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when GOWLAND HOPKINS showed that diseases maybe caused, without the intervention of toxic agents,merely by deficiency in nutrients needed in minuteamounts. Later research, however, has indicatedthat the body’s requirements for aneurine (B1) arerelated to the carbohydrate intake ; and on thisbasis the starch in polished rice might be lookedon as toxic to fowls suffering from aneurine deficiency.Apart from these early surmises, MELLANBY mustbe given full credit for the introduction and practicalproof of the " toxamin ’’ theory. About 20 yearsago he found that dogs whose diets containedcertain cereal products---$-particularly oatmeal-wereabnormally liable to rickets. BRUCE and CALLOW subse-quently showed that the anti-calcifying propertiesof cereals were due to the presence of phyticacid, which is a phosphorylated form of the vitamininositol. HARRISON and MELLANBY confirmed that

phytic acid had the same rachitogenic effects as

cereals in dogs, while McCANCE reported that calciummetabolism was disturbed in human subjects subsistingon a diet consisting largely of wholemeal bread,which is rich in phytic acid.

Investigations in many other fields have sincedemonstrated that a wide variety of natural sub-stances may interfere with the action of differentvitamins. Thus vitamins A and E are opposed byrancid fats,- vitamin E by cod-liver oil, vitamin Kby dicoumarol present in spoilt sweet clover,vitamin B1 by some forms of raw fish and by sub-stances present in ferns, nicotinic acid by maize, andbiotin by the avidin present in raw egg-white. Inaddition to these natural antagonists many artificialanti-vitamins have been synthesised. The first

representatives of this class to be discovered were thesulphonamides, which were used in infections beforetheir biological significance was fully understood.The WOODS-FILDES theory that they exert theirbacteriostatic action by competition with p-amino-benzoic acid, and the later recognition of this substanceas a vitamin either by itself or as a component ofpteroylglutamic acid, have now amply justified theclassification of these well-known therapeutic agentsas anti-vitamins.- Artificial anti-vitamins opposingthe actions of vitamins B1, C, E, K, nicotinic amide,

- riboflav ine, biotin, adermin, pantothenic acid, inositol,and choline have been synthesised. Some of thevitamins they antagonise are no less important thanp-a.minobenzoic acid for the nutrition of bacteria,but few of the anti-vitamins so far tested show promiseof rivalling the sulphonamides in the treatment ofinfections. Their mode of action appears to dependon their close chemical similarity to the actualvitamins, which allows them to displace the vitaminin its association with essential enzyme systems, thusrendering these systems ineffective. Clearly, therefore,the artificial analogues must differ widely in their modeof action from most of the naturally occurringantagonists,- which seldom bear a close chemicalresemblance to the vitamins which they oppose.KODICEK contends that the term " toxamin " shouldbe applied to all substances which interfere with theaction of vitamins, whereas " anti-vitamin

" should bereserved for the substances which act by reason ofchemical analogy. On this basis dicoumarol whichwas discovered iii spoilt sweet clover through thesevere outbreak 6f hæmorrhagic disease which it

caused in cattle, may reasonably be classed as a

naturally occurring anti-vitamin ; and inoidentallythe use of dicoumarol in the treatment of thrombosisis an instructive illustration of the application of

veterinary research to human medicine.The existence of toxamins adds greatly to the

perplexities of the analyst called on to estimate thevitamin values of a food. For most vitamins he hasboth chemical and biological methods of testing at hisdisposal. If he uses chemical tests he will learn howmuch of a particular vitamin is present, but he willnot know whether the vitamin can be efficientlyabsorbed from the food or whether the food containstoxamins which will prevent the vitamin fromexerting its full activity. A biological test, on the otherhand will measure the total physiological activity ofthe food, as influenced by the efficiency of absorptionof the vitamin and the presence or absence of toxamins,but will not tell him the actual amount of vitaminpresent. Measurements of vitamin contents " bychemical methods and of vitamin activities " bybiological methods, therefore, may sometimes givewidely divergent results. Neither result can beconsidered more essentially right than the other, andthe choice will depend on the question which theanalyst has set out to answer. To avoid ambiguity,data on the vitamin values of foods should be

accompanied by an indication of the method ofestimation used.

