1292
tice, part time in community care (group practice, health centre, domiciliary). The consultant could then revert to
consulting, and the primary-care physician would benefit by his closer contact, and by continuing to work in the milieu where he was trained. The hospital would be in reality a part of the community. Such a change in roles and functions would ease the hospital-practitioner shortage and benefit the training of junior hospital doctors, the majority of whom eventually become primary-care practitioners. It would, however, exacerbate the shortage within primary care. To overcome this shortage, the primary-care physician would become much more a referral point in the group or health-centre practice, with more of his present functions More job being assumed by nurse-practitioners, &c. satisfaction would result all round. Such a redefining of the role of the primary-care physician would do more to integrate care and to promote community care than any structural reorganisation. Reorganisation must be made at the periphery, within the community. The rest of the reorganisation services would flow from this first step. It is quite apparent that the attempt to supply a physicianmanned service-both primary and referral-is beyond the economic and social capacity of any nation, developed or not. This is at last achieving recognition, and many stratagems are being adopted throughout the world-the medical assistant in Africa and elsewhere, the feldsher in the U.S.S.R., the Medex and physician’s assistant in the U.S.A., the expanded role of nurses in Canada and the U.S.A., the rural health technician in Guatemala, and so on. With expanding need deriving from population growth, new programmes such as family planning, the vast accumulation of medical knowledge of this century, and the critical necessity to apply such knowledge effectively and rapidly, The joint U.N.C.F./ new stratagems must be applied. W.H.O. proposals now being adopted by the executive board of U.N.C.F. recognises this need as urgent. For the United Kingdom I believe that a devolution of functions is probably the best to nurses, pharmacists, midwives, &c., route. It is not, however, likely to be an easy route, and your leader should have remarked Department of Tropical Community Health, School of Tropical Medicine, Liverpool L3 5QA.
on
the difficulties.
REX FENDALL.
THE CONSULTANTS’ INCREASE
SIR,-The B.M.A. has now advised consultants to stop working to contract, and extra pay has been awarded to them. All doctors, of course, know that the dispute has been on much more than pay and that many other matters are still at stake. But many lay people do not realise this and think (helped by misrepresentation of our case) that yet another body of people, who are already well-off, have used their power to make others suffer, and have thus demanded more money for this than the country can afford. Can nothing be done to show (as I believe is true) that many doctors are more concerned with the state of the N.H. S. than with our own earnings ? May I return to a proposal which had little support in the bitterness of January, but which might get more sympathy now ? This is that any senior consultant willing to do so should relinquish part of his increase, not to the Government but to his own hospital, where it could form a fund for maintenance and development to be used at the discretion of the Medical Committee. It would, of course, be easier to decide to give this back before we have actually got it. I would not press younger consultants, for they have had to suffer a good deal of hardship, but perhaps anyone drawing over E8000 a year from the N.H.S. might
consider contributing 1 % of it, with higher rates for higher salaries. The total would not be impressive; the gesture might be. If the idealistic reason does not appeal, some might prefer a more material one. As far as I can see the only hope to help the country’s financial position is that some groups should give up something. Could the doctors give a lead here ? Who knows but that it might be followed by senior Civil Servants and even Cabinet Ministers ? If so, it might in the long run make the money we actually do get worth more.
Department of Psychological Medicine, University College Hospital, Gower Street, London WC1E 6AU.
R. F. TREDGOLD.
DOES T4-TOXICOSIS EXIST ?
