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DEEP-VEIN THROMBOSIS
459
carcinogenic hydrocarbon.The tar may differ from cigarette smoke in its carcinogenic properties, for not only are volatile compounds lost in preparing the tar, but chemical reactions during processing may lead to new carcinogenic substances. Furthermore, tobacco smoke may contain transient, chemically highly reactive, carcia
absent from the tar. Dayhas investigated the effects of storage and the use of gentler techniques in preparing the condensate on the carcinogenicity of tobacco tar, and compared the carcinogenicity of the neutral fraction (which contains the known carcinogenic aromatic hydrocarbons such as 3,4-benzpyrene) with the whole tar. The experiment was planned to demonstrate comparatively small differences in activity between the various test substances, and the results are carefully analysed in a statistical appendix.8About 8000 pathogen-free albino mice were used. Groups of mice were kept untreated or were painted with acetone, whole cigarette-smoke condensate which had been stored for six months, whole cigarette-smoke condensate which had been neither dried nor stored for more than twenty-four hours, or the neutral (acid and alkali extracted) fraction of whole cigarette-smoke condensate which had not been stored for more than one month. Day concludes that the relative tumorigenicity of the test substances, even when working with 8000 mice, is uncertain. The neutral fraction was about 50% as effective in inducing tumours as was the twenty-four-hour condensate. The stored condensate had approximately the same activity as the neutral fraction at the two lower dose levels but was equally as effective as the twenty-four-hour condensate at the highest dose level. No attempt was made to explain this observation. The experiment, although an interesting essay in quantitative carcinogenesis, is remote from the practical problem of cigarette smoking and lung cancer in man. It suffers, as do all laboratory attempts at replicating human disease, from differences in response between animals and man, and also from a lack of certainty that the tobacco tar applied to the mouse skin contained the same carcinogens as does the tobacco smoke which reaches the human lung. Although Day’s experiment shows that storage for twenty-four hours or for six months makes only a slight difference to the tumorigenic potential of the condensate, it does nothing to show what happens in the possibly vital minutes or seconds after the production of the cigarette smoke. The need is for a new technique which will more clearly mimic what happens in man. nogens which
are
DEEP-VEIN THROMBOSIS
ANYTHING which will diminish the risk of thrombosis in the veins of the legs will be hailed as a godsend; for it is here that pulmonary emboli commonly have their origin. Arguing from the well-documented belief that stasis in the veins promotes the formation of clots, Doran and White 9 set out to test whether electrical stimulation of the calfmuscles during lengthy operations would reduce the frequency of postoperative deep venous thrombosis. In the course of a long operation, particularly when relaxant anaesthetic agents are being administered, venous flow in the legs may be reduced to a seventh of the preoperative 6. 7. 8. 9.
Gellhorn, A. Cancer Res. 1958, 18, 510. Day, T. D. Br. J. Cancer, 1967, 21, 56. Paige, W. S. ibid. p. 69. Doran, F. S. A., White, H. M. Br. J. Surg. 1967, 54, 686.
rate." The calf-muscles cannot exercise their proper function of pumping the blood back to the heart, and the stage is then set for thrombosis, with the possible consequence of dissemination of clots into the systemic circulation. Various ways of overcoming this sequence of events have been devised-supporting the ankles, for instance, to leave the calf-muscles freedom of action, or firm bandaging of the legs to compress the veins-but the results have been inconclusive. Doran and White devised an ingenious method of controlling their results. They stimulated the calfmuscles of one leg in each patient (the other leg acting as control) and then established that in the 200 stimulated legs none showed local signs of deep femoral thrombosis - Persistent deep tenderness, massive oedema, Homan’s sign-in the first postoperative week, whereas, of the 200 unstimulated legs, 7 showed local signs of deep femoral thrombosis. Persistent deep tenderness was elicited in the second and subsequent postoperative weeks in 16 legsin 13 of the unstimulated legs and in 3 of the stimulated group. Massive oedema appeared in 9 legs-7 unstimulated legs and 2 stimulated. Two patients in the series had fatal pulmonary emboli without.any warning positive signs in the legs. Seven had non-fatal pulmonary emboli (five of these without previous warning). At necropsy, the fatal clots were found to have originated in the calf of the leg that had not been stimulated. Admittedly, the clinical diagnosis of thrombosis in the deep femoral veins is often uncertain; and, indeed, the finding that there were no positive leg-signs in the two fatal cases and in five of the non-fatal cases of pulmonary embolism bears this out. Doran and White concede the point. Nevertheless, their mathematical analysis of their results leads them to conclude that electrical stimulation of the calf-muscles 10 ought to reduce the frequency of deep femoral thrombosis.
