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tion at three, four, and five months." On this regimenfor infants no cases of poliomyelitis have been officiallyrecognised as due to the vaccine-possibly because noprogramme of adult immunisation has been undertaken.SABIN 16 also takes the U.S. report 12 to task for notclearly stating that oral vaccine is the vaccine of choicefor routine immunisation of children, since he believesthe immunity conferred by attenuated vaccine is

superior. The Surgeon General’s committee did notcomment on this issue. We have argued previously thatin a community with a well-organised health servicethere are considerable merits in using an inactivatedpoliovaccine, especially if it can be incorporated in aquadruple vaccine.

DANE 18 has reported higher titres of antibody after aninactivated vaccine than after an attenuated one, whereasSABIN 16 believes that the antibody response to inactivatedvaccine is only of a low order and very often transitory.The antibody response to an inactivated vaccine dependschiefly on the mass of antigenic material, and this isstandardised in the poliovaccine component of the

quadruple vaccine available in this country.19 There

are, however, doubts about the ability of inactivatedvaccine to confer a longlasting immunity or to produceherd immunity. Presumably these are the reasons forthe reservations about quadruple vaccines recentlyexpressed by Sir GEORGE GODBER, chief medical officerof the Ministry of Health, in a letter to medical officersof health. The rate of fall in antibody titre seems to bethe same after either poliovirus infection or inactivatedvaccine,2O so that with potent inactivated vaccine theduration of immunity should be longlasting, just as it isto other non-living antigens, such as tetanus toxoid.21In Sweden, where only inactivated poliovaccine has beenused, a herd immunity has certainly been conferred bythe vaccine. Not only have there been no cases of polio-myelitis but there has also been an absence of poliovirusin sewage surveys. Thus, the degree of alimentaryimmunity conferred by potent inactivated vaccine seemsadequate to confer herd immunity.The elimination of poliomyelitis by both inactivated

and attenuated vaccines raises a problem that has alreadybeen faced for diphtheria-how to maintain future

immunity by a simple and widely acceptable immunisa-tion schedule. It is mainly for this reason that we haveargued in favour of a combined vaccine, based oninactivated poliovaccine, as the most likely means ofachieving high rates of immunisation to diphtheria,tetanus, pertussis, and poliomyelitis. This method hasthe added attraction that new antigens can be added asnecessary-for example, immunisation against measleswould be greatly simplified if it could be established thatmeasles vaccine can be effectively added to a quadruplevaccine. Recent results by BROWN 22 suggest that thiscan be done.

17. Butler, N. R., Benson, P. F., Urquhart, J., Goffe, A. P., Knight, G. J.,Pollock, T. M. Brit. med. J. Aug. 15, 1964, p. 418.

18. Dane, D. S. Proc. R. Soc. Med. 1964, 57, 462.19. Beale, A. J., Ungar, J. Lancet, 1962, ii, 805.20. ibid. 1960, ii, 33.21. Gottlieb, S., McLaughlin, F. X., Levine, L., Latham, W. C., Edsall, G.

Amer. J. publ. Hlth, 1964, 54, 961.22. Brown, G. C. Seminar on Epidemiology and Prevention of Measles and

Rubella. Paris, 1964.

Necrosis of the Anterior Pituitaryand Zona Glomerulosa of the Adrenal

MOTHERS whose delivery is complicated by suchconditions as retained placenta, postpartum hxmor-rhage, and ruptured uterus may pass into severe

circulatory collapse lasting a few hours. In such an

event, ischaemic necrosis of the anterior lobe of the

pituitary is common, and it is usually massive: in halfthe cases 95-99% of the lobe is destroyed. A similarpituitary necrosis sometimes complicates diabetesmellitus, but the lesion is usually much smaller than inthe obstetric patients. Small necroses may also be foundat necropsy in patients dying of other causes, sometimesassociated with raised intracranial pressure. 1 Themassive necroses, particularly the obstetric ones, are ofconsiderable clinical importance because the patientslater suffer from permanent hypopituitarism and, afteryears of ill-health, most of them die of this condition.The necrosis has all the characters of simple infarction

