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CALCITONIN IN SEARCH OF A FUNCTION
771
Health Service Prospects,1 a book sponsored jointly by the Nuffield Provincial Hospitals Trust and The Lancet, and published on the journal’s 150th anniversary, relates the achievements and hopes of some of the many countries which haveembarked on this search. The book’s record is supplied by those closely engaged in such endeavours in 11 countries, and summaries appear in a supplement to this issue. Observers and historians who may see the World Health Assembly’s principles as self-evident axioms will wonder why effective health services take so long to evolve. Some could find part of the answer in a neglect of the Assembly’s insistence on " the recognition by all medical workers of their high degree of social responsibility to society ": others may point to a continuing failure to devote to health care an adequate fraction of the community’s resources, without which the keenest sense of social responsibility will wilt.. Yet the biggest spenders do not always produce the best health services and the secret is not to be found in money alone. If Britain’s National Health Service has a warning for others, perhaps it lies in the retarded evolution of its administrative machinery. A formula partly imposed by the antenatal circumstances of a health service will seldom provide a durable working structure Yet Britain has without need of early reform. waited 25 years before subjecting the N.H.S. to a substantial reorganisation, the need for which was apparent almost before the service began. For its success, a health-care system must be a dynamic and evolving organism, a part of the whole national provision for the people’s welfare. It should be controlled by administrators who not only believe wholeheartedly in the aims of the service but also have access to enough day-to-day and year-to-year information by which to set and adjust their course with reasonable prospects of avoiding the rocks. For Ghana, Dr FRED SAi expresses a keen need for a well-founded health plan, derived from a hard scrutiny of reality; and few nations can profess that they are very different from Ghana in that respect. Where, for instance, would truly rational plans have placed cardiac transplantation in the scale of health priorities of certain countries in 1968 ? If the prime key to top-class health-service administration is, as our book suggests, informed planning, some plans might be fortified by testing them regionally before they are applied nationally. Would Britain have waited so long to reshape the N.H.S. if she had been more ready to try things out here and there ? The contributors to Health Service Prospects describe and envisage various forms of political
prejudice, and self-interest.
1. Health Service Prospects: an International Survey. Edited by I. DOUGLAS-WILSON and GORDON MCLACHLAN. Pp. 360. Published (except in North America) by The Lancet and the Nuffield Provincial Hospitals Trust; obtainable from The Lancet, 7 Adam Street, London WC2N 6AD. £6.00 net. Published in North America by Little, Brown and Co., 34 Beacon Street, Boston, MA 02106. 815.00.
control in health-care systems, ranging from modest to total control. The spectrum runs from the blend of Government with private sector, portrayed by Mr WALTER J. MCNERNEY for the United States, to the uncompromising systems of Russia, China, and Cuba. Control there must be: and few advocates still have the voice to argue against the State’s duty to intervene in the provision of health care for its citizens. For one thing, where they are necessary the " challenges to professional despotism " must come from the State, ultimately supported, it is to be hoped, by the majority of the profession. The call to " keep medicine out of politics " is muted now at the meetings of the British Medical Association (for it was as fruitless as the efforts of the Marylebone Cricket Club to keep their game apolitical). The march of events and the reasonable aspirations of the populace have long made political decisions essential; and the successful health service will be one in which politicians and professionals advance more or less harmoniously-or with just a touch of stimulating abrasion. Anything approaching bickering and recrimination will surely destroy an enterprise whose fulfilment depends, as that of a health service does, on the morale of those who operate it. That country, east or west, which has espoused the lofty aims of the World Health Assembly has, in fact, started a redistribution of its wealth; and from that course it must never be deterred by the cries and threats of the dispossessed and the short-sighted. One country, like Cuba, may have seized a sudden opportunity; another may have progressed more circumspectly, like Britain. Each has taken the right decision; and each hopes to advance, by her own roads, towards the further relief of distress and disease for which all social revolution strives. CALCITONIN IN SEARCH OF A FUNCTION A PERSISTING puzzle in understanding calcitonin is that it does not seem to be missed. Extra calcitonin has now been given to man and animals in great numbers of experiments and as treatment in Paget’s disease of bone and other conditions.3 Only rarely has its source been removed as far as possible, so that effects of lack could be looked for. Total thyroidectomy should leave little calcitonin, yet neither man nor rat becomes strikingly hypercalcxmic postoperatively; calcitonin’s function is not obvious.4 Any more elusive effects ought to show when calcium turnover is most rapid. A pregnant woman has about 1 kg. of calcium stored in her skeleton 5; she provides some 30 g. for her infant, mostly in the last three months of pregnancy,and then some 40 g. more over six months if she breast-feeds for that time.7 But a cow with a good milk yield may 2. Tudor Hart, J. Lancet, Sept. 15, 1973, p. 611. 3. Lancet, 1971, i, 1168. 4. Catt, K. J. An ABC of Endocrinology. London, 1971. 5. Widdowson, E. M., McCance, R. A., Spray, C. M. Clin. Sci. 6. 7.
