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likely to be related to the dose of contained steroids.Minor side-effects, which are usually an acute eventat the beginning of treatment, are of relatively littleimportance. Far more critical are the potentialdangers of cancer, metabolic effects includingpyridoxine deficiency,’ 7 and cardiovascular effects

including myocardial infarction,8,9 hypertension,loand thromboembolism. With respect to the last, therisk associated with low oestrogen doses is probablysmall; with respect to cancer, particularly of thebreast and endometrium, the balance may even bein favour of treatment, since some work suggeststhat the incidence may actually be reduced,l1 andthere is no study which suggests an increase. A" risk " specific to the postmenopausal period is

breakthrough bleeding from a partly stimulated

endometrium, which in the untreated patient woulddemand a full investigation to exclude neoplasia.Precisely how this situation should be managed inthe patient on long-term steroid therapy is at presentunresolved.The prospect of universal treatment of a large

section of the female population is clearly a glitteringcommercial prize for the pharmaceutical manufac-turer. Several products are already available, and itis certain that the next few years will see the intro-duction of a wide variety of agents supposedlydesigned for use in postmenopausal women. These

compounds will all contain an oestrogen, but in

widely differing doses, and some, in addition, willcontain a progesterone or an androgen. The pros andcons of different combinations, and of cyclicalversus continuous treatment, will be argued adnauseam and, given the difficulties of this type ofstudy, it is unlikely that definitive answers will

emerge for several decades. Meanwhile there wouldbe good arguments for planning a large-scale andlong-term controlled survey of the use of the simplesttherapy-oestrogen replacement. Unless such a

survey is started soon, there is a strong danger thatin this areas, as in others, proper medical caution maybe overtaken by public demand.

FOLATE-RESPONSIVE SCHIZOPHRENIA

OF the many metabolic hypotheses about the causesof schizophrenia, none has proved entirely satisfactory;probably there are many contributing factors. Thelatest suggestion is methylenetetrahydrofolate-reductasedeficiency. Freeman, Finkelstein, and Mudd 12 havedescribed a 15-year-old schizophrenic girl with verylow levels of this enzyme which converts 5,10-

7. Adams, P. W., Wynn, V., Rose, D. P., Seed, M., Folkard, J.,Strong, R. ibid. 1973, i, 897.

8. Mann, J. I., Vessey, M. P., Thorogood, M., Doll, R. Br. med. J.1975, ii, 241.

9. Mann, J. I., Inman, W. H. W. ibid. p. 245.10. Spellacy, W. N., Birk, S. A. Am. J. Obstet. Gynec. 1972, 112, 912.11. Burch, J. C., Byrd, B. F., Vaughn, W. K. ibid. 1974, 118, 778.12. Freeman, J. M., Finkelstein, J. D., Mudd, S. H. New Engl. J. Med.

1975, 292, 491.

methylenetetrahydrofolate to 5-methyltetrahydro-folate. Inability to produce 5-methyltetrahydrofolatemeans that the methyl group from this compoundcannot be used by 5-methyltetrahydrofolate-homo-cysteine-methyltransferase to convert homocysteineinto methionine. Deficient methylenetetrahydrofolatereductase therefore causes homocystinasmia and

homocystinuria responsive to folic acid, which pre-sumably acts by increasing the production of 5-methyl-tetrahydrofolate by the residual methylenetetrahydro-folate reductase. More fascinating than this, however,was the way in which the schizophrenic behaviour alsoseemed to be folate responsive.When not taking folic acid the patient had thought

disorder, loss of contact with her surroundings,hallucinations, delusions, and catatonic posturing.When folate therapy was started her psychotic featureswere thought to improve gradually, and this happenedfour times though pyridoxine was given with thefolic acid on two of these occasions. Furthermore,when the folate was stopped and the serum-folatedeclined, the psychotic behaviour recurred. The wayin which both the homocystinuria and the psychosisseemed to respond to folate suggests very stronglythat the low activity of methylenetetrahydrofolatereductase played an important part in this patient’spsychotic behaviour. Unfortunately, however, thetrials of folate therapy were apparently not conductedon a double-blind basis, so subjective bias may haveinfluenced the observations. On family investigationit emerged that the patient’s sister also had homo-

