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CYANACETIC ACID HYDRAZIDE
388 described a method of irradiation of the cells of the stomach to reduce acid secretion in conjunction with When there is available a simple and antrectomy. certain method of reducing gastric secretion by vagotomy, is it justifiable to injure the potentially unstable cells of the stomach-and, who knows, those of the pancreas and kidneys We were assured that the dose was small and harmless but it seems to me a sinister coincidence that I have seen two cases of carcinoma of the cardia appear within eighteen months of irradiation of the lower dorsal spine for arthritis. Moreover, should the acini recover their normal powers of secretion, these patients would seem to be likely candidates for stomal ulceration. I submit that progressive investigation must not be confused with change for the sake of change, and that, used selectively in chronic peptic ulcer, the B.I and B.n operations can give a high degree of satisfaction to patients and surgeons alike. D. LANG STEVENSON. Ilford. Essex. SASKATCHEWAN AND SHEFFIELD SiR, Your editorial of July 3 naturally attracted our attention and I wish to thank you for the recognition given to our efforts here to provide needed hospital care to the population of this rural province. At the same time, it may be useful to correct certain minor errors in your account and to offer certain explanations of the unusually high volume of hospital care in Saskatchewan. As to the errors, the Saskatchewan Hospital Services Plan provides for hospitalisation of unlimited duration within the province : the only condition is that the attending physician declares the patient to need the hospital care. The limitation of 60 days per year applies only to hospitalisation of beneficiaries outside of this province, which accounts for less than 3% of cases. The exclusion of care for tuberculosis, mental disease, and blood for transfusions is due, of course, to the fact that these needs are met by other public programmes. Outpatient services, however, are not now covered, except in one area of the province, with 50,000 population, which enjoys a comprehensive medical-care insurance programme. The increase in hospital beds since 1947 has been great, but not quite so great as that implied by the figures you published. The bed capacity in 1947 was 3966, rather than 2966, a figure which rose to 5692 in 1952. It is not quite correct, however, to speak of " beds in existence," since these figures apply to what we speak of as " rated capacity," which is a measure of the number of
hospital can physically accommodate within proper hygienic and medical standards. Because of the high demand for hospitalisation in this prairie region, the beds actually set up in our hospitals have always been somewhat higher-and even more so since the inauguration of our hospital insurance plan. At the end of 1953, for example, the beds actually in existence in general hospitals, or our " bed complement " as we call it, was
beds
a
6211 beds.
As for the reason for our high supply of general hospital beds-which incidentally is the highest of any province or State on this continent-special factors are relevant. Most important, without a doubt, is the system of universal hospital insurance which has covered our population since 1947-the first such programme on this continent. This has made it possible for hospitals to operate and expand, with financial security. Along with this has been an energetic effort on the part of provincial and local governments to support hospital construction and expansion, with some financial aid from the national government since 1948. (The great majority of construction costs, however, are borne by the local people in the communities where our 160 hospitals have been built.) Highly important, however, is the nature of our population settlement and the role played by the hospital in
this setting. Our 861,000 residents are extremely thinly settled on these vast wheat-growing plains ; the density is 3.04 persons per sq. mile. Doctors likewise are thinly settled and most of them practise in isolation or with only one, two, or three colleagues in the community. Under these circumstances, the hospital is used for the treatment of illness, and must be so used, much more frequently than in a highly urban setting like Sheffield With distances or almost any community in England. so great, it is extremely difficult for the doctor to treat a seriously ill patient at home and equally difficult for such a patient to make frequent visits to the doctor’s surgeryor his " office " as we would say. In our urban centres In 1952, we find the rate of hospitalisation much lower. the rate of hospital discharges per 1000 population in our cities (places of 5000 population or more) was 172 per 1000, compared with 216 per 1000 in the rest of the province. And, incidentally, even with our 7-2 beds per 1000 population and 2139 days of patient care per 1000 population per year, many of our hospitals have waitinglists. We are still seeking the answer on the absolute need for hospital beds. Any advice would be appreciated, as would any visitors from Sheffield or elsewhere in Britain who would like to come over and studv our efforts to find the answer. Provincial Health Building
F. B. ROTH
Regina, Saskatchewan, Canada.
