- Email: [email protected]
EFFECT OF ORAL CONTRACEPTIVES ON GLUCOSE TOLERANCE
857
mathematical evidence that it
was ineffective for prewhich cases would dicting develop cancer. The " distance " discriminant which was introduced in that report was insufficiently defined there for us to be able to calculate our own points for their fig. 2. Although we have very little data on cases with thyroid dysfunction, Sneddon et al. (1968) have found significantly low values for the discriminant in both hypothyroid and hyperthyroid patients. The figures they cite are not corrected for age, but it seems likely that this makes only a slight difference to their levels
significance. might be expected that the intentional heterogeneity of conditions included in the operation controls (group 2) would lead to an increase in scatter in the discriminant. This expectation is borne out by the
of
It
values of the standard deviation with decades shown in table V, and by the values of s in table vi. For the most part, the standard deviations were larger in group 2 and its subgroups than in the early-breast-cancer group 3 and its subgroups. The increase was not, however, as large as might have been expected. The Ratio We calculated the ratio
(aetiocholanolone in g. per twenty-four hours: 17-OHc.s. in mg. per twenty-four hours) because, judging from fig. 1 of Bulbrook et al. (1960), this ratio was just as effective for the discrimination discussed in that paper as was their discriminant. In our series a ratio of 70 is equivalent to a zero discriminant ; larger values of the ratio go with positive discriminants, and vice versa. Conclusion
The standard errors of the estimates of the mean discriminants in the various groups and subgroups of patients and controls are so large that our results give very little encouragement to the view that the discriminant, which after all was an entirely empirical index, may be affected specifically in any way in early breast cancer. The operation controls (group 2) show a wide variability, probably due to the differing nature and severity of the diseases included, and also to a variability in the response of the individual patients to such diseases. It is not clear whether a definite group in the operation control series could be segregated which would constantly show a low discriminant; if this were so, the non-specificity of the discriminant with regard to early breast cancer would be reduced to a partial specificity shared by only a few diseases. The role of admission to hospital per se is also not clear, but this factor may be of importance in the selection of suitable control groups. The research was supported by the North West Cancer Research Fund. We thank Mrs. G. Burton for her valuable assistance in performing the assays, Mr. El Rifi for his help in collecting some of the specimens, and Mr. A. C. Brewer for allowing us to investigate his patients. We thank Mr. Hayward and Dr. Bulbrook for kindly allowing us to use their unpublished data. Requests for reprints should be addressed to J. C. D., Endocrine Unit, Liverpool Clinic, Myrtle Street, Liverpool 7. REFERENCES
Atkins, H., Bulbrook R. D., Falconer, M. A., Hayward, J. L., MacLean, K. S., Schurr, P. H. (1968a) Lancet, ii, 1255. (1968b) ibid. p. 1261. Bond, W. H. (1967) in The Treatment of Carcinoma of the Breast (edited by A. S. Jarrett); p. 26. Amsterdam. Bulbrook, R. D., Greenwood, F. C., Hayward, J. L. (1960) Lancet, i, 1154. Hayward, J. L. (1967a) ibid. i, 519. — — — — — —
—
EFFECT OF ORAL CONTRACEPTIVES ON GLUCOSE TOLERANCE
J. CLINCH*
A. C. TURNBULL T. KHOSLA
FROM THE WELSH NATIONAL SCHOOL OF
MEDICINE, CARDIFF
women were each given two intravenous glucose-tolerance tests to detect alterations in glucose tolerance caused by oral contraceptives, one before starting therapy and one after four months’ medication. A very-low-dose contraceptive significantly improved glucose tolerance, while stronger preparations caused slight deterioration. The mean blood-glucose values during the second test were higher than in the first
42
Summary
in 32 of the 42
women.
