- Email: [email protected]
LEUKÆMIA CLUSTERS
783
dealing with heavy mixed cultures, that large numbers of plates can be discarded rapidly as devoid of Pseudomonas pyocyanea, neisseria, or vibrios if no coloured colonies have appeared. Finally, it may be noted that many commercial samples of tetramethyl p-phenylene diamine hydrochloride contain traces of impurities and that, whereas solutions of the pure substance give transient colour reactions, those prepared from the impure products give persistent colour to the reacting colonies. This reaction has been used for many years in the recognition of pseudomonas colonies in cultures of urinary sediments,6 and it is particularly valuable in detecting colonies of pseudomonas overgrown by swarming proteus. Bacteriological Research Unit, advantage, in
Western General
Hospital, Edinburgh.
J. W. MCLEOD.
LEUKÆMIA CLUSTERS
SIR,-Dr. Eileen Wood (Sept. 14) suggests that analysis of the
geographical siting of individual leukaemia cases on large-scale maps may yield useful information. We have done such a topographical surveyof leukaemias (119 cases) over the period 1953-62, in the area served by St. James’ Hospital. Bearing in mind the defects inherent in a survey based on material from a small group of hospitals with one large central hospital, our findings tend to show a dissimilarity in the topographical distribution of acute leukxmias on the one hand and of chronic lymphatic leukaemia on the other. The former had a tendency to focal distribution, whereas the latter were apparently scattered at random. It would be interesting to hear whether other observations elsewhere agree with these findings. Pathological Laboratory, St. James’ Hospital, London, S.W.12.
ALEXANDER SWAN.
TREATMENT OF NON-UNION
SIR,-It is quite obvious from Professor Fraenkel’s letter (Sept. 7) that I have not made myself plain. My contention is that the solution of the problem of nonunion may well lie in the fields of clinical research rather than the narrower confines of the laboratory. Because of the nature of the problem the vast majority of the clinical material, in this country at any rate, is to be found in the non-teaching hospitals. The lack of diagnostic and operation indices makes the gathering of this material virtually impossible. I did suggest an administrative mechanism whereby this clinical material could be made available both by better staffed and organised medical records departments and by means of temporary schedules of notifiable conditions (much on the lines of infectious diseases). If, of course, consultants wished to notify the conditions under investigation this is then presumably up to them to collect the few shillings for their trouble. Having located the clinical material, then I suggest that it is essential for someone, probably a research registrar or possibly an itinerant consultant, to go round and review records and preferably patients. I suggested this research work should be attached to a teaching unit and I naturally- assumed that one of the senior consultant staff would be in charge of the project and take a lively interest in its work. I suspect that Professor Fraenkel does not appreciate the formidable difficulties presented to the busy surgeon with wide interests outside his profession wishing to undertake clinical research in many non-teaching hospitals. If I may be permitted an instance. I am at the moment investigating a 10 years’ series of fractures of the neck of the femur. The 6. 7.
Gould, J. C., McLeod, J. W. ibid. 1960, 79, 295. Swan, A., Petrelli, M., Surtees, J. S. Proceedings of 9th Congress of European Society of Hæmatology, Lisbon, 1963. In the press.
only way in which I can extract the records is by going steadily through the operation registers of three operating-theatres and the admission books of six wards. This has to be done without anv
clerical
or
medical assistance.
GUY
RIGBY-JONES.
INSULIN ANTIBODIES
SIR, The article by Dr. Pav and others (Aug. 3) is a important contribution to our knowledge of diabetes. There are, however, implications to be drawn from this report which evidently may have not been considered. very
During the past several years we have reported on the prevalence of a disseminated proliferative angiopathy in maturityonset diabetes which not only involves the eye, kidney, islets of Langerhans, and peripheral nerves, but also occurs in other organs and in the placenta of diabetic mothers.1-7 These vascvlar lesions as well as others (hyalinisation of islets of Langerhans, nodular hyaline glomerulosclerosis, and retinal vascular aneurysms) linked with diabetes have been shown by fluorescence microscopy specifically to bind fluorescein-conjugated insulin.67We have interpreted these observations as indicating that insulin antibodies are present in these various lesions which bind the fluorescent insulin. More recently, in as yet unreported experiments, we have succeeded in demonstrating that complement is also present in these lesions. Such reactions have been found in diabetic subjects who have never received endogenous insulin as well as in those who have been on hormone therapy. They have also been found in a very small proportion of non-diabetic subjects. On the basis of these observations and certain other considerations we have proposed the concept that maturity-onset diabetes may be an autoimmune disease involving the development of a hypersensitivity to an altered endogenous insulin. Pav et al. have interpreted the occurrence of circulating insulin antibodies in 4% of healthy subjects and in 25% of diabetic individuals who have never received insulin as also being due to some alteration in endogenous insulin which renders the hormone antigenic. They suggested that such an alteration in insulin may be the consequence of an inflammatory process in the pancreas. Our hypothesis is an entirely different one. We view maturityonset diabetes as essentially an ageing process. Evidence is at hand 8-1° showing that glucose tolerance deteriorates with age, although, in many instances, it does not become sufficiently abnormal to warrant a diagnosis of definitive diabetes. The incidence of diabetes also increases with advancing age." Recently, Comfort 12 has reviewed evidence linking mutations, autoimmunity, and ageing. Such a linking is based on the occurrence of "a progressive accumulation of faulty copying in clonally dividing cells " with advancing age. This may take place in lymphoid cells as proposed by Burnet 13, in which case there would occur a change in the self-recognition mechanism of the body. It might also occur in a variety of parenchymal cells and result in an altered synthesis of secretory products of such cells. In the case under consideration, if it occurs in the beta cells of the islets of Langerhans, an altered insulin might result. Our studies are aimed at testing this possibility. Several known phenomena support this thesis. The incidence of hyalinisation of the islets of Langerhans increases 1. 2. 3. 4. 5.
