- Email: [email protected]
Cooling Off
28
test, which utilises a mixture of cyanocobalamin labelled with cobalt-57 bound to gastric juice and free cyanocobalamin labelled with cobalt-58, has been introduced by BELL and his colleagues 6; it has the advantages that only one urine collection is needed and it is not dependent on commercially produced intrinsic-factor preparations which vary in activity. This mixture, available under the name , Dicopac ’,* can be used by any laboratory which has the appropriate discriminating apparatus; for once, the new test is no more expensive than the old. In both the Schilling test and the dicopac test " a flushing " dose of 1 mg. of unlabelled cobalamin is 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 in adolescents and young adults with steatorrhoea who may not, however, have had symptoms of coeliac disease in childhood. Folic-acid-deficiency anaemia without steatorrhoea seems to be more common than Its association with the was previously thought. last trimester of pregnancy is well known, and the reasons for its development are clearly understood. STREIFF2 draws attention to its occurrence in other groups, especially in elderly people on relatively poor diets and in alcoholics. He points out that cooking severely reduces the folate content of some foods, such as cabbage and egg, but in others, such as milk and white meat, there is little effect; some of the newer methods of preparing food for market also diminish the folate content, particularly cooked frozen foods and lyophilised meats and vegetables. Patients with chronic hxmolytic anaemias may need much more folic acid than usual. STREIFF reminds us that HERBERT7 showed that body stores of folate are sufficient for a mere 4 to 6 months and that a low serum-folate level appears a mere 3 weeks after supplies of folic acid are completely cut off; but it is 19 weeks before clinical anaemia appears and the marrow shows megaloblastic change. Nevertheless, these figures show why nutritional folate deficiency is much more likely to develop than vitamin-B12 deficiency. Such anaemias have been reported in this country in Sheffield,8Liverpool,9 and Bristol.lo For the diagnosis of folic-acid-deficiency anaemia STREIFF2 thinks that the results of the serum folate and vitamin-B12 assays are needed, together with the results of a clinical trial of oral folic acid; unfortunately there is at present no test of absorption for folic 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 complex equipment. The serum-folate level in normal subjects should be above 3 ng. per ml. and in deficient patients is usually 2 ng. per ml. or less; the serumvitamin-B12 level is variable but is rarely as low as the 50 pg. per ml. seen in vitamin-B12 deficiency. For clinical trial, very small doses of folic acid should be used to avoid a clinical response to the wrong agent, and a dose of 200 {ig. daily is recommended; during the trial the diet must be controlled and should 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 is essential to remember that no active material must be given before the diagnostic tests, since either vitamin B12 or folic acid given in pharmacological doses can completely change the marrow picture within 48 hours, even when the wrong agent has been 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 promote a remission. Maintenance with 1 mg. intramuscularly every month is sufficient thereafter. The minimum daily requirement of folic acid for an adult is now estimated at 50-100 ng., and in pregnancy 300-400 jig. daily is needed. In folic-aciddeficient patients 5 mg. orally daily for 4 weeks is more than sufficient, according to STREIFF, to treat the anaemia and restore tissue stores to normal. But when the anaemia has been treated, steps must be taken to correct the cause whenever possible; of course, in pernicious anaemia this cannot be done, and treatment for life is the rule.
