1363 used by Hillyard et al. to describe our work8 are misleading. Our results were not in the least "equivocal" or lacking "precision and conviction". The great majority of normal plasmas depressed the assay bound/free ratio by 20-50%, which is not "the top of the displacement curve". We eliminated the effect of the possible diurnal variation (reported in just four subjects3) by drawing blood at the same hour, and we eliminated the possible confounding effect of sex-steroid drugs by studying only persons taking no medications at all. These facts are all clearly presented in our paper.8 In their original paper,9 Hillyard et al. measured plasma-calcitonin values in twelve men and nine women at 9 A.M. and noon. The mean calcitonin values were higher in the women at both times (not statistically significant), but Hillyard et al. provided no explanation for the serious discrepancy between this finding and their latest study. Pregnancy and oral-contraceptive therapy raise the concentrations of many substances in plasma, and Hillyard et al. provide no evidence of an effort to establish that non-specific factors do not interfere with their assay in that circumstance. As was stated in our publications,’,8I fully agree that relative calcitonin deficiency among women deserves study as a possibly contributory factor in age and sex related bone loss. The
terms
Endocrine Research Unit,
Department of Medicine, Mayo Clinic, Rochester, Minnesota 55901, U.S.A.
HUNTER
HEATH, III
CHOLERA RESEARCH IN BANGLADESH that Dr McCord (June 3, p. 1207) his allegations that unethical research was done at the Cholera Research Laboratory in Dacca. As a one-time member of the C.R.L. committee which was responsible for the maintenance of ethical standards I must nevertheless protest at his attack. McCord cites examples of research procedures which, in his view, would not have been done given "the same situation in the U.S.A. at the same time". But they were, on volunteers, as at Dacca, and on subjects who had less to gain than the Dacca patients. The committee would never have agreed to the use of procedures which were not of very low risk and which were not in common use elsewhere. McCord states that clinical research is only ethical if it subjects the patient to "no risk which is not justified by the health benefit to the individual undergoing an experimental procedure". Adoption of this criterion would bring nearly all clinical research to a halt, for even a simple comparison of two possible treatments carries a risk. If his criterion had been applied at the C.R.L. many hundreds of thousands of people including Bangladeshi patients of the C.R.L. would have died of cholera, for the Dacca solution could not have been developed. The acceptance of risk is necessary in all clinical research, but it is the duty of the investigator to ensure that it is minimal, that the patient is aware of the risk and discomfort involved, and that he gives informed consent. McCord seems to link literacy with the ability to give informed consent. This is an insult to the intelligence of the Bangladeshi community; moreover, the ability to read or write or to sign a consent form is not a requirement in British law which has been adopted in Bangladesh. It is difficult to explain complex procedures to uneducated patients but it is possible to give sufficient understanding to obtain valid consent, and this was done. McCord complains that the Bangladeshi community did not benefit from the presence of the C.R.L. It did. Not only was a regimen developed which saved many lives in many countries
SIR,-I
has
am glad to partly withdrawn
including Bangladesh 9.
see
but also the individual
patients
who
Hillyard, C. J., Cooke, T. J. C., Coombes, R. C., Evans, I. M. A., MacIntyre, I. Clin. Endocr. 1977, 6, 291.
