- Email: [email protected]
AGEING AND AGE-ASSOCIATED DISEASE
1191
mammals, with their much more sophisticated immune mechanisms, fail ? Descendants of synapsids forming an evolutionary bridge between reptiles and mammals still laid eggs, but already suckled their young much like the At this stage of the phylogenesis, the conceptus of an allogeneic mating was still safely encased in the egg, thus protected from potential immunological hostility of the mother. Nature’s multiple attempts at the development of the placenta suggest that viviparity has evolved independently on several occasions.6 With the evolution of the mammalian placenta some 100 million years ago, a formidable immunological task arose : it became necessary to compromise the maternal adaptive immune system because it posed a threat to the allogeneic conceptus. In the normal maternal/fetal relationship of rodents and man, with their villous hasmochorial allantoic placentae,6there is cellular traffic between mother and fetus, and maternal lymphocytes are present in the newborn.7-9 Newborn Fl hybrids succumb to runt (homologous or allogeneic) disease caused by injected parental lymphoid cells. 10 Mothers reject fetal grafts." Thus, the mother recognises, and with the cell-mediated faculty attempts the rejection of, the concepThe fetus may pre-empt tus of an allogeneic mating. maternal immune reactions by a massive release of embryonic antigens entering the maternal circulation, by the production of trophoblastic mucin or fibrin, and by other means.But for the phenomenal evolution of the placental mammals, the installation of a braking mechanism into the machinery of adaptive immunity was of absolute necessity. It is proposed that immunological enhancement, as mediated by blocking antibodies, evolved with the main purpose of protecting the conceptus. Observation of larger fetuses and placentae as a result of allogeneic mating in mice,12 and of further increase of placental size in mice immunised to paternal antigens of the fetus," suggested the role of immunological enhancement in the maintenance of an allogeneic conceptus. Immune responses engendered in mice by multiparity further supported this view.14 The Hellstroms and Brawn showed finally that murine maternal lymphocytes damage fetal cells in vitro and that this cell-mediated immune reaction is readily amenable to abrogation by blocking antibodies of maternal sera.15 Nature then, at least in certain instances, solved the homograft problem of allogeneic mating by the development and utilisation of a humoral immunological enhancement. Acquisition of the placenta, and with it an immunological system for safeguarding the allogeneic conceptus, however, opened a loophole in the highly integrated structure of mammalian adaptive immunity. Some tumours, imitating embryonic growth morphologically and biologically by derepression of fetal genes and by the resynthesis of fetal substances and antigens, continue to take advantage of immunological enhancement, as can be documented in experimental tumours 16-19 and in-vitro systems of human tumours.2°
platypus.
D. R. S. in Human Transplantation (edited by F. T. Rapaport and J. Dausset); p. 565. New York, 1968. 7. Taylor, A. I., Polani, P. E. Lancet, 1965, i, 1226. 8. Kadowaki, J. I., Thompson, R. I., Zuelzer, W. W., Woolley, P. V., Brough, A. J., Gruber, D. ibid. 1965, ii, 1152. 9. Barnes, R. D., Holliday, J. Blood, 1970, 36, 480. 10. Billingham, R. E. New Engl. J. Med. 1970, 270, 667, 720. 11. Woodruff, M. F. A. Proc. R. Soc. B, 1958, 148, 68. 12. Billington, W. D. Nature, 1964, 202, 317. 13. James, A. D. ibid. 1965, 205, 613. 14. Kaliss, N., Dagg, M. K. Transplantation, 1964, 2, 416. 15. Hellström, K. E., Hellström, I., Brawn, J. Nature, 1969, 224, 914. 16. Gorer, P. A., Kaliss, N. Cancer Res. 1959, 19, 824. 17. Kaliss, N. Ann. N.Y. Acad. Sci. 1962, 101, 64. 18. Hutchin, P. Surgery Gynec. Obstet. 1968, 126, 1331. 19. Sinkovics, J. G., Drewinko, B., Thornell, E. Lancet, 1970, i, 139. 20. Hellström, I., Hellström, K. E., Evans, C. A., Heppner, G., Pierce, G. E., Yang, J. P. S. Proc. natn. Acad. Sci. U.S.A. 1969, 62, 362. 6.