SIR,-We
were
very interested in the
and his
reply by Dr
colleagues (April 12, p. 868). The
Kirkegaard thyrotoxic patient they described was a 70-year-old woman with " serum T3 within 95% normal range and serum T4 exceeding 95% normal range ". It has been shown that serum-T3 levels fall with age, and we assume that the rather low normal range (35-153 ng. per 100 ml.) Dr Kirkegaard quoted is adjusted for the geriatric population. If this is the case their patient truly has T4-toxicosis. In the Canterbury area of New Zealand, thyrotoxicosis is most prevalent in the 50 + age-group, and a previous report by Dr Kirkegaard2 indicates a similar situation in Denmark. It is therefore essential, before the estimation of total serum-triiodothyronine becomes a routine thyroid-function test, that each laboratory establishes a normal range for different age-groups. Dr Hadden and his colleagues (March 29, p. 754) show a good correlation between serum-T3 and the free-thyroxine index in both euthyroid and thyrotoxic patients. These results are similar to our initial experience3 in a group of 137 patients representing a wide range of thyroid disease, where we correlated total serum-T3 and total serum-T4 levels (r=0-866). However, widely discordant serum-T3 and serum-T4 results do occur in patients with nonthyroidal illness, in patients with thyroidal enzyme defects,5 and in other clinical situations where there is an increased thyroid-stimulating-hormone effect upon the thyroid gland-e.g., after iodine-131 therapy.In relapse of thyrotoxicosis, too, serum-T3 and serum-T4 may be discordant. In this situation the serum-T3 may rise before the serum-T4, but occasionally the reverse may occur. We have one such example, a 22-year-old woman who showed clinical evidence of relapse after a course of antithyroid drugs (serum-T4=12-3 µg. per 100 ml. (normal 3-5-10-0 fg. per 100 ml.), serum-T3=118 ng. per 100 ml. (75-175 ng. per 100 ml.). Although triiodothyronine is thought to be the physiologically more important thyroid hormone, the estimation of the free-thyroxine index at present seems to be the best screening test for thyroid dysfunction. The discordant T3 and T4 results found in many conditions indicates that serum-T3 levels should not be interpreted in isolation. This is particularly important in patients with non-thyroidal illness. We believe that both T3 and T4 toxicosis exist and 1. 2. 3. 4.
5. 6. 7.
Rubenstein, H. A., Butler, V. P., Werner, S. C. J. clin. Endocr. 1973, 37, 247. Ronnov-Jessen, V., Kirkegaard, C. Br. med. J. 1973, i, 41. Sadler, W. A., Brownlie, B. E. W. N.Z. med. J. 1975, 81, 328. Carter, J. N., Eastman, C. J., Corcoran, J. M., Lazarus, L. Lancet, 1974, ii, 971. Gomez-Pan, A., Evered, D. C., Hall, R. Br. med. J. 1974, ii, 152. Sterling, K., Brenner, M. A., Newman, E. S., Odell, W. D., Bellabarba, D. J. clin. Endocr. 1971, 33, 729. Marsden, P., Howorth, P. J. M., Chalkley, S., Acosta, M., Leatherdale, B., McKerron, C. G. Lancet, 1975, i, 944.
1293 that T3 radioimmunoassay is index of
not
the ultimate
laboratory
Christchurch Hospital,
Christchurch, New Zealand.
J. G. TURNER B. E. W. BROWNLIE W. A. SADLER C. A. JENSEN.
PLASMA IRON AND IRON-BINDING CAPACITY SIR,-Of course it all depends on what you mean by the anaemia of chronic disorders. If, like me, you mean the anaemia found in inflammatory and malignant conditions and characterised by reduced numbers of sideroblasts in the marrow and increased haemosiderin within macrophages, and exclude that found in myxoedema, uraemia, and liver disorders, then I stick to my assertion (May 10, p. 1090) that these ;are " likely to have hypochromic, microcytic red cells ". If I may quote a more comprehensive and up-to-date textbook than that cited by Dr Zilva (May 24, p. 1191),"... hypochromia has been observed in 23 to 50% of patients with chronic infection, 50 to 100% of patients with rheumatoid arthritis, and 44 to 64% of patients with cancer."1 I agree that many cases of iron deficiency can be distinguished from this condition on hasmatological grounds alone, but as Dr Turnbull has indicated (May 24, p. 1191), many cannot. I also agree with your correspondents who complain that serum-irons are over-requested, and what a wonderful world it would be if pathologists alone could make requests of the laboratory. But in the real world are they more abused than Bl2s and folates, or even haemoglobins and plasma-electrolytes ? By all means, let us encourage a greater dialogue with clinicians, but, please, biochemists, don’t stop doing the test. If haematologists have to set it up themselves, what will the coefficient of variation be then ? Royal Victoria Hospital, Boscombe, Bournemouth BH1 4JG.
the
was
thyrotoxicosis.
Nuclear Medicine Department,
In the 3 remaining patients the cholesterol altered constituent, but in none did it exceed 300 mg. per 100 ml. Basal immunoreactive insulin levels and blood-glucose were normal in all the patients.
lipolytic activity). most
Our study does not confirm Casaretto’s reported results but agrees with Beaumont’s experience. However, we cannot support Beaumont’s hypothesis that normal bloodlipids could be due to the alternate-day corticosteroid therapy, since we have observed normal lipid levels with daily corticosteroid treatment.