treated at the C.R.L. had the benefits of first-class management. The mortality-rate there was lower than anywhere else in the world. The local community knew the benefits and flocked to the C.R.L. for treatment. Finally, McCord considers "The development of an indigenous research capacity a primary goal, more important than the production of research results however important they may be in the short run". Would he set in the balance a probable 1 million lives saved as a result of about ten years work by foreigners ? It is doubtful if even ten years of research training would have been sufficient to enable Bangladeshi scientists to reach this point. In any event Bangladeshi scientists were trained and were in part responsible for the gains in knowledge which made this laboratory outstandingly successful in the development of a regimen for management of an internationally important group of diseases. were
29 Heath Drive, London NW3 7SB
G. M. BULL
BLOOD-LEAD LEVELS IN MOTHERS AND THEIR CHILDREN
SIR,-Absorption of lead from the diet is greater in young than in adult animals, 1,2 and it has been suggested that this is true of man also.3 We have compared blood-lead levels in adults and children in families exposed to a significant source of pollution. We studied mother-and-child pairs living in two housing estates in north Wales; one estate had lead water piping, the other copper. Where there was more than one child below 16 years of age, the youngest was selected. Venous blood was taken from adults and older children and capillary blood from the younger children. Lead was estimated in an N.H.S. supra-regional lead laboratory with excellent reproducibility.’ MEAN
+S.D. BLOOD-LEAD LEVELS
IN PAIRS MOTHERS AND
CHILDREN IN THE SAME HOUSES ON ESTATES WITH COPPER OR LEAD WATER PIPES
The table summarises the results. In the copper-piped estate the blood-lead levels were all very low, and probably represent no more than "background" exposure to lead. The children tended to have higher blood-lead values than their mothers, and the scatter of individual levels was greater, probably due to pica and so on. However, in the lead-piped estate, where water was an important source of lead and blood-leads were high, both the mean and the scatter about the mean were almost identical in the mothers and their children. These data suggest that, with regard to lead in domestic water, children are not at a risk which is substantially greater than that of adults. This result was unexpected because we had anticipated that children, whatever their proportionate absorption of ingested lead might be, would drink most of their fluid as water, diluted fruit juice, and the like, whereas adults would 1. Kostial, K., Simonovic, I., Pisonic, M. Envir. Res. 1971, 4, 360. 2. Forbes, G. B., Reina, J. C. J. Nutr. 1972, 102, 647. 3. Alexander, F. W., Delves, H. T., Clayton, B. E. in Environmental Health Aspects of Lead, p. 319. Commission of the European Communities Directorate General for Dissemination of Knowledge Centre for Information and Documentation, Luxembourg, 1973. 4. Beasley, W. H., Broughton, P. M. E., Delves, H. T., Elwood, P C. Br. med.
J. 1974, i, 576.
1364 of their fluid as tea, in which much of the lead is likely to have been precipitated before drinking. The lead piping on the estate has now been removed and the fall in the blood-lead levels is being monitored. consume most
M.R.C.
Epidemiology Unit (South Wales),
4 Richmond Road, Cardiff CF2 3AS
P. C. ELWOOD H. THOMAS
N.H.S. Supraregional Lead Laboratory, Leeds
M. SHELTAWY
IMMUNOREACTIVE MOTILINS?
SiR,-Like Dr Sundler and colleagues, we have also found that Yanaihara’s antibody stains a population of small intestinal non-enterochromaffin cells (fig. 1). This is in contrast to the findings using our own antibody (M4) which clearly stains only a subpopulation of the enterochromaffin cells.’,2 Yanaihara’s antiserum, raised to synthetic motilin, is C-terminally directed and thus immunocytochemical staining is quenched by prior addition of either the intact molecule or synthetic fragments composed of residues 12-22 and 7-22 at a concentration of 2nmoVml of diluted antiserum (1:400). In comparison our own antibody recognises the entire motilin molecule, so the staining produced is abolished only by prior addition of whole motilin at a concentration of 2nmol/ml of diluted antiserum (1:100). After the application of the semithin/thin technique, the cells identified by Yanaihara’s antiserum were shown to contain small granules of medium density (fig. 2). These cells seem to have been previously included in the ubiquitous D1 cell
group of the Lausanne classification.’ Their peptide product has yet to be definitively proven. Taking into account the fact that with our antisera only a minor population of enterochromaffin cells, confined to the duodenal and jejunal mucosa, have been shown to contain motilin, it is perhaps to be expected that Modlin et al. would not find raised serum-motilin levels in their patients with carcinoid tumours.4 Their series contained lung, gastric, and ileal carcinoids only and did not include the rare duodenal-jejunal carcinoids in which the motilin-producing enterochromaffin cells might have been found. We suggest, therefore, that the 3. 4.
Solcia, E. and others, ibid. p. 40. Modlin, I. M., Bloom, S. R., Christofides, N. Lancet, 1977, ii, 979.
Pearse, A. G. E., Polak, J. M., Bloom, S. R., Adams, C., Dryburgh, J. R., Brown, J. C. Virchons Arch. B. Cell Path. 1974, 16, 111. 2. Heitz, P., Polak, J. M., Pearse, A. G. E. in Gut Hormones (edited by S. R. Bloom); p. 332. Edinburgh 1978. 1.
