HYPERMETHIONINÆMIA IN ACUTE TYROSINOSIS

1132 able for the sort of propaganda which Mr. Kitchin agrees can obscure the truth. Professor Eysenck in his comments (Oct. 30) on your annotation (Oct. 16) cites Poche et al.1, who found no association between lung cancer and smoking in an autopsy series, without commenting on Berkson’s criticisms of such studies 2; while in his book he gives in great detail Berkson’s criticisms of the hypothesis that cigarette smoking causes lung cancer. Nor does he refer to the technical dificiencies of Poche’s study, to which attention has been drawn elsewhere.3 Why should one isolated study with technical deficiencies be preferred to the evidence of over 40 surveys in which an association has been found between cigarette smoking and lung cancer ? Professor Eysenck concentrates his criticisms on the numerous careful studies that appear to confound his personal views, but happily accepts those studies, however misleading, which support him. Postgraduate Medical School, Ducane Road, C. M. FLETCHER. London, W.12.

METHYLENE-BLUE IN ALCOHOL-INDUCED HYPOGLYCEMIA the SIR,-Although taking of alcohol seldom brings on does so in the glycogen-depleted it sometimes hypoglycxmia chronic alcoholic who has no gluconeogenic reserve. Moreover, hypoglycxmia has been reported in properly selected patients who had merely fasted overnight and were then given alcohol.4 Many physiological mechanisms have been suggested to account for the hypoglycxmia, inciting increased insulin (or insulinlike) activity, depressed gluconeogenesis from aminoacid precursors, abnormal ratios of diphosphopyridine nucleotide and reduced diphosphopyridine nucleotide (D.P.H./D.P.N.2H), mitochondrial reoxidation of D.P.N.2H, and reduced catecholamine excretion.5-7 Methylene-blue has been used to treat lactic-acid acidosis because it aids the oxidation of D.P.N.2H.8 In view of this and the decreased D.P.N./D.P.N.2H ratio in alcoholic hypoglycaemia, intravenous methylene-blue was given to a selected group of alcohol hypoglycxmics to determine its effects on blood-sugars. This over-production of D.P.N.2H probably accounts also for the increased lactate levels, and hence for the decreased urate secretion (gout) in some alcoholics. Thirteen patients were fasted for periods ranging from 36 to 90 hours, with only water, black coffee, and tea being permitted. After the fast, each patient was given intravenously 1 litre of a 15% by volume solution of pure ethyl alcohol in physiological saline solution over a 4-hour period. Venous blood-samples were withdrawn for determining glucose levels (NelsonSomogyi method) before the intravenous infusion was begun, each hour for the first 3 hours after the infusion was begun, and then every 2 hours until 12 hours had elapsed. At this point, methylene-blue, 3 mg. per kg. of body-weight, was slowly infused intravenously. Blood was then withdrawn for glucose determinations every 30 minutes for the next 2 hours, at which time the test was concluded and the patient was fed. Most of the patients were drowsy and slept deeply during the alcohol infusion, and many vomited towards the end of the infusion. Recovery was generally prompt after the alcohol administration was concluded; but, despite normal levels for their blood-sugar, a few patients seemed confused the next morning. Of the thirteen patients, five were diabetic (taking oral substitutes or less than 40 units of insulin); four were controls; and four were documented Laennec cirrhotics. Three of the diabetics had significant depression of their blood-sugar levels 1. 2. 3. 4.

5. 6. 7. 8.

Poche, R., Mittman, O., Kneller, O. Z. Krebsforsch, 1964, 66, 87. Berkson, J. Proc. Staff. Meet. Mayo Clin. 1955, 30, 319. Koller, S. Z. Krebsforsch. 1964, 66, 852. Freinkel, N., Singer, D. L., Arky, R. A., Bleicher, S., Anderson, J. B., Silbert, C. K. J. clin. Invest. 1963, 42, 1112. Arky, R. A., Freinkel, N. Archs intern. Med. 1964, 114, 501. Field, J. B. Presented at Regional Meeting, American College of Physicians, Detroit, Michigan. Nov. 21, 1963. Kahil, M. E., Cashaw, J., Simons, E. L., Brown, H. J. Lab. clin. Med. 1964, 64, 808. Tranquada, R. E., Berstein, S., Grant, W. J. Archs intern. Med. 1964, 114, 13.

within 12 hours, but only two of these responded to methyleneblue by their fasting blood-sugar levels reverting to preinfusion levels. The fourth diabetic gave no blood-sugar response to infused alcohol. A paradoxical hyperglycxmia occurred in the fifth diabetic during and after alcohol infusion. This may have been on the basis of reoxidation of D.P.N.2H in the cytoplasm (extramitochondrial system) as opposed to the oxidation that occurs in the mitochondria (yielding hypo-

glycoemia).-49 lo

Three of the four controls became hypoglycsemic (as low as 38 mg. per 100 ml.) within 12 hours, but only one responded to

methylene-blue. None of the cirrhotics became hypoglycaemic. Perhaps there increased peripheral utilisation of glucose or abnormal quantities of alcohol dehydrogenase in their livers. Though methylene-blue may serve as an adjunct in alcohol hypoglycsemia to repair a biochemical deficit, continuous glucose infusions are apparently required to restore normal bloodsugar levels in all cases of alcohol-induced hypoglycaemia. Department of Medicine, Graduate Hospital, SIGMUND R. GREENBERG University of Pennsylvania, JOHN H. KERR. Philadelphia 19146.

