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ultraviolet light, reduced dietary intake, and (inpatients with steatorrhoea) malabsorption.The presence of secondary hyperparathyroidism in

osteomalacia is controversial. Initial studies revealednormal urinary and plasma hydroxyproline and plasmaparathyroid hormone concentrations and no bone,radiological, or histological changes of

hyperparathyroidism.21 More recently occasional casesof secondary hyperparathyroidism have been

reported, and DIBBLE et al. 20 found evidence of it infive of nine osteomalacic patients. This observation, ifconfirmed, will suggest that parathyroid hormonemaintains the normal plasma total and ionised calciumconcentrations and that patients might requiresupplements of calcium as well as vitamin D. 21Hepatic osteomalacia can be healed by various

metabolites of vitamin D including D2,22 D3,2325-OHD3, 7,22 1-alpha-hydroxyvitamin D3,24 and

1,25-dihydroxyvitamin D3.25 The choice seems

arbitrary. In favour of 1-alpha vitamin D3 and

1,25-dihydroxy vitamin D3 are their short half-lives inthe event of hypercalcaemia and a narrow dose range;against them is their expense. They can be taken orally,but the intramuscular route may be preferable whenthere is steatorrhoea. Although osteomalacia can

probably be healed with doses approachingphysiological replacement levels, there is much to besaid for adjusting the dose to symptoms and plasmacalcium and phosphate concentrations. The place ofultraviolet light as a primary therapy, and of calciumand phosphate supplements, is not yet known.

CRYPTOCOCCOSIS

CRYPTOCOCCOSIS is a subacute or chronic infection caused

by the yeast Cryptococcus neoformans. The presumed portal ofentry is the respiratory tract, but meningitis is the most

frequently recognised form of the disease. Althoughcryptococcosis is not common it is widely distributed

throughout the world and more cases have been reportedfrom the U.S.A., Australia, and the Far East’ than fromelsewhere. In the United Kingdom between 5 and 9 new casesare diagnosed annually. There is some evidence that

cryptococcosis is being diagnosed more frequently thanformerly,3 although it is not clear whether this has followed

20. Dibble JB, Sheridan P, Hampshire R, Hardy GJ, Losowsky MS. Evidence forsecondary hyperparathyroidism in the osteomalacia associated with chronic liverdisease. Clin Endocrinol (Oxf) 1981; 15: 373-83.

21. Cundy T, Kanis JA, Heynen G, et al. Failure to heal vitamin D-deficiency rickets andsuppress secondary hyperparathyroidism with conventional doses of1,25-dihydroxyvitamin D3. Br Med J 1982; 284: 883-85.

22. Compston JE, Horton LWL, Thompson RPH. Treatment of osteomalacia associatedwith primary biliary cirrhosis with parenteral vitamin D2 or oral 25-hydroxyvitaminD3. Gut 1979; 20: 133-36.

23. Klass HJ, Warnes TW, Davies M, Mawer EB Vitamin D in primary biliary cirrhosis.Gut (in press).

24. Compston JE, Crowe JP, Horton LWL. Treatment of osteomalacia associated withprimary biliary cirrhosis with oral 1-alpha-hydroxy vitamin D3. Br Med J 1978; i:

78-81.25. Long RG, Varghese Z, Meinhard E, Skinner RK, Wills MR, Sherlock S Parenteral

1,25-dihydroxycholecalciferol in hepatic osteomalacia. Br Med J 1978; i: 75-77.1. Pathmanathan R, Tuck Soon SH. Cryptococcosis in the University Hospital, Kuala

Lumpur and review of published cases. Trans Roy Soc Trop Med Hyg 1982; 76:21-24.

2. Hay RJ, Mackenzie DWR, Campbell CK, Philpot CM Cryptococcosis in the UnitedKingdom and the Irish Republic: an analysis of 69 cases. J Infection 1980; 2: 13-22.

3. Kaufman L, Blumer S. Cryptococcosis: the awakening giant. PAHO Sci Publ 1978;356: 176-82.

an increased awareness of the infection or a real change in thenumbers of new cases. Whatever the reason, cryptococcosisstill carries a substantial case fatality rate.