Kirby,
This subject was discussed at the 20th Annual Meeting of the Society of Pelvic Surgeons, Houston, Texas, Nov. 11-13, 1970.
University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas.
JOSEPH G. SINKOVICS PHILIP J. DISAIA FELIX N. RUTLEDGE.
AGEING AND AGE-ASSOCIATED DISEASE
SIR,-Of the letters and editorials you have lately pubon ageing,1-4 none explains the differences between ageing phenomena (genetically programmed) and ageassociated pathological phenomena (acquired or initiated by external events). This distinction must be made, or there will be no progress. I have proposed the dictum that temporal programming is relatively invariant 5 and this should be a basis for making the distinction. Consider three categories of phenomenon. Category1 (time-dependent).-Here changes occur equally with time irrespective of species. This is exemplified by the fluorescence of collagen and elastir., which increases lished
approximately 1% a year.This is presumably controlled by thermodynamic phenomena and is temperature-dependent and oxygen-pressure dependent. Category-1 phenomena are of greater relevance to long-lived organisms than to short-lived organisms. Category 2 (age/lifespan-dependent).-Here changes are more rapid in short-lived animals than in long-lived animals. For example, hyaluronic acid in the skin of mice decreases 30% between the ages of 8 months and two years,7 whereas there are roughly similar decreases in the dog and in man over the total lifespan from the time when growth ceases. This follows predictably from the operation of the genetic programme, although it may be modified by external factors. The point is that, for every variable, the amount of change is highly predictable and equal within narrow limits for each individual within the species. Age/lifespan variables differ in the way in which they are modified by the environment, and the dispersion of data is
of the extent to which this happens. For example, hyaluronic-acid content in the skin of miceand calcium in their bones9 (as well as the half-life values of these constituents) show highly reproducible decreases with age under ordinary circumstances. Carcass protein and its half-life varies much more, decreasing approximately 14% in male mice between the ages of 8 months and 2 years.1o a measure
Category 3 (age-associated pathological changes).-Here finds changes which are not predictable, and, contrary to the dictum, can be determined only by examination of the site and degree of involvement. Thus atherosclerosis, lipofuscin accumulation, and the various types of immune phenomena are highly unpredictable on an individual basis because of their wide variability as to site and degree. Therefore they result from exogenous factors operating over time. Category-2 changes effect susceptibility to the progenitors of category 3, and category-3 changes may modify the rate of progression of those of category 2. Changes induced by category 3 may become self-perpetuating. In order to make progress in gerontology it is necessary, firstly, to detect, measure, explain, and determine the one
1. Comfort, A. Lancet, Aug. 29, 1970, p. 463. 2. ibid. p. 451. 3. ibid. Sept. 19, 1970, p. 598. 4. Field, E. J. ibid. Oct. 10, 1970, p. 780. 5. Sobel, H. Gerontologist, 1967, 7, 93. 6. Sobel, H., Hewlett, M. J., Sacker, I. M., Lee, K. D., Proc. VII int. Congr. Geront. 1966, 2, 1. 7. Sobel, H. J. Geront. 1970, 25, 102. 8. Sobel, H., Hewlett, M. J., Harriri, F. Unpublished. 9. Sobel, H. Unpublished.
10. Sobel,
H., Bowman, R. Unpublished.
Hoshek, S.
1192 consequence to the organism of as many category-2 phenomena as possible; secondly, to determine systematically how environmental factors affect them and their rate of progression; and, thirdly, to determine how the progression of changes may relate to mortality and morbidity.
Department of Biochemistry, Colorado State University, Fort Collins, Colorado.
HARRY SOBEL.
