904 arsenic depends on whether it is taken in organic or inorganic form (pentavalent or trivalent).’ I have extended the work to which Dr Eaton refers and confirmed that opium is adulterated by some unknown arsenic compound to increase its aphrodisiac activity and that the arsenic concentration can be very high. It is mostly in salt form and can be extracted without boiling with hydrochloric acid, in contrast to the arsenic present in food (see figure). Arsenic compounds prepared in
TOTAL
Total arsenic content in arsenic.
INORGANIC FREE
opium compared
with
inorganic,
free
our area are based on the trivalent oxide form known as Bhasma. Since no history of arsenic intake from any other source was available and in view of the nature of the arsenic with which the opium was adulterated, I am convinced that the adulteration was responsible for the neuropathy. In this area the syndrome of "arsenicosis" is not uncommon2 consisting of neuropathy, skin pigmentation, exfoliation of skin and hepatomegaly; and contaminated water adulterated chewing tobacco, indigenous drugs,3 and adulterated opium are some of’ the sources of arsenic. We have found higher arsenic concentrations in 20% of livers obtained after accidental death, when compared with concentrations in normal liver reported from the West.4 These high-arsenic livers often show portal fibrosis, which has been reported by others.5
for levodopa this figure can be lowered further still by combination with a decarboxylase inhibitor. Amantadine, but not levodopa or bromocriptine, sometimes causes ankle cedema, and may cause a cardiomyopathy.’ However, an association between amantadine and heart-failure is not proven. Amantadine 100-300 mg daily for 2-6 weeks causes livedo reticularis, a mottled blue discoloration of the skin due to prominence of the normal pattern of venous drainage, in approximately 50% of all elderly patients. Livedo is accompanied by redema in 5-10% of cases, but oedema is unlikely to be due to heartfailure, being accompanied by a redistribution of body fluid between different fluid compartments rather than by an increase in total body water or by an electrolyte disturbance.2 Livedo and cedema are normally confined to the legs and may result from the catecholamine-releasing action of amantadine in certain vascular beds. Oedema responds to salt restriction and/or diuretics. We have not seen it get worse or more extensive in any parkinsonian patient treated with amantadine for up to seven years. 4 of 89 parkinsonian patients on amantadine 100-600 mg daily, and 2 of 64 patients not on amantadine but taking levodopa 0 5-8 g daily, have developed angina, dyspnoea, pulmonary congestion, or distension of neck veins during treatment. 1 of these 6 patients had a cardiac arrhythmia, 2 had angina, 3 had myocardial infarction, and 5 had electrocardiographic evidence of ischasmic heart-disease. All these patients were aged over sixty. 2 of the 4 on amantadine had had ankle cedema before heart-failure developed but 2 had not. All 4 patients were also taking levodopa alone or combined with a decarboxylase inhibitor, and 3 were also taking anticholinergic drugs. The signs of cardiac failure responded to diuretics and digoxin, and amantadine and levodopa were continued. Treatment for Parkinson’s disease increases the patient’s mobility and may have been indirectly responsible for the signs of ischaemic heart-disease. However, we have not observed any patient in whom heart-failure seemed to be due directly to depletion of catecholamines in the heart by amantadine and in whom there was no other obvious cause for heart-failure. Theoretically amantadine could deplete myocardial noradrenaline stores, and this possibility may, perhaps, be avoided by the addition of levodopa. On balance, the benefits of antiparkinsonian treatment outweigh the risk of provoking cardiac disorders, and if necessary to restore mobility, levodopa, bromocriptine, or amantadine should not be witheld in parkinsonian patients who also have heart-disease. J. D. PARKES University Department of Neurology, C. D. MARSDEN King’s College Hospital, London SE5. P. PRICE
LEVAMISOLE AND AGRANULOCYTOSIS
SIR,-Agranulocytosis has developed
Institute of Medical Education and Research, Chandigarh 160011, India
D. V. DATTA
patients on levami-
as a fall in granulocyte levels to of the granulocyte/lymphocyte reversal 600/ul ratio. 12 This condition should be distinguished from the leukopenia which is spontaneously reversible even when levamisole is continued. Levamisole-induced agranulocytosis has the characteristics
We
regard agranulocytosis or
Postgraduate
in
sole.3-11 It is potentially fatal if unrecognised and untreated.
