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INDOMETHACIN IN CHOLERA DIARRHŒA
1024 INDOMETHACIN IN CHOLERA DIARRHŒA
SiR,—Dr Nalin (Sept. 11,
p. 576) reported that aspirin and in doses high enough to cause salicylate intoxication, did not alter cholera-induced secretion in anaesthetised dogs. He concluded that his protocol should be followed before clinical trials of other new anti-cholera drugs are carried out and that a clinical trial of salicylates in cholera is unwarranted. There is a serious flaw in Dr Nalin’s experiments. In 5 of the 8 dogs studied, water fluxes were measured 2 h after the jejunum was exposed to the enterotoxin. The post-salicylate flux measurements were made 5 or 7 h after toxin exposure. Studies by Carpenter et al.’ in the dog showed that the rate of fluid production from jejunal loops did not reach a peak until the 4th or 5th hour after toxin exposure. One might conclude that perhaps salicylates were effective in Dr Nalin’s studies in that they may actually have suppressed maximal secretion. We have no way of knowing, for no control studies are
sodium
salicylate,
reported. From our own studies2 and others3 4 we agree that salicylates are probably relatively ineffective in controlling choleratoxin-induced secretion. However, another anti-inflammatory compound, indomethacin, can significantly alter the secretory component as well as the motor component of cholera.5 We believe that a double-blind clinical trial is warranted. True, effective treatment is available in the form of sugar and salineb and tetracycline prophylaxis,7 but certain antiinflammatory drugs may provide a therapeutic advantage in large-scale epidemics, if proved effective.
possible. Cortical biopsy is a simple procedure carried ’J,: under local anaesthesia, and it could be done for early diagnoses and genetic counselling in subjects with a family histon j: Kufs’ disease.
is
Department of Neurosurgery, Mount Sinai School of Medicine, New York, N. Y. 10029, U S.A.
ROBERT A. BRODNER
JAE M. NOH
ANTENATAL DIAGNOSIS OF HURLER DISEASE
SiR,—The use of analysis of glycosaminoglycans in amnIOtic fluid for the antenatal diagnosis of mucopo!ysacchando& was questioned again recently when a normal result was obtained, at 16 weeks’ gestation, in a pregnancy ultimate shown to be affected by Hurler disease.’I We have successfully diagnosed Hurler disease at 14 and 16 weeks’ gestation in two successive pregnancies in the same family, using new microtechniques for the analysis of ammotic-fluid glycosaminoglycans. These methods, described elsewhere, involve isolation of glycosaminoglycans from amniotic fluid, separation by two-dimensional electrophoresis, and estimation of the individual glycosaminoglycan components.’-’ Besides chondroitin sulphate and hyaluronic acid, the components normally present, abnormal amounts of dermatan sulphate and heparan sulphate were demonstrated in the amniotic fluids from both suspect pregnancies (table). The twoGLYCOSAMINOGLYCAN CONTENT OF AMNIOTIC FLUID 11B TWO PREGNANCIES AFFECTED BY HURLER DISEASE
Divisions of
Gastroenterology, Departments of Medicine, Veterans Administration Hospital, and College of Medicine, University of Florida, Gainesville, Florida 32601, U.S.A. Departments of Pharmacology and Veterinary Medicine, College of Medicine, University of Florida
JOHN
R. MATHIAS
GERALD M. CARLSON
In control
tts/cs
EARLY DIAGNOSIS OF KUFS’ DISEASE
SIR,-We have recently studied a 24-year-old man with an occipital astrocytoma and a family history of a dominantly inherited form of Kufs’ disease, which has been documented by clinical, genetic, and pathomorphological criteria.8Kufs’ disease is an adult type of neuronal ceroid-lipofuscinosis and most commonly presents as dementia, cerebellar ataxia, involuntary movements, myoclonus, and seizures.8-lo Age of onset appears to be uniform within families, and in this man’s family it presents at age 31.8 In our patient, a cortical biopsy was performed at the time of occipital craniotomy for tumour removal, and a definitive diagnosis of Kufs’ disease was established some 7 yr before its expected clinical onset. This is the first reported demonstration that the histopathological changes indicative of Kufs’ disease occur before its clinical presentation and that early diagnosis Carpenter, C C. J, Sack, B. R, Feeley, J. C., Steenberg, R. W. J clin invest 1968, 47, 1210 2. Mathias, J. R., Carlson, G M, DiMarino, A. J., Bertiger, G, Cohen, S. in International Motility Symposium. Herentals, Belgium, 1976. 3 Jacoby, H. I., Marshall, C J. Nature, 1972, 235, 163. 4. Finck, A D., Katz, R. L. ibid. 1972, 238, 273 5 Mathias, J R., Carlson, G M, DiMarino, A. J, Bertiger, G, Morton, H. E, Cohen, S J clin. Invest. 1976, 58, 91. 6 Nalin, D R Trop geogr Med 1972, 24, 101. 7 McCormack, W M , Chowdhury, A. M., Jahanigir, N., Ahmed, A B. F., Mosley, W H Bull. Wld Hlth Org. 1968, 38, 787. 8 Boehme, D. H., Cottrell, J. C., Leonberg, S. C., Zeman, W Brain, 1971, 94, 1
745. 9.
