847
USA. In Germany, randomised controlled trials have In the
Netherlands, feelings about the absolute property right to one’s own body, and everything which derives from it, ran so high that the least obtrusive of serological surveys-a completely anonymous human immunodeficiency virus seroprevalence survey on leftover samples destined for waste-collection-was forbidden by become
next to
governmental
impossible.
decree. As
a
measure
of cultural
relativism in medical ethics, similar practices
were
in Britain
by officially condoned and encouraged bodies with at least the same degree of respectability.66 Medical journals have a tradition of championing ethical concerns. Their editors keep a wary eye on authors and ask for more details, even if it is stated that the project was approved by the local ethics committee and "informed consent" is mentioned in passing. Given this track record, the time might have come to debate where to draw the line on ethical and juridical interference with medical research. Thereby, the deep be haughtily dismissed as "the grousings by an odd researcher or two"? Ingelfmger4 long ago voiced the suspicion that, just as there are unethical physicians who might talk their patients into some treatment for personal gain or career motives, there might be the odd unethical ethicist who is making a career by slandering medicine for the same very human reasons. concern
of medical researchers should
not
A first item on the agenda for observational research is to question profoundly the notion that use of old notes and leftover material is in principle unacceptable unless informed consent is obtained or the research is judged to be of overriding public health importance. (The latter judgment is, naturally, the domain of certain committees that are strongholds for publicity conscious ethicists, lawyers, and the inevitable local politician.) Should we not ponder the inverse ruling, at least for the sake of argument and critical reflection: that all observational research in which the patient
is essentially a non-participant (since only administrative or material leftovers from normal medical care are used) should be free from constraints, save for the time-honoured guarantee of medical
confidentiality? This would include medical record linkage for the early detection of side-effects or unanticipated benefits of treatment, as well as retrospective serodiagnosis. When patients have to be approached anew to obtain additional information for the purpose of the research only, some fairly general rules might suffice, so long as no invasive procedures were contemplated. For randomised controlled trials, we might discuss instances in which the "informed consent" is not necessary, detrimental to the research, or only a lip-service to prevailing fashions. Finally, we might pause to question the wisdom of national medical ethics committees, as proposed by some British enthusiasts.9 Such committees will lead to further bureaucratisation of medical ethics, and
eventually to total alienation from bedside medicine. 10
1. Hill AB. Medical ethics and controlled trials. Br Med J 1963; i: 1043-49. 2. Chalmers TC, Frank CS, Reitman D. Minimizing the three stages of
publication bias. JAMA 1990, 263: 1392-95. 3. Chalmers I, Silverman WA. Professional and public double standards on clinical experimentation. Controlled Clin Trials 1987; 8: 388-91. 4. Ingelfinger FJ. The unethical in medical ethics. Ann Intern Med 1975; 83: 264-69. 5. Rothman KJ. The epidemiologist’s lament. Am J Publ Health 1981; 71: 1309-11. 6. Gill ON, Adler MW, Day NE. Monitoring the prevalence of HIV: foundations for a programme of unlinked anonymous testing in England and Wales. Br Med J 1989; 299: 1295-98. 7. Caplan AL. Is there an obligation to participate in biomedical research? In: Spicker SF, Alon I, de Vries A, Engelhardt HT, eds. The use of human beings in research. Dordrecht: Kluwer, 1988: 229-48. 8. Last JM. Guidelines on ethics for epidemiologists. Int J Epidemiol 1990; 19: 226-69. 9. Lock S. Monitoring research ethical committees. Br Med J 1990; 300: 61-62. 10. Siegler M. Ethics committees, decisions by bureaucracy. Hastings Cent Rep 1986; 16: 22-24.
