DARKNESS OUT OF LIGHT

615

sweating and tender swelling of the brcasts. when the

same

In the

next

cycle,

dose inhibited ovulation, this patient had the

happy experience as the others. In one cycle, the 50-mg. dose was given in the luteal phase only for 10 days; this made no difference to the cycle though it reduced the premenstrual symptoms. In one cycle, 50 mg. was given for 8 days only (4 days before and 4 days after the expected day of ovulation); ovulation was inhibited during medication but occurred 2 days after the drug was stopped. This was similar to experiences with the oral progestogens: if these are to inhibit ovulation they have to be given in adequate dosage early in the cycle (usually from the 5th day); when given later they only delay ovulation. Endometrial biopsies were performed in patient 1. On the 17th day of the cycle. The endometrium seemed thick; the glands were still small and round, without secretion, and the cells still columnar, several layers thick in places, with the nuclei at the base; the stroma was fairly dense and compact, with small dark cells and no oedema. On the 24th day of the cycle the glands were tortuous and the cells still columnar, with some subnuclear vacuolation; the stroma was dense with some small dark cells, but no oedema or decidual change. Withdrawal bleeding occurred in all eight cycles (including the seven in which ovulation was inhibited) though it was scantier than the patients’ normal periods. Bell et al. reported no menstrual bleeding, but their subjects were women of a younger age-group and, possibly, age may determine these different results. If, as Bell et al. suggest, this compound works through suppression of ovarian activity, this has an interesting bearing on the cause of menopausal symptoms. The endometrial-biopsy findings suggest that the early endometrial changes are retarded and that no secretory changes follow; thus, there seems to be more suppression of luteal than of follicular activity. In one patient the medication was withdrawn after two cycles; she reverted immediately to normal, ovulation occurring in the next cycle. These trials are being extended with a daily dose of 75 mg. and in some cases this dose is being given throughout the cycle. same

Council for the Investigation of Fertility Control, Sloane Street, London, S.W.1.

ELEANOR MEARS Medical Secretary.

MALNUTRITION

SiR,ņIagree with Professor Williams’ views (Aug. 18, p. 342) on malnutrition in underdeveloped countries. Malnutrition among pre-school-age children is widespread in Aden. Most of the patients come to outpatient departments for treatment of the acute and intermittent associated conditions mentioned by Dr. Williams. These include bronchitis, infections of the upper respiratory tract and middle ear, staphylococcal skin infections, and gastroenteritis. Many children receive treatment for two or more of these conditions inside a month. The solution of the malnutrition problem will depend on climate, racial customs, endemic diseases, and educational standards. The chief limitation is shortage of money, and the second is staff inadequacy (so few indigenes reach a sufficiently high standard of general education to qualify them for training). This second fate is especially important in the case of women in Arab countries where most of them observe purdah. Obviously, these difficulties are worst in countries where there are no universities or medical schools. From a short-term viewpoint, I believe more could be done in each territory to use existing facilities, with the cooperation, where available, of voluntary workers, such as the Red Cross. Expert advice and guidance would be necessary both for the short-term solution and for its integration with long-term plans. Could not the international organisations such as W.H.O.

provide the nutrition specialists to study the situation various territories and advise accordingly?

in the

JANET BOALER.

Aden.

MANIPULATIVE TREATMENT IN GENERAL PRACTICE

SIR,-The view that a painful range of movement should never be forced is widely held and has recently been endorsed by Mr. Tucker (Sept. 1), but I would submit that it is mistaken. Movement must often be taken beyond the painless range achieve the necessary effect, and part of the skill that the manipulator must acquire is how to apply limited and carefully controlled force with good result in cases where indiscriminate forcing of full range might be disastrous. An important safeguard is the Cyriax training whereby each manoeuvre is followed by re-examination and reassessment. A manoeuvre is thus only repeated or another tried when the results of the previous one have become apparent, and force is only increased when it is clear that rather less force has already had a good effect. Forcing can, of course, be harmful if ill-judged; but to ban it altogether is not merely to play safe (which might be defended) but is to rob manipulation of half its promise to the to

patient. London,

JENNIFER HICKLING.

W.1.

