- Email: [email protected]
CYCLOPHOSPHAMIDE IN ADULT-ONSET NEPHROTIC SYNDROME
aged 45-64 that
was found in 1951 had disappeared by 1961.9 Dr. Roberts and Mrs. Lloyd produce no evidence, but suggest that differences m the social-class composition of the towns may explain the greater increase in deathrates in those where the water became softer compared with those in which it became harder. This requires more detailed study, but in the meantime we have looked at the social-class composition of towns in 1951, and grouped them into quarters according to the proportion of persons in social classes IV and v. Those in the quarter with the highest proportion showed an average increase of 157 per 100,000 in male I.H.D. death-rates at ages 45-64 between 1948-54 and 1958-64, and this increase fell to 150 in the second quarter and 134 and 135 in the third and fourth quarters, respectively. This is as suggested. However, if the county boroughs in the " changes " paper are identified, it is seen that, relative to other towns in the same quarter, those towns where the water had been softened have experienced a larger increase, and those where the water was hardened have experienced a smaller increase. This is so for 9 out of the 11towns, and it is of interest that the 2 towns not in line are the smallest of all the county boroughs, Canterbury and Burton-on-Trent. We would point out that our findings related to all cardiovascular disease and femals death rates, which behaved differently vis-a-vis social class mortality. Finally, we have never stated (and it is not our view) " that soft-water supplies should be artificially hardened to lower I.H.D. mortality ", but believe rather that " the technical problems of increasing the hardness of soft water should now be explored ".8 This misquotation is unfortunate in view of the need to carry the water industry in further research into these difficult questions. We are left, then, with these major external environmental correlations with cardiovascular mortality:the hardness of the local water-supply; local rainfall; and latitudewhich has not been considered here.Manifestly, the first two are related, though meanwhile it has not been possible to get far in separating them. As said, we ourselves think that water hardness is the more promising both scientifically and practically. We hope that serious attention to and criticism of the " water story " will not be diverted by misleading conclusions based on inadequate data.
M.R.C. Social Medicine Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT.
M. D. CRAWFORD M. J. GARDNER J. N. MORRIS.
ORAL DIAZOXIDE FOR MALIGNANT HYPERTENSION were interested to read the letter by Dr. Pohl SIR,-We and Dr. Thurston (June 3, p. 1231) recommending the use of oral diazoxide as a final attempt to treat severe hypertension before bilateral nephrectomy. We have had a disappointing experience with this drug in such cases. During a trial of oral diazoxide in ten patients with severe hypertension and renal failure we were faced with two serious complications. In a 26-year-old man in terminal renal failure secondary to chronic
glomerulonephritis and malignant hypertension, who had been on dialysis since September, 1971, we tried oral diazoxide in a final attempt to control this hypertension before proceeding to bilateral nephrectomy. After 4 months of oral diazoxide (400 mg. per day) the patient developed a clearcut clinical, biological, and radiological picture of acute pancreatitis. The plasma-level of diazoxide 24 hours after the onset of pancreatitis was 38 jg. per ml. When the drug was stopped the patient improved quickly, and 11 days later serum-amylase levels were normal. 9. Registrar General’s Decennial Supplement England and Wales 1961: occupational mortality tables. H.M. Stationery Office, 1971.
The second patient, a 37-year-old woman with malignant hypertension and renal failure (creatinine clearance 35 ml. per minute), was given a therapeutic trial with oral diazoxide (300 mg. per day). 10 days after starting the drug she developed a diabetic ketoacidosis. The plasma-level of
diazoxide on admission was 58 g. per ml. When diazoxide withdrawn the patient recovered. There was no suggestion, in intravenous glucose-tolerance tests or in family history, of a prediabetic state in either patient, and blood-glucose levels have remained normal. In our opinion oral diazoxide is contraindicated for hypertension in chronic renal failure-a verdict shared by others.1.a was
Renal Division,
Department of Medicine:
University Hospital, 9.000 Ghent, Belgium.
M. DE BROE M. MUSSCHE S. RINGOIR.
Nephrological Clinic, Maria’s Voorzienigheid Hospital, 8.500
Kortrijk, Belgium.
