- Email: [email protected]
Filariasis
386
after any procedure aimed at inducing specific immunological tolerance in a mature recipient by damaging immunologically competent cells. SHACKMAN and DEMPSTER 18 report a remarkable case of successful homotransplantation between brothers whose ages differed by more than twenty years; the recipient has survived twelve months to date, in good health. Renal grafting between identical twins is already well established; but these reports of success show that the procedure is passing out of the hazardous experimental phase and can now be more widely applied. A Nuffield centre for transplantation surgery is to be set up in Edinburgh under the directorship of Prof. M. F. A. WOODRUFF, and the Department of Health for Scotland has guaranteed the running costs for the first five years. This should stimulate efforts to improve renal transplantation. The possibility of inducing tolerance by biological methods less drastic than irradiation needs exploring; partial tolerance of skin transplants has already been induced in human infants before the development of immunological maturity.19 The role of graft versus host in the process of rejection is still not c1ear.2O-22 Moreover, the long-term results of homotransplantation have yet to be assessed. Do transplanted kidneys eventually succumb to disease similar to that which destroyed the patient’s own kidneys ? For how long and by what means can kidneys on the brink of rejection be tided over to maintain satisfactory function. And what place have cortisone and azotasmia in the production of tolerance ?
Filariasis
half-century the commoner and more deadly tropical infections, such as malaria and yellow fever, have been largely controlled; and attention can now be turned to infections, such as schistosomiasis and filariasis, which cripple rather than kill. Filariasis, due to the worms Wuchereria bancrofti and Brugia malayi, is IN the past
known to medical students as the cause of the grotesque deformities of the legs and genitals which are termed elephantiasis. The larval worms (micromarise) behave remarkably, swarming at night in the peripheral blood from which they disappear almost completely by day. Owing to their presence in the blood at night they can be transmitted by blood-sucking mosquitoes. During the day the micromarias accumulate in the lungs, where the oxygen tension is high. They hold themselves in the pulmonary capillaries by some force which is increased by rises in the oxygen tension and decreased by falls; this force seems to be switched on and off every twelve hours by some mysterious mechanism inside the micronlarise. A report by a W.H.O. expert committee 23 describes filariasis in different parts of the world. The spread of this infection is favoured by the urbanisation taking 18. 19. 20. 21. 22.
23.
Shackman, R., Dempster, W. J. Unpublished. Woodruff, M. F. A. The Transplantation of Tissues and Organs; p. 129. Springfield, III., 1960. Dempster, W. J. Brit. J. Surg. 1953, 40, 447. Simonsen, M., Buermann, J., Gammeltoft, A., Jensen, F., Jorgensen, K. Acta path. microbiol. scand. 1953, 32, 1. Hume, D., Jackson, B. T., Zukoski, C. F., Lee, H. M., Kauffman H. M., Egdahl, R. H. Ann. Surg. 1960, 152, 354. Report of Expert Committee on Filariasis (Wuchereria and Brugia Infections). Tech. Rep. Wld Hlth Org. no. 233. Geneva, 1962.
place in many parts of the tropics. Congregation of people, with increased water-supplies but deficient drainage and sanitation, favours the breeding of the main mosquito vector which is of the group Culex pipiens fatigans and which breeds particularly in and near latrines. Moreover, grouping of people facilitates transmission of the infection from one person to another. This regrouping has already taken place in Ceylon and India and is now proceeding in Africa; in South America there is the same tendency in the Guianas and in the Amazon delta near Belem. The Culex pipiens group of mosquitoes is now due for more intensive study. Many different races exist within it, some of which transmit filariae well and some poorly; but the reasons for these differences and the adaptability of the different strains are poorly understood. In general, the culicine mosquitoes are not very susceptible to the residual insecticides, such as dicophane (D.D.T.), which have proved so effective against the anophelines which carry malaria. The adult culicines rapidly become resistant; and although they are probably more sensitive to‘ Baytex ’, malathion, or dieldrin, the use of these compounds is limited by their toxicity. C. fatigans is best controlled by improving sanitation so as to restrict their breeding. Such sanitary measures are simple in theory but often difficult to enforce in practice, since they require a well-organised and adequately staffed health service and the intelligent cooperation of the local populace. Insecticides to kill the larvae must be secondary to these measures. Chlorinated hydrocarbons such as dicophane often fail because of the development of resistance; but organophosphorus compounds are more promising. But even if all the mosquitoes in an area were eliminated, the infection would not die out for five or ten years or more, since filarial worms are long-lived. And any relaxation in mosquito control would allow spread of the infection once again. Campaigns to control filariasis have therefore been based on eradication of the worms themselves, rather than on control of the insect vector. In this respect, the fight against filariasis has been the obverse of that against malaria, in which the emphasis has lain on control of the mosquitoes by dicophane while chemotherapy against the malaria parasite in man has received only slight attention. The best compound for destroying the filarial worms in man is diethylcarbamazine (’ Hetrazan’,’, Banocide’, ’ Notezine ’). This rapidly destroys the microfilarix of W. bancrofti and B. malayi and it almost certainly kills the adult worms also. It is usually given by mouth and is remarkably free from dangerous complications, although it may cause minor toxic effects such as nausea, vomiting, or headache. Destruction of the microfilaria: may cause allergic reactions, such as pyrexia, lasting for one to three days. These side-effects may be a great obstacle to persuading populations to accept the tablets. The source of infection with W. bancrofti or B. malayi is another man, since these worms live only in man and there is no animal reservoir (except in parts of Malaya, where similar worms are found in monkeys). Consequently, if all the people in a district could be adequately treated for destruction of their worms, there would be no