GASTRIC ACID SECRETION IN CHOLERA PATIENTS cholera is extremely sensitive to the action SIR,- Vibrio of acids. 1-3 Gastric juice, with its low pH, would therefore form one of the first barriers to the establishment of the vibrio within the host. Napier and Gupta 4 demonstrated that vibrios survived for a minimum of 24 hours in specimens of gastric juice free from acid but succumbed immediately if the pH of the gastric juice was less than 4-75. In the naturally acquired disease it is impossible to measure the gastric pH at the time of vibrio ingestion, since this time is unknown. Furthermore, during the early stage of cholera there is often much emesis and reflux of intestinal contents into the stomach. It is possible, however, to determine whether individuals who develop cholera have any defect in their ability to produce gastric acid. We studied the range of gastric acidity in the convalescent cholera patients and the degree, if any, of
achlorhydria or hypoacidity. The 16 patients studied were adults (15
years and over) who had been admitted to the ward of the Pakistan-SEATO Cholera Research Laboratory with clinical cholera and who had a positive culture of Vibrio cholera. In all patients the vibrio was classical biotype, Inaba serotype. All patients were treated with intravenous rehydration; none received antibiotics or other medication. Only 1 patient gave a history of previous gastrointestinal diseasesymptoms of peptic ulcer. During the convalescent period, which ranged from 1 to 6 days, a maximum histamine stimulation test was performed after an overnight fast. Histamine phosphate, 40 g. per kg. per hour, was infused5 over 1 hour; 15-minute collections of gastric juice were begun at 30 and 45 minutes, since this has been shown to be the time of maximum gastric-acid secretion following histamine stimulation.s Of the 16 patients only 1 had evidence of hypochlorhydria, with a basal pH of 7-2. After histamine this patient had a maximum acid secretion of 2-71 meq. per hour. The mean values for basal pH and acid secretion and maximum acid secretion in the remaining 15 patients are as follows:
the first line of defence in cholera.
This work was supported in part by research agreement no. 196802 between the National Institutes of Health, Bethesda, Maryland, U.S.A., and the Pakistan-SEATO Cholera Research Tahnratnrv- Dacca. Fast Pakistan. Pakistan-SEATO Cholera Research Laboratory, Dacca 2, East Pakistan.
1.
2. 3. 4. 5.
Kolle, W., Schurmann, W. in Handbuch der pathogenen mikroorganismen (edited by W. Kolle and A. von Wassermann); vol. IV, p. 1. Tena, 1912. Parya, G., Ghosh, S. K. Indian med. Gaz. 1945, 80, 390. Read, W. D. B., Pandit, S. R., Das, P. C. Indian J. med. Res. 1939, 27, 1. Napier, E., Gupta, S. K. Indian med. Gaz. 1942, 77, 717. Lawrie, J. H., Smith, G. M. R., Forrest, A. P. M. Lancet, 1964, ii, 270.
6.
Konturek, S. J., Oleksy, J. Gastroenterology, 1967, 53, 912.
RICHARD A. CASH JAMIUL ALAM K. M. TOAHA.
DOWN’S SYNDROME AND INFECTIOUS HEPATITIS
SIR,-Epidemiological interest in Down’s syndrome (D.s.) has been centred on its possible non-random distribution with respect to time, space, and such diseaseprocesses as infectious hepatitis (LH.).1 This approach does not differentiate between the biological process responsible for the syndrome-namely, nondisjunction-and the clinical expression of the syndrome, which is due to the triple dose of genes on chromosome 21. This distinction that if l.H., for example, is astiologically related to it should also be responsible for the non-random D.s., occurrence of other aneuploid conditions such as 13 trisomy, 18 trisomy, XXY, XYY. Like D.s., these chromosome disorders arise by nondisjunction, their incidence in the population (i.e., viability) as well as their clinical expression being a reflection of the gene content of their chromosomes. Investigating D.s. alone is an extremely incomplete way of sampling chromosome disorders presumably originating from the same biological mechanism. Proper analysis requires knowledge of the outcome of all human fertilisations. With one possible exception,2previous investigators concluding that non-randomness was biologically important based their analysis solely on live births and did not include conceptions that failed to complete gestation. The incidence of chromosome aberrations in non-viable products of conception exceeds that in a comparable live-born population by 20 times. If 15 % of all conceptions terminate in spontaneous abortion, then chromosome aberrations in this population contribute up to 4 times the number observed in the live born. Previous investigators basing their interpretations on the phenotypic recognition of D.s. studied less than 5% of the chromosome aberrations in the population. If the chromosome constitutions of all human fertilisations were known, chromosome aberrations might prove to be randomly distributed in time, space, and with respect to various pathogenic organisms. Department of Pediatrics, Wyler Children’s Hospital, means
University of Chicago, Chicago, Illinois 60637.
