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ESTIMATING ENDOGENOUS RENIN
1157
CHLOROQUINE IN PULMONARY SARCOIDOSIS SiR,ŅThe criteria for the diagnosis of sarcoidosis, have been often discussed. At practically every conference on sarcoidosis attempts have been made to define the disease. In the investigation carried out by the British Tuberculosis Association, and referred to by you (April 6, p. 736), reliable criteria seem to have been established. The xtiology of sarcoidosis is unknown; its clinical manifestations are of varied morphology but the majority fit into a clinical entity. In general sarcoid patients not only fail to react to tuberculin and other antigens evoking a delayed response, but they are also not readily sensitised by B.C.G. or by contact allergens. The results of twin and family studies indicate a genetic predisposition to the diesase which might support the growing concept of the disease as a granulomatous hyper-
sensitivity.! The effect of chloroquine is somewhat surprising, since in our investigation2 comprising fifteen patients with sarcoidosis of the skin of whom twelve had pulmonary involvement (criteria for diagnosis being those defined at the 3rd International Conference of Sarcoidosis), doubtful improvement was observed in two patients as assessed by radiological examination, while the remaining thirteen cases were unaffected. The duration of treatment was from 12 to 21 months (average 13-5 months) with an average total dose per patient of 311 g. hydroxychloroquine and a daily dose of 500-1000 mg. The lesions of the skin showed the same lack of response to this treatment. Reversible ocular complications were observed in
patients. We, too, have the impression that corticosteroids can suppress
ten
the lesions both in the skin and in other organs, but the only indication for prescribing them is progression of the pulmonary lesions. Careful observation of a group of untreated patients with sarcoidosis in order to follow the spontaneous course over several years would be extremely valuable. Department of Dermatology, Finsen Institute, Strandboulevarden 49, Copenhagen, Denmark.
HOLGER BRODTHAGEN.
ESTIMATING ENDOGENOUS RENIN SIR,-We write to report results similar to those of Dr. Haas and his colleagues (March 30, p. 657). In the course of work which led to a method for the assay of renin activity in plasma,3 we were unable to seperate renin from other plasma-proteins without large and variable loss: it was therefore proposed that the action of renin on the substrate already present in plasma should be measured. Having determined the Michaelis constant (Km) for this reaction it was intended that a correction should be applied from measurement of the substrate concentration in each plasma. However, it became apparent that the velocity of the reaction depended upon a factor other than total substrate concentration, possibly an activator or an inhibitor, possibly another form of substrate. For this reason the velocity of angiotensin formation was also measured when a known quantity of human renin (approximately 1 x 10-3 Goldblatt units [G.u.] per ml.) was allowed to react with each plasma. From this measurement, and from assay of angiotensin formed when plasma was incubated alone, the concentration of renin in a number of normal plasmas was calculated. In 28 plasmas the renin concentration ranged from 0· 10 x 10-4 to 1-20 x 10-4 (mean 0-49 x 10-4) G.u. per ml. (It is noted that Dr. Haas and his collegaues used serum: in our method plasma was used.) However, it remains to be determined whether a correction applied from measurement of the velocity of angiotensin formation after addition of a known quantity of renin (or from measurement of total substrate concentration) will add to the usefulness of 1. 2. 3.
Epstein, W. Progr. Allergy, 1967, 11, 51. Brodthagen, H., Gilg, I. 4th Int. Conf. Sarcoidosis, Paris, 1967. Pickens, P. T., Bumpus, F. M., Lloyd, A. M., Smeby, R. R., Page, I. H.: Circulation Res. 1965, 17, 438.
renin assay. The complexity of the reactions in which renin angiotensin are concerned has been compared to that of blood-clotting 4; and it is possible that, as in the latter process, a simple test depending on several factors (and therefore measuring no one factor accurately) may nevertheless be of value. P. T. PICKENS. Welsh National School of Medicine, Cardiff, Glam. F. M. BUMPUS. Cleveland Clinic, Cleveland, Ohio, U.S.A. a
and
BILE-SALTS AFTER ILEAL RESECTION SIR,-Iread Dr. Heaton’s letter last week (p. 1093) with interest. In view of the complexity of the problem it would be unwise to attempt to comment on the interesting but unpublished information referred to in his letter 6-8 until all the data become available and one can make a critical assessment of the results. Although Dr. McLeod has not had an opportunity to see this letter I am sure he will agree with me when I say we are both eagerly awaiting these publications. M.R.C. Gastroenterology Research Central Middlesex Hospital, London, N.W.10.
Unit,
H. S. WIGGINS.
PROTEIN CONTAMINANTS IN BENZYLPENICILLIN SiR,ŅI have just read the article by Dr. Diirsch (May 11, p. 1005). I can stand only by my own experience with a fair sampling of commercial pencillins. My memory at this late date does not permit me to state dogmatically that they all contained penicilloyl protein, but certainly most of them did. In all fairness, I must state that Squibb penicillins were not among those which I tested. Commenting specifically on Dr. Diirsch’s techniques, I cannot understand the difficulties he encountered in the dialysis of penicillin solutions. Fairly straightforward dialysis techniques sufficed in the work I have reported, and in a paper9 two be published. I would suggest that Dr. Dursch re-examine his penicillins by the method of gel filtration, which is simple and effective for the unequivocal isolation of penicilloyl-protein complexes from penicillins. Alternatively the newer techniques of membrane ultrafiltration could be advantageously applied to the isolation of the penicilloyl
proteins.