MEDICALLY ASSISTED CONCEPTION This month, the House of Lords will be considering the Commons amendments to the Human Fertilisation and Embryology Bill-the final stages in the passage of the Bill before it receives Royal Assent. Then, for the first time in the UK, unlicensed research on human preimplantation embryos will become a statutory offence. However, provided a licence is issued, research with human preimplantation embryos up to 14 days after fertilisation will be permitted, within certain defined limits. The UK is the first country to introduce legislation to regulate this type of treatment and allow such research. However, the law has not been drafted hastily. When the Bill finally reaches the statute books, it will be the culmination of many years’ debate and discussion, brought to public awareness in 1978 with the birth of Louise Brown, the world’s first "test-tube baby", followed by the report of the Committee of Inquiry into Human Fertilisation and Embryology (the Warnock report) in 1984, and by several attempts to ban research on human preimplantation embryos, beginning with Enoch Powell’s Private Member’s "Unborn Children (Protection)" Bill later the same year. The stage is now set in the UK for licensed assisted conception treatment and research to proceed, within statutory guidelines. The hope is that this work will lead to advances in the rate of successful pregnancy following in-vitro fertilisation (IVF) and in associated techniques for the treatment of infertility, and also promote a better understanding of human gametogenesis, fertilisation, and embryogenesis. Research in this last area should ultimately lead to better methods of diagnosis and treatment for disorders caused by a failure to undergo these processes normally (eg, male infertility, miscarriage, and congenital abnormality) and to the development of new forms of
contraception. A report by
committee of the American Institute of Medicine and the National Research Council recommended that a similar system for monitoring and regulation of IVF and associated research should be introduced in the USA. However, the importance of the report extends beyond a recognition of the need for legislation and continued research-it also serves to highlight the need for input from the scientific community if the potential for improvement in IVF is to be realised. Thus, the committee, composed of many of the leading developmental biologists in the USA, has reviewed the current understanding of mammalian reproduction in a series of workshop papers. The report a
848
contains
substantial amount of information, derived primarily from mammalian research-gametogenesis, fertilisation and embryogenesis, implantation, and maternal recognition of pregnancy are all covered. The relevance of this basic research to both human IVF and the husbandry of domestic species is also described. The information is clearly presented, with suggestions that future research be concentrated in certain areas--eg, the role of growth factors in gametogenesis and embryogenesis; definition of the metabolic requirements of the preimplantation embryo at different stages; and identification of substances produced by preimplantation embryos that signal to the uterus and corpus luteum. The first successful birth following human IVF came as no great surprise to developmental biologists, for whom it represented little more than an extrapolation of work that had become routine in animals. The unique feature of assisted conception procedures, compared with other areas of medicine, is the unprecedented degree of cooperation that is required between the scientific and medical communities. The report emphasises that this cooperation must continue and extend if there are to be further developments in assisted conception. Research into clinical aspects of IVF holds only limited potential for advance, through improved methods for oocyte retrieval and ovarian hyperstimulation and an increased understanding of reproductive endocrinology. By far the greatest potential for advance lies in the area of developmental embryology, where the crucial importance of communication between clinicians and scientists must be recognised. Thus the report serves not only as a plea to the US Government to examine the need for legislation to regulate assisted conception, but also as a reminder of the need for continued scientific research, and for better communication between scientists and clinicians in order to improve its success. Legitimisation of this research is necessary so that government funds may be made available for the implementation of research projects with both animals and human preimplantation embryos. We must all recognise the danger that a lack of communication between those involved in clinical assisted conception and their basic research counterparts might push the clinical practice of IVF beyond the limits of its scientific foundations. a
1. Institute of Medicine. Medically assisted conception. National Academy Press, 1989.
Washington, DC:
IS CLUBBING A GROWTH DISORDER?
