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STATE OF THE N.H.S.

SIR,-Your Sept. 11 editorial must not be allowed to pass withoutcomment. Lancet editorials are justly respected and are usuallyconcerned with matters medical or truly medicopolitical-but thisforay into the wider realms of politics, with its series of judgmentsand assumptions, displays the shallow ineptitude that one mightexpect from, say, a monastic education followed by untutoredreading of old copies of Left Book Club volumes.The industrial action of the past few weeks has not been

jeopardising the National Health Service; despite all the rhetoric,most employees, part-time or full-time, remain committed to theService and will continue to aim at excellence.

Advising the Government in an ex-cathedra manner to give moremoney now and to insist on further negotiations adds to theturbulent hot air blowing from so many sources; and to suggest thatsuspension of all industrial action would follow and that negotia-tions with a trade union leadership acutely and anxiously aware oftheir justly declining powers might be successful, places theproposer of this course of action deep in cloud cuckoo land.Substantiation of overmanning at all levels is easy to come by for

those with open eyes and ears, and the Secretary of State’s firmnessin dealing with the obese, demanding, and sluggish sacred cow ofthe N.H.S. is surely a first step in the development of a new healthservice, efficient in both cost effectiveness and maintenance ofstandards, as recently advocated so eloquently by Prof. RudolphKlein.

It is easy to label as shrill or unyielding those who are steadfast andwho accept opprobium from the professional protest industry of thepseudo-proletariat of the educated Left. The Prime Minister enjoysenormous support from those with real responsibility, rich andpoor, and these people must recognise that if sectional interests defya democratically elected government, a call for the use of troops tomaintain essential services is wholly reasonable.The evident decline in the N.H.S. should be our main concern,

but I suggest that the elegant atmosphere of Adam Street has led tothat facile view, so beloved of that section of the community who canprotest without any prospect of having to construct or manage thenation’s life, which sees the development of private medicine as themajor cause of the decline of the N.H.S. A more balanced viewwould be that this development is partly a response to lack ofconfidence in the N.H.S., partly a feature of any affluent society(which we still are, by world standards), and largely an expression ofthe wish of many citizens to think and be treated as free individuals,a view encouraged in principle by most intellectuals of good willand tolerant idealism of both the Left and the Right.To say that Mrs Thatcher lacks concern, is depriving and

downgrading the N.H.S., and sees it as a woeful extravagance, is toendorse the simplistic style of desperate protest that we have cometo expect from an opposition desperately seeking some support butwithout its own constructive ideas in confronting a Governmentwhich accepts responsibility for putting through unpopular, longoverdue, and desperately necessary economic measures.The N.H.S. does provide reasonable value for money, but merely

to dole out cash to patch the cracks and shore up the sagging wallswill in the end do the N.H.S. as much harm as have decades of

compromise with trade unions who openly denied responsibilitywhile demanding power have inflicted on British industry.The current strife should bring all concerned to their senses, to

think constructively about how the Health Service should bedeveloped in future. In the meantime constructive ideas would be aswelcome from The Lancet as from anywhere else.

St James’ Hospital, London SW12 J. S. KIRKHAM

SIR,-Sir George Godber (Sept. 11, p. 612) says that "insufficientrevenue is allocated [to the N.H.S.] in England and Wales, but notto Scotland and Northern Ireland". Is the favoured positionenjoyed, for example, by Scotland, reflected in its indices of

comparative morbidity, the sensitivity of its care for the mentallyhandicapped, the effectiveness of its preventive services, and so on?If not, a similar extra 10% allocated to England and Wales under thepresent system might not be the answer to our ills.

Whixley Hospital, Whixley, York YO5 8DR T. L. PILKINGTON

BETA-ADRENORECEPTOR ANTAGONISTS ANDDIPLOPIA

SIR,-A man aged 52 attended an outpatient clinic because oftransitory double vision. He had been prescribed oxprenolol forangina pectoris and it had been intended to replace this withpropranolol. The patient misunderstood the instructions and addedthe propranolol to the oxprenolol. An hour after taking themedication he experienced diplopia whilst driving. He suspectedthe new drug so stopped taking propranolol but continued to takeoxprenolol. Diplopia did not recur when he was on oxprenolol aloneor when propranolol was substituted.The adverse reactions register of the Committee on Safety of

Medicines contains 9495 reports of adverse reactions to beta-

adrenoreceptor antagonists; 32 reports refer to diplopia, excludingthe above case. Clinical details of these reports were examined and,on the basis of factors such as time of onset, other drugs taken,disappearance of symptoms when the drug was stopped, re-

emergence of symptoms on re-exposure, and presence of a dose-response relationship, drug-culpability was assessed as "probable","possible", or "unlikely".In 24 patients, diplopia was considered probably drug-related. In