1951, 10, 113. M. E. C. Archs Dis. Childh. Widdowson, M., Spray, 1951, 26, 205. Fourman, P., Royer, P. Calcium Metabolism and the Bone. Oxford, 1968.
772
give 40 g. of calcium in a single day in milk-about 0-5% of its store.8 Neither can compete with a first-class laying hen, which has a mere 20 g. of calcium in store but provides 2 g. for its daily egg.9 Birds may therefore be especially dependent on calcitonin (and in addition they are convenient for experiment since they produce it mostly in a conveniently separated The secretionorgan, the ultimobranchial gland). rate is indeed much higher in geese than in pigs,lO but removal of the ultimobranchial gland in chicks (not in laying hens) was without effects on the skeleton and the plasma-calcium level, even after three months. 111 Similar experiments in young rats have used thyroidectomy and thyroid-hormone replacement as a way to calcitonin. But the effects on bone are either or undetectable. 13 Basal plasma-calcium in unchanged-though young pigs it rises the first hours after over two operation. 14 slowly What does change is the rate at which an injected load of calcium is dispersed into bone, and this is slow in the absence of calcitonin, so that plasmacalcium remains high for longer. 12 This matter of speed is probably central in any function attributed to calcitonin. Its speed of action was one of the first features that drew attention to it: it worked faster than the oppositely acting parathyroid hormone. Changes in parathyroid hormone secretion may be able to counteract changing plasma-calcium levels so long as they do not change too fast, and can apparently even meet the excess calcitonin secretion in medullary carcinoma of the thyroid, so that hypocalcxmia is not usual in this condition. So when does a sudden calcium load occur naturally ? Presumably the answer is: after drinking or eating a lot of calcium. In fact, a sceptic might suggest that in phylogeny calcitonin first appears in the cartilaginous fishes 15-creatures not yet capable of producing bone-and serves to avert inappropriate calcification if they drink too much sea-water (413 mg. of calcium per litre 16), but is a functionless hormone in man, for whom drinking too much sea-water is an uncommon hazard. However, from rat experiments Gray and Munson provided the first evidence that calcitonin lack in mammals did allow an abnormal rise in plasmacalcium after an intragastric dose of calcium. 117 Plasmacalcium was still high after two hours, and later similar findings were recorded with rats eating spontaneously, 18 though hamsters may be different. 19 What might be the results of calcitonin lack in man ? Presumably a great deal depends on how much calcium is absorbed by the individual, and how quickly. If he absorbs modest amounts at modest rates, an adult might experience no consequences
remove
small 12 level is
whatever. With large intakes, things could be otherwise ; for example, a pint of cow’s milk contains about 680 mg. of calcium, 2of which a quarter might be absorbed. If it ever arrived in the plasma suddenly and stayed there, plasma-calcium would rise about 7 mg. per 100 ml.-a lethal change. The results of calcitonin lack coupled with high and abrupt calcium intake might therefore resemble those of the milkpoisoning encountered in obsessive dieters with peptic ulcer, who drink around a gallon a day and have The excess a grossly excessive calcium intake. 21, 22 calcium evokes various symptoms of hypercalcasmia, and is deposited, not particularly in bone, but in kidney and other abnormal sites-which accords with the lack of bone changes in rats deprived of calcitonin. 12 Physiological function tends to be evoked by the earliest available signal. If calcitonin is really what directs sudden large intakes of calcium out of plasma into bone, its secretion-rate might reasonably rise to some extent even before absorption of calcium begins, after the analogy of the dribbling Pavlov dog getting ready for its meal. And indeed circulating gastrin acts directly on the thyroid to elicit increased calcitonin secretion. 23This curious link, not at first glance easy to understand, may be perfectly appropriate, providing extra calcitonin in advance of expected need.