V. BOSTEELS.
CYCLOPHOSPHAMIDE IN ADULT-ONSET NEPHROTIC SYNDROME
SIR,-We
were
interested in the paper of Dr. Uldall and
his colleagues
(June 10, p. 1250) advocating the use of cyclophosphamide in some adult-onset nephrotic patients with a minimal change " lesion in renal biopsy. Recently, we reported briefly3 the results of cyclophosphamide treatment in 15 patients drawn from a total of 45 with onset of a nephrotic syndrome and a " minimal change " lesion on biopsy. Our conclusions were that behaviour of these patients, and the place of cyclophosphamide, were the same as in the childhood-onset group: in the rather common (74% of our 45) multiple-relapsing patient, if corticosteroid be required in doses producing dangerous or undesirable side-effects (11 patients treated); and in the less common patient who is resistant to corticosteroid treatment in conventional dosage (4 patients treated). We have not used cyclophosphamide as primary 4 "
treatment either in children
or in adults, as Dr. Uldall has done in 2 of his patients, because of fears of its longterm toxicity. 12 of the 15 patients responded to cyclophosphamide with complete loss of proteinuria; 11 remain in remission 6-38 months later, 4 having relapsed. These results and those of Dr. Uldall re-emphasise the in any nephrotic suggestion that the critical distinction " is those with a minimal between patient change " lesion and those with any other histological appearance. We would agree that unless amyloid is stained for routinely in all renal biopsies (and preferably sought by electron microscopy) it will be missed from time to time in early cases. We also adopted this policy of routine staining after being misled by an initial biopsy on which amyloid was not sought and not diagnosed. It is often forgotten how common primary amyloidosis is as a cause of the nephrotic syndrome in adults-from 8% to 15% in most series.5 An interesting feature of our patients has been the presence of the nephrotic syndrome with a " minimal change " pattern in 4 patients over the age of 70, and we have since Great care is seen two further patients in this group. needed in their management, since the danger of sepsis, hypovolamua and cardiovascular collapse, and corticosteroid toxicity are especially prominent and other co-
C. T., Pentecost, B. L., Samaan, N. A. Lancet, 1962, ii, 735. Okun, R., Patterson Russell, R., Wilson, W. R. Archs intern. Med. 1963, 112, 882. 3. Cameron, J. S., Ogg, C. S., White, R. H. R. in Glomerulonephritis (edited by P. Kincaid-Smith and T. Mathew). New York, 1972 (in the press). 4. Tsao, Y. C., Yeung, C. H. Archs Dis. Childh. 1970, 46, 327. 5. Sharpstone, P., Cameron, J. S., Ogg, C. S. Br. med. J. 1969, ii, 533. 1. 2.
Dollery,
1398 incidental diseases may be present. We have not yet used cyclophosphamide in this elderly group, but 3 of these 8 patients were treated with corticosteroids and all responded promptly, 1 with the loss of over 30 kg. of oedema j the others were managed conservatively because of coincidental osteoporosis and cardiovascular disease. Guy’s Hospital, London SE1 9RT.
J. S. CAMERON C. S. OGG.
times normal for the operation period and give rise to bleeding, as encountered by Mr. Gordon-Smith and his colleagues (and also by Mr. Charnley 4). I find less of a problem with 10,000 units of heparin subcutaneously given the night before operation. I also note that the Gordon-Smith report does not mention the use of a method of heparin control. In the long run, as I have experienced it in now close to 1300 cases, the Dale and Laidlaw coagulometer, a rapid convenient method of control of heparin dosage, becomes an important adiunct if problems are to be avoided. Department of Pathology, Mount Vernon Hospital, Mount Vernon, New York 10550, U.S.A.
ISOCHROMOSOMES AND MALIGNANT GROWTH
SIR,-Mr. Lobb and others (April 15, precise identification of chromosomes
p.
849)
state
that
may reveal that isochromosomes are common in malignant tissues. While this may be true for isochromosome 17 in myeloid leukaemia it does not seem to hold for other types of malignant growth. In a detailed analysis of 3 cases of untreated cancer of the ovary we were able to trace the origin of most of the numerous " new " chromosomes present in all cells. Translocation, inversion, and deletion had been responsible for the new chromosomes, but we did not find a single isochromosome. Euratom Unit for Human Radiation L. TIEPOLO and Cytogenetics and Department of Obstetrics and
Gynæcology, University of Pavia, Via Forlanini, 14, Pavia, Italy.