387
fresh infections and the disease would be eradicated-or at all, on the grounds that the condition was selfat any rate reduced to a low level. (Worms are fundalimiting; that the symptoms, if any, were trivial and were unrelieved by operation; and that operation someand which from bacteria protozoa mentally different times resulted in atrophy of the affected testis. Of late can multiply indefinitely from a single individual which has entered a new host. One worm stays one worm until years, however, some fresh thinking has been devoted to it meets another worm of the opposite sex and mates; this subject. and even then the next generation must pass out of the Exactly how varicoceles arise is even now uncertain. introduced afresh before the and be host’s body process One suggestion was that the left testicular vein (most can be repeated. Furthermore, a few worms are usually commonly affected) had fewer competent valves than well tolerated by the host and clinical lesions are the vein on the right side. This is now known not to be so. Again, the left renal vein, into which the left produced only when large numbers are present.) in of the world has shown that testicular vein empties, has been likened to a nut Experience many parts if at least 80% of the population at risk is treated with clamped in a nutcracker between the root of the superior five or more doses of diethylcarbamazine, 4-6 mg. per mesenteric artery and the aorta; and in the erect posture kg. body-weight, the percentage of people infected and the small intestine is alleged to drag on the artery, thus the number of microfilariae in each individual are greatly retarding the flow in the left renal and testicular veinsreduced. The doses of diethylcarbamazine may be given a supposition not easily proved. Hitherto the veins on five or six consecutive days or once weekly or which are varicose have been assumed to be the twelve for nine to twelve The times. schedule to twenty anastomosing in a vine-like cluster (hence the monthly monthly is probably more effective and less likely to produce toxic name, pampiniform plexus) and ascending in three effects, but the weekly courses are often more convenient longitudinal groups, surrounding the testicular artery to administer. If this treatment can be repeated for towards the deep inguinal ring. But HANLEY and several years, as has been done by KESSEL et al. 24 in HARRISON, from their study of injection preparations, Tahiti, filariasis can be practically wiped out. The assert that the cremasteric veins (which drain into the procedure is undoubtedly effective. The difficulty lies inferior epigastric vein) and not the testicular veins are in securing the cooperation of the local populace, and at fault. If this is so, explanations for varicosity based this difficulty becomes greater the greater the number of on the anatomical pathway of the left testicular vein are people involved. In some parts of India, where the invalid, and the preponderance of left-sided varicocele is population is enormous, it has proved insuperable. even more difficult to explain. Propaganda, personal approach, securing the cooperation The most distressing disturbance associated with of leaders of local opinion, are all extremely important. varicocele is subfertility; and the cause of this is equally The dose schedules have been modified so as to give the in animals2 and in man3 raised scrotal Both puzzling. least opportunity for defaulting. This has been carried temperature has been shown to reduce spermatogenesis. to the most drastic limits in some parts of China,25 where Investigation of sterility in cryptorchidism established infected people are given a single large dose of 1-0 g. in that for normal spermatogenesis the temperature inside the evening and are then housed together in temporary the scrotal sac must be at least 2’5°C lower than the barracks so that they can sleep it off overnight. Apparently rectal temperature.4 HANLEYshowed that a large 50% vomit. This procedure seems to demand both close varicocele sometimes reduces the temperature differcontrol of, and sturdy stoicism in, the people concerned. ential to as little as 0.1 °C. This, he argued, was the Another proposal has been to incorporate diethyl- cause of low-density sperm-counts and subfertility in carbamazine in the salt used in the district. If this were long-standing cases of varicocele. But how do the feasible it would greatly simplify distribution and testicular vessels exert a thermoregulatory effect ? persuasion; but it has not yet been tried. Attempts According to one ingenious hypothesis, the testicular have been made to develop arsenical compounds, such veins are arranged round the testicular artery like a as melarsenoxide dimercaptosuccinate, which could be radiator, providing a heat-exchange mechanism between
given as a single intramuscular injection. These compounds certainly destroy the adult worms, and so remove the source of further micronlarise; but a few people have a dangerous idiosyncrasy to arsenicals, and much more experience is needed before these drugs can be regarded as safe enough for widespread use. Varicocele
FOR years, entrants to the Services were rejected if they were found to have a varicocele. When they were referred for treatment, the usual procedure was to transfix the pampiniform plexus of veins in the inguinal canal at two levels, an inch or two apart, and to tie the ligatures together. But surgeons commonly refused to operate 24.
