- Email: [email protected]
PLASMA EXCHANGE IN MYASTHENIA GRAVIS
190 It was the persistence of i.c.Ab in polyendocrine disease tients that led to the detection of i.c.Ab in the first place!5 16paWhile the prevalence of i.c.Ab during the first year of diabetes (either from onset of symptoms or from diagnosis) is between 50%’ and 60%F-14 the incidence in our experience does continue to fall to as little as 5% and does not plateau at 10-20% after a few years (as Lendrum et al. state) except in diabetics with associated autoimmune disorders (26%).14 The finding of i.c.Ab in 3 (1.7%) of 177 random subjects without known autoimmune disease (Lendrum et al. included no normal controls in their study) raises some doubt as to whether the i.c.Ab immunofluorescence test was being read below the level that separates the specific from the non-specific with titres of 1/1, 1/1, and 1/2 in the 3 positive "controls". The observation of 0.5% positive i.c.Ab in 434 non-diabetic subjects without autoimmune disease (1 in 360 blood donors or healthy unrelated friends of patients, and 1 in 74 hospital controls) were in relation to titres of 1/32 and lIS!31 of these 2 positive controls, a 45-year old female, was subsequently shown to have a diabetic glucose-tolerance test although she was
symptom-free5
If i.c.Ab titres are measured serially in individual patients at intervals of 5-12 years (i.e., by going back to the deepfreeze and finding earlier samples from the same patients), then the mean titre falls in those who were positive within 1 year and within 5 years of diagnosis of diabetes, but not in those who were positive more than 5 years from diagnosis.14 Whether or not the persistence of i.c.Ab correlates with an increased prevalence of thyrogastric antibodies can only be determined by comparing the prevalence of thyrogastric antibodies in a sufficient number of i.c.Ab-positive and of i.c.Abnegative insulin-dependent diabetics of the same sex, age, and duration of diabetes (e.g., 5-10 years). It is difficult to make a normal person form autoantibodies without that person having some diathesis towards autoimmunity,17Although Lendrum et all concluded that there was no correlation between the presence of i.c.Ab and any HLA type, there is a correlation between the persistence of i.c.Ab and HLA-BS.1420 B8 is associated with immunopathogenic disorders, including autoimmune chronic adrenalitiS2 and thyrotoxicosis. 22 Lendrum et al.1are probably not correct in suggesting that all insulin-dependent diabetics may have i.c.Ab at some stage in the development of their illness.*" A subject with a strong genetic susceptibility to islet viral infection would appear to be able to experience severe B-cell destruction with the development of insulin-dependent diabetes without the formation of islet-cell antibodies either before, during the acute phase, or during the convalescent phase of the viral infection and the onset of diabetes. 24 It is time that we left the simplistic but conventional classification of diabetes according to treatment required (insulin or not) or age of onset. It is unfortunate that Cudworth 25 used type-i diabetes to be synonymous with insulin-dependent, juvenile-onset diabetes and type 11 to be synonymous with maturity-onset insulin-independent diabetes. This simply reiterates the old conventional clinical classification, and does not fully utilise the new knowledge in terms of autoimmunity either acting on its own, or interacting with viral infection. The new knowledge of islet-cell autoimmunity should allow the different disease processes resulting in the common syn15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
Bottazzo, G. F., Florin-Chnstensen, A., Doniach, D. Lancet, 1974, ii, 1279. McCuish, A. C., Barnes, E. W., Irvine, W. J., Duncan, L. J. P. ibid. p. 1529. Irvine, W. J., Gray, R. S., McCallum, C. J. Lancet, 1976, ii, 1097. Irvine, W. J. Q. Jl exp. Physiol. 1964, 49, 324. Lendrum, R., Walker, G., Cudworth, A. G., A. G., Woodrow, J. C., Gamble, D. R. Br. med. J. 1976, i, 1565. Morris, P. J., Vaughan, H., Irvine, W. J., McCallum, C. J., Gray, R. S., Campbell, C. J., Duncan, L. J. P., Farquhar, J. W. Lancet, 1976, ii, 652. Platz, P., Ryder, L., Stuab-Nielsen, L., Svejgaard, A., Thomsen, M., Christy, M., Nerup, J. ibid. 1974, ii, 289. Grumet, C., Conishi, J., Payne, R., Criss, J. P., Clin. Res. 1973, 21, 493. Irvine, W. J. Lancet (in the press). Byam, N., Hull, B., Irvine, W. J., Hamilton, P. J. Unpublished. Cudworth, A. G. Br. J. Hosp. Med. 1976, 16, 207.