less, with
a
AMANTADINE-INDUCED HEART-FAILURE
SiR,—It is difficult
bromocriptine,
or
to
know whether
to
prescribe levodopa,
amantadine for patients with Parkinson’s
disease who also have heart-disease, because all these drugs may be cardiotoxic. However, levodopa and bromocriptine cause cardiac arrhythmias in less than 1% of all patients, and 1. Schroeder, H. A.,
Balassa, J. J. J. chron. Dis. 1966, 19, 85. 2. Datta, D V , Kaul, M. K. J. Ass.Physns India, 1976, 24, 599. 3. Datta, D. V., Singh, I., Kaul, M. K. Postgrad.Inst.Bull. (in the press). 4. Kingslay, G. R., Schaffert, R. R. Analyt. Chem. 1951, 23, 914. 5. Morris, J. S., Schmid, M., Newmen, S., Schene, P. J., Path, M. R. C., Sherlock, S. Gastroenterology, 1974, 66, 86.
1. Vale, J. A., Maclean, K. S. Lancet, 1976, i, 548. 2. Parkes, J. D., Baxter, R. C. H., Curzon, G., Knill-Jones, R. P., Knott, P J., Marsden, C. D., Tattersall, R., Vollum, D. ibid. 1971, i, 1083. 3. Rosenthal, M., Trabert, U., Müller, W.Lancet, 1976, i, 369. 4. Graber, H., Takacs, L., Vedrödy, K. ibid. 1976, u, 1248. 5. Sany, J., Morlock, G., Kalfa, G., Serre, H.Nouv.Presse méd. 1976, 5, 1148. 6. Leca, A. P., Le Porrier, M., Prier, A., Camus, J. P.ibid.p. 1212. 7. Ruuskanen, O., Remes, M., Mäkelä, A. L., Isomäki, H., Toivanen, A Lancet, 1976, ii, 958. 8. Williams, I. A. ibid. 1976, i, 1080. 9. Clara, R., Germanes, J. ibid. 1977, i, 47. 10. Vanholder, R., Van Hove, W. ibid. p. 100. 11. Willoughby, M L. N., Baird, G. M., Campbell, A. M. ibid.p. 657. 12. Pisciotta, A. V. Clin. Pharm. Ther. 1971, 12, 13.
905
type-1 agranulocytosis. Although the bone-marrow may temporarily lack promyelocytes, granulocytes are apparently selectively destroyed without bone-marrow toxicity." 12 Antibodies which agglutinate granulocytes in the presence of of
levamisole have been found in the serum of a few patients with levamisole-induced agranulocytosis.’ 8 Levamisole thus seems
hapten on the leucocyte membrane. The condition is spontaneously reversible upon discontinuation of treatment. Reversible agranulocytosis has also been described with pyrazolone derivatives (such as phenylbutazone) and other commonly used drugs such as gold salts, sulphonamides, and phenothiazines.lO As with these other drugs, the frequency of levamisoleinduced agranulocytosis is much higher in rheumatoid arthritis than in other diseases. Our best estimate at present is that the frequency is approximately 3% in patients with severe rheumatic diseases, whereas this complication is rare in other conditions. The figure in rheumatoid arthritis is based on data obtained from pilot studies in as yet small numbers of severely affected patients. Only as their number increases and those treated become representative of the total population of rheumatoid subjects will the true frequency become known. The patient’s disease, his immunological profile, drug interaction, and/or previous sensitisation to other drugs may all be predis-
to act as a
memorandum on the Treatment and Supervision of Heroin Addiction. Paragraph 8, on outpatient services, stated: "Some addicts will not accept withdrawal treatment, at any rate to start with, and complete refusal of supplies will not cure their addiction-it will merely throw them on the black market and encourage the development of an organized illicit traffic on a scale hitherto unknown in this country." I agree with you that "it would be oversanguine to suppose that the system of treatment and control conceived 10 years ago did not, in the light of experience and changing circumstances, require critical review and probably some revision." At the same time, it would be a sad day if one were to see a rising tide of crime on the streets of London to support a 10-year heroin habit because of a change of policy at the national level. I trust that your plea, that the report of the special committee of the Advisory Council on the Misuse of Drugs be published, is successful. Division of Resource National Institute on
Rockville, Maryland 20852, U.S.A.