J. MASRAMON A. CARALPS M. LLORACH R. COMPANYS A. BRULLES J. LLOVERAS J. ANDREU.
Unidad de Trasplante Renal, Catedra de Urologia (Facultad de Medicina),
Hospital Clínico y Provincial, Barcelona, Spain.
TOXICITY OF ASPARAGINASES are being used in the is obtained from Escherichia coli (Escherichia asparaginase), the other from the plant pathogen, Erwinia carotovora (Erwinia asparaginase). Although they appear to be equally effective as antileuksemic agents.l some reports suggest that they differ in toxicity.2.3 To clarify this I examined the records of patients with acute leukasmia who have been treated with asparaginase at three London hospitals. The doses used were similar at each hospital, either 200 i.u. per kg. body-weight or 6000 i.u. per sq.m. bodysurface area of reconstituted freeze-dried asparaginase. There were no deaths attributable to enzyme therapy but toxicity interrupted 12 of the 31 (39%) courses of Escherichia
SiR,—Two bacterial asparaginases
treatment
of acute leukaemia:
one
FREQUENCY OF SERIOUS TOXICITY
*
TERRY HAMBLIN. * Serious toxicity asparaginase changed or discontinued. t Course=at least 3 full doses given without toxicity or one =
HYPERLIPIDÆMIA AFTER RENAL
SiR,-Casaretto et awl. reported a significant rise in basal plasma-levels of triglyceride, cholesterol, and immunoreactive insulin after successful renal transplantation in 37 patients receiving an average dose of 17 mg. of prednisolone per day. They found that hyperlipoproteinxmia was a general feature in these patients. In contrast, Beaumont et al. (March 15, p. 599) find normal serum-lipid profiles in 78% of 42 successfully
transplanted patients receiving an average dose of 22 mg. of prednisone every other day. The remaining 22% show hyperlipidaemia, but they are significantly more obese and older. Both the normal subjects and the hyperlipidaemic patients show normal basal immunoreactive insulin levels. Beaumont and his colleagues postulate that this high percentage of patients with normal blood-lipid levels cquld be due to the alternate-day corticosteroid therapy. In 19 an
patients with successful renal transplantation treated with prednisone per day for at least
average dose of 12 mg. of
3 months and with serum-creatinine levels below 20 mg. per 100 ml., we found 16 (84%) with no change in any of the lipid parameters studied (overnight-fasting cholesterol, triglycerides, free fatty acids, free glycerol, lipidogram in cellulose acetate, thin-layer chromatography of neutral lipids, and post-heparin 1. Wintrobe, M. M. Clinical Hæmatology; p. 673. Philadelphia,1974. 2. Casaretto, A., Marchioro, T. L., Goldsmith, R., Bagdade, J. D. Lancet, 1974, i, 481.
or more
full doses if toxicity developed.
TRANSPLANTATION
asparaginase and 9 of the 46 (20%) Erwinia courses (see accompanying table). Allergic reactions were the commonest side-effects, and their occurrence always led to a change or discontinuance of asparaginase. They did not appear until at least ten days after the start of enzyme treatment unless the patient had been treated previously with the same type of enzyme. 11 patients were re-exposed to the same asparaginase;
1 of the 5 Escherichia-treated and 1 of the 6 Erwinia-treated had an anaphylactic reaction; the former required intravenous hydrocortisone, the latter recovered without treatment.
10
patients were given the alternative enzyme because of hypersensitivity-3 sensitive to Erwinia, 7 to Escherichia asparaginase. In all of these, enzyme therapy was continued satisfactorily without cross-toxicity. In 2 cases asparaginases were substituted because of vomiting, but without benefit. One child was given Erwinia asparaginase intravenously twice weekly for fifty-four weeks, except for gaps of one week every 8 weeks when prednisone and arabinosyl cytosine were given. No toxicity occurred during this 1. 2. 3.