Deputy Minister, Saskatchewan.
CYANACETIC ACID HYDRAZIDE
SiR,-The report from the Continent of the tuberculostatic effect of cyanacetic acid hydrazide (C.À.H.),1--3and its clinical trial in this country, prompt us to give a brief account of our own observations. We have studied the in-vitro and in-vivo action of the drug against Jtfycobacterium tuberculosis, using both H37Rv and isoniazidresistant strains. In Dubos-Middlebrook medium containing albumin and ’Tween 80,’ we found the minimum inhibitory concentration of c.A.H. against the normal strain of H37Rv to be about 3 !J.g. per ml. Under the same conditions the minimum inhibitory concentration of p-a.minosalicylic acid is about 10 !J.g. per ml. and that"of isoniazid about 0-03 &mgr;g. per ml. Against a resistant strain, the be of which could inhibited by 7 (Ag. of isoniazid growth per ml., a concentration of 30 jig. of C.A.H. per ml. was required for inhibition of growth. The in-vivo activity of the substance was measured by survival and corneal tests in mice. Using an isoniazidsensitive strain, concentrations of up to 0-04% of C.A.H. in the diet of infected mice had no protective action against the infection, whereas 0-004% of isoniazid protected 80-100% of the animals. Using an isoniazidresistant strain, C.A.11. was similarly ineffective. The toxicity of c.A.ri. was investigated on mice, rats, and guineapigs. The approximate acute oral LD50 for mice was found to be 250 mg. per kg. body.weight (agreeing with published figures) and the comparable figure for isoniazid was 140 mg. From chronic toxicity tests, it appeared that 80 mg. per kg. is a toxic dose of C.A.H. in all three species of animal and that isoniazid is less toxic in rats and guineapigs and rather more toxic in mice. Summarising our results, it seems that cyanacetic acid hydrazide is considerably less active than isoniazid against ]}I. tuberculosis H37Rv and has very little activity against an isoniazid-resistant strain of the organism. Its toxicity is of the same order as that of isoniazid, being somewhat dependent upon the species of animal used. "
Valdecasas, F., Salva, J. A., Puig Muset, P. 1952, 19, 275. 2. Hartl, W. Schweiz. Zschr. Tuberk. 1954, 11, 65. 3. Scheu, H. Ibid, p. 77. 1. Garcia
Med. clin.
389 These results, although very diHeonrt)in, may not value, necessarily indicate that the drug is of no <’)ini<’a! since we are aware of isolated reports of benefit in a Funall number of patients. E. M. BAVIN Smith & Nephew Research Ltd., D. E. SEYMOUR. Hunsdon, Ware, Herts. CEREBRAL BASIS OF TEMPERAMENT AND PERSONALITY
SiR,ņMay
I reflect upon the letter
by
Dr.
Alan
McGlashan in your issue of July 31?f He writes that " few ... now deny that temperament and personality have a cerebral aspect ; and perhaps fewer still deny that they have a psychic aspect of precisely equal validity. It is both possible. and rational to approach the problems ... from the cerebral aspect or from the psychic aspect ..." and " it is true that the link between psyche and soma ... is still to seek "
(my
own
contain
italics).
It
seems
to
me
that these statements
antitheses. a cardinal Being problem of psychology and psychiatry, it would be very interesting to see just what is the essence of a rational approach from the psychic aspect when the link between psyche and soma is still to seek. The perusal of his deduction leaves one with the impression that he still dwells on the lines of the psychophysical parallelism of Descartes the monadology of Leibnitz, 3ond the Freudian statement that there is a science of mind as distinct from the science of matter. This proposition of dual existence which is said to be never intersecting and yet constantly interacting is clearly inadmissible in the absence of medieval thinkimr. But the ways of science and religion have long parted. While the cerebral aspect has developed into a serious science, the psychic aspect has remained, as it were, a little more than a theological and teleological dogmatism of the rationalistic school of philosophy. Where are the proofs for the psychic aspect of precisely equal validity," say, in the absence of hearing and vision f I suggest that this dualism is apparent rather than real. The link could never be established without the destruction of the very theory which bore it. In this internal contradiction lies the fate of the rationalistic thinking. In fact, this reducing process is well advanced already. The Kantian idea of Space as related to Matter has been resolved by Einstein in his " Theory of Relativity " resulting in the realisation of nuclear fission. And I believe that it contains also the answer for the remaining part of the problem-namely the mind, whose dimensions are expressed by the terms of Time. J. W. MULLNER. Nottingham.
