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USA. In Germany, randomised controlled trials havebecome next to impossible. In the Netherlands,feelings about the absolute property right to one’s ownbody, and everything which derives from it, ran sohigh that the least obtrusive of serological surveys-acompletely anonymous human immunodeficiencyvirus seroprevalence survey on leftover samplesdestined for waste-collection-was forbidden bygovernmental decree. As a measure of cultural

relativism in medical ethics, similar practices wereofficially condoned and encouraged in Britain bybodies with at least the same degree of respectability.6 6

Medical journals have a tradition of championingethical concerns. Their editors keep a wary eye onauthors and ask for more details, even if it is stated thatthe project was approved by the local ethics committeeand "informed consent" is mentioned in passing.Given this track record, the time might have come todebate where to draw the line on ethical and juridicalinterference with medical research. Thereby, the deepconcern of medical researchers should not be

haughtily dismissed as "the grousings by an oddresearcher or two"? Ingelfmger4 long ago voiced thesuspicion that, just as there are unethical physicianswho might talk their patients into some treatment forpersonal gain or career motives, there might be theodd unethical ethicist who is making a career byslandering medicine for the same very human reasons.A first item on the agenda for observational research

is to question profoundly the notion that use of oldnotes and leftover material is in principle unacceptableunless informed consent is obtained or the research is

judged to be of overriding public health importance.(The latter judgment is, naturally, the domain ofcertain committees that are strongholds for publicityconscious ethicists, lawyers, and the inevitable localpolitician.) Should we not ponder the inverse ruling,at least for the sake of argument and critical reflection:that all observational research in which the patientis essentially a non-participant (since onlyadministrative or material leftovers from normalmedical care are used) should be free from constraints,save for the time-honoured guarantee of medical

confidentiality? This would include medical recordlinkage for the early detection of side-effects or

unanticipated benefits of treatment, as well as

retrospective serodiagnosis. When patients have to beapproached anew to obtain additional information forthe purpose of the research only, some fairly generalrules might suffice, so long as no invasive procedureswere contemplated. For randomised controlled trials,we might discuss instances in which the "informedconsent" is not necessary, detrimental to the research,or only a lip-service to prevailing fashions. Finally, wemight pause to question the wisdom of nationalmedical ethics committees, as proposed by someBritish enthusiasts.9 Such committees will lead tofurther 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 inEngland 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 ofhuman 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 CentRep 1986; 16: 22-24.

MEDICALLY ASSISTED CONCEPTION

This month, the House of Lords will be considering theCommons amendments to the Human Fertilisation and

Embryology Bill-the final stages in the passage of the Billbefore it receives Royal Assent. Then, for the first time inthe UK, unlicensed research on human preimplantationembryos will become a statutory offence. However,provided a licence is issued, research with human

preimplantation embryos up to 14 days after fertilisation willbe 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 Billfinally reaches the statute books, it will be the culmination ofmany years’ debate and discussion, brought to publicawareness in 1978 with the birth of Louise Brown, theworld’s first "test-tube baby", followed by the report of theCommittee of Inquiry into Human Fertilisation and

Embryology (the Warnock report) in 1984, and by severalattempts to ban research on human preimplantationembryos, 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 toadvances in the rate of successful pregnancy followingin-vitro fertilisation (IVF) and in associated techniques forthe treatment of infertility, and also promote a betterunderstanding of human gametogenesis, fertilisation, andembryogenesis. Research in this last area should ultimatelylead to better methods of diagnosis and treatment fordisorders caused by a failure to undergo these processesnormally (eg, male infertility, miscarriage, and congenitalabnormality) and to the development of new forms ofcontraception.A report by a committee of the American Institute of

Medicine and the National Research Council recommendedthat a similar system for monitoring and regulation of IVFand associated research should be introduced in the USA.

However, the importance of the report extends beyond arecognition of the need for legislation and continuedresearch-it also serves to highlight the need for input fromthe scientific community if the potential for improvement inIVF is to be realised. Thus, the committee, composed ofmany of the leading developmental biologists in the USA,has reviewed the current understanding of mammalianreproduction in a series of workshop papers. The report

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contains a substantial amount of information, derived

primarily from mammalian research-gametogenesis,fertilisation and embryogenesis, implantation, and maternalrecognition of pregnancy are all covered. The relevance ofthis basic research to both human IVF and the husbandry ofdomestic species is also described. The information is clearlypresented, with suggestions that future research beconcentrated in certain areas--eg, the role of growth factorsin gametogenesis and embryogenesis; definition of themetabolic requirements of the preimplantation embryo atdifferent stages; and identification of substances producedby preimplantation embryos that signal to the uterus andcorpus luteum.The first successful birth following human IVF came as

no great surprise to developmental biologists, for whom itrepresented little more than an extrapolation of work thathad become routine in animals. The unique feature ofassisted conception procedures, compared with other areasof medicine, is the unprecedented degree of cooperation thatis required between the scientific and medical communities.The report emphasises that this cooperation must continueand extend if there are to be further developments in assistedconception. Research into clinical aspects of IVF holds onlylimited potential for advance, through improved methodsfor oocyte retrieval and ovarian hyperstimulation and anincreased understanding of reproductive endocrinology. Byfar the greatest potential for advance lies in the area ofdevelopmental embryology, where the crucial importance ofcommunication between clinicians and scientists must be

recognised. Thus the report serves not only as a plea to theUS Government to examine the need for legislation toregulate assisted conception, but also as a reminder of theneed for continued scientific research, and for bettercommunication between scientists and clinicians in order to

improve its success. Legitimisation of this research is

necessary so that government funds may be made availablefor the implementation of research projects with bothanimals and human preimplantation embryos. We must allrecognise the danger that a lack of communication betweenthose involved in clinical assisted conception and their basicresearch counterparts might push the clinical practice ofIVF beyond the limits of its scientific foundations.