6. 7. 8. 9.
10. 11. 12. 13.
Burstein, R., Soule, S. D., Blumenthal, H. T. Amer. J. Obstet. Gynec. 1959, 74, 96. Goldenberg, S., Alex, M., Blumenthal, H. T. Diabetes, 1959, 8, 261. Blumenthal, H. T., Alex, M., Goldenberg, S. Arch. Path. 1960, 70, 13. Blumenthal, H. T., Alex, M., Goldenberg, S. Amer. J. Med. 1961, 31, 1961. Alex, M., Baron, E. C., Goldenberg, S., Blumenthal, H. T. Circulation, 1962, 25, 663. Berns, A. W., Owens, C. T., Hirata, Y., Blumenthal, H. T. Diabetes, 1962, 11, 296, 308. Berns, A. W., Owens, C. T., Blumenthal, H. T. In the press. De Sandre, G., Ghiotto, G. Gior. Gerontol. 1959, 7, 685. Gottfried, S. P., Fels, K. S., Clifford, R. C. Amer. J. med. Sci. 1961, 242, 475. Brandt, R. L. in Aging Around the World: Medical and Clinical Aspects of Aging (edited by H. T. Blumenthal); p. 3. New York, 1960. Wilkerson, H. L. C., Krall, L. P. J. Amer. med. Ass. 1947, 135, 1947. Comfort, A. Lancet, 1963, ii, 138. Burnet, F. M. Brit. med. J. 1959, ii, 645.
dealing with heavy mixed cultures, that large numbers of plates can be discarded rapidly as devoid of Pseudomonas pyocyanea, neisseria, or vibrios if no coloured colonies have appeared. Finally, it may be noted that many commercial samples of tetramethyl p-phenylene diamine hydrochloride contain traces of impurities and that, whereas solutions of the pure substance give transient colour reactions, those prepared from the impure products give persistent colour to the reacting colonies. This reaction has been used for many years in the recognition of pseudomonas colonies in cultures of urinary sediments,6 and it is particularly valuable in detecting colonies of pseudomonas overgrown by swarming proteus. Bacteriological Research Unit, advantage, in
Western General
Hospital, Edinburgh.
J. W. MCLEOD.
LEUKÆMIA CLUSTERS
SIR,-Dr. Eileen Wood (Sept. 14) suggests that analysis of the
geographical siting of individual leukaemia cases on large-scale maps may yield useful information. We have done such a topographical surveyof leukaemias (119 cases) over the period 1953-62, in the area served by St. James’ Hospital. Bearing in mind the defects inherent in a survey based on material from a small group of hospitals with one large central hospital, our findings tend to show a dissimilarity in the topographical distribution of acute leukxmias on the one hand and of chronic lymphatic leukaemia on the other. The former had a tendency to focal distribution, whereas the latter were apparently scattered at random. It would be interesting to hear whether other observations elsewhere agree with these findings. Pathological Laboratory, St. James’ Hospital, London, S.W.12.
ALEXANDER SWAN.
TREATMENT OF NON-UNION
SIR,-It is quite obvious from Professor Fraenkel’s letter (Sept. 7) that I have not made myself plain. My contention is that the solution of the problem of nonunion may well lie in the fields of clinical research rather than the narrower confines of the laboratory. Because of the nature of the problem the vast majority of the clinical material, in this country at any rate, is to be found in the non-teaching hospitals. The lack of diagnostic and operation indices makes the gathering of this material virtually impossible. I did suggest an administrative mechanism whereby this clinical material could be made available both by better staffed and organised medical records departments and by means of temporary schedules of notifiable conditions (much on the lines of infectious diseases). If, of course, consultants wished to notify the conditions under investigation this is then presumably up to them to collect the few shillings for their trouble. Having located the clinical material, then I suggest that it is essential for someone, probably a research registrar or possibly an itinerant consultant, to go round and review records and preferably patients. I suggested this research work should be attached to a teaching unit and I naturally- assumed that one of the senior consultant staff would be in charge of the project and take a lively interest in its work. I suspect that Professor Fraenkel does not appreciate the formidable difficulties presented to the busy surgeon with wide interests outside his profession wishing to undertake clinical research in many non-teaching hospitals. If I may be permitted an instance. I am at the moment investigating a 10 years’ series of fractures of the neck of the femur. The 6. 7.