DOUBT exists
Introduction whether oral
contraceptives are diabetogenic. Gershberg et al. (1964), Wynn and Doar (1966), and Spellacy and Carlson (1966) have suggested that they adversely affect carbohydrate tolerance. More recently Pi-sunyer and Oster (1968) decided that any such effect is dose-dependent and does not occur with modern low-dosage therapy. A small study in Cardiff has confirmed this and implies that these drugs may actually improve carbohydrate tolerance. as
to
Materials and Methods of childbearing age with no family history of diabetes underwent an intravenous glucose-tolerance test. They then started taking an oral contraceptive and in the fourth cycle had another glucose-tolerance test as near as possible to the same day of the cycle as the first test. All tests were performed in the fasting state after the patient had rested for fifteen minutes. Three initial capillary samples were taken to estimate the fasting blood-glucose level before an intravenous injection of 50 ml. of 50% dextrose. Subsequent capillary samples were taken at four and ten minutes after completion of the injection and then every ten minutes for an hour. Blood-glucose was estimated by the glucose-oxidase method on an ’AutoAnalyzer ’. The fasting level was subtracted from each result to give a net " increment". By plotting these incremental readings against time on semilogarithmic paper and fitting " a straight line through them an increment index " (Duncan 1956) can be obtained which expresses the rate of fall in the blood-glucose level. The higher the index the faster the fall. In practice the points do not always fall exactly along a straight line and judgment of exactly where the line should be is not always easy. In our study this problem was overcome by using computer methods to find the linear-regression equations of logarithm (base 10) of increments on time (minutes) for each of the 42 subjects, and separately for the set of responses recorded before and while taking oral contraceptives. This gave 42
women
"
"
* Present address: Aberdeen Maternity Hospital, Foresterhill, Aberdeen.
(1967b) in Current Concepts in Breast Cancer (edited by Segaloff); p. 120. Baltimore. Spicer, C. C., Thomas, B. S. (1962a) Lancet, ii, 1235. (1962b) ibid. p. 1238. Cancer Bull. (1965) 17, 1106. Cope, C. L. (1965) Adrenal Steroids and Disease p. 210. London. Hayward, J. L., Bulbrook, R. D. (1968) Personal communication. Greenwood, F. C. (1961) Mem. Soc. Endocr. 10, 144. James, V. H. T. (1961) J. Endocr. 22, 195. Kellie, A. E., Wade, A. P. (1957) Biochem. J. 66, 196. Metcalf, M. G. (1963) J. Endocr. 26, 415. Nabarro, J. D. N. (1960) Lancet, i, 1292. Sneddon, A., Steel, J. M., Strong, J. A. (1968) ibid. ii, 892. Snedecor, G. W. (1952) Biometrics, 8, 85. Thomas, B. S., Bulbrook, R. D. (1964) J. Chromat. 14, 28. Willis, R. A. (1967) The Pathology of Tumours; p. 230. London. —
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— —
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—
—
—
—
—
A.
858 MEAN AND STANDARD DEVIATIONS OF DIFFERENCES IN SLOPES (INCREMENT INDICES) OF FALLS IN BLOOD-GLUCOSE LEVEL IN 42 WOMEN BEFORE AND WHILE ON ORAL CONTRACEPTIVES
Note: Slope responses in groups B and C on analysis of variances.
are
significantly different
from A
regression coefficients (or slopes) for each patient. The goodness " of fits as judged by the percentage of reduction attributable to linear regression ranged from 78 % to 98 % in the 84 regression fits. In only 1 instance was the linear fit unsatisfactory ; this was due to a recording error in the original data,
two "
and the case
excluded from the series. Statistical tests of done on the differences in slope values before significance and while on oral contraceptives under the alternative hypothesis of some difference. was
were
Results
The accompanying table shows the computerised results in three groups of patients. Group A took one contraceptive tablet daily containing 0-05 mg. mestranol and 1-0 mg. norethisterone. Group B took two of these tablets daily. The patients in group C were on a variety of oral contraceptives prescribed by their general practitioners or family-planning advisers, all of which contained a larger dose of hormone than the tablet of group A. The slope (or increment index) was significantly increased in In both the other groups group-A patients (P<0-02). the slope (index) was reduced, but not significantly so. However, although the slope was increased in group A, the mean value of the blood-glucose readings in all groups was higher when the patients were taking oral contraceptives. This occurred in 32 out of the 42 cases whether the mean was calculated from the absolute glucose values or the incremental values (P<0-005). Discussion
