749

Letters to the Editor

EXPERIMENTS AT

THE WILLOWBROOK STATE SCHOOL

STEPHEN GOLDBY.The Radcliffe Infirmary,

Oxford OX2 6HE.

SIR,-You have referred to the work of Krugman andhis colleagues at the Willowbrook State School in threeeditorials. In the first article 2 the work was cited as anotable study of hepatitis and a model for this type ofinvestigation. No comment was made on the rightness ofattempting to infect mentally retarded children with hepa-titis for experimental purposes, in an institution where thedisease was already endemic.The second editorial 3 again did not remark on the ethics

of the study, but the third 4 sounded a note of doubt asto the justification for extending these experiments. Thereason given was that some children might have been mademore susceptible to serious hepatitis as the result of theadministration of previously heated icterogenic material.

I believe that not only this last experiment, but the wholeof Krugman’s study, is quite unjustifiable, whatever theaims, and however academically or therapeutically impor-tant are the results. I am amazed that the work was pub-lished and that it has been actively supported editorially bythe Journal of the American Medical Association 5 and byIngelfinger in the 1967-68 Year Book of Medicine. To myknowledge only the British Journal of Hospital Medicine 7has clearly stated the ethical position on these experimentsand shown that it was indefensible to give potentiallydangerous infected material to children, particularly thosewho were mentally retarded, with or without parentalconsent, when no benefit to the child could conceivablyresult.Krugman and Giles have continued to publish the

results of their study, and in a recent paper 8 go to somelength to describe their method of obtaining parental consentand list a number of influential medical boards and com-mittees that have approved the study. They point outagain that, in their opinion, their work conforms to theWorld Medical Association Draft Code of Ethics onHuman Experimentation.9 They also say that hepatitis isstill highly endemic in the school.This attempted defence is irrelevant to the central issue.

Is it right to perform an experiment on a normal or men-tally retarded child when no benefit can result to thatindividual ? I think that the answer is no, and that the

question of parental consent is irrelevant. In my view thestudies of Krugman serve only to show that there is a seriousloophole in the Draft Code, which under General Principlesand Definitions puts the onus of consent for experimenta-tion on children on the parent or guardian. It is this sectionthat is quoted by Krugman. I would class his work as

" experiments conducted solely for the acquisition of

knowledge ", under which heading the code states that" Persons retained in mental hospital or hospitals formental defectives should not be used for human experi-ment ". Krugman may believe that his experiments werefor the benefit of his patients, meaning the individualpatients used in the study. If this is his belief he has adifficult case to defend. The duty of a paediatrician in asituation such as exists at Willowbrook State School is toattempt to improve that situation, not to turn it to his

1. Krugman, S., Giles, J. P., Hammond, J. J. Am. med. Ass. 1967, 200,365.

2. Lancet, 1969, ii, 577.3. ibid. 1970, ii, 347.4. ibid. March 6, 1971, p. 487.5. J. Am. med. Ass. 1967, 200, 406.6. Yb. Med. 1967-68, p. 429.7. Hosp. Med. 1968, 2, 759.8. Krugman, S., Giles, J. P. J. Am. med. Ass. 1970, 212, 1019.9. Br. med. J. 1962, ii, 1119.

advantage for experimental purposes, however lofty theaims.

Every new reference to the work of Krugman and Gilesadds to its apparent ethical respectability, and in my viewsuch references should stop, or at least be heavily qualified.The editorial attitude of The Lancet to the work should bereviewed and openly stated. The issue is too important tobe ignored.

If Krugman and Giles are keen to continue their experi-ments I suggest that they invite the parents of the childreninvolved to participate. I wonder what the responsewould be.

* * * Dr. Goldby asks The Lancet a question it ought tohave faced long ago. The journal’s eagerness to discuss allthe events in the elucidation of the spread of hepatitis leftit exposed to these criticisms, which we accept. TheWillowbrook experiments have always carried a hope thathepatitis might one day be prevented there and in othersituations where infection seems almost inevitable; butthat could not justify the giving of infected material tochildren who would not directly benefit. Dr. Krugmanand Dr. Giles argue that " the artificial induction of

hepatitis implies a ’ therapeutic’ effect because of the

immunity which is conferred ". It is hard to accept thatview, even when applied to a school where a very highproportion of children will, in existing conditions, beinfected anyway.-ED. L.