drome of diabetes to be more accurately analysed irrespective of the age of clinical presentation. Moreover, it should facilitate the recognition of different stages within the same disease process. This in turn might help to make better sense of the genetic aspects of diabetes which to date have been in such a
tangle. Endocrine Unit and
Department of Therapeutics, Royal Infirmary, Edinburgh EH3 9YW
W. J. IRVINE
PLASMA EXCHANGE IN MYASTHENIA GRAVIS were interested in the article by Pinching et al.1 the use of plasma exchange in myasthenia gravis, and would like to report a case which we have treated by this technique and make some cautionary comments on the potential of plasmapheresis in the management of intractable myasthenia. The patient was a 36-year-old woman who presented with severe myasthenia in 1974 having, for 8 years, noted occasional diplopia when tired. Thymectomy was carried out 6 months later and led to considerable improvement, but she was still significantly disabled and was restricted to very light housework and was unable to do her own shopping because her exercise tolerance was limited to 100 m. We decided to try plasmapheresis, and in December, 1975, eight exchanges were carried out with a Haemonetics cell separator over 14 days, and 12 litres of plasma were removed and replaced with purifiedprotein fraction. Concurrently she was treated with azathioprine 100 mg daily. There was some improvement at first in that her voice became stronger, and the time which she could hold her arm outstretched increased from 45 to 60 s. Immediately after the procedure she was able to go out shopping, but after a few weeks she reverted to her former state, and is now restricted to light housework and can walk only about 100 m. The straight arm-raising test has stabilised at 45 s. She did not tolerate the azathioprine which was stopped after 3 months. There was certainly an immediate improvement, but this was short-lived, and we were unable to convince ourselves that we were not observing a placebo effect. A similar consideration may apply to the patients treated by Pinching et al. who also improved clinically. The placebo effect of plasmapheresis must be considerable. Several doctors and technical staff are in constant attendance for about 2 h at each session to a total of up to 20 h. This attention must be very impressive to a patient who may hitherto have received relatively little notice, since doctors do tend to turn the other way when faced with untreatable disorders. Our patient desperately wanted the technique to work, both for herself and because she appreciated that we were very enthusiastic about what might prove to be an important advance in treatment. Mass enthusiasm is infectious. At a later stage the patients treated by Pinching et al. were started on immunosuppressive therapy which can on its own be beneficial in myasthenia. The dose of steroids was also reduced significantly, and one of our patients has improved after a reduction in steroid dosage, and it is possible that a steroid-resistant myasthenic would eventually develop a steroid myopathy which would improve on reducing the steroid dosage. Plasmapheresis was only one of several measures, and the conclusion that plasma removal was the main factor leading to improvement may not be justified. We do, however, agree with Pinching et al. that on theoretical grounds, plasmapheresis may find a place in the management of myasthenia, but further trials under controlled conditions will be required to establish its value. We would also point out that an immediate response might not be expected if the myoneural junction has been subjected to sustained antibody attack for several years with resulting structural damage. Even if the antibody action is stopped completely it might take some time for the end-plates to recover, and prolonged plasma-
SiR,-We
on
1.Pinching, A. J., Peters, D. K., Davis, J.
N. Lancet,
1976, ii, 1373.
191
pheresis and immunosuppression over many months may be required, but this would present formidable logistic problems. An alternative approach might be to treat early cases before thymectomy. RONALD FINN P. M. COATES
Royal Southern Hospital, Liverpool L8 5SH
OCCULT OSTEOMALACIA IN HEALTHY PAKISTANIS
SIR,-Professor Rab and Dr Baseer state’ that after three treatment with calciferol, the high serum-alkalinephosphatase was corrected in all but two of their presumed osteomalacia patients. Women in late pregnancy have rising months’
values for this constituent, and this makes the fall seem rather the situation becomes clear when one considers that women in late pregnancy treated for three months will have passed into the postnatal period. The inference that the fall was due to treatment is not valid because the changed values seen during pregnancy will revert to the nonpregnant levels after delivery. Alkaline phosphatase values will fall, irrespective of vitamin-D treatment. Nor is it satisfactory to treat only patients who show biochemical abnormalities because I found that values for a whole population of pregnant Asian women were shifted in the direction of biochemical osteomalacia.1 Consequently the whole population need treatment with vitamin D. The comparison of a group of pregnant women with a group of non-pregnant women is also not valid. There is a significant difference in many constituents between healthy pregnant and healthy non-pregnant women. A satisfactory comparison group would have to be a matched group of healthy pregnant women who were not vitamin-D deficient. Professor Rab and Dr Baseer do not make clear what control group was used for their criteria of normality. The lower limit of the serum-calcium range in table 1 is 8.15 mg/dl in normal women. In table II, however, they exclude as abnormal all values below 8.5 mgldl. Are they using textbook normal values for Caucasian women? The p value-for serum-calcium in table i seems wrong. The correct value is >0.05 (i.e., no significant difference) which accords with their statement in the paragraph headed "serumcalcium". I do not quarrel with the general thesis that there are abnormalities due to lack of vitamin D unless there is adequate supplementation through the skin. However, a more suitable control group and more information on which the conclusions were reached are needed.