be harmful. M. ROSENTHAL A. ST J. DIXON Y. BREYSSE P. FRANCHIMONT E. C. HUSKISSON K. L. SCHMIDT Y. SCHUERMANS E. VEYS T. L. VISCHER Consultant rheumatologists to the steering committee of the E.U.L.A.R. Multicentre Study on Levamisole in Rheumatoid Arthritis
Janssen Pharmaceutica, B-2340 Beerse, Belgium Janssen Pharmaceutical Ltd,
Marlow, Bucks SL7
1ET
W. K. AMERY P. A. J. JANSSEN J. DE CREPE J. BRUGMANS SYMOENS J.
A. L. MACNAIR
DRUG-DEPENDENCE CLINICS
SIR,—I read with much interest and some dismay your edi(Feb 19, p. 405) in which you suggest that tighter pre-
torial
scribing and the general switch from heroin to methadone may have made the clinics less attractive to potential patients, so that addicts will see little gain in registration and will prefer continue on the black market. I also believe that a recent tendency for many clinics to refuse to continue to supply addicts (some of whom have been on continuous treatment since 1968) with methadone and/or heroin for self-injection is causing many of them to drop out of treatment and return to the street and to criminal activities to support their habit. On March 7, 1967, the Minister of Health issued a hospital
RICHARD V. PHILLIPSON
SOYBEAN-PROTEIN DIET AND PLASMA-CHOLESTEROL
13
posing factors.5 Agranulocytosis may happen at any time, and it has developed as long as two years after the start of treatment. It is often accompanied by sudden illness. In patients with rheumatic diseases, regular blood examinations are recommended, but a clear warning to the patient that he must return to his doctor as soon as he experiences suggestive symptoms is still the most efficient measure to detect this adverse reaction early. Sudden fever, shivering, and infection (sore throat, ulceration) clearly call for an immediate blood examination. Rapid and spontaneous recovery is the rule when the drug is withdrawn. Infection should be treated appropriately. Corticosteroids and blood transfusions should be avoided and might
Development, Drug Abuse,
SIR,-Although the hypocholesterolaemic effect of soybeanprotein reported by Dr Sirtori and his colleagues (Feb. 5, p. 275) in patients with type-n hyperlipoproteinamua is remarkable, their report does not disprove the value of a low-lipid/ low-cholesterol diet. They did not state how strictly the patients adhered to the low-lipid diet, and whether plasma-cholesterol concentrations altered during the three months the patients were on this diet. Levy et al. reported a fall from 440 to 330 mg/dl using the same diet. Furthermore, the downward trend of plasma-cholesterol in the cross-over trial, which compared the effect of a soybean-protein diet with that of a low-lipid diet, might be due to the high P/S ratio (polyunsaturated/saturated fat) in both diets. The addition of cholesterol to the diet did not modify the hypocholesterolsemic effect of soybean protein. This lack of effect of cholesterol could be caused by the very low dietary lipid content and the high P/S ratio. There is evidence of an inter-action between the effect of dietary cholesterol, fat level,23 and degree of saturation of dietary fat, although there are conflicting reports.’ 5 Unfortunately, Sirtori et al. did not state whether dietary cholesterol affected plasma-lipids in patients on the control low-lipid diet. Extrapolation of the effect of soybean protein to other vegetable proteins is not warranted. Our experiments6 with rabbits do not support the suggestion that animal proteins as such induce higher plasma-cholesterol levels than vegetable proteins. We demonstrated that hypercholesterolaemia in casein-fed rabbits could be largely prevented by replacing part of the casein by other animal proteins, such as gelatin and fish protein. We suggest that this is due to differences in aminoacid composition between the proteins. It would be interesting to investigate whether the observed effect is a general one or confined to the type-n patient. If its effect can be confirmed in controlled long-term studies, soybean protein might be a very useful adjunct to treatment.
to
11. Pisciotta, A. V. Sem. Hemat. 1973,10, 279. 12 Lobuglio, A. New Engl. J. Med. 1976, 295, 1533. 13 Hennemann, H. H., Schief, A. Dt. med. Wschr. 1975, 100, 519.
Department of Human Nutrition, Agricultural University, Wageningen, Netherlands
R. J. J. HERMUS M. STASSE-WOLTHUIS J. G. A. J. HAUTVAST
R. I., Bonnell, M., Ernst, N. D. J. Am. diet. Ass. 1971, 58, 406. Grande, F., Anderson, J. T., Chlouverakis, C., Proja, M., Keys, A. J. Nutr. 1965, 87, 52. 3. Keys, A., Grande, F., Anderson, J. T. Am. J. clin. Nutr. 1974, 27, 188. 4. Brown, H. B. Proc. 2nd int. Symp. Atherosclerosis. 1969, p. 426. 5. Anderson, J. F., Grande, F., Keys, A. Am. J. clin. Nutr. 1976, 29, 1184. 6. Hermus, R. J. J. PH.D. thesis. (Agric. Res. Rep. 838, Pudoc, Wageningen). 7. Hamilton, R. M. G., Carroll, K. K. Atherosclerosis, 1976, 24, 47. 1. 2.