DARKNESS OUT OF LIGHT

SIR,-Dr. Warnock is a distinguished contributor to the literature of Wilson’s disease and it is with some hesitation that I take issue with him; but in his letter of Sept. 8 he refuses to accept the general principle that the publication of obscure cases with a diagnosis that may well be incorrect does not confuse the issue. With regard to his own cases he may be on safer ground though I believe even this point is debatable. However, when it comes to the statement that " darkness out of light " is due to "... the accumulation of a mass of abstruse, and (to some extent) irrelevant biochemical data ..." I can under no circumstances agree with him. When we finally understand the disease in all its ramifications the biochemical disturbances will surely fall into place, and that each will have a place is the one thing of which we can at present be reasonably sure.

To turn from the general to the particular, no-one would wish deprive Dr. Warnock and Dr. Neill of their priority in observing disturbances of copper metabolism in severe hepatic disease, least of all Mrs. Briggs and myself, and we have made no attempt to do so though we are, I maintain, entitled to disagree with some of their conclusions. In fact in the paper quoted13 cases were reported, the first with undeniable Wilson’s disease, the second, a cousin of the first, on whom it is impossible to draw any conclusions on the published data, and the third, a patient with portal systemic encephalopathy, who developed failure of caeruloplasmin synthesis as a result That patients with this syndrome may of liver damage. closely mimic patients with Wilson’s disease is not denied but need cause no intellectual difficulty. The brain can respond to an almost unlimited number of different insults in only a limited number of ways, and because two of these may occasionally coincide does not mean they share more than a to

final common path. As to the nature of Dr. Warnock and Dr. Neill’s final conclusions drawn from these cases it was not possible to be certain, as the following quotation from their paper may show: The present case (their case 3) may, perhaps, indicate that ordinary hepatic cirrhosis is capable of undergoing a metamorphosis-resulting in both structural and metabolic changes of the kind associated with hepatolenticular degeneration"

1.

Warnock,

C. G., Neill, D. W.

Brain, 1958, 81, 258.

616

which, if true, would support Greenfield’s contention.2 But we reject the conclusion that it is, in fact, a case of Wilson’s disease unless, and until, the presence of corneal pigment and tissue copper storage can be proved ". Apparently I was at fault in thinking that this statement showed some degree of uncertainty in the authors’ minds as to the final outcome of their third case, but I believe I was not alone in drawing this

must

deduction. Department of Experimental Medicine, University of Cambridge.

J. M. WALSHE.

TREATMENT OF TRAVELLER’S DIARRHŒA WITH ALBUMIN TANNATE

SIR,--Your annotation on Travellers’ Diarrhoea (July 14) prompts me to describe the treatment I have used for 30 years both personally and for my patients. The treatment consists of albumin tannate (tannin albumin-

ate,Albutannin ’, ’ Tannalbin ’) 1 g. once every hour (2 tablets) chewed and washed down with some water. In 90% of cases this will stop diarrhoea and abdominal pains in a daily cases, when the diarrhoea has not cominfection with shigella organisms should pletely stopped, heavy be assumed, and sulphaguanidine tablets added. In this way shigella infections will be cured in 2 or 3 days at the most. When amrebae are suspected di-iodohydroxyquinoline (’Diodoquin ’) should be taken in a dosage of 2 g. a day. Albumin tannate has an astringent effect which contracts the pores of the intestines, thus stopping the

dose of 5-10 g. In

rare

of bacterial toxins and preventing water loss. denuded ulcers, and by precipitation it inactivates irritants, bacterial toxins, alkaloids, glycosides, &c., and evacuates these substances. Albuminate tannate is insoluble, and hence tasteless, non-irritating, and not poisonous. Being cured so quickly and effectively, the traveller need not forgo any pleasing food; for no diet is required with this therapy.

resorption It also

covers

Department of Applied Pharmacology, University-Hadassah Medical School, Jerusalem, Israel.

Hebrew

F. G. SULMAN.

THYROTOXICOSIS AND VITAMIN B12 SiR,—The death of a patient with thyroid storm and

macrocytic ansemia drew our attention to a relationship thyrotoxicosis and vitamin B12. Instances of concurrent thyrotoxicosis and macrocytic anaemia are not unknown.34 Sure and Easterling5 found that vitamin-B12 prevented death and weight loss in experimental thyrobetween

toxicosis in the rat. Ziffer vitamin-B12 levels lowered in and pernicious anaemia.

al.found the serumpatients with thyrotoxicosis et

We gave 1.0 mg. of vitamin B12 daily intramuscularly for varying lengths of time to 7 thyrotoxic patients. In each subject the diagnosis was clearly established by the characteristic clinical picture, thyroid 1311-uptake studies, and the values for serum-cholesterol and protein bound iodine. The results were as follows:

The first 4 of these patients were studied for a long time. The others were studied briefly mostly in regard to the thyroid uptake of 1311. The surprising increase of the thyroid uptake of 131 was found in all patients except 1. There is no known explanation for its decrease in this patient, about whom the 2. 3. 4. 5. 6.