DEXAMETHASONE TREATMENT IN

HERPES-SIMPLEX ENCEPHALITIS

SIR,-It was very interesting and most encouraging toread the report by Dr. Upton and his colleagues (Feb. 6,p. 290) that acute necrotising encephalitis could be favour-ably influenced by the prompt administration of dexa-methasone. We nevertheless feel that a word of warning isopportune. The effect of cortisone on the evolution of viraldisease is a matter of controversy. There is experimentalproof that it will inhibit both the production of interferon 1and of viral antibodies. 2 In animals there is little doubtthat steroids often lead to the exaltation of virus virulence. 3,4It is true that clinical experience has not always borne outthe dire forebodings of virologists, yet it is also true that,with particular reference to herpes-simplex virus infection,the exhibition of steroids has often led to a worsening ofthe disease and occasionally disastrous results.5-9 It mayof course be that the special circumstances of brain-tissueinfection invalidates these arguments and that the claimof your correspondents will be substantiated.We would also like to raise our voice in objection to what

we believe to be unjustified criticism of idoxuridine (I.D.U.)by Dr. Upton and his colleagues. We concede that this

drug is far from ideal, but it is wrong to ascribe the highmortality of acute necrotising encephalitis to its use: thedisease had an extremely poor prognosis in the days long1. Kilbourne, E. D., Smart, K. M., Pokorny, B. A. Nature, 1961,

190, 650.2. Imman, Z. E., Hammon, W. Proc. Soc. exp. Biol. Med. 1957,

95, 6.3. Coid, C. R., Tobin, J. O’H., Beswick, T. S. L. J. Path. Bact.

1960, 79, 325.4. Kilbourne, E. D., Wilson, C. B., Perrier, D. J. clin. Invest. 1956,

35, 362.5. Bernheim, M., Sohier, R., Larbre, F., Riffat, C. Revue lyonn. méd.

1958, 7, 877.6. Osterhout, S., Hudnell, A. B. Clin. Res. 1963, 11, 211.7. Spirito, L., Braito, A. G. Mal. infett. parassit. 1966, 18, 763.8. Montgomerie, J. Z., Becroft, D. M. O., Croxson, M., Doak, P. B.,

North, J. D. K. Lancet, 1969, ii, 867.9. Longson, M., M.D. thesis, University of Manchester, 1970.

750

before viral chemotherapy.9 9 There is no evidence that theacute toxic effects of i.D.u. are anything but transient.9-11In our hands the changes in liver function and blood, andthe damage to skin appendages, produced by the drug in adose of up to 500 mg. per kg. body-weight have been onlytemporary. It is true that the volume of fluid required toinfuse the very insoluble drug may present a particularproblem in the management of a patient with cerebraloedema; in such cases it may well be that cytarabine 12will prove to be a better choice. In our very limitedexperience the intravenous injection of this substance inamounts of up to 25 mg. per kg. body-weight, in divideddoses, appears safe.

MAURICE LONGSONT. S. L. BESWICK.

Virology Laboratory,Department of Clinical Pathology,

Manchester Royal Infirmary,Manchester M13 9WL.

HORIZON ON MEDICAL EDUCATION

PHILIP RHODES.St. Thomas’s Hospital Medical School,

London S.E.1.

SIR,—I had not intended to say anything about theB.B.C.’s film on medical education in the Horizon series,March 15, which was made in this medical school, butwhen someone of Mrs. Claire Rayner’s intelligence quotesthe film in support of her viewpoint (March 27, p. 647) it is

time to put the record straight. The editor and the produ-cers of the film came to us with a biased attitude to present-day medical education and then by selection of materialthey supported their erroneous beliefs. Whatever else this

may be it is certainly bad journalism, and it is surprising tofind that Mrs. Rayner did not recognise it as such.The film-makers had a free run of the medical school

and hospital because I was told by them that they wereimpressed by our approach to medical education, with afair emphasis on psychology, general practice, and socialmedicine. They chose not to show anything of these,though they spent some time with the professor of socialmedicine and about 12 hours with our senior lecturer /consultant in general practice, of which two hours weretaken up with filming. None of this was shown. It is

scarcely necessary to’detail other areas where large amountsof film were exposed which might have given viewers abalanced appreciation of medical education today, butwhich were discarded since they did not support the pro-ducers’ thesis that the education of doctors did not fit themfor the conditions of today. This may or may not be true,but 45 minutes of biased journalism can hardly support ordeny the validity of the statement. Moreover television

requires visual images, which cannot treat of all the subtle-ties in a matter of the complexity of education.