Levy,
TOTAL
Total arsenic content in arsenic.
INORGANIC FREE
opium compared
with
inorganic,
free
our area are based on the trivalent oxide form known as Bhasma. Since no history of arsenic intake from any other source was available and in view of the nature of the arsenic with which the opium was adulterated, I am convinced that the adulteration was responsible for the neuropathy. In this area the syndrome of "arsenicosis" is not uncommon2 consisting of neuropathy, skin pigmentation, exfoliation of skin and hepatomegaly; and contaminated water adulterated chewing tobacco, indigenous drugs,3 and adulterated opium are some of’ the sources of arsenic. We have found higher arsenic concentrations in 20% of livers obtained after accidental death, when compared with concentrations in normal liver reported from the West.4 These high-arsenic livers often show portal fibrosis, which has been reported by others.5
for levodopa this figure can be lowered further still by combination with a decarboxylase inhibitor. Amantadine, but not levodopa or bromocriptine, sometimes causes ankle cedema, and may cause a cardiomyopathy.’ However, an association between amantadine and heart-failure is not proven. Amantadine 100-300 mg daily for 2-6 weeks causes livedo reticularis, a mottled blue discoloration of the skin due to prominence of the normal pattern of venous drainage, in approximately 50% of all elderly patients. Livedo is accompanied by redema in 5-10% of cases, but oedema is unlikely to be due to heartfailure, being accompanied by a redistribution of body fluid between different fluid compartments rather than by an increase in total body water or by an electrolyte disturbance.2 Livedo and cedema are normally confined to the legs and may result from the catecholamine-releasing action of amantadine in certain vascular beds. Oedema responds to salt restriction and/or diuretics. We have not seen it get worse or more extensive in any parkinsonian patient treated with amantadine for up to seven years. 4 of 89 parkinsonian patients on amantadine 100-600 mg daily, and 2 of 64 patients not on amantadine but taking levodopa 0 5-8 g daily, have developed angina, dyspnoea, pulmonary congestion, or distension of neck veins during treatment. 1 of these 6 patients had a cardiac arrhythmia, 2 had angina, 3 had myocardial infarction, and 5 had electrocardiographic evidence of ischasmic heart-disease. All these patients were aged over sixty. 2 of the 4 on amantadine had had ankle cedema before heart-failure developed but 2 had not. All 4 patients were also taking levodopa alone or combined with a decarboxylase inhibitor, and 3 were also taking anticholinergic drugs. The signs of cardiac failure responded to diuretics and digoxin, and amantadine and levodopa were continued. Treatment for Parkinson’s disease increases the patient’s mobility and may have been indirectly responsible for the signs of ischaemic heart-disease. However, we have not observed any patient in whom heart-failure seemed to be due directly to depletion of catecholamines in the heart by amantadine and in whom there was no other obvious cause for heart-failure. Theoretically amantadine could deplete myocardial noradrenaline stores, and this possibility may, perhaps, be avoided by the addition of levodopa. On balance, the benefits of antiparkinsonian treatment outweigh the risk of provoking cardiac disorders, and if necessary to restore mobility, levodopa, bromocriptine, or amantadine should not be witheld in parkinsonian patients who also have heart-disease. J. D. PARKES University Department of Neurology, C. D. MARSDEN King’s College Hospital, London SE5. P. PRICE
LEVAMISOLE AND AGRANULOCYTOSIS
SIR,-Agranulocytosis has developed
Institute of Medical Education and Research, Chandigarh 160011, India
D. V. DATTA
patients on levami-
as a fall in granulocyte levels to of the granulocyte/lymphocyte reversal 600/ul ratio. 12 This condition should be distinguished from the leukopenia which is spontaneously reversible even when levamisole is continued. Levamisole-induced agranulocytosis has the characteristics
We
regard agranulocytosis or
Postgraduate
in
sole.3-11 It is potentially fatal if unrecognised and untreated.
less, with
a
AMANTADINE-INDUCED HEART-FAILURE
SiR,—It is difficult
bromocriptine,
or
to
know whether
to
prescribe levodopa,
amantadine for patients with Parkinson’s
disease who also have heart-disease, because all these drugs may be cardiotoxic. However, levodopa and bromocriptine cause cardiac arrhythmias in less than 1% of all patients, and 1. Schroeder, H. A.,
Balassa, J. J. J. chron. Dis. 1966, 19, 85. 2. Datta, D V , Kaul, M. K. J. Ass.Physns India, 1976, 24, 599. 3. Datta, D. V., Singh, I., Kaul, M. K. Postgrad.Inst.Bull. (in the press). 4. Kingslay, G. R., Schaffert, R. R. Analyt. Chem. 1951, 23, 914. 5. Morris, J. S., Schmid, M., Newmen, S., Schene, P. J., Path, M. R. C., Sherlock, S. Gastroenterology, 1974, 66, 86.