C. neoformans can be isolated from pigeon excreta, thepercentage of positive isolates varying in different parts of theworld. The relation between risk of disease and exposure toenvironmental sources of the organism has not been clearlyestablished. Individual cases of cryptococcosis can only rarelybe linked to a contact with pigeon droppings. There is,however, a subacute pulmonary form of cryptococcosiswhich may resolve without specific chemotherapy, and

’ preliminary studies with a skin-test antigen prepared from C.neoformans have shown that up to 48% of a healthypopulation may have been sensitised to the organism.4 Bothfindings suggest that subclinical cryptococcosis may be quitefrequent but that progressive disease seldom followsinhalation of the organism. The underlying clinical state ofthe patient may influence the outcome of exposure: in certainparts of the world, most patients with cryptococcosis have aserious underlying illness such as sarcoidosis, Hodgkin’sdisease, or systemic lupus erythematosus or are receivingsystemic corticosteroid therapy.The initial focus of infection is usually the lung. In human

tissue, cells of C. neoformans usually possess a large mucoidcapsule and range from 6 to 15 µm in diameter. Ruiz andBulmer5 report that, in the vicinity ofa pigeon nesting site, airsamples contained substantial numbers of smaller

cryptococcal cells 4-7 µm in diameter-an optimum size forlung deposition. The primary lung focus may resolve

spontaneously, but sometimes a well circumscribed

granuloma or cryptococcoma develops which is detected on aroutine chest X-ray. Extrapulmonary infections includingmeningitis follow dissemination from the lungs. Between 12and 15% of patients with cryptococcosis present with skinlesions and there may be no overt sign of infection elsewhere.However, there is no clear evidence that cutaneous forms ofcryptococcosis follow inoculation and most such cases

probably represent dissemination from a primary focus in thelungs. For this reason it is particularly important to

investigate patients with apparently solitary cryptococcallesions for evidence of the infection in other organs.Confirmation of the diagnosis by laboratory procedures

may present difficulties, although with repeated samplingcultures can usually be obtained. One test of majorimportance is the latex agglutination reaction for

cryptococcal polysaccharide antigen 6 in serum or

cerebrospinal fluid (CSF). It is positive in up to 96% of casesand has both diagnostic and prognostic value. It is also asimple and quick screening procedure for patients withmeningitis of unknown cause. False-positive reactions mayoccur-for instance, in patients who have circulating or CSFrheumatoid factor-but can be eliminated by pretreatment ofsamples with dithiothreitol.There has been considerable progress in the treatment of

cryptococcosis. For cryptococcal meningitis, combined

amphotericin B and flucytosine7 has been a major advance.This regimen sterilises CSF faster than amphotericin B alone

4. Bennett JE, Hasenclever HF, Baum GL. Evaluation of a skin test for cryptococcosisAm Rev Resp Dis 1965; 91: 616.

5. Ruiz A, Bulmer GS. Particle size of airborne Cryptococcus neoformans in a tower. ApplEnviron Microbiol 1981; 41: 1225-29.

6. Bloomfield N, Gordon MA, Elmendorf DF. Detection of Cryptococcus neoformansantigen in body fluids by latex particle agglutination. Proc Soc Exp Biol Med 1963,114: 64-67.

7. Bennett JE, Dismukes WE, Duma RJ, et al. Amphotericin B-flucytosine in

cryptococcal meningitis. N Engl J Med 1979; 301: 126-31.

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and the lower dose of amphotericin B means less toxicity.Both drugs may also be given in combination for other formsof cryptococcosis. There are considerable advantages to bederived from multicentre studies ofantifungal regimens sincea single unit seldom encounters enough patients with

systemic mycoses to contribute anything more than anecdotalexperience. Our present understanding of the value of theimidazole drugs, such as intravenous or intraventricularmiconazole,8 or ketoconazole, in cryptococcosis is a case inpoint. Experience has been patchy and variable and it is notpossible to assess their role in the management of thisinfection. An objective multicentre study of antifungalchemotherapy depends particularly on the use of definedcriteria for diagnosis and recovery. Lately there has been animaginative attempt to establish such guidelines9 forassessment of drug therapy in systemic mycoses such ascryptococcosis.