TUMOURS OF THE THYMUS
THE thymus gland, although predominantly associated with the maturation of the lymphoid system, produces its effects, at least in part, through a humoral factor released from its lymphoepithelial cells.l1 The first indication that the thymus is intimately linked with development of the immune response to foreign antigens was the case of the patient who had recurrent bacterial infection characteristic of agammaglobulinaemia and a massive tumour of the thymus which had apparently entirely replaced the normal thymic tissue.12 By 1964, seven similar cases had been reported, thus virtually eliminating a purely chance association. The other major clinical manifestation of thymic dysfunction is myasthenia gravis-a disorder of muscular weakness resulting from impaired transmission of the nervous impulse across the myoneural junction. In some 15 % of the patients a tumour of the thymus is also present.13 But, although agammaglobulinaEmia and myasthenia gravis are by far the commonest clinical forms of thymic disorder, other disturbances, particularly of the lymphohaemopoietic systems, such as pancytopenia, aplastic anaemia, leucopenia, and eosinopenia, have been recorded. Doran, F. S. A., Drury, M., Sivyer, A. ibid. 1964, 51, 486. Osoba, D., Miller, J. F. A. P. Nature, Lond. 1963, 199, 653. MacLean, L. D., Zak, S. G., Varco, R. L., Good, R. A. Surgery, St. Louis, 1956, 40, 1010. 13. Keynes, G. L. Lancet, 1954, i, 1197.
10. 11. 12.
carcinogenic hydrocarbon.The tar may differ from cigarette smoke in its carcinogenic properties, for not only are volatile compounds lost in preparing the tar, but chemical reactions during processing may lead to new carcinogenic substances. Furthermore, tobacco smoke may contain transient, chemically highly reactive, carcia
absent from the tar. Dayhas investigated the effects of storage and the use of gentler techniques in preparing the condensate on the carcinogenicity of tobacco tar, and compared the carcinogenicity of the neutral fraction (which contains the known carcinogenic aromatic hydrocarbons such as 3,4-benzpyrene) with the whole tar. The experiment was planned to demonstrate comparatively small differences in activity between the various test substances, and the results are carefully analysed in a statistical appendix.8About 8000 pathogen-free albino mice were used. Groups of mice were kept untreated or were painted with acetone, whole cigarette-smoke condensate which had been stored for six months, whole cigarette-smoke condensate which had been neither dried nor stored for more than twenty-four hours, or the neutral (acid and alkali extracted) fraction of whole cigarette-smoke condensate which had not been stored for more than one month. Day concludes that the relative tumorigenicity of the test substances, even when working with 8000 mice, is uncertain. The neutral fraction was about 50% as effective in inducing tumours as was the twenty-four-hour condensate. The stored condensate had approximately the same activity as the neutral fraction at the two lower dose levels but was equally as effective as the twenty-four-hour condensate at the highest dose level. No attempt was made to explain this observation. The experiment, although an interesting essay in quantitative carcinogenesis, is remote from the practical problem of cigarette smoking and lung cancer in man. It suffers, as do all laboratory attempts at replicating human disease, from differences in response between animals and man, and also from a lack of certainty that the tobacco tar applied to the mouse skin contained the same carcinogens as does the tobacco smoke which reaches the human lung. Although Day’s experiment shows that storage for twenty-four hours or for six months makes only a slight difference to the tumorigenic potential of the condensate, it does nothing to show what happens in the possibly vital minutes or seconds after the production of the cigarette smoke. The need is for a new technique which will more clearly mimic what happens in man. nogens which
are
DEEP-VEIN THROMBOSIS
ANYTHING which will diminish the risk of thrombosis in the veins of the legs will be hailed as a godsend; for it is here that pulmonary emboli commonly have their origin. Arguing from the well-documented belief that stasis in the veins promotes the formation of clots, Doran and White 9 set out to test whether electrical stimulation of the calfmuscles during lengthy operations would reduce the frequency of postoperative deep venous thrombosis. In the course of a long operation, particularly when relaxant anaesthetic agents are being administered, venous flow in the legs may be reduced to a seventh of the preoperative 6. 7. 8. 9.
