- Email: [email protected]
CHLOROMYCETIN: MEDICAL IMPERIALISM
414
Ruddle,l in his experiments on inducing somatic-cell mutations of pig kidney cells in vitro, found a clone with The behaviour of the an abnormally long chromosome. cells of that clone was very similar to the breast-carcinoma cells obtained from fresh pleural fluid reported here. Atkin and Brand-ao2 found in histological sections a similar situation in a carcinoma-in-situ of the cervix uteri. Attempts to establish long-term cell-lines and detailed analysis of the chromosome constitution of this neoplasm are in progress. This investigation was supported in part by Research Contract N01 CB-23869 from the National Institutes of Health, and Research Grant VC-21C from the American Cancer Society. Fig. 1-Metaphase from pleural effusion from
a
patient with
Departments of Biology and Medicine, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute,
adenocarcinoma of the breast.
Arrows indicate two extraordinarily long chromosomes. The normal chromosome no. 1 is indicated for comparison.
Houston, Texas 77025, U.S.A.
T. C. Hsu SEN PATHAK RELDA CAILLEAU SALLY R. COWLES.
KWASHIORKOR AND TUBERCULOSIS
Fig. 2—Anaphase of
a tumour cell, showing division of a long chromosome whose centromeres reach the poles but whose free ends remain near the equator.
This photograph was taken from colcemid pretreatment.
a
preparation without
SIR,;-Dr Pearson (July 6, p. 47) highlights the difficulties in diagnosing tuberculosis in children with severe mal. nutrition when the tuberculin test is negative. A useful clinical sign, noted while I was working in Sierra Leom in the 1960s, was the accelerated B.C.G. response. In a non. infected child the reaction to intradermal B.C.G. given b3 syringe does not begin until at least 2 weeks, and usua1IJ longer, after inoculation. Where tuberculous infectior exists, the B.c.G. reaction is accelerated, and the nodule anc slight pinkness in the skin become gradually more obvious from about the fifth day onwards. This seemed a reliable sign in the presence of severe malnutrition, even in children who were almost moribund. A therapeutic trial with antituberculous drugs can begin as soon as the diagnosis is suspected and apparently does not interfere with the development of the B.C.G. reaction. It was also found in a few cases that the Mantoux 1/1000 (10 tuberculin units of old tuberculin or purified protein derivative) given into the forearm skin might remain negative for several weeks, but as the child improved, pinkness and a weal developed 4 or 5 weeks after the intradermal injection. This was an unexpected observation, and Dr Pearson and others may be more familiar with it. Department of Child Health,
University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP. Fig. 3-Interphase
chromosomes seemed
definitely heteroploid,
to be beaded. The cells were but the stemline number was not
determined because there were insufficient metaphase spreads. In most metaphsses there was either 1 or 2 very long subtelocentric marker chromosomes (fig. 1). The marker
chromosome(s) apparently divided normally during anaphase, but, because of their extraordinary length their free ends remained near the equator, whereas the centromeres reached the poles (fig. 2). The free ends thus became projections of the daughter nuclei when interphase ensued (fig. 3). A large number of interphase nuclei of this sample showed one or more projections. A random reading of 181 nuclei showed the distribution as follows.
The percentage of nuclei with
55-8%.
CHRISTINE E. COOPER.
nuclei showing nuclear projections.
projections
was
thus
CHLOROMYCETIN: MEDICAL IMPERIALISM SIR,-Dr Walsh (Aug. 3, p. 282) takes Dr Schrier and Mr Berger3 to task for suggesting that Parke-Davis ignores the basic precepts of good medical practice and by economic power forces upon the underdeveloped countries unacceptable medical standards. He also states that ParkeDavis labelling for ’Chloromycetin ’ is " standardised worldwide and contains indications and warnings compatible with good standards of medical practice ". Several years ago, while visiting an old colleague of mine in a well-known medical institution in Calcutta, I came across a medical representative from Parke-Davis. He was discussing with my friend the various usages of chloromycetin and happened to mention urinary-tract infection as 1. 2.
3.
Ruddle, F. H. J. natn. Cancer Inst. 1962, 28, 1247. Atkin, N. B., Brandāo, H. J. S. J. Obstet. Gynæc. Br. Commonw. 1968, 75, 211. Schrier, H. A., Berger, L. Lancet, 1974, i, 1161.