1. Vale, J. A., Maclean, K. S. Lancet, 1976, i, 548. 2. Parkes, J. D., Baxter, R. C. H., Curzon, G., Knill-Jones, R. P., Knott, P J., Marsden, C. D., Tattersall, R., Vollum, D. ibid. 1971, i, 1083. 3. Rosenthal, M., Trabert, U., Müller, W.Lancet, 1976, i, 369. 4. Graber, H., Takacs, L., Vedrödy, K. ibid. 1976, u, 1248. 5. Sany, J., Morlock, G., Kalfa, G., Serre, H.Nouv.Presse méd. 1976, 5, 1148. 6. Leca, A. P., Le Porrier, M., Prier, A., Camus, J. P.ibid.p. 1212. 7. Ruuskanen, O., Remes, M., Mäkelä, A. L., Isomäki, H., Toivanen, A Lancet, 1976, ii, 958. 8. Williams, I. A. ibid. 1976, i, 1080. 9. Clara, R., Germanes, J. ibid. 1977, i, 47. 10. Vanholder, R., Van Hove, W. ibid. p. 100. 11. Willoughby, M L. N., Baird, G. M., Campbell, A. M. ibid.p. 657. 12. Pisciotta, A. V. Clin. Pharm. Ther. 1971, 12, 13.
905
type-1 agranulocytosis. Although the bone-marrow may temporarily lack promyelocytes, granulocytes are apparently selectively destroyed without bone-marrow toxicity." 12 Antibodies which agglutinate granulocytes in the presence of of
levamisole have been found in the serum of a few patients with levamisole-induced agranulocytosis.’ 8 Levamisole thus seems
hapten on the leucocyte membrane. The condition is spontaneously reversible upon discontinuation of treatment. Reversible agranulocytosis has also been described with pyrazolone derivatives (such as phenylbutazone) and other commonly used drugs such as gold salts, sulphonamides, and phenothiazines.lO As with these other drugs, the frequency of levamisoleinduced agranulocytosis is much higher in rheumatoid arthritis than in other diseases. Our best estimate at present is that the frequency is approximately 3% in patients with severe rheumatic diseases, whereas this complication is rare in other conditions. The figure in rheumatoid arthritis is based on data obtained from pilot studies in as yet small numbers of severely affected patients. Only as their number increases and those treated become representative of the total population of rheumatoid subjects will the true frequency become known. The patient’s disease, his immunological profile, drug interaction, and/or previous sensitisation to other drugs may all be predis-
to act as a
memorandum on the Treatment and Supervision of Heroin Addiction. Paragraph 8, on outpatient services, stated: "Some addicts will not accept withdrawal treatment, at any rate to start with, and complete refusal of supplies will not cure their addiction-it will merely throw them on the black market and encourage the development of an organized illicit traffic on a scale hitherto unknown in this country." I agree with you that "it would be oversanguine to suppose that the system of treatment and control conceived 10 years ago did not, in the light of experience and changing circumstances, require critical review and probably some revision." At the same time, it would be a sad day if one were to see a rising tide of crime on the streets of London to support a 10-year heroin habit because of a change of policy at the national level. I trust that your plea, that the report of the special committee of the Advisory Council on the Misuse of Drugs be published, is successful. Division of Resource National Institute on
Rockville, Maryland 20852, U.S.A.