Apparently the majority of individuals who develop naturally acquired cholera have normal gastric secretion. This does not, however, rule out low levels of gastric acid at the time of vibrio ingestion, since food taken at that time might protect the vibrio while in the stomach. Moreover, large draughts of water might dilute the gastric acid sufficiently to allow the vibrios to pass unharmed into the duodenum.4 The gastric emptying-time might also play a major part in determining the role of the stomach as
naturally acquired human
EUGENE PERGAMENT.
LEG ULCERS AND DRUG ABUSE
SIR,-To the many causes of leg ulcers, drug abuse has added another. Barbiturate or analgesic tablets are dissolved in any available water and injected into a subcutaneous vein, often on the anterior or medial surface of the leg. Ulceration appears rapidly and becomes chronic. I have seen three men in their early twenties with peculiar ulcers on their legs. They said at first that the lesions were caused by corrosive or caustic substances or by burns. But the appearances were not typical. When this cause of leg ulceration is kept in mind, diagnosis is easy because of the unusual and artificial 1. 2.
Doxiadis, S. A., Pantelakis, S. N., Valaes, T. N. Lancet, 1970, i, 897. Pergament, E., Kadotani, T., Sato, H. Am. J. Obstet. Gynec. 1969, 104, 984.
mammals, with their much more sophisticated immune mechanisms, fail ? Descendants of synapsids forming an evolutionary bridge between reptiles and mammals still laid eggs, but already suckled their young much like the At this stage of the phylogenesis, the conceptus of an allogeneic mating was still safely encased in the egg, thus protected from potential immunological hostility of the mother. Nature’s multiple attempts at the development of the placenta suggest that viviparity has evolved independently on several occasions.6 With the evolution of the mammalian placenta some 100 million years ago, a formidable immunological task arose : it became necessary to compromise the maternal adaptive immune system because it posed a threat to the allogeneic conceptus. In the normal maternal/fetal relationship of rodents and man, with their villous hasmochorial allantoic placentae,6there is cellular traffic between mother and fetus, and maternal lymphocytes are present in the newborn.7-9 Newborn Fl hybrids succumb to runt (homologous or allogeneic) disease caused by injected parental lymphoid cells. 10 Mothers reject fetal grafts." Thus, the mother recognises, and with the cell-mediated faculty attempts the rejection of, the concepThe fetus may pre-empt tus of an allogeneic mating. maternal immune reactions by a massive release of embryonic antigens entering the maternal circulation, by the production of trophoblastic mucin or fibrin, and by other means.But for the phenomenal evolution of the placental mammals, the installation of a braking mechanism into the machinery of adaptive immunity was of absolute necessity. It is proposed that immunological enhancement, as mediated by blocking antibodies, evolved with the main purpose of protecting the conceptus. Observation of larger fetuses and placentae as a result of allogeneic mating in mice,12 and of further increase of placental size in mice immunised to paternal antigens of the fetus," suggested the role of immunological enhancement in the maintenance of an allogeneic conceptus. Immune responses engendered in mice by multiparity further supported this view.14 The Hellstroms and Brawn showed finally that murine maternal lymphocytes damage fetal cells in vitro and that this cell-mediated immune reaction is readily amenable to abrogation by blocking antibodies of maternal sera.15 Nature then, at least in certain instances, solved the homograft problem of allogeneic mating by the development and utilisation of a humoral immunological enhancement. Acquisition of the placenta, and with it an immunological system for safeguarding the allogeneic conceptus, however, opened a loophole in the highly integrated structure of mammalian adaptive immunity. Some tumours, imitating embryonic growth morphologically and biologically by derepression of fetal genes and by the resynthesis of fetal substances and antigens, continue to take advantage of immunological enhancement, as can be documented in experimental tumours 16-19 and in-vitro systems of human tumours.2°
platypus.