Cooling Off THE medical profession and the new Government have sensibly found a quick way back from the brink to which the British Medical Association was bundling the National Health Service. After his talks with doctors’ and dentists’ representatives last Friday, Sir KEITH JOSEPH, Mr. HEATH’S Secretary of State for Social Services, went so far as to write the letter reproduced on p. 37. But just how far is that? The Government, in return for the renewal of doctors’ cooperation in N.H.S. administration and in the signing of certificates, has withdrawn from the Prices and Incomes Board the second 15% of the Review Body’s recommendations referred to it by the Labour Government and has undertakento re-establish an independent review body to advise the Government on doctors’ and dentists’ pay. Not, it has been noted, the Review Body (our Review Body, as the doctors often called it), but a review body. Sir KEITH reiterates the Royal Commission’s proviso that "obviously compelling reasons" would be needed to justify rejection or modification of the body’s advice;
29
and the Government would explain any such reasons it found. Moreover, the body’s recommendations would not be subjected to any second appraisal (such as that of a Prices and Incomes Board)-except by the Government itself. From these slight comforts the B.M.A. has taken heart and sense enough to stop its harassment of the N.H.S., to subdue its talk of resignation, and to accept the Government’s offer to enter into very early discussions on the matters of pay now taken back from the Prices and Incomes Board. The right decision has thus been reached by an unnecessarily painful path. Much of the conflict might have been avoided if Mr. WILSON’S Government had not been so tactless towards the B.M.A. and towards the Review Body itself: firstly, in seeking to postpone publication of the Body’s report until after the general election; and, secondly, in explaining unsatisfactorily the referral of the 15% to the Prices and Incomes Board. All the same, the B.M.A. had no justification for rushing in suspicion and rage to the barricades on June 4, the day the referral was announced. For the Association has now put aside (for good, it is to be hoped) the weapons of non-cooperation and resignation, and yet the situation on June 27 was little different from that on June 4, when the war-cry went up. The Government, not the Prices and Incomes
Board, is to make the decision on the outstanding 15%; and, like any other Government, it reserves the withhold part or all of it if the country’s economic situation cannot bear the cost. The assur" ance of a Government explanation of any obviously compelling reasons " has, it seems, weighed heavily in the apparent rapid restoration of the profession’s trust in politicians, though a newly elected Government 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 independent review body has been reaffirmed. Despite the B.M.A.’s insistence, however, that it has been fighting tooth and nail for that lost principle and not for money, nothing that happened on June 4 did in fact destroy the principle. The events of that day merely illustrated again that such a body’s function is and always must be advisory. Apparently believing otherwise, the old Review Body dispatched itself by resigning. The " principle " was and still is intact.
right
to
Fortunately, after all, relations between Government and profession are now some way towards repair; and the direct negotiations which, but for the onset of the general election, might have taken place weeks ago can now begin. But the most important move is the re-establishment of a review body (perhaps of entirely new members), one of whose prime objects is, in fact, to avoid too many face-to-face negotiations between doctors and Governments, which have led to much friction in the past. Sir KEITH JOSEPH’S letter gives little away, but it is as much as
the
could reasonably expect; and the B.M.A., sustained by its supporters’ shouts of victory, may now turn with relief to the more agreeable task of fortifying the National Health Service.
profession
IS LYONISATION TOTAL IN MAN?
ACCORDING to Lyon’s hypothesisonly one of the X chromosomes in the somatic cells of mammalian females is genetically active. Early in embryonic life either the maternally or paternally derived X chromosome becomes inactivated; the choice of X chromosome is random in each cell but once made remains fixed. Genetical inactivation provides a mechanism for dosage compensation for the presence of a second X chromosome in normal female cells. Recently, two groups of workers 2have used the premise that the PhI (Philadelphia chromosome)-positive bone-marrow cells in chronic myeloid leukaemia represent a single clone to test the application of the Lyon hypothesis to the sexlinked Xg blood-group system of man. Both groups agreed in that they were unable to demonstrate genetical inactivation of the Xg locus. The single or multicellular origin of tumours is a subject of general current interest which has been discussed4 in relation to Burkitt’s lymphoma. Populations of tumour cells may be identifiable by chromosome markers. A common marker chromosome in a cell population is suggestive but not conclusive evidence of origin from a single cell, since similar chromosomal changes could arise in more than one cell either spontaneously or after exposure to a noxious agent. Another approach to the study of clonal origin is the use of cellular markers, such as isoenzymes, that exhibit genetic polymorphism. The cells of heterozygous individuals carry the genetic information for two different biochemical patterns. In certain circumstances, although populations of cells show the expected heterozygous phenotype, individual cells, or a population of cells of single clonal origin, may express the product of but a single allele. Such is the situation in some sex-linked genetic systems in mammals, to which the Lyon hypothesis is known to apply.I> Of the loci on the X chromosome in man that have been demonstrated to undergo inactivation, that for glucose-6-phosphate dehydrogenase (G.-6-P.D.) has been skilfully exploited to give information about the single or multiple origin of tumours.6,7 The A and B types of G.-6-P.D. are electrophoretically distinguishable ; both are found in fibroblast cultures made from skin biopsies of heterozygous females, but clones of normal or malignant cells show only type A or B but not both. It is not known whether the process of inactivation includes all the loci on the X chromosome. This doubt applies particularly to the blood-group locus, Xg. Two
two
1. 2.
