276 suffered may be attributable to this drug. We report this case as an example of the toxic effects which have occurred with the use of continual modest dosage. The drug has been withdrawn for four months now, but there seems little change in either the ocular or cutaneous manifestations. Connaught Hospital,
R. K. MALLYA M. D. R. MORRIS.
Walthamstow, London E17 9LW.
add a further possible case of practolol-induced peritoneal disease to the three reported by Dr Brown and his colleagues (Dec. 21, p. 1477). A woman of 58 had a six months’ history of abdominal distension and an acute episode of pain and vomiting. A firm mass Barium meal showed was palpable in the lower abdomen. dilatation of the stomach and duodenal loop, possibly due to adhesion at the duodenojejunal flexure. The remaining loops of small bowel appeared adherent to each other. Lymphangiogram and intravenous pyelogram were normal. At laparotomy a sheet of thickened peritoneum covered all the viscera and pelvic brim. There were adhesions between loops of bowel, and the palpable mass was thought to have been due to dilated loops of large bowel. The appearances suggested a chronic peritonitis, possibly tuberculous. Biopsy of the peritoneum showed a mixed acute and chronic inflammatory cell infiltrate without evidence of tuberculosis, the appearances being similar to that in the second case reported by Dr Brown and his colleagues (fig. 4, p. 1479). Cultures of peritoneum and peritoneal
SIR,-We should like
to
fluid were negative. There was no history of abdominal disease or surgery. She had been taking practolol (200 mg. daily) for four years, in conjunction with digoxin and frusemide for poorly controlled atrial fibrillation and heart-failure due to mitral-valve disease. Of particular interest was the associated development of keratoconjunctivitis sicca, a psoriasiform rash,l.2and a positive anti-nuclear factor test2 (titre 1/20) while taking practolol. The presence of these previously documented adverse reactions lends further support to the postulated link between practolol and peritoneal disease. -
Medical Unit, London Hospital, Whitechapel, London E1 1BB.
M. MINTON A. NEWLAND G. KNOWLES A. TURNBULL.
GENE DOSAGE EFFECT IN TRISOMY 21 SIR,-We read with interest your editorial (Dec. 28, p. 1554) on trisomy 21. We do not agree that no gene has been assigned to chromosome 21 and that no correlation between gene dosage and the activity of gene products has been established. Tan et awl. demonstrated that antiviral protein gene and indophenol oxidase gene (superoxide dismutase) (EC. 1. 15.1.1.) were both sited on chromosome 21. We have demonstrated4 that superoxide-dismutase activity (S.O.D.A.) is increased in the erythrocytes of trisomic-21 children. Their S.O.D.A. is found to be 1-4 times higher than for normal children. We think this is the first demonstration of a gene dosage effect in a trisomic condition. Likewise, Tan et awl. reported that trisomic-21 fibroblasts are 3-7 times more sensitive to protection by human interferon than normal diploid cells. These observations open a new field for research. P.-M. SINET D. ALLARD Hôpital des Enfants Malades, 149 rue de Sèvres, Paris 15e.
J. LEJEUNE H. JEROME.
Downie, C. C. Letter from I.C.I. Felix, R. H., Ive, F. A., Dahl, M. G. C. Br. med. J. 1974, iv, 321. Tan, Y. H., Tischfield, J., Ruddle, F. M. J. exp. Med. 1973, 137, 317. 4. Sinet, P.-M., Allard, D., Lejeune, J., Jerome, H. C. r. Acad. Sci. Paris, 1974, 278, 3267. 5. Tan, Y. H., Schneider, E. L., Tischfield, J., Epstein, C. J., Ruddle, F. H. Science, 1974, 186, 61. 1. 2. 3.
PREDNISONE IN DUCHENNE MUSCULAR DYSTROPHY
SiR,—The history of Duchenne muscular dystrophy (D.M.D.) is replete with therapeutic claims, all of which on more careful clinical analysis have been invalidated. Each new report of benefit is followed by another wave of disillusion among the families of patients and by an unnecessary effort by the scientific community to correct the impressions conveyed by well-meaning investigators. This is not to suggest that we must be so critical as to delay the application of any truly effective treatment. However, when the same mistake is made repeatedly, it behoves subsequent investigators to insist on unequivocally meaningful and clear-cut evidence. We fear that the report on prednisone in D.M.D. by Professor Drachman and his co-workers (Dec. 14, p. 1409) will prove another source of disappointment. They seem In our opinion they unaware of previous relevant studies. have presented a poorly constructed clinical investigation and conclusions unjustified by the data. The fact that this study was carried out by a group of workers whose academic standing is deservedly high increases our concern. Scattered reports of the efficacy of steroids in D.M.D. began to appear in the 1950s, but Dowben1 was the first to claim significant benefit. He claimed that only 8% of 37 patients with various forms of progressive muscular dystrophy continued to deteriorate while taking the anabolic steroid, 1-methyl-delta-androstenolone, either alone or in combination with digitoxin. Within the next least five studies 2-6 demonstrated lack of benefit from anabolic steroids. Unreported trials by eight other centres treating about 300 patients with D.M.D. also failed to produce significant benefit.44 Siegel et al.,7 in a three-year, well-controlled, double-blind trial failed to demonstrate significant improvement with prednisolone.
two years,
however,
at
.
