- Email: [email protected]
IPRATROPIUM BROMIDE NEBULISER THERAPY AND AIRWAY SUBMUCOSAL GLAND SECRETION
823
higher in calorie density with no osmotic penalty. With only slight changes (i.e., deletion of salt(s) and addition of some source of protein, adapted for local preferences) enhanced nutrition after and
RETINOBLASTOMA AND ESTERASE D
SIR,-Professor Howard’s hypothesis (Aug. 28, esterase
D is identical with
one
p.
490)
retinoblastoma locus
that
neglects
diarrhoea can be achieved. In this way a combined approach to the two main killers of children during and after diarrhoea may be addressed now with materials available in every home. The need noted by Rohde and Northrup 1 for fluid and electrolyte malnutrition and protein energy malnutrition to be managed together, can now be met. A further dividend of cereals, including rice, is release of glucose, peptides, and aminoacids in the upper intestine, adding more effective carrier molecules for sodium transport and consequent water absorption at the appropriate site.
several points. Review of the forty or so published cases with constitutional deletions involving the long arm of chromosome 13 in association with retinoblastoma reveals the sub-band 13q 14 to be the minimum deleted segment common to all, as noted by Yunis et al.and Sparkes et a1.2 If the putative 50 000 structural genes of man3are evenly distributed throughout the genome, a deletion of a single sub-band may involve more than 100 structural genes plus many more DNA sequences which may have regulatory or control function.4 It seems more likely that the esterase D locus provides a useful screening marker for children presenting with retinoblastoma2 rather than necessarily being aetiologically related. Nevertheless, although normal esterase D levels are found in people with non-deletion (sporadic and single gene) retinoblastoma and family studies have not demonstrated linkage of the single gene cases with either the esterase D polymorphism or cytogenetic markers on chromosome 13,6the reports of abnormalities (albeit not invariably present) of chromosome 13 in the retinoblastomas from persons with normal constitutional karyotypes7,8 suggests that DNA sequences (gene(s)) in the sub-band 13ql4 may be involved in all forms of retinoblastoma.
International Centre for Diarrhoeal
IPRATROPIUM BROMIDE NEBULISER THERAPY AND AIRWAY SUBMUCOSAL GLAND SECRETION
SiR,—Crompton is worried that increased sputum viscosity may result from long-term use of the antimuscarinic agent ipratropium bromide (’Atrovent’) taken by inhalation for relief of asthmatic bronchospasm. The source of his concern is the fact that anticholinergic drugs cause a sensation of a dry mouth in some
’
Molecular Biology, Medical Research Council Centre, University Medical School,
Laboratory of
patients.
CEREAL-BASED ORAL REHYDRATION SOLUTIONS
SiR,-The comments of Dr Nalin and Dr Cash (July 17, p. 155) raise the issue of whether the higher sodium concentration (120 mmol/1) used in early studies on oral rehydration solutions (ORS) is related to lower failure rates in severe cholera and cholera-like diarrhoea. This can only be settled by a controlled clinical trial of the. two glucose-based solutions. There are several differences between the rice powder electrolyte study9 and the study of Cash and Nalin.10 They gave ORS via nasogastric tube rather than by voluntary drinking by the patients. They used tetracycline, which reduces stool volume and enhances success rates. Most important, the intravenous fluid in their study was continued until demonstrated positive gut balance was observed. If necessary it was restarted if negative gut balance occurred while oral therapy continued. Thus the rate of success depends on how one defines failure. In the study of rice powder electrolyte therapy negative gut balance associated with reappearance of signs of dehydration was an indication to restart intravenous fluid. This was termed a failure. Since diarrhoea leads to malnutrition in addition to electrolyte losses it is important to address both problems together. The cereal-based ORS does this. It is cheap, available in homes, 1. Yunis
JJ, Ramsay N Retinoblastoma and subband deletion of chromosome 13. Am Dis Child 1978; 132: 161-63.
VA, Ruddle FH. The Science 1977, 196: 390-405.
4.
J
Sparkes RS, Sparkes MC, Wilson MG, Towner JW, Benedict W, Murphree AL, Yunis JJ. Regional Assignment of genes for human esterase D and retinoblastoma to chromosome band 13q14. Science 1980, 208: 1042-44.
3. McKusick
status
of the gene map of the human chromosomes.
