520
tients, both those with primary haematological and those with non-haematological disease, have received alkylating agents such as cyclophosphamide, chlorambucil, or melphalan, so it is possible that leukaemogenesis is related to the "radiomi-
_
metic" action of this group of drugs: their complex cytotoxic action involves nucleoprotein damage. Chromosomal abnormalities have been observed, for example, after cyclophosphamide therapy. Nevertheless, genetic damage is not seen only with alkylating agents: similar changes have been observed with many anticancer drugs which are classified as antimetabolites rather than radiomimetic agents.24 However produced, genetic damage to the hxmopoietic stem cell can probably set the stage for leukxmia. Indeed, a similar mechanism has been postulated for the leukxmogenic action of benzene, and for the rare cases of leukxmia after chloramphenicol-induced marrow aplasia. Another possibility is that the immunosuppressant action of the drugs compromises host resistance: of course, many patients with haematological neoplasms already have abnormalities of the immune system as a feature of the disease process. In non-neoplastic disorders therapy has usually been given to suppress the production of autoantibodies: the interaction between chronic antigenic stimulation and
immunodepression might’ predispose to malignant change. The difficulty here is that A.M.L. is rare in patients with primary immunodeficiency diseases, though there is a much increased incidence of neoplasms of the lymphoreticular system (including acute lymphoblastic leukaemia).25 Only one case has been recorded in which A.M.L. followed azathioprine therapy for renal transplantation, although here again there is an increased incidence of tumours, notably lymphomas. Can anything be done to reduce the risk of leukaemia in these patients? Although morphological changes in the marrow, such as sideroblastosis, have been observed by several workers, and recognised in retrospect as preleukaemic, their interpretation at the time can be difficult. Many patients on cytotoxic drugs show evidence of dyserythropoiesis and dysmyelopoiesis, though this usually disappears within a short time of stopping therapy. In any case, a diagnosis of preleukaemia implies irreversible marrow damage, though in practice evolution into A.M.L. may be long delayed. SULTAN 21 suggests that bone-marrow cultures may help. Incipient marrow damage results in a reduced colony-forming capacity, and SULTAN found that, after withdrawal of chlorambucil given for autoimmune disease, the marrow took several months to recover its normal capacity to form colonies. Patients with preleuksemia often show permanent al24. Scott, D. Proc. IX int. Chemother. Congr. 1976, 7, 95. 25. Kersey, J. H., Spector, B. D., Good, R. A. Int. J. Cancer, 26. Sultan, C. Blood Cells, 1976, 2, 78.
1973, 12, 333.
terations in colony-forming capacity.27 An attempt monitor bone-marrow function by this method, though time-consuming, would probably provide a better early-warning system than routine bloodcounts or morphological examination of marrow. Perhaps, too, alkylating agents. should be dropped in favour of antimetabolites whenever there is a choice, though antimetabolites are probably not without risk of oncogenesis. Meanwhile it is reassuring that the incidence of leukxmia in these patients is still very small. For example, in 900 cases of Hodgkin’s disease KAPLAN 21 observed only 3 of acute leukaemia: 1 of these patients had received chemotherapy alone. We concluded in 1971 by quoting HOLLAND29: "Late death from leukemia after a definite remission from myeloma is to be preferred to early death without remission". A similar philosophy must govern cytotoxic-drug therapy in other diseases. to
GROUP-B STREPTOCOCCI IN THE NEWBORN THE emergence of group-B streptococci as serious pathogens in the newborn presents an epidemiological challenge. Although these organisms have long been known to cause bovine mastitis, until 1960 there were remarkably few reports implicating them in human disease. 12 Since then the incidence of neonatal group-B streptococcal infection has risen sharply, both in the United States and in Europe.3-9 Finch and his colleaguesl° in a retrospective survey in London found an incidence of 1 in 900 deliveries, while Eickhoff1 in the U.S.A. showed that as many as 1 in 500 babies acquired infections due to group-B streptococci. At present, they are second only to Escherichia coli in causing neonatal meningitis. There are two patterns of group-B infection in the newborn. The early form presents with acute respiratory distress, apncea, shock, septicaemia, and meningitis; onset is usually within 24 hours of delivery, though the interval may be as long as 10 days. Organisms may be cultured from many sites, including blood, umbilicus, nasopharynx, skin, and meconium. Clinically and radiologically, the condition may closely resemble hyalinemembrane disease. 