R. A., Oei, T. L., Joosten, E. M. G. and Binkhorst, R. A. (1985) Muscle and Nerve, 8, 523. 26. Stalberg, E., Ekstedt,J. and Broman, A. (1972) Journal of Neurology, Neurosurgery and Psychiatry, 37, 540. 27. Schwartz, M. S., Stalberg, E., Schiller, H. H. and Thiele, B. (1976) Journal of the Neurological Sciences, 27, 303. 28. Ekstedt, J. and Stalberg, E. (1970) Electroencephalography and Clinical Neurophysiology, 27, 557. 29. Stalberg, E. and Thiele, B. (1975) Journal of Neurology, Neurosurgery and Psychiatry, 38, 874. 30. Stalberg, E. and Fawcett, P. R. W. (1982) Journal of Neurology, Neurosurgery and Psychiatry, 45, 870. 31. Thiele, B. and Bohle, A. (1978) Zeitschrift fur EEG-EMG, 9, 125. 32. Stalberg, E. and Antoni, L. (1983) Progress in Clinical Neurophysiology 10, pp. 186-234. (ed J. E. Desmedt.) Basel: Karger. 33. Wani, A. and Guha, S. (1980) Medical and Biological Engineering, 18, 719. 34. Andreassen, S. and Jorgensen, N. (1981) Electroencephalography and Clinical Neurophysiology, 52, 116S. 35. Kugelberg, E. (1949) Journal of Neurology, Neurosurgery and Psychiatry, 12, 129. 36. Buchthal, F., Guld, C. and Rosenfalck, P. (1959) Acta Physiologica Scandinavica, 32, 200. 37. Hayward, M. (1977) Journal of the Neurological Sciences, 33, 397. 38. Hayward, M. (1983) Progress in Clinical Neurophysiology, 10, pp. 128- 49. (edj. E. Desmedt.) Basel: Karger. 39. DeLuca, C.J., LeFever, R. S., McCue, M. P. and Xenakis, A. P. (1982) Journal of Physiology (Lond), 329, 113. 40. Radda, G. K., Bore, P. J., Gadian, D. G. et al. (1982) Nature, 295, 608. 41. Gadian, D. R., Radda, G. K., Ross, B. D. et al. (1981) Lancet, 2, 774. 42. Taylor, D. J., Bore, P. J., Styles, P., Gadian, D. G. and Radda, G. K. (1983) Molecular Biology and Medicine, 1, 77. 43. Chance, B., Eleff, S., Leigh, J. S. Jr., Sokolow, D. and Sapega, A. (1981) Proceedings of the National Academy of Sciences USA, 78, 6714. 44. Chance, B., Eleff, S., Bank, W., Leigh, J. S. Jr. and Warnell, R. (1982) Proceedings of the National Academy of Sciences USA, 79, 7714. 45. Edwards, R. H. T., Dawson, M. J., Wilkie, D. R., Gordon, R. E. and Shaw, D. (1982) Lancet, 1, 725. 46. Wilkie, D. R., Dawson, M. J., Edwards, R. H. T., Gordon, R. E. and Shaw, D. (1984), Contractile mechanisms in muscle Vol. II, pp.33- 347. (ed G. H. Pollack and H. Sugied.) New York: Plenum Press. 47. Edwards, R. H. T., Griffiths, R. D. and Cady, E. B. (1985) Clinical Physiology, 5, 93. 48. Ross, B. D., Radda, G. K., Gadian, D. G., Rocker, G., Esiri, M. and Falconer-Smith, J. (1981) New England Journal of Medicine, 304, 1338. 49. Dubac, D., Jehenson, P., Fardeau, M., Syrota, A. and Tran Dinh, S. (1985) Proceedings of the Society of Magnetic Resonance in Medicine, August 1985, pp.463-464. 50. Arnold, D. L., Taylor, D. J. and Radda, G. K. (1985) Annals of Neurology, in press. 51. Edwards, R. H. T., Griffiths, R. D., Radda, G. K. and Taylor, D. T. (1985) Proceedings of the Society of Magnetic Resonance in Medicine. August 1985, pp..1221-1222. 52. Griffiths, R. D., Cady, E. B., Edwards, R. H. T. and Wilkie, D. R. (1985) Muscle and Nerve, in press. 53. Williams, S. R., Gadian, D. G., Proctor, E., Sprague, D. B. and Talbot, D. F. (1985) Journal of Magnetic Resonance in Medicine, in press. 54. Williams, S. R., Gadian, D. G., Proctor, E., Sprague, D. B. and Talbot, D. F. (1985) Proceedings of the Society of Magnetic Resonance in Medicine, August 1985, pp.558-559. 55. lies, R. A., Chalmers, R. A., Jago, J. R. and Williams, S. R. (1985) ibid., pp.728-729. 56. Griffiths, R. D. and Edwards, R. H. T. (1985) In Subcellular Pathology: A biochemical approach to organelle damage, (ed T. J. Peters.) London: Chapman & Hall, in press. 57. Barany, M., Doyle, D. D., Graff, G., Westler, W. M. and Markley, J. L. (1984) Magnetic Resonance in Medicine, 1, 30. 58. Jue, T., Shulman, G. I., Alger, J. R., Arias-Mendoza, F., Rothman, D. L. and Shulman, R. G. (1985) Proceedings of the Society of Magnetic Resonance in Medicine, August 1985, pp. 6-7. 59. Cady, E. B., Gardener, J. E. and Edwards, R. H. T. (1983) European Journal of Clinical Investigation, 13, 469. 60. Heckmatt, J. Z., Leeman, S. and Dubowitz, V. (1982) Journal of Paediatrics, 101, 656. 61. Heckmatt, J. Z., Dubowitz, V. and Leeman, S. (1980) Lancet, 1, 1389. 62. Grindrod, S., Tofts, P. and Edwards, R. H. T. (1983) European Journal of Clinical Investigation, 13, 465. 63. Weinreb, J. C., Cohen, J. M. and Maravilla, K. R. (1985) Magnetic Resonance Imaging, 3, 199. 64. Jones, D. A., Round, J. M., Edwards, R. H. T., Grindrod, S. R. and Tofts, P. S. (1983) Journal of the Neurological Sciences, 60, 307. 65. Bulcke, J. A. L. and Baert, A. L. (1982) Clinical and Radiological Aspects of Myopathies, New York: Springer. 66. Newham, D. J., Tolfree, S. E. J. and Edwards, R. H. T. (1985) Clinical Science, 68, 76P. Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 55

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The Immunology of Cytomegalovirus Infection J. G. E .SISSONS, MD, FRCFJ Senior Lecturer in Medicine and Virology, Departments of Medicine and Virology, Royal Postgraduate Medical School, London Persistent virus infections are often advanced as possible causes for diseases of unknown aetiology. This is logical enough, given the evidence that persistent virus infections in animals, and in certain specific instances in humans, may indeed be associated with various chronic diseases. There are a number of possible strategies for pursuing research in this area: (a) to look for new viruses in diseases of unknown aetiology; (b) to ask whether a particular known virus is associated with a particular disease; (c) to endeavour to learn as much as possible about the biology of a given persistent virus, and see what one learns about its association with disease. Options (a) and (b) are relatively 'high risk', and while well worth pursuing, the third option is perhaps safer and will more predictably yield useful information. In the last few years we have been studying human cytomegalovirus (HCMV), attempting to understand how the virus persists in the normal host, and how perturbation of this relationship leads to disease. The Clinical Problem Primary infection with HCMV in the normal subject is usually asymptomatic but may be associated with the syndrome of infectious mononucleosis (about 10 per cent of infectious mononucleosis is said to be due to HCMV and associated with a negative monospot test). In immunosuppressed subjects, however, primary HCMV infection can produce severe illness, with dissemination and involvement of lungs, liver, gut, eye and other sites. In pregnancy, primary maternal infection is more likely to lead to congenital infection in the neonate than to reactivation of maternal infectionfl]. Following primary infection, -the virus persists in the host, as do the other herpes viruses. In contrast to herpes simplex and varicella zoster, which establish classical latency in neuronal cells, it now seems more likely that Epstein-Barr virus (EBV), and probably HCMV as well, may replicate at low level for much of the time in the healthy carrier without producing symptoms. EBV persists in B cells and prob- ably in oropharyngeal epithelial cells[2] but the exact site(s) at which HCMV persists in the normal infected individual is still uncertain. The virus probably persists in epithelial cells in the salivary gland and in the kidney; although it is commonly stated that HCMV persists in lymphocytes and/or macrophages, the hard evidence for this is lacking. Major reactivation and dissemination may occur if the host is immunosuppressed. Iatrogenic im- munosuppression in the context of organ or bone marrow transplantation has been the most frequent setting for severe HCMV infection, but HCMV is now also one of the most frequent causes of morbidity and death in patients with the acquired immunodeficiency syndrome (AIDS)[3], In many ways HCMV is the most enigmatic of the herpes viruses, and it is partly for this reason that it has been a 'soft candidate' for implication in diseases of unknown aetiology. HCMV has been rather speculative- ly associated with a number of such diseases, from atherosclerosis to disorders of the central nervous system. As with other herpes viruses, HCMV is also a candidate oncogenic virus and has been proposed as a cause of African Kaposi's sarcoma. These various disease associ- ations will all remain speculative until more convincing data emerge, particularly from careful DNA hybridisa- tion studies. Virology and Molecular Biology Some knowledge of the molecular virology of HCMV is an essential prerequisite to understanding its immunol- ogy and biology. HCMV is the largest of the human herpes viruses, with a linear double-stranded DNA gen- ome of about 235 kilobases (Fig.l). This has the capacity to code for up to 150 proteins but as yet the precise number and nature of these proteins is unresolved. However the complete nucleotide sequence of the virus will probably be known soon and this will enable much of the protein structure to be deduced from the primary sequence. Most work on the molecular biology of the herpes viruses has been done with herpes simplex, so more is known about it than about the other herpes viruses, for which it tends to serve as a prototype. As with other herpes viruses, synthesis of the virus- specified proteins occurs in a regulated cascade, expres- sion of one set of proteins being essential for expression of the next (Fig.l). The immediate early (IE) proteins are expressed shortly after the virus infects a cell. Some of them are 'trans acting factors' that can stimulate tran- scription of the genes for the virus IE proteins (see below), and, although this is presumably their true function, they can also stimulate transcription of inducible cellular genes[4]. Some of the IE proteins are DNA binding proteins, and the 'trans' refers to their ability to activate transcription from transcription units on duplex DNA other than that on which they themselves are encoded. The virus early proteins are then expressed: little is known of their function, but one of them is the virus DNA 40 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 polymerase. Unlike herpes simplex, HCMV does not encode its own thymidine kinase, and this explains its lack of sensitivity to acycloguanosine (Acyclovir). The next event is replication of the virus DNA, following which the > virus late proteins are expressed: the late proteins are the structural proteins of the virus particle. It is important to emphasise that the IE and early proteins are only ex- pressed in the infected cell and not in the virion particle itself, which is particularly pertinent when considering the specificity of the immune response. Little is known of the precise molecular events in the host which determine reactivation of latent virus, or affect the subsequent transcription of the virus genome, although they are likely to be of great importance in the pathogenesis of HCMV infection. Immunology The presence of serum antibody is used as a marker of infection with the herpes viruses (as it is for other viruses) and thus as evidence for the carriage of latent virus. Antibody is probably important in neutralising virus in the fluid phase and perhaps in diminishing the severity of primary infection. Yet immunoglobulin deficiency is not associated with particularly severe herpes virus infections, and reactivation occurs in seropositive subjects despite the presence of serum antibody. Hence it is generally assumed that T cell immunity is likely to be of more importance in controlling these large DNA viruses within the infected host. Evidence to back this assumption comes from the considerable body of work on EBV: normal subjects seropositive for EBV have a high frequency of memory cytotoxic T cells in their peripheral blood, which show specificity for EBV-transformed B cells. These T cells are presumed to play an important role in vivo by preventing the continued growth of EBV-transformed B cells[5]. In attempting to understand the immunological control of HCMV it seems more logical to examine T-cell responses in the asymptomatic persistently infected host rather than in patients with symptomatic HCMV infec- tion in whom such responses are presumably likely to be defective. In order to determine the nature and specificity of circulating memory T cells responding to HCMV in normal seropositive subjects, we used the technique of secondary in vitro stimulation with antigen and subse- quent expansion of the responding cells in interleukin-2 (IL-2) dependent culture. IL-2 is a growth factor released by stimulated T cells which permits the continued growth of antigen-activated T cells (and is in this sense an autocrine growth factor); this allows the accumulation of sufficient T cells for their function to be assessed and also permits attempts at their cloning[6]. We were especially interested to see if cytotoxic T cells specific for HCMV were present, because of the evidence on EBV already mentioned and because the role of this effector T cell has been particularly well studied in experimental models of virus infection[7]. We found that when peripheral blood mononuclear cells from seropositive subjects were stimulated in vitro with HCMV antigen, which consisted of virus particles, the T-cell lines generated were of helper (T4) phenotype and did not kill HCMV-infected target cells. However, if HCMV infected fibroblasts were used as the stimulating antigen, most of the responding T cells were of the T8 phenotype. These T cells were cytotoxic, killing HCMV- infected fibroblast targets and showing the property of HLA restriction; i.e. they would only lyse virus-infected target cells with which they shared class I MHC antigens, the hallmark of virus-specific cytotoxic T cells. They also killed cells which had been infected with HCMV for only six hours[8] (Fig. 2). These experiments suggested that there were memory T cells in the peripheral blood of