multiple
tant, a,nd Brunner goes
ship
search for
response to the request, in your leader of for additional information concerning links between cancer and other metabolic processes, and with specific reference to the association of bronehogenic carcinoma with neurologic and myopathic phenomena, I should like to comment on the possible relationship between malignancy and collagen disorders. There is some evidence that there may be an association, if not an eetiological relationship, between bronchogenic carcinoma and deriiiatoniyositis 1 ; and there are a number of documented examples of other collagen disorders occurring in association with malignancy of the ovary, stomach, breast, and reticulo-endothelial system.2-5 It is conceivable that the example you cite of Jarcho’s syndrome may fall in this collagen category. Dermatomyositis appears to be the commoner collagen concormi-
SlR,—In
July 10,
1. McCombs, R. 31, 1148.
P., MacMahon,
H. E.
Med. Clin. N. Amer.
1949,
2. Dostrovsky, A., Sagher, F. Brit. J. Derm. 1946, 58, 52. 3. Lipman, M. P., Tober, J. N. Gastroenterol. 1950, 16, 188. 4. Cottel, C. E. Amer. J. med. Sci. 1952, 224, 160. 5. Brunner, J., Lobriaco, R. U. Ann. intern. Med. 1951, 34, 1269.
far
as
in all
cases
of dermato-
myositis, as is done in acanthosis nigrioans. Although the exact nature of this phenomenon is not clear, it is tempting to suggest a type of allergic sensitivity reaction, similar to those seen in infection or drug toxicity. The sensitising agent in this instance might be the degradation products of degenerating malignant tissue. Evidence for such an allergic basis is provided by the frequent occurrence of eosinophilia, and the development of urticaria, erythema multiforme, and erythema nodosum in these disorders. Finally, the association of acanthosis
nigricans
and
carcinoma, in approximately 50% of cases of the former condition, offers another example of the curious relationthat
ship
may exist
between
malignancy
and other
processes.
The
Johns Hopkins Hospital, Baltimore, Maryland.
PAUL J. ROSCH.
SURVIVAL OF CARTILAGE HOMOGRAFTS
SIR,—In the Simpson Smith memorial lecture, published in your issue of Aug. 7, Professor Rob says in of his conclusion : "... with the certain identical twins and the possible exception of the cornea - a successful homologous graft has yet to be achieved." In experiments recently completed in this department, cartilage homografts survived in the rabbit eighteen This confirms results months after implantation.’ recorded by Gillies (1920), Loeb (1926), Peer (1938 and 1939), together with more recent work. To suggest that homografts of cornea and cartilage survive because they are avascular merely begs the question, or rather ignores the question of the particular chemical structure of cartilasre and cornea.
exception
Department of Anatomy, University of Glasgow.
"
MALIGNANCY AND COLLAGEN DISORDERS
to say that the relationenough to justify an intense
so
frequently malignancy as a routine
occurs
GEORGE M. WYBURN.