Fig. 1-800 nm section of human duodenum. Upper: stained with Yanaihara’s motilin antiserum. Circle encloses positive motilin-containing cell. Arrow indicates negative enterochromaffin (EC) cell. Lower: same section restained by Masson’s silver method. Arrow indicates EC cell. Circle encloses motilin-containing cell. (Reduced to 6/7 of x 1500.)
Fig. 2-Human duodenum. Upper: 800 nm section stained with Yanaihara’s antiserum. Arrow indicates positive motilin-containing cell. (x1500.) Lower: serial thin section (60 nm). Arrow indicates motilin-containcell (x 3000). Insert shows detail of secretory granules in part of same cell (x 18,000).
ing
terms
Endocrine Research Unit,
Department of Medicine, Mayo Clinic, Rochester, Minnesota 55901, U.S.A.
HUNTER
HEATH, III
CHOLERA RESEARCH IN BANGLADESH that Dr McCord (June 3, p. 1207) his allegations that unethical research was done at the Cholera Research Laboratory in Dacca. As a one-time member of the C.R.L. committee which was responsible for the maintenance of ethical standards I must nevertheless protest at his attack. McCord cites examples of research procedures which, in his view, would not have been done given "the same situation in the U.S.A. at the same time". But they were, on volunteers, as at Dacca, and on subjects who had less to gain than the Dacca patients. The committee would never have agreed to the use of procedures which were not of very low risk and which were not in common use elsewhere. McCord states that clinical research is only ethical if it subjects the patient to "no risk which is not justified by the health benefit to the individual undergoing an experimental procedure". Adoption of this criterion would bring nearly all clinical research to a halt, for even a simple comparison of two possible treatments carries a risk. If his criterion had been applied at the C.R.L. many hundreds of thousands of people including Bangladeshi patients of the C.R.L. would have died of cholera, for the Dacca solution could not have been developed. The acceptance of risk is necessary in all clinical research, but it is the duty of the investigator to ensure that it is minimal, that the patient is aware of the risk and discomfort involved, and that he gives informed consent. McCord seems to link literacy with the ability to give informed consent. This is an insult to the intelligence of the Bangladeshi community; moreover, the ability to read or write or to sign a consent form is not a requirement in British law which has been adopted in Bangladesh. It is difficult to explain complex procedures to uneducated patients but it is possible to give sufficient understanding to obtain valid consent, and this was done. McCord complains that the Bangladeshi community did not benefit from the presence of the C.R.L. It did. Not only was a regimen developed which saved many lives in many countries
SIR,-I
has
am glad to partly withdrawn
including Bangladesh 9.
see
but also the individual
patients
who
Hillyard, C. J., Cooke, T. J. C., Coombes, R. C., Evans, I. M. A., MacIntyre, I. Clin. Endocr. 1977, 6, 291.
treated at the C.R.L. had the benefits of first-class management. The mortality-rate there was lower than anywhere else in the world. The local community knew the benefits and flocked to the C.R.L. for treatment. Finally, McCord considers "The development of an indigenous research capacity a primary goal, more important than the production of research results however important they may be in the short run". Would he set in the balance a probable 1 million lives saved as a result of about ten years work by foreigners ? It is doubtful if even ten years of research training would have been sufficient to enable Bangladeshi scientists to reach this point. In any event Bangladeshi scientists were trained and were in part responsible for the gains in knowledge which made this laboratory outstandingly successful in the development of a regimen for management of an internationally important group of diseases. were
29 Heath Drive, London NW3 7SB
G. M. BULL
BLOOD-LEAD LEVELS IN MOTHERS AND THEIR CHILDREN
SIR,-Absorption of lead from the diet is greater in young than in adult animals, 1,2 and it has been suggested that this is true of man also.3 We have compared blood-lead levels in adults and children in families exposed to a significant source of pollution. We studied mother-and-child pairs living in two housing estates in north Wales; one estate had lead water piping, the other copper. Where there was more than one child below 16 years of age, the youngest was selected. Venous blood was taken from adults and older children and capillary blood from the younger children. Lead was estimated in an N.H.S. supra-regional lead laboratory with excellent reproducibility.’ MEAN
+S.D. BLOOD-LEAD LEVELS
IN PAIRS MOTHERS AND
CHILDREN IN THE SAME HOUSES ON ESTATES WITH COPPER OR LEAD WATER PIPES
The table summarises the results. In the copper-piped estate the blood-lead levels were all very low, and probably represent no more than "background" exposure to lead. The children tended to have higher blood-lead values than their mothers, and the scatter of individual levels was greater, probably due to pica and so on. However, in the lead-piped estate, where water was an important source of lead and blood-leads were high, both the mean and the scatter about the mean were almost identical in the mothers and their children. These data suggest that, with regard to lead in domestic water, children are not at a risk which is substantially greater than that of adults. This result was unexpected because we had anticipated that children, whatever their proportionate absorption of ingested lead might be, would drink most of their fluid as water, diluted fruit juice, and the like, whereas adults would 1. Kostial, K., Simonovic, I., Pisonic, M. Envir. Res. 1971, 4, 360. 2. Forbes, G. B., Reina, J. C. J. Nutr. 1972, 102, 647. 3. Alexander, F. W., Delves, H. T., Clayton, B. E. in Environmental Health Aspects of Lead, p. 319. Commission of the European Communities Directorate General for Dissemination of Knowledge Centre for Information and Documentation, Luxembourg, 1973. 4. Beasley, W. H., Broughton, P. M. E., Delves, H. T., Elwood, P C. Br. med.
