- Email: [email protected]
SERUM-ZINC AND HEALING OF VENOUS LEG ULCERS
41 TABLE II-PEAK INSULIN VALUES
this labile pool from a larger storage compartment.3 In the isolated perfused rat pancreas, D.P.H. inhibits both phases of I.R.I. release. Diazoxide inhibits I.R.I. release from the labile pool, but continues to allow insulin to be provided by the larger storage compartment. These studies suggest that D.P.H. has a theoretical advantage over diazoxide for blockade of insulin release. The results obtained in our patient are consistent with this view. D.P.H. therefore appears to be a promising agent in the treatment of selected patients with insulinoma. Pro-insulin levels were measured by Dr. Phillip Gorden, National Institute of Arthritis and Metabolic Diseases, Bethesda.
Endocrinology Branch, Medical Service, Naval Hospital, National Naval Medical Center, Bethesda, Maryland 20014, U.S.A.
M. S. COHEN R. H. BOWER S. M. FIDLER R. E. JOHNSONBAUGH J. SODE.
surgical patients with acute conditions in the Government surgical unit at Queen Mary Hospital. In addition, the percentage of dry cerumen among breast-cancer patients surviving five years or more was compared with that in patients whose cancer was diagnosed in 1971. To examine further whether cerumen type might reflect an intrinsic factor influencing the survival of breast-cancer patients, the system described by Bloom and Richardson9 was used to determine histological grade in a number of breast-cancer patients with known cerumen types. As the accompanying table shows, we found no significant differences in the frequencies of the allele for dry cerumen in breast-cancer patients, inpatients with various other malignant diseases, patients with thyrotoxicosis, and control patients and subjects. No correlation was found between the percentage of wet cerumen among breastcancer patients who had survived for five years or more and that in patients whose cancers were diagnosed in 1971; however, it should be emphasised that survival is related to early diagnosis and treatment, No significant relationship was found between cerumen type and the histological grade of the tumour. Thus, results of the present large-scale case-control study of Chinese women in Hong Kong do not support the hypothesis of a genetic apocrine factor in susceptibility to breast cancer. If an association exists it must be an indirect one.
EVIDENCE AGAINST ASSOCIATION BETWEEN WET CERUMEN AND BREAST CANCER
G. W. Hooper Foundation, University of California, School of Medicine, San Francisco, California 94122, U.S.A.
Radiotherapy Division, Queen Mary Hospital, University of Hong Kong, Hong Kong.
SIR,-Petrakissuggested a possible association between wet cerumen and human breast cancer. The hypothesis was formed following the observation of a correlation in several countries between the frequency of the wet allele and the mortality-rate from breast cancer. The hypothesis seemed reasonable because the breast and the ceruminous gland, in addition to being apocrine glands, share many biochemical A twofold but statistically insignificant characteristics. higher proportion of wet cerumen was found among 31 Japanese women in California with breast cancer than in Japanese control women. It was noted that statistical confirmation of these case-control studies would require far larger numbers of Japanese women with breast cancer than are found in California. We now report a test of the hypothesis among Chinese women in Hong Kong, a population significantly dimorphic for cerumen. Methods for examining the external ear canal and the defining characteristics of the cerumen types have been described. Patients with breast cancer or other malignant diseases were seen at the radiotherapy division at Queen Mary Hospital and at Nam Long Hospital, both in Hong Kong. The control group consisted of healthy individuals and outpatients at various clinics in Hong Kong and 7. 8.
Petrakis, N. L. Science, 1971, 173, 347. Matsunaga, E. Ann. hum. Genet. 1962, 25, 273. CERUMEN PHENOTYPES AND
FREQUENCY
ROY ING NICHOLAS L. PETRAKIS.
H. C. Ho.
SERUM-ZINC AND HEALING OF VENOUS LEG ULCERS
SIR,-We were very interested in the work of Dr. Hallbook and Dr. Lanner (Oct. 14, p. 780) and in their findings of a direct relation between serum-zinc levels and healing of leg ulcers. This adds to the accumulating evidence of a possible role for zinc in tissue repair. It seems from their paper, however, that serum-zinc levels in legulcer patients were compared with an arbitrary value of 110 tig. per 100 ml., implying that levels below that figure were subnormal. In a healthy population, serum-zinc levels fall in a range distributed around a mean value, so that figures below or above this mean may also be considered normal. The mean serum-zinc level in the group of patients under discussion is calculated to be 116 g. per 100 ml. and, in the light of the reference value used, this does not support the view that zinc deficiency is a 9.
