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PROTEIN REQUIREMENTS
573
malignancy which are associated with thrombo-embolic sequelae. There is a case also for anticoagulant therapy in operations which are associated with a prolonged period of immobilisation."
investigations of SEVITT and GALLAGHER 3 at the Birmingham Accident Hospital yielded good evidence for the regular use of prophylactic phenindione after accidents involving the lower limbs, especially in elderly patients. There are, however, difficulties in the acceptance of these propositions; and in articles on earlier The
pages of this issue Dr. R. D. EASTHAM deals with two of them. In the first paper Dr. EASTHAM records an attempt to estimate the effect of a monoamine-oxidase inhibitor on platelet adhesiveness: it has been claimed that such drugs would reduce the risk of coronary thrombosis by reducing platelet adhesiveness. The trial had to be abandoned, after only 10 patients had been treated, owing to the undesirable side-effects of the drug; but the observations sufficed to show that the drug did not have the effect claimed. In the second paper Dr. EASTHAM reports once again on the changes in blood coagulability in patients awaiting surgical operations; he also studied a group who had had recent gastrointestinal-tract haemorrhage. He carried out a considerable battery " of tests, but relied particularly on a modified plasma-recalcified clottingtime " of his own devising. The test showed significantly shortened clotting-times in three groups of patients: in 31 on the fifth day after their operation; in 58 before their operations, who were later proved to have carcinomas; and in 32 who had had gastrointestinal haemorrhages shortly before the test. Similar tests, also claimed to be useful in detecting the likelihood of thrombotic complications after operations, have been proposed by NYE et al.4 and by MIALE.5 If these results are significant, we ought to consider regular administration of anticoagulants at least to patients suspected of having carcinomas who are to undergo operation; and the results support those-such as POLLER-who would give anticoagulants to a wide range of patients. Today, for most doctors, administration of anticoagulants means the use of phenindione or one of the related drugs. But EASTHAM suggests that recent work on the serum factors that promote clotting after thrombosis indicates that phenindione is hardly suitable. When blood clots, a " serum thrombotic accelerator " is released which produces rapid intravascular clotting. This accelerator is still present in fresh sera from haemophilic patients and from patients deficient in factors v, VII, and x; but when Christmas factor (ix), factor xi, or factor xii are deficient, this serum-accelerator activity is much reduced or even absent. Phenindione and similar drugs in therapeutic doses do not depress the activity of factors xi and xii and they reduce Christmas factor activity to not less than 30%-probably insufficient to produce any effect. Consequently, says EASTHAM, phenindione and similar drugs can at best only be partly effective, and we are Sevitt, S., Gallagher, N. G. Lancet, 1959, ii, 981. Nye, S. W., Graham, J. B., Brinkhous, K. M. Amer. J. med. Sci. 1962, 243, 279. 5. Miale, J. B. B. J. Amer. med. Ass. 1963, 195, 752.
3. 4.
perhaps wasting time and effort in carrying out all the prothrombin-time tests necessary to ensure safe prophylaxis against thrombosis with these drugs. EASTHAM draws attention to the virtues of heparin, which inhibits thromboplastin and interferes with the thrombin-fibrinogen reaction, the final stage in clot formation. Furthermore O’BRIEN6 has shown that heparin has no effect on platelet adhesiveness; hence the drug should not prevent hmmostasis in severed or damaged blood-vessels. VON FRANCKEN et al.advocated the use of heparin to treat bleeding in patients whose blood showed hypercoagulability and in whom increased fibrinolysis was found. Their patients had had surgical operations or had had recent gastrointestinal-tract haemorrhage. After administration of heparin the reduced coagulation and recalcification times in the blood returned to normal and excessive fibrinolysis disappeared. VERSTRAETE et al.,8 reporting on two cases successfully treated with heparin, suggested that intravascular clotting caused an actual depletion of clotting factors and that heparin restored normality by stopping the clotting; one of their patients had a gastric carcinoma, and superficial phlebitis developed when the
heparin
was
stopped.
The value of prophylaxis against thrombosis or even of treatment of existing thrombosis in spontaneous disease or after surgery is still disputed. The use of different tests for assessing liability to thrombosis and the efficacy of treatment makes comparison more difficult; every technique has its often impassioned advocates. But work we have cited shows that understanding of the thrombotic processes is being steadily
extended.