Kessel, J. F., Thooris, G. C., Bambridge,
2, 1050. 25. Li Huei-Han. Chin. med. J. 1959, 78, 148.
B.
J. trop. Med. Hyg. 1953,
the arterial and the venous supply of the testis. But this does not explain how varicose veins in one testis diminish spermatogenesis in the second testis. Whatever the mechanism, HANLEY and HARRISONmaintain that ligation of the cremasteric veins through a scrotal incision will yield satisfactory results in cases where the testes are well formed. Of 100 patients who were operated on, spermatogenesis was improved and pain8 relieved in about 80. The Palomoand Ivanissevich operations of retroperitoneal ligation in the region of 1. 2. 3. 4. 5. 6. 7. 8.
Hanley, H. G., Harrison, R. G. Brit. J. Surg. 1962, 50, 64. Harrison, R. G., Weiner, J. S. J. exp. Biol. 1949, 26, 304. MacLeod, J., Hotchkiss, R. S. Endocrinology, 1941, 28, 780. Davidson, H. A. Practitioner, 173, 703. Hanley, H. G. Proceedings of the 2nd World Congress on Fertility and Sterility, Naples, 1956, vol. II, p. 953. Harrison, R. G. Brit. med. J. 1954, ii, 300. Palomo, A. J. Urol. 1949, 61, 604. Ivanissevich, O. J. int. Coll. Surg. 1960, 34, 742.
after any procedure aimed at inducing specific immunological tolerance in a mature recipient by damaging immunologically competent cells. SHACKMAN and DEMPSTER 18 report a remarkable case of successful homotransplantation between brothers whose ages differed by more than twenty years; the recipient has survived twelve months to date, in good health. Renal grafting between identical twins is already well established; but these reports of success show that the procedure is passing out of the hazardous experimental phase and can now be more widely applied. A Nuffield centre for transplantation surgery is to be set up in Edinburgh under the directorship of Prof. M. F. A. WOODRUFF, and the Department of Health for Scotland has guaranteed the running costs for the first five years. This should stimulate efforts to improve renal transplantation. The possibility of inducing tolerance by biological methods less drastic than irradiation needs exploring; partial tolerance of skin transplants has already been induced in human infants before the development of immunological maturity.19 The role of graft versus host in the process of rejection is still not c1ear.2O-22 Moreover, the long-term results of homotransplantation have yet to be assessed. Do transplanted kidneys eventually succumb to disease similar to that which destroyed the patient’s own kidneys ? For how long and by what means can kidneys on the brink of rejection be tided over to maintain satisfactory function. And what place have cortisone and azotasmia in the production of tolerance ?
Filariasis
half-century the commoner and more deadly tropical infections, such as malaria and yellow fever, have been largely controlled; and attention can now be turned to infections, such as schistosomiasis and filariasis, which cripple rather than kill. Filariasis, due to the worms Wuchereria bancrofti and Brugia malayi, is IN the past
known to medical students as the cause of the grotesque deformities of the legs and genitals which are termed elephantiasis. The larval worms (micromarise) behave remarkably, swarming at night in the peripheral blood from which they disappear almost completely by day. Owing to their presence in the blood at night they can be transmitted by blood-sucking mosquitoes. During the day the micromarias accumulate in the lungs, where the oxygen tension is high. They hold themselves in the pulmonary capillaries by some force which is increased by rises in the oxygen tension and decreased by falls; this force seems to be switched on and off every twelve hours by some mysterious mechanism inside the micronlarise. A report by a W.H.O. expert committee 23 describes filariasis in different parts of the world. The spread of this infection is favoured by the urbanisation taking 18. 19. 20. 21. 22.
23.