Gosney and colleagues lately suggested that finger clubbing may be linked to high growth hormone concentrations. They studied 60 patients with bronchial carcinomas and 13 control subjects; in this group the plasma growth hormone concentrations were significantly higher when clubbing was present than when it was absent. A relation between high concentrations of the hormone and hypertrophic osteoarthropathy, in which clubbing is almost invariably a prominent feature, was first proposed over twenty years ago,2 but subsequent studies showed only a poor correlation. One patient was described in whom hypertrophic osteoarthropathy was associated with replacement of the anterior pituitary by a large metastasis from a bronchial carcinoma.’ If there is an association between high growth hormone concentrations and finger clubbing it is surprising that clubbing is not a feature of acromegaly. There are two more reasons why the conclusions of Gosney et al need to be
carefully. First, their criteria for assessing finger clubbing were not precisely defined, so some patients may have been incorrectly designated as being clubbed or not clubbed. Second, the reported correlation between the growth hormone concentration and the presence of finger clubbing seems to be almost entirely attributable to 3 of the 21 patients with clubbing in whom the concentrations were very high. For many years the underlying mechanism of clubbing was thought to be vasodilatation in the tips of the digits8 rather than excessive growth of cellular tissue in the nail bed. This view was challenged by Pineda et al,9 who found that new bone formation as well as soft tissue changes were common in both fmger clubbing and hypertrophic osteoarthropathy. Dickinson and Martin10 proposed an alternative to growth hormone as a cause of these changes: they suggested that megakaryocytes and clumps of platelets might be preferentially streamed into the blood vessels of the digits and release platelet-derived growth factor. The resulting increased capillary permeability, fibroblast activity, and arterial smooth muscle hyperplasia could cause clubbing. Tumour necrosis factor alpha also promotes angiogenesis. Braegger et al11 note that high serum concentrations of this cytokine are seen in many of the conditions associated with clubbing and suggest that TNF could also be responsible for the increased vascularity of clubbed fingers. The bony changes in clubbed fingers described by Pineda et al have not been confirmed by other groups and further evidence concerning the relative importance of growth factors and vasodilators has come from careful angiographic studies carried out at necropsy.12 There were no differences in the number or length of the small arteries or veins in clubbed and unclubbed fingers and toes. The number of Suquet-Hoyer canals-the characteristic arteriovenous
assessed
of the nail beds- was the same in both groups. These findings suggest that the increased blood flow into clubbed fingers13 is due to vasodilatation rather than to hyperplasia of vessels in the nail bed. The nature of the vasodilator is still uncertain. Many contenders--eg, ferritin, prostaglandins, bradykinin, and 5-hydroxytryptamine-have been studied and shown to be irrelevant. In normal individuals the vasodilator is probably inactivated by the lungs and finger clubbing occurs only when this process is defective or is bypassed by a right-to-left shunt. Growth hormone is unlikely to act as a vasodilator and whether or not it has any role in the development of clubbing remains to be established. anastomoses
Gosney MA, Gosney JR, Lye M. Plasma growth hormone and digital clubbing in carcinoma of the bronchus. Thorax 1990; 45: 545-47. 2. Steiner H, Dahlback O, Waldenstrom J. Ectopic growth-hormone production and osteoarthropathy in carcinoma of the bronchus. Lancet 1.
1968 i: 783-85. 3.
Dupont B, Hoyer I, Borgeskov S, Nerup J. Plasma growth hormone and hypertrophic osteoarthropathy in carcinoma of the bronchus. Acta Med Scand 1970; 188: 25-30.
Riyami AM, Anderson EG. Hypertrophic pulmonary osteoarthropathy a clinical and biochemical study. Br J Dis Chest 1974; 68: 193-96. 5. Mukherjee SK. Growth hormone secreting carcinoma of the lung and hypertrophic osteoarthropathy. Age Ageing 1975; 4: 95-98. 6. Epstein O, Ajdukiewicz AB, Dick R, Sherlock S. Hypertrophic hepatic osteoarthropathy: clinical, roentgenologic, biochemical, hormonal and cardiorespiratory studies and review of the literature. Am J Med 1979;
4.
67: 88-92. 7. Bloom W. 8.
Pituitary implications in hypertrophic pulmonary osteoarthropathy. Ann Intern Med 1948; 29: 361-70. Shneerson JM. Digital clubbing and hypertrophic osteoarthropathy. the underlying mechanisms. Br J Dis Chest 1981; 75: 113-31.