Gould, J. C., McLeod, J. W. ibid. 1960, 79, 295. Swan, A., Petrelli, M., Surtees, J. S. Proceedings of 9th Congress of European Society of Hæmatology, Lisbon, 1963. In the press.
only way in which I can extract the records is by going steadily through the operation registers of three operating-theatres and the admission books of six wards. This has to be done without anv
clerical
or
medical assistance.
GUY
RIGBY-JONES.
INSULIN ANTIBODIES
SIR, The article by Dr. Pav and others (Aug. 3) is a important contribution to our knowledge of diabetes. There are, however, implications to be drawn from this report which evidently may have not been considered. very
During the past several years we have reported on the prevalence of a disseminated proliferative angiopathy in maturityonset diabetes which not only involves the eye, kidney, islets of Langerhans, and peripheral nerves, but also occurs in other organs and in the placenta of diabetic mothers.1-7 These vascvlar lesions as well as others (hyalinisation of islets of Langerhans, nodular hyaline glomerulosclerosis, and retinal vascular aneurysms) linked with diabetes have been shown by fluorescence microscopy specifically to bind fluorescein-conjugated insulin.67We have interpreted these observations as indicating that insulin antibodies are present in these various lesions which bind the fluorescent insulin. More recently, in as yet unreported experiments, we have succeeded in demonstrating that complement is also present in these lesions. Such reactions have been found in diabetic subjects who have never received endogenous insulin as well as in those who have been on hormone therapy. They have also been found in a very small proportion of non-diabetic subjects. On the basis of these observations and certain other considerations we have proposed the concept that maturity-onset diabetes may be an autoimmune disease involving the development of a hypersensitivity to an altered endogenous insulin. Pav et al. have interpreted the occurrence of circulating insulin antibodies in 4% of healthy subjects and in 25% of diabetic individuals who have never received insulin as also being due to some alteration in endogenous insulin which renders the hormone antigenic. They suggested that such an alteration in insulin may be the consequence of an inflammatory process in the pancreas. Our hypothesis is an entirely different one. We view maturityonset diabetes as essentially an ageing process. Evidence is at hand 8-1° showing that glucose tolerance deteriorates with age, although, in many instances, it does not become sufficiently abnormal to warrant a diagnosis of definitive diabetes. The incidence of diabetes also increases with advancing age." Recently, Comfort 12 has reviewed evidence linking mutations, autoimmunity, and ageing. Such a linking is based on the occurrence of "a progressive accumulation of faulty copying in clonally dividing cells " with advancing age. This may take place in lymphoid cells as proposed by Burnet 13, in which case there would occur a change in the self-recognition mechanism of the body. It might also occur in a variety of parenchymal cells and result in an altered synthesis of secretory products of such cells. In the case under consideration, if it occurs in the beta cells of the islets of Langerhans, an altered insulin might result. Our studies are aimed at testing this possibility. Several known phenomena support this thesis. The incidence of hyalinisation of the islets of Langerhans increases 1. 2. 3. 4. 5.
6. 7. 8. 9.
10. 11. 12. 13.
Burstein, R., Soule, S. D., Blumenthal, H. T. Amer. J. Obstet. Gynec. 1959, 74, 96. Goldenberg, S., Alex, M., Blumenthal, H. T. Diabetes, 1959, 8, 261. Blumenthal, H. T., Alex, M., Goldenberg, S. Arch. Path. 1960, 70, 13. Blumenthal, H. T., Alex, M., Goldenberg, S. Amer. J. Med. 1961, 31, 1961. Alex, M., Baron, E. C., Goldenberg, S., Blumenthal, H. T. Circulation, 1962, 25, 663. Berns, A. W., Owens, C. T., Hirata, Y., Blumenthal, H. T. Diabetes, 1962, 11, 296, 308. Berns, A. W., Owens, C. T., Blumenthal, H. T. In the press. De Sandre, G., Ghiotto, G. Gior. Gerontol. 1959, 7, 685. Gottfried, S. P., Fels, K. S., Clifford, R. C. Amer. J. med. Sci. 1961, 242, 475. Brandt, R. L. in Aging Around the World: Medical and Clinical Aspects of Aging (edited by H. T. Blumenthal); p. 3. New York, 1960. Wilkerson, H. L. C., Krall, L. P. J. Amer. med. Ass. 1947, 135, 1947. Comfort, A. Lancet, 1963, ii, 138. Burnet, F. M. Brit. med. J. 1959, ii, 645.