Schmidtke J, Epplen JT Sequence organization of animal nuclear DNA. Hum Genet
1980; 55:
1-18.
5. Funderbunk L, Sparkes RS, Sparkes MC, Field L. Linkage analysis in a retinoblastoma 6. 7.
8.
family polymorphic at the esterase D locus. Am J Hum Genet 1980; 32: 107A. Morten JEN, Harnden DG, Bundey S. Family studies on the chromosomal location of the retinoblastoma gene. J Med Genet 1982; 19: 120-24. Hashem N, Khalifa S Retinoblastoma: a model of hereditary fragile chromosomal regions. Hum Hered 1975; 25: 35-49. Balaban G, Gilbert F, Nichols W, Meadows AT, Shields J. Abnormalities of
chromosome number 13 in retinoblastoms from individuals with normal constitutional karyotypes. Cancer Genet Cytogenet 1982; 6: 213-21. AM, Sarkar SA, Hossain M, Molla A, Greenough WB III. Rice powder electrolyte solution as oral therapy in diarrhoea due to Vibrio cholerae and Escherichia coli Lancet 1982; i: 1317-19 10. Cash RA, Nalin DR, Rochat R, Reller LB, Haque ZA, Rahman ASMM. A clinical trial of oral therapy in a rural cholera-treatment center. Am J Trop Med Hyg 1970; 19: 653-56. 9. Molla
on the regulation of airway submucosal gland secretion pertinent here. Direct measurement of secretion rates from airway submucosal gland duct openings can be made with a micropipette collection technique; even large doses of atropine sulphate (0’55 mg/kg, i.v.) did not affect basal secretory rates significantly,3 indicating that non-vagal influences are involved in basal secretion. This is in contrast to salivary glands, where atropine reduces gland flow to almost zero.4 Little is known about the effects on mucus secretion of long-term treatment with any drug. Although muscarinic antagonists do not block baseline secretory rates, they do prevent increases in secretion that occur during vagal reflex stimulation;3in disease, ifvagal reflex stimulation of gland secretion occurs, the response to stimulation will be prevented by this class of drugs. Although Crompton only considers possible deleterious effects, muscarinic antagonists might have beneficial effects in some patients. For example, if excessive secretions are produced abnormally by reflex stimulation, muscarinic antagonists could have a beneficial effect on mucociliary clearance and on efficiency of cough. Airway submucosal gland hypertrophy is characteristic of
Studies
R. F. MUELLER
Cambridge CB2 2QH
2.
W. B. GREENOUGH, III A. M. MOLLA
Disease Research, G.P.O. Box 128, Dacca-2, Bangladesh
are
asthmatic and chronic bronchitic patients, and the mechanism is unknown. Experimental studies show that beta-adrenergic agents increase the size of submucosal glands,5and this might be cited as concern over possible long-term effects of treatment class of drugs. There have even been sugestions that longterm therapy with muscarinic antagonists might decrease or reverse
grounds
for
with this
the hypertrophy and improve the patient’s status. The fact that many clinical studies have been done with muscarinic antagonists in patients with airways diseases without a single report, to my knowledge, of the deleterious effects suggested by Crompton is reassuring. Cardiovascular Research Institute and Departments of Medicine and
Physiology,
University of California, San Francisco, California 94143, U.S.A.
JAY A. NADEL
Northrup RS Taking science where the diarrhoeais In- Acute diarrhoea in (Ciba Found Symp). Amsterdam: Elsevier, 1976: 339-66. 1. Crompton GK. Sputum viscosity and long-term ipratropium bromide nebuliser therapy. Lancer 1982; i: 1243. 2. Nadel JA. Autonomic control of airway smooth muscle and airway secretions Am Rev Respir Dis 1977, 115: 117-26. 3. German VF, Ueki IF, Nadel JA. Micropipette measurement of airway submucosal gland secretion Laryngeal reflex Am Rev Respir Dis 1980; 122: 413-16. 4. Schneyer LH, Young JA, Schneyer CA. Salivary secretion of electrolytes. Physiol Rev 1972; 52: 720-77. 5. Sturgess J, Reid L The effect of isoprenaline and pilocarpine on (a) bronchial mucussecreting tissue and (b) pancreas, salivary glands, heart, thymus, liver and spleen. Br J Exp Pathol 1973, 54: 388-403.