’
We agree that neuromuscular
dysfunction, especially in evaluate. Nonetheless this should not preclude efforts to standardise and measure as many indices of weakness as possible. Such an attempt was made in three of the studies 2,6,7 with considerable Until we have a reliable success, even in children. biochemical indicator of worsening or improvement, it will be necessary to improve available quantitative techniques. Certainly parents’ assessments and measurements of strength by crude clinical ratings are not indicators of any statistical reliability. We have all seen apparent improvement in D.M.D. treated with prednisone when a diagnosis of children, is difficult
to strenuous
polymyositis had mistakenly been made; and, especially between the ages of 5 and 7 years, untreated patients may seemingly improve spontaneously as the processes of normal growth and development temporarily outstrip deterioration due to the disease process. The reasons given by the authors for the omission of any control cannot be accepted. Controls are even more mandatory when studying the effects of a drug such as prednisone which has prominentside-effects such as euphoria and sense of well-being. We agree that a reliable double-blind study with this drug is made difficult by its
recognisable side-effects. Nonetheless, by using a singledose alternate-day schedule (as was eventually done) these At the very least, clinical assessments can be minimised. 1. Dowben, R. M. New Engl. J. Med. 1963, 268, 912. 2. Barwick, D. D., Walton, J. N., Newell, D. J. Neurology, 1963, 13, 12. 3. Gamstorp, I. Acta pœdiat. scand. 1964, 53, 570. 4. Charash, L. Pediatrics, 1965, 36, 402. 5. Heyck, H., Laudahn, G., Leiders, C. J., Müller-Stephann, H., Schmidt-Peter, P. Acta pœdiat. scand. 1965, 54, 205. 6. Fowler, W. M., Pearson, C. M., Egstrom, G. H., Gardner, G. W. New Engl. J. Med. 1965, 272, 875. 7. Siegel, I. M., Miller, J. E., Ray, R. D. Illinois med. J. 1974, 145, 32.
R. K. MALLYA M. D. R. MORRIS.
Walthamstow, London E17 9LW.
add a further possible case of practolol-induced peritoneal disease to the three reported by Dr Brown and his colleagues (Dec. 21, p. 1477). A woman of 58 had a six months’ history of abdominal distension and an acute episode of pain and vomiting. A firm mass Barium meal showed was palpable in the lower abdomen. dilatation of the stomach and duodenal loop, possibly due to adhesion at the duodenojejunal flexure. The remaining loops of small bowel appeared adherent to each other. Lymphangiogram and intravenous pyelogram were normal. At laparotomy a sheet of thickened peritoneum covered all the viscera and pelvic brim. There were adhesions between loops of bowel, and the palpable mass was thought to have been due to dilated loops of large bowel. The appearances suggested a chronic peritonitis, possibly tuberculous. Biopsy of the peritoneum showed a mixed acute and chronic inflammatory cell infiltrate without evidence of tuberculosis, the appearances being similar to that in the second case reported by Dr Brown and his colleagues (fig. 4, p. 1479). Cultures of peritoneum and peritoneal
SIR,-We should like
to
fluid were negative. There was no history of abdominal disease or surgery. She had been taking practolol (200 mg. daily) for four years, in conjunction with digoxin and frusemide for poorly controlled atrial fibrillation and heart-failure due to mitral-valve disease. Of particular interest was the associated development of keratoconjunctivitis sicca, a psoriasiform rash,l.2and a positive anti-nuclear factor test2 (titre 1/20) while taking practolol. The presence of these previously documented adverse reactions lends further support to the postulated link between practolol and peritoneal disease. -
Medical Unit, London Hospital, Whitechapel, London E1 1BB.