Lyon, M. F. Nature, Lond. 1961, 190, 372. 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.
test, which utilises a mixture of cyanocobalamin labelled with cobalt-57 bound to gastric juice and free cyanocobalamin labelled with cobalt-58, has been introduced by BELL and his colleagues 6; it has the advantages that only one urine collection is needed and it is not dependent on commercially produced intrinsic-factor preparations which vary in activity. This mixture, available under the name , Dicopac ’,* can be used by any laboratory which has the appropriate discriminating apparatus; for once, the new test is no more expensive than the old. In both the Schilling test and the dicopac test " a flushing " dose of 1 mg. of unlabelled cobalamin is 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 in adolescents and young adults with steatorrhoea who may not, however, have had symptoms of coeliac disease in childhood. Folic-acid-deficiency anaemia without steatorrhoea seems to be more common than Its association with the was previously thought. last trimester of pregnancy is well known, and the reasons for its development are clearly understood. STREIFF2 draws attention to its occurrence in other groups, especially in elderly people on relatively poor diets and in alcoholics. He points out that cooking severely reduces the folate content of some foods, such as cabbage and egg, but in others, such as milk and white meat, there is little effect; some of the newer methods of preparing food for market also diminish the folate content, particularly cooked frozen foods and lyophilised meats and vegetables. Patients with chronic hxmolytic anaemias may need much more folic acid than usual. STREIFF reminds us that HERBERT7 showed that body stores of folate are sufficient for a mere 4 to 6 months and that a low serum-folate level appears a mere 3 weeks after supplies of folic acid are completely cut off; but it is 19 weeks before clinical anaemia appears and the marrow shows megaloblastic change. Nevertheless, these figures show why nutritional folate deficiency is much more likely to develop than vitamin-B12 deficiency. Such anaemias have been reported in this country in Sheffield,8Liverpool,9 and Bristol.lo For the diagnosis of folic-acid-deficiency anaemia STREIFF2 thinks that the results of the serum folate and vitamin-B12 assays are needed, together with the results of a clinical trial of oral folic acid; unfortunately there is at present no test of absorption for folic 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 complex equipment. The serum-folate level in normal subjects should be above 3 ng. per ml. and in deficient patients is usually 2 ng. per ml. or less; the serumvitamin-B12 level is variable but is rarely as low as the 50 pg. per ml. seen in vitamin-B12 deficiency. For clinical trial, very small doses of folic acid should be used to avoid a clinical response to the wrong agent, and a dose of 200 {ig. daily is recommended; during the trial the diet must be controlled and should 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 is essential to remember that no active material must be given before the diagnostic tests, since either vitamin B12 or folic acid given in pharmacological doses can completely change the marrow picture within 48 hours, even when the wrong agent has been 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 promote a remission. Maintenance with 1 mg. intramuscularly every month is sufficient thereafter. The minimum daily requirement of folic acid for an adult is now estimated at 50-100 ng., and in pregnancy 300-400 jig. daily is needed. In folic-aciddeficient patients 5 mg. orally daily for 4 weeks is more than sufficient, according to STREIFF, to treat the anaemia and restore tissue stores to normal. But when the anaemia has been treated, steps must be taken to correct the cause whenever possible; of course, in pernicious anaemia this cannot be done, and treatment for life is the rule.