11. Rohde JE,
childhood
higher in calorie density with no osmotic penalty. With only slight changes (i.e., deletion of salt(s) and addition of some source of protein, adapted for local preferences) enhanced nutrition after and
RETINOBLASTOMA AND ESTERASE D
SIR,-Professor Howard’s hypothesis (Aug. 28, esterase
D is identical with
one
p.
490)
retinoblastoma locus
that
neglects
diarrhoea can be achieved. In this way a combined approach to the two main killers of children during and after diarrhoea may be addressed now with materials available in every home. The need noted by Rohde and Northrup 1 for fluid and electrolyte malnutrition and protein energy malnutrition to be managed together, can now be met. A further dividend of cereals, including rice, is release of glucose, peptides, and aminoacids in the upper intestine, adding more effective carrier molecules for sodium transport and consequent water absorption at the appropriate site.
several points. Review of the forty or so published cases with constitutional deletions involving the long arm of chromosome 13 in association with retinoblastoma reveals the sub-band 13q 14 to be the minimum deleted segment common to all, as noted by Yunis et al.and Sparkes et a1.2 If the putative 50 000 structural genes of man3are evenly distributed throughout the genome, a deletion of a single sub-band may involve more than 100 structural genes plus many more DNA sequences which may have regulatory or control function.4 It seems more likely that the esterase D locus provides a useful screening marker for children presenting with retinoblastoma2 rather than necessarily being aetiologically related. Nevertheless, although normal esterase D levels are found in people with non-deletion (sporadic and single gene) retinoblastoma and family studies have not demonstrated linkage of the single gene cases with either the esterase D polymorphism or cytogenetic markers on chromosome 13,6the reports of abnormalities (albeit not invariably present) of chromosome 13 in the retinoblastomas from persons with normal constitutional karyotypes7,8 suggests that DNA sequences (gene(s)) in the sub-band 13ql4 may be involved in all forms of retinoblastoma.
International Centre for Diarrhoeal
IPRATROPIUM BROMIDE NEBULISER THERAPY AND AIRWAY SUBMUCOSAL GLAND SECRETION
SiR,—Crompton is worried that increased sputum viscosity may result from long-term use of the antimuscarinic agent ipratropium bromide (’Atrovent’) taken by inhalation for relief of asthmatic bronchospasm. The source of his concern is the fact that anticholinergic drugs cause a sensation of a dry mouth in some
’
Molecular Biology, Medical Research Council Centre, University Medical School,
Laboratory of
patients.
CEREAL-BASED ORAL REHYDRATION SOLUTIONS
SiR,-The comments of Dr Nalin and Dr Cash (July 17, p. 155) raise the issue of whether the higher sodium concentration (120 mmol/1) used in early studies on oral rehydration solutions (ORS) is related to lower failure rates in severe cholera and cholera-like diarrhoea. This can only be settled by a controlled clinical trial of the. two glucose-based solutions. There are several differences between the rice powder electrolyte study9 and the study of Cash and Nalin.10 They gave ORS via nasogastric tube rather than by voluntary drinking by the patients. They used tetracycline, which reduces stool volume and enhances success rates. Most important, the intravenous fluid in their study was continued until demonstrated positive gut balance was observed. If necessary it was restarted if negative gut balance occurred while oral therapy continued. Thus the rate of success depends on how one defines failure. In the study of rice powder electrolyte therapy negative gut balance associated with reappearance of signs of dehydration was an indication to restart intravenous fluid. This was termed a failure. Since diarrhoea leads to malnutrition in addition to electrolyte losses it is important to address both problems together. The cereal-based ORS does this. It is cheap, available in homes, 1. Yunis
JJ, Ramsay N Retinoblastoma and subband deletion of chromosome 13. Am Dis Child 1978; 132: 161-63.
VA, Ruddle FH. The Science 1977, 196: 390-405.
4.
J
Sparkes RS, Sparkes MC, Wilson MG, Towner JW, Benedict W, Murphree AL, Yunis JJ. Regional Assignment of genes for human esterase D and retinoblastoma to chromosome band 13q14. Science 1980, 208: 1042-44.
3. McKusick
status
of the gene map of the human chromosomes.
Schmidtke J, Epplen JT Sequence organization of animal nuclear DNA. Hum Genet
1980; 55:
1-18.