M. MINTON A. NEWLAND G. KNOWLES A. TURNBULL.
GENE DOSAGE EFFECT IN TRISOMY 21 SIR,-We read with interest your editorial (Dec. 28, p. 1554) on trisomy 21. We do not agree that no gene has been assigned to chromosome 21 and that no correlation between gene dosage and the activity of gene products has been established. Tan et awl. demonstrated that antiviral protein gene and indophenol oxidase gene (superoxide dismutase) (EC. 1. 15.1.1.) were both sited on chromosome 21. We have demonstrated4 that superoxide-dismutase activity (S.O.D.A.) is increased in the erythrocytes of trisomic-21 children. Their S.O.D.A. is found to be 1-4 times higher than for normal children. We think this is the first demonstration of a gene dosage effect in a trisomic condition. Likewise, Tan et awl. reported that trisomic-21 fibroblasts are 3-7 times more sensitive to protection by human interferon than normal diploid cells. These observations open a new field for research. P.-M. SINET D. ALLARD Hôpital des Enfants Malades, 149 rue de Sèvres, Paris 15e.
J. LEJEUNE H. JEROME.
Downie, C. C. Letter from I.C.I. Felix, R. H., Ive, F. A., Dahl, M. G. C. Br. med. J. 1974, iv, 321. Tan, Y. H., Tischfield, J., Ruddle, F. M. J. exp. Med. 1973, 137, 317. 4. Sinet, P.-M., Allard, D., Lejeune, J., Jerome, H. C. r. Acad. Sci. Paris, 1974, 278, 3267. 5. Tan, Y. H., Schneider, E. L., Tischfield, J., Epstein, C. J., Ruddle, F. H. Science, 1974, 186, 61. 1. 2. 3.
PREDNISONE IN DUCHENNE MUSCULAR DYSTROPHY
SiR,—The history of Duchenne muscular dystrophy (D.M.D.) is replete with therapeutic claims, all of which on more careful clinical analysis have been invalidated. Each new report of benefit is followed by another wave of disillusion among the families of patients and by an unnecessary effort by the scientific community to correct the impressions conveyed by well-meaning investigators. This is not to suggest that we must be so critical as to delay the application of any truly effective treatment. However, when the same mistake is made repeatedly, it behoves subsequent investigators to insist on unequivocally meaningful and clear-cut evidence. We fear that the report on prednisone in D.M.D. by Professor Drachman and his co-workers (Dec. 14, p. 1409) will prove another source of disappointment. They seem In our opinion they unaware of previous relevant studies. have presented a poorly constructed clinical investigation and conclusions unjustified by the data. The fact that this study was carried out by a group of workers whose academic standing is deservedly high increases our concern. Scattered reports of the efficacy of steroids in D.M.D. began to appear in the 1950s, but Dowben1 was the first to claim significant benefit. He claimed that only 8% of 37 patients with various forms of progressive muscular dystrophy continued to deteriorate while taking the anabolic steroid, 1-methyl-delta-androstenolone, either alone or in combination with digitoxin. Within the next least five studies 2-6 demonstrated lack of benefit from anabolic steroids. Unreported trials by eight other centres treating about 300 patients with D.M.D. also failed to produce significant benefit.44 Siegel et al.,7 in a three-year, well-controlled, double-blind trial failed to demonstrate significant improvement with prednisolone.
two years,
however,
at
.
’
We agree that neuromuscular
dysfunction, especially in evaluate. Nonetheless this should not preclude efforts to standardise and measure as many indices of weakness as possible. Such an attempt was made in three of the studies 2,6,7 with considerable Until we have a reliable success, even in children. biochemical indicator of worsening or improvement, it will be necessary to improve available quantitative techniques. Certainly parents’ assessments and measurements of strength by crude clinical ratings are not indicators of any statistical reliability. We have all seen apparent improvement in D.M.D. treated with prednisone when a diagnosis of children, is difficult
to strenuous
polymyositis had mistakenly been made; and, especially between the ages of 5 and 7 years, untreated patients may seemingly improve spontaneously as the processes of normal growth and development temporarily outstrip deterioration due to the disease process. The reasons given by the authors for the omission of any control cannot be accepted. Controls are even more mandatory when studying the effects of a drug such as prednisone which has prominentside-effects such as euphoria and sense of well-being. We agree that a reliable double-blind study with this drug is made difficult by its
recognisable side-effects. Nonetheless, by using a singledose alternate-day schedule (as was eventually done) these At the very least, clinical assessments can be minimised. 1. Dowben, R. M. New Engl. J. Med. 1963, 268, 912. 2. Barwick, D. D., Walton, J. N., Newell, D. J. Neurology, 1963, 13, 12. 3. Gamstorp, I. Acta pœdiat. scand. 1964, 53, 570. 4. Charash, L. Pediatrics, 1965, 36, 402. 5. Heyck, H., Laudahn, G., Leiders, C. J., Müller-Stephann, H., Schmidt-Peter, P. Acta pœdiat. scand. 1965, 54, 205. 6. Fowler, W. M., Pearson, C. M., Egstrom, G. H., Gardner, G. W. New Engl. J. Med. 1965, 272, 875. 7. Siegel, I. M., Miller, J. E., Ray, R. D. Illinois med. J. 1974, 145, 32.