D. R. S. in Human Transplantation (edited by F. T. Rapaport and J. Dausset); p. 565. New York, 1968. 7. Taylor, A. I., Polani, P. E. Lancet, 1965, i, 1226. 8. Kadowaki, J. I., Thompson, R. I., Zuelzer, W. W., Woolley, P. V., Brough, A. J., Gruber, D. ibid. 1965, ii, 1152. 9. Barnes, R. D., Holliday, J. Blood, 1970, 36, 480. 10. Billingham, R. E. New Engl. J. Med. 1970, 270, 667, 720. 11. Woodruff, M. F. A. Proc. R. Soc. B, 1958, 148, 68. 12. Billington, W. D. Nature, 1964, 202, 317. 13. James, A. D. ibid. 1965, 205, 613. 14. Kaliss, N., Dagg, M. K. Transplantation, 1964, 2, 416. 15. Hellström, K. E., Hellström, I., Brawn, J. Nature, 1969, 224, 914. 16. Gorer, P. A., Kaliss, N. Cancer Res. 1959, 19, 824. 17. Kaliss, N. Ann. N.Y. Acad. Sci. 1962, 101, 64. 18. Hutchin, P. Surgery Gynec. Obstet. 1968, 126, 1331. 19. Sinkovics, J. G., Drewinko, B., Thornell, E. Lancet, 1970, i, 139. 20. Hellström, I., Hellström, K. E., Evans, C. A., Heppner, G., Pierce, G. E., Yang, J. P. S. Proc. natn. Acad. Sci. U.S.A. 1969, 62, 362. 6.
Kirby,
This subject was discussed at the 20th Annual Meeting of the Society of Pelvic Surgeons, Houston, Texas, Nov. 11-13, 1970.
University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas.
JOSEPH G. SINKOVICS PHILIP J. DISAIA FELIX N. RUTLEDGE.
AGEING AND AGE-ASSOCIATED DISEASE
SIR,-Of the letters and editorials you have lately pubon ageing,1-4 none explains the differences between ageing phenomena (genetically programmed) and ageassociated pathological phenomena (acquired or initiated by external events). This distinction must be made, or there will be no progress. I have proposed the dictum that temporal programming is relatively invariant 5 and this should be a basis for making the distinction. Consider three categories of phenomenon. Category1 (time-dependent).-Here changes occur equally with time irrespective of species. This is exemplified by the fluorescence of collagen and elastir., which increases lished
approximately 1% a year.This is presumably controlled by thermodynamic phenomena and is temperature-dependent and oxygen-pressure dependent. Category-1 phenomena are of greater relevance to long-lived organisms than to short-lived organisms. Category 2 (age/lifespan-dependent).-Here changes are more rapid in short-lived animals than in long-lived animals. For example, hyaluronic acid in the skin of mice decreases 30% between the ages of 8 months and two years,7 whereas there are roughly similar decreases in the dog and in man over the total lifespan from the time when growth ceases. This follows predictably from the operation of the genetic programme, although it may be modified by external factors. The point is that, for every variable, the amount of change is highly predictable and equal within narrow limits for each individual within the species. Age/lifespan variables differ in the way in which they are modified by the environment, and the dispersion of data is
of the extent to which this happens. For example, hyaluronic-acid content in the skin of miceand calcium in their bones9 (as well as the half-life values of these constituents) show highly reproducible decreases with age under ordinary circumstances. Carcass protein and its half-life varies much more, decreasing approximately 14% in male mice between the ages of 8 months and 2 years.1o a measure