60-75% of the babies die, often within 48 hours of onset. The fact that strains (typically type B Ia) from mother and baby are usually identical suggests that infection is transmitted directly from mother to child during delivery. There is a link with maternal complications, particularly premature labour Milner, G R., Testa, N. G., Geary, C. G., Dexter, T. M., Muldal, S., Maclver, J. E., Lajtha, L. J. Br. J. Hœmat. (in the press). 28. Kaplan, H. S. Blood Cells, 1976, 2, 80. 29 Holland, J. F. New Engl. J. Med. 1970, 283, 1165. 1. Fry, R. M. Lancet, 1938, i, 199. 2. Nyhan, W. L., Fousek, M. D. Pediatrics, 1958, 22, 268. 3. Baker, C. J., Barrett, F. F. J. Pediat. 1973, 83, 919. 4. Franciosi, R. A., Knostman, J. D., Zimmerman, R. A. ibid. p. 707. 5. Barton, L. L., Feigin, R. D., Lms, R. ibid. 1973, 82, 719. 6. Baker, C. J., et. al. ibid. p. 724. 7. Eickhoff, T. C., et. al. New Engl. J. Med. 1964, 27, 1221. 8. Harper, I. J. clin. Path. 1971, 24, 438. 9. Quirante, J., Ceballos, R., Cassady, G. Am. J. Dis. Childh. 1974, 128, 659. 10. Finch, R. G., French, G. L., Phillips, I. Br. med. J. 1976, i, 1245. 27.
521
and prolonged rupture of membranes. In contrast, the second type of infection presents, usually after the 10th day of life, as purulent meningitis. The mortality-rate is lower (14-18%) and streptococci isolated are usually B III serotypes. Perhaps babies aquire this infection from their own bacterial flora or from their attendants; the still uncertain. Should women be screened for group-B streptococci in late pregnancy? Some workers claim that detection of the carrier state (with prophylactic chemotherapy before delivery)15 is worth while,4 13 14 but not everyone agrees.3 For British women in the third trimester of pregnancy the carriage-rate is about 6%," but a rate as high as 25% has been reported from the U.S.A3: this variation may reflect geographical and sociological differences. 1-2% of infants are colonised. Fathers harbouring urethral group-B streptococci, and throat carriers amongst nursery staff, may act as reservoirs of infection. Standard laboratory methods of culture and serological identification of streptococci are time-consuming, but more rapid techniques have been devised. Under certain cultural conditions group-B streptococci produce pigment,16 and a method 17 based on this property may prove a useful means of screening for the carrier state. Serological identification may be carried out rapidly by the coagglutination method described by Christensen and his colleagues.18 A commercial kit (’Phadebact’) enables streptococci of groups A, B, C, and G to be readily identified. Pcnicillin is the treatment of choice both for established infection and for eradication of the carrier state. Because group-B streptococci are killed more slowly than group-A streptococci,19 a combination of penicillin and gentamicin is often recommended. Therapy should be continued for 10-14 days after sterilisation of blood or cerebrospinal fluid. The effectiveness of penicillin in treatment of the carrier state has been questioned. Paredes et a1.2° have recorded several cases in which infection returned after successful treatment, and they attributed this to failure of penicillin to eradicate group-B streptococci from the throat. Poor excretion of penicillin in saliva has been blamed for disappointing results in the treatment of meningococcal carriage, and the same may apply to group-B streptococci. The pathogenesis and epidemiology of group-B streptococcal infection are incompletely understood. We need to know the extent of hospital cross-infection and to assess methods of prevention. The new laboratory techniques will contribute both in diagnosis and research. Meanwhile, a special bacteriological eye must be kept on the babies of known carrier mothers and on those born after complicated pregnancy and delivery:2’bacteriological surveillance of these infants should ensure prompt and adequate treatment if infection arises. route is
11. Katzenstein, A., Davis, C., Braude, A. J. inf. Dis. 1976, 133, 430. 12. McCracken, G. H. J. Pediat. 1973, 82, 703. 13. Rogers, K. B. Archs Dis. Childh. 1970, 45, 147. 14. Hood, M., Janney, A., Dameron, G. Am. J. Obstet. Gynec. 1961, 82, 809. 15. Eickhoff, T. C., et al. J. Pediat. 1973, 83, 1097. 16. Fallon, R. J. J. clin. Path. 1974, 27, 902. 17 Islam, A. K. M. S. Lancet, 1977, i, 259. 18 Christensen, P., Kahlmeter, G., Jonsson, S., Kronvall, G. Infect. Immun.