surprising. However,
Biochemistry Department, Royal Infirmary,
Department of Medicine, Jinnah Postgraduate Medical Centre, Karachi, Pakistan
S. M. RAB
BIGUANIDES AND LACTICACIDOSIS
SIR,-Metformin is replacing phenformin as the biguanide of choice in the treatment of obese maturity-onset diabetics because of the association between phenformin therapy and lacticacidosis. This complication has rarely been observed with metformin and usually only with overdosage.2 Metformin has been said to have no effect on lactate metabolism,3 whereas phenformin increased blood-lactate concentration in diabetics.4 Phenformin inhibited renal ammonium (NH4+) production in vitroand in man it decreased the renal capacity for NH4excretion after an acid load.6These two actions may be significant precipitating factors towards lacticacidosis in paTABLE I-BLOOD-LACTATE LEVELS DURING INTRAVENOUS GLUCOSE-TOLERANCE TEST
Metformin dose 500 mg three times twice daily.
a
day
(MEANtS.D.)
and
phenformin dose
50 mg
tients
A. T. HOWARTH
Bradford BD9 6RH
SIR,-Professor Rab and Dr Baseer
state that "the only [dietary] vitamin D for the vast majority was cooking oil". They refer to groups who, both by their low economic status and their religious beliefs, are largely vegans. The few dietary sources of vitamin D are either animal or fish; none will be found in cooking oil since this will certainly be of vegetable origin. source of
Dietitic Department, Middlesex Hospital, London W1
letters have been *reply * Thesefollows.-ED.L.
analyse the isoenzymes; alkaline phosphatase was not the only index of abnormality used in our study. It would have been ideal to treat a whole population with vitamin, which is what we asked for in our concluding remarks. Unfortunately, the economic situation, lack of supervision, and inability of the patients to persevere with a long course make the task difficult. We agree with Dr Howarth’s suggestion about controls, and will take this up when we measure vitamin-D concentrations in serum. The lower limit for serum-calcium is an arbitrary figure of 8.5 mg/dl taken from a study in Asians.’ The p value in tablei should be >0.05. I am glad that Dr Howarth concurs in our general message, and I would welcome collaboration in a more detailed study which is at the moment beyond our reach. The cooking oil used was vegetable oil supplemented with vitamins A and D. However, poorer families cannot afford adequate amounts of this oil in their diet.
MARJORIE MCLAUGHLIN shown
to
Professor Rab, whose
S)R,—I agree with Dr Howarth that serum-alkaline-phosphatase values are raised in late pregnancy, but we did try to 1. Rab, S. M., Baseer, A. Lancet, 1976, ii, 1211. 2. Howarth A. T. J. clin Path. 1976, 29, 981.
taking phenformin, particularly in the presence of renal, hepatic, or cardiac insufficiency. We have compared the effects of metformin and phenformin on blood-lactate levels after an intravenous glucose load (25 g) and on renal NH+ excretion after an oral acid load (ammonium chloride 0.1 g/kg body-weight) using the short acid loading test described by Wrong and Davies.7 The patients were maturity-onset diabetics controlled on one of the biguanides. They were studied three times one month apartfirstly, while taking their current biguanide, secondly on diet alone, and finally on the second biguanide. In all but one patient the blood-lactate at all times after the glucose load was higher during biguanide therapy than during 1. Holmes, A.