normal seropositive people which were directed predomi- nantly at the virus early and/or immediate early proteins which are only expressed in the infected cell and not in the virus particle itself. In further experiments we found that such T-cell lines could lyse target cells treated with phosphonoformate, an inhibitor of the virus DNA poly- merase which prevents virus DNA replication and expres- sion of the late proteins (and is now incidentally marketed as a drug for the treatment of HCMV?Foscarnet). The experiment provides further evidence that T cells are directed to those proteins which are only expressed in the infected cell. In what are probably analogous results, it has recently been reported that a high proportion of cytotoxic T cells in mice infected with mouse CMV show HCMV DNA 11 110 1 235 Kb Ul Us ? Early proteins f Late proteins Fig. 1. Schematic view of genome and protein synthesis of human cytomegalovirus. The virus has a linear double-stranded DNA genome divided into long and short unique DNA sequences (UL and Us) which are each bounded by inverted repeat sequences. Within the infected cell the proteins specified by the virus are expressed in three sequential phases, the immediate early and early proteins are only expressed in the cell, and virus DNA replication cannot occur until they have been expressed. Following virus DNA replication the late proteins are expressed: they are the only proteins actually present in the virus particle. The times refer to the approximate timing of expression and progeny virus production in tissue culture. Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 41 specificity for the immediate early protein of that virus[9]. T cells with this sort of specificity could obviously provide a 'surveillance' mechanism for eliminating HCMV-infected cells before release of progeny virus, but more work will be needed to determine if this is what actually happens in vivo. There is work showing that HCMV-specific cytotoxic T cells may be detected directly in the peripheral blood of patients (bone marrow trans- plant recipients) with active HCMV infection, and that their presence correlates with recovery[10]. However, one problem with this sort of direct approach, without secondary stimulation in vitro, is that it is difficult to get enough cells to analyse their specificity for particular viral proteins. The existence of cytotoxic T cells does not necessarily imply that other T-cell-dependent mechanisms are unim- portant in host defence. Helper T-cell lines with similar specificity for the HCMV early proteins can also be established from normal seropositive subjects, as might be expected. In addition to providing help for the devel- opment of other effector T-cell responses, such helper cells could in theory have an effector function. T cells mediating delayed hypersensitivity (DH) are important in resistance to herpes virus infections in experimental models in micefll]; DH is probably mediated principally by helper T cells releasing gamma interferon which activates macrophages at the site. It is difficult to study DH in human systems because this would have to be done mainly in vitro, and so far we do not know how important it is in HCMV, or in any human virus infection. Non-Specific Immunity Natural killer (NK) cells are found among peripheral blood mononuclear cells and are so called for their ability to kill virus-infected (and tumour) cells without showing conventional immunological specificity or memory. Their cytotoxic activity is enhanced by interferons and by interleukin-2. The extent to which they are primarily of monocyte or T-cell lineage is uncertain: however, a proportion of NK cells do have T-cell markers, and the balance of current evidence favours their being more related to T cells. There is increasing evidence from experimental models that NK cells have a role in limiting the severity of virus infection in the period immediately following infection, particularly before the development of specific T-cell immunity; this has been shown better for mouse CMV infection than for other viruses[12]. We have also looked at the stage at which CMV infected cells become susceptible to being killed by natu- ral killer cells. We found that when CMV infected cells expressed the virus early antigens they became markedly more susceptible to being killed by NK cells[ 13] (Fig. 3). The actual target structures recognised by NK cells have not been defined, but are almost certainly not viral proteins; it is more likely that NK cells recognise some normal cell surface component whose expression is modi- fied or enhanced by the infecting virus[14]. The import- ance of NK cells in the containment of human virus infections remains to be determined, although it seems unlikely that it will be more than adjunctive to that of specific T-cell immunity. CMV and Immunosuppression There is experimental evidence that mouse CMV can exert immunosuppressive effects by infecting macro- phages. There is somewhat anecdotal clinical evidence that HCMV may also produce immunosuppression; it is said that patients with active HCMV infection are more prone to infection with other opportunists such as fungi. 50-| s3 25H 75% HLA Match .X JL 75% HLA Match HLA Mismatch 48 6h 48 6h 48h 6h j CMV infected targets J ? HSV infected targets | | Uninfected targets Fig. 2. An example of the specificity of a cytotoxic T-cell line established in response to HCMVfrom a normal seropositive donor, assessed by release of radioactive chromium from target cells. This T-cell line kills HCMV infected cells, including those which have only been infected for six hours, but does not kill herpes simplex virus infected cells. Only HLA-matched HCMV-infected cells are killed. 42 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 There have been more concrete reports of monocytes from patients with primary HCMV infection having a reduced ability to support the lectin-induced proliferation of human peripheral blood T cells[ 15]. We have exam- ined possible mechanisms by which HCMV might pro- duce such effects, by infecting monocytes with HCMV in vitro; these HCMV-infected monocytes were no longer able to produce interleukin-1 (IL-1) activity[16], IL-1 is required as a second signal for T-cell activation during antigen presentation, and has an increasingly recognised number of other biological activities[17], Further experi- ments showed that this loss of IL-1 activity was due to the release of an inhibitor of IL-1 from the virus-infected cells, abrogating the action of IL-1 on the responding cells[ 16] (Fig. 4). This IL-1 inhibitor appears to be a normal cellular protein whose release is induced by the virus. Despite this clear biological consequence of HCMV infection, the infected monocytes show no evi- dence of virus replication and there is little or no expres- sion of viral proteins, so the molecular mechanism of the effect remains uncertain. The whole question of the extent to which HCMV infects