Shackman, R., Dempster, W. J. Unpublished. Woodruff, M. F. A. The Transplantation of Tissues and Organs; p. 129. Springfield, III., 1960. Dempster, W. J. Brit. J. Surg. 1953, 40, 447. Simonsen, M., Buermann, J., Gammeltoft, A., Jensen, F., Jorgensen, K. Acta path. microbiol. scand. 1953, 32, 1. Hume, D., Jackson, B. T., Zukoski, C. F., Lee, H. M., Kauffman H. M., Egdahl, R. H. Ann. Surg. 1960, 152, 354. Report of Expert Committee on Filariasis (Wuchereria and Brugia Infections). Tech. Rep. Wld Hlth Org. no. 233. Geneva, 1962.
place in many parts of the tropics. Congregation of people, with increased water-supplies but deficient drainage and sanitation, favours the breeding of the main mosquito vector which is of the group Culex pipiens fatigans and which breeds particularly in and near latrines. Moreover, grouping of people facilitates transmission of the infection from one person to another. This regrouping has already taken place in Ceylon and India and is now proceeding in Africa; in South America there is the same tendency in the Guianas and in the Amazon delta near Belem. The Culex pipiens group of mosquitoes is now due for more intensive study. Many different races exist within it, some of which transmit filariae well and some poorly; but the reasons for these differences and the adaptability of the different strains are poorly understood. In general, the culicine mosquitoes are not very susceptible to the residual insecticides, such as dicophane (D.D.T.), which have proved so effective against the anophelines which carry malaria. The adult culicines rapidly become resistant; and although they are probably more sensitive to‘ Baytex ’, malathion, or dieldrin, the use of these compounds is limited by their toxicity. C. fatigans is best controlled by improving sanitation so as to restrict their breeding. Such sanitary measures are simple in theory but often difficult to enforce in practice, since they require a well-organised and adequately staffed health service and the intelligent cooperation of the local populace. Insecticides to kill the larvae must be secondary to these measures. Chlorinated hydrocarbons such as dicophane often fail because of the development of resistance; but organophosphorus compounds are more promising. But even if all the mosquitoes in an area were eliminated, the infection would not die out for five or ten years or more, since filarial worms are long-lived. And any relaxation in mosquito control would allow spread of the infection once again. Campaigns to control filariasis have therefore been based on eradication of the worms themselves, rather than on control of the insect vector. In this respect, the fight against filariasis has been the obverse of that against malaria, in which the emphasis has lain on control of the mosquitoes by dicophane while chemotherapy against the malaria parasite in man has received only slight attention. The best compound for destroying the filarial worms in man is diethylcarbamazine (’ Hetrazan’,’, Banocide’, ’ Notezine ’). This rapidly destroys the microfilarix of W. bancrofti and B. malayi and it almost certainly kills the adult worms also. It is usually given by mouth and is remarkably free from dangerous complications, although it may cause minor toxic effects such as nausea, vomiting, or headache. Destruction of the microfilaria: may cause allergic reactions, such as pyrexia, lasting for one to three days. These side-effects may be a great obstacle to persuading populations to accept the tablets. The source of infection with W. bancrofti or B. malayi is another man, since these worms live only in man and there is no animal reservoir (except in parts of Malaya, where similar worms are found in monkeys). Consequently, if all the people in a district could be adequately treated for destruction of their worms, there would be no
387
fresh infections and the disease would be eradicated-or at all, on the grounds that the condition was selfat any rate reduced to a low level. (Worms are fundalimiting; that the symptoms, if any, were trivial and were unrelieved by operation; and that operation someand which from bacteria protozoa mentally different times resulted in atrophy of the affected testis. Of late can multiply indefinitely from a single individual which has entered a new host. One worm stays one worm until years, however, some fresh thinking has been devoted to it meets another worm of the opposite sex and mates; this subject. and even then the next generation must pass out of the Exactly how varicoceles arise is even now uncertain. introduced afresh before the and be host’s body process One suggestion was that the left testicular vein (most can be repeated. Furthermore, a few worms are usually commonly affected) had fewer competent valves than well tolerated by the host and clinical lesions are the vein on the right side. This is now known not to be so. Again, the left renal vein, into which the left produced only when large numbers are present.) in of the world has shown that testicular vein empties, has been likened to a nut Experience many parts if at least 80% of the population at risk is treated with clamped in a nutcracker between the root of the superior five or more doses of