Bloom,
H.
J. G., Richardson, W. W. Br. J. Cancer, 1957, 11,
OF ALLELE FOR DRY CERUMEN AMONG CHINESE PATIENTS IN HONG KONG
359.
42 feature of
venous leg ulcers. The fact that zinc-treated patients healed equally well regardless of their initial serum-zinc levels suggests that zinc therapy may be acting through other mechanisms than simple correction of a deficiency ".
TREATMENT OF BREAST CANCER
Gardner and I treated two cases of cholecystitis with both preparations with apparently good results, but I would not now draw any inference from these cases. We also treated a few cases of gallstones for over a year with deoxycholic acid. In retrospect, our dosage was probably timorous. We did not have any success. I am not able to discuss the authors’ theory; determination of the solubilising capacity depends, as they note, on spot analysis " of bile obtained from the duodenum, and it could not be expected to reflect the diurnal changes of gallbladder bile during filling, concentration, and emptying
SIR,-While sharing the dissatisfaction of Dr. Edelstyn and Dr. MacRae (Dec. 16, p. 1307) with presentday localised treatment of breast cancer, I feel disquiet
It is a pity, however, that the authors did not reverse the methodology and proceed to test the validity of the solubilising-capacity ratio by their clinical results. Their
the prospect of a trial of combination chemotherapy’in the earlier stages of the disease. Cyclical combination chemotherapy as usually advocated at present means the repeated administration of a combination of drugs such as cyclophosphamide, methotrexate, 5-fluorouracil, and a vinca alkaloid, which may produce
graph shows fifteen of these ratios before and after 3 months’
"
Skin Hospital,
M. M. MOLOKHIA B. PORTNOY.
Quay Street, Manchester M3 3HL.
"
phases.
at
distressing side-effects including nausea, vomiting, and epilation, beside the risk of bone-marrow depression. While we all wish to explore every avenue that may lead reduction in the toll of breast cancer, I trust that our of responsibility towards the individual patient and our concern for her welfare will lead us to exercise the greatest care before subjecting her to anything that In our anxiety to may only increase her distress. reduce the ravages of breast cancer let us not forget the dictum " Primum non nocere ".
treatment; of these, five cases show an increase of this ratio of between 30 and 75 %. I ask now if these were the cases with the maximum radiological improvement ? 37 Clifton Hill, St. John’s Wood, London N.W.8.
HUGH GAINSBOROUGH.
to a
SCURVY IN THE ANTARCTIC
sense
Department of Radiotherapy, The London Hospital,
SIR,-Dr. Butson’s account (Nov. 25, p. 1146) of the development of scurvy in the Antarctic is fascinating. I am wondering how he would explain the scorbutic-like signs in husky dogs during his journey in 1947. Ascorbic acid is not a dietary essential for these animals because they are capable of synthesising the vitamin. 5 Elm
B. S. MANTELL.
London E.1.
Court,
Rydens Road, Walton-on-Thames KT12 3AD.
GALLSTONE DISSOLUTION BY CHENODEOXYCHOLIC ACID
gallstone dissolution by Dr. Bell and his colleagues (Dec. 9, p. 1213) is very encouraging. Over 40 years ago John Addyman Gardner and I1 were led by three sets of data to attempt such dissolution by using mixed deoxycholic acids. Wieland and his associates2 had enunciated " the choleic-acid principle " following their demonstration that the sodium salt of deoxycholic acid could combine with many water-insoluble substances such as higher fatty acids, cholesterol, strychnine, &c., to form stable chemical compounds soluble in water: this principle was not applicable to certain synthetic conjugated acids, including the anthropodeoxycholic acid which, however, could take up small quantities of some SIR The contribution
1. 2.
Gardner, J. A., Gainsborough, H. Q. Jl Med. 1930, 23, 465. Wieland, H., Sorge, H. Hoppe-Seylers Z. physiol. Chem. 97,
SMALL DOSES OF SUBCUTANEOUS HEPARIN AND POSTOPERATIVE DEEP
on
water-insoluble substances. This latter acid was identical with chenodeoxycholic acid found in human, goose, and ox bile. Secondly, Neubauer3 had shown that deoxycholic acid could increase the flow of hepatic bile which, a year later, Brugsch and Horsterspreferred to describe as a choleretic action to distinguish it from cholagogic, which was gallbladder emptying. Thirdly, we knew from Harley and Barratt5 and from Aoyama 6 that human gallstones placed in the dog’s gallbladder disappeared within 6 months if there was no infection. There was available to us at that time an oral preparation of deoxycholic acid, probably prepared from ox bile, and also an intravenous preparation of a keto-acid-dehydrocholic acid, said to be a powerful choleretic.