N.Z. AND S.S.P.E.
from the welter of neurovirology because each has
Two diseases have stood
today’s alphabetical appeared to have a single well-established cause: subacute sclerosing panencephalitis (s.s.P.E.), which has been attributed to a measles-like agent, 24 and progressive multifocal leukoencephalopathy (P.M.L.), an even less common disorder apparently due to one of the papovaviruses. 25 Alas, such simplicity has not lasted and multiple causal agents have now been proposed for both conditions. P.M.L. may apparently be caused by either of the two different papovaviruses: by IC-virus, 26I which is related to the polyoma subgroup; or by SV40, which belongs to a different class of the papova agents." S.S.P.E. has also been attributed, by one group of workers in particular, to two viruses acting in concert.211-11 The second virus, which has not been a general finding, has been partly identified as a member of the papova group. 211- 3Indirect support for hypotheses involving two viruses in the genesis of S.S.P.E., perhaps as a zoonosis, has come from epidemiological studies showing a relative preponderance of cases of 8.S.P.E. in 20. 21.
8. Kleiber, M., Luick, J. R. Ann. N.Y. Acad. Sci. 1956, 64, 299. 9. Hurwitz, S., Bar, A. Am. J. clin. Nutr. 1969, 22, 391. 10. Bates, R. F. L., Bruce, J., Care, A. D. J. Endocr. 1969, 45, xiv. 11. Brown, D. M., Perey, D. Y. E., Dent, P. B., Good, R. A. Proc. Soc. exp. Biol. Med. 1969, 130, 1001. 12. Kumar, M. A., Sturtridge, W. C. J. Physiol., Lond. 1973, 233, 33. 13. Sammon, P. J., Stacey, R. E., Bronner, F. Biochem. Med. 1969, 3, 252. 14. Swaminathan, R., Bates, R. F. L., Care, A. D. J. Endocr. 1972, 54, 525. 15. Copp, D. H., Cockcroft, D. W., Kueh, Y. Science, 1967, 158, 924. 16. Holden, W. S. (editor) Water Treatment and Examination. London, 1970. 17. Gray, T. K., Munson, P. L. Science, 1969, 166, 512. 18. Milhaud, G., Perault-Staub, A.-M., Staub, J.-F. J. Physiol., Lond. 1972, 222, 559. 19. Biddulph, D. M., Hirsch, P. F. Endocrinology, 1973, 92, 1328.
out
22. 23. 24. 25. 26. 27.
28. 29.
30.
R. A., Widdowson, E. M. The Composition of Foods. London, 1969. Burnett, C. H., Commons, R. R., Albright, F., Howard, J. E. New Engl. J. Med. 1949, 240, 787. McQueen, E. G. Lancet, 1952, ii, 67. Cooper, C. W., Schwesinger, W. H., Ontjes, D. A., Mahgoub, A. M., Munson, P. L. Endocrinology, 1973, 91, 1079. Lancet, 1972, ii, 263. ZuRhein, G. M. Progr. med. Virol. 1971, 11, 185. Padgett, B. L., Walker, D. L., ZuRhein, G. M. Lancet, 1971, i, 1257. Weiner, L. P., Herndon, R. M., Narayan, O., Johnson, R. T., Shah, K., Rubinstein, L. J., Preziosi, T. J., Conley, F. K. New Engl. J. med. 1972, 286, 385. Barbanti Brodano, G., Oyanagi, S., Katz, M., Koprowski, H. Proc. Soc. exp. Biol. Med. 1970, 134, 230. Koprowski, H., Barbanti Brodano, G., Katz, M. Nature, 1970, 225, 1045. Müller, D., ter Meulen, V., Katz, M., Koprowski, H. Lab. Invest. 1971, 25, 337.