be harmful. M. ROSENTHAL A. ST J. DIXON Y. BREYSSE P. FRANCHIMONT E. C. HUSKISSON K. L. SCHMIDT Y. SCHUERMANS E. VEYS T. L. VISCHER Consultant rheumatologists to the steering committee of the E.U.L.A.R. Multicentre Study on Levamisole in Rheumatoid Arthritis
Janssen Pharmaceutica, B-2340 Beerse, Belgium Janssen Pharmaceutical Ltd,
Marlow, Bucks SL7
1ET
W. K. AMERY P. A. J. JANSSEN J. DE CREPE J. BRUGMANS SYMOENS J.
A. L. MACNAIR
DRUG-DEPENDENCE CLINICS
SIR,—I read with much interest and some dismay your edi(Feb 19, p. 405) in which you suggest that tighter pre-
torial
scribing and the general switch from heroin to methadone may have made the clinics less attractive to potential patients, so that addicts will see little gain in registration and will prefer continue on the black market. I also believe that a recent tendency for many clinics to refuse to continue to supply addicts (some of whom have been on continuous treatment since 1968) with methadone and/or heroin for self-injection is causing many of them to drop out of treatment and return to the street and to criminal activities to support their habit. On March 7, 1967, the Minister of Health issued a hospital
RICHARD V. PHILLIPSON
SOYBEAN-PROTEIN DIET AND PLASMA-CHOLESTEROL
13
posing factors.5 Agranulocytosis may happen at any time, and it has developed as long as two years after the start of treatment. It is often accompanied by sudden illness. In patients with rheumatic diseases, regular blood examinations are recommended, but a clear warning to the patient that he must return to his doctor as soon as he experiences suggestive symptoms is still the most efficient measure to detect this adverse reaction early. Sudden fever, shivering, and infection (sore throat, ulceration) clearly call for an immediate blood examination. Rapid and spontaneous recovery is the rule when the drug is withdrawn. Infection should be treated appropriately. Corticosteroids and blood transfusions should be avoided and might
Development, Drug Abuse,
SIR,-Although the hypocholesterolaemic effect of soybeanprotein reported by Dr Sirtori and his colleagues (Feb. 5, p. 275) in patients with type-n hyperlipoproteinamua is remarkable, their report does not disprove the value of a low-lipid/ low-cholesterol diet. They did not state how strictly the patients adhered to the low-lipid diet, and whether plasma-cholesterol concentrations altered during the three months the patients were on this diet. Levy et al. reported a fall from 440 to 330 mg/dl using the same diet. Furthermore, the downward trend of plasma-cholesterol in the cross-over trial, which compared the effect of a soybean-protein diet with that of a low-lipid diet, might be due to the high P/S ratio (polyunsaturated/saturated fat) in both diets. The addition of cholesterol to the diet did not modify the hypocholesterolsemic effect of soybean protein. This lack of effect of cholesterol could be caused by the very low dietary lipid content and the high P/S ratio. There is evidence of an inter-action between the effect of dietary cholesterol, fat level,23 and degree of saturation of dietary fat, although there are conflicting reports.’ 5 Unfortunately, Sirtori et al. did not state whether dietary cholesterol affected plasma-lipids in patients on the control low-lipid diet. Extrapolation of the effect of soybean protein to other vegetable proteins is not warranted. Our experiments6 with rabbits do not support the suggestion that animal proteins as such induce higher plasma-cholesterol levels than vegetable proteins. We demonstrated that hypercholesterolaemia in casein-fed rabbits could be largely prevented by replacing part of the casein by other animal proteins, such as gelatin and fish protein. We suggest that this is due to differences in aminoacid composition between the proteins. It would be interesting to investigate whether the observed effect is a general one or confined to the type-n patient. If its effect can be confirmed in controlled long-term studies, soybean protein might be a very useful adjunct to treatment.
to
11. Pisciotta, A. V. Sem. Hemat. 1973,10, 279. 12 Lobuglio, A. New Engl. J. Med. 1976, 295, 1533. 13 Hennemann, H. H., Schief, A. Dt. med. Wschr. 1975, 100, 519.
Department of Human Nutrition, Agricultural University, Wageningen, Netherlands
R. J. J. HERMUS M. STASSE-WOLTHUIS J. G. A. J. HAUTVAST
R. I., Bonnell, M., Ernst, N. D. J. Am. diet. Ass. 1971, 58, 406. Grande, F., Anderson, J. T., Chlouverakis, C., Proja, M., Keys, A. J. Nutr. 1965, 87, 52. 3. Keys, A., Grande, F., Anderson, J. T. Am. J. clin. Nutr. 1974, 27, 188. 4. Brown, H. B. Proc. 2nd int. Symp. Atherosclerosis. 1969, p. 426. 5. Anderson, J. F., Grande, F., Keys, A. Am. J. clin. Nutr. 1976, 29, 1184. 6. Hermus, R. J. J. PH.D. thesis. (Agric. Res. Rep. 838, Pudoc, Wageningen). 7. Hamilton, R. M. G., Carroll, K. K. Atherosclerosis, 1976, 24, 47. 1. 2.
Levy,