SYMPHYSIOTOMY your review of Aug. 7 of Mr. Aleck Bourne’s of Obstetrics and Gyrccccotogy, you say : " The
SIR,—In
Synopsis
author of a medical textbook, as he hints in his preface, is constantly tempted to retain matter which he knows to be outdated, merely because examiners will demand to be informed about the archaic ; and it is doubtless for this reason that symphysiotomy and pubiotomy still find a corner in the new edition." It would appear from this statement that you regard the operation of symphysiotomy as both outdated and archaic. This astonishing statement cannot be allowed to go unchallenged. The operation of symphysiotomy, if correctly performed, is not only a simple and safe operation but in a suitable case eminently satisfactory for both mother and child ; and it has the additional benefit of permanently enlarging the maternal pelvis, and making operative -interference unnecessary in future pregnancies. This operation fell into disrepute when abdominal surgery became safe, and cæsarean section capable of performance by the " veriest tyro." In recent years it has been revived in these islands by Spain and Barry at the National Maternity Hospital in Dublin. Since then, judging by the reports of the discussions at various scientific meetings, it has become the subject of heated discussion and emotional outbursts. Without entering into the more controversial indications for its use, I think that it can safely be stated that for the expectant mother who has had a trial of labour, or who is seen for the first time with the cervix fully dilated and the head impacted in the mid-strait, and who, one feels, could be delivered per via naturales with a. small increase in pelvic size, there is no more satisfactory operation than that of symphysiotomy. The patient. has less discomfort than after a csesarean section and can walk without difficulty in 10 to 14 days. 1.
Transplant. Bull. IV., July, 1954, p. 136.
hospital can physically accommodate within proper hygienic and medical standards. Because of the high demand for hospitalisation in this prairie region, the beds actually set up in our hospitals have always been somewhat higher-and even more so since the inauguration of our hospital insurance plan. At the end of 1953, for example, the beds actually in existence in general hospitals, or our " bed complement " as we call it, was
beds
a
6211 beds.
As for the reason for our high supply of general hospital beds-which incidentally is the highest of any province or State on this continent-special factors are relevant. Most important, without a doubt, is the system of universal hospital insurance which has covered our population since 1947-the first such programme on this continent. This has made it possible for hospitals to operate and expand, with financial security. Along with this has been an energetic effort on the part of provincial and local governments to support hospital construction and expansion, with some financial aid from the national government since 1948. (The great majority of construction costs, however, are borne by the local people in the communities where our 160 hospitals have been built.) Highly important, however, is the nature of our population settlement and the role played by the hospital in
this setting. Our 861,000 residents are extremely thinly settled on these vast wheat-growing plains ; the density is 3.04 persons per sq. mile. Doctors likewise are thinly settled and most of them practise in isolation or with only one, two, or three colleagues in the community. Under these circumstances, the hospital is used for the treatment of illness, and must be so used, much more frequently than in a highly urban setting like Sheffield With distances or almost any community in England. so great, it is extremely difficult for the doctor to treat a seriously ill patient at home and equally difficult for such a patient to make frequent visits to the doctor’s surgeryor his " office " as we would say. In our urban centres In 1952, we find the rate of hospitalisation much lower. the rate of hospital discharges per 1000 population in our cities (places of 5000 population or more) was 172 per 1000, compared with 216 per 1000 in the rest of the province. And, incidentally, even with our 7-2 beds per 1000 population and 2139 days of patient care per 1000 population per year, many of our hospitals have waitinglists. We are still seeking the answer on the absolute need for hospital beds. Any advice would be appreciated, as would any visitors from Sheffield or elsewhere in Britain who would like to come over and studv our efforts to find the answer. Provincial Health Building
F. B. ROTH
Regina, Saskatchewan, Canada.
Deputy Minister, Saskatchewan.