415 of the indications. When I pointed out to him the various reasons why the drug would in fact be a very bad choice in treating such a condition, the man politely produced a chloromycetin data-sheet,’’ and I was amazed to note the mention of urinary-tract infection quite high up in the list of indications. I remember commenting to my friend that Parke-Davis would not dream of producing such literature for promotional purposes in Britain, and it was clear to me that the company was pursuing a different set of standards in countries such as India and was taking advantage of the complete lack of any continuing postgraduate educational system for general practitioners in that part of the world. Is this an example of sound medical practice, or medical
one
imperialism ? Department of Infectious Diseases, Monsall Hospital, Manchester, and Department of Community Medicine, University of Manchester.
B. K. MANDAL.
THYROTROPHIN-RELEASING HORMONE IN DEPRESSION SIR,-We were interested by Dr Hutton’s findings and the points he raised (July 6, p. 53) concerning our trial.1 The trial we reported was concerned with the efficacy of thyrotrophin-releasing hormone (T.R.H.) in the treatment of depressed outpatients, and the biochemical investigations were directed towards ensuring that the prolonged administration of T.R.H. was not inducing hyperthyroidism. We did not undertake T.R.H. tests in these patients because we were conducting a separate metabolic study in another group of untreated depressed outpatients (to be published). Since our biochemical tests were carried out at fortnightly intervals, we would not expect to detect the short-term changes referred to by Dr Hutton because of feedback mechanisms. The results of our metabolic paper show no evidence of an abnormality in the response to T.R.H. of depressed outpatients with illness similar to that of our published group. The paper from Kastin’s groupwhich showed T.R.H. to be ineffective in the treatment of depression also demonstrated that three out of eight severely depressed patients had diminished responses to T.R.H., and they suggest that the diminished response may have diagnostic implications. However, the patients we reported were not suffering from the same type of depression. Dr Hutton raises the question of dosage. The use of T.R.H. in the treatment of depression is limited by the danger of inducing hyperthyroidism. Two doses of 80 mg. T.R.H. daily can cause a significant increase in circulating thyroidhormone levels, and five doses of 80 mg. produce clinical hyperthyroidism in healthy volunteers. We agree that there is a possibility of response to a higher dosage, but the dosage required would approximate to or exceed that at which hyperthyroidism is induced. We agree with Dr Hutton in not wishing to discard an endocrinological approach to depression or indeed to psychiatry as a whole. Our negative result merely shows that T.R.H. was ineffective under the conditions of the trial. It certainly does not imply that an endocrinological approach should be discarded. Psychiatry has seen many new treatments introduced with an enthusiasm which later proved unwarranted. It is because the endocrinological approach is so important that its hypotheses should be thoroughly evaluated and then modified in the face of observation. It seems that earlier reports on the antidepressant effect of T.R.H. were overoptimistic and that hypotheses about its action have to be revised. 1 2.
Mountjoy, C. Q., Price, J. S., Weller, M., Hunter, P., Hall, R., Dewar, J. H. Lancet, 1974, i, 958. Ehrensing, R. H., Kastin, A. J., Schalch, D. S., Friesen, H. G., Varragas, J. R., Schally, A. V. Am. J. Psychiat. 1974, 131, 714.
We wonder whether Dr Hutton’s own results might be assays being performed in different
explained by his batches.
Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP.
C. Q. MOUNTJOY R. HALL.
CRYPTORCHIDISM SIR,—Dr Pardo-Mindan, in his interesting comment1 on our paper 2 believes that bilateral biopsy is essential to - establish conclusions in the study of maldescended testes. His belief is based on a study of thirty-two cases of unilateral cryptorchidism which involved a biopsy of normal scrotal testes in twenty-four cases. He disagrees with our conclusions on the grounds that our biopsies were confined to maldescended testes and that we therefore failed to distinguish the " dysgenetic testes ". Eight of his cases had dysgenetic testes where " the histological picture was exactly the same in both testes, with an index of fertility and a number of spermatogonial cells which varied without relation to age or position of the testes." If these testes contained spermatogonia and half of them descended normally to the scrotum it is not clear in what way they were dysgenetic nor what part the " dysgenesis " plays in maldescent. The age at which orchidopexy should be performed for maldescent of the testes is controversial, and the aim of our investigation was to study the spermatogenic potential of maldescended testes at various ages. We believe that histological examination of the maldescended testis at the time of orchidopexy yields useful information on this problem and gives some indication of the likely outcome of the operation without recourse to biopsy of normal scrotal
glands. for Sick Children, Glasgow. Department of Pathology, Western General Hospital,
Royal Hospital
Edinburgh. Professorial Surgical Unit, Hospital for Sick Children, London.