The intravenous glucose-tolerance test was used in preference to the oral test because of its reproducibility (Amatuzio et al. 1953). It also conveniently expresses glucose tolerance in a single figure. Our results confirm the suggestion of Pi-sunyer and Oster (1968) that any effect oral contraceptives have on carbohydrate tolerance is dose-dependent. However, our paper is the first to report actual improvement in carbohydrate tolerance. This could be because small doses of steroid stimulate insulin secretion more than enough to counter any glucocorticoid effect of the drug, while with larger doses the pancreas is unable to respond adequately. Such a situation would mimic pregnancy in normal women, when carbohydrate tolerance is improved slightly over the non-pregnant state, the improvement being most striking in the first and second trimesters and becoming less near the end of pregnancy (Silverstone et al. 1961, Sutherland et al. 1968). There have also been reports of exogenous oestrogens stimulating insulin production in non-pregnant women (Beck and Wells 1968). The finding that mean blood-glucose values are higher in women on oral contraceptives implies that though the pancreatic response and the peripheral action of insulin are adequate they may be slightly delayed, thus allowing a higher than normal value to develop after the intravenous
injection. It is impossible to say whether or not such delay in insulin response represents a diabetic tendency, particularly when it is followed by an increased rate of fall in blood-glucose level. However, this situation is presumably preferable to having a delayed fall in bloodglucose level, and it therefore seems advisable to encourage doctors to prescribe the lowest-dose oral contraceptive suitable for their patients. a
We thank the administrative and medical staff of the South Wales branch of the Family Planning Association; the general practitioners and local-authority doctors, who referred patients for this study; and the department of physics, University College, Cardiff, for access to the S.T.C. Zebra computer. The tablets for groups A and B were supplied by Syntex Pharmaceuticals Ltd. One of us (J. C.) was in receipt of a Hodge Foundation Scholarship. Requests for reprints should be addressed to J. C. REFERENCES
Amatuzio, D. S., Stutzman, F. L., Vanderbilt, M. J., Nesbitt, S. (1953) J. Clin. Invest. 32, 428. Beck, P., Wells, S. A. (1968) Diabetes, 17, suppl. p. 307. Duncan, L. J. P. (1956) Q. Jl exp. Physiol. 41, 85. Gershberg, H., Javier, Z., Hulse, M. (1964) Diabetes, 13, 378. Pi-Sunyer, F. X., Oster, S. (1968) Obstet. Gynec., N.Y. 31, 482. Silverstone, F. A., Solomons, E., Rubricus, J. (1961) J. clin. Invest. 40, 2180. Spellacy, W. N., Carlson, K. L. (1966) Am. J. Obstet. Gynec. 95, 474. Sutherland, H. W., Stowers, J. M., Mackenzie, C., Duncan, R. O. (1968) Medical and Scientific section of British Diabetic Association Meeting.
Aberdeen, Sept. 28, 1968. Wynn, V., Doar, J. W. H. (1966) Lancet, ii,
715.
IgM METABOLISM IN CŒLIAC DISEASE A. G. COOPER G. W. HEPNER &dag er;
D. L. BROWN
FROM THE DEPARTMENT OF MEDICAL
SCHOOL,
HÆMATOLOGY,
*
ROYAL POSTGRADUATE
AND THE MEDICAL RESEARCH COUNCIL INTESTINAL
MALABSORPTION
UNIT,
HAMMERSMITH
HOSPITAL, LONDON W.12
The metabolism of radioiodinated IgM (cold agglutinin) was studied in eleven with untreated cœliac disease and eight patients patients treated with a gluten-free diet. The catabolism and distribution of IgM were normal in every case, suggesting that the hypomacroglobulinæmia which was present in six untreated patients and two treated patients was due to defective synthesis of IgM. This apparently acquired defect of IgM synthesis, responding to a gluten-free diet, may be a further manifestation of the lymphoreticular dysfunction associated with cœliac disease.
Summary
Introduction
Hobbs and Hepner (1968) found IgM deficiency in about two-thirds of patients with untreated cceliac disease; in most cases this deficiency was converted to normal by a gluten-free diet. Usually, the concentrations of other immunoglobulins were within normal limits. The nature of this apparently acquired deficiency of IgM is not known, although Hobbs and Hepner (1968) suggested that defective synthesis of IgM might be a possible cause. We describe here the catabolism and distribution of labelled IgM (purified cold agglutinin) in patients with untreated cceliac disease and in patients who had been treated with a gluten-free diet.