Kay, H. E. M., Fairley, G. H., Knapton, P. J. Colloques int. C.N.R.S., 1971, no. 197 : l’asparaginase, p. 295. Ohnuma, T., Holland, J. F., Meyer, P. Cancer, N.Y. 1972, 30, 376. Ohnuma, T., Holland, J. F., Meyer, P. Proc. Am. Ass. Cancer Res. 1972, 13, 117 (abstr. 465).
tice, part time in community care (group practice, health centre, domiciliary). The consultant could then revert to
consulting, and the primary-care physician would benefit by his closer contact, and by continuing to work in the milieu where he was trained. The hospital would be in reality a part of the community. Such a change in roles and functions would ease the hospital-practitioner shortage and benefit the training of junior hospital doctors, the majority of whom eventually become primary-care practitioners. It would, however, exacerbate the shortage within primary care. To overcome this shortage, the primary-care physician would become much more a referral point in the group or health-centre practice, with more of his present functions More job being assumed by nurse-practitioners, &c. satisfaction would result all round. Such a redefining of the role of the primary-care physician would do more to integrate care and to promote community care than any structural reorganisation. Reorganisation must be made at the periphery, within the community. The rest of the reorganisation services would flow from this first step. It is quite apparent that the attempt to supply a physicianmanned service-both primary and referral-is beyond the economic and social capacity of any nation, developed or not. This is at last achieving recognition, and many stratagems are being adopted throughout the world-the medical assistant in Africa and elsewhere, the feldsher in the U.S.S.R., the Medex and physician’s assistant in the U.S.A., the expanded role of nurses in Canada and the U.S.A., the rural health technician in Guatemala, and so on. With expanding need deriving from population growth, new programmes such as family planning, the vast accumulation of medical knowledge of this century, and the critical necessity to apply such knowledge effectively and rapidly, The joint U.N.C.F./ new stratagems must be applied. W.H.O. proposals now being adopted by the executive board of U.N.C.F. recognises this need as urgent. For the United Kingdom I believe that a devolution of functions is probably the best to nurses, pharmacists, midwives, &c., route. It is not, however, likely to be an easy route, and your leader should have remarked Department of Tropical Community Health, School of Tropical Medicine, Liverpool L3 5QA.
on
the difficulties.
REX FENDALL.
THE CONSULTANTS’ INCREASE
SIR,-The B.M.A. has now advised consultants to stop working to contract, and extra pay has been awarded to them. All doctors, of course, know that the dispute has been on much more than pay and that many other matters are still at stake. But many lay people do not realise this and think (helped by misrepresentation of our case) that yet another body of people, who are already well-off, have used their power to make others suffer, and have thus demanded more money for this than the country can afford. Can nothing be done to show (as I believe is true) that many doctors are more concerned with the state of the N.H. S. than with our own earnings ? May I return to a proposal which had little support in the bitterness of January, but which might get more sympathy now ? This is that any senior consultant willing to do so should relinquish part of his increase, not to the Government but to his own hospital, where it could form a fund for maintenance and development to be used at the discretion of the Medical Committee. It would, of course, be easier to decide to give this back before we have actually got it. I would not press younger consultants, for they have had to suffer a good deal of hardship, but perhaps anyone drawing over E8000 a year from the N.H.S. might
consider contributing 1 % of it, with higher rates for higher salaries. The total would not be impressive; the gesture might be. If the idealistic reason does not appeal, some might prefer a more material one. As far as I can see the only hope to help the country’s financial position is that some groups should give up something. Could the doctors give a lead here ? Who knows but that it might be followed by senior Civil Servants and even Cabinet Ministers ? If so, it might in the long run make the money we actually do get worth more.
Department of Psychological Medicine, University College Hospital, Gower Street, London WC1E 6AU.
R. F. TREDGOLD.
DOES T4-TOXICOSIS EXIST ?