and must be ascribed to local vascular occlusion. Thenature of this occlusion has been the subject of muchargument, because the information so far available aboutthe course of events has been obtained only from thehistological study of the pituitary vessels in patients whodie at known times after delivery. A recent inter-

pretation 2 postulates that during the period of generalcirculatory collapse there is a temporary intense spasmin the vessels supplying the anterior lobe, and that thisarrests the blood-flow for long enough to cause death ofthe distal parts of the vascular tree as well as of theparenchyma. When the spasm relaxes, some bloodtrickles into the dead vessels and undergoes thrombosisthere, but this secondary thrombosis is of no real con-sequence since the parenchyma is already dead. Analternative explanation is that the pituitary vessels areobstructed as part of a disseminated intravascular

coagulation,3 but this view has recently been severelycriticised.4 Other hypotheses, such as the effect of

pressure by the diaphragma sellae, have little to supportthem.

For the past thirty years many workers have tried toreproduce pituitary necrosis in animals by variousmethods, such as severe bleeding at the time of delivery;but none have been successful. Now, on p. 919,KovAcs and his collaborators show that the lesion can be

produced by the intravenous injection of hexadimethrine.The infarction is almost identical in pattern and appear-ances to human pituitary necrosis, and it is very probablethat the local pathogenesis is similar. Thus this experi-mental model has great possibilities and should providedirect answers to many questions.

Hexadimethrine also produces lesions in other organs.Those in the kidney and the deeper zones of the adrenalcortex have been previously studied but the veryinteresting lesion of the zona glomerulosa of the adrenalcortex seems to have been overlooked. CARROLL and his

coworkers, in another paper in this issue, find that doses1. Wolman, L. J. Path. Bact. 1956, 72, 575.2. Sheehan, H. L., Stanfield, J. P. Acta endocr., Kbh. 1961, 37, 479.3. Beernink, F. J., McKay, D. G. Amer. J. Obstet. Gynec. 1962, 84, 318.4. Eisenberg, J. J. S. Afr. J. Obstet. Gynœc. 1964, 2, 57.5. Selye, H., Gabbiani, G., Tuchweber, B. Med. exp., Basel, 1963, 8, 74.

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which are insufficient to damage the deeper zones producea necrosis strictly confined to the zona glomerulosa, andwithin a few days this zone has disappeared completely.The lesion is clearly toxic and not vascular in origin.

It is commonly accepted that the functions of theadrenal cortex are divided in a way that corresponds toits histological zones, and that the zona glomerulosa isthe essential site of production of aldosterone. If the

deeper layers of the adrenal cortex are deprived offunction by hypophysectomy, aldosterone continues tobe secreted and the electrolyte balance remains essen-tially unaffected. The same effect is obtained in the dogif the deeper layers of the cortex are destroyed by aspecific cytotoxin such as D.D.D. (dichlorodiphenyl-dichloroethane).’ The discovery of a method of pro-ducing the complementary lesion-the destruction ofthe zona glomerulosa while the inner layers are left6. Symington, T. Brit. med. Bull. 1962, 18, 117.7. Nichols, J. The Adrenal Cortex (edited by H. D. Moon). New York, 1961.

intact-gives further opportunities for analysing thefunction of this zone.

In addition to the toxic damage to the glomerulosa,large doses of hexadimethrine produce a patchy or

confluent infarction of the zona fasciculata and zona reti-cularis, apparently due to an occlusive vasospasm in thecortical arteries similar to that postulated in the pituitary.Lesions of this kind are found rather commonly atnecropsy in human beings, and can be produced experi-mentally by a wide variety of substances. When thepatient or the animal dies, the lesion may still be in theearly stage of

" hxmorrhage " or red infarction, but ifsurvival is longer it progresses to the stage of an ordinarywhite infarct. These ischaemic necroses of the deepcortex have been studied extensively in the past fewyears; and hexadimethrine is an addition to the list ofknown agents which produce this particular effect.8 9

