- Email: [email protected]
HIGH-DENSITY LIPOPROTEIN AND ATHEROSCLEROSIS
691
Only in HBsAg-negative cases with C.A.H. and high inflammatory activity a linear deposition of IgG at the membranes of isolated rabbit hepatocytes could be observed. The antibody could be absorbed by human liver-specific lipoprotein (H.L.P. i) as isolated and characterised by Meyer zum Buschenfelde and Miescher.6 This fraction is an organ-specific but not species-specific membrane antigen. The detection of IgG on rabbit hepatocytes did not correlate with the antibody activity measured by passive hasmagglutination technique using H.L.P. I as antigen. The results show that in serum of patients with HB,,Agnegative C.A.H. and high inflammatory activity a cytophilic antibody occurs which is directed against native liverspecific membrane antigen. The corresponding antigen of the membrane-fixed IgG in HBsAg-positive cases is still unknown. Second Department of Internal Medicine, University of Mainz, 65 Mainz, Langenbeckstrasse 1, Germany.
U. HOPF K. H. MEYER W. ARNOLD.
ZUM
BÜSCHENFELDE
PARVOVIRUS-LIKE PARTICLES IN HUMAN FÆCES
SIR,-With reference should like
offer
to
your leader of Feb. 1
(p. 257)
additional information regarding the 22 nm. particles in human fseces. In our recent paper 8 we showed that these particles were identical in size, morphology, and buoyant density to known animal parvoviruses. As a result of this work we feel justified in stating that the 22 nm. fsecal particles are parvoviruses. Furthermore, we have shown that known isometric bacteriophages of the same order of size as these human parvoviruses are morphologically distinct. In work shortly to be published we have shown that the frequency of antibody to these human parvoviruses in an adolescent population is of the order of 30% to 40%, which is far higher than has been reported for known isometric bacteriophages. For example, the frequency of humoral antibody in the general population to 0 X 174, which is a member of a group of common small isometric bacteriophages9 and is also a potent immunological antigen, 10 , 11 is less than 5%." We realise that final classification of this human parvovirus awaits isolation of the virus in cell-culture. we
to
some
W. K. PAVER E. O. CAUL S. K. R. CLARKE.
Public Health Laboratory,
Myrtle Road, Kingsdown, Bristol BS2 8EL.
BILIRUBIN LEVELS IN NEONATES
SIR,-Dr Calder and his colleagues (Dec. 7, p. 1339) puzzling that bilirubin levels in infants delivered by
find it
caesarean
section
are
lower than those in infants delivered
vaginally. I suggest that this is due
to
the fact that the infant born
by cassarean section is always above the level of the placenta, and therefore receives less blood than the vaginally delivered infant who is kept below placental level. Several years ago 6. 7.
8.
Meyer zum Büschenfelde, K. H., Miescher, P. A. ibid. 1972, 10, 89. Hopf, U., Meyer zum Büschenfelde, K. H., Freudenberg, J. ibid. 1974, 16, 117. Paver, W. K., Caul, E. O., Clarke, S. K. R. J. gen. Virol. 1974, 22, 447.
Bradley, D. E. Nature, 1962, 195, 622. Ching, Y. C., Davis, S. D., Wedgewood, R. J. J. clin. Invest. 1966, 45, 1593. 11. Peacock, D. B., Jones, J. V., Gough, M. Clin. exp. Immun. 1973, 13,
Dr Mavis Gunter demonstrated that the infant weighed several ounces less when held above placental level than when he was lowered and weighed beneath this level. The delivery of less blood to the caesarean infant means fewer red cells and therefore less haemolysis and lower bilirubin. 71 Collins
Street, Melbourne, Victoria 3000, Australia.