C. ZARA O. ZUFFARDI
M. FRACCARO.
J. G. SHARNOFF.
CEREBROVASCULAR DISEASE AND HYPERLIPOPROTEINÆMIA SIR,-Some types of hyperlipidasmia are known to predispose to coronary heart-diseaseand peripheral vascular disease.’,The role of abnormal lipid patterns in the pathogenesis of cerebrovascular disease is less well established. We have studied, in a pilot project, 13 men and 13 women (age range 41-74) with cerebrovascular disease ranging from transient cerebral ischxmic attacks to established strokes. Very-low-density lipoproteins were measured by micronephelometry7 as modified by Farid and Anderson.g Total cholesterol was measured by ’AutoAnalyzer’, and S particles (&bgr;-lipoprotein) were calculated therefrom by
extrapolation.9 6 men (46%) and
PREVENTION OF POSTOPERATIVE THROMBOSIS
SIR,-I was indeed pleased to see the results of Mr. Gordon-Smith and his colleagues (May 27, p. 1133). It adds further confirmation to the results obtained by myself,l Mr. Kakkar and his associates,2 and Mr. Williams 3 illustrating the efficacy of prophylactic heparin in low dose in the prevention of thrombosis associated with operation and of fatal pulmonary thromboembolism. I must agree with one conclusion-namely, that the 125Ifibrinogen-uptake studies indicate the likelihood that legvein thrombosis is being prevented, but does not indicate that embolism is prevented. Nevertheless, if leg-vein thrombosis is prevented then one may assume that fatal pulmonary thromboembolism will surely also be prevented. The study further confirms our earlier contention that the operation period is the most critical period of hypercoagulation, as measured by either the Lee-White method or preferably by the Dale and Laidlaw coagulometer. However, I believe the study also reflects the fact that the short periods of heparinisation-namely, the two and five or even seven days-gave rise to thrombotic complications if the patients were not as yet mobilised after operation. This is not clear from the report. I, on the other hand, had detected a second critical period needing heparinisation-the period of postoperative mobilisation of the patient. Thus, I am certain that longer prophylaxis to the point of reactivation or discharge will also avoid the few failures. I am also somewhat disturbed by the dosage schedule used by Mr. Kakkar and his colleagues and by Mr. GordonSmith and his co-workers. Although 5000 units of heparin sodium is relatively small given subcutaneously in comparison to earlier intravenous methods still in vogue, it is still somewhat dangerous given one hour before surgery. This may raise the levels of coagulation to two to three Sharnoff, J. G., DeBlasio, G. Lancet, 1970, ii, 1006. Kakkar, V. V., Field, E. S., Nicolaides, A. N., Flute, P. T., Wessler, S., Yin, E. T. ibid. 1971, ii, 669. 3. Williams, H. T. ibid. p. 950. 1. 2.
6 women (46%) had normal lipid patterns. 6 of the men showed a Fredrickson type-iv pattern of hyperlipoproteinaemia,1O and 1 (8%) a Fredrickson type-II pattern. Of the 7 (54%) women with abnormal lipid patterns, 4 (30%) showed Fredrickson type iv, 2 (16%) Fredrickson type II, and 1 (8%) type MS.9 LIPOPROTEIN TYPES: BOTH SEXES DIVIDED INTO THOSE SUSTAINING A CARDIOVASCULAR ACCIDENT BEFORE OR AFTER THE AGE OF 55
Differences between the sexes were seen when the age which the cerebrovascular ischaemicepisode occurredwas considered. Of 6 women below the age of 55, 5 were found to have abnormal lipid patterns; only 2 out of 7 aged 55 or more showed such abnormalities. On the other hand, 4 out of 8 men whose ischxmic episodes occurred at the age of 55 or over had hyperlipoproteinoemia, and 3 out of 5 under 55 showed abnormal lipoprotein patterns (see accompanying at
table). 4. 5. 6. 7. 8. 9.
10.
Charnley, J. Personal communication. Heinle, R. A., Levy, R. I., Fredrickson, D. S., Gorlin, R. Am. J. Cardiol. 1969, 24, 178. Greenhalgh, R. M., Lewis, B., Rosengarten, D. S., Calnan, J. S., Mervart, I., Martin, P. Lancet, 1971, ii, 947. Stone, M. C., Thorp, J. M. Clinica chim. Acta, 1966, 14, 812. Farid, N. R., Anderson, J. ibid. (in the press). Stone, M. C., Thorp, J. M., Mills, G. L., Dick, T. B. S. ibid. 1971, 31, 333. Fredrickson, D. S., Ley, R. I., Lees, R. S. New Engl. J. Med. 1967, 276, 34, 94, 148, 215, 273.