USA. In Germany, randomised controlled trials have In the
Netherlands, feelings about the absolute property right to one’s own body, and everything which derives from it, ran so high that the least obtrusive of serological surveys-a completely anonymous human immunodeficiency virus seroprevalence survey on leftover samples destined for waste-collection-was forbidden by become
next to
governmental
impossible.
decree. As
a
measure
of cultural
relativism in medical ethics, similar practices
were
in Britain
by officially condoned and encouraged bodies with at least the same degree of respectability.66 Medical journals have a tradition of championing ethical concerns. Their editors keep a wary eye on authors and ask for more details, even if it is stated that the project was approved by the local ethics committee and "informed consent" is mentioned in passing. Given this track record, the time might have come to debate where to draw the line on ethical and juridical interference with medical research. Thereby, the deep be haughtily dismissed as "the grousings by an odd researcher or two"? Ingelfmger4 long ago voiced the suspicion that, just as there are unethical physicians who might talk their patients into some treatment for personal gain or career motives, there might be the odd unethical ethicist who is making a career by slandering medicine for the same very human reasons. concern
of medical researchers should
not
A first item on the agenda for observational research is to question profoundly the notion that use of old notes and leftover material is in principle unacceptable unless informed consent is obtained or the research is judged to be of overriding public health importance. (The latter judgment is, naturally, the domain of certain committees that are strongholds for publicity conscious ethicists, lawyers, and the inevitable local politician.) Should we not ponder the inverse ruling, at least for the sake of argument and critical reflection: that all observational research in which the patient
is essentially a non-participant (since only administrative or material leftovers from normal medical care are used) should be free from constraints, save for the time-honoured guarantee of medical
confidentiality? This would include medical record linkage for the early detection of side-effects or unanticipated benefits of treatment, as well as retrospective serodiagnosis. When patients have to be approached anew to obtain additional information for the purpose of the research only, some fairly general rules might suffice, so long as no invasive procedures were contemplated. For randomised controlled trials, we might discuss instances in which the "informed consent" is not necessary, detrimental to the research, or only a lip-service to prevailing fashions. Finally, we might pause to question the wisdom of national medical ethics committees, as proposed by some British enthusiasts.9 Such committees will lead to further bureaucratisation of medical ethics, and
eventually to total alienation from bedside medicine. 10
1. Hill AB. Medical ethics and controlled trials. Br Med J 1963; i: 1043-49. 2. Chalmers TC, Frank CS, Reitman D. Minimizing the three stages of
publication bias. JAMA 1990, 263: 1392-95. 3. Chalmers I, Silverman WA. Professional and public double standards on clinical experimentation. Controlled Clin Trials 1987; 8: 388-91. 4. Ingelfinger FJ. The unethical in medical ethics. Ann Intern Med 1975; 83: 264-69. 5. Rothman KJ. The epidemiologist’s lament. Am J Publ Health 1981; 71: 1309-11. 6. Gill ON, Adler MW, Day NE. Monitoring the prevalence of HIV: foundations for a programme of unlinked anonymous testing in England and Wales. Br Med J 1989; 299: 1295-98. 7. Caplan AL. Is there an obligation to participate in biomedical research? In: Spicker SF, Alon I, de Vries A, Engelhardt HT, eds. The use of human beings in research. Dordrecht: Kluwer, 1988: 229-48. 8. Last JM. Guidelines on ethics for epidemiologists. Int J Epidemiol 1990; 19: 226-69. 9. Lock S. Monitoring research ethical committees. Br Med J 1990; 300: 61-62. 10. Siegler M. Ethics committees, decisions by bureaucracy. Hastings Cent Rep 1986; 16: 22-24.