J. G. FEINBERG.
PRE-ECLAMPTIC TOXAEMIA IN SMOKERS SIR,-In attributing differences in the prevalence of pretoxaemia in smokers and non-smokers to nicotine, the eclamptic " chief active constituent " in tobacco smoke, Dr. Duffus and Professor MacGillivray (May 11, p. 994) have overlooked the possible role of cyanide,11which is present in at least equimolecular concentrations. 10 Thiocyanate is the main detoxication product in vivo of heavy cyanide exposure,12 being present in higher concentrations in the body-fluids of smokers than of non-smokers. 113-115 Metabolic interrelations of cyanide and thiocyanate have been discussed at length elsewhere,is 1-5 16 mainly in relation to disorders 4. 5. 6. 7. 8. 9. 10.
11. 12. 13. 14.
15. 16.
Peart, W. S. Pharmac. Rev. 1965, 17, 143. Garbutt, J., Heaton, K. W., Lack, L., Tyor, M. P. Unpublished. Heaton, K. W., Lack, L., Tyor, M. P. Unpublished. Heaton, K. W., Austad, W. I., Lack, L., Tyor, M. P. Gastroenterology (in the press). Heaton, K. W., Austad, W. I., Lack, L., Tyor, M. P. ibid. 1967, 52, 1092 (abstract). Feinberg. J. G. Int. Archs. Allergy appl. Immun. (in the press). Surgeon-General (U.S.). Report on Smoking and Health. Public Health Service Publication no. 1103. U.S. Department of Health, Education and Welfare, 1964. Darby, P. W., Wilson, J. Br. J. Ophthal. 1967, 51, 336. Boxer, G. E., Rickards, J. C. Archs Biochem. 1952, 39, 7. Wilson, J. Clin. Sci. 1965, 29, 505. Matthews, D. M., Wilson, J., Zilkha, K. J. J. Neurol. Neurosurg. Psychiat. 1965, 28, 426. Wilson, J., Matthews, D. M. Clin. Sci. 1966, 31, 1. Wilson, J., Langman, M. J. S. Nature, Lond. 1966, 212, 787.
CHLOROQUINE IN PULMONARY SARCOIDOSIS SiR,ŅThe criteria for the diagnosis of sarcoidosis, have been often discussed. At practically every conference on sarcoidosis attempts have been made to define the disease. In the investigation carried out by the British Tuberculosis Association, and referred to by you (April 6, p. 736), reliable criteria seem to have been established. The xtiology of sarcoidosis is unknown; its clinical manifestations are of varied morphology but the majority fit into a clinical entity. In general sarcoid patients not only fail to react to tuberculin and other antigens evoking a delayed response, but they are also not readily sensitised by B.C.G. or by contact allergens. The results of twin and family studies indicate a genetic predisposition to the diesase which might support the growing concept of the disease as a granulomatous hyper-
sensitivity.! The effect of chloroquine is somewhat surprising, since in our investigation2 comprising fifteen patients with sarcoidosis of the skin of whom twelve had pulmonary involvement (criteria for diagnosis being those defined at the 3rd International Conference of Sarcoidosis), doubtful improvement was observed in two patients as assessed by radiological examination, while the remaining thirteen cases were unaffected. The duration of treatment was from 12 to 21 months (average 13-5 months) with an average total dose per patient of 311 g. hydroxychloroquine and a daily dose of 500-1000 mg. The lesions of the skin showed the same lack of response to this treatment. Reversible ocular complications were observed in
patients. We, too, have the impression that corticosteroids can suppress
ten
the lesions both in the skin and in other organs, but the only indication for prescribing them is progression of the pulmonary lesions. Careful observation of a group of untreated patients with sarcoidosis in order to follow the spontaneous course over several years would be extremely valuable. Department of Dermatology, Finsen Institute, Strandboulevarden 49, Copenhagen, Denmark.
HOLGER BRODTHAGEN.
ESTIMATING ENDOGENOUS RENIN SIR,-We write to report results similar to those of Dr. Haas and his colleagues (March 30, p. 657). In the course of work which led to a method for the assay of renin activity in plasma,3 we were unable to seperate renin from other plasma-proteins without large and variable loss: it was therefore proposed that the action of renin on the substrate already present in plasma should be measured. Having determined the Michaelis constant (Km) for this reaction it was intended that a correction should be applied from measurement of the substrate concentration in each plasma. However, it became apparent that the velocity of the reaction depended upon a factor other than total substrate concentration, possibly an activator or an inhibitor, possibly another form of substrate. For this reason the velocity of angiotensin formation was also measured when a known quantity of human renin (approximately 1 x 10-3 Goldblatt units [G.u.] per ml.) was allowed to react with each plasma. From this measurement, and from assay of angiotensin formed when plasma was incubated alone, the concentration of renin in a number of normal plasmas was calculated. In 28 plasmas the renin concentration ranged from 0· 10 x 10-4 to 1-20 x 10-4 (mean 0-49 x 10-4) G.u. per ml. (It is noted that Dr. Haas and his collegaues used serum: in our method plasma was used.) However, it remains to be determined whether a correction applied from measurement of the velocity of angiotensin formation after addition of a known quantity of renin (or from measurement of total substrate concentration) will add to the usefulness of 1. 2. 3.