1. Institute of Medicine. Medically assisted conception. Washington, DC:National Academy Press, 1989.

IS CLUBBING A GROWTH DISORDER?

Gosney and colleagues lately suggested that finger clubbingmay be linked to high growth hormone concentrations.They studied 60 patients with bronchial carcinomas and 13control subjects; in this group the plasma growth hormoneconcentrations were significantly higher when clubbing waspresent than when it was absent. A relation between highconcentrations of the hormone and hypertrophicosteoarthropathy, in which clubbing is almost invariably aprominent feature, was first proposed over twenty yearsago,2 but subsequent studies showed only a poorcorrelation. One patient was described in whom

hypertrophic osteoarthropathy was associated with

replacement of the anterior pituitary by a large metastasisfrom a bronchial carcinoma.’

If there is an association between high growth hormoneconcentrations and finger clubbing it is surprising thatclubbing is not a feature of acromegaly. There are two morereasons why the conclusions of Gosney et al need to be

assessed carefully. First, their criteria for assessing fingerclubbing were not precisely defined, so some patients mayhave been incorrectly designated as being clubbed or notclubbed. Second, the reported correlation between the

growth hormone concentration and the presence of fingerclubbing seems to be almost entirely attributable to 3 of the21 patients with clubbing in whom the concentrations werevery high.

For many years the underlying mechanism of clubbingwas thought to be vasodilatation in the tips of the digits8rather than excessive growth of cellular tissue in the nail bed.This view was challenged by Pineda et al,9 who found thatnew bone formation as well as soft tissue changes werecommon in both fmger clubbing and hypertrophicosteoarthropathy. Dickinson and Martin10 proposed analternative to growth hormone as a cause of these changes:they suggested that megakaryocytes and clumps of plateletsmight be preferentially streamed into the blood vessels of thedigits and release platelet-derived growth factor. The

resulting increased capillary permeability, fibroblastactivity, and arterial smooth muscle hyperplasia could causeclubbing. Tumour necrosis factor alpha also promotesangiogenesis. Braegger et al11 note that high serum

concentrations of this cytokine are seen in many of theconditions associated with clubbing and suggest that TNFcould also be responsible for the increased vascularity ofclubbed fingers.The bony changes in clubbed fingers described by Pineda

et al have not been confirmed by other groups and furtherevidence concerning the relative importance of growthfactors and vasodilators has come from careful angiographicstudies carried out at necropsy.12 There were no differencesin the number or length of the small arteries or veins inclubbed and unclubbed fingers and toes. The number ofSuquet-Hoyer canals-the characteristic arteriovenousanastomoses of the nail beds- was the same in both groups.These findings suggest that the increased blood flow intoclubbed 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, and5-hydroxytryptamine-have been studied and shown to beirrelevant. In normal individuals the vasodilator is probablyinactivated by the lungs and finger clubbing occurs onlywhen this process is defective or is bypassed by a

right-to-left shunt. Growth hormone is unlikely to act as avasodilator and whether or not it has any role in the

development of clubbing remains to be established.

1. Gosney MA, Gosney JR, Lye M. Plasma growth hormone and digitalclubbing in carcinoma of the bronchus. Thorax 1990; 45: 545-47.

2. Steiner H, Dahlback O, Waldenstrom J. Ectopic growth-hormoneproduction and osteoarthropathy in carcinoma of the bronchus. Lancet1968 i: 783-85.

3. Dupont B, Hoyer I, Borgeskov S, Nerup J. Plasma growth hormone andhypertrophic osteoarthropathy in carcinoma of the bronchus. ActaMed Scand 1970; 188: 25-30.

4. Riyami AM, Anderson EG. Hypertrophic pulmonary osteoarthropathya clinical and biochemical study. Br J Dis Chest 1974; 68: 193-96.

5. Mukherjee SK. Growth hormone secreting carcinoma of the lung andhypertrophic osteoarthropathy. Age Ageing 1975; 4: 95-98.

6. Epstein O, Ajdukiewicz AB, Dick R, Sherlock S. Hypertrophic hepaticosteoarthropathy: clinical, roentgenologic, biochemical, hormonal andcardiorespiratory studies and review of the literature. Am J Med 1979;67: 88-92.

7. Bloom W. Pituitary implications in hypertrophic pulmonaryosteoarthropathy. Ann Intern Med 1948; 29: 361-70.

8. Shneerson JM. Digital clubbing and hypertrophic osteoarthropathy. theunderlying mechanisms. Br J Dis Chest 1981; 75: 113-31.