4 others the relationship was considered possible only, eitherbecause the report was unclear or because other drugs had beentaken concomitantly, which, though not clearly causative, mighthave influenced the clinical picture. Of the other 4, 1 had been

taking at least six other drugs, 1 was on perhexiline, 1 was takinglevodopa/carbidopa, and 1 had true mild myasthenia gravis.The 24 probably drug-related reactions were associated with

propranolol (4), practolol (4), atenolol (4), oxprenolol (3), pindolol(3), nadolol (2), and acebutolol, metoprolol, sotalol, and timolol (Ieach). Positive regression was recorded in 14 ofthe reports and therewere no reports of persistence of the symptom after withdrawal ofthe drug. In 1 case the symptom regressed while the patientcontinued to take the beta-blocker at the original dose. 4 wererechallenged or continued to take the drug in the presence oftransient symptoms: symptoms recurred every time the drug wastaken. In 3 cases (all propranolol) the symptoms disappeared on dosereduction. Another patient’s symptoms appeared only when thedose of atenolol was increased. These facts, together with theadditive effects in the case which prompted this investigation,suggest a dose response. The doses were all well within therecommended therapeutic range.

13 patients were women (mean age 62) and 11 were men (mean age63). Hypertension and effort angina were the usual indications fortreatment.

An association, in these 24 cases, between beta-blockade, anddiplopia, is indisputable. The variety of the beta-blockers and theabsence of any relationship to physical properties such as polaritysuggest a peripheral rather than a central mechanism. There areseveral sites at which interference with catecholamines could

modify neuromuscular function. 1,2 The most relevant might seemto be a direct effect on the muscle membrane; however,interference with acetylcholine-mediated depolarisation at theneuromuscular junction3 and a direct local anaesthetic action on thesarcolemma4 could also be considered.Beta-blockers may worsen myasthenia gravis.5,6 1 patient with

myasthenic symptoms whilst under treatment with beta-blockers5 5

had diplopia only, and this symptom regressed when oxprenolol wasstopped. There were no overt signs of true myasthenia gravis.Another patient had had recurrent diplopia whilst taking practololand, later, bilateral ptosis (which was greatly improved byedrophonium), but all symptoms had disappeared a few days after

1. Bowman WC, Raper C. Adrenotropic receptirs in skeletal muscle. Ann N Y Acad Sci1967; 139: 741-53.

2. Bowman WC, Raper C. Effects of sympathomimetic amines on neuromusculartransmission. Br J Pharmac Chemother 1966, 27: 313-31.

3. Werman R, Wislicki L. Propranolol, a curariform and cholinomimetic agent at the frogneuromuscular junction. Comp Gen Pharmac 1970; 2: 69-81.

4. Myrhe L, Roed A, Aars H. Inhibitory effect of propranolol on tetanic contraction inrabbit. Eur J Pharmacol 1977; 42: 355-61.

5. Herishanu Y, Rosenberg P Beta-blockers and myasthenia gravis. Ann Intern Med 1975;83: 834-35.

6. Shaivitz SA. Timolol and myasthenia gravis. JAMA 1979; 242: 1611-12.7. Hughes RO, Zacharias FJ. Myasthenic syndrome during treatment with practolol. Br

Med J 1976: i: 460-61.

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withdrawal of practolol and did not recur.Beta-blockers can therefore unmask or precipitate myasthenia

gravis and can also produce a "myasthenic" symptom (diplopia) inpatients who appear otherwise neurologically normal. Diplopiaconstitutes only 0’ 25% of the total suspected adverse reactions tobeta-blockers notified to the Committee on Safety of Medicines oversixteen years. However, awareness of the possibility could preventunnecessary clinical investigation. The patient reported by Hughesand Zacharias illustrates that the condition can go unrecognised formonths.

I thank Sir James Black, F.R.S., and Prof. Duncan Vere for their helpfulcomments.

Medicines Division, D.H.S.S.,Market Towers,1 Nine Elms Lane,London SW8 5NQ J.C.P. WEBER

POSSIBLE PROTECTIVE ROLE AGAINSTALCOHOLISM FOR ALDEHYDE DEHYDROGENASE

ISOZYME DEFICIENCY IN JAPAN

SIR,-NAD-dependent aldehyde dehydrogenase (ALDH, EC1.2.1.3) catalyses the oxidation of several aldehydes in humantissues. Two major isozymes of ALDH (I and II) have beencharacterised in the human liver and differ in their electrophoretic,biochemical, and catalytic properties as well as in their subcellularlocalisation. 1,2 Isozyn I migrates more anodically in starch gel, hasa lower pI than isozyme II, and shows higher affinity for

acetaldehyde (lower Km value).We have found that in about 50% of Japanese post-mortem liver

extracts isozyme I was missing.3,4 Subsequent studies showed thatthe deficiency of isozyme I may be responsible for alcohol sensitivityassociated with facial flushing commonly observed in Japanese andother Mongoloid peoples.5,6 Similar reactions are observed inpatients drinking alcohol while under disulfiram treatment.

Japanese subjects found deficient in ALDH isozyme I showed

higher blood acetaldehyde levels and experienced flushingsymptoms after moderate alcohol intake. Acetaldehyde may beexerting a biphasic effect in human beings by causing an aversion toalcohol among individuals deficient in ALDH I isozyme and byreinforcing alcohol consumption among chronic alcoholics. A

population genetic survey using hair root lysates as the source of theenzyme activity demonstrated that the isozyme deficiency isconfined to Oriental populations of Mongoloid origin(unpublished).