Annotations PROTEIN
REQUIREMENTS figures for the composition of foods had been agreed upon, it was relatively simple to determine the calorie intakes of men and women working at different tasks, and, in the absence of any demonstrable change of weight in the course of the period of observation, the figures for calorie intakes become figures for calorie requirements. There has indeed been a sense of agreement about calories since the classical work of Voit,99 Rubner,lo Atwater, and Lusk,l1 and in general terms the figures have been confirmed again and again.12 Not so protein requirements, which have been a matter for debate and controversy since the experiments of Sivén,13 Hindhede,14 and Chittenden 15 in the early years of this ONCE
century. We still have less accurate information about them than we have, say, about the requirements of vitamin Bl, which was discovered long after the controversy about protein requirements was well under way. The latest contribution to the subject has been the 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
O’Brien, J. R. J. clin. Path. 1961, 14, 140. Francken, I., Johansson, L., Olsson, P., Zetterqvist, E. Lancet, 1963, i, 70. Verstraete, M., Amery, A., Vermylen, C., Robyn, G. ibid. p. 446. Voit, C. in Handbuch der Physiologie; vol. 6, p. 519. Leipzig, 1881. Rubner, M. in Handbuch der Ernährungstherapie; vol. 1, p. 153. Leipzig, 1903. Lusk, G. The Science of Nutrition. Philadelphia and London, 1931. Roine, P., Pekkarinen, M., Karvonen, M. Voeding, 1964, 25, 383. Sivén, V. O. Skand. Arch. Physiol. 1901, 11, 308. Hindhede, M. ibid. 1912, 27, 87. Chittenden, R. H. Physiological Economy in Nutrition. New York,
von
1904.
574 of a working party set up by the Ministry of Health to examine the matter in this country at the request of the World Health Organisation and the Food and
report 16
Agriculture Organisation. The whole party reported on the quantitative requirements for proteins in health and disease; and they also divided into four groups, which dealt with protein metabolism and its regulation, the protein values of foods, the requirements for protein in health, and the effects of disease on protein requirements. The report also contains valuable appendices by various members of the working party on their own special areas of knowledge, and some recommendations about further work that might confine the problem more conveniently. Scientists and administrators not engaged in this work probably have little inkling of the difficulties which this working party had to face. No two proteins are chemically the same, nor have they the same value as foods. Furthermore, all foods except pure fats and sugar contain protein in appreciable amounts, and it is well known that proteins contribute 10-12% of the calories to all diets. Consequently the intake of protein varies with the intake of calories; but the requirements of protein do not vary for the same reason as those of calories, although in certain circumstances they depend upon the intake of calories. Added to all this, there is the certainty that no two individuals, even in health, will make equally good use of the proteins in their diet, and the differences may be large. The suggestions of the working party in terms of g. per kg. body-weight per day are:
thalidomide-induced deformities varies from about 430 to 150; but, says the report, the number probably lies between 200 and 250. Records were obtained of altogether 894 deformed children. Of this total 194 (22%) had at least one absent or vestigial limb, and 832 had some kind of limb deformity. Among babies with a defined limb deformity, the proportion with absent or vestigial limbs decreased from 45% in the group born to mothers who had certainly had thalidomide to 14% in those born to mothers who had not taken thalidomide. It seems that single limb deformities may only rarely have been caused by thalidomide. The survey suggests strongly that thalidomide can also cause malformations of the ear, eye, heart, kidney, and gut. In a preface Sir George Godber, chief medical officer to the Ministry, observes that this tragic episode involved fewer families than was feared at one time, and that the relief available to individual children has been improved. " Yet each case was a personal disaster which no amount of subsequent help can wholly relieve. The small compensations the incident has brought within our health services are in improved control of drugs, a better understanding of some factors in the xtiology of congenital defects and acceleration of progress in the development of artificial limbs." POLONIUM
THE search for carcinogens is endless, and investigations into the pollution of common environments by potentially harmful agents proceed without pause. Marsdenhas lately discussed the possible significance of polonium as a carcinogenic contaminant of air, cigarette smoke, and
