28

test, which utilises a mixture of cyanocobalaminlabelled with cobalt-57 bound to gastric juice andfree cyanocobalamin labelled with cobalt-58, hasbeen introduced by BELL and his colleagues 6; it hasthe advantages that only one urine collection isneeded and it is not dependent on commerciallyproduced intrinsic-factor preparations which varyin activity. This mixture, available under the name,

Dicopac ’,* can be used by any laboratory whichhas the appropriate discriminating apparatus; foronce, the new test is no more expensive than theold. In both the Schilling test and the dicopac testa "

flushing " dose of 1 mg. of unlabelled cobalaminis given, so treatment begins when the test is used.The association of megaloblastic anaemia due to

folic-acid deficiency with the steatorrhoea syndromes,both non-tropical and tropical, is well established.In temperate climates it is particularly seen inadolescents and young adults with steatorrhoea who

may not, however, have had symptoms of coeliacdisease in childhood. Folic-acid-deficiency anaemiawithout steatorrhoea seems to be more common thanwas previously thought. Its association with thelast trimester of pregnancy is well known, and thereasons for its development are clearly understood.STREIFF 2 draws attention to its occurrence in other

groups, especially in elderly people on relatively poordiets and in alcoholics. He points out that cookingseverely reduces the folate content of some foods,such as cabbage and egg, but in others, such asmilk and white meat, there is little effect; some ofthe newer methods of preparing food for marketalso diminish the folate content, particularly cookedfrozen foods and lyophilised meats and vegetables.Patients with chronic hxmolytic anaemias may needmuch more folic acid than usual. STREIFF reminds usthat HERBERT 7 showed that body stores of folateare sufficient for a mere 4 to 6 months and that a lowserum-folate level appears a mere 3 weeks after suppliesof folic acid are completely cut off; but it is 19 weeksbefore clinical anaemia appears and the marrowshows megaloblastic change. Nevertheless, these

figures show why nutritional folate deficiency ismuch more likely to develop than vitamin-B12deficiency. Such anaemias have been reported inthis country in Sheffield,8 Liverpool,9 and Bristol.lo

For the diagnosis of folic-acid-deficiency anaemiaSTREIFF 2 thinks that the results of the serum folateand vitamin-B12 assays are needed, together withthe results of a clinical trial of oral folic acid; unfor-tunately there is at present no test of absorption forfolic acid like the tests available for vitamin B12,since the only effective labelled compound is tritiated* Obtainable from the Radiochemical Centre, Amersham, Bucks.6. Bell, T. K., Bridges, J. M., Nelson, M. G. J. clin. Path. 1965,

18, 611.7. Herbert, V. Trans. Ass. Am. Physns, 1962, 75, 307.8. Varadi, S., Elvis, A. Lancet, 1964, i, 1162.9. Forshaw, J., Moorhouse, E. H., Harwood, L. ibid. p. 1004.

10. Read, A. E., Gough, K. R., Pardoe, J. L., Nicholas, A. Br. med. J.1965, ii, 843.

folic acid, the estimation of which demands complexequipment. The serum-folate level in normal sub-jects should be above 3 ng. per ml. and in deficientpatients is usually 2 ng. per ml. or less; the serum-vitamin-B12 level is variable but is rarely as low asthe 50 pg. per ml. seen in vitamin-B12 deficiency.For clinical trial, very small doses of folic acid shouldbe used to avoid a clinical response to the wrongagent, and a dose of 200 {ig. daily is recommended;during the trial the diet must be controlled andshould not include large amounts of liver, fresh fruit,green vegetables, or fruit juices.Once the diagnosis is established, treatment of

megaloblastic anaemia is straightforward. But it isessential to remember that no active material mustbe given before the diagnostic tests, since eithervitamin B12 or folic acid given in pharmacologicaldoses can completely change the marrow picturewithin 48 hours, even when the wrong agent hasbeen used. For vitamin-B12 deficiency it is usual

today to give hydroxycobalamin intramuscularly,and 100 g. a day for 7-10 days is enough to pro-mote a remission. Maintenance with 1 mg. intra-muscularly every month is sufficient thereafter. Theminimum daily requirement of folic acid for an

adult is now estimated at 50-100 ng., and in preg-nancy 300-400 jig. daily is needed. In folic-acid-deficient patients 5 mg. orally daily for 4 weeks ismore than sufficient, according to STREIFF, to treatthe anaemia and restore tissue stores to normal.But when the anaemia has been treated, steps mustbe taken to correct the cause whenever possible; ofcourse, in pernicious anaemia this cannot be done,and treatment for life is the rule.

Cooling OffTHE medical profession and the new Government

have sensibly found a quick way back from the brinkto which the British Medical Association was bundlingthe National Health Service. After his talks withdoctors’ and dentists’ representatives last Friday,Sir KEITH JOSEPH, Mr. HEATH’S Secretary of Statefor Social Services, went so far as to write theletter reproduced on p. 37. But just how far isthat? The Government, in return for the renewalof doctors’ cooperation in N.H.S. administration andin the signing of certificates, has withdrawn from thePrices and Incomes Board the second 15% of theReview Body’s recommendations referred to it by theLabour Government and has undertakento re-establishan independent review body to advise the Govern-ment on doctors’ and dentists’ pay. Not, it has beennoted, the Review Body (our Review Body, as thedoctors often called it), but a review body. Sir KEITHreiterates the Royal Commission’s proviso that

"obviously compelling reasons" would be needed tojustify rejection or modification of the body’s advice;

29

and the Government would explain any such reasonsit found. Moreover, the body’s recommendationswould not be subjected to any second appraisal (suchas that of a Prices and Incomes Board)-except bythe Government itself.