Histoplasmosis and Pulmonary TuberculosisTHE resemblance between tuberculosis and some

fungus infections of the lung has long been recognised,particularly in the United States. Coccidioidomycosis,for example, can sometimes only be distinguished fromtuberculosis by careful examination of the sputum andthe specific skin-tests to tuberculin and coccidioidin :while torulosis, as DANIEL and his colleagues ilately showed in these columns, can simulatetuberculosis of the nervous system very closely.No condition recognised by mycologists has givenrise to such intense speculation within recent yearsas histoplasmosis, an infection with the fungusHistoplasma capsulatum, which is sometimes known as"

Darling’s disease," the acute form of which has beenknown since 1906. The early cases recorded-presentedwith fever, ulceration of the mouth and gastro-intestinaltract, enlargement of the liver, spleen, and lymph-glands, anaemia, and leucopenia. It was confusedwith kala-azar until the causative organism was

found either in the blood or more often in affectedtissue, particularly the lymph-glands and bone-marrow. Isolated reports appeared subsequently,but the real extent of the infection did not begin tobe suspected until 1945, when CHRISTIE and his

colleagues 2 in Tennessee, after observing a fatal case in a child, prepared histoplasmin, -a substancewhich on injection produced a specific skin reactionin people who had been infected with the fungus.Further studies showed that histoplasmin sensitivitywas unexpectedly common; that such sensitivitywas sometimes associated with pulmonary calcification,usually multiple and sometimes massive but oftenmiliary in type ;. and that many people With dis-

1. Daniel P. M., Schiller, F., Vollum, R. L. Lancet, Jan. 15, p. 53.2. Christie, A., Patterson, J. C. Amer. J. publ. Hlth, 1945, 35, 1131.

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seminated pulmonary calcifications reacted positivelyto histoplasmin but not to tuberculin. Furthermore,sensitivity to histoplasmin seemed to be more or lessconfined to a rigid geographical area in the MiddleWest of the U.S.A. Since most of the histoplasminreactors gave no past history of illness it is evidentthat infection with the fungus can occur in a sub-clinical form : there appears, in fact, to be a gradationin severity from the acute generalised histoplasmosisdescribed by DARLING to the subclinical form, inferredfrom the results of skin testing. which may or may notbe associated with multiple calcifications in the lungsubstance. For example, in five cases which cameto necropsy HOLT 3 has noted lung changes rangingfrom miliary parenchymatous lesions, with hilar

lymph-glandular enlargement, to patchy pneumonitisand larger areas of pulmonary consolidation.The many writers on this subject in the last five

years have emphasised the close similarity betweenhistoplasmosis and tuberculous infection ; they havealso cast doubt on the fairly general assumptionthat calcified deposits in the lung substance, symptom-less and discovered accidentally by X ray, are alwaysthe result of tuberculosis. But calcification, even

though symptomless, is the end-result of a previouslyactive focus, and such foci in histoplasmosis have onlyrarely been recognised and studied. EDWARDS and

colleagues 4 have now tried to bridge this gap in adetailed and comprehensive study of the pulmonaryinfiltrates and mediastinal lymph-glands enlargementobserved among 12,803 student nurses who were

systematically tested for sensitivity to both tuberculinand histoplasmin. Of these nurses 224 showed