foods. Polonium-210 RaF emits a particles and has a half-life of 138 days. It has been detected in soil, air, and some waters, notably those of artesian wells. It is present in at least some plant tissues, which have taken it from the soil or the air. Marsden is particularly concerned with the polonium in the exhaust gases of petrol engines and in and on tobacco leaves. Soil polonium is derived from the parent rock, so that, if the rock is processed for lead, polonium is apt to accompany the lead and enter compounds subsequently formed from it, conferring on them some radioactivity. Thus lead tetraethyl, the common " anti-knock " petrol additive, contains polonium. Combustion in the cylinders of the engine volatilises the polonium, which passes to the exhaust system of the vehicle, where some is deposited and the rest escapes into the atmosphere. The leaves of tobacco plants grown in different parts of the world were found to contain polonium, and it is believed that the contamination came largely from soil and only slightly from atmospheric fallout. All the tobacco was of Virginia type. Polonium salts volatilise easily at relatively low temperatures: hence slowly burning tobacco produces smoke which, if not adequately filtered, could well be a source of inhaled particles. It is estimated that inhaling the smoke of 25 cigarettes in a day could result in the deposition on the respiratory mucosa of something like 8 picocuries of polonium per day. Inhaled polonium is taken up by soft tissues rather than bone. Contamination of drinking-water from artesian wells does not at this stage seem to be very important, and there is usually much heavier contamination of the water by radon. some
One of the most satisfactory aspects of the report is the refusal of the working party to commit itself to any firm figures which might be seized upon as yardsticks by which to make comparisons and on which to base claims. We just do not know how much protein Mr. A, Mrs. B, or Miss C requires, and the labour of trying to find out resembles the trials of Sisyphus. In other words, we may never succeed. THALIDOMIDE a non-barbiturate hypnotic synthesised in became available in the United 1956, Germany in 1958. In November, 1961, Dr. W. Lenz, of Kingdom that this drug apparently had teratoHamburg, reported effects when administered to women early in genic pregnancy; and the drug was withdrawn from the British market on Dec. 2, 1961. The Ministry of Health has now published a useful survey of affected children born in England and Wales between the beginning of 1960 and the end of August, 1962.17 The survey, which is limited to liveborn children, shows that at least 349 malformed children were born to mothers who had certainly or probably taken thalidomide; and, of these, 267 survived at the time of the survey. Of the malformations in a further 366 children (of whom 295 survived), at least some are thought to have been attributable to the drug. The estimate of surviving children with
THALIDOMIDE,
in
16. Requirements of Man for Protein. Rep. publ. Hlth med. Subj., Lond. 1964, no. 111. H.M. Stationery Office, London. Pp. 90. 5s. 6d. 17. Deformities Caused by Thalidomide. Rep. publ. Hlth med. Subj., Lond. 1964, no. 112. H.M. Stationery Office. Pp. 70. 6s. 6d.
1.
Marsden, E. Nature, Lond. 1964, 203,
230.
malignancy which are associated with thrombo-embolic sequelae. There is a case also for anticoagulant therapy in operations which are associated with a prolonged period of immobilisation."
investigations of SEVITT and GALLAGHER 3 at the Birmingham Accident Hospital yielded good evidence for the regular use of prophylactic phenindione after accidents involving the lower limbs, especially in elderly patients. There are, however, difficulties in the acceptance of these propositions; and in articles on earlier The
pages of this issue Dr. R. D. EASTHAM deals with two of them. In the first paper Dr. EASTHAM records an attempt to estimate the effect of a monoamine-oxidase inhibitor on platelet adhesiveness: it has been claimed that such drugs would reduce the risk of coronary thrombosis by reducing platelet adhesiveness. The trial had to be abandoned, after only 10 patients had been treated, owing to the undesirable side-effects of the drug; but the observations sufficed to show that the drug did not have the effect claimed. In the second paper Dr. EASTHAM reports once again on the changes in blood coagulability in patients awaiting surgical operations; he also studied a group who had had recent gastrointestinal-tract haemorrhage. He carried out a considerable battery " of tests, but relied particularly on a modified plasma-recalcified clottingtime " of his own devising. The test showed significantly shortened clotting-times in three groups of patients: in 31 on the fifth day after their operation; in 58 before their operations, who were later proved to have carcinomas; and in 32 who had had gastrointestinal haemorrhages shortly before the test. Similar tests, also claimed to be useful in detecting the likelihood of thrombotic complications after operations, have been proposed by NYE et al.4 and by MIALE.5 If these results are significant, we ought to consider regular administration of anticoagulants at least to patients suspected of having carcinomas who are to undergo operation; and the results support those-such as POLLER-who would give anticoagulants to a wide range of patients. Today, for most doctors, administration of anticoagulants means the use of phenindione or one of the related drugs. But EASTHAM suggests that recent work on the serum factors that promote clotting after thrombosis indicates that phenindione is hardly suitable. When blood clots, a " serum thrombotic accelerator " is released which produces rapid intravascular clotting. This accelerator is still present in fresh sera from haemophilic patients and from patients deficient in factors v, VII, and x; but when Christmas factor (ix), factor xi, or factor xii are deficient, this serum-accelerator activity is much reduced or even absent. Phenindione and similar drugs in therapeutic doses do not depress the activity of factors xi and xii and they reduce Christmas factor activity to not less than 30%-probably insufficient to produce any effect. Consequently, says EASTHAM, phenindione and similar drugs can at best only be partly effective, and we are Sevitt, S., Gallagher, N. G. Lancet, 1959, ii, 981. Nye, S. W., Graham, J. B., Brinkhous, K. M. Amer. J. med. Sci. 1962, 243, 279. 5. Miale, J. B. B. J. Amer. med. Ass. 1963, 195, 752.