McCance,
Health Service Prospects,1 a book sponsored jointly by the Nuffield Provincial Hospitals Trust and The Lancet, and published on the journal’s 150th anniversary, relates the achievements and hopes of some of the many countries which haveembarked on this search. The book’s record is supplied by those closely engaged in such endeavours in 11 countries, and summaries appear in a supplement to this issue. Observers and historians who may see the World Health Assembly’s principles as self-evident axioms will wonder why effective health services take so long to evolve. Some could find part of the answer in a neglect of the Assembly’s insistence on " the recognition by all medical workers of their high degree of social responsibility to society ": others may point to a continuing failure to devote to health care an adequate fraction of the community’s resources, without which the keenest sense of social responsibility will wilt.. Yet the biggest spenders do not always produce the best health services and the secret is not to be found in money alone. If Britain’s National Health Service has a warning for others, perhaps it lies in the retarded evolution of its administrative machinery. A formula partly imposed by the antenatal circumstances of a health service will seldom provide a durable working structure Yet Britain has without need of early reform. waited 25 years before subjecting the N.H.S. to a substantial reorganisation, the need for which was apparent almost before the service began. For its success, a health-care system must be a dynamic and evolving organism, a part of the whole national provision for the people’s welfare. It should be controlled by administrators who not only believe wholeheartedly in the aims of the service but also have access to enough day-to-day and year-to-year information by which to set and adjust their course with reasonable prospects of avoiding the rocks. For Ghana, Dr FRED SAi expresses a keen need for a well-founded health plan, derived from a hard scrutiny of reality; and few nations can profess that they are very different from Ghana in that respect. Where, for instance, would truly rational plans have placed cardiac transplantation in the scale of health priorities of certain countries in 1968 ? If the prime key to top-class health-service administration is, as our book suggests, informed planning, some plans might be fortified by testing them regionally before they are applied nationally. Would Britain have waited so long to reshape the N.H.S. if she had been more ready to try things out here and there ? The contributors to Health Service Prospects describe and envisage various forms of political
prejudice, and self-interest.
1. Health Service Prospects: an International Survey. Edited by I. DOUGLAS-WILSON and GORDON MCLACHLAN. Pp. 360. Published (except in North America) by The Lancet and the Nuffield Provincial Hospitals Trust; obtainable from The Lancet, 7 Adam Street, London WC2N 6AD. £6.00 net. Published in North America by Little, Brown and Co., 34 Beacon Street, Boston, MA 02106. 815.00.
control in health-care systems, ranging from modest to total control. The spectrum runs from the blend of Government with private sector, portrayed by Mr WALTER J. MCNERNEY for the United States, to the uncompromising systems of Russia, China, and Cuba. Control there must be: and few advocates still have the voice to argue against the State’s duty to intervene in the provision of health care for its citizens. For one thing, where they are necessary the " challenges to professional despotism " must come from the State, ultimately supported, it is to be hoped, by the majority of the profession. The call to " keep medicine out of politics " is muted now at the meetings of the British Medical Association (for it was as fruitless as the efforts of the Marylebone Cricket Club to keep their game apolitical). The march of events and the reasonable aspirations of the populace have long made political decisions essential; and the successful health service will be one in which politicians and professionals advance more or less harmoniously-or with just a touch of stimulating abrasion. Anything approaching bickering and recrimination will surely destroy an enterprise whose fulfilment depends, as that of a health service does, on the morale of those who operate it. That country, east or west, which has espoused the lofty aims of the World Health Assembly has, in fact, started a redistribution of its wealth; and from that course it must never be deterred by the cries and threats of the dispossessed and the short-sighted. One country, like Cuba, may have seized a sudden opportunity; another may have progressed more circumspectly, like Britain. Each has taken the right decision; and each hopes to advance, by her own roads, towards the further relief of distress and disease for which all social revolution strives. CALCITONIN IN SEARCH OF A FUNCTION A PERSISTING puzzle in understanding calcitonin is that it does not seem to be missed. Extra calcitonin has now been given to man and animals in great numbers of experiments and as treatment in Paget’s disease of bone and other conditions.3 Only rarely has its source been removed as far as possible, so that effects of lack could be looked for. Total thyroidectomy should leave little calcitonin, yet neither man nor rat becomes strikingly hypercalcxmic postoperatively; calcitonin’s function is not obvious.4 Any more elusive effects ought to show when calcium turnover is most rapid. A pregnant woman has about 1 kg. of calcium stored in her skeleton 5; she provides some 30 g. for her infant, mostly in the last three months of pregnancy,and then some 40 g. more over six months if she breast-feeds for that time.7 But a cow with a good milk yield may 2. Tudor Hart, J. Lancet, Sept. 15, 1973, p. 611. 3. Lancet, 1971, i, 1168. 4. Catt, K. J. An ABC of Endocrinology. London, 1971. 5. Widdowson, E. M., McCance, R. A., Spray, C. M. Clin. Sci. 6. 7.