HIGH-DENSITY LIPOPROTEIN AND ATHEROSCLEROSIS SIR,-Dr G. J. Miller and Dr N. E. Miller (Jan. 4, p. 16) hypothesise that a reduction in plasma-high-density-lipoprotein (H.D.L.) concentration may accelerate the development of atherosclerosis by impairing the clearance of cholesterol from the arterial wall. Apart from their own work, showing a negative correlation between plasmaH.D.L.-cholesterol concentration and cholesterol-pool sizes, the bulk of their argument is based upon an inverse relationship between H.D.L.-cholesterol concentration and several predictive factors for the development of coronary heart-disease (C.H.D.) revealed by an exhaustive search of the epidemiological literature. Using reported data from 13 studies, Miller and Miller have shown a statistically significant negative correlation between L.D.L.-cholesterol and H.D.L.-cholesterol concentration by plotting the means of these variables obtained from each individual study, but without reference to the variance of these means or to the numbers and age-structures of the populations from which the means are derived. We consider that The negative correlation they found may be spurious and due to a combination of population differences, age effects, and the use of different analytical techniques in the studies cited (which varied in publication date from 1953 to 1974). A more valid approach would be to seek correlations between H.D.L.-cholesterol and L.D.L.-cholesterol within the same population group. However, in our study of 1005, randomly selected, London local-government employees1 we have shown a statistically significant positive correlation between H.D.L.-cholesteroland total-cholesterol concentrations for both men (n=502, r=0-33, and women (n=503, r=0-47, p<0001). This p<0-001) significant positive relationship persists when multiple regression analysis is used to correct for the possible independent effects on H.D.L.-cholesterol concentration of age, degree of obesity, fasting-plasma-triglyceride, and
blood-sugar. Again using multiple regression analysis we found no statistically significant, independent correlation between H.D.L.-cholesterol concentration, on the one hand, and either degree of obesity, fasting blood-sugar, or log. triglyceride concentration (three other possible risk factors for c.H.D.), on the other. The hypothesis of an inverse relationship between H.D.L.cholesterol concentration and other risk factors for C.H.D. is thus not supported when analyses are made within a population group and due allowance is made by multivariate methods for interrelationships between risk factors
dependence on age. In fact our own study showed positive relationship between H.D.L.-cholesterol concentra-
and their a
tion and total-cholesterol concentration and rather contradicts the hypothesis that a lowered plasma-H.D.L. concentration may hasten the development of atherosclerosis. Department of Medicine, Guy’s Hospital Medical School, London SE1 9RT.
9. 10.
497.
KATE CAMPBELL.
JOHN H. FULLER R. J. JARRETT H. KEEN S. L. PINNEY.
Fuller, J. H., Jarrett, R. J., Keen, H., Pinney, S. Proceedings of 1st International Congress on Obesity, London, 1974 (in the press). 2. Burstein, M., Samaille, J. Clinica chim. Acta, 1958, 3, 320. 1.
692
SIR,-We agree with the hypothesis of Dr G. J. Miller and Dr N. E. Miller (Jan. 4, p. 16) about a possible antiatherogenic role of plasma - high - density - lipoproteins (H.D.L.). Both Glueck1 and ourselves2 have lately recognised a familial hyperlipoproteinmmia in which most of the cholesterol is carried as H.D.L. (oc) cholesterol. In members of these families no signs of cardiovascular involvement have been found. Moreover, in our series, few patients with familial type-IIA hyperlipoproteinarmia have xanthomata, unlike such patients from other countries. Also, the frequency of ischaemic heart-disease among the families in our series is rather low. Other authors have supported the view that essential hypercholesterolaemia is a " relatively benign trait 11.3 In this respect, it is interesting that, in our patients with type-II hyperlipoproteinsemia, values of H.D.L.cholesterol are higher than those quoted by previous authors.
A reciprocal behaviour of low-density-lipoprotein (L.D.L.)cholesterol and H.D.L.-cholesterol is not supported by our
findings, as we have recorded a positive correlation (r= +0-31) between the two parameters. A positive correlation has been previously quoted in Eskimos4 and in one American group. The complex process of lipid influx and efflux in the arterial wall is shown best by the ratio of plasma-levels of L.D.L.H.D.L. cholesterol.
The trend of the ratio from the highest values in type the lowest value in normal people seems to correlate better with the expected frequencies of cardiovascular disease in hyperlipoproteinamlia states. IIA to
Regional Hospital, Unit for Atherosclerosis and
Hyperlipæmias, Venice, Italy.
P. AVOGARO G. CAZZOLATO M. PAIS.
TREATMENT OF SMALL-CELL CARCINOMA OF BRONCHUS SIR,-A randomised study evaluating the results of treatment with radiotherapy versus chemotherapy in small-cell carcinoma of the bronchus is a timely and laudable effort (Jan. 18, p. 129). It is unfortunate, however, that Dr Laing and his co-workers selected as their chemotherapy a treatment that includes the more toxic but probably less effective alkylating agent nitrogen mustard,8 and a drug (prednisolone) that may have deleterious effects on the survival of patients with lung cancer, as reported in a randomised study by the Veterans Administration
Lung Cancer Study Group.’7
Cyclophosphamide seems to be the most effective single agent in the treatment of small-cell anaplastic carcinoma, 1. 2. 3.