From these slight comforts the B.M.A. has takenheart and sense enough to stop its harassment of theN.H.S., to subdue its talk of resignation, and toaccept the Government’s offer to enter into veryearly discussions on the matters of pay now takenback from the Prices and Incomes Board. The rightdecision has thus been reached by an unnecessarilypainful path. Much of the conflict might have beenavoided if Mr. WILSON’S Government had not beenso tactless towards the B.M.A. and towards theReview Body itself: firstly, in seeking to postponepublication of the Body’s report until after the generalelection; and, secondly, in explaining unsatisfactorilythe referral of the 15% to the Prices and IncomesBoard. All the same, the B.M.A. had no justificationfor rushing in suspicion and rage to the barricades onJune 4, the day the referral was announced. For theAssociation has now put aside (for good, it is to behoped) the weapons of non-cooperation and resigna-tion, and yet the situation on June 27 was littledifferent from that on June 4, when the war-cry wentup. The Government, not the Prices and IncomesBoard, is to make the decision on the outstanding15%; and, like any other Government, it reserves theright to withhold part or all of it if the country’seconomic situation cannot bear the cost. The assur-ance of a Government explanation of any " obviouslycompelling reasons " has, it seems, weighed heavilyin the apparent rapid restoration of the profession’strust in politicians, though a newly elected Govern-ment need never have to look very far back to find

reasons, in its predecessor’s alleged mismanagement,for rejecting a pay claim. The principle of an inde-pendent review body has been reaffirmed. Despitethe B.M.A.’s insistence, however, that it has been

fighting tooth and nail for that lost principle and notfor money, nothing that happened on June 4 did infact destroy the principle. The events of that daymerely illustrated again that such a body’s functionis and always must be advisory. Apparently believingotherwise, the old Review Body dispatched itself byresigning. The " principle " was and still is intact.

Fortunately, after all, relations between Govern-ment and profession are now some way towardsrepair; and the direct negotiations which, but for theonset of the general election, might have taken placeweeks ago can now begin. But the most importantmove is the re-establishment of a review body (perhapsof entirely new members), one of whose primeobjects is, in fact, to avoid too many face-to-facenegotiations between doctors and Governments,which have led to much friction in the past. Sir KEITHJOSEPH’S letter gives little away, but it is as much as

the profession could reasonably expect; and the

B.M.A., sustained by its supporters’ shouts of victory,may now turn with relief to the more agreeable taskof fortifying the National Health Service.

IS LYONISATION TOTAL IN MAN?

ACCORDING to Lyon’s hypothesis only one of thetwo X chromosomes in the somatic cells of mammalianfemales is genetically active. Early in embryonic lifeeither the maternally or paternally derived X chromo-some becomes inactivated; the choice of X chromosomeis random in each cell but once made remains fixed.Genetical inactivation provides a mechanism for dosagecompensation for the presence of a second X chromo-some in normal female cells. Recently, two groups ofworkers 2 have used the premise that the PhI (Phila-delphia chromosome)-positive bone-marrow cells inchronic myeloid leukaemia represent a single clone totest the application of the Lyon hypothesis to the sex-linked Xg blood-group system of man. Both groupsagreed in that they were unable to demonstrate geneti-cal inactivation of the Xg locus.The single or multicellular origin of tumours is a

subject of general current interest which has been dis-cussed 4 in relation to Burkitt’s lymphoma. Populationsof tumour cells may be identifiable by chromosomemarkers. A common marker chromosome in a cell

population is suggestive but not conclusive evidence oforigin from a single cell, since similar chromosomalchanges could arise in more than one cell either spon-taneously or after exposure to a noxious agent.

Another approach to the study of clonal origin is theuse of cellular markers, such as isoenzymes, thatexhibit genetic polymorphism. The cells of heterozy-gous individuals carry the genetic information for twodifferent biochemical patterns. In certain circum-stances, although populations of cells show the expectedheterozygous phenotype, individual cells, or a popula-tion of cells of single clonal origin, may express theproduct of but a single allele. Such is the situation insome sex-linked genetic systems in mammals, to whichthe Lyon hypothesis is known to apply. I>

Of the loci on the X chromosome in man that havebeen demonstrated to undergo inactivation, that forglucose-6-phosphate dehydrogenase (G.-6-P.D.) hasbeen skilfully exploited to give information about thesingle or multiple origin of tumours. 6,7 The A and Btypes of G.-6-P.D. are electrophoretically distinguish-able ; both are found in fibroblast cultures made fromskin biopsies of heterozygous females, but clones ofnormal or malignant cells show only type A or B butnot both.

It is not known whether the process of inactivationincludes all the loci on the X chromosome. This doubt

applies particularly to the blood-group locus, Xg. Two1. Lyon, M. F. Nature, Lond. 1961, 190, 372.2. Fiaklow, P. J., Lisker, R., Giblett, E. R., Zavala, C. ibid. 1970, 266,

367.3. Lawler, S. D., Sanger, R. Lancet, 1970, i, 584.4. ibid. p. 400.5. Davidson, R. G., Nitowsky, H. M., Childs, B. Proc. natn. Acad.

Sci. U.S.A. 1963, 50, 481.6. Linder, D., Gartler, S. M. Science, N.Y. 1965, 150, 67.7. Gartler, S. M., Ziprowski, L., Zrakowski, A., Ezra, R., Szeinberg,

A., Adam, A. Am. J. hum. Genet. 1966, 18, 282.