J. 1974, i, 576.
1364 of their fluid as tea, in which much of the lead is likely to have been precipitated before drinking. The lead piping on the estate has now been removed and the fall in the blood-lead levels is being monitored. consume most
M.R.C.
Epidemiology Unit (South Wales),
4 Richmond Road, Cardiff CF2 3AS
P. C. ELWOOD H. THOMAS
N.H.S. Supraregional Lead Laboratory, Leeds
M. SHELTAWY
IMMUNOREACTIVE MOTILINS?
SiR,-Like Dr Sundler and colleagues, we have also found that Yanaihara’s antibody stains a population of small intestinal non-enterochromaffin cells (fig. 1). This is in contrast to the findings using our own antibody (M4) which clearly stains only a subpopulation of the enterochromaffin cells.’,2 Yanaihara’s antiserum, raised to synthetic motilin, is C-terminally directed and thus immunocytochemical staining is quenched by prior addition of either the intact molecule or synthetic fragments composed of residues 12-22 and 7-22 at a concentration of 2nmoVml of diluted antiserum (1:400). In comparison our own antibody recognises the entire motilin molecule, so the staining produced is abolished only by prior addition of whole motilin at a concentration of 2nmol/ml of diluted antiserum (1:100). After the application of the semithin/thin technique, the cells identified by Yanaihara’s antiserum were shown to contain small granules of medium density (fig. 2). These cells seem to have been previously included in the ubiquitous D1 cell
group of the Lausanne classification.’ Their peptide product has yet to be definitively proven. Taking into account the fact that with our antisera only a minor population of enterochromaffin cells, confined to the duodenal and jejunal mucosa, have been shown to contain motilin, it is perhaps to be expected that Modlin et al. would not find raised serum-motilin levels in their patients with carcinoid tumours.4 Their series contained lung, gastric, and ileal carcinoids only and did not include the rare duodenal-jejunal carcinoids in which the motilin-producing enterochromaffin cells might have been found. We suggest, therefore, that the 3. 4.
Solcia, E. and others, ibid. p. 40. Modlin, I. M., Bloom, S. R., Christofides, N. Lancet, 1977, ii, 979.
Pearse, A. G. E., Polak, J. M., Bloom, S. R., Adams, C., Dryburgh, J. R., Brown, J. C. Virchons Arch. B. Cell Path. 1974, 16, 111. 2. Heitz, P., Polak, J. M., Pearse, A. G. E. in Gut Hormones (edited by S. R. Bloom); p. 332. Edinburgh 1978. 1.
Fig. 1-800 nm section of human duodenum. Upper: stained with Yanaihara’s motilin antiserum. Circle encloses positive motilin-containing cell. Arrow indicates negative enterochromaffin (EC) cell. Lower: same section restained by Masson’s silver method. Arrow indicates EC cell. Circle encloses motilin-containing cell. (Reduced to 6/7 of x 1500.)
Fig. 2-Human duodenum. Upper: 800 nm section stained with Yanaihara’s antiserum. Arrow indicates positive motilin-containing cell. (x1500.) Lower: serial thin section (60 nm). Arrow indicates motilin-containcell (x 3000). Insert shows detail of secretory granules in part of same cell (x 18,000).
ing