CYANACETIC ACID HYDRAZIDE
SiR,-The report from the Continent of the tuberculostatic effect of cyanacetic acid hydrazide (C.À.H.),1--3and its clinical trial in this country, prompt us to give a brief account of our own observations. We have studied the in-vitro and in-vivo action of the drug against Jtfycobacterium tuberculosis, using both H37Rv and isoniazidresistant strains. In Dubos-Middlebrook medium containing albumin and ’Tween 80,’ we found the minimum inhibitory concentration of c.A.H. against the normal strain of H37Rv to be about 3 !J.g. per ml. Under the same conditions the minimum inhibitory concentration of p-a.minosalicylic acid is about 10 !J.g. per ml. and that"of isoniazid about 0-03 &mgr;g. per ml. Against a resistant strain, the be of which could inhibited by 7 (Ag. of isoniazid growth per ml., a concentration of 30 jig. of C.A.H. per ml. was required for inhibition of growth. The in-vivo activity of the substance was measured by survival and corneal tests in mice. Using an isoniazidsensitive strain, concentrations of up to 0-04% of C.A.H. in the diet of infected mice had no protective action against the infection, whereas 0-004% of isoniazid protected 80-100% of the animals. Using an isoniazidresistant strain, C.A.11. was similarly ineffective. The toxicity of c.A.ri. was investigated on mice, rats, and guineapigs. The approximate acute oral LD50 for mice was found to be 250 mg. per kg. body.weight (agreeing with published figures) and the comparable figure for isoniazid was 140 mg. From chronic toxicity tests, it appeared that 80 mg. per kg. is a toxic dose of C.A.H. in all three species of animal and that isoniazid is less toxic in rats and guineapigs and rather more toxic in mice. Summarising our results, it seems that cyanacetic acid hydrazide is considerably less active than isoniazid against ]}I. tuberculosis H37Rv and has very little activity against an isoniazid-resistant strain of the organism. Its toxicity is of the same order as that of isoniazid, being somewhat dependent upon the species of animal used. "
Valdecasas, F., Salva, J. A., Puig Muset, P. 1952, 19, 275. 2. Hartl, W. Schweiz. Zschr. Tuberk. 1954, 11, 65. 3. Scheu, H. Ibid, p. 77. 1. Garcia
Med. clin.
389 These results, although very diHeonrt)in, may not value, necessarily indicate that the drug is of no <’)ini<’a! since we are aware of isolated reports of benefit in a Funall number of patients. E. M. BAVIN Smith & Nephew Research Ltd., D. E. SEYMOUR. Hunsdon, Ware, Herts. CEREBRAL BASIS OF TEMPERAMENT AND PERSONALITY
SiR,ņMay
I reflect upon the letter
by
Dr.
Alan
McGlashan in your issue of July 31?f He writes that " few ... now deny that temperament and personality have a cerebral aspect ; and perhaps fewer still deny that they have a psychic aspect of precisely equal validity. It is both possible. and rational to approach the problems ... from the cerebral aspect or from the psychic aspect ..." and " it is true that the link between psyche and soma ... is still to seek "
(my
own
contain
italics).
It
seems
to
me
that these statements
antitheses. a cardinal Being problem of psychology and psychiatry, it would be very interesting to see just what is the essence of a rational approach from the psychic aspect when the link between psyche and soma is still to seek. The perusal of his deduction leaves one with the impression that he still dwells on the lines of the psychophysical parallelism of Descartes the monadology of Leibnitz, 3ond the Freudian statement that there is a science of mind as distinct from the science of matter. This proposition of dual existence which is said to be never intersecting and yet constantly interacting is clearly inadmissible in the absence of medieval thinkimr. But the ways of science and religion have long parted. While the cerebral aspect has developed into a serious science, the psychic aspect has remained, as it were, a little more than a theological and teleological dogmatism of the rationalistic school of philosophy. Where are the proofs for the psychic aspect of precisely equal validity," say, in the absence of hearing and vision f I suggest that this dualism is apparent rather than real. The link could never be established without the destruction of the very theory which bore it. In this internal contradiction lies the fate of the rationalistic thinking. In fact, this reducing process is well advanced already. The Kantian idea of Space as related to Matter has been resolved by Einstein in his " Theory of Relativity " resulting in the realisation of nuclear fission. And I believe that it contains also the answer for the remaining part of the problem-namely the mind, whose dimensions are expressed by the terms of Time. J. W. MULLNER. Nottingham.
multiple
tant, a,nd Brunner goes
ship
search for
response to the request, in your leader of for additional information concerning links between cancer and other metabolic processes, and with specific reference to the association of bronehogenic carcinoma with neurologic and myopathic phenomena, I should like to comment on the possible relationship between malignancy and collagen disorders. There is some evidence that there may be an association, if not an eetiological relationship, between bronchogenic carcinoma and deriiiatoniyositis 1 ; and there are a number of documented examples of other collagen disorders occurring in association with malignancy of the ovary, stomach, breast, and reticulo-endothelial system.2-5 It is conceivable that the example you cite of Jarcho’s syndrome may fall in this collagen category. Dermatomyositis appears to be the commoner collagen concormi-
SlR,—In
July 10,
1. McCombs, R. 31, 1148.
P., MacMahon,
H. E.
Med. Clin. N. Amer.