TUMOUR GROWTH FORE AND AFT

ALL good gardeners know where to put their favouriteplants to get the best growth. Those interested in the growthof cells in mammalian garden sites make heavier weather ofthe problem. Oncologists allude often and cosily to the idea ofseed and soil in relation to tumour growth. This concept hasat least the virtue of clarity though the underlyingmechanisms remain obscure. In a recent article,’ Auerbachand Auerbach add considerable precision to one facet of thismatter, though whether their review of anterior-posteriordifferences in growth sites in mammals contributes to ourbasic understanding of why such big differences are observedis more questionable.The basic findings which prompted the Auerbachs to look

carefully at fore and aft as sites of, inter alia, tumour growthare quite straightforward. During studies of tumour

implantation, seemingly capricious results were obtained inrelation to whether immune regulation was exercised-aphenomenon familiar to tumour immunologists. TheAuerbachs ascertained that the location of the tumour

implant even to within a few millimetres within the trunkskin could make a big difference to the result obtained. Theyexpanded their studies to include normal tissue transplants, astudy of drug efficacy, and various physiological indices suchas blood flow and ageing. The results surprised andfascinated them. They also found many earlier reports whichwere germane.When carcinogenic pellets were implanted in the inguinal

regions of rats and mice, the resultant mammary tumourswere much more likely to be thoracic than abdominal (ratsand mice have ten breasts in two groups, three pairs thoracicand two abdominal). Tumours implanted in the cranialregions of adult mice grew much better than did comparablebut more caudal implants. This was true for all the tumoursthey tested and was not obviously related to any kind ofimmunological phenomenon. Anteriorly placed skin

allografts healed more quickly and grew longer than thoseplaced more posteriorly. The Auerbachs also draw attention

8. Graybill JR, Levine HB. Successful treatment of cryptococcal meningitis withintraventricular miconazole. Arch Intern Med 1977; 138: 814-16.

9. Dismukes WE, Bennett JE, Drutz DJ, Graybill JR, Remington JS, Stevens DA.Criteria for evaluation of therapeutic response to antifungal drugs. Rev Infect Dis1980;2: 535.

1. Auerbach R, Auerbach W. Regional differences in the growth of normal and neoplasticcells. Science 1982; 215: 127-34

to the fact that irradiated mice go grey starting from the noseend and moving backwards. All in all it seemed clear that the"soil" at the front end of a rodent is much richer than at theback end. Various explanations are offered-polarity in bloodflow; differences in patterns ofinnervation; and, rather moreabstrusely, gradients residual from embryogenesis. Nonealone seems totally to fit the bill.The corollary for those who transplant tumours in

laboratory animals is very clear; beware, for despite the factthat you have animals of the same sex, age, and strain and theyare housed in the same box, there is another residualuncontrolled variable that you should take account of. For theclinicians the lesson is less obvious. It could easily be, if youstand a four-legged animal on its hind legs, that the pattern ofdistribution of good growth environments for tumoursaround the body is altered. This rather orwellian experimentis not likely to be accomplished, but if the findings of theAuerbachs are indeed relevant to man there should be

striking differences in the head to toe frequency or size orrapidity of growths of primary or metastatic tumours in man.Surely there is a computer somewhere bursting to tell us theanswer if only the correct question is fed into it.

OSLER’S "ENDURING MONUMENT" IN PERIL

IN 1836, the Congress of the United States set up theLibrary of the Army Surgeon General’s Office and in sodoing it wrought better than it knew, for it created two of theworld’s greatest medical institutions. The library became theNational Library of Medicine, which since 1879 has prepareda monthly list of journal articles and so contributed

enormously to medical science. From most of the world’simportant medical journals, every article can be found andtraced by its correct citation; and computers, first byMEDLARS and now by MEDLINE, can speedily providethe information needed by a research worker. Nothing canadequately replace the Index Medicus. This is not to disparage

, other sources of information such as the commercially pub-lished Current Contents and Excerpta Medica, but it has fallento the president of Excerpta Medica to attack the whole basisof Index Medicus and thus to imperil its function andusefulness.’ The argument put forward is that the IndexMedicus should charge prices that would reflect’the total costsof its production, rather than be subsidised by the U.S.taxpayer. These costs, for "fair competition", would includeexpenditure on journals, indexing, and editing; personnel;computer purchase and operation; and dissemination ofinformation, all of which would inflate the costs of IndexMedicus fivefold at least. The principle on which the NationalMedical Library now operates is that scientific informationabout health, disease and its prevention, diagnosis,treatment, and underlying biological processes is a publicresource for the public good; and to press the Americanpublic to pay an artificially inflated price for access to a database the public already owns hardly squares with the notionof "fairness". The matter is still before the U.S. Congress,and resistance is growing fast. Let medical research workersin Britain and elsewhere-and indeed all interested in

health-join in support to maintain the Index Medicus and itsadmirable services as they are and mobilise opinion againstthese unpleasing manoeuvres.

1 Sherrington A. Index Medicus jeopardized, Can Med Assoc J 1982; 126: 459-60.