Patients, Materials, and Methods Patients Five male and thirteen female patients with coeliac disease volunteered for this study (cases 1-18). Their ages ranged from * Present address: Blood Research Laboratory, Naval Hospital, Chelsea, Massachusetts. † Present address: Mount Sinai Hospital, New York, N.Y.
mathematical evidence that it
was ineffective for prewhich cases would dicting develop cancer. The " distance " discriminant which was introduced in that report was insufficiently defined there for us to be able to calculate our own points for their fig. 2. Although we have very little data on cases with thyroid dysfunction, Sneddon et al. (1968) have found significantly low values for the discriminant in both hypothyroid and hyperthyroid patients. The figures they cite are not corrected for age, but it seems likely that this makes only a slight difference to their levels
significance. might be expected that the intentional heterogeneity of conditions included in the operation controls (group 2) would lead to an increase in scatter in the discriminant. This expectation is borne out by the
of
It
values of the standard deviation with decades shown in table V, and by the values of s in table vi. For the most part, the standard deviations were larger in group 2 and its subgroups than in the early-breast-cancer group 3 and its subgroups. The increase was not, however, as large as might have been expected. The Ratio We calculated the ratio
(aetiocholanolone in g. per twenty-four hours: 17-OHc.s. in mg. per twenty-four hours) because, judging from fig. 1 of Bulbrook et al. (1960), this ratio was just as effective for the discrimination discussed in that paper as was their discriminant. In our series a ratio of 70 is equivalent to a zero discriminant ; larger values of the ratio go with positive discriminants, and vice versa. Conclusion
The standard errors of the estimates of the mean discriminants in the various groups and subgroups of patients and controls are so large that our results give very little encouragement to the view that the discriminant, which after all was an entirely empirical index, may be affected specifically in any way in early breast cancer. The operation controls (group 2) show a wide variability, probably due to the differing nature and severity of the diseases included, and also to a variability in the response of the individual patients to such diseases. It is not clear whether a definite group in the operation control series could be segregated which would constantly show a low discriminant; if this were so, the non-specificity of the discriminant with regard to early breast cancer would be reduced to a partial specificity shared by only a few diseases. The role of admission to hospital per se is also not clear, but this factor may be of importance in the selection of suitable control groups. The research was supported by the North West Cancer Research Fund. We thank Mrs. G. Burton for her valuable assistance in performing the assays, Mr. El Rifi for his help in collecting some of the specimens, and Mr. A. C. Brewer for allowing us to investigate his patients. We thank Mr. Hayward and Dr. Bulbrook for kindly allowing us to use their unpublished data. Requests for reprints should be addressed to J. C. D., Endocrine Unit, Liverpool Clinic, Myrtle Street, Liverpool 7. REFERENCES
Atkins, H., Bulbrook R. D., Falconer, M. A., Hayward, J. L., MacLean, K. S., Schurr, P. H. (1968a) Lancet, ii, 1255. (1968b) ibid. p. 1261. Bond, W. H. (1967) in The Treatment of Carcinoma of the Breast (edited by A. S. Jarrett); p. 26. Amsterdam. Bulbrook, R. D., Greenwood, F. C., Hayward, J. L. (1960) Lancet, i, 1154. Hayward, J. L. (1967a) ibid. i, 519. — — — — — —
—
EFFECT OF ORAL CONTRACEPTIVES ON GLUCOSE TOLERANCE
J. CLINCH*
A. C. TURNBULL T. KHOSLA
FROM THE WELSH NATIONAL SCHOOL OF
MEDICINE, CARDIFF
women were each given two intravenous glucose-tolerance tests to detect alterations in glucose tolerance caused by oral contraceptives, one before starting therapy and one after four months’ medication. A very-low-dose contraceptive significantly improved glucose tolerance, while stronger preparations caused slight deterioration. The mean blood-glucose values during the second test were higher than in the first
42
Summary
in 32 of the 42
women.