4. 5.
6. 7.
Glueck, C. J. Clin. Res. (in the press). Avogaro, P., Cazzolato, G. Atherosclerosis (in the press). Harlan, W. R., Graham, J. B., Estes, H. Medicine, Baltimore, 1966, 77, 45. Bang, H. O., Dyerberg, J., Nielsen, A. B. Lancet, 1971, i, 1143. Ewing, A. M., Freeman, N. K., Lindgren, F. T. in Advances in Lipid Research (edited by R. Paoletti and D. Kritchevsky); vol. III, p. 25. New York, 1965. Green, R. A., Humphrey, E., Close, H., Patno, M. E. Am. J. Med. 1969, 46, 516. Wolf, J., Spear, P., Yesner, R., Patno, M. E. ibid. 1960, 29, 1008.
with a regression-rate higher than 50%,8 and since combination chemotherapy is probably more effective than single-agent treatment in small-cell carcinoma,9-11 a combination including cyclophosphamide would have been a much better choice for a randomised study. This is in retrospect particularly important, in view of the excessive mortality in the patients over age 55 treated by chemotherapy, which implies intolerance to the treatment used (nitrogen mustard, vinblastine, procarbazine, and predni-
solone). In addition, it has to be pointed out that a direct comparison, using survival between the two modalities of treatment, is hampered by the fact that almost a third of the patients (10/32) treated with radiotherapy received in addition. We agree with the conclusion of Laing et al. that, in view of the systemic nature of the disease at onset, a combination of chemotherapy and radiotherapy is worth evaluating. We would not, however, want readers to believe that their investigation has conclusively demonstrated lack of efficacy of current chemotherapeutic regimens for small-cell carcinoma of the lung, and the superiority of local radiotherapy. Division of Medical Oncology,
chemotherapy
Albert Einstein College of Medicine, Bronx, N.Y. 10461, U.S.A. Medical Department C, Bispebjerg Hospital, and Finsen Institute, Copenhagen, Denmark.
FRANCO M. MUGGIA. HEINE H. HANSEN.
PER DOMBERNOWSKY.
MANAGEMENT OF INTRACRANIAL ANEURYSMS Atkinson SIR,-Mr (Jan. 4, p. 5) described a new to the management of intracranial aneurysms. approach While his approach may well be beneficial, I think that he got his arguments wrong. He stresses the role of atherosclerosis-even so far as to call this " the main event to haemorrhage from intracranial aneurysms". To the contrary I feel that by him (and by many of my clinical colleagues) far too much stress is laid upon atherosclerosis in this respect. In my view, the two main aetiological factors in the bursting of intracranial vessels, whether subarachnoid or intracranial, are weak spots in the vessel walls and arterial hyp-rtension. With the exception of mycotic and (if they exist at all) primary atherosclerotic aneurysms, the weak spots may be assumed to be of congenital origin and their evolution into microaneurysms or even macroscopically visible aneurysms to be an effect of systemic hypertension. 11 Atherosclerotic changes in the neighbourhood of or within aneurysms are easily interpreted as secondary to the occurrence of eddy-formation (and may have some contributory significance in the way suggested by Mr Atkinson). Development of atherosclerosis, far from leading to haemorrhage, in general seems rather to protect against it-this would account for the increase in lesions resulting from vascular insufficiency with increasing age, whereas haemorrhages show an earlier peak. In my view, as in Mr Atkinson’s, lowering the intraarterial pressure is beneficial. My reason for arguing against his principles lies in the different practical consequences of both views: emphasis on hypertension entails
leading
Selawry, O. S., Hansen, H. H. in Cancer Medicine (edited by J. F. Holland and E. Frei); p. 1506. Philadelphia, 1973. 9. Hansen, H. H., Selawry, O. S., Carr, D., Sealy, R., Simon, R. Proceedings of 11th International Cancer Congress, Florence,
8.
1974, p. 592. Edmonson, J. H., Stolbach, L., Mittelman, A., Lagakos, S. W. ibid. p. 591. 11. Alberto, P. Cancer Chemother. Rep. 1973, 4, 199. 12. Cole, F. M., Yates, P. O. J. Path. Bact. 1967, 93, 393.