1951, 10, 113. M. E. C. Archs Dis. Childh. Widdowson, M., Spray, 1951, 26, 205. Fourman, P., Royer, P. Calcium Metabolism and the Bone. Oxford, 1968.
772
give 40 g. of calcium in a single day in milk-about 0-5% of its store.8 Neither can compete with a first-class laying hen, which has a mere 20 g. of calcium in store but provides 2 g. for its daily egg.9 Birds may therefore be especially dependent on calcitonin (and in addition they are convenient for experiment since they produce it mostly in a conveniently separated The secretionorgan, the ultimobranchial gland). rate is indeed much higher in geese than in pigs,lO but removal of the ultimobranchial gland in chicks (not in laying hens) was without effects on the skeleton and the plasma-calcium level, even after three months. 111 Similar experiments in young rats have used thyroidectomy and thyroid-hormone replacement as a way to calcitonin. But the effects on bone are either or undetectable. 13 Basal plasma-calcium in unchanged-though young pigs it rises the first hours after over two operation. 14 slowly What does change is the rate at which an injected load of calcium is dispersed into bone, and this is slow in the absence of calcitonin, so that plasmacalcium remains high for longer. 12 This matter of speed is probably central in any function attributed to calcitonin. Its speed of action was one of the first features that drew attention to it: it worked faster than the oppositely acting parathyroid hormone. Changes in parathyroid hormone secretion may be able to counteract changing plasma-calcium levels so long as they do not change too fast, and can apparently even meet the excess calcitonin secretion in medullary carcinoma of the thyroid, so that hypocalcxmia is not usual in this condition. So when does a sudden calcium load occur naturally ? Presumably the answer is: after drinking or eating a lot of calcium. In fact, a sceptic might suggest that in phylogeny calcitonin first appears in the cartilaginous fishes 15-creatures not yet capable of producing bone-and serves to avert inappropriate calcification if they drink too much sea-water (413 mg. of calcium per litre 16), but is a functionless hormone in man, for whom drinking too much sea-water is an uncommon hazard. However, from rat experiments Gray and Munson provided the first evidence that calcitonin lack in mammals did allow an abnormal rise in plasmacalcium after an intragastric dose of calcium. 117 Plasmacalcium was still high after two hours, and later similar findings were recorded with rats eating spontaneously, 18 though hamsters may be different. 19 What might be the results of calcitonin lack in man ? Presumably a great deal depends on how much calcium is absorbed by the individual, and how quickly. If he absorbs modest amounts at modest rates, an adult might experience no consequences
remove
small 12 level is
whatever. With large intakes, things could be otherwise ; for example, a pint of cow’s milk contains about 680 mg. of calcium, 2of which a quarter might be absorbed. If it ever arrived in the plasma suddenly and stayed there, plasma-calcium would rise about 7 mg. per 100 ml.-a lethal change. The results of calcitonin lack coupled with high and abrupt calcium intake might therefore resemble those of the milkpoisoning encountered in obsessive dieters with peptic ulcer, who drink around a gallon a day and have The excess a grossly excessive calcium intake. 21, 22 calcium evokes various symptoms of hypercalcasmia, and is deposited, not particularly in bone, but in kidney and other abnormal sites-which accords with the lack of bone changes in rats deprived of calcitonin. 12 Physiological function tends to be evoked by the earliest available signal. If calcitonin is really what directs sudden large intakes of calcium out of plasma into bone, its secretion-rate might reasonably rise to some extent even before absorption of calcium begins, after the analogy of the dribbling Pavlov dog getting ready for its meal. And indeed circulating gastrin acts directly on the thyroid to elicit increased calcitonin secretion. 23This curious link, not at first glance easy to understand, may be perfectly appropriate, providing extra calcitonin in advance of expected need.