1.
3. Neubauer, E. Biochem. Zeit. Berlin, 1922, 80, 556. 4. Brugsch, T., Horsters, H. Z. ges. exp. Med. 1923, 88, 367. 5. Harley, V., Barratt, W. J Physiol., Lond. 1903, 29, 341. 6. Aoyama, T. Beitr. path. Anat. 1914, 57, 168.
J. A. SALMON.
VENOUS THROMBOSIS
SIR,—Isympathise with Dr. Poole-Wilson’s bewilder(Nov. 18, p. 1089) over the current obsession with
ment
" low-dose
heparin " as the long-sought elixir for postoperative deep-vein thrombosis and subsequent pulmonary embolism. This obsession will lead to a muddle unless we are careful. The important point, the one that is being obscured, is the time, relative to the operation, at which the heparin is given. Ten years ago we discovered that the venous stasis which predisposes to thrombosis in the deep veins of the leg in surgical patients develops during the operation and not a week later in the ward.1 It has been stated that 90%% of all postoperative deep-vein thrombosis starts in the
operating-theatre.2 Sevitt and Gallagher3 had clearly shown, even earlier, that heparin effectively prevented deep-vein thrombosis in elderly patients, provided it was started preoperatively. Admittedly, it is biochemically more elegant to prevent the conversion of prothrombin into thrombin by preoperatively neutralising activated factor x (Stuart) by stimulating antithrombin ill with a dose of 5000 units of heparin than crudely preventing the conversion of fibrinogen into fibrin by thrombin with a dose of 10,000 units of
heparin. The claim is that 10,000 units results in
postoperative
1916, Doran, F. S. A., Drury, M., Sivyer, A. Br. J. Surg. 1964, 51, 486. Nicolaides, A. N., Dupont, P. A., Desai, S., Lewis, J. D., Douglas, J. N., Dodsworth, H., Fourides, G., Luck, R. J., Jamieson, C. W. Lancet, 1972, ii, 890. 3. Sevitt, S., Gallagher, N. G. ibid. 1959, ii, 981.
1. 2.
this labile pool from a larger storage compartment.3 In the isolated perfused rat pancreas, D.P.H. inhibits both phases of I.R.I. release. Diazoxide inhibits I.R.I. release from the labile pool, but continues to allow insulin to be provided by the larger storage compartment. These studies suggest that D.P.H. has a theoretical advantage over diazoxide for blockade of insulin release. The results obtained in our patient are consistent with this view. D.P.H. therefore appears to be a promising agent in the treatment of selected patients with insulinoma. Pro-insulin levels were measured by Dr. Phillip Gorden, National Institute of Arthritis and Metabolic Diseases, Bethesda.
Endocrinology Branch, Medical Service, Naval Hospital, National Naval Medical Center, Bethesda, Maryland 20014, U.S.A.
M. S. COHEN R. H. BOWER S. M. FIDLER R. E. JOHNSONBAUGH J. SODE.
surgical patients with acute conditions in the Government surgical unit at Queen Mary Hospital. In addition, the percentage of dry cerumen among breast-cancer patients surviving five years or more was compared with that in patients whose cancer was diagnosed in 1971. To examine further whether cerumen type might reflect an intrinsic factor influencing the survival of breast-cancer patients, the system described by Bloom and Richardson9 was used to determine histological grade in a number of breast-cancer patients with known cerumen types. As the accompanying table shows, we found no significant differences in the frequencies of the allele for dry cerumen in breast-cancer patients, inpatients with various other malignant diseases, patients with thyrotoxicosis, and control patients and subjects. No correlation was found between the percentage of wet cerumen among breastcancer patients who had survived for five years or more and that in patients whose cancers were diagnosed in 1971; however, it should be emphasised that survival is related to early diagnosis and treatment, No significant relationship was found between cerumen type and the histological grade of the tumour. Thus, results of the present large-scale case-control study of Chinese women in Hong Kong do not support the hypothesis of a genetic apocrine factor in susceptibility to breast cancer. If an association exists it must be an indirect one.
EVIDENCE AGAINST ASSOCIATION BETWEEN WET CERUMEN AND BREAST CANCER
G. W. Hooper Foundation, University of California, School of Medicine, San Francisco, California 94122, U.S.A.
Radiotherapy Division, Queen Mary Hospital, University of Hong Kong, Hong Kong.