3. 4.
perhaps wasting time and effort in carrying out all the prothrombin-time tests necessary to ensure safe prophylaxis against thrombosis with these drugs. EASTHAM draws attention to the virtues of heparin, which inhibits thromboplastin and interferes with the thrombin-fibrinogen reaction, the final stage in clot formation. Furthermore O’BRIEN6 has shown that heparin has no effect on platelet adhesiveness; hence the drug should not prevent hmmostasis in severed or damaged blood-vessels. VON FRANCKEN et al.advocated the use of heparin to treat bleeding in patients whose blood showed hypercoagulability and in whom increased fibrinolysis was found. Their patients had had surgical operations or had had recent gastrointestinal-tract haemorrhage. After administration of heparin the reduced coagulation and recalcification times in the blood returned to normal and excessive fibrinolysis disappeared. VERSTRAETE et al.,8 reporting on two cases successfully treated with heparin, suggested that intravascular clotting caused an actual depletion of clotting factors and that heparin restored normality by stopping the clotting; one of their patients had a gastric carcinoma, and superficial phlebitis developed when the
heparin
was
stopped.
The value of prophylaxis against thrombosis or even of treatment of existing thrombosis in spontaneous disease or after surgery is still disputed. The use of different tests for assessing liability to thrombosis and the efficacy of treatment makes comparison more difficult; every technique has its often impassioned advocates. But work we have cited shows that understanding of the thrombotic processes is being steadily
extended.
Annotations PROTEIN
REQUIREMENTS figures for the composition of foods had been agreed upon, it was relatively simple to determine the calorie intakes of men and women working at different tasks, and, in the absence of any demonstrable change of weight in the course of the period of observation, the figures for calorie intakes become figures for calorie requirements. There has indeed been a sense of agreement about calories since the classical work of Voit,99 Rubner,lo Atwater, and Lusk,l1 and in general terms the figures have been confirmed again and again.12 Not so protein requirements, which have been a matter for debate and controversy since the experiments of Sivén,13 Hindhede,14 and Chittenden 15 in the early years of this ONCE
century. We still have less accurate information about them than we have, say, about the requirements of vitamin Bl, which was discovered long after the controversy about protein requirements was well under way. The latest contribution to the subject has been the 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
O’Brien, J. R. J. clin. Path. 1961, 14, 140. Francken, I., Johansson, L., Olsson, P., Zetterqvist, E. Lancet, 1963, i, 70. Verstraete, M., Amery, A., Vermylen, C., Robyn, G. ibid. p. 446. Voit, C. in Handbuch der Physiologie; vol. 6, p. 519. Leipzig, 1881. Rubner, M. in Handbuch der Ernährungstherapie; vol. 1, p. 153. Leipzig, 1903. Lusk, G. The Science of Nutrition. Philadelphia and London, 1931. Roine, P., Pekkarinen, M., Karvonen, M. Voeding, 1964, 25, 383. Sivén, V. O. Skand. Arch. Physiol. 1901, 11, 308. Hindhede, M. ibid. 1912, 27, 87. Chittenden, R. H. Physiological Economy in Nutrition. New York,
von
1904.