MEDICALLY ASSISTED CONCEPTION This month, the House of Lords will be considering the Commons amendments to the Human Fertilisation and Embryology Bill-the final stages in the passage of the Bill before it receives Royal Assent. Then, for the first time in the UK, unlicensed research on human preimplantation embryos will become a statutory offence. However, provided a licence is issued, research with human preimplantation embryos up to 14 days after fertilisation will be permitted, within certain defined limits. The UK is the first country to introduce legislation to regulate this type of treatment and allow such research. However, the law has not been drafted hastily. When the Bill finally reaches the statute books, it will be the culmination of many years’ debate and discussion, brought to public awareness in 1978 with the birth of Louise Brown, the world’s first "test-tube baby", followed by the report of the Committee of Inquiry into Human Fertilisation and Embryology (the Warnock report) in 1984, and by several attempts to ban research on human preimplantation embryos, beginning with Enoch Powell’s Private Member’s "Unborn Children (Protection)" Bill later the same year. The stage is now set in the UK for licensed assisted conception treatment and research to proceed, within statutory guidelines. The hope is that this work will lead to advances in the rate of successful pregnancy following in-vitro fertilisation (IVF) and in associated techniques for the treatment of infertility, and also promote a better understanding of human gametogenesis, fertilisation, and embryogenesis. Research in this last area should ultimately lead to better methods of diagnosis and treatment for disorders caused by a failure to undergo these processes normally (eg, male infertility, miscarriage, and congenital abnormality) and to the development of new forms of
contraception. A report by
committee of the American Institute of Medicine and the National Research Council recommended that a similar system for monitoring and regulation of IVF and associated research should be introduced in the USA. However, the importance of the report extends beyond a recognition of the need for legislation and continued research-it also serves to highlight the need for input from the scientific community if the potential for improvement in IVF is to be realised. Thus, the committee, composed of many of the leading developmental biologists in the USA, has reviewed the current understanding of mammalian reproduction in a series of workshop papers. The report a
848
contains
substantial amount of information, derived primarily from mammalian research-gametogenesis, fertilisation and embryogenesis, implantation, and maternal recognition of pregnancy are all covered. The relevance of this basic research to both human IVF and the husbandry of domestic species is also described. The information is clearly presented, with suggestions that future research be concentrated in certain areas--eg, the role of growth factors in gametogenesis and embryogenesis; definition of the metabolic requirements of the preimplantation embryo at different stages; and identification of substances produced by preimplantation embryos that signal to the uterus and corpus luteum. The first successful birth following human IVF came as no great surprise to developmental biologists, for whom it represented little more than an extrapolation of work that had become routine in animals. The unique feature of assisted conception procedures, compared with other areas of medicine, is the unprecedented degree of cooperation that is required between the scientific and medical communities. The report emphasises that this cooperation must continue and extend if there are to be further developments in assisted conception. Research into clinical aspects of IVF holds only limited potential for advance, through improved methods for oocyte retrieval and ovarian hyperstimulation and an increased understanding of reproductive endocrinology. By far the greatest potential for advance lies in the area of developmental embryology, where the crucial importance of communication between clinicians and scientists must be recognised. Thus the report serves not only as a plea to the US Government to examine the need for legislation to regulate assisted conception, but also as a reminder of the need for continued scientific research, and for better communication between scientists and clinicians in order to improve its success. Legitimisation of this research is necessary so that government funds may be made available for the implementation of research projects with both animals and human preimplantation embryos. We must all recognise the danger that a lack of communication between those involved in clinical assisted conception and their basic research counterparts might push the clinical practice of IVF beyond the limits of its scientific foundations. a
1. Institute of Medicine. Medically assisted conception. National Academy Press, 1989.
Washington, DC:
IS CLUBBING A GROWTH DISORDER?