10.
Only in HBsAg-negative cases with C.A.H. and high inflammatory activity a linear deposition of IgG at the membranes of isolated rabbit hepatocytes could be observed. The antibody could be absorbed by human liver-specific lipoprotein (H.L.P. i) as isolated and characterised by Meyer zum Buschenfelde and Miescher.6 This fraction is an organ-specific but not species-specific membrane antigen. The detection of IgG on rabbit hepatocytes did not correlate with the antibody activity measured by passive hasmagglutination technique using H.L.P. I as antigen. The results show that in serum of patients with HB,,Agnegative C.A.H. and high inflammatory activity a cytophilic antibody occurs which is directed against native liverspecific membrane antigen. The corresponding antigen of the membrane-fixed IgG in HBsAg-positive cases is still unknown. Second Department of Internal Medicine, University of Mainz, 65 Mainz, Langenbeckstrasse 1, Germany.
U. HOPF K. H. MEYER W. ARNOLD.
ZUM
BÜSCHENFELDE
PARVOVIRUS-LIKE PARTICLES IN HUMAN FÆCES
SIR,-With reference should like
offer
to
your leader of Feb. 1
(p. 257)
additional information regarding the 22 nm. particles in human fseces. In our recent paper 8 we showed that these particles were identical in size, morphology, and buoyant density to known animal parvoviruses. As a result of this work we feel justified in stating that the 22 nm. fsecal particles are parvoviruses. Furthermore, we have shown that known isometric bacteriophages of the same order of size as these human parvoviruses are morphologically distinct. In work shortly to be published we have shown that the frequency of antibody to these human parvoviruses in an adolescent population is of the order of 30% to 40%, which is far higher than has been reported for known isometric bacteriophages. For example, the frequency of humoral antibody in the general population to 0 X 174, which is a member of a group of common small isometric bacteriophages9 and is also a potent immunological antigen, 10 , 11 is less than 5%." We realise that final classification of this human parvovirus awaits isolation of the virus in cell-culture. we
to
some
W. K. PAVER E. O. CAUL S. K. R. CLARKE.
Public Health Laboratory,
Myrtle Road, Kingsdown, Bristol BS2 8EL.
BILIRUBIN LEVELS IN NEONATES
SIR,-Dr Calder and his colleagues (Dec. 7, p. 1339) puzzling that bilirubin levels in infants delivered by
find it
caesarean
section
are
lower than those in infants delivered
vaginally. I suggest that this is due
to
the fact that the infant born
by cassarean section is always above the level of the placenta, and therefore receives less blood than the vaginally delivered infant who is kept below placental level. Several years ago 6. 7.
8.
Meyer zum Büschenfelde, K. H., Miescher, P. A. ibid. 1972, 10, 89. Hopf, U., Meyer zum Büschenfelde, K. H., Freudenberg, J. ibid. 1974, 16, 117. Paver, W. K., Caul, E. O., Clarke, S. K. R. J. gen. Virol. 1974, 22, 447.
Bradley, D. E. Nature, 1962, 195, 622. Ching, Y. C., Davis, S. D., Wedgewood, R. J. J. clin. Invest. 1966, 45, 1593. 11. Peacock, D. B., Jones, J. V., Gough, M. Clin. exp. Immun. 1973, 13,
Dr Mavis Gunter demonstrated that the infant weighed several ounces less when held above placental level than when he was lowered and weighed beneath this level. The delivery of less blood to the caesarean infant means fewer red cells and therefore less haemolysis and lower bilirubin. 71 Collins
Street, Melbourne, Victoria 3000, Australia.