1 Greenfield NJ, Pietruszko R. Two aldehyde dehydrogenases from human liver.Isolation via affinity chromatography and characterization ofthe isozymes. BiochimBiophys Acta 1977; 483: 35-45.

2. Harada S, Agarwal DP, Goedde HW. Electrophoretic and biochemical studies ofhuman aldehyde dehydrogenase isozymes in various tissues. Life Sci 1980; 26:1773-80.

3. Harada S, Misawa S, Agarwal DP, Goedde HW. Liver alcohol dehydrogenase andaldehyde dehydrogenase in the Japanese: Isozyme variation and its possible role inalcohol intoxication. Am J Hum Genet 1980; 32: 8-15.

4. Goedde HW, Harada S, Agarwal DP. Racial differences in alcohol sensitivity: a newhypothesis. Hum Genet 1979; 51: 331-34.

5 Goedde HW, Agarwal DP, Harada S. Genetic studies on alcohol metabolizingenzymes: Detection of isozymes in human hair roots. Enzyme 1980; 25: 281-86.

6. Agarwal DP, Harada S, Goedde HW. Racial differences in biological sensitivity toethanol: The role of alcohol dehydrogenase and aldehyde dehydrogenase isozymes.Alcoholism Clin Exp Res 1981; 5: 12-16.

7. Harada S, Agarwal DP, Goedde HW. Aldehyde dehydrogenase deficiency as cause offacial flushing reactions to alcohol in Japanese. Lancet 1981; ii 982.

FREQUENCY OF ALDH ISOZYME I DEFICIENCY IN ALCOHOLICS, NON-

ALCOHOLICS, AND NORMAL CONTROLS FROM JAPAN

We have now looked at the frequency of ALDH isozyme I

deficiency in alcoholics, schizophrenics, drug dependents, andnormal subjects from Japan. The ALDH isozyme pattern wasdetermined according to the method reported previously.5 Theresults are summarised in the table.The frequency of ALDH isozyme I deficiency in the normal

healthy population in Japan was found to be about 41%. Amongalcoholics, however, only 2 - 3’Vo individuals had the isozymedeficiency. There was no significant difference between alcoholicswith liver disorders and those with mental disorders. The frequencyof deficiency in schizophrenics and drug dependents was similar tothat in normal controls.These observations hint at a protective role for ALDH isozymes

in alcoholism. Individuals deficient in isozyme I may refrain fromexcessive drinking due to initial alcohol sensitivity and flushingreactions caused by raised blood acetaldehyde levels. This mayexplain why alcoholism in Japan has always been less common thanin European and North American countries. Further

epidemiological and population studies are under way.

Institute of Human Genetics,University of Hamburg,2000 Hamburg 54, West Germany

National Hospital of Alcoholics,Kurihama, Kanagawa, Japan

Utsunomiya Hospital,Utsunomiya Tochigi, Japan

S. HARADAD. P. AGARWALH. W. GOEDDE

S. TAGAKI

B. ISHIKAWA

CUTS, MEDICAL SCHOOLS, AND THE N.H.S.

SIR,-Professor Mitchell (Sept. 4) draws attention to the plight ofmedical schools when either the National Health Service or the

University Grants Committee (U.G.C.) cuts its contribution. Herightly points out that it is the total cost of educating a student thatcounts, not the part costs to N.H.S. or U.G.C. which, for historicalreasons, vary greatly in proportion between different schools.However, give-and-take only really works when there is plenty ofgive and not much take. Only in times of growth does such a systemwork well. I suggest that we would be better off with only onepaymaster and that several factors, including the U.G.C. cuts,indicate that this should be the Department of Health and SocialSecurity. In an attempt to meet the U.G.C. and D.H.S.S. demandfor a considerable expansion in the number of medical studentswithout overburdening universities with the very heavy costs, moreand more clinical academic posts have been funded indirectly by theN.H.S., and in some places 50% of the academic staff costs come tothe university from the D.H.S.S. The cuts in the number of stafffunded by the university will totally unbalance the structure ofmany clinical schools, whose reduced research and postgraduateteaching programmes will no longer justify separate universitystatus.

The D.H.S.S. decision to allow full-time consultants 10%additional earning from private practice has had reverberations inthe universities where no clear parallel policy has emerged, and thelaw of the jungle, with the sky the limit, is beginning to apply. Someacademics have established large private practices, in a few cases forthe benefit of departmental research funds but often for their ownpockets. The corruption of academic activity that this is bringing,with the reduction of research time (and interest) and an unseemlyscramble for the juiciest cases, brings to mind the Gadarene swine.A complication of this is that N.H.S. colleagues in teaching

hospitals are increasingly resentful of the way that heads ofacademic units are able to use the fame and status of their

departments as a form of unfair publicity and competition. It isthese N.H.S. clinicians who do most of the teaching of medicalstudents for very little financial reward, and any reluctance on theirpart to continue to do so will result in the collapse of the British styleof clinical education.Should we not be thinking of ways of restructuring medical

education rather than accepting the need to force more and morequarts into pint pots? The universities would be quite happy toprovide a three or four year course in medical science leading to an