Category 3 (age-associated pathological changes).-Here finds changes which are not predictable, and, contrary to the dictum, can be determined only by examination of the site and degree of involvement. Thus atherosclerosis, lipofuscin accumulation, and the various types of immune phenomena are highly unpredictable on an individual basis because of their wide variability as to site and degree. Therefore they result from exogenous factors operating over time. Category-2 changes effect susceptibility to the progenitors of category 3, and category-3 changes may modify the rate of progression of those of category 2. Changes induced by category 3 may become self-perpetuating. In order to make progress in gerontology it is necessary, firstly, to detect, measure, explain, and determine the one
1. Comfort, A. Lancet, Aug. 29, 1970, p. 463. 2. ibid. p. 451. 3. ibid. Sept. 19, 1970, p. 598. 4. Field, E. J. ibid. Oct. 10, 1970, p. 780. 5. Sobel, H. Gerontologist, 1967, 7, 93. 6. Sobel, H., Hewlett, M. J., Sacker, I. M., Lee, K. D., Proc. VII int. Congr. Geront. 1966, 2, 1. 7. Sobel, H. J. Geront. 1970, 25, 102. 8. Sobel, H., Hewlett, M. J., Harriri, F. Unpublished. 9. Sobel, H. Unpublished.
10. Sobel,
H., Bowman, R. Unpublished.
Hoshek, S.
1192 consequence to the organism of as many category-2 phenomena as possible; secondly, to determine systematically how environmental factors affect them and their rate of progression; and, thirdly, to determine how the progression of changes may relate to mortality and morbidity.
Department of Biochemistry, Colorado State University, Fort Collins, Colorado.
HARRY SOBEL.
GASTRIC ACID SECRETION IN CHOLERA PATIENTS cholera is extremely sensitive to the action SIR,- Vibrio of acids. 1-3 Gastric juice, with its low pH, would therefore form one of the first barriers to the establishment of the vibrio within the host. Napier and Gupta 4 demonstrated that vibrios survived for a minimum of 24 hours in specimens of gastric juice free from acid but succumbed immediately if the pH of the gastric juice was less than 4-75. In the naturally acquired disease it is impossible to measure the gastric pH at the time of vibrio ingestion, since this time is unknown. Furthermore, during the early stage of cholera there is often much emesis and reflux of intestinal contents into the stomach. It is possible, however, to determine whether individuals who develop cholera have any defect in their ability to produce gastric acid. We studied the range of gastric acidity in the convalescent cholera patients and the degree, if any, of
achlorhydria or hypoacidity. The 16 patients studied were adults (15
years and over) who had been admitted to the ward of the Pakistan-SEATO Cholera Research Laboratory with clinical cholera and who had a positive culture of Vibrio cholera. In all patients the vibrio was classical biotype, Inaba serotype. All patients were treated with intravenous rehydration; none received antibiotics or other medication. Only 1 patient gave a history of previous gastrointestinal diseasesymptoms of peptic ulcer. During the convalescent period, which ranged from 1 to 6 days, a maximum histamine stimulation test was performed after an overnight fast. Histamine phosphate, 40 g. per kg. per hour, was infused5 over 1 hour; 15-minute collections of gastric juice were begun at 30 and 45 minutes, since this has been shown to be the time of maximum gastric-acid secretion following histamine stimulation.s Of the 16 patients only 1 had evidence of hypochlorhydria, with a basal pH of 7-2. After histamine this patient had a maximum acid secretion of 2-71 meq. per hour. The mean values for basal pH and acid secretion and maximum acid secretion in the remaining 15 patients are as follows:
the first line of defence in cholera.
This work was supported in part by research agreement no. 196802 between the National Institutes of Health, Bethesda, Maryland, U.S.A., and the Pakistan-SEATO Cholera Research Tahnratnrv- Dacca. Fast Pakistan. Pakistan-SEATO Cholera Research Laboratory, Dacca 2, East Pakistan.