HIGH-DENSITY LIPOPROTEIN AND ATHEROSCLEROSIS SIR,-Dr G. J. Miller and Dr N. E. Miller (Jan. 4, p. 16) hypothesise that a reduction in plasma-high-density-lipoprotein (H.D.L.) concentration may accelerate the development of atherosclerosis by impairing the clearance of cholesterol from the arterial wall. Apart from their own work, showing a negative correlation between plasmaH.D.L.-cholesterol concentration and cholesterol-pool sizes, the bulk of their argument is based upon an inverse relationship between H.D.L.-cholesterol concentration and several predictive factors for the development of coronary heart-disease (C.H.D.) revealed by an exhaustive search of the epidemiological literature. Using reported data from 13 studies, Miller and Miller have shown a statistically significant negative correlation between L.D.L.-cholesterol and H.D.L.-cholesterol concentration by plotting the means of these variables obtained from each individual study, but without reference to the variance of these means or to the numbers and age-structures of the populations from which the means are derived. We consider that The negative correlation they found may be spurious and due to a combination of population differences, age effects, and the use of different analytical techniques in the studies cited (which varied in publication date from 1953 to 1974). A more valid approach would be to seek correlations between H.D.L.-cholesterol and L.D.L.-cholesterol within the same population group. However, in our study of 1005, randomly selected, London local-government employees1 we have shown a statistically significant positive correlation between H.D.L.-cholesteroland total-cholesterol concentrations for both men (n=502, r=0-33, and women (n=503, r=0-47, p<0001). This p<0-001) significant positive relationship persists when multiple regression analysis is used to correct for the possible independent effects on H.D.L.-cholesterol concentration of age, degree of obesity, fasting-plasma-triglyceride, and
blood-sugar. Again using multiple regression analysis we found no statistically significant, independent correlation between H.D.L.-cholesterol concentration, on the one hand, and either degree of obesity, fasting blood-sugar, or log. triglyceride concentration (three other possible risk factors for c.H.D.), on the other. The hypothesis of an inverse relationship between H.D.L.cholesterol concentration and other risk factors for C.H.D. is thus not supported when analyses are made within a population group and due allowance is made by multivariate methods for interrelationships between risk factors
dependence on age. In fact our own study showed positive relationship between H.D.L.-cholesterol concentra-
and their a
tion and total-cholesterol concentration and rather contradicts the hypothesis that a lowered plasma-H.D.L. concentration may hasten the development of atherosclerosis. Department of Medicine, Guy’s Hospital Medical School, London SE1 9RT.
9. 10.
497.
KATE CAMPBELL.
JOHN H. FULLER R. J. JARRETT H. KEEN S. L. PINNEY.
Fuller, J. H., Jarrett, R. J., Keen, H., Pinney, S. Proceedings of 1st International Congress on Obesity, London, 1974 (in the press). 2. Burstein, M., Samaille, J. Clinica chim. Acta, 1958, 3, 320. 1.
692
SIR,-We agree with the hypothesis of Dr G. J. Miller and Dr N. E. Miller (Jan. 4, p. 16) about a possible antiatherogenic role of plasma - high - density - lipoproteins (H.D.L.). Both Glueck1 and ourselves2 have lately recognised a familial hyperlipoproteinmmia in which most of the cholesterol is carried as H.D.L. (oc) cholesterol. In members of these families no signs of cardiovascular involvement have been found. Moreover, in our series, few patients with familial type-IIA hyperlipoproteinarmia have xanthomata, unlike such patients from other countries. Also, the frequency of ischaemic heart-disease among the families in our series is rather low. Other authors have supported the view that essential hypercholesterolaemia is a " relatively benign trait 11.3 In this respect, it is interesting that, in our patients with type-II hyperlipoproteinsemia, values of H.D.L.cholesterol are higher than those quoted by previous authors.
A reciprocal behaviour of low-density-lipoprotein (L.D.L.)cholesterol and H.D.L.-cholesterol is not supported by our
findings, as we have recorded a positive correlation (r= +0-31) between the two parameters. A positive correlation has been previously quoted in Eskimos4 and in one American group. The complex process of lipid influx and efflux in the arterial wall is shown best by the ratio of plasma-levels of L.D.L.H.D.L. cholesterol.
The trend of the ratio from the highest values in type the lowest value in normal people seems to correlate better with the expected frequencies of cardiovascular disease in hyperlipoproteinamlia states. IIA to
Regional Hospital, Unit for Atherosclerosis and
Hyperlipæmias, Venice, Italy.
P. AVOGARO G. CAZZOLATO M. PAIS.
TREATMENT OF SMALL-CELL CARCINOMA OF BRONCHUS SIR,-A randomised study evaluating the results of treatment with radiotherapy versus chemotherapy in small-cell carcinoma of the bronchus is a timely and laudable effort (Jan. 18, p. 129). It is unfortunate, however, that Dr Laing and his co-workers selected as their chemotherapy a treatment that includes the more toxic but probably less effective alkylating agent nitrogen mustard,8 and a drug (prednisolone) that may have deleterious effects on the survival of patients with lung cancer, as reported in a randomised study by the Veterans Administration
Lung Cancer Study Group.’7
Cyclophosphamide seems to be the most effective single agent in the treatment of small-cell anaplastic carcinoma, 1. 2. 3.