Gellhorn, A. Cancer Res. 1958, 18, 510. Day, T. D. Br. J. Cancer, 1967, 21, 56. Paige, W. S. ibid. p. 69. Doran, F. S. A., White, H. M. Br. J. Surg. 1967, 54, 686.
rate." The calf-muscles cannot exercise their proper function of pumping the blood back to the heart, and the stage is then set for thrombosis, with the possible consequence of dissemination of clots into the systemic circulation. Various ways of overcoming this sequence of events have been devised-supporting the ankles, for instance, to leave the calf-muscles freedom of action, or firm bandaging of the legs to compress the veins-but the results have been inconclusive. Doran and White devised an ingenious method of controlling their results. They stimulated the calfmuscles of one leg in each patient (the other leg acting as control) and then established that in the 200 stimulated legs none showed local signs of deep femoral thrombosis - Persistent deep tenderness, massive oedema, Homan’s sign-in the first postoperative week, whereas, of the 200 unstimulated legs, 7 showed local signs of deep femoral thrombosis. Persistent deep tenderness was elicited in the second and subsequent postoperative weeks in 16 legsin 13 of the unstimulated legs and in 3 of the stimulated group. Massive oedema appeared in 9 legs-7 unstimulated legs and 2 stimulated. Two patients in the series had fatal pulmonary emboli without.any warning positive signs in the legs. Seven had non-fatal pulmonary emboli (five of these without previous warning). At necropsy, the fatal clots were found to have originated in the calf of the leg that had not been stimulated. Admittedly, the clinical diagnosis of thrombosis in the deep femoral veins is often uncertain; and, indeed, the finding that there were no positive leg-signs in the two fatal cases and in five of the non-fatal cases of pulmonary embolism bears this out. Doran and White concede the point. Nevertheless, their mathematical analysis of their results leads them to conclude that electrical stimulation of the calf-muscles 10 ought to reduce the frequency of deep femoral thrombosis.
TUMOURS OF THE THYMUS
THE thymus gland, although predominantly associated with the maturation of the lymphoid system, produces its effects, at least in part, through a humoral factor released from its lymphoepithelial cells.l1 The first indication that the thymus is intimately linked with development of the immune response to foreign antigens was the case of the patient who had recurrent bacterial infection characteristic of agammaglobulinaemia and a massive tumour of the thymus which had apparently entirely replaced the normal thymic tissue.12 By 1964, seven similar cases had been reported, thus virtually eliminating a purely chance association. The other major clinical manifestation of thymic dysfunction is myasthenia gravis-a disorder of muscular weakness resulting from impaired transmission of the nervous impulse across the myoneural junction. In some 15 % of the patients a tumour of the thymus is also present.13 But, although agammaglobulinaEmia and myasthenia gravis are by far the commonest clinical forms of thymic disorder, other disturbances, particularly of the lymphohaemopoietic systems, such as pancytopenia, aplastic anaemia, leucopenia, and eosinopenia, have been recorded. Doran, F. S. A., Drury, M., Sivyer, A. ibid. 1964, 51, 486. Osoba, D., Miller, J. F. A. P. Nature, Lond. 1963, 199, 653. MacLean, L. D., Zak, S. G., Varco, R. L., Good, R. A. Surgery, St. Louis, 1956, 40, 1010. 13. Keynes, G. L. Lancet, 1954, i, 1197.
10. 11. 12.