10
Brodner, R. A., Noh, J. M., Fine, E. J. J. Neurol Neurosurg. Psychiat. 1976,
39, 231. Kufs, H. Z.
ges. Neurol.
Psychiat. 1929, 122,
395.
samples (12 SUbjecI>,
ratios were
14-16 weeks’ gestal1on)
DS was not
ddw,j "I
less than 0.1
GAG=Glycosammoglycan cs=Chondroitin sulphate HA=Hyaluromc acid Ds=Dermatan sulphate Hs=Heparan sulphate
dimensional electrophoretic patterns were similar to those obtained at 21 weeks’ gestation in a previously reported pregnancy affected by Hurler disease.2 By measuring the relate proportions of the individual glycosaminoglycans in amniotic fluid, abnormal components could be compared quantitativch with the chondroitin-sulphate component which acted asa convenient internal marker. Each pregnancy was terminate! 8 weeks after amniocentesis, after the diagnosis of Hurler disease had been confirmed by the demonstration of abnorma 35S-sulphate incorporation and an absence of o:-L-idurOOld3,e activity in cultured amniotic-fluid cells. Further con6rman was provided by the demonstration of an 18-20 fold increase in the glycosaminoglycan content of the liver of each abonw’ We strongly recommend that ammotic-fluid glycosaminogiscans be analysed in conjunction with studies on cultured amniotic-fluid cells, for the antenatal diagnosis of Hurler i’’ ease. Even in early pregnancy (e.g., 14 weeks’ gestation. r abnormal content of dermatan and heparan sulphates .r amniotic fluid would strongly suggest that the fetus Ila’ affected by mucopolysaccharidosis and would obviate the n to wait for the results of more time-consuming tests. Hovevr. we wonder whether some of the methods used for the apai%s, 1 2. 3.
Logan, R
W Br med. J. 1976, i, 711 Whiteman, P Lancet, 1973, i, 1249. Whiteman, P in Inborn Errors of Skin, Hair and Connective Tissue (edited by J Holton and J Ireland), p. 251 Lancaster, 1975 4. Newton, D J, Scott, J E., Whiteman, P. Analyt. Biochem 1974. 62, 268.
SiR,—Dr Nalin (Sept. 11,
p. 576) reported that aspirin and in doses high enough to cause salicylate intoxication, did not alter cholera-induced secretion in anaesthetised dogs. He concluded that his protocol should be followed before clinical trials of other new anti-cholera drugs are carried out and that a clinical trial of salicylates in cholera is unwarranted. There is a serious flaw in Dr Nalin’s experiments. In 5 of the 8 dogs studied, water fluxes were measured 2 h after the jejunum was exposed to the enterotoxin. The post-salicylate flux measurements were made 5 or 7 h after toxin exposure. Studies by Carpenter et al.’ in the dog showed that the rate of fluid production from jejunal loops did not reach a peak until the 4th or 5th hour after toxin exposure. One might conclude that perhaps salicylates were effective in Dr Nalin’s studies in that they may actually have suppressed maximal secretion. We have no way of knowing, for no control studies are
sodium
salicylate,
reported. From our own studies2 and others3 4 we agree that salicylates are probably relatively ineffective in controlling choleratoxin-induced secretion. However, another anti-inflammatory compound, indomethacin, can significantly alter the secretory component as well as the motor component of cholera.5 We believe that a double-blind clinical trial is warranted. True, effective treatment is available in the form of sugar and salineb and tetracycline prophylaxis,7 but certain antiinflammatory drugs may provide a therapeutic advantage in large-scale epidemics, if proved effective.
possible. Cortical biopsy is a simple procedure carried ’J,: under local anaesthesia, and it could be done for early diagnoses and genetic counselling in subjects with a family histon j: Kufs’ disease.
is
Department of Neurosurgery, Mount Sinai School of Medicine, New York, N. Y. 10029, U S.A.