immunocompetent cells (lymphocytes and macro- phages) is controversial. It seems clear that normal resting lymphocytes and monocytes/macrophages do not replicate the virus but there are reports that expression of the CMV major IE protein occurs in a small proportion (a few per cent) of peripheral blood mononuclear cells, following their infection in vitro[ 18]. It is possible that such limited expression of virus proteins could have functional consequences, for instance by virtue of the 'trans acting' factors discussed above. However, it is important to emphasise that there is no firm evidence as yet that any of these cells are a normal site of latency for HCMV. In addition to these possible effects on macrophages, there is one report that HCMV can also act as a polyclonal B cell activator[19]. If confirmed it would be of considerable interest. Implications for Therapy In the absence, at least until very recently, of effective specific chemotherapy, there have been several alterna- 100-1 PBL Adhered 2h @ 37? Nylon wool column IFNa 1000u ml"1 18h @ 37? 6h 51Cr release assay (J 50 A ?I r~ Uninf IEA I -?? ? ? Fig. 3. Natural killer (NK) cells were prepared from peripheral blood lymphocytes (PBL) as shown on the left, using a interferon (IFNa) to enhance their killing capacity. Their ability to kill HCMV-infected cells was then assessed in a chromium release assay. HCM V-infected cells became more susceptible to being killed by NK cells at the stage when the virus early proteins or antigens (EA) were expressed. Uninf = uninfected; IEA = immediate early antigen; LA = late antigen. o x It u 3 CO a 3 8 c n ? <D 03 ? C s is ?? E > -C X 12 3 4 Time (days) Fig. 4. HCMV abolishes the production of interleukin-1 (IL- 1) activity from normal human monocytes. IL-1 activity was constitutively produced by normal monocytes maintained in culture for 1-4 days (A). Production of IL-1 was not affected by infection of the monocytes with heat-inactivated HCMV (O), but was abrogated by infection with live virus (See text forfurther details. Uninf = uninfected; Con A - concanavi- lin A; AH = heat inactivated. Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 43 tive approaches to the treatment of HCMV infection on which an understanding of the immunology of HCMV has some bearing. There has been considerable interest in the prophylactic and therapeutic use of human immuno- globulin containing antibody to HCMV. There is some evidence that its prophylactic administration to seronega- tive bone-marrow transplant recipients lessens the fre- quency and severity of primary HCMV infection in this susceptible population[20]. It has also been used for the treatment of HCMV disease but without conclusive evidence of its efficacy. Indeed, as severe HCMV disease, from reactivation, may occur in the presence of serum antibody, it would be surprising if administration of further antibody were particularly effective. There have also been attempts to develop HCMV vaccines. The 'vaccines' reported to date are derived from HCMV isolates that have been passaged in tissue culture and are used as live vaccines; it should be emphasised that there is no marker for determining attenuation in such viruses. They have been administered to susceptible seronegative subjects before renal trans- plantation but there is no conclusive evidence that they prevent infection with wild type HCMV[21]. There are theoretical objections to the use of live persistent virus vaccines that will presumably persist for life in the recipient and could conceivably have oncogenic potential. Therefore sub-unit vaccines (devoid of virus genetic material) seem a more attractive possibility, but their development demands a knowledge of which HCMV proteins are the relevant antigens. Finally, we do not know how effective any such vaccines are in inducing effector T-cell immunity, or indeed whether this matters for conferring immunity to primary infection. The best prospect for effective treatment for HCMV will almost certainly come from specific chemotherapy, and there are promising new antiviral agents such as the nucleoside analogue 9-( 1,3 dihydroxy-2-propoxy-methyl) guanine (DHPG). What is becoming clear, however, especially from the experience of treating patients with AIDS who have active HCMV disease, is that even specific chemotherapy is likely to be of limited value in the absence of an effective immune response. In these patients the HCMV disease is likely to recrudesce as soon as chemotherapy is stopped, emphasising the importance of intact T-cell immunity in containing virus replication at local sites and preventing dissemination. Using inter- leukin-2, attempts have been made to restore T-cell responses to HCMV in AIDS patients, but although IL-2 may improve their T-cell responses in vitro, it has not yet proved effective as an 'immunomodulator' in vivo[22\. There is clearly still much to be learned, particularly in molecular terms, about the relationship between HCMV and the persistently infected human host. New knowledge should tell us how HCMV produces the diseases we already suspect it of causing, and may perhaps reveal other hitherto unsuspected pathogenetic effects, as well as providing further basic information on the fascinating problem of virus persistence. Acknowledgements The work described above was carried out by Doctors L. K. Borysiewicz, B. D. Rodgers, and D. M. Scott, and with the aid of grants from the MRC and Wellcome Trust. J. G. P. Sissons is a Wellcome Trust Senior Lecturer. This article is based on a paper read at the Conference on Infectious Diseases held at the Royal College of Physicians in May 1985. ? References 1. Stagno, S., Pass, R. F., Dworsky, M. E. et al. (1982) New England Journal of Medicine, 306, 945. 2. Sixby, J. W., Nedrud, J. G., Raalo-Traub, N., Hanes, R. A. and Pagano, J. S. (1984) New England Journal of Medicine, 310, 1225. 3. Hirsch, M. S., Schooley, R. T., Ho, D. D. and Kaplan, J. C. (1984) Review of Infectious Diseases, 6, 726. 4. Everett, R. D. (1984) The Embo Journal, 3, 3135. 5. Rickinson, A. B., Yao, Q. Y. and Wallace, L. E. (1985) British Medical Bulletin, 41, 75. 6. Smith, K. A. and Ruscetti, F. W. (1981) Advances in Immunology, 31, 137. 7. Zinkernagal, R. M. and Doherty, P. C. (1979) Advances in Immunology, 27, 52. 8. Borysiewicz, L. K., Morris, S., Page, J. D. and Sissons, J. G. P. (1983) European Journal of Immunology, 13, 804. 9. Reddehase, M. J., Keil, G. M. and Koszinowski, U. H. (1984) European Journal of Immunology, 1, 56. 10. Quinnan, G. V., Kirmani, N., Esber, E. et al. (1981) Journal of Immunology, 126, 2036. 11. Nash, A. A. (1985) British Medical Bulletin, 41, 41. 12. Bukowski, J. F., Warner, J. F., Dennert, G. and Welsh, R. M. (1985) Journal of Experimental Medicine, 161, 40. 13. Borysiewicz, L. K., Rogers, S., Morris, S., Graham, S. and Sissons, J. G. P. (1985) Journal of Immunology, 134, 2695. 14. Borysiewicz, L. K., Graham, S. and Sissons, J. G. P. (1984) Immunobiology, 167, 182. 15. Carney, W. P. and Hirsch, M. S. (1981) Journal of Infectious Diseases, 144, 47. 16. Rodgers, B. C., Scott, D. M., Mundin, J. and Sissons, J. G. P. (1985) Journal of Virology, 54, in press. 17. Dinarello, C. A. (1984) Review of Infectious Diseases, 6, 51. 18. Rice, G. P. A., Schrier, R. D. and Oldstone, M. B. A. (1984) Proceedings of the National Academy of Sciences, 81, 6134. 19. Hutt-Fletcher, L. M., Balachandran, N. and Elkins, M. H. ? (1983) Journal of Experimental Medicine, 158, 2171. 20. Winston, D. J., Pollard, R. B., Ho, W. G. et al. (1982) Annals of Internal Medicine, 97, 11. 21. Plotkin, S. A., Friedman, H. M., Fleisher, G. R. et al. (1984) Lancet, 2, 528. 22. Rook, A. H., Masur, H., Land, C. et al. (1983) Journal of Clinical Investigation, 72, 398. 44 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986