574 of a working party set up by the Ministry of Health to examine the matter in this country at the request of the World Health Organisation and the Food and
report 16
Agriculture Organisation. The whole party reported on the quantitative requirements for proteins in health and disease; and they also divided into four groups, which dealt with protein metabolism and its regulation, the protein values of foods, the requirements for protein in health, and the effects of disease on protein requirements. The report also contains valuable appendices by various members of the working party on their own special areas of knowledge, and some recommendations about further work that might confine the problem more conveniently. Scientists and administrators not engaged in this work probably have little inkling of the difficulties which this working party had to face. No two proteins are chemically the same, nor have they the same value as foods. Furthermore, all foods except pure fats and sugar contain protein in appreciable amounts, and it is well known that proteins contribute 10-12% of the calories to all diets. Consequently the intake of protein varies with the intake of calories; but the requirements of protein do not vary for the same reason as those of calories, although in certain circumstances they depend upon the intake of calories. Added to all this, there is the certainty that no two individuals, even in health, will make equally good use of the proteins in their diet, and the differences may be large. The suggestions of the working party in terms of g. per kg. body-weight per day are:
thalidomide-induced deformities varies from about 430 to 150; but, says the report, the number probably lies between 200 and 250. Records were obtained of altogether 894 deformed children. Of this total 194 (22%) had at least one absent or vestigial limb, and 832 had some kind of limb deformity. Among babies with a defined limb deformity, the proportion with absent or vestigial limbs decreased from 45% in the group born to mothers who had certainly had thalidomide to 14% in those born to mothers who had not taken thalidomide. It seems that single limb deformities may only rarely have been caused by thalidomide. The survey suggests strongly that thalidomide can also cause malformations of the ear, eye, heart, kidney, and gut. In a preface Sir George Godber, chief medical officer to the Ministry, observes that this tragic episode involved fewer families than was feared at one time, and that the relief available to individual children has been improved. " Yet each case was a personal disaster which no amount of subsequent help can wholly relieve. The small compensations the incident has brought within our health services are in improved control of drugs, a better understanding of some factors in the xtiology of congenital defects and acceleration of progress in the development of artificial limbs." POLONIUM
THE search for carcinogens is endless, and investigations into the pollution of common environments by potentially harmful agents proceed without pause. Marsdenhas lately discussed the possible significance of polonium as a carcinogenic contaminant of air, cigarette smoke, and
foods. Polonium-210 RaF emits a particles and has a half-life of 138 days. It has been detected in soil, air, and some waters, notably those of artesian wells. It is present in at least some plant tissues, which have taken it from the soil or the air. Marsden is particularly concerned with the polonium in the exhaust gases of petrol engines and in and on tobacco leaves. Soil polonium is derived from the parent rock, so that, if the rock is processed for lead, polonium is apt to accompany the lead and enter compounds subsequently formed from it, conferring on them some radioactivity. Thus lead tetraethyl, the common " anti-knock " petrol additive, contains polonium. Combustion in the cylinders of the engine volatilises the polonium, which passes to the exhaust system of the vehicle, where some is deposited and the rest escapes into the atmosphere. The leaves of tobacco plants grown in different parts of the world were found to contain polonium, and it is believed that the contamination came largely from soil and only slightly from atmospheric fallout. All the tobacco was of Virginia type. Polonium salts volatilise easily at relatively low temperatures: hence slowly burning tobacco produces smoke which, if not adequately filtered, could well be a source of inhaled particles. It is estimated that inhaling the smoke of 25 cigarettes in a day could result in the deposition on the respiratory mucosa of something like 8 picocuries of polonium per day. Inhaled polonium is taken up by soft tissues rather than bone. Contamination of drinking-water from artesian wells does not at this stage seem to be very important, and there is usually much heavier contamination of the water by radon. some
One of the most satisfactory aspects of the report is the refusal of the working party to commit itself to any firm figures which might be seized upon as yardsticks by which to make comparisons and on which to base claims. We just do not know how much protein Mr. A, Mrs. B, or Miss C requires, and the labour of trying to find out resembles the trials of Sisyphus. In other words, we may never succeed. THALIDOMIDE a non-barbiturate hypnotic synthesised in became available in the United 1956, Germany in 1958. In November, 1961, Dr. W. Lenz, of Kingdom that this drug apparently had teratoHamburg, reported effects when administered to women early in genic pregnancy; and the drug was withdrawn from the British market on Dec. 2, 1961. The Ministry of Health has now published a useful survey of affected children born in England and Wales between the beginning of 1960 and the end of August, 1962.17 The survey, which is limited to liveborn children, shows that at least 349 malformed children were born to mothers who had certainly or probably taken thalidomide; and, of these, 267 survived at the time of the survey. Of the malformations in a further 366 children (of whom 295 survived), at least some are thought to have been attributable to the drug. The estimate of surviving children with
THALIDOMIDE,
in
16. Requirements of Man for Protein. Rep. publ. Hlth med. Subj., Lond. 1964, no. 111. H.M. Stationery Office, London. Pp. 90. 5s. 6d. 17. Deformities Caused by Thalidomide. Rep. publ. Hlth med. Subj., Lond. 1964, no. 112. H.M. Stationery Office. Pp. 70. 6s. 6d.
1.
Marsden, E. Nature, Lond. 1964, 203,
230.