DOUBT exists
Introduction whether oral
contraceptives are diabetogenic. Gershberg et al. (1964), Wynn and Doar (1966), and Spellacy and Carlson (1966) have suggested that they adversely affect carbohydrate tolerance. More recently Pi-sunyer and Oster (1968) decided that any such effect is dose-dependent and does not occur with modern low-dosage therapy. A small study in Cardiff has confirmed this and implies that these drugs may actually improve carbohydrate tolerance. as
to
Materials and Methods of childbearing age with no family history of diabetes underwent an intravenous glucose-tolerance test. They then started taking an oral contraceptive and in the fourth cycle had another glucose-tolerance test as near as possible to the same day of the cycle as the first test. All tests were performed in the fasting state after the patient had rested for fifteen minutes. Three initial capillary samples were taken to estimate the fasting blood-glucose level before an intravenous injection of 50 ml. of 50% dextrose. Subsequent capillary samples were taken at four and ten minutes after completion of the injection and then every ten minutes for an hour. Blood-glucose was estimated by the glucose-oxidase method on an ’AutoAnalyzer ’. The fasting level was subtracted from each result to give a net " increment". By plotting these incremental readings against time on semilogarithmic paper and fitting " a straight line through them an increment index " (Duncan 1956) can be obtained which expresses the rate of fall in the blood-glucose level. The higher the index the faster the fall. In practice the points do not always fall exactly along a straight line and judgment of exactly where the line should be is not always easy. In our study this problem was overcome by using computer methods to find the linear-regression equations of logarithm (base 10) of increments on time (minutes) for each of the 42 subjects, and separately for the set of responses recorded before and while taking oral contraceptives. This gave 42
women
"
"
* Present address: Aberdeen Maternity Hospital, Foresterhill, Aberdeen.
(1967b) in Current Concepts in Breast Cancer (edited by Segaloff); p. 120. Baltimore. Spicer, C. C., Thomas, B. S. (1962a) Lancet, ii, 1235. (1962b) ibid. p. 1238. Cancer Bull. (1965) 17, 1106. Cope, C. L. (1965) Adrenal Steroids and Disease p. 210. London. Hayward, J. L., Bulbrook, R. D. (1968) Personal communication. Greenwood, F. C. (1961) Mem. Soc. Endocr. 10, 144. James, V. H. T. (1961) J. Endocr. 22, 195. Kellie, A. E., Wade, A. P. (1957) Biochem. J. 66, 196. Metcalf, M. G. (1963) J. Endocr. 26, 415. Nabarro, J. D. N. (1960) Lancet, i, 1292. Sneddon, A., Steel, J. M., Strong, J. A. (1968) ibid. ii, 892. Snedecor, G. W. (1952) Biometrics, 8, 85. Thomas, B. S., Bulbrook, R. D. (1964) J. Chromat. 14, 28. Willis, R. A. (1967) The Pathology of Tumours; p. 230. London. —
—
— —
—
—
—
—
—
—
A.
858 MEAN AND STANDARD DEVIATIONS OF DIFFERENCES IN SLOPES (INCREMENT INDICES) OF FALLS IN BLOOD-GLUCOSE LEVEL IN 42 WOMEN BEFORE AND WHILE ON ORAL CONTRACEPTIVES
Note: Slope responses in groups B and C on analysis of variances.
are
significantly different
from A
regression coefficients (or slopes) for each patient. The goodness " of fits as judged by the percentage of reduction attributable to linear regression ranged from 78 % to 98 % in the 84 regression fits. In only 1 instance was the linear fit unsatisfactory ; this was due to a recording error in the original data,
two "
and the case
excluded from the series. Statistical tests of done on the differences in slope values before significance and while on oral contraceptives under the alternative hypothesis of some difference. was
were
Results
The accompanying table shows the computerised results in three groups of patients. Group A took one contraceptive tablet daily containing 0-05 mg. mestranol and 1-0 mg. norethisterone. Group B took two of these tablets daily. The patients in group C were on a variety of oral contraceptives prescribed by their general practitioners or family-planning advisers, all of which contained a larger dose of hormone than the tablet of group A. The slope (or increment index) was significantly increased in In both the other groups group-A patients (P<0-02). the slope (index) was reduced, but not significantly so. However, although the slope was increased in group A, the mean value of the blood-glucose readings in all groups was higher when the patients were taking oral contraceptives. This occurred in 32 out of the 42 cases whether the mean was calculated from the absolute glucose values or the incremental values (P<0-005). Discussion