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An Epidemiological Assessment of Neonatal Screening for Dislocation of the Hip IAN'LECK, MB, PhD, DSc, FRCP, FFCM Professor of Community Medicine, University of Manchester Screening for congenital dislocation of the hip was re- cently described in The Lancet as 'a mess'fl]. This article attempts to assess the deficiencies of screening by measur- ing it against the main criteria that any population-wide screening programme should meet. These criteria are that the disorder to be detected should be important and of known natural history and be best treated early, before the usual clinical time of presentation; the screening test should be accurate and safe, the treatment should be effective and its indications agreed; and both test and treatment should be practicable and worth the cost. In this article the term 'dislocation of the hip' (DH) will be used of cases in which the femoral head is either totally outside the acetabulum (luxation) or only in partial contact with it (subluxation); and the screening pro- cedures considered will be those undertaken to detect neonates who, if untreated, would present clinically with DH on one or both sides when they began to walk. Importance of DH Importance depends on frequency, severity and duration. As to frequency, records made before the introduction of screening suggest that, without it, DH would become clinically apparent in early childhood in 0.8-1.6 per 1,000 children born in Scandinavia, North America and the UK (the regions where most of the available data on screening originated). Much higher figures have been reported for Amerindian, Japanese and Lapp communi- ties whose methods of cradling or clothing infants tend to keep their hips extended and adducted (Fig. 1, left side). Severity is more difficult to quantify, but a DH that is severe enough to produce clinical signs in the infant or toddler will tend, if untreated, to lead to the formation of a false acetabulum, to degenerative changes, and to the knee joint problems and other consequences of limping caused by the affected leg being shorter than the other. The duration of these problems in the untreated is of course life-long. The dislocated hip may be even more important than these facts would suggest, since the cases that present in early childhood may be only the tip of an iceberg. The number of children with hips in which the signs of subluxation, laxity or other dysplasia can be elicited at birth greatly exceeds one per 1,000, and although many of these hips may become normal later, it is widely assumed that an 'unknown number . . . persist as dys- piasia or subluxation into adult life and ultimately be- come painful due to the development of secondary osteo- arthritis'^]. DISLOCATION reported in persons not screened neonatally NEONATAL INSTABILITY reported on screening 100 80- 60- 40- 20- 10 8 6-j 4 2-\ 11 0.8-1 7 (Cree-Ojibwa amerindians) . 5 (Navajo amerindians) O 9 AA 8, 10 (Australia) om 6, 2 ?A 4, 3 A 37 (Brittany) O## 46, 23, 42 ? A 11, 43 (New Zealand) ? 38 & 39 ? A 16.35 O# 36. 41 OO 28, 45 A 46 A 33 A A 15, 20 (New Zealand) ? ? 22, 34 OB 29, 11 O# A A A 47, 24, 8, 17, 40 (Australia) OO* 30, 31, 25 OA 49, if O 44 100 -80 -60 -40 20 -10 -8 -6 -4 -2 to, Fig. 1. Prevalence per 1, 000 (logarithmic scale) of clinically diagnosed dislocation of the hip(s) in populations not studied neonatally, and of neonatal instability of hip(s) in screened populations. Screened hips have been assumed to exhibit insta- bility if the published data were consistent with their being clinically dislocated or dislocatable. (Numbers show where sources appear in the list of references.) O = UK # = Scandinavia (excluding predominantly Lapp series) A = North America (excluding predominantly Amerindian series) ? = Japan A = Other 56 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 J Natural History of DH Epidemiological data suggest that DH has the natural history shown in Fig. 2 [ 13]. Most of the risk factors fall into two groups, one associated with decreases in the resistance of the hip to dislocation and the other with external constraints. The risk factors affecting resistance include shallowness of the acetabulum and a generalised laxity of connective tissue (both of which are reported to be relatively common in children with DH and their relatives) and the female genotype (which may make joints liable to become lax under the influence of ovarian hormones). The risk factors that may owe their effects to external constraints include at least three in which these constraints are likely to be prenatal (oligohydramnios, primigravidity?when the uterus is 'tighter' than sub- sequently?and breech presentation), one which may operate before and/or after birth (birth around the coldest time of year, which is when both women in late preg- nancy and newborn infants are most likely to be well wrapped up), and one with postnatal effects (membership ?f an ethnic group in which infants' legs are kept i extended and adducted; the prevalence of DH has fallen sharply in Japanese communities in which this practice has been abandonedf 11 ]). Most of the above risk factors that are likely to act prenatally appear to apply both to neonatal instability of the hips as detected by screening tests and to established DH in unscreened toddlers[14]. For this reason and because it seems inherently more likely that a hip which is dislocated or dislocatable at birth will remain abnormal than that a stable hip will become so, it is generally v assumed that the unstable hip of the neonate and the dislocated hip of the toddler are early and late stages of the same process?although the fact that neonatal insta- bility is almost always treated when found means that we have little direct evidence as to what happens if it is not. Two points, however, are well established from studies of children who have been screened for dislocated and dislocatable hips at birth. The first is that the prevalence of these abnormalities in screened neonates tends to be much higher than the prevalence of recognised DH in toddlers who were not screened at birth (Fig. 1). Second, most of