1.
2. 3. 4. 5.
Kolle, W., Schurmann, W. in Handbuch der pathogenen mikroorganismen (edited by W. Kolle and A. von Wassermann); vol. IV, p. 1. Tena, 1912. Parya, G., Ghosh, S. K. Indian med. Gaz. 1945, 80, 390. Read, W. D. B., Pandit, S. R., Das, P. C. Indian J. med. Res. 1939, 27, 1. Napier, E., Gupta, S. K. Indian med. Gaz. 1942, 77, 717. Lawrie, J. H., Smith, G. M. R., Forrest, A. P. M. Lancet, 1964, ii, 270.
6.
Konturek, S. J., Oleksy, J. Gastroenterology, 1967, 53, 912.
RICHARD A. CASH JAMIUL ALAM K. M. TOAHA.
DOWN’S SYNDROME AND INFECTIOUS HEPATITIS
SIR,-Epidemiological interest in Down’s syndrome (D.s.) has been centred on its possible non-random distribution with respect to time, space, and such diseaseprocesses as infectious hepatitis (LH.).1 This approach does not differentiate between the biological process responsible for the syndrome-namely, nondisjunction-and the clinical expression of the syndrome, which is due to the triple dose of genes on chromosome 21. This distinction that if l.H., for example, is astiologically related to it should also be responsible for the non-random D.s., occurrence of other aneuploid conditions such as 13 trisomy, 18 trisomy, XXY, XYY. Like D.s., these chromosome disorders arise by nondisjunction, their incidence in the population (i.e., viability) as well as their clinical expression being a reflection of the gene content of their chromosomes. Investigating D.s. alone is an extremely incomplete way of sampling chromosome disorders presumably originating from the same biological mechanism. Proper analysis requires knowledge of the outcome of all human fertilisations. With one possible exception,2previous investigators concluding that non-randomness was biologically important based their analysis solely on live births and did not include conceptions that failed to complete gestation. The incidence of chromosome aberrations in non-viable products of conception exceeds that in a comparable live-born population by 20 times. If 15 % of all conceptions terminate in spontaneous abortion, then chromosome aberrations in this population contribute up to 4 times the number observed in the live born. Previous investigators basing their interpretations on the phenotypic recognition of D.s. studied less than 5% of the chromosome aberrations in the population. If the chromosome constitutions of all human fertilisations were known, chromosome aberrations might prove to be randomly distributed in time, space, and with respect to various pathogenic organisms. Department of Pediatrics, Wyler Children’s Hospital, means
University of Chicago, Chicago, Illinois 60637.
Apparently the majority of individuals who develop naturally acquired cholera have normal gastric secretion. This does not, however, rule out low levels of gastric acid at the time of vibrio ingestion, since food taken at that time might protect the vibrio while in the stomach. Moreover, large draughts of water might dilute the gastric acid sufficiently to allow the vibrios to pass unharmed into the duodenum.4 The gastric emptying-time might also play a major part in determining the role of the stomach as
naturally acquired human
EUGENE PERGAMENT.
LEG ULCERS AND DRUG ABUSE
SIR,-To the many causes of leg ulcers, drug abuse has added another. Barbiturate or analgesic tablets are dissolved in any available water and injected into a subcutaneous vein, often on the anterior or medial surface of the leg. Ulceration appears rapidly and becomes chronic. I have seen three men in their early twenties with peculiar ulcers on their legs. They said at first that the lesions were caused by corrosive or caustic substances or by burns. But the appearances were not typical. When this cause of leg ulceration is kept in mind, diagnosis is easy because of the unusual and artificial 1. 2.
Doxiadis, S. A., Pantelakis, S. N., Valaes, T. N. Lancet, 1970, i, 897. Pergament, E., Kadotani, T., Sato, H. Am. J. Obstet. Gynec. 1969, 104, 984.