CARCINOGENIC PROPERTIES OF WEAR

PARTICLES FROM PROSTHESES MADE

IN COBALT-CHROMIUM ALLOY

G. K. MCKEE.

SIR,-This contribution 13 lacks one essential additionin its title, as it should state, " in rats ". In all fairness tothe authors, the possibility of such criticism being made ismentioned, but it is essential to realise that this is a veryvalid criticism.

10. Calabresi, P., Cardoso, S. S., Finch, S. C., Kligerman, M. M.,Von Essen, C. F., Chu, M. Y., Welch, A. D. Cancer Res. 1961,21, 550.

11. Silk, B. R., Roome, A. P. C. H. Lancet, 1970, i, 411.12. Juel-Jensen, B. E. Br. med. J. 1970, ii, 154.13. Heath, J. L., Freeman, M. A. R., Swanson, S. A. V. Lancet, March

20, 1971, p. 564.

At Norwich, chrome-cobalt alloy has been used forboth components of a total prosthetic replacement of a jointsince 1956 and it has been used in many other centres since1960. Several thousands of these implants must have beeninserted and of all the complications encountered the onethat has never been seen at Norwich, or as far as I am awarereported elsewhere, is that of tumour formation.

In assessing the importance of this article it should,therefore, be realised that the results apply only to rats, aspecies of animal particularly prone to tumour formation,and that this is in striking contrast to clinical experience inhundreds of cases over a period of fourteen years. It wouldseem, therefore, that any alarm over similar reactions

occurring in the human body from the wear particles onchrome-cobalt alloy are groundless.

Finally, I would like to add that some years ago a similarscare was introduced in regard to tumour formation byplastics in rats, but again this has not been encountered inclinical experience, again over literally thousands of casesand over a period of at least ten years.

Norwich. G. K. McKEE.

AORTIC PERMEABILITY, LIPIDS, ANDATHEROSCLEROSIS

SIR,-In the early stages of cholesterol-induced athero-genesis in rabbits, Magnani and Coccheri 1 demonstratedblue areas of enhanced permeability of the aortic intima inanimals injected intravenously with trypan-blue 15 hoursbefore being killed. The location of these areas was

reminiscent of the topography of the lipid accumulationpattern observed in the later stages of the disease. Klynstraet al. 2,3 3 found the in-vitro rate of permeation of trypan-bluein the intima of apparently normal thoracic aortas fromyoung pigs to be site-dependent. A specific pattern ofblue and white areas resulted. The sudanophilic streaks andspots in the intima of old pigs lay almost exclusivelywithin these blue areas of enhanced permeability. These

findings led to work on the chemical composition of theblue and white areas of the aortic intima. The trypan-blue-stained and the white areas of the intimas of 37 aortasof pigs 6 months old, prepared by the method of Klynstraand Bottcher 3 were separately pooled and analysed for lipidcontent. The results for the methanol-chloroform-extrac-table lipids were as follows:

Lipid 17hite areas Blue areas(mg.!g. dry tissue):Total lipid .... 29 24

Phospholipids.... 22 9-6Cholesterol-esters 1.5 6-7

The levels of triglycerides and free cholesterol did not differsignificantly. We have lately learned from Schwartz 4that such white and blue areas were observed by themin the aortas of 2-month-old pigs given intravenous in-jections of Evans-blue 3 hours before being killed. The onlydivergence from the lipid pattern seen in his investigationwas in the phospholipid level, which was about 25% lowerin the blue areas than in the white areas. Cholesterol-esterlevels in both the blue and the white areas were low, anddid not exceed 1 mg. per g. dry weight.In the early stages of human atherosclerosis there are

increases in total lipid content of the aortic intima (lesionsremoved) and a shift in the lipid composition.5,G 6 This

1. Magnani, B., Coccheri, S. G. Clin. med. 1960, 41, 1103.2. Klynstra, F. B., Boelsma-van Houte, E., Böttcher, C. J. F. Lancet,

1967, ii, 1150.3. Klynstra, F. B., Böttcher, C. J. F. Atherosclerosis, 1970, 11, 451.4. Somer, J. B., Schwartz, C. J. ibid. (in the press).5. Böttcher, C. J. F. in Evolution of the Atherosclerotic Plaque (edited

by R. J. Jones); p. 109. Chicago, 1964.6. Smith, E. B., Slater, R. S., Chu, P. K. J. atheroscler. Res. 1968, 8,

399.