the reports of screened populations (Fig. 1) make reference to children in whom hip abnormalities were not detected and treated as a result of screening but who were later diagnosed as having DH. In Fig. 3 the proportions of children in this category are plotted against the propor- tions in the same series in whom screening led to treat- ment. Like an earlier analysis reported by Parkin[51], Fig. 3 reveals no association between the frequency with which neonatal instability is treated and the prevalence of cases presenting late?suggesting that screening pro- grammes with a high yield of cases of instability have in general had no more success than those with a low yield in picking up infants at risk of lasting dislocation. However, the prevalence of late cases in nearly three-quarters of the screening studies was below the lower limit of the range for unscreened populations, even though the figures for late cases in some of these studies included children whose hips only appeared unstable a few months after birth and might never have progressed to established DH in early childhood. This evidence that treating neonatal instability pre- vents some cases of DH in early childhood provides further support for the view that these two conditions are early and late stages of the same process. However, the higher prevalence of neonatal instability in the screened than of childhood DH in the unscreened indicates that most cases of the former do not progress to the latter if left untreated. Presumably the cases most likely to progress are the most unstable and those in which there is most interference with hip flexion and abduction during infan- cy. There is probably more than one explanation for the finding that hips that appear stable in the neonate Fig. 2. Suggested natural history of 'congenital' hip dislocation. Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 57 sometimes manifest DH later. Sometimes abnormalities are present at birth which standard screening tests do not detect?notably irreducible dislocation?or which are missed because the observer is inexperienced; but there are also well-documented cases on record in which hips that an experienced examiner had found to be clinically stable at birth showed increasingly obvious dysplasia on radiological follow-up and eventually became dislocat- ed^]. In picturing the natural history of DH, we should therefore envisage some cases as developing de novo after birth, perhaps as a result of postnatal constraints interact- ing with a genetic predisposition in the way portrayed by the interrupted line in Fig. 2. One component of the genetic predisposition in these cases may be acetabular shallowness, to which the parents of children with estab- lished DH seem to be more predisposed than parents whose children's hips were unstable at birth[53]. It is not possible to estimate how many cases of DH involve hips that were stable at birth, although the data shown in Fig. 3 (which are confined to populations of European origin) could be interpreted as suggesting that careful neonatal screening can detect instability in a substantial majority of the 0.8-1.6/1000 infants in such populations who would develop DH if unscreened. In the higher-risk communities (e.g. in Japan) in which infants' legs are kept extended and adducted, we should expect screening to be less sensitive if such postnatal constraints can indeed lead to DH in initially stable hips. This expectation is borne out by a report that, in a series of Japanese infants of whom 2.7 per cent had DH according to a one-year follow-up, less than one-fifth of this 2.7 per cent had shown signs of instability one week after birth[27]. Best Time for Treatment of DH The question whether DH is best treated earlier than the time at which unscreened cases present ignores the neonates whose hips are unstable at birth but would stabilise later even if not treated, and focuses our atten- tion on those who, without treatment, would present with clinical DH as toddlers. If splinting in abduction, the recommended early treatment, is effective, they must clearly stand to benefit by receiving this treatment, partly because otherwise their hips will become more abnormal, and also because neonatal treatment is less radical than the alternative later treatment, probably carries less risk of ischaemic necrosis of the femoral head (the main hazard of later treatment)[51], and comes at a time when it is likely to have less impact on the physical and psychosocial development of the child and on family life. Accuracy of Neonatal Screening for DH Although radiographic and clinical methods have both been advocated for neonatal screening, radiography can- not really be regarded as suitable for general use, given its hazards and the fact that the head of the femur and much of the pelvis are not yet ossified. The most widely used clinical procedure has two parts. The first is the Ortolani test of abducting the flexed thigh, which is designed to enable the already dislocated hip to be detected by causing the femoral head to slip into the acetabulum, when a 'clunk' should be felt or heard. The second part, introduced by Barlow to identify unstable hips which the Ortolani test misses because they are not already dislocat- ed, is to see whether dislocation followed by reduction can be detected if one presses first on the lesser trochanter and then on the greater while holding the thigh in 90? of flexion and 45? of abduction. It is debatable how accurately these signs pick out unstable hips. Some workers[49,54] have argued that the other clicks and grating sensations which these ma- noeuvres sometimes cause should also be accepted as evidence of instability, although this view is not generally held[l,55]. However, it seems beyond debate that these tests for dislocation and dislocatability are far from accurate in identifying future cases of established DH, given that the latter are far less common than are positive tests (Fig. 1) and sometimes arise in infants in whom the tests were negative (Fig. 3). The figures which these results yield for the standard indices of accuracy?sensi- tivity, specificity, and predictive value of a positive test? are of course very variable, because of the wide variations in the frequency both of positive tests and of 'false negatives' (negative tests in infants who are later found to have DH). Table 1 shows estimates of accuracy for what may be regarded as the best available recent English data, based on prolonged follow-up of a large series of Bristol infants screened by a teaching unit with particular exper- ? CO .<2 -C "O t E ^ O o -5 ? ? O ^ CO = 3- CD CD <U ? "5 S ro CD g *- T3 3.0- 2.0- 1.0- 0.8- 0.6- 0.4- 0.3- 0.2- 0.1 - 0.08- 0.06- P = 0.044 ? 5? 035 Infants treated for neonatal hip joint instability (per 1000 births) Fig. 3. Prevalence of infants in screened British, Scandina- vian, North American and Australasian populations who were not treated for neonatal instability of the hip but in whom DH was diagnosed later, plotted against proportions of infants who were so treated (logarithmic scales). Cases described as being of dysplasia alone have been excluded. (Numbers show where sources appear in the list of references.) 