5. Funderbunk L, Sparkes RS, Sparkes MC, Field L. Linkage analysis in a retinoblastoma 6. 7.
8.
family polymorphic at the esterase D locus. Am J Hum Genet 1980; 32: 107A. Morten JEN, Harnden DG, Bundey S. Family studies on the chromosomal location of the retinoblastoma gene. J Med Genet 1982; 19: 120-24. Hashem N, Khalifa S Retinoblastoma: a model of hereditary fragile chromosomal regions. Hum Hered 1975; 25: 35-49. Balaban G, Gilbert F, Nichols W, Meadows AT, Shields J. Abnormalities of
chromosome number 13 in retinoblastoms from individuals with normal constitutional karyotypes. Cancer Genet Cytogenet 1982; 6: 213-21. AM, Sarkar SA, Hossain M, Molla A, Greenough WB III. Rice powder electrolyte solution as oral therapy in diarrhoea due to Vibrio cholerae and Escherichia coli Lancet 1982; i: 1317-19 10. Cash RA, Nalin DR, Rochat R, Reller LB, Haque ZA, Rahman ASMM. A clinical trial of oral therapy in a rural cholera-treatment center. Am J Trop Med Hyg 1970; 19: 653-56. 9. Molla
on the regulation of airway submucosal gland secretion pertinent here. Direct measurement of secretion rates from airway submucosal gland duct openings can be made with a micropipette collection technique; even large doses of atropine sulphate (0’55 mg/kg, i.v.) did not affect basal secretory rates significantly,3 indicating that non-vagal influences are involved in basal secretion. This is in contrast to salivary glands, where atropine reduces gland flow to almost zero.4 Little is known about the effects on mucus secretion of long-term treatment with any drug. Although muscarinic antagonists do not block baseline secretory rates, they do prevent increases in secretion that occur during vagal reflex stimulation;3in disease, ifvagal reflex stimulation of gland secretion occurs, the response to stimulation will be prevented by this class of drugs. Although Crompton only considers possible deleterious effects, muscarinic antagonists might have beneficial effects in some patients. For example, if excessive secretions are produced abnormally by reflex stimulation, muscarinic antagonists could have a beneficial effect on mucociliary clearance and on efficiency of cough. Airway submucosal gland hypertrophy is characteristic of
Studies
R. F. MUELLER
Cambridge CB2 2QH
2.
W. B. GREENOUGH, III A. M. MOLLA
Disease Research, G.P.O. Box 128, Dacca-2, Bangladesh
are
asthmatic and chronic bronchitic patients, and the mechanism is unknown. Experimental studies show that beta-adrenergic agents increase the size of submucosal glands,5and this might be cited as concern over possible long-term effects of treatment class of drugs. There have even been sugestions that longterm therapy with muscarinic antagonists might decrease or reverse
grounds
for
with this
the hypertrophy and improve the patient’s status. The fact that many clinical studies have been done with muscarinic antagonists in patients with airways diseases without a single report, to my knowledge, of the deleterious effects suggested by Crompton is reassuring. Cardiovascular Research Institute and Departments of Medicine and
Physiology,
University of California, San Francisco, California 94143, U.S.A.
JAY A. NADEL
Northrup RS Taking science where the diarrhoeais In- Acute diarrhoea in (Ciba Found Symp). Amsterdam: Elsevier, 1976: 339-66. 1. Crompton GK. Sputum viscosity and long-term ipratropium bromide nebuliser therapy. Lancer 1982; i: 1243. 2. Nadel JA. Autonomic control of airway smooth muscle and airway secretions Am Rev Respir Dis 1977, 115: 117-26. 3. German VF, Ueki IF, Nadel JA. Micropipette measurement of airway submucosal gland secretion Laryngeal reflex Am Rev Respir Dis 1980; 122: 413-16. 4. Schneyer LH, Young JA, Schneyer CA. Salivary secretion of electrolytes. Physiol Rev 1972; 52: 720-77. 5. Sturgess J, Reid L The effect of isoprenaline and pilocarpine on (a) bronchial mucussecreting tissue and (b) pancreas, salivary glands, heart, thymus, liver and spleen. Br J Exp Pathol 1973, 54: 388-403.
11. Rohde JE,
childhood