diethylcarbamazine, 4-6 mg. per mesenteric artery and the aorta; and in the erect posture kg. body-weight, the percentage of people infected and the small intestine is alleged to drag on the artery, thus the number of microfilariae in each individual are greatly retarding the flow in the left renal and testicular veinsreduced. The doses of diethylcarbamazine may be given a supposition not easily proved. Hitherto the veins on five or six consecutive days or once weekly or which are varicose have been assumed to be the twelve for nine to twelve The times. schedule to twenty anastomosing in a vine-like cluster (hence the monthly monthly is probably more effective and less likely to produce toxic name, pampiniform plexus) and ascending in three effects, but the weekly courses are often more convenient longitudinal groups, surrounding the testicular artery to administer. If this treatment can be repeated for towards the deep inguinal ring. But HANLEY and several years, as has been done by KESSEL et al. 24 in HARRISON, from their study of injection preparations, Tahiti, filariasis can be practically wiped out. The assert that the cremasteric veins (which drain into the procedure is undoubtedly effective. The difficulty lies inferior epigastric vein) and not the testicular veins are in securing the cooperation of the local populace, and at fault. If this is so, explanations for varicosity based this difficulty becomes greater the greater the number of on the anatomical pathway of the left testicular vein are people involved. In some parts of India, where the invalid, and the preponderance of left-sided varicocele is population is enormous, it has proved insuperable. even more difficult to explain. Propaganda, personal approach, securing the cooperation The most distressing disturbance associated with of leaders of local opinion, are all extremely important. varicocele is subfertility; and the cause of this is equally The dose schedules have been modified so as to give the in animals2 and in man3 raised scrotal Both puzzling. least opportunity for defaulting. This has been carried temperature has been shown to reduce spermatogenesis. to the most drastic limits in some parts of China,25 where Investigation of sterility in cryptorchidism established infected people are given a single large dose of 1-0 g. in that for normal spermatogenesis the temperature inside the evening and are then housed together in temporary the scrotal sac must be at least 2’5°C lower than the barracks so that they can sleep it off overnight. Apparently rectal temperature.4 HANLEYshowed that a large 50% vomit. This procedure seems to demand both close varicocele sometimes reduces the temperature differcontrol of, and sturdy stoicism in, the people concerned. ential to as little as 0.1 °C. This, he argued, was the Another proposal has been to incorporate diethyl- cause of low-density sperm-counts and subfertility in carbamazine in the salt used in the district. If this were long-standing cases of varicocele. But how do the feasible it would greatly simplify distribution and testicular vessels exert a thermoregulatory effect ? persuasion; but it has not yet been tried. Attempts According to one ingenious hypothesis, the testicular have been made to develop arsenical compounds, such veins are arranged round the testicular artery like a as melarsenoxide dimercaptosuccinate, which could be radiator, providing a heat-exchange mechanism between
given as a single intramuscular injection. These compounds certainly destroy the adult worms, and so remove the source of further micronlarise; but a few people have a dangerous idiosyncrasy to arsenicals, and much more experience is needed before these drugs can be regarded as safe enough for widespread use. Varicocele
FOR years, entrants to the Services were rejected if they were found to have a varicocele. When they were referred for treatment, the usual procedure was to transfix the pampiniform plexus of veins in the inguinal canal at two levels, an inch or two apart, and to tie the ligatures together. But surgeons commonly refused to operate 24.
Kessel, J. F., Thooris, G. C., Bambridge,
2, 1050. 25. Li Huei-Han. Chin. med. J. 1959, 78, 148.
B.
J. trop. Med. Hyg. 1953,
the arterial and the venous supply of the testis. But this does not explain how varicose veins in one testis diminish spermatogenesis in the second testis. Whatever the mechanism, HANLEY and HARRISONmaintain that ligation of the cremasteric veins through a scrotal incision will yield satisfactory results in cases where the testes are well formed. Of 100 patients who were operated on, spermatogenesis was improved and pain8 relieved in about 80. The Palomoand Ivanissevich operations of retroperitoneal ligation in the region of 1. 2. 3. 4. 5. 6. 7. 8.
Hanley, H. G., Harrison, R. G. Brit. J. Surg. 1962, 50, 64. Harrison, R. G., Weiner, J. S. J. exp. Biol. 1949, 26, 304. MacLeod, J., Hotchkiss, R. S. Endocrinology, 1941, 28, 780. Davidson, H. A. Practitioner, 173, 703. Hanley, H. G. Proceedings of the 2nd World Congress on Fertility and Sterility, Naples, 1956, vol. II, p. 953. Harrison, R. G. Brit. med. J. 1954, ii, 300. Palomo, A. J. Urol. 1949, 61, 604. Ivanissevich, O. J. int. Coll. Surg. 1960, 34, 742.