58 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 Table 1. Indices of accuracy yielded by a series of 23,002 screened Bristol children[48], given the assumption that DH occurs in 1.25/1,000 unscreened children (midpoint of range for non-Lapp populations of European origin in Fig. 1). Screening test result Total Positive Negative Prognosis if not treated: Dislocation 19 10 29 No dislocation 426 22,547 22,973 Total 445 22,557 23,002 Sensitivity = ||= 66% Specificity = 22973 = 98 Odds against developing established dislocation, given a positive test result, = 19:426 = 1:22. tise in this field[48,55], The most disappointing of these figures is the estimate that even in such a favourable setting the test yields as many as 22 false positive results for every one true positive. The reason for this figure being so large when sensitivity and specificity are as high as 66 per cent and 98 per cent respectively is the relatively low prevalence of DH; with a test of this accuracy the number of true positive results will only exceed the number of false positives for conditions affecting over 2.9 per cent of subjects. Safety of Neonatal Screening for DH It has been suggested that one of the manipulations involved in screening?the manoeuvre described by Bar- low for seeing whether the hip can be dislocated?may itself render some hip joints less stable[42]. Although this hypothesis has received very little attention, it should perhaps be borne in mind as a possible reason why there have been screened series in which the reported preva- lence of late-diagnosed cases of DH (Fig. 2), and even the proportions of all infants undergoing surgical operations for DH[9,30,49], exceeded the overall prevalence of DH in unscreened populations. A rigorous test of the hypoth- esis that screening (perhaps when inexpertly performed) can be harmful would be to screen but not treat a group of neonates so that they and an unscreened group could be compared for the subsequent prevalence of DH; but this would raise ethical problems. Indications for Treating Neonatal Hip Joint Instability The clinician who accepts both the possible benefits of early treatment and the limitations of early screening for DH faces a major problem. Should every neonate in whom the results of screening appear positive be immedi- ately subjected to some form of splinting in abduction, even though most of these neonates would not develop DH even if left untreated; or should the numbers treated unnecessarily be reduced by restricting splinting to those whose hips are still abnormal at some later date, even though the latter children may by this time be harder to treat? Not surprisingly, there is no agreed answer to this question. In 1981, Parkin[51] pointed out that different authorities had recommended policies of (a) immediate treatment of all cases with evidence of instability; (b) a few weeks' observation of all cases followed by treatment of those remaining abnormal; and (c) a combined ap- proach whereby those in whom screening provides evi- dence of spontaneous dislocation are treated immediately while those whose hips only appear dislocatable are observed for a few weeks and then treated if the abnor- mality persists. More recent papers indicate that the first two of these policies still have their advocates among experienced British workers[9,48]. Disagreement about the indications for treatment is also implicit in the above-quoted debate about the clinical signs that should be treated as evidence of instability. Even among the minority who accept as evidence not only signs that the hip is or can be dislocated but also other clicks and grating sensations, there are some who splint hips on the basis of such evidence alone[54] while others do no more initially in cases with the latter signs only than follow them up, splinting at a later stage those that then prove to be dislocated, dislocatable, or radiologically abnormal[49]. Effectiveness of Treatment of Neonatal Hip Joint Instability The treatment of neonatal instability of the hip joint has been advocated as a measure for preventing osteoarthro- sis^] as well as established dislocation of the hip. It is unlikely that we shall be able to evaluate its effectiveness against osteoarthrosis, much the commoner condition, until data based on follow-up of screened and unscreened populations for several decades become available. Even the success of neonatal treatment in preventing estab- lished dislocation of the hip cannot be fully evaluated, since there appear to have been no randomised clinical trials. The most that published data enable one to do (and this applies in a small number of studies only) is to examine the overall frequency of significant residual abnormalities in screened populations, including cases both in children given early treatment for instability and in other children. Table 2 shows the proportions of children in these studies whose residual abnormalities were apparently considered significant enough to be submitted to surgical operations. As will be clear from the final column of the table, it is questionable whether each figure relates to precisely the same surgical procedures: the procedures included in the Aberdeen statistics for operative treat- ment were not specified, and the papers from Edinburgh and Uppsala made no mention of adductor tenotomies. The most informative sets of results appear to be the two from England. Neither of these suggests that neonatal screening and treatment are highly effective: in the Mansfield series the proportion requiring surgery was Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 59 Table 2. Frequency of surgery for DH in screened populations. Place Proportion undergoing surgery (per 1000 total population) Population size Splinted as neonate Not splinted as neonate Total (No. in brackets) Nature of surgery (No.) Uppsala, Sweden[23] Aberdeen, Scotland[28] Edinburgh, Scotland[29] Aberdeen, Scotland[9] Bristol, England[48] Mansfield, England[49] 11,868 71,169* 31,961 53,033 23,002 7,864 0.25 0.42 0.67(8) Open reduction (2), closed reduction (6) 0.11 1.10 1.21(86) 'In-patient operative treatment' 0.22 0.13 .0.35(11) Surgical reduction (9), excision of limbus only (1), derotation osteotomy (1) 0.19 1.64 1.83(97) 'Operated on' 0.22 0.43 0.65(15) 'Open surgery' (7), adductor tenotomy (8) 0.25 1.14 1.40(11) Adductor tenotomy ( +open reduction in 1) 'Estimated number remaining through follow-up period. close to what might have been expected in the absence of screening, and even the proportion for Bristol (the centre of expertise from which the figures in Table 1 also came) only seems to have been halved by the screening pro- gramme. However, these findings may reflect more discredit on the screening