Cooling Off THE medical profession and the new Government have sensibly found a quick way back from the brink to which the British Medical Association was bundling the National Health Service. After his talks with doctors’ and dentists’ representatives last Friday, Sir KEITH JOSEPH, Mr. HEATH’S Secretary of State for Social Services, went so far as to write the letter reproduced on p. 37. But just how far is that? The Government, in return for the renewal of doctors’ cooperation in N.H.S. administration and in the signing of certificates, has withdrawn from the Prices and Incomes Board the second 15% of the Review Body’s recommendations referred to it by the Labour Government and has undertakento re-establish an independent review body to advise the Government on doctors’ and dentists’ pay. Not, it has been noted, the Review Body (our Review Body, as the doctors often called it), but a review body. Sir KEITH reiterates the Royal Commission’s proviso that "obviously compelling reasons" would be needed to justify rejection or modification of the body’s advice;
29
and the Government would explain any such reasons it found. Moreover, the body’s recommendations would not be subjected to any second appraisal (such as that of a Prices and Incomes Board)-except by the Government itself. From these slight comforts the B.M.A. has taken heart and sense enough to stop its harassment of the N.H.S., to subdue its talk of resignation, and to accept the Government’s offer to enter into very early discussions on the matters of pay now taken back from the Prices and Incomes Board. The right decision has thus been reached by an unnecessarily painful path. Much of the conflict might have been avoided if Mr. WILSON’S Government had not been so tactless towards the B.M.A. and towards the Review Body itself: firstly, in seeking to postpone publication of the Body’s report until after the general election; and, secondly, in explaining unsatisfactorily the referral of the 15% to the Prices and Incomes Board. All the same, the B.M.A. had no justification for rushing in suspicion and rage to the barricades on June 4, the day the referral was announced. For the Association has now put aside (for good, it is to be hoped) the weapons of non-cooperation and resignation, and yet the situation on June 27 was little different from that on June 4, when the war-cry went up. The Government, not the Prices and Incomes
Board, is to make the decision on the outstanding 15%; and, like any other Government, it reserves the withhold part or all of it if the country’s economic situation cannot bear the cost. The assur" ance of a Government explanation of any obviously compelling reasons " has, it seems, weighed heavily in the apparent rapid restoration of the profession’s trust in politicians, though a newly elected Government 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 independent review body has been reaffirmed. Despite the B.M.A.’s insistence, however, that it has been fighting tooth and nail for that lost principle and not for money, nothing that happened on June 4 did in fact destroy the principle. The events of that day merely illustrated again that such a body’s function is and always must be advisory. Apparently believing otherwise, the old Review Body dispatched itself by resigning. The " principle " was and still is intact.
right
to
Fortunately, after all, relations between Government and profession are now some way towards repair; and the direct negotiations which, but for the onset of the general election, might have taken place weeks ago can now begin. But the most important move is the re-establishment of a review body (perhaps of entirely new members), one of whose prime objects is, in fact, to avoid too many face-to-face negotiations between doctors and Governments, which have led to much friction in the past. Sir KEITH JOSEPH’S letter gives little away, but it is as much as
the
could reasonably expect; and the B.M.A., sustained by its supporters’ shouts of victory, may now turn with relief to the more agreeable task of fortifying the National Health Service.
profession
IS LYONISATION TOTAL IN MAN?
ACCORDING to Lyon’s hypothesisonly one of the X chromosomes in the somatic cells of mammalian females is genetically active. Early in embryonic life either the maternally or paternally derived X chromosome becomes inactivated; the choice of X chromosome is random in each cell but once made remains fixed. Genetical inactivation provides a mechanism for dosage compensation for the presence of a second X chromosome in normal female cells. Recently, two groups of workers 2have used the premise that the PhI (Philadelphia chromosome)-positive bone-marrow cells in chronic myeloid leukaemia represent a single clone to test the application of the Lyon hypothesis to the sexlinked Xg blood-group system of man. Both groups agreed in that they were unable to demonstrate genetical inactivation of the Xg locus. The single or multicellular origin of tumours is a subject of general current interest which has been discussed4 in relation to Burkitt’s lymphoma. Populations of tumour cells may be identifiable by chromosome markers. A common marker chromosome in a cell population is suggestive but not conclusive evidence of origin from a single cell, since similar chromosomal changes could arise in more than one cell either spontaneously or after exposure to a noxious agent. Another approach to the study of clonal origin is the use of cellular markers, such as isoenzymes, that exhibit genetic polymorphism. The cells of heterozygous individuals carry the genetic information for two different biochemical patterns. In certain circumstances, although populations of cells show the expected heterozygous phenotype, individual cells, or a population of cells of single clonal origin, may express the product of but a single allele. Such is the situation in some sex-linked genetic systems in mammals, to which the Lyon hypothesis is known to apply.I> Of the loci on the X chromosome in man that have been demonstrated to undergo inactivation, that for glucose-6-phosphate dehydrogenase (G.-6-P.D.) has been skilfully exploited to give information about the single or multiple origin of tumours.6,7 The A and B types of G.-6-P.D. are electrophoretically distinguishable ; both are found in fibroblast cultures made from skin biopsies of heterozygous females, but clones of normal or malignant cells show only type A or B but not both. It is not known whether the process of inactivation includes all the loci on the X chromosome. This doubt applies particularly to the blood-group locus, Xg. Two
two
1. 2.
Lyon, M. F. Nature, Lond. 1961, 190, 372. 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.