SIR,-We
were
very interested in the
and his
reply by Dr
colleagues (April 12, p. 868). The
Kirkegaard thyrotoxic patient they described was a 70-year-old woman with " serum T3 within 95% normal range and serum T4 exceeding 95% normal range ". It has been shown that serum-T3 levels fall with age, and we assume that the rather low normal range (35-153 ng. per 100 ml.) Dr Kirkegaard quoted is adjusted for the geriatric population. If this is the case their patient truly has T4-toxicosis. In the Canterbury area of New Zealand, thyrotoxicosis is most prevalent in the 50 + age-group, and a previous report by Dr Kirkegaard2 indicates a similar situation in Denmark. It is therefore essential, before the estimation of total serum-triiodothyronine becomes a routine thyroid-function test, that each laboratory establishes a normal range for different age-groups. Dr Hadden and his colleagues (March 29, p. 754) show a good correlation between serum-T3 and the free-thyroxine index in both euthyroid and thyrotoxic patients. These results are similar to our initial experience3 in a group of 137 patients representing a wide range of thyroid disease, where we correlated total serum-T3 and total serum-T4 levels (r=0-866). However, widely discordant serum-T3 and serum-T4 results do occur in patients with nonthyroidal illness, in patients with thyroidal enzyme defects,5 and in other clinical situations where there is an increased thyroid-stimulating-hormone effect upon the thyroid gland-e.g., after iodine-131 therapy.In relapse of thyrotoxicosis, too, serum-T3 and serum-T4 may be discordant. In this situation the serum-T3 may rise before the serum-T4, but occasionally the reverse may occur. We have one such example, a 22-year-old woman who showed clinical evidence of relapse after a course of antithyroid drugs (serum-T4=12-3 µg. per 100 ml. (normal 3-5-10-0 fg. per 100 ml.), serum-T3=118 ng. per 100 ml. (75-175 ng. per 100 ml.). Although triiodothyronine is thought to be the physiologically more important thyroid hormone, the estimation of the free-thyroxine index at present seems to be the best screening test for thyroid dysfunction. The discordant T3 and T4 results found in many conditions indicates that serum-T3 levels should not be interpreted in isolation. This is particularly important in patients with non-thyroidal illness. We believe that both T3 and T4 toxicosis exist and 1. 2. 3. 4.
5. 6. 7.
Rubenstein, H. A., Butler, V. P., Werner, S. C. J. clin. Endocr. 1973, 37, 247. Ronnov-Jessen, V., Kirkegaard, C. Br. med. J. 1973, i, 41. Sadler, W. A., Brownlie, B. E. W. N.Z. med. J. 1975, 81, 328. Carter, J. N., Eastman, C. J., Corcoran, J. M., Lazarus, L. Lancet, 1974, ii, 971. Gomez-Pan, A., Evered, D. C., Hall, R. Br. med. J. 1974, ii, 152. Sterling, K., Brenner, M. A., Newman, E. S., Odell, W. D., Bellabarba, D. J. clin. Endocr. 1971, 33, 729. Marsden, P., Howorth, P. J. M., Chalkley, S., Acosta, M., Leatherdale, B., McKerron, C. G. Lancet, 1975, i, 944.
1293 that T3 radioimmunoassay is index of
not
the ultimate
laboratory
Christchurch Hospital,
Christchurch, New Zealand.
J. G. TURNER B. E. W. BROWNLIE W. A. SADLER C. A. JENSEN.
PLASMA IRON AND IRON-BINDING CAPACITY SIR,-Of course it all depends on what you mean by the anaemia of chronic disorders. If, like me, you mean the anaemia found in inflammatory and malignant conditions and characterised by reduced numbers of sideroblasts in the marrow and increased haemosiderin within macrophages, and exclude that found in myxoedema, uraemia, and liver disorders, then I stick to my assertion (May 10, p. 1090) that these ;are " likely to have hypochromic, microcytic red cells ". If I may quote a more comprehensive and up-to-date textbook than that cited by Dr Zilva (May 24, p. 1191),"... hypochromia has been observed in 23 to 50% of patients with chronic infection, 50 to 100% of patients with rheumatoid arthritis, and 44 to 64% of patients with cancer."1 I agree that many cases of iron deficiency can be distinguished from this condition on hasmatological grounds alone, but as Dr Turnbull has indicated (May 24, p. 1191), many cannot. I also agree with your correspondents who complain that serum-irons are over-requested, and what a wonderful world it would be if pathologists alone could make requests of the laboratory. But in the real world are they more abused than Bl2s and folates, or even haemoglobins and plasma-electrolytes ? By all means, let us encourage a greater dialogue with clinicians, but, please, biochemists, don’t stop doing the test. If haematologists have to set it up themselves, what will the coefficient of variation be then ? Royal Victoria Hospital, Boscombe, Bournemouth BH1 4JG.
the
was
thyrotoxicosis.
Nuclear Medicine Department,
In the 3 remaining patients the cholesterol altered constituent, but in none did it exceed 300 mg. per 100 ml. Basal immunoreactive insulin levels and blood-glucose were normal in all the patients.
lipolytic activity). most
Our study does not confirm Casaretto’s reported results but agrees with Beaumont’s experience. However, we cannot support Beaumont’s hypothesis that normal bloodlipids could be due to the alternate-day corticosteroid therapy, since we have observed normal lipid levels with daily corticosteroid treatment.