pulmonary infiltrates, classified into (1) nodular,(2) poorly circumscribed, (3) fibrotic, and (4) " non-specific " infiltrates, naturally of diverse aetiology.Only 0.26% of the infiltrates were found in the groupwhich reacted to neither antigen. Further analysisrevealed an association between the tvpe of infiltrateand the type of antigenic sensitivity. Thus, for nodularinfiltrates, among nurses who reacted to histoplasminalone the rate was 3.4%; whereas among the tuber-culin reactors who did not react to histoplasminit was 0-4%. The opposite was true of poorlycircumscribed infiltrates, which were found in 1.9% ofnurses who reacted to tuberculin alone comparedwith 0-4% of those reacting to histoplasmin alone.Other points of difference suggested by this surveywere : first, that the poorly circumscribed infiltratesassociated with a positive tuberculin reaction tendedto occupy the upper parts of the lungs, whereas thenodular infiltrates found in histoplasmin reactorswere universally distributed ; and secondly, thatcalcification seemed more common in the nodular.infiltrates of the histoplasmin reactors than in the othergroups. Enlargement of the mediastinal lymph-glandswas observed 38 times : 31 of these nurses reacted tohistoplasmin alone, 4 to both antigens, and 3 to neitherantigen. None reacted to tuberculin alone.These studies should ’not be regarded as supplyingfinal proof, but they forcibly suggest that histo-plasmosis in the United States is a disease to be,reckoned with as a source of pulmonary calcification.On this side of the Atlantic the infection has not yet3. Holt, J. F. Amer. J. Roentgenol. 1947, 58, 717.4. Edwards. L. B., Lewis, I., Palmer, C. E. Publ. Hlth Rep.

Wash. 1948, 63, 1569.

been demonstrated, so far as we are aware : of several .hundred people living in Holland none were found toreact to histoplasmin,5 and a, small investigationby McWEErrEY and his colleagues on 320 Dublinchildren was completely negative. We mustnevertheless be on the watch.

Annotations

THE WRONG DRUG

DOCTORS and nurses are still not always fully aware ofthe potency of the local anaesthetics they handle everyday, and of the ease with which these drugs, improperlyused, can kill. Distressing and needless deaths still occurin our hospitals-and not by any means only in thesmallest ones-because a drug is injected either in mistakefor another or in gross overdosage. One of the commonmistakes is to inject a more potent local anaesthetic (thenames of all of them end in " ... caine ") in the beliefthat it is procaine. The drug is injected in a dose manytimes its proper one, and the patient dies. Lately anothersuch report has been added to the already long list ofsimilar cases. A young man was to have a nasal operation.A liquid which the surgeon believed to be procaine wasinjected. It was in fact cocaine and the patient died.Once again the coroner expressed the hope that, to,avoida repetition of this accident, drugs would be identifiedby distinctive colours and those responsible for them

‘

would be more careful. But neither publicity _ norcoroners’ admonitions have sufficed to prevent thesedistressing errors. The injection of cocaine instead ofprocaine is but one example of mistaken identity.Alcohol and thiopentone, as well as antiseptics ofvarious kinds, have also been injected, instead of localanaesthetics, into nerves, with disastrous results. Eventhe fear of litigation, and the possibility of heavy damagessuch as have been imposed in another case of thisnature, have not been effective. In the long run the onlyremedy lies in teaching medical students the dangers ofthese drugs and the dire results that follow their confu-sion. At present students, and even budding surgeons,receive little instruction on local anaesthetic drugs apartfrom what they are taught by professional pharmaco-logists early in’their career. It might be better if thisinformation was given them shortly before their quali-fication by someone familiar with the drugs throughdaily use. ’

In the case of local anaesthetics the two suggestionscommonly put forward are for the solutions to be dis-tinctively coloured, and for the names of the drugs to beso dissimilar in sound that they could not be confusedeven in the most indistinct telephone conversation.Either suggestion would undoubtedly help to preventaccidents if adopted on a national scale, with the backingof the British Pharmacopœia and defence societies, andif non-observance carried legal penalties. But manyhospitals already colour their cocaine red ; and at leastone death occurred because the pharmacist omitted todo so and the solution was assumed to be procaine. Toreduce the chances of error precautions of this sort mustbe backed by a heightened awareness of the possibilityfor danger. It is still not uncommon, for example, tohear Nupercaiiie’ referred to as Percaine ’ at scientificmeetings, though the -latter name was given up somesix years ago 9 because there had been confusion betweenpercaine, cocaine, and procaine. Then if " dangerous5. Quoted by Christie and Patterson.6. McWeeney, F. J., Crowe, M., Dunleavy, E., Magnon, M.J. med. Ass. Eire, 1846, 19, 163.7. Manchester Guardian, Jan. 12, 1949.8. Lancet, 1947, i, 571.9. Ibid, 1942, ii. 221, 340.