M., Enoch, B. A., Taylor, J. I., Jones, M. E. Q. Jl Med. 1973, 42, 125. 2. Lebacq, E. G., Tirzmalis, A. Lancet, 1972, i, 314. 3. Sterne, J. Metabolism, 1964, 13, 791. 4. Varma, S. K., Heaney, S. J., Whyte, W. G., Walker, R. S. Br. med. J. 1972, i, 205 5. Alleyne, G. A. O., Besterman, H. S., Flores, H. Clin. Sci. 6. Rooth, G., Bandman, U. Br. med. J. 1973, iv, 256. 7. Wrong, O., Davies, H. E. F. Q. Jl Med. 1959, 28, 259.
1971, 40, 107.
symptom-free5
If i.c.Ab titres are measured serially in individual patients at intervals of 5-12 years (i.e., by going back to the deepfreeze and finding earlier samples from the same patients), then the mean titre falls in those who were positive within 1 year and within 5 years of diagnosis of diabetes, but not in those who were positive more than 5 years from diagnosis.14 Whether or not the persistence of i.c.Ab correlates with an increased prevalence of thyrogastric antibodies can only be determined by comparing the prevalence of thyrogastric antibodies in a sufficient number of i.c.Ab-positive and of i.c.Abnegative insulin-dependent diabetics of the same sex, age, and duration of diabetes (e.g., 5-10 years). It is difficult to make a normal person form autoantibodies without that person having some diathesis towards autoimmunity,17Although Lendrum et all concluded that there was no correlation between the presence of i.c.Ab and any HLA type, there is a correlation between the persistence of i.c.Ab and HLA-BS.1420 B8 is associated with immunopathogenic disorders, including autoimmune chronic adrenalitiS2 and thyrotoxicosis. 22 Lendrum et al.1are probably not correct in suggesting that all insulin-dependent diabetics may have i.c.Ab at some stage in the development of their illness.*" A subject with a strong genetic susceptibility to islet viral infection would appear to be able to experience severe B-cell destruction with the development of insulin-dependent diabetes without the formation of islet-cell antibodies either before, during the acute phase, or during the convalescent phase of the viral infection and the onset of diabetes. 24 It is time that we left the simplistic but conventional classification of diabetes according to treatment required (insulin or not) or age of onset. It is unfortunate that Cudworth 25 used type-i diabetes to be synonymous with insulin-dependent, juvenile-onset diabetes and type 11 to be synonymous with maturity-onset insulin-independent diabetes. This simply reiterates the old conventional clinical classification, and does not fully utilise the new knowledge in terms of autoimmunity either acting on its own, or interacting with viral infection. The new knowledge of islet-cell autoimmunity should allow the different disease processes resulting in the common syn15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
Bottazzo, G. F., Florin-Chnstensen, A., Doniach, D. Lancet, 1974, ii, 1279. McCuish, A. C., Barnes, E. W., Irvine, W. J., Duncan, L. J. P. ibid. p. 1529. Irvine, W. J., Gray, R. S., McCallum, C. J. Lancet, 1976, ii, 1097. Irvine, W. J. Q. Jl exp. Physiol. 1964, 49, 324. Lendrum, R., Walker, G., Cudworth, A. G., A. G., Woodrow, J. C., Gamble, D. R. Br. med. J. 1976, i, 1565. Morris, P. J., Vaughan, H., Irvine, W. J., McCallum, C. J., Gray, R. S., Campbell, C. J., Duncan, L. J. P., Farquhar, J. W. Lancet, 1976, ii, 652. Platz, P., Ryder, L., Stuab-Nielsen, L., Svejgaard, A., Thomsen, M., Christy, M., Nerup, J. ibid. 1974, ii, 289. Grumet, C., Conishi, J., Payne, R., Criss, J. P., Clin. Res. 1973, 21, 493. Irvine, W. J. Lancet (in the press). Byam, N., Hull, B., Irvine, W. J., Hamilton, P. J. Unpublished. Cudworth, A. G. Br. J. Hosp. Med. 1976, 16, 207.