1949,
2. Dostrovsky, A., Sagher, F. Brit. J. Derm. 1946, 58, 52. 3. Lipman, M. P., Tober, J. N. Gastroenterol. 1950, 16, 188. 4. Cottel, C. E. Amer. J. med. Sci. 1952, 224, 160. 5. Brunner, J., Lobriaco, R. U. Ann. intern. Med. 1951, 34, 1269.
far
as
in all
cases
of dermato-
myositis, as is done in acanthosis nigrioans. Although the exact nature of this phenomenon is not clear, it is tempting to suggest a type of allergic sensitivity reaction, similar to those seen in infection or drug toxicity. The sensitising agent in this instance might be the degradation products of degenerating malignant tissue. Evidence for such an allergic basis is provided by the frequent occurrence of eosinophilia, and the development of urticaria, erythema multiforme, and erythema nodosum in these disorders. Finally, the association of acanthosis
nigricans
and
carcinoma, in approximately 50% of cases of the former condition, offers another example of the curious relationthat
ship
may exist
between
malignancy
and other
processes.
The
Johns Hopkins Hospital, Baltimore, Maryland.
PAUL J. ROSCH.
SURVIVAL OF CARTILAGE HOMOGRAFTS
SIR,—In the Simpson Smith memorial lecture, published in your issue of Aug. 7, Professor Rob says in of his conclusion : "... with the certain identical twins and the possible exception of the cornea - a successful homologous graft has yet to be achieved." In experiments recently completed in this department, cartilage homografts survived in the rabbit eighteen This confirms results months after implantation.’ recorded by Gillies (1920), Loeb (1926), Peer (1938 and 1939), together with more recent work. To suggest that homografts of cornea and cartilage survive because they are avascular merely begs the question, or rather ignores the question of the particular chemical structure of cartilasre and cornea.
exception
Department of Anatomy, University of Glasgow.
"
MALIGNANCY AND COLLAGEN DISORDERS
to say that the relationenough to justify an intense
so
frequently malignancy as a routine
occurs
GEORGE M. WYBURN.
SYMPHYSIOTOMY your review of Aug. 7 of Mr. Aleck Bourne’s of Obstetrics and Gyrccccotogy, you say : " The
SIR,—In
Synopsis
author of a medical textbook, as he hints in his preface, is constantly tempted to retain matter which he knows to be outdated, merely because examiners will demand to be informed about the archaic ; and it is doubtless for this reason that symphysiotomy and pubiotomy still find a corner in the new edition." It would appear from this statement that you regard the operation of symphysiotomy as both outdated and archaic. This astonishing statement cannot be allowed to go unchallenged. The operation of symphysiotomy, if correctly performed, is not only a simple and safe operation but in a suitable case eminently satisfactory for both mother and child ; and it has the additional benefit of permanently enlarging the maternal pelvis, and making operative -interference unnecessary in future pregnancies. This operation fell into disrepute when abdominal surgery became safe, and cæsarean section capable of performance by the " veriest tyro." In recent years it has been revived in these islands by Spain and Barry at the National Maternity Hospital in Dublin. Since then, judging by the reports of the discussions at various scientific meetings, it has become the subject of heated discussion and emotional outbursts. Without entering into the more controversial indications for its use, I think that it can safely be stated that for the expectant mother who has had a trial of labour, or who is seen for the first time with the cervix fully dilated and the head impacted in the mid-strait, and who, one feels, could be delivered per via naturales with a. small increase in pelvic size, there is no more satisfactory operation than that of symphysiotomy. The patient. has less discomfort than after a csesarean section and can walk without difficulty in 10 to 14 days. 1.
Transplant. Bull. IV., July, 1954, p. 136.