was found in 1951 had disappeared by 1961.9 Dr. Roberts and Mrs. Lloyd produce no evidence, but suggest that differences m the social-class composition of the towns may explain the greater increase in deathrates in those where the water became softer compared with those in which it became harder. This requires more detailed study, but in the meantime we have looked at the social-class composition of towns in 1951, and grouped them into quarters according to the proportion of persons in social classes IV and v. Those in the quarter with the highest proportion showed an average increase of 157 per 100,000 in male I.H.D. death-rates at ages 45-64 between 1948-54 and 1958-64, and this increase fell to 150 in the second quarter and 134 and 135 in the third and fourth quarters, respectively. This is as suggested. However, if the county boroughs in the " changes " paper are identified, it is seen that, relative to other towns in the same quarter, those towns where the water had been softened have experienced a larger increase, and those where the water was hardened have experienced a smaller increase. This is so for 9 out of the 11towns, and it is of interest that the 2 towns not in line are the smallest of all the county boroughs, Canterbury and Burton-on-Trent. We would point out that our findings related to all cardiovascular disease and femals death rates, which behaved differently vis-a-vis social class mortality. Finally, we have never stated (and it is not our view) " that soft-water supplies should be artificially hardened to lower I.H.D. mortality ", but believe rather that " the technical problems of increasing the hardness of soft water should now be explored ".8 This misquotation is unfortunate in view of the need to carry the water industry in further research into these difficult questions. We are left, then, with these major external environmental correlations with cardiovascular mortality:the hardness of the local water-supply; local rainfall; and latitudewhich has not been considered here.Manifestly, the first two are related, though meanwhile it has not been possible to get far in separating them. As said, we ourselves think that water hardness is the more promising both scientifically and practically. We hope that serious attention to and criticism of the " water story " will not be diverted by misleading conclusions based on inadequate data.
M.R.C. Social Medicine Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT.
M. D. CRAWFORD M. J. GARDNER J. N. MORRIS.
ORAL DIAZOXIDE FOR MALIGNANT HYPERTENSION were interested to read the letter by Dr. Pohl SIR,-We and Dr. Thurston (June 3, p. 1231) recommending the use of oral diazoxide as a final attempt to treat severe hypertension before bilateral nephrectomy. We have had a disappointing experience with this drug in such cases. During a trial of oral diazoxide in ten patients with severe hypertension and renal failure we were faced with two serious complications. In a 26-year-old man in terminal renal failure secondary to chronic
glomerulonephritis and malignant hypertension, who had been on dialysis since September, 1971, we tried oral diazoxide in a final attempt to control this hypertension before proceeding to bilateral nephrectomy. After 4 months of oral diazoxide (400 mg. per day) the patient developed a clearcut clinical, biological, and radiological picture of acute pancreatitis. The plasma-level of diazoxide 24 hours after the onset of pancreatitis was 38 jg. per ml. When the drug was stopped the patient improved quickly, and 11 days later serum-amylase levels were normal. 9. Registrar General’s Decennial Supplement England and Wales 1961: occupational mortality tables. H.M. Stationery Office, 1971.
The second patient, a 37-year-old woman with malignant hypertension and renal failure (creatinine clearance 35 ml. per minute), was given a therapeutic trial with oral diazoxide (300 mg. per day). 10 days after starting the drug she developed a diabetic ketoacidosis. The plasma-level of
diazoxide on admission was 58 g. per ml. When diazoxide withdrawn the patient recovered. There was no suggestion, in intravenous glucose-tolerance tests or in family history, of a prediabetic state in either patient, and blood-glucose levels have remained normal. In our opinion oral diazoxide is contraindicated for hypertension in chronic renal failure-a verdict shared by others.1.a was
Renal Division,
Department of Medicine:
University Hospital, 9.000 Ghent, Belgium.
M. DE BROE M. MUSSCHE S. RINGOIR.
Nephrological Clinic, Maria’s Voorzienigheid Hospital, 8.500
Kortrijk, Belgium.