A. J. DOUGALL. N. MACLEAN. A. W. WILKINSON.
HÆMAGGLUTINATION-INHIBITION SLIDE TEST FOR HEPATITIS-B ANTIGEN SIR,-We read with interest the paper of Mr Cayzer and his colleagues,3 describing a rapid hasmagglutination test for the detection of hepatitis-B antigen (HBAg). of Several reports have appeared on the reversed passive hsmagglutination and haEmagglutinationinhibition tests.4-7 However, the published procedures are laborious and time-consuming. In our passive haemagmethod, both formalinised human glutination-inhibition " 0 " and sheep erythrocytes have been coated with HBAg after tannin treatment. Purified HBAg has been prepared by gel filtration after pepsin treatment. Both human and animal anti-HBAg antisera may. be used in the test. For detecting HBAg on a slide, one drop of diluted antiserum is mixed with one drop of undiluted test serum. One drop of sensitised cell suspension is then added. After 5 minutes agglutination indicates that no antigen is present.
application
Pardo-Mindan, F. J. Lancet, 1974, i, 1345. Dougall, A. J., Maclean, N., Wilkinson, A.W. ibid. p. 771. Cayzer, I., Dane, D. S., Cameron, C. H., Denning, J. V. Lancet, 1974, i, 947. 4. Vyas, G. N., Shulman, N. R. Science, 1970, 170, 332. 5. Mayumi, M., Okochi, K., Nishioka, K. Vox. sang. 1971, 20, 178. 6. Reesink, H. W., Duimel, W. J. M., Brummelhuis, H. G. J. ibid. 1973, 24, 528. 7. Hopkins, R., Das, P. C. Br. J. Hæmat. 1973, 25, 619. 8. Halmosdi, G., Perkedi, J., Valló, D. Kisérl. Orvostud. (in the press). 1. 2. 3.
Ruddle,l in his experiments on inducing somatic-cell mutations of pig kidney cells in vitro, found a clone with The behaviour of the an abnormally long chromosome. cells of that clone was very similar to the breast-carcinoma cells obtained from fresh pleural fluid reported here. Atkin and Brand-ao2 found in histological sections a similar situation in a carcinoma-in-situ of the cervix uteri. Attempts to establish long-term cell-lines and detailed analysis of the chromosome constitution of this neoplasm are in progress. This investigation was supported in part by Research Contract N01 CB-23869 from the National Institutes of Health, and Research Grant VC-21C from the American Cancer Society. Fig. 1-Metaphase from pleural effusion from
a
patient with
Departments of Biology and Medicine, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute,
adenocarcinoma of the breast.
Arrows indicate two extraordinarily long chromosomes. The normal chromosome no. 1 is indicated for comparison.
Houston, Texas 77025, U.S.A.
T. C. Hsu SEN PATHAK RELDA CAILLEAU SALLY R. COWLES.
KWASHIORKOR AND TUBERCULOSIS
Fig. 2—Anaphase of
a tumour cell, showing division of a long chromosome whose centromeres reach the poles but whose free ends remain near the equator.
This photograph was taken from colcemid pretreatment.