4. 5.
6. 7.
Glueck, C. J. Clin. Res. (in the press). Avogaro, P., Cazzolato, G. Atherosclerosis (in the press). Harlan, W. R., Graham, J. B., Estes, H. Medicine, Baltimore, 1966, 77, 45. Bang, H. O., Dyerberg, J., Nielsen, A. B. Lancet, 1971, i, 1143. Ewing, A. M., Freeman, N. K., Lindgren, F. T. in Advances in Lipid Research (edited by R. Paoletti and D. Kritchevsky); vol. III, p. 25. New York, 1965. Green, R. A., Humphrey, E., Close, H., Patno, M. E. Am. J. Med. 1969, 46, 516. Wolf, J., Spear, P., Yesner, R., Patno, M. E. ibid. 1960, 29, 1008.
with a regression-rate higher than 50%,8 and since combination chemotherapy is probably more effective than single-agent treatment in small-cell carcinoma,9-11 a combination including cyclophosphamide would have been a much better choice for a randomised study. This is in retrospect particularly important, in view of the excessive mortality in the patients over age 55 treated by chemotherapy, which implies intolerance to the treatment used (nitrogen mustard, vinblastine, procarbazine, and predni-
solone). In addition, it has to be pointed out that a direct comparison, using survival between the two modalities of treatment, is hampered by the fact that almost a third of the patients (10/32) treated with radiotherapy received in addition. We agree with the conclusion of Laing et al. that, in view of the systemic nature of the disease at onset, a combination of chemotherapy and radiotherapy is worth evaluating. We would not, however, want readers to believe that their investigation has conclusively demonstrated lack of efficacy of current chemotherapeutic regimens for small-cell carcinoma of the lung, and the superiority of local radiotherapy. Division of Medical Oncology,
chemotherapy
Albert Einstein College of Medicine, Bronx, N.Y. 10461, U.S.A. Medical Department C, Bispebjerg Hospital, and Finsen Institute, Copenhagen, Denmark.
FRANCO M. MUGGIA. HEINE H. HANSEN.
PER DOMBERNOWSKY.
MANAGEMENT OF INTRACRANIAL ANEURYSMS Atkinson SIR,-Mr (Jan. 4, p. 5) described a new to the management of intracranial aneurysms. approach While his approach may well be beneficial, I think that he got his arguments wrong. He stresses the role of atherosclerosis-even so far as to call this " the main event to haemorrhage from intracranial aneurysms". To the contrary I feel that by him (and by many of my clinical colleagues) far too much stress is laid upon atherosclerosis in this respect. In my view, the two main aetiological factors in the bursting of intracranial vessels, whether subarachnoid or intracranial, are weak spots in the vessel walls and arterial hyp-rtension. With the exception of mycotic and (if they exist at all) primary atherosclerotic aneurysms, the weak spots may be assumed to be of congenital origin and their evolution into microaneurysms or even macroscopically visible aneurysms to be an effect of systemic hypertension. 11 Atherosclerotic changes in the neighbourhood of or within aneurysms are easily interpreted as secondary to the occurrence of eddy-formation (and may have some contributory significance in the way suggested by Mr Atkinson). Development of atherosclerosis, far from leading to haemorrhage, in general seems rather to protect against it-this would account for the increase in lesions resulting from vascular insufficiency with increasing age, whereas haemorrhages show an earlier peak. In my view, as in Mr Atkinson’s, lowering the intraarterial pressure is beneficial. My reason for arguing against his principles lies in the different practical consequences of both views: emphasis on hypertension entails
leading
Selawry, O. S., Hansen, H. H. in Cancer Medicine (edited by J. F. Holland and E. Frei); p. 1506. Philadelphia, 1973. 9. Hansen, H. H., Selawry, O. S., Carr, D., Sealy, R., Simon, R. Proceedings of 11th International Cancer Congress, Florence,
8.
1974, p. 592. Edmonson, J. H., Stolbach, L., Mittelman, A., Lagakos, S. W. ibid. p. 591. 11. Alberto, P. Cancer Chemother. Rep. 1973, 4, 199. 12. Cole, F. M., Yates, P. O. J. Path. Bact. 1967, 93, 393.
10.