V. BOSTEELS.
CYCLOPHOSPHAMIDE IN ADULT-ONSET NEPHROTIC SYNDROME
SIR,-We
were
interested in the paper of Dr. Uldall and
his colleagues
(June 10, p. 1250) advocating the use of cyclophosphamide in some adult-onset nephrotic patients with a minimal change " lesion in renal biopsy. Recently, we reported briefly3 the results of cyclophosphamide treatment in 15 patients drawn from a total of 45 with onset of a nephrotic syndrome and a " minimal change " lesion on biopsy. Our conclusions were that behaviour of these patients, and the place of cyclophosphamide, were the same as in the childhood-onset group: in the rather common (74% of our 45) multiple-relapsing patient, if corticosteroid be required in doses producing dangerous or undesirable side-effects (11 patients treated); and in the less common patient who is resistant to corticosteroid treatment in conventional dosage (4 patients treated). We have not used cyclophosphamide as primary 4 "
treatment either in children
or in adults, as Dr. Uldall has done in 2 of his patients, because of fears of its longterm toxicity. 12 of the 15 patients responded to cyclophosphamide with complete loss of proteinuria; 11 remain in remission 6-38 months later, 4 having relapsed. These results and those of Dr. Uldall re-emphasise the in any nephrotic suggestion that the critical distinction " is those with a minimal between patient change " lesion and those with any other histological appearance. We would agree that unless amyloid is stained for routinely in all renal biopsies (and preferably sought by electron microscopy) it will be missed from time to time in early cases. We also adopted this policy of routine staining after being misled by an initial biopsy on which amyloid was not sought and not diagnosed. It is often forgotten how common primary amyloidosis is as a cause of the nephrotic syndrome in adults-from 8% to 15% in most series.5 An interesting feature of our patients has been the presence of the nephrotic syndrome with a " minimal change " pattern in 4 patients over the age of 70, and we have since Great care is seen two further patients in this group. needed in their management, since the danger of sepsis, hypovolamua and cardiovascular collapse, and corticosteroid toxicity are especially prominent and other co-
C. T., Pentecost, B. L., Samaan, N. A. Lancet, 1962, ii, 735. Okun, R., Patterson Russell, R., Wilson, W. R. Archs intern. Med. 1963, 112, 882. 3. Cameron, J. S., Ogg, C. S., White, R. H. R. in Glomerulonephritis (edited by P. Kincaid-Smith and T. Mathew). New York, 1972 (in the press). 4. Tsao, Y. C., Yeung, C. H. Archs Dis. Childh. 1970, 46, 327. 5. Sharpstone, P., Cameron, J. S., Ogg, C. S. Br. med. J. 1969, ii, 533. 1. 2.
Dollery,
1398 incidental diseases may be present. We have not yet used cyclophosphamide in this elderly group, but 3 of these 8 patients were treated with corticosteroids and all responded promptly, 1 with the loss of over 30 kg. of oedema j the others were managed conservatively because of coincidental osteoporosis and cardiovascular disease. Guy’s Hospital, London SE1 9RT.
J. S. CAMERON C. S. OGG.
times normal for the operation period and give rise to bleeding, as encountered by Mr. Gordon-Smith and his colleagues (and also by Mr. Charnley 4). I find less of a problem with 10,000 units of heparin subcutaneously given the night before operation. I also note that the Gordon-Smith report does not mention the use of a method of heparin control. In the long run, as I have experienced it in now close to 1300 cases, the Dale and Laidlaw coagulometer, a rapid convenient method of control of heparin dosage, becomes an important adiunct if problems are to be avoided. Department of Pathology, Mount Vernon Hospital, Mount Vernon, New York 10550, U.S.A.
ISOCHROMOSOMES AND MALIGNANT GROWTH
SIR,-Mr. Lobb and others (April 15, precise identification of chromosomes
p.
849)
state
that
may reveal that isochromosomes are common in malignant tissues. While this may be true for isochromosome 17 in myeloid leukaemia it does not seem to hold for other types of malignant growth. In a detailed analysis of 3 cases of untreated cancer of the ovary we were able to trace the origin of most of the numerous " new " chromosomes present in all cells. Translocation, inversion, and deletion had been responsible for the new chromosomes, but we did not find a single isochromosome. Euratom Unit for Human Radiation L. TIEPOLO and Cytogenetics and Department of Obstetrics and
Gynæcology, University of Pavia, Via Forlanini, 14, Pavia, Italy.