The intravenous glucose-tolerance test was used in preference to the oral test because of its reproducibility (Amatuzio et al. 1953). It also conveniently expresses glucose tolerance in a single figure. Our results confirm the suggestion of Pi-sunyer and Oster (1968) that any effect oral contraceptives have on carbohydrate tolerance is dose-dependent. However, our paper is the first to report actual improvement in carbohydrate tolerance. This could be because small doses of steroid stimulate insulin secretion more than enough to counter any glucocorticoid effect of the drug, while with larger doses the pancreas is unable to respond adequately. Such a situation would mimic pregnancy in normal women, when carbohydrate tolerance is improved slightly over the non-pregnant state, the improvement being most striking in the first and second trimesters and becoming less near the end of pregnancy (Silverstone et al. 1961, Sutherland et al. 1968). There have also been reports of exogenous oestrogens stimulating insulin production in non-pregnant women (Beck and Wells 1968). The finding that mean blood-glucose values are higher in women on oral contraceptives implies that though the pancreatic response and the peripheral action of insulin are adequate they may be slightly delayed, thus allowing a higher than normal value to develop after the intravenous
injection. It is impossible to say whether or not such delay in insulin response represents a diabetic tendency, particularly when it is followed by an increased rate of fall in blood-glucose level. However, this situation is presumably preferable to having a delayed fall in bloodglucose level, and it therefore seems advisable to encourage doctors to prescribe the lowest-dose oral contraceptive suitable for their patients. a
We thank the administrative and medical staff of the South Wales branch of the Family Planning Association; the general practitioners and local-authority doctors, who referred patients for this study; and the department of physics, University College, Cardiff, for access to the S.T.C. Zebra computer. The tablets for groups A and B were supplied by Syntex Pharmaceuticals Ltd. One of us (J. C.) was in receipt of a Hodge Foundation Scholarship. Requests for reprints should be addressed to J. C. REFERENCES
Amatuzio, D. S., Stutzman, F. L., Vanderbilt, M. J., Nesbitt, S. (1953) J. Clin. Invest. 32, 428. Beck, P., Wells, S. A. (1968) Diabetes, 17, suppl. p. 307. Duncan, L. J. P. (1956) Q. Jl exp. Physiol. 41, 85. Gershberg, H., Javier, Z., Hulse, M. (1964) Diabetes, 13, 378. Pi-Sunyer, F. X., Oster, S. (1968) Obstet. Gynec., N.Y. 31, 482. Silverstone, F. A., Solomons, E., Rubricus, J. (1961) J. clin. Invest. 40, 2180. Spellacy, W. N., Carlson, K. L. (1966) Am. J. Obstet. Gynec. 95, 474. Sutherland, H. W., Stowers, J. M., Mackenzie, C., Duncan, R. O. (1968) Medical and Scientific section of British Diabetic Association Meeting.
Aberdeen, Sept. 28, 1968. Wynn, V., Doar, J. W. H. (1966) Lancet, ii,
715.
IgM METABOLISM IN CŒLIAC DISEASE A. G. COOPER G. W. HEPNER &dag er;
D. L. BROWN
FROM THE DEPARTMENT OF MEDICAL
SCHOOL,
HÆMATOLOGY,
*
ROYAL POSTGRADUATE
AND THE MEDICAL RESEARCH COUNCIL INTESTINAL
MALABSORPTION
UNIT,
HAMMERSMITH
HOSPITAL, LONDON W.12
The metabolism of radioiodinated IgM (cold agglutinin) was studied in eleven with untreated cœliac disease and eight patients patients treated with a gluten-free diet. The catabolism and distribution of IgM were normal in every case, suggesting that the hypomacroglobulinæmia which was present in six untreated patients and two treated patients was due to defective synthesis of IgM. This apparently acquired defect of IgM synthesis, responding to a gluten-free diet, may be a further manifestation of the lymphoreticular dysfunction associated with cœliac disease.
Summary
Introduction
Hobbs and Hepner (1968) found IgM deficiency in about two-thirds of patients with untreated cceliac disease; in most cases this deficiency was converted to normal by a gluten-free diet. Usually, the concentrations of other immunoglobulins were within normal limits. The nature of this apparently acquired deficiency of IgM is not known, although Hobbs and Hepner (1968) suggested that defective synthesis of IgM might be a possible cause. We describe here the catabolism and distribution of labelled IgM (purified cold agglutinin) in patients with untreated cceliac disease and in patients who had been treated with a gluten-free diet.
Patients, Materials, and Methods Patients Five male and thirteen female patients with coeliac disease volunteered for this study (cases 1-18). Their ages ranged from * Present address: Blood Research Laboratory, Naval Hospital, Chelsea, Massachusetts. † Present address: Mount Sinai Hospital, New York, N.Y.