Greenfield, J. G. Proc. R. Soc. Med. 1954, 47, 150. Bistrom, O. Acta chir. scand. 1946, suppl. 114, Meulengracht, E., Hartfall, S. J. Guys. Hosp. Rep. 1934, 84, Sure, B., Easterling, L. J. Nutr. 1950, 42, 221. Ziffer, H., Gutman, A., Pasher, I., Sobotka, H., Baker, H. Biol. Med. 1957, 96, 229.

only other noteworthy thing was a moderately severe thyrotoxic myopathy. Those patients who received the vitamin for protracted periods became less distressed by the thyrotoxic state than before, but the thyrotoxicosis did not abate. Transient cardiac arrhythmias ranging from extrasystoles to atrial flutterfibrillation were observed in most of the subjects 48-72 hours after they began to take the vitamin. All showed a 0’4-0’7°F fall in basal temperature after vitamin Bl2’ Serum-cholesterol, protein-bound iodine, and magnesium levels did not change significantly during the study. We speculated that the rise of the thyroid-uptake of 131 after vitamin B12 could be understood on the assumption that the vitamin is a component of the mechanisms for the trapping and/or binding of iodine by the thyroid

gland. An experiment which revealed that vitamin B12 can oxidise iodide seems to support this view. We did this as follows: 100 mg. of potassium iodide was added to 1 ml. of 0-1% aqueous solution of vitamin B12 at roomtemperature. The colour changed to brown, and when starch was added it turned blue. The protective effect of vitamin Bl2 against thyrotoxicosis shown in the prevention of death and weight gain in the thyrotoxic rat,5 and by the fall of basal temperature and gain of weight in our thyrotoxic patients may be due to the ability of vitamin B12 to protect against the uncoupling of oxidativephosphorylation by thyroxine-an effect7 which has been established in studies with thyrotoxic rats.’ Oxidative-phosphorylation is responsible, for the efficient use of energy carried on by the respiratory enzyme chains in the mitochondria.8 Cytochrome oxidase, the terminal member in the chain of respirtory enzymes, serves to pass electrons to oxygen. It is of interest that cyanide, sulphide, azide, and carbon monoxide inhibit cytochrome oxidase and have been found also to prevent the in vitro formation of thyroxine.9 Cyanide and sulphide have been shown to react chemically with vitamin B12.1o It is curious that cytochrome-oxidase preparations have never been successfully freed completely of copper," and that the absorption spectra of copper and cobalt are quite similar, which conceivably could lead to confusion of copper and cobalt by spectrophotometric methods. This circumstantial evidence has prompted us to wonder how one can be certain that cytochrome oxidase is not vitamin B12 or its derivative instead of an iron cytochrome as is now accepted. At any rate, the molecular structure of vitamin Bl2 places it in the same general category as the cytochromes since it contains a porphyria ring although one somewhat different from those typical of the hemes. Its metal is cobalt instead of iron. as

The apparent paradox that in hyperthyroid subjects vitamin B12 would cause both an increase of thyroid 1311uptake and an increase in the tolerance to thyrotoxicosis is compatible with the interpretation that it adds to the efficiency of some fundamental process common to many tissues. The enhancement of oxidative-phosphorylation could satisfy this description. This amounts to a more efficient use of energy which might permit a concurrent increase of thyroid function and weight gain in thyrotoxic subjects. Weight gain here is viewed as simply the result of a switch to positive energy balance, whereas an increase of thyroid function could be expected provided its rate had been held down by the limited availability of useful energy. 7. Gershoff, S. N., Vitale, J. J., Antonocicz, I., Nakamura, M., Hellerstein, E. E. J. biol. Chem. 1958, 231, 849. 8. Judah, J. D. J. pharm., Lond. 1959, 11, 1. 9. Schachner, H., Franklin, A. L., Chaikoff, I. L. J. biol. Chem. 1943,151, 191.

25.

Kaczka, E. A., Wolf, D. E., Kuehl, F. A., Jr., Folkers. J. Amer. chem. Soc. 1951, 73, 3569. 11. Slater, E. Advanc. Enzymol. 1958, 20, 147. 10.

Soc. exp.