C. ZARA O. ZUFFARDI
M. FRACCARO.
J. G. SHARNOFF.
CEREBROVASCULAR DISEASE AND HYPERLIPOPROTEINÆMIA SIR,-Some types of hyperlipidasmia are known to predispose to coronary heart-diseaseand peripheral vascular disease.’,The role of abnormal lipid patterns in the pathogenesis of cerebrovascular disease is less well established. We have studied, in a pilot project, 13 men and 13 women (age range 41-74) with cerebrovascular disease ranging from transient cerebral ischxmic attacks to established strokes. Very-low-density lipoproteins were measured by micronephelometry7 as modified by Farid and Anderson.g Total cholesterol was measured by ’AutoAnalyzer’, and S particles (&bgr;-lipoprotein) were calculated therefrom by
extrapolation.9 6 men (46%) and
PREVENTION OF POSTOPERATIVE THROMBOSIS
SIR,-I was indeed pleased to see the results of Mr. Gordon-Smith and his colleagues (May 27, p. 1133). It adds further confirmation to the results obtained by myself,l Mr. Kakkar and his associates,2 and Mr. Williams 3 illustrating the efficacy of prophylactic heparin in low dose in the prevention of thrombosis associated with operation and of fatal pulmonary thromboembolism. I must agree with one conclusion-namely, that the 125Ifibrinogen-uptake studies indicate the likelihood that legvein thrombosis is being prevented, but does not indicate that embolism is prevented. Nevertheless, if leg-vein thrombosis is prevented then one may assume that fatal pulmonary thromboembolism will surely also be prevented. The study further confirms our earlier contention that the operation period is the most critical period of hypercoagulation, as measured by either the Lee-White method or preferably by the Dale and Laidlaw coagulometer. However, I believe the study also reflects the fact that the short periods of heparinisation-namely, the two and five or even seven days-gave rise to thrombotic complications if the patients were not as yet mobilised after operation. This is not clear from the report. I, on the other hand, had detected a second critical period needing heparinisation-the period of postoperative mobilisation of the patient. Thus, I am certain that longer prophylaxis to the point of reactivation or discharge will also avoid the few failures. I am also somewhat disturbed by the dosage schedule used by Mr. Kakkar and his colleagues and by Mr. GordonSmith and his co-workers. Although 5000 units of heparin sodium is relatively small given subcutaneously in comparison to earlier intravenous methods still in vogue, it is still somewhat dangerous given one hour before surgery. This may raise the levels of coagulation to two to three Sharnoff, J. G., DeBlasio, G. Lancet, 1970, ii, 1006. Kakkar, V. V., Field, E. S., Nicolaides, A. N., Flute, P. T., Wessler, S., Yin, E. T. ibid. 1971, ii, 669. 3. Williams, H. T. ibid. p. 950. 1. 2.
6 women (46%) had normal lipid patterns. 6 of the men showed a Fredrickson type-iv pattern of hyperlipoproteinaemia,1O and 1 (8%) a Fredrickson type-II pattern. Of the 7 (54%) women with abnormal lipid patterns, 4 (30%) showed Fredrickson type iv, 2 (16%) Fredrickson type II, and 1 (8%) type MS.9 LIPOPROTEIN TYPES: BOTH SEXES DIVIDED INTO THOSE SUSTAINING A CARDIOVASCULAR ACCIDENT BEFORE OR AFTER THE AGE OF 55
Differences between the sexes were seen when the age which the cerebrovascular ischaemicepisode occurredwas considered. Of 6 women below the age of 55, 5 were found to have abnormal lipid patterns; only 2 out of 7 aged 55 or more showed such abnormalities. On the other hand, 4 out of 8 men whose ischxmic episodes occurred at the age of 55 or over had hyperlipoproteinoemia, and 3 out of 5 under 55 showed abnormal lipoprotein patterns (see accompanying at
table). 4. 5. 6. 7. 8. 9.
10.
Charnley, J. Personal communication. Heinle, R. A., Levy, R. I., Fredrickson, D. S., Gorlin, R. Am. J. Cardiol. 1969, 24, 178. Greenhalgh, R. M., Lewis, B., Rosengarten, D. S., Calnan, J. S., Mervart, I., Martin, P. Lancet, 1971, ii, 947. Stone, M. C., Thorp, J. M. Clinica chim. Acta, 1966, 14, 812. Farid, N. R., Anderson, J. ibid. (in the press). Stone, M. C., Thorp, J. M., Mills, G. L., Dick, T. B. S. ibid. 1971, 31, 333. Fredrickson, D. S., Ley, R. I., Lees, R. S. New Engl. J. Med. 1967, 276, 34, 94, 148, 215, 273.