drome of diabetes to be more accurately analysed irrespective of the age of clinical presentation. Moreover, it should facilitate the recognition of different stages within the same disease process. This in turn might help to make better sense of the genetic aspects of diabetes which to date have been in such a
tangle. Endocrine Unit and
Department of Therapeutics, Royal Infirmary, Edinburgh EH3 9YW
W. J. IRVINE
PLASMA EXCHANGE IN MYASTHENIA GRAVIS were interested in the article by Pinching et al.1 the use of plasma exchange in myasthenia gravis, and would like to report a case which we have treated by this technique and make some cautionary comments on the potential of plasmapheresis in the management of intractable myasthenia. The patient was a 36-year-old woman who presented with severe myasthenia in 1974 having, for 8 years, noted occasional diplopia when tired. Thymectomy was carried out 6 months later and led to considerable improvement, but she was still significantly disabled and was restricted to very light housework and was unable to do her own shopping because her exercise tolerance was limited to 100 m. We decided to try plasmapheresis, and in December, 1975, eight exchanges were carried out with a Haemonetics cell separator over 14 days, and 12 litres of plasma were removed and replaced with purifiedprotein fraction. Concurrently she was treated with azathioprine 100 mg daily. There was some improvement at first in that her voice became stronger, and the time which she could hold her arm outstretched increased from 45 to 60 s. Immediately after the procedure she was able to go out shopping, but after a few weeks she reverted to her former state, and is now restricted to light housework and can walk only about 100 m. The straight arm-raising test has stabilised at 45 s. She did not tolerate the azathioprine which was stopped after 3 months. There was certainly an immediate improvement, but this was short-lived, and we were unable to convince ourselves that we were not observing a placebo effect. A similar consideration may apply to the patients treated by Pinching et al. who also improved clinically. The placebo effect of plasmapheresis must be considerable. Several doctors and technical staff are in constant attendance for about 2 h at each session to a total of up to 20 h. This attention must be very impressive to a patient who may hitherto have received relatively little notice, since doctors do tend to turn the other way when faced with untreatable disorders. Our patient desperately wanted the technique to work, both for herself and because she appreciated that we were very enthusiastic about what might prove to be an important advance in treatment. Mass enthusiasm is infectious. At a later stage the patients treated by Pinching et al. were started on immunosuppressive therapy which can on its own be beneficial in myasthenia. The dose of steroids was also reduced significantly, and one of our patients has improved after a reduction in steroid dosage, and it is possible that a steroid-resistant myasthenic would eventually develop a steroid myopathy which would improve on reducing the steroid dosage. Plasmapheresis was only one of several measures, and the conclusion that plasma removal was the main factor leading to improvement may not be justified. We do, however, agree with Pinching et al. that on theoretical grounds, plasmapheresis may find a place in the management of myasthenia, but further trials under controlled conditions will be required to establish its value. We would also point out that an immediate response might not be expected if the myoneural junction has been subjected to sustained antibody attack for several years with resulting structural damage. Even if the antibody action is stopped completely it might take some time for the end-plates to recover, and prolonged plasma-
SiR,-We
on
1.Pinching, A. J., Peters, D. K., Davis, J.
N. Lancet,
1976, ii, 1373.
191
pheresis and immunosuppression over many months may be required, but this would present formidable logistic problems. An alternative approach might be to treat early cases before thymectomy. RONALD FINN P. M. COATES
Royal Southern Hospital, Liverpool L8 5SH
OCCULT OSTEOMALACIA IN HEALTHY PAKISTANIS
SIR,-Professor Rab and Dr Baseer state’ that after three treatment with calciferol, the high serum-alkalinephosphatase was corrected in all but two of their presumed osteomalacia patients. Women in late pregnancy have rising months’
values for this constituent, and this makes the fall seem rather the situation becomes clear when one considers that women in late pregnancy treated for three months will have passed into the postnatal period. The inference that the fall was due to treatment is not valid because the changed values seen during pregnancy will revert to the nonpregnant levels after delivery. Alkaline phosphatase values will fall, irrespective of vitamin-D treatment. Nor is it satisfactory to treat only patients who show biochemical abnormalities because I found that values for a whole population of pregnant Asian women were shifted in the direction of biochemical osteomalacia.1 Consequently the whole population need treatment with vitamin D. The comparison of a group of pregnant women with a group of non-pregnant women is also not valid. There is a significant difference in many constituents between healthy pregnant and healthy non-pregnant women. A satisfactory comparison group would have to be a matched group of healthy pregnant women who were not vitamin-D deficient. Professor Rab and Dr Baseer do not make clear what control group was used for their criteria of normality. The lower limit of the serum-calcium range in table 1 is 8.15 mg/dl in normal women. In table II, however, they exclude as abnormal all values below 8.5 mgldl. Are they using textbook normal values for Caucasian women? The p value-for serum-calcium in table i seems wrong. The correct value is >0.05 (i.e., no significant difference) which accords with their statement in the paragraph headed "serumcalcium". I do not quarrel with the general thesis that there are abnormalities due to lack of vitamin D unless there is adequate supplementation through the skin. However, a more suitable control group and more information on which the conclusions were reached are needed.