cystinuria due to a similar biochemical lesion. Therewas no evidence, however, of a psychotic disorder inthe sister though her i.Q. was only 62. Interestingly,the non-psychotic sister had a normal level of mono-amine-oxidase inhibitor in platelets whereas the

psychotic patient had a low level. A low plateletmonoamine-oxidase concentration is thought to indicategenetic susceptibility to schizophrenia," and this maybe why only one of the girls with low methylene-tetrahydrofolate reductase developed a psychoticdisorder.

At present one can only speculate about the relationbetween deficiency of this reductase and schizophrenia.Mudd and Freeman 14 have suggested that deficient5-methyltetrahydrofolate might lead to a build-up ofdopamine because conversion to N-methyldopaminedepends on this folate derivative.15 Furthermore, thedeficiency of monoamine oxidase in their patient wouldalso tend to increase dopamine concentrations. Severalother workers have attempted to relate schizophreniato dopamine metabolism. Stein and Wise,16 forexample, have induced " catatonia " in the rat bygiving dopamine, and Matthysse 17 has suggested thatantipsychotic drugs act by enhancing dopamineturnover in the brain.

These speculations are not inconsistent with theeffects of methionine supplementation in schizophrenia.

13. Wyatt, R. J., Murphy, D. L., Belmaker, R., et al. Science, 1973,179, 916.

14. Mudd, S. H., Freeman, J. M. J. psychiat. Res. 1974, 11, 259.15. Lauduron, P. Adv. Neuropsychopharmac. (in the press) (cited by

Mudd and Freeman 14).16. Stein, L., Wise, C. D. Science, 1971, 171, 1032.17. Matthysse, S. Fedn Proc. 1973, 32, 200.

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Clinical work has established that methionine enhances

psychotic behaviour," and this may be related to thefact that this compound prevents the accumulation of5-methyltetrahydrofolate.l9 Freeman, Finkelstein, andMudd’s patient therefore offers us some more cluesabout the biochemical basis of schizophrenia.Obviously their patient’s disorder is quite uncommon;no cases of homocystinuria were found in an earliersurvey of 300 schizophrenics. 20 Nevertheless, thesearch will be on to find similar cases-particularly inview of the possibility of a therapeutic response to asubstance as harmless as folic acid.

THE IMAGE OF CANCER

A FEATURE of Marie Curie Foundation symposia,which are attended by medical workers and others insome way concerned with the care of cancer patients,is a generous allocation of time for audience participa-tion. The questions asked provide some insight intothe erroneous beliefs and prejudices that even

moderately well-informed people may hold about thecausation, manifestations, and curability of cancerousdiseases. 21 1 The title of this year’s symposium onMay 13 was Cancer and the Nation, and the themerunning through it was the need to convey to ordinarypeople factual information about cancer-particularlyabout prevention and about the improved prospectsin certain forms of the disease. Prof. R. A. Sellwood

(Manchester) illustrated the unjustifiably gloomy imageof cancer held by medical students, nurses, and generalpractitioners by reference to a survey carried out byEasson.22 Those taking part in the survey were asked,given early diagnosis and facilities for modem treat-ment, what proportions of sufferers of certain forms ofcancer (such as carcinomas of larynx, breast, andcervix, seminoma of the testis, and Hodgkin’s disease)survive for 5 years or longer. For all groups questionedand for all the cancers the answers indicated a degreeof pessimism that is quite unsupported by actualsurvival data. General practitioners and nurses weresomewhat more pessimistic than medical students.