8. Huggins, C., Morii, S. J. exp. Med. 1961, 114, 741.9. Wirtschafter, Z. T., Walsh, F. R. Endocrinology, 1963, 72, 725.

Annotations

ETHICS AND EXPERIMENT

THE ethical considerations arising from experimentson human beings were the subject of a statement 1 in thereport of the Medical Research Council for 1962-63; and,as we remarked 2 last week, it is a statement that shouldbe studied by everyone who is directly or indirectlyinvolved in medical research. But the M.R.C. code startsfrom the assumption that the question of the experimentis worth asking; and, in the opening address last week inthe British Postgraduate Medical Federation’s annualseries of lectures on the Scientific Basis of Medicine, SirRobert Platt observed that not all experiments were goodones. We were inclined to underestimate the extent of

biological variation, which was such that a controlled trialwas not always possible. Inquiries into the value of anti-coagulant treatment in coronary-artery disease had beenan uncertain success because so many variables were

involved; and Sir Robert doubted whether the work onthe steroid treatment of nephrosis would produce anymore satisfactory results.

Bradford Hill had said that a controlled trial was

justified only if the doctor in charge could genuinely saythat he had no opinion as to which of two or more reme-dies was the more likely to be successful. And Sir Robertheld that the use of placebos could not be defended unlessthe patient’s full cooperation had been secured.4A passion for scientific experiment might have impeded

progress by the methods of direct observation and thetesting of hypothesis. " Why experiment, why not think ?"was Sir Robert’s provocative question. It was often saidthat it was the prepared mind which made importantdiscoveries; but, he added dryly, it often waited a longtime before making them: we must not discount thepotential of the unprepared mind.

Medicine often found itself uneasy in an academic

atmosphere. Why not, Sir Robert reflected, put some ofthe new medical schools alongside colleges of technology,where arts and crafts were already respectable and sciencewas definitely the servant ? ? Such juxtaposition might

1. See Lancet, July 18, 1964, p. 139.2. ibid. Oct. 24, 1964, p. 899.3. Bradford Hill, A. Brit. med. J. 1963, i, 1043.4. Platt, R. Lancet, 1963, ii, 1156.

foster a valuable collaboration between industry andmedicine.

Turning to commercial ethics in medicine, Sir Robertsaid that a pharmaceutical firm had recently announcedthe withdrawal of one of their drugs from the market" pending further investigation

" because it might havebeen responsible for 10 cases of jaundice. This seemeda small item beside the thousands of yearly deaths fromcancer of the lung. No-one expected cigarettes to bewithdrawn from the market; but how much more digni-fied it would be if tobacco manufacturers stopped tryingto deny the evidence against cigarettes and announcedthat they were withdrawing their advertisements

" pend-ing further investigation ".Of the preventive measures that raised ethical ques-

tions, contraception was today outstanding; and whatevermight be the best answer to the threat of overpopulation,we might have to wait a century or more to know theresults of an acceptable method of contraception. SirRobert was uneasy about any method that involved

regular interference with the hormonal cycle. He saw apersisting reticence to give advice to the young about sex.In this and other ways, we gave far too little thought tothe mental health of the community. Compared withthe improvement and maintenance of that health, thetransplantation of a kidney seemed of little importance.

LASERS AND CARIES

THE dentist and Mr. James Bond have both beentaking an interest in lasers. Preliminary experiments 1on the impact of the laser beam on dental caries has

prompted the comment 2 that it "provides the first

glimmer of hope that the painful days of the dentist’sdrill may now be numbered "-a bit unfair on the dental

surgeon, since it has been possible for many years toprevent the pain of cavity preparation by local anxsthesia,and even the unpleasant pressure, vibration, and bone-conducted noise of the drill have now been eliminated

by the newer air-turbine instruments. But that is besidethe point, and any new method of attacking dental cariesmust be closely examined.

Dental surgery might be regarded as embracing1. Goldman, L., Hornby, P., Meyer, R., Goldman, B. Nature, Lond.

1964, 203, 417.2. New Scientist, 1964, no. 405, p. 451.