surprising. However,
Biochemistry Department, Royal Infirmary,
Department of Medicine, Jinnah Postgraduate Medical Centre, Karachi, Pakistan
S. M. RAB
BIGUANIDES AND LACTICACIDOSIS
SIR,-Metformin is replacing phenformin as the biguanide of choice in the treatment of obese maturity-onset diabetics because of the association between phenformin therapy and lacticacidosis. This complication has rarely been observed with metformin and usually only with overdosage.2 Metformin has been said to have no effect on lactate metabolism,3 whereas phenformin increased blood-lactate concentration in diabetics.4 Phenformin inhibited renal ammonium (NH4+) production in vitroand in man it decreased the renal capacity for NH4excretion after an acid load.6These two actions may be significant precipitating factors towards lacticacidosis in paTABLE I-BLOOD-LACTATE LEVELS DURING INTRAVENOUS GLUCOSE-TOLERANCE TEST
Metformin dose 500 mg three times twice daily.
a
day
(MEANtS.D.)
and
phenformin dose
50 mg
tients
A. T. HOWARTH
Bradford BD9 6RH
SIR,-Professor Rab and Dr Baseer
state that "the only [dietary] vitamin D for the vast majority was cooking oil". They refer to groups who, both by their low economic status and their religious beliefs, are largely vegans. The few dietary sources of vitamin D are either animal or fish; none will be found in cooking oil since this will certainly be of vegetable origin. source of
Dietitic Department, Middlesex Hospital, London W1
letters have been *reply * Thesefollows.-ED.L.
analyse the isoenzymes; alkaline phosphatase was not the only index of abnormality used in our study. It would have been ideal to treat a whole population with vitamin, which is what we asked for in our concluding remarks. Unfortunately, the economic situation, lack of supervision, and inability of the patients to persevere with a long course make the task difficult. We agree with Dr Howarth’s suggestion about controls, and will take this up when we measure vitamin-D concentrations in serum. The lower limit for serum-calcium is an arbitrary figure of 8.5 mg/dl taken from a study in Asians.’ The p value in tablei should be >0.05. I am glad that Dr Howarth concurs in our general message, and I would welcome collaboration in a more detailed study which is at the moment beyond our reach. The cooking oil used was vegetable oil supplemented with vitamins A and D. However, poorer families cannot afford adequate amounts of this oil in their diet.
MARJORIE MCLAUGHLIN shown
to
Professor Rab, whose
S)R,—I agree with Dr Howarth that serum-alkaline-phosphatase values are raised in late pregnancy, but we did try to 1. Rab, S. M., Baseer, A. Lancet, 1976, ii, 1211. 2. Howarth A. T. J. clin Path. 1976, 29, 981.
taking phenformin, particularly in the presence of renal, hepatic, or cardiac insufficiency. We have compared the effects of metformin and phenformin on blood-lactate levels after an intravenous glucose load (25 g) and on renal NH+ excretion after an oral acid load (ammonium chloride 0.1 g/kg body-weight) using the short acid loading test described by Wrong and Davies.7 The patients were maturity-onset diabetics controlled on one of the biguanides. They were studied three times one month apartfirstly, while taking their current biguanide, secondly on diet alone, and finally on the second biguanide. In all but one patient the blood-lactate at all times after the glucose load was higher during biguanide therapy than during 1. Holmes, A.
M., Enoch, B. A., Taylor, J. I., Jones, M. E. Q. Jl Med. 1973, 42, 125. 2. Lebacq, E. G., Tirzmalis, A. Lancet, 1972, i, 314. 3. Sterne, J. Metabolism, 1964, 13, 791. 4. Varma, S. K., Heaney, S. J., Whyte, W. G., Walker, R. S. Br. med. J. 1972, i, 205 5. Alleyne, G. A. O., Besterman, H. S., Flores, H. Clin. Sci. 6. Rooth, G., Bandman, U. Br. med. J. 1973, iv, 256. 7. Wrong, O., Davies, H. E. F. Q. Jl Med. 1959, 28, 259.
1971, 40, 107.