ROBERT A. BRODNER
JAE M. NOH
ANTENATAL DIAGNOSIS OF HURLER DISEASE
SiR,—The use of analysis of glycosaminoglycans in amnIOtic fluid for the antenatal diagnosis of mucopo!ysacchando& was questioned again recently when a normal result was obtained, at 16 weeks’ gestation, in a pregnancy ultimate shown to be affected by Hurler disease.’I We have successfully diagnosed Hurler disease at 14 and 16 weeks’ gestation in two successive pregnancies in the same family, using new microtechniques for the analysis of ammotic-fluid glycosaminoglycans. These methods, described elsewhere, involve isolation of glycosaminoglycans from amniotic fluid, separation by two-dimensional electrophoresis, and estimation of the individual glycosaminoglycan components.’-’ Besides chondroitin sulphate and hyaluronic acid, the components normally present, abnormal amounts of dermatan sulphate and heparan sulphate were demonstrated in the amniotic fluids from both suspect pregnancies (table). The twoGLYCOSAMINOGLYCAN CONTENT OF AMNIOTIC FLUID 11B TWO PREGNANCIES AFFECTED BY HURLER DISEASE
Divisions of
Gastroenterology, Departments of Medicine, Veterans Administration Hospital, and College of Medicine, University of Florida, Gainesville, Florida 32601, U.S.A. Departments of Pharmacology and Veterinary Medicine, College of Medicine, University of Florida
JOHN
R. MATHIAS
GERALD M. CARLSON
In control
tts/cs
EARLY DIAGNOSIS OF KUFS’ DISEASE
SIR,-We have recently studied a 24-year-old man with an occipital astrocytoma and a family history of a dominantly inherited form of Kufs’ disease, which has been documented by clinical, genetic, and pathomorphological criteria.8Kufs’ disease is an adult type of neuronal ceroid-lipofuscinosis and most commonly presents as dementia, cerebellar ataxia, involuntary movements, myoclonus, and seizures.8-lo Age of onset appears to be uniform within families, and in this man’s family it presents at age 31.8 In our patient, a cortical biopsy was performed at the time of occipital craniotomy for tumour removal, and a definitive diagnosis of Kufs’ disease was established some 7 yr before its expected clinical onset. This is the first reported demonstration that the histopathological changes indicative of Kufs’ disease occur before its clinical presentation and that early diagnosis Carpenter, C C. J, Sack, B. R, Feeley, J. C., Steenberg, R. W. J clin invest 1968, 47, 1210 2. Mathias, J. R., Carlson, G M, DiMarino, A. J., Bertiger, G, Cohen, S. in International Motility Symposium. Herentals, Belgium, 1976. 3 Jacoby, H. I., Marshall, C J. Nature, 1972, 235, 163. 4. Finck, A D., Katz, R. L. ibid. 1972, 238, 273 5 Mathias, J R., Carlson, G M, DiMarino, A. J, Bertiger, G, Morton, H. E, Cohen, S J clin. Invest. 1976, 58, 91. 6 Nalin, D R Trop geogr Med 1972, 24, 101. 7 McCormack, W M , Chowdhury, A. M., Jahanigir, N., Ahmed, A B. F., Mosley, W H Bull. Wld Hlth Org. 1968, 38, 787. 8 Boehme, D. H., Cottrell, J. C., Leonberg, S. C., Zeman, W Brain, 1971, 94, 1
745. 9.
10
Brodner, R. A., Noh, J. M., Fine, E. J. J. Neurol Neurosurg. Psychiat. 1976,
39, 231. Kufs, H. Z.
ges. Neurol.
Psychiat. 1929, 122,
395.
samples (12 SUbjecI>,
ratios were
14-16 weeks’ gestal1on)
DS was not
ddw,j "I
less than 0.1
GAG=Glycosammoglycan cs=Chondroitin sulphate HA=Hyaluromc acid Ds=Dermatan sulphate Hs=Heparan sulphate
dimensional electrophoretic patterns were similar to those obtained at 21 weeks’ gestation in a previously reported pregnancy affected by Hurler disease.2 By measuring the relate proportions of the individual glycosaminoglycans in amniotic fluid, abnormal components could be compared quantitativch with the chondroitin-sulphate component which acted asa convenient internal marker. Each pregnancy was terminate! 8 weeks after amniocentesis, after the diagnosis of Hurler disease had been confirmed by the demonstration of abnorma 35S-sulphate incorporation and an absence of o:-L-idurOOld3,e activity in cultured amniotic-fluid cells. Further con6rman was provided by the demonstration of an 18-20 fold increase in the glycosaminoglycan content of the liver of each abonw’ We strongly recommend that ammotic-fluid glycosaminogiscans be analysed in conjunction with studies on cultured amniotic-fluid cells, for the antenatal diagnosis of Hurler i’’ ease. Even in early pregnancy (e.g., 14 weeks’ gestation. r abnormal content of dermatan and heparan sulphates .r amniotic fluid would strongly suggest that the fetus Ila’ affected by mucopolysaccharidosis and would obviate the n to wait for the results of more time-consuming tests. Hovevr. we wonder whether some of the methods used for the apai%s, 1 2. 3.
Logan, R
W Br med. J. 1976, i, 711 Whiteman, P Lancet, 1973, i, 1249. Whiteman, P in Inborn Errors of Skin, Hair and Connective Tissue (edited by J Holton and J Ireland), p. 251 Lancaster, 1975 4. Newton, D J, Scott, J E., Whiteman, P. Analyt. Biochem 1974. 62, 268.