a
preparation without
SIR,;-Dr Pearson (July 6, p. 47) highlights the difficulties in diagnosing tuberculosis in children with severe mal. nutrition when the tuberculin test is negative. A useful clinical sign, noted while I was working in Sierra Leom in the 1960s, was the accelerated B.C.G. response. In a non. infected child the reaction to intradermal B.C.G. given b3 syringe does not begin until at least 2 weeks, and usua1IJ longer, after inoculation. Where tuberculous infectior exists, the B.c.G. reaction is accelerated, and the nodule anc slight pinkness in the skin become gradually more obvious from about the fifth day onwards. This seemed a reliable sign in the presence of severe malnutrition, even in children who were almost moribund. A therapeutic trial with antituberculous drugs can begin as soon as the diagnosis is suspected and apparently does not interfere with the development of the B.C.G. reaction. It was also found in a few cases that the Mantoux 1/1000 (10 tuberculin units of old tuberculin or purified protein derivative) given into the forearm skin might remain negative for several weeks, but as the child improved, pinkness and a weal developed 4 or 5 weeks after the intradermal injection. This was an unexpected observation, and Dr Pearson and others may be more familiar with it. Department of Child Health,
University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP. Fig. 3-Interphase
chromosomes seemed
definitely heteroploid,
to be beaded. The cells were but the stemline number was not
determined because there were insufficient metaphase spreads. In most metaphsses there was either 1 or 2 very long subtelocentric marker chromosomes (fig. 1). The marker
chromosome(s) apparently divided normally during anaphase, but, because of their extraordinary length their free ends remained near the equator, whereas the centromeres reached the poles (fig. 2). The free ends thus became projections of the daughter nuclei when interphase ensued (fig. 3). A large number of interphase nuclei of this sample showed one or more projections. A random reading of 181 nuclei showed the distribution as follows.
The percentage of nuclei with
55-8%.
CHRISTINE E. COOPER.
nuclei showing nuclear projections.
projections
was
thus
CHLOROMYCETIN: MEDICAL IMPERIALISM SIR,-Dr Walsh (Aug. 3, p. 282) takes Dr Schrier and Mr Berger3 to task for suggesting that Parke-Davis ignores the basic precepts of good medical practice and by economic power forces upon the underdeveloped countries unacceptable medical standards. He also states that ParkeDavis labelling for ’Chloromycetin ’ is " standardised worldwide and contains indications and warnings compatible with good standards of medical practice ". Several years ago, while visiting an old colleague of mine in a well-known medical institution in Calcutta, I came across a medical representative from Parke-Davis. He was discussing with my friend the various usages of chloromycetin and happened to mention urinary-tract infection as 1. 2.
3.
Ruddle, F. H. J. natn. Cancer Inst. 1962, 28, 1247. Atkin, N. B., Brandāo, H. J. S. J. Obstet. Gynæc. Br. Commonw. 1968, 75, 211. Schrier, H. A., Berger, L. Lancet, 1974, i, 1161.
415 of the indications. When I pointed out to him the various reasons why the drug would in fact be a very bad choice in treating such a condition, the man politely produced a chloromycetin data-sheet,’’ and I was amazed to note the mention of urinary-tract infection quite high up in the list of indications. I remember commenting to my friend that Parke-Davis would not dream of producing such literature for promotional purposes in Britain, and it was clear to me that the company was pursuing a different set of standards in countries such as India and was taking advantage of the complete lack of any continuing postgraduate educational system for general practitioners in that part of the world. Is this an example of sound medical practice, or medical
one
imperialism ? Department of Infectious Diseases, Monsall Hospital, Manchester, and Department of Community Medicine, University of Manchester.
B. K. MANDAL.
THYROTROPHIN-RELEASING HORMONE IN DEPRESSION SIR,-We were interested by Dr Hutton’s findings and the points he raised (July 6, p. 53) concerning our trial.1 The trial we reported was concerned with the efficacy of thyrotrophin-releasing hormone (T.R.H.) in the treatment of depressed outpatients, and the biochemical investigations were directed towards ensuring that the prolonged administration of T.R.H. was not inducing hyperthyroidism. We did not undertake T.R.H. tests in these patients because we were conducting a separate metabolic study in another group of untreated depressed outpatients (to be published). Since our biochemical tests were carried out at fortnightly intervals, we would not expect to detect the short-term changes referred to by Dr Hutton because of feedback mechanisms. The results of our metabolic paper show no evidence of an abnormality in the response to T.R.H. of depressed outpatients with illness similar to that of our published group. The paper from Kastin’s groupwhich showed T.R.H. to be ineffective in the treatment of depression also demonstrated that three out of eight severely depressed patients had diminished responses to T.R.H., and they suggest that the diminished response may have diagnostic implications. However, the patients we reported were not suffering from the same type of depression. Dr Hutton raises the question of dosage. The use of T.R.H. in the treatment of depression is limited by the danger of inducing hyperthyroidism. Two doses of 80 mg. T.R.H. daily can cause a significant increase in circulating thyroidhormone levels, and five doses of 80 mg. produce clinical hyperthyroidism in healthy volunteers. We agree that there is a possibility of response to a higher dosage, but the dosage required would approximate to or exceed that at which hyperthyroidism is induced. We agree with Dr Hutton in not wishing to discard an endocrinological approach to depression or indeed to psychiatry as a whole. Our negative result merely shows that T.R.H. was ineffective under the conditions of the trial. It certainly does not imply that an endocrinological approach should be discarded. Psychiatry has seen many new treatments introduced with an enthusiasm which later proved unwarranted. It is because the endocrinological approach is so important that its hypotheses should be thoroughly evaluated and then modified in the face of observation. It seems that earlier reports on the antidepressant effect of T.R.H. were overoptimistic and that hypotheses about its action have to be revised. 1 2.