N.Z. AND S.S.P.E.
from the welter of neurovirology because each has
Two diseases have stood
today’s alphabetical appeared to have a single well-established cause: subacute sclerosing panencephalitis (s.s.P.E.), which has been attributed to a measles-like agent, 24 and progressive multifocal leukoencephalopathy (P.M.L.), an even less common disorder apparently due to one of the papovaviruses. 25 Alas, such simplicity has not lasted and multiple causal agents have now been proposed for both conditions. P.M.L. may apparently be caused by either of the two different papovaviruses: by IC-virus, 26I which is related to the polyoma subgroup; or by SV40, which belongs to a different class of the papova agents." S.S.P.E. has also been attributed, by one group of workers in particular, to two viruses acting in concert.211-11 The second virus, which has not been a general finding, has been partly identified as a member of the papova group. 211- 3Indirect support for hypotheses involving two viruses in the genesis of S.S.P.E., perhaps as a zoonosis, has come from epidemiological studies showing a relative preponderance of cases of 8.S.P.E. in 20. 21.
8. Kleiber, M., Luick, J. R. Ann. N.Y. Acad. Sci. 1956, 64, 299. 9. Hurwitz, S., Bar, A. Am. J. clin. Nutr. 1969, 22, 391. 10. Bates, R. F. L., Bruce, J., Care, A. D. J. Endocr. 1969, 45, xiv. 11. Brown, D. M., Perey, D. Y. E., Dent, P. B., Good, R. A. Proc. Soc. exp. Biol. Med. 1969, 130, 1001. 12. Kumar, M. A., Sturtridge, W. C. J. Physiol., Lond. 1973, 233, 33. 13. Sammon, P. J., Stacey, R. E., Bronner, F. Biochem. Med. 1969, 3, 252. 14. Swaminathan, R., Bates, R. F. L., Care, A. D. J. Endocr. 1972, 54, 525. 15. Copp, D. H., Cockcroft, D. W., Kueh, Y. Science, 1967, 158, 924. 16. Holden, W. S. (editor) Water Treatment and Examination. London, 1970. 17. Gray, T. K., Munson, P. L. Science, 1969, 166, 512. 18. Milhaud, G., Perault-Staub, A.-M., Staub, J.-F. J. Physiol., Lond. 1972, 222, 559. 19. Biddulph, D. M., Hirsch, P. F. Endocrinology, 1973, 92, 1328.
out
22. 23. 24. 25. 26. 27.
28. 29.
30.
R. A., Widdowson, E. M. The Composition of Foods. London, 1969. Burnett, C. H., Commons, R. R., Albright, F., Howard, J. E. New Engl. J. Med. 1949, 240, 787. McQueen, E. G. Lancet, 1952, ii, 67. Cooper, C. W., Schwesinger, W. H., Ontjes, D. A., Mahgoub, A. M., Munson, P. L. Endocrinology, 1973, 91, 1079. Lancet, 1972, ii, 263. ZuRhein, G. M. Progr. med. Virol. 1971, 11, 185. Padgett, B. L., Walker, D. L., ZuRhein, G. M. Lancet, 1971, i, 1257. Weiner, L. P., Herndon, R. M., Narayan, O., Johnson, R. T., Shah, K., Rubinstein, L. J., Preziosi, T. J., Conley, F. K. New Engl. J. med. 1972, 286, 385. Barbanti Brodano, G., Oyanagi, S., Katz, M., Koprowski, H. Proc. Soc. exp. Biol. Med. 1970, 134, 230. Koprowski, H., Barbanti Brodano, G., Katz, M. Nature, 1970, 225, 1045. Müller, D., ter Meulen, V., Katz, M., Koprowski, H. Lab. Invest. 1971, 25, 337.
McCance,