J. MASRAMON A. CARALPS M. LLORACH R. COMPANYS A. BRULLES J. LLOVERAS J. ANDREU.
Unidad de Trasplante Renal, Catedra de Urologia (Facultad de Medicina),
Hospital Clínico y Provincial, Barcelona, Spain.
TOXICITY OF ASPARAGINASES are being used in the is obtained from Escherichia coli (Escherichia asparaginase), the other from the plant pathogen, Erwinia carotovora (Erwinia asparaginase). Although they appear to be equally effective as antileuksemic agents.l some reports suggest that they differ in toxicity.2.3 To clarify this I examined the records of patients with acute leukasmia who have been treated with asparaginase at three London hospitals. The doses used were similar at each hospital, either 200 i.u. per kg. body-weight or 6000 i.u. per sq.m. bodysurface area of reconstituted freeze-dried asparaginase. There were no deaths attributable to enzyme therapy but toxicity interrupted 12 of the 31 (39%) courses of Escherichia
SiR,—Two bacterial asparaginases
treatment
of acute leukaemia:
one
FREQUENCY OF SERIOUS TOXICITY
*
TERRY HAMBLIN. * Serious toxicity asparaginase changed or discontinued. t Course=at least 3 full doses given without toxicity or one =
HYPERLIPIDÆMIA AFTER RENAL
SiR,-Casaretto et awl. reported a significant rise in basal plasma-levels of triglyceride, cholesterol, and immunoreactive insulin after successful renal transplantation in 37 patients receiving an average dose of 17 mg. of prednisolone per day. They found that hyperlipoproteinxmia was a general feature in these patients. In contrast, Beaumont et al. (March 15, p. 599) find normal serum-lipid profiles in 78% of 42 successfully
transplanted patients receiving an average dose of 22 mg. of prednisone every other day. The remaining 22% show hyperlipidaemia, but they are significantly more obese and older. Both the normal subjects and the hyperlipidaemic patients show normal basal immunoreactive insulin levels. Beaumont and his colleagues postulate that this high percentage of patients with normal blood-lipid levels cquld be due to the alternate-day corticosteroid therapy. In 19 an
patients with successful renal transplantation treated with prednisone per day for at least
average dose of 12 mg. of
3 months and with serum-creatinine levels below 20 mg. per 100 ml., we found 16 (84%) with no change in any of the lipid parameters studied (overnight-fasting cholesterol, triglycerides, free fatty acids, free glycerol, lipidogram in cellulose acetate, thin-layer chromatography of neutral lipids, and post-heparin 1. Wintrobe, M. M. Clinical Hæmatology; p. 673. Philadelphia,1974. 2. Casaretto, A., Marchioro, T. L., Goldsmith, R., Bagdade, J. D. Lancet, 1974, i, 481.
or more
full doses if toxicity developed.
TRANSPLANTATION
asparaginase and 9 of the 46 (20%) Erwinia courses (see accompanying table). Allergic reactions were the commonest side-effects, and their occurrence always led to a change or discontinuance of asparaginase. They did not appear until at least ten days after the start of enzyme treatment unless the patient had been treated previously with the same type of enzyme. 11 patients were re-exposed to the same asparaginase;
1 of the 5 Escherichia-treated and 1 of the 6 Erwinia-treated had an anaphylactic reaction; the former required intravenous hydrocortisone, the latter recovered without treatment.
10
patients were given the alternative enzyme because of hypersensitivity-3 sensitive to Erwinia, 7 to Escherichia asparaginase. In all of these, enzyme therapy was continued satisfactorily without cross-toxicity. In 2 cases asparaginases were substituted because of vomiting, but without benefit. One child was given Erwinia asparaginase intravenously twice weekly for fifty-four weeks, except for gaps of one week every 8 weeks when prednisone and arabinosyl cytosine were given. No toxicity occurred during this 1. 2. 3.
Kay, H. E. M., Fairley, G. H., Knapton, P. J. Colloques int. C.N.R.S., 1971, no. 197 : l’asparaginase, p. 295. Ohnuma, T., Holland, J. F., Meyer, P. Cancer, N.Y. 1972, 30, 376. Ohnuma, T., Holland, J. F., Meyer, P. Proc. Am. Ass. Cancer Res. 1972, 13, 117 (abstr. 465).