Mountjoy, C. Q., Price, J. S., Weller, M., Hunter, P., Hall, R., Dewar, J. H. Lancet, 1974, i, 958. Ehrensing, R. H., Kastin, A. J., Schalch, D. S., Friesen, H. G., Varragas, J. R., Schally, A. V. Am. J. Psychiat. 1974, 131, 714.
We wonder whether Dr Hutton’s own results might be assays being performed in different
explained by his batches.
Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP.
C. Q. MOUNTJOY R. HALL.
CRYPTORCHIDISM SIR,—Dr Pardo-Mindan, in his interesting comment1 on our paper 2 believes that bilateral biopsy is essential to - establish conclusions in the study of maldescended testes. His belief is based on a study of thirty-two cases of unilateral cryptorchidism which involved a biopsy of normal scrotal testes in twenty-four cases. He disagrees with our conclusions on the grounds that our biopsies were confined to maldescended testes and that we therefore failed to distinguish the " dysgenetic testes ". Eight of his cases had dysgenetic testes where " the histological picture was exactly the same in both testes, with an index of fertility and a number of spermatogonial cells which varied without relation to age or position of the testes." If these testes contained spermatogonia and half of them descended normally to the scrotum it is not clear in what way they were dysgenetic nor what part the " dysgenesis " plays in maldescent. The age at which orchidopexy should be performed for maldescent of the testes is controversial, and the aim of our investigation was to study the spermatogenic potential of maldescended testes at various ages. We believe that histological examination of the maldescended testis at the time of orchidopexy yields useful information on this problem and gives some indication of the likely outcome of the operation without recourse to biopsy of normal scrotal
glands. for Sick Children, Glasgow. Department of Pathology, Western General Hospital,
Royal Hospital
Edinburgh. Professorial Surgical Unit, Hospital for Sick Children, London.
A. J. DOUGALL. N. MACLEAN. A. W. WILKINSON.
HÆMAGGLUTINATION-INHIBITION SLIDE TEST FOR HEPATITIS-B ANTIGEN SIR,-We read with interest the paper of Mr Cayzer and his colleagues,3 describing a rapid hasmagglutination test for the detection of hepatitis-B antigen (HBAg). of Several reports have appeared on the reversed passive hsmagglutination and haEmagglutinationinhibition tests.4-7 However, the published procedures are laborious and time-consuming. In our passive haemagmethod, both formalinised human glutination-inhibition " 0 " and sheep erythrocytes have been coated with HBAg after tannin treatment. Purified HBAg has been prepared by gel filtration after pepsin treatment. Both human and animal anti-HBAg antisera may. be used in the test. For detecting HBAg on a slide, one drop of diluted antiserum is mixed with one drop of undiluted test serum. One drop of sensitised cell suspension is then added. After 5 minutes agglutination indicates that no antigen is present.
application
Pardo-Mindan, F. J. Lancet, 1974, i, 1345. Dougall, A. J., Maclean, N., Wilkinson, A.W. ibid. p. 771. Cayzer, I., Dane, D. S., Cameron, C. H., Denning, J. V. Lancet, 1974, i, 947. 4. Vyas, G. N., Shulman, N. R. Science, 1970, 170, 332. 5. Mayumi, M., Okochi, K., Nishioka, K. Vox. sang. 1971, 20, 178. 6. Reesink, H. W., Duimel, W. J. M., Brummelhuis, H. G. J. ibid. 1973, 24, 528. 7. Hopkins, R., Das, P. C. Br. J. Hæmat. 1973, 25, 619. 8. Halmosdi, G., Perkedi, J., Valló, D. Kisérl. Orvostud. (in the press). 1. 2. 3.