Gosney and colleagues lately suggested that finger clubbing may be linked to high growth hormone concentrations. They studied 60 patients with bronchial carcinomas and 13 control subjects; in this group the plasma growth hormone concentrations were significantly higher when clubbing was present than when it was absent. A relation between high concentrations of the hormone and hypertrophic osteoarthropathy, in which clubbing is almost invariably a prominent feature, was first proposed over twenty years ago,2 but subsequent studies showed only a poor correlation. One patient was described in whom hypertrophic osteoarthropathy was associated with replacement of the anterior pituitary by a large metastasis from a bronchial carcinoma.’ If there is an association between high growth hormone concentrations and finger clubbing it is surprising that clubbing is not a feature of acromegaly. There are two more reasons why the conclusions of Gosney et al need to be
carefully. First, their criteria for assessing finger clubbing were not precisely defined, so some patients may have been incorrectly designated as being clubbed or not clubbed. Second, the reported correlation between the growth hormone concentration and the presence of finger clubbing seems to be almost entirely attributable to 3 of the 21 patients with clubbing in whom the concentrations were very high. For many years the underlying mechanism of clubbing was thought to be vasodilatation in the tips of the digits8 rather than excessive growth of cellular tissue in the nail bed. This view was challenged by Pineda et al,9 who found that new bone formation as well as soft tissue changes were common in both fmger clubbing and hypertrophic osteoarthropathy. Dickinson and Martin10 proposed an alternative to growth hormone as a cause of these changes: they suggested that megakaryocytes and clumps of platelets might be preferentially streamed into the blood vessels of the digits and release platelet-derived growth factor. The resulting increased capillary permeability, fibroblast activity, and arterial smooth muscle hyperplasia could cause clubbing. Tumour necrosis factor alpha also promotes angiogenesis. Braegger et al11 note that high serum concentrations of this cytokine are seen in many of the conditions associated with clubbing and suggest that TNF could also be responsible for the increased vascularity of clubbed fingers. The bony changes in clubbed fingers described by Pineda et al have not been confirmed by other groups and further evidence concerning the relative importance of growth factors and vasodilators has come from careful angiographic studies carried out at necropsy.12 There were no differences in the number or length of the small arteries or veins in clubbed and unclubbed fingers and toes. The number of Suquet-Hoyer canals-the characteristic arteriovenous
assessed
of the nail beds- was the same in both groups. These findings suggest that the increased blood flow into clubbed fingers13 is due to vasodilatation rather than to hyperplasia of vessels in the nail bed. The nature of the vasodilator is still uncertain. Many contenders--eg, ferritin, prostaglandins, bradykinin, and 5-hydroxytryptamine-have been studied and shown to be irrelevant. In normal individuals the vasodilator is probably inactivated by the lungs and finger clubbing occurs only when this process is defective or is bypassed by a right-to-left shunt. Growth hormone is unlikely to act as a vasodilator and whether or not it has any role in the development of clubbing remains to be established. anastomoses
Gosney MA, Gosney JR, Lye M. Plasma growth hormone and digital clubbing in carcinoma of the bronchus. Thorax 1990; 45: 545-47. 2. Steiner H, Dahlback O, Waldenstrom J. Ectopic growth-hormone production and osteoarthropathy in carcinoma of the bronchus. Lancet 1.
1968 i: 783-85. 3.
Dupont B, Hoyer I, Borgeskov S, Nerup J. Plasma growth hormone and hypertrophic osteoarthropathy in carcinoma of the bronchus. Acta Med Scand 1970; 188: 25-30.
Riyami AM, Anderson EG. Hypertrophic pulmonary osteoarthropathy a clinical and biochemical study. Br J Dis Chest 1974; 68: 193-96. 5. Mukherjee SK. Growth hormone secreting carcinoma of the lung and hypertrophic osteoarthropathy. Age Ageing 1975; 4: 95-98. 6. Epstein O, Ajdukiewicz AB, Dick R, Sherlock S. Hypertrophic hepatic osteoarthropathy: clinical, roentgenologic, biochemical, hormonal and cardiorespiratory studies and review of the literature. Am J Med 1979;
4.
67: 88-92. 7. Bloom W. 8.
Pituitary implications in hypertrophic pulmonary osteoarthropathy. Ann Intern Med 1948; 29: 361-70. Shneerson JM. Digital clubbing and hypertrophic osteoarthropathy. the underlying mechanisms. Br J Dis Chest 1981; 75: 113-31.