was

ECTOPIC PREGNANCY Gulshan writes (Oct. 16) that the diagnosis of SIR,-Dr. in his area is " commonly... so obvious ectopic pregnancy that pouch-of-Douglas puncture... is not called for ". Why is such a simple and safe procedure as needle aspiration of the pouch of Douglas not more appealing to clinicians? If abortions (and complications of abortions), pelvic inflammatory disease, and ovarian cysts are rare in Dr. Gulshan’s area, perhaps the diagnosis of ectopic pregnancy is always obvious ". But, in my experience in the southern United States, the clinical differential diagnosis of these conditions is often difficult. The finding of a few drops of clear peritoneal fluid, or of cloudy fluid, on culdocentesis may save an unnecessary surgical procedure in a woman with a septic abortion or a severe episode of salpingo-oophoritis-conditions in which surgical exploration of the abdominal cavity offers little of therapeutic value. "

San Francisco, California.

,-.-.

TOM BREWER.

HYPERMETHIONINÆMIA IN ACUTE TYROSINOSIS SiR,ŃTyrosinosis in children is an inherited metabolic disorder characterised by liver cirrhosis, renal tubular defects with vitamin-D-resistant rickets, and abnormal tyrosine metabolism.11-13 The primary enzyme defect seems to be lack of p-hydroxyphenylpyruvate oxidase.13-15 Diet low in phenylalanine and tyrosine normalises the metabolism in this disease.1216 Three different laboratories have reported on hypermethioninaemia combined with hypertyrosyluria and hypertyrosinaemia as in tyrosinosis.1-7-19All these cases were investigated in the terminal stage of the disease, just before the patients died. In one of the Swedish cases of tyrosinosis 20 there was also hypermethioninxmia, but only temporarily in an acute stage. We therefore supposed that methioninasmia was a symptom in the acute or terminal stage in tyrosinosis. We have investigated two sisters, both of whom had tyrosinosis with pronounced hypertyrosinamlia, hypertyrosinuria, 9. Freinkel, N., Cohen, A. K., Arky, R. A., Foster, A. E. J. clin. Endocr. Metab. 1965, 25, 76. 10. Lieber, C. S., Davidson, C. S. Am. J. Med. 1962, 33, 319. 11. Zetterström, R. Ann. N.Y. Acad. Sci. 1963, 111, 220. 12. Halvorsen, S., Gjessing, L. R. Br. med. J. 1964, ii, 1171. 13. Sakai, K., Kitagawa, T., Yoshioka, K. Jilei. med. J. 1959, 6, 15. 14. Gentz, J., Jagenburg, O. R., Zetterstrom, R. J. Pediat. 1965, 66, 670. 15. Taniguchi, K., Gjessing, L. R. Br. med. J. 1965, i, 968. 16. Palmgren, B. Symposium on Tyrosinosis. Oslo, 1965 (in the press). 17. Sass-Kortsak, A., Jackson, S. H., Scriver, C. Abstracts of the American Pediatric Society 74th Annual Meeting, 1964; p. 74. 18. Greenberg, R. E., Chase, H. P., Lovrien, E., Hurwitz, R., Efron, M. L. ibid. p. 142.

19. 20.

Perry, T. L., Hardwick, D. F., Dixon, G. H., Dolman, C. L., Hansen, S. Pediatrics, Springfield, 1965, 36, 236. Fritzell, S., Jagenburg, O. R., Schnürer, L.-B. Acta pœdiat., Stockh. 1964, 53, 18.

1133 and p-hydroxyphenylpyruvic-acid-uria.21 One of these children died aged 3 months. She had pronounced hypermethioninaemia with 2-3 times more methionine than tyrosine in the serum and in the ascites fluid. Her sister survived. When she was 1 year old she had 5 times more tyrosine than methionine in her serum, and her methionine level was normal. Since these two cases were in sisters with very similar manifestations except in regard to the methionine content in the blood, we assume that hypermethioninaemia is a terminal symptom in tyrosinosis, present in the acute stage or just before death with seriously damaged liver function, but absent in surviving chronic cases. Dikemark Hospital,

Asker, Norway. Paediatric Research Laboratory,

Rikshospitalet, Oslo, Norway.

LEIV R. GJESSING SVERRE HALVORSEN.