procedure than on the treat- ment: in both the English series and in three of the others a substantial majority of the operations were carried out in children who had not been selected for splinting when originally screened. The different types of abduction splints have not been compared here because epidemiological data on their relative merits are lacking. However, the keeping of infants with unstable hips in double nappies, which has been advocated as an alternative to the use of special splints, seems to emerge as particularly ineffective from a recent report; when splinting was replaced by double nappies in Southampton, the percentage of cases respond- ing to treatment among those diagnosed by screening fell from 92 to 55[56]. Table 3. Health care costs of screening and not screening a population of 100,000 with a distribution like that estimated for the Bristol population in Tables 1 and 2, given unit costs based on British Columbia experience in 1981?2[57]. Type of care Number of recipients Cost (Canadian for each recipient for total population Requirements if screening is omitted Surgical treatment Requirements if screening is practised Screening Splinting Surgical treatment 125 100,000 1,935 65 Ratio of costs with screening to costs without screening = |' = 0-97:1 9,133 1.90 167 9,133 1,141,625 190,000 323,145 593,645 106,790 Practicability of Providing Screening and Treatment for Neonatal Hip Joint Instability For a screening programme to be practicable, it must have both the ability to reach those for whom it is intended and the resources to screen and, where neces- sary, treat them. These conditions are readily attainable by screening for DH in countries such as Britain where almost all births occur in hospitals, so that the neonates to be screened form a captive population, and staff are available who can be trained to carry out the screening. Cost of Providing Screening and Treatment for Neonatal Hip Joint Instability Estimates of the current financial costs of screening and splinting for neonatal instability and of surgical treatment for established DH in the UK are not readily available, but figures have been published for British Columbia in 1981?82[57 ] which can be used to make an approximate 60 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 J assessment of the relative health service costs of screening and not screening. When these figures are applied to the Bristol-based statistics in Tables 1 and 2, screening emerges as marginally more economical (Table 3). More than half the estimated health care costs associ- ated with screening are attributable to surgical treatment of children in whom early splinting either failed or was not carried out. However, the British Columbia workers assumed that the cost of surgical treatment per case for these groups was the same as for unscreened children with DH. If, as is possible, the former tended to require less treatment than the latter, or if the accuracy of screening or the effectiveness of splinting in early infancy were to improve, the financial advantages of screening could increase considerably. The converse is, of course, equally true. To try to quantify and compare the costs for infants and their families which policies of screening and not screening incur would involve many other aspects of life besides money. It could be that the two policies are as finely balanced in respect of these costs as in respect of the costs of health care; the main difference between the two policies in both cases may be that, with screening as compared to without, the costs are shared between many more individuals. Conclusions There seem to be four main problem areas in the field of neonatal screening and treatment for hip joint instability as currently practised. 1. False Positives. Most of the screened cases in which unstable hips are reported are 'false positives', at least in the sense that they would not present later with estab- lished DH if untreated. Although it is widely believed that these false positives have a predisposition to osteoarthro- sis, which may be reduced by treating the neonatal instability, this hypothesis has not been tested epidemio- logically. It is therefore at least possible that several infants? more than ten in many areas?suffer unneces- sary splinting for every one who benefits from this procedure. 2. False Negatives. The prevalence of 'false negatives' (cases in which a hip that appeared stable when screened !s later reported to be dislocated) in screened populations varies widely, but averages about half as much as the prevalence of DH in unscreened populations. In other words, the number of false negative results yielded by screening tests seems to be of the same order as the number of true positives. It is not known how often in these false negative cases instability is present but missed at birth and how often it develops later. 3- Treatment Policies. There are at least three questions about treatment on which experts differ. First, should the mdications for treatment include abnormal physical signs short of those accepted as manifestations of dislocation and dislocatability? Second, should treatment be started nnmediately in all in whom the relevant signs (however defined) are observed, or postponed for a few weeks and confined to those in whom signs persist? Third, what type of splint should be used? 4. Outcome of Early Treatment. Although there are some screened populations in which established DH is substan- tially less common than in the unscreened, there are others in which it is so common as to raise the possibility that, at least in some hands, one or more of the pro- cedures involved in screening may actually increase prevalence. The example of Bristol shows that, even at a centre of expertise, screening may do no more than halve the frequency of established DH and have negligible effects on health care costs. It should be noted that there are unanswered questions in all these four areas. Some of the more important of these questions?whether unstable hips other than those which would progress to established DH benefit from splinting in early infancy, and whether screening pro- cedures can themselves predispose to DH?may be ex- tremely hard to answer, the former because very long follow-up would be needed and the latter because of the ethical problem mentioned when the safety of screening was discussed. However, it should be possible to set up randomised clinical trials which would answer ethically and relatively quickly the three questions listed under 'treatment policies'. These trials should be designed to enable the costs and benefits of current neonatal screen- ing and treatment policies to be compared as comprehen- sively as possible. The costs and benefits of the best of these policies should then be compared with those of the policies of screening later in infancy and of not screening but treating DH when it presents clinically. 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