SIR,-Petrakissuggested a possible association between wet cerumen and human breast cancer. The hypothesis was formed following the observation of a correlation in several countries between the frequency of the wet allele and the mortality-rate from breast cancer. The hypothesis seemed reasonable because the breast and the ceruminous gland, in addition to being apocrine glands, share many biochemical A twofold but statistically insignificant characteristics. higher proportion of wet cerumen was found among 31 Japanese women in California with breast cancer than in Japanese control women. It was noted that statistical confirmation of these case-control studies would require far larger numbers of Japanese women with breast cancer than are found in California. We now report a test of the hypothesis among Chinese women in Hong Kong, a population significantly dimorphic for cerumen. Methods for examining the external ear canal and the defining characteristics of the cerumen types have been described. Patients with breast cancer or other malignant diseases were seen at the radiotherapy division at Queen Mary Hospital and at Nam Long Hospital, both in Hong Kong. The control group consisted of healthy individuals and outpatients at various clinics in Hong Kong and 7. 8.
Petrakis, N. L. Science, 1971, 173, 347. Matsunaga, E. Ann. hum. Genet. 1962, 25, 273. CERUMEN PHENOTYPES AND
FREQUENCY
ROY ING NICHOLAS L. PETRAKIS.
H. C. Ho.
SERUM-ZINC AND HEALING OF VENOUS LEG ULCERS
SIR,-We were very interested in the work of Dr. Hallbook and Dr. Lanner (Oct. 14, p. 780) and in their findings of a direct relation between serum-zinc levels and healing of leg ulcers. This adds to the accumulating evidence of a possible role for zinc in tissue repair. It seems from their paper, however, that serum-zinc levels in legulcer patients were compared with an arbitrary value of 110 tig. per 100 ml., implying that levels below that figure were subnormal. In a healthy population, serum-zinc levels fall in a range distributed around a mean value, so that figures below or above this mean may also be considered normal. The mean serum-zinc level in the group of patients under discussion is calculated to be 116 g. per 100 ml. and, in the light of the reference value used, this does not support the view that zinc deficiency is a 9.
Bloom,
H.
J. G., Richardson, W. W. Br. J. Cancer, 1957, 11,
OF ALLELE FOR DRY CERUMEN AMONG CHINESE PATIENTS IN HONG KONG
359.
42 feature of
venous leg ulcers. The fact that zinc-treated patients healed equally well regardless of their initial serum-zinc levels suggests that zinc therapy may be acting through other mechanisms than simple correction of a deficiency ".
TREATMENT OF BREAST CANCER
Gardner and I treated two cases of cholecystitis with both preparations with apparently good results, but I would not now draw any inference from these cases. We also treated a few cases of gallstones for over a year with deoxycholic acid. In retrospect, our dosage was probably timorous. We did not have any success. I am not able to discuss the authors’ theory; determination of the solubilising capacity depends, as they note, on spot analysis " of bile obtained from the duodenum, and it could not be expected to reflect the diurnal changes of gallbladder bile during filling, concentration, and emptying
SIR,-While sharing the dissatisfaction of Dr. Edelstyn and Dr. MacRae (Dec. 16, p. 1307) with presentday localised treatment of breast cancer, I feel disquiet
It is a pity, however, that the authors did not reverse the methodology and proceed to test the validity of the solubilising-capacity ratio by their clinical results. Their
the prospect of a trial of combination chemotherapy’in the earlier stages of the disease. Cyclical combination chemotherapy as usually advocated at present means the repeated administration of a combination of drugs such as cyclophosphamide, methotrexate, 5-fluorouracil, and a vinca alkaloid, which may produce
graph shows fifteen of these ratios before and after 3 months’
"
Skin Hospital,
M. M. MOLOKHIA B. PORTNOY.
Quay Street, Manchester M3 3HL.
"
phases.
at
distressing side-effects including nausea, vomiting, and epilation, beside the risk of bone-marrow depression. While we all wish to explore every avenue that may lead reduction in the toll of breast cancer, I trust that our of responsibility towards the individual patient and our concern for her welfare will lead us to exercise the greatest care before subjecting her to anything that In our anxiety to may only increase her distress. reduce the ravages of breast cancer let us not forget the dictum " Primum non nocere ".
treatment; of these, five cases show an increase of this ratio of between 30 and 75 %. I ask now if these were the cases with the maximum radiological improvement ? 37 Clifton Hill, St. John’s Wood, London N.W.8.