INTEGRATION IN THE N.H.S. delight, a relief, and a belated stimulus to read Dr. Ellis Smith’s plea for integration in the National Health Service (Nov. 13). Once upon a time a committee, called the Medical Services Review Committee, worked for four years to produce a report 22 in which the predominant theme was integration of the politically tripartite N.H.S. The least responsive part of the profession to the suggestions in the report were the medical officers of health-or, at least, the society which represents them-and this despite the fact that they stood to gain more in status, increased fields of activity, and symbiosis with their hospital and general practitioner colleagues than any other group in the profession. The Medical Services Review Committee envisaged, in their suggestions, that social, preventive, environmental, or epidemiological medicine would become the spearhead of future developments in medicine, and expressed the hope that an expanded sphere of influence for the medical officer of health might be the means of achieving this object. Dr. Ellis Smith’s views may imply a new appreciation of the situation by his colleagues-at a time when recrudescence of interest in the Medical Services Review Committee’s report is becoming more obvious in many quarters. Whatever the administrative machinery required, medicine in this country will never regain its pristine robust health until its three parts are again fused into one profession. ARTHUR PORRITT. London, W.1.

SIR,-It

was a

THE ORGANISATION OF THE N.H.S. SIR,-Dr. Discombe’s article (Nov. 13) on the National Health Service, and particularly the hospital service, is very

timely. The hospital in which I work has recently been visited by senior officials of the regional board. It is a temporary hospital built during the 1914-18 war, and the building programme has recently been put back a number of years, leaving us with bits of old and bits of new, which are going to be even more difficult and frustrating to work in than the entirely old (but fairly unified) hospital. The object of the officials’ visit was to see what was the least money that could be spent to make the temporary buildings habitable and usable as a "hospital" for the now greatly prolonged time before we get our own completely

It appears to me that all doctors who have anything to do with the hospital service, whether as administrators or clinicians, have a duty to impress on all their contacts, official or personal, the following: 1. The hospital service is slowly running down. Its plant is becoming more inadequate every day, and its doctors, both senior and junior, more overworked and frustrated, knowing much about modern diagnostic and treatment methods yet in many instances not being able to apply them. 2. It does not appear possible to finance the hospitals from direct Exchequer funds, either now or in the future. 3. Therefore these courses are open to the Government: (a) to continue as at present with an ever-worsening hospital service; (b) to raise money by other means. I am no financier, but even I can think of several methods. This country has a mania for gambling. Why not a hospital sweep as in Ireland ? Or a bond issue ? Or, unpalatable as it may be to politicians, make the patient pay something ?

Only when enough people are aware of the facts can pressure be applied to politicians of all parties to make them face the facts and act. Beckenham, F. G. HERMAN. Kent. LONDON TEACHING-HOSPITAL TEACHING SIR,-As a London University medical student nearing finals, I feel that the course has been inadequate and that the old teaching hospitals of London have had their day. Admittedly the medical schools have to conform to the syllabus laid down by the university. But the second M.B. examination should be reformed. The pathology examination should take place early in the clinical period and not be part of finals. The examiners require a type of knowledge which leads to unreasoning rote-learning. But even if the syllabus were reformed-as it would be if the consultants and medical-school staff were interested-the teaching-hospital system would still be unsound. Hospital staff are rightly more concerned with the patients than with the students. The curriculum tends to be disorganised, the teaching to be didactic, unsystematic, and uninspiring; practical details tend to submerge basic principles; and nonhospital specialties such as social medicine, public health, experimental pathology, and tropical medicine tend to be neglected. The medical student is isolated socially and intellectually from students of other subjects. The circumstance that his teachers are also his potential employers leads to a stifling of criticism and an obsequious conformity. Above all he lacks a broad education. The medical profession is an influential body; its members must not be ignorant and narrow-minded. Nowadays every doctor must learn to keep up with technical advances, to examine critically what he reads in journals, and to adjust himself to the changing pattern of medical care. He requires therefore an academic background which the teaching hospital cannot provide. Much of medicine can only be taught at the bedside. The rest is better taught elsewhere. R. J. ROWLATT. London, S.W.9. AGRONOMY AND HEALTH

SIR,-In my article (Oct. 2) two thoughts were expressed: non-fragmentation of learning, and the other, the

new one.

one, the

After the meeting I remarked to one of the officials, a doctor, that this seemed to be an exercise in futility, in that we had spent a morning trying to reach the minimal standard possible, rather than working on a plan to make a local service of a high standard with adequate facilities for diagnosis and treatment. He seemed surprised, and said in effect that it was his job to carry out board policy and that it was up to the politicians, not the administrators, to change things and provide enough

need for the universities of underdeveloped territories to teach their students vocational skills. The article dealt with education at two levels-at the level of the illiterate group and the level of the university undergraduate group. As a belated postscript I would like to refer briefly to higher learning, and the founding of an institute of higher learning devoted solely to the interests of the less-privileged countries. The purpose of such an institute would be to give an understanding to present leaders and potential future leaders of the need for a balanced ecological process. The interrelationship of the various government ministries and departments, the interactions of the public sector and the private sector, the coordina-

money. 21.

Halvorsen, S., Pande, H., Gjessing, press).

L. R. Archs Dis. Childh.

22. A Review of the Medical Services in Great Britain. see Lancet, 1962, ii, 925.

(in the

London, 1962.