Epstein, W. Progr. Allergy, 1967, 11, 51. Brodthagen, H., Gilg, I. 4th Int. Conf. Sarcoidosis, Paris, 1967. Pickens, P. T., Bumpus, F. M., Lloyd, A. M., Smeby, R. R., Page, I. H.: Circulation Res. 1965, 17, 438.
renin assay. The complexity of the reactions in which renin angiotensin are concerned has been compared to that of blood-clotting 4; and it is possible that, as in the latter process, a simple test depending on several factors (and therefore measuring no one factor accurately) may nevertheless be of value. P. T. PICKENS. Welsh National School of Medicine, Cardiff, Glam. F. M. BUMPUS. Cleveland Clinic, Cleveland, Ohio, U.S.A. a
and
BILE-SALTS AFTER ILEAL RESECTION SIR,-Iread Dr. Heaton’s letter last week (p. 1093) with interest. In view of the complexity of the problem it would be unwise to attempt to comment on the interesting but unpublished information referred to in his letter 6-8 until all the data become available and one can make a critical assessment of the results. Although Dr. McLeod has not had an opportunity to see this letter I am sure he will agree with me when I say we are both eagerly awaiting these publications. M.R.C. Gastroenterology Research Central Middlesex Hospital, London, N.W.10.
Unit,
H. S. WIGGINS.
PROTEIN CONTAMINANTS IN BENZYLPENICILLIN SiR,ŅI have just read the article by Dr. Diirsch (May 11, p. 1005). I can stand only by my own experience with a fair sampling of commercial pencillins. My memory at this late date does not permit me to state dogmatically that they all contained penicilloyl protein, but certainly most of them did. In all fairness, I must state that Squibb penicillins were not among those which I tested. Commenting specifically on Dr. Diirsch’s techniques, I cannot understand the difficulties he encountered in the dialysis of penicillin solutions. Fairly straightforward dialysis techniques sufficed in the work I have reported, and in a paper9 two be published. I would suggest that Dr. Dursch re-examine his penicillins by the method of gel filtration, which is simple and effective for the unequivocal isolation of penicilloyl-protein complexes from penicillins. Alternatively the newer techniques of membrane ultrafiltration could be advantageously applied to the isolation of the penicilloyl
proteins.
J. G. FEINBERG.
PRE-ECLAMPTIC TOXAEMIA IN SMOKERS SIR,-In attributing differences in the prevalence of pretoxaemia in smokers and non-smokers to nicotine, the eclamptic " chief active constituent " in tobacco smoke, Dr. Duffus and Professor MacGillivray (May 11, p. 994) have overlooked the possible role of cyanide,11which is present in at least equimolecular concentrations. 10 Thiocyanate is the main detoxication product in vivo of heavy cyanide exposure,12 being present in higher concentrations in the body-fluids of smokers than of non-smokers. 113-115 Metabolic interrelations of cyanide and thiocyanate have been discussed at length elsewhere,is 1-5 16 mainly in relation to disorders 4. 5. 6. 7. 8. 9. 10.
11. 12. 13. 14.
15. 16.
Peart, W. S. Pharmac. Rev. 1965, 17, 143. Garbutt, J., Heaton, K. W., Lack, L., Tyor, M. P. Unpublished. Heaton, K. W., Lack, L., Tyor, M. P. Unpublished. Heaton, K. W., Austad, W. I., Lack, L., Tyor, M. P. Gastroenterology (in the press). Heaton, K. W., Austad, W. I., Lack, L., Tyor, M. P. ibid. 1967, 52, 1092 (abstract). Feinberg. J. G. Int. Archs. Allergy appl. Immun. (in the press). Surgeon-General (U.S.). Report on Smoking and Health. Public Health Service Publication no. 1103. U.S. Department of Health, Education and Welfare, 1964. Darby, P. W., Wilson, J. Br. J. Ophthal. 1967, 51, 336. Boxer, G. E., Rickards, J. C. Archs Biochem. 1952, 39, 7. Wilson, J. Clin. Sci. 1965, 29, 505. Matthews, D. M., Wilson, J., Zilkha, K. J. J. Neurol. Neurosurg. Psychiat. 1965, 28, 426. Wilson, J., Matthews, D. M. Clin. Sci. 1966, 31, 1. Wilson, J., Langman, M. J. S. Nature, Lond. 1966, 212, 787.