HUGH GAINSBOROUGH.
to a
SCURVY IN THE ANTARCTIC
sense
Department of Radiotherapy, The London Hospital,
SIR,-Dr. Butson’s account (Nov. 25, p. 1146) of the development of scurvy in the Antarctic is fascinating. I am wondering how he would explain the scorbutic-like signs in husky dogs during his journey in 1947. Ascorbic acid is not a dietary essential for these animals because they are capable of synthesising the vitamin. 5 Elm
B. S. MANTELL.
London E.1.
Court,
Rydens Road, Walton-on-Thames KT12 3AD.
GALLSTONE DISSOLUTION BY CHENODEOXYCHOLIC ACID
gallstone dissolution by Dr. Bell and his colleagues (Dec. 9, p. 1213) is very encouraging. Over 40 years ago John Addyman Gardner and I1 were led by three sets of data to attempt such dissolution by using mixed deoxycholic acids. Wieland and his associates2 had enunciated " the choleic-acid principle " following their demonstration that the sodium salt of deoxycholic acid could combine with many water-insoluble substances such as higher fatty acids, cholesterol, strychnine, &c., to form stable chemical compounds soluble in water: this principle was not applicable to certain synthetic conjugated acids, including the anthropodeoxycholic acid which, however, could take up small quantities of some SIR The contribution
1. 2.
Gardner, J. A., Gainsborough, H. Q. Jl Med. 1930, 23, 465. Wieland, H., Sorge, H. Hoppe-Seylers Z. physiol. Chem. 97,
SMALL DOSES OF SUBCUTANEOUS HEPARIN AND POSTOPERATIVE DEEP
on
water-insoluble substances. This latter acid was identical with chenodeoxycholic acid found in human, goose, and ox bile. Secondly, Neubauer3 had shown that deoxycholic acid could increase the flow of hepatic bile which, a year later, Brugsch and Horsterspreferred to describe as a choleretic action to distinguish it from cholagogic, which was gallbladder emptying. Thirdly, we knew from Harley and Barratt5 and from Aoyama 6 that human gallstones placed in the dog’s gallbladder disappeared within 6 months if there was no infection. There was available to us at that time an oral preparation of deoxycholic acid, probably prepared from ox bile, and also an intravenous preparation of a keto-acid-dehydrocholic acid, said to be a powerful choleretic.
1.
3. Neubauer, E. Biochem. Zeit. Berlin, 1922, 80, 556. 4. Brugsch, T., Horsters, H. Z. ges. exp. Med. 1923, 88, 367. 5. Harley, V., Barratt, W. J Physiol., Lond. 1903, 29, 341. 6. Aoyama, T. Beitr. path. Anat. 1914, 57, 168.
J. A. SALMON.
VENOUS THROMBOSIS
SIR,—Isympathise with Dr. Poole-Wilson’s bewilder(Nov. 18, p. 1089) over the current obsession with
ment
" low-dose
heparin " as the long-sought elixir for postoperative deep-vein thrombosis and subsequent pulmonary embolism. This obsession will lead to a muddle unless we are careful. The important point, the one that is being obscured, is the time, relative to the operation, at which the heparin is given. Ten years ago we discovered that the venous stasis which predisposes to thrombosis in the deep veins of the leg in surgical patients develops during the operation and not a week later in the ward.1 It has been stated that 90%% of all postoperative deep-vein thrombosis starts in the
operating-theatre.2 Sevitt and Gallagher3 had clearly shown, even earlier, that heparin effectively prevented deep-vein thrombosis in elderly patients, provided it was started preoperatively. Admittedly, it is biochemically more elegant to prevent the conversion of prothrombin into thrombin by preoperatively neutralising activated factor x (Stuart) by stimulating antithrombin ill with a dose of 5000 units of heparin than crudely preventing the conversion of fibrinogen into fibrin by thrombin with a dose of 10,000 units of
heparin. The claim is that 10,000 units results in
postoperative
1916, Doran, F. S. A., Drury, M., Sivyer, A. Br. J. Surg. 1964, 51, 486. Nicolaides, A. N., Dupont, P. A., Desai, S., Lewis, J. D., Douglas, J. N., Dodsworth, H., Fourides, G., Luck, R. J., Jamieson, C. W. Lancet, 1972, ii, 890. 3. Sevitt, S., Gallagher, N. G. ibid. 1959, ii, 981.
1. 2.