Perhaps the most disturbing feature of the survey isthat some of the same individuals, questioned againafter 3 years’ instruction in the facts about cancer

prognosis, had become more rather than less pessimistic.One possible reason may be that they were asked aboutthe prognosis of early cancers, whereas their mostimpressive experiences as doctors, students, or nurseshad been in connection with patients with the diseasein its more advanced stages. Nevertheless, it is aserious matter that the image of cancer is substantiallyworse than the reality. For one thing, it discouragespersons with suspicious signs or symptoms which

might be due to early cancers from seeking medicalopinion, and even from submitting themselves to

screening tests aimed at detecting the presence of

18. Pollin, W., Cardon, P. V., Ketty, S. S. Science, 1961, 133, 104.19. Buerhring, K. U., Batra, K. K., Stokstad, E. L. R. Biochem. biophys.

Acta, 1972, 279, 498.20. Gershon, E. S., Schader, R. I. Archs gen. Psychiat. 1969, 21, 82.21. Cancer—the Patient and the Family. Proceedings of Symposium

held on May 14, 1974 (edited by R. W. Raven). Marie CurieMemorial Foundation, 1975.

22. Easson, E. C. Cancer of the Uterine Cervix. London, 1973.

precancerous changes or of early symptomless disease.In this regard doctors and nurses set a poor exampleby not having suspicious signs and symptoms in-

vestigated. But a more serious implication of Easson’sfindings may be that doctors who hold an undulypessimistic view of the prognosis of cancer and arenot really aware or convinced of the value of earlydiagnosis in many forms of the disease transmittheir gloomy attitude, albeit unwittingly, to their

patients.On the matter of prevention of cancer, several of

the speakers stressed the importance of smoking as acontributory cause of lung cancer. The foreverstartling facts are that, in Britain, 40% of all cancerdeaths in men and 10% in women are from lungcancer, and that the large majority of those affectedare smokers. Punitive taxation, abolition of advertising,and prohibition of smoking itself were among themeasures proposed by Mr R. W. Raven, the chairmanand principal organiser of the symposium. The

practicability of such extreme measures is dubious,but public expression of such views is an indicationof how strongly some members of the medical pro-fession now feel about the ravages of diseases due to

smoking.The possible significance of the 1974 Health and

Safety at Work Act in relation to the future preventionof cancer was stressed by Dr F. J. C. Roe. As a

consequence of the passing of the Act " any personwho manufactures or supplies any substance for useat work" has " to ensure, so far as is reasonablypracticable, that the substance is safe and without riskto health when properly used ". Where there is anydoubt he is obliged under the law to see that appropriatesafety tests are carried out. These are statutory dutiesfor the employer. But the Law also makes demands ofthe employee: " It shall be the duty of every employeeat work to take reasonable care for the health and

safety of himself and of other persons who may beaffected by his acts or omissions at work". Theenforcement of this law and its proper functioningshould in the long run reduce the toll of industrialcancer. For deaths from some forms of cancer (e.g.,stomach, lung, bladder, rectum, cervix) but not forothers (colon, prostate, brain, breast, corpus uteri)there is a pronounced social-class trend,23 the rates forsocial class v being from two to six times higher thanfor social class i. Why should this be ? Greater

exposure of members of social class v to industrial

carcinogens and their more liberal indulgence in thesmoking habit provide part of the answer. But otherfactors such as different dietary habits, lack of facilitiesfor refrigeration of food, greater exposure to air

pollution, and poor standards of personal hygienemight also be implicated. It is then, perhaps, reasonableto hope that better protection of people at work coupled

_ with better standards of living for the unskilled will bereflected in low incidence-rates for some forms ofcancer. Meanwhile, we must try to bring up to datethe image of cancer that lay people hold, so that theytake advantage of the services which exist for detectingand dealing effectively with precancerous states andearly cancers.23. Registrar General’s Decennial Supplement. England and Wales

Life Tables. H.M. Stationery Office, 1968.