1975, 7, 881. 19. Schauf, V., Deveikis, A., Riff, L., Serota, A.J. Pediat. 1976, 89, 194. 20. Paredes, A., Wong, P., Yow, M. D. ibid. p. 191. 21. Berg, T., Hallander, H. O., Nathorst-Windahl, G., Nordlander, I-M. Scand. J inf. Dis. 1977, 9, 19.
INCONTINENT WOMEN INVOLUNTARY loss of urine is a cruel and embarrassing symptom which curtails many physical and social activities ; laughter and sudden movements become perilous, and shopping expeditions become major undertakings which have to be planned from one public convenience to another. Yet this is a common problem, which despite its restrictions and its expense in padding and underclothing, is often borne in silence by women for many years before aid is sought. Unfortunately, for many the arrival at the outpatient clinic often marks a new start, rather than an end to their problems. The less discerning gynaecologist often fails to probe the true characteristics of the incontinence and, blindly believing that prolapse is intimately related to a bladder-neck weakness, wields the scalpel willy-nilly along the anterior vaginal wall leaving the retropubic approach as a reserve for his failures. During the past decade there has been considerable pooling of research and cooperation between urologists, gynaecologists, neurologists, and physiologists who have graduated, with the help of transducers and multichannel recorders, from the somewhat static procedures of cystoscopy and pyelography to dynamic investigations. Pressure recordings have now added a new dimension to cine-cystourethrography and have enabled a more accurate differentiation of incontinence caused by urethral incompetence from that initiated by uninhibited detrusor activity.2 Patients who simply complain of, and demonstrably suffer from, a synchronous urine loss following a rise of intra-abdominal pressure, without an alteration of normal micturition patterns, seldom have to be subjected to any form of detailed analysis. However, in a patient with urinary frequency, urgency incontinence, or unconscious urinary loss, or in one who has not responded to previous surgery, then the full battery of modern urodynamic investigations must be invoked. Bladder-neck surgery (which carries a multitude of operative eponyms) will benefit only those patients with demonstrable weakness of the urethral sphincter mechanism and is unlikely to lessen3 and may even aggravate the symptoms of urgency and frequency. The success of such procedures will depend on the surgeon’s ability to select his patients, his technical skill, and the nature of the tissues to be sutured; for there is no doubt that the most satisfactory results will be obtained at the first operative encounter, when the tissues are mobile and free of fibrotic scar tissue. The technique tends to be a matter of personal choice; the gynaecologist has traditionally approached the problem vaginally, but it is becoming increasingly apparent that the bladder neck can be much more satisfactorily elevated and more firmly fixed by retropubic surgery, in which the anterior vaginal wall is hitched and tethered to Cooper’s ligaments.4 The reports of cure range widely from 60%5 to 90%.4 Unfortunately, many reviewers of a particular technique analyse a small number of cases and rarely define their criteria in measuring success. Objective and long-term follow-up with an analysis of the causes 1. International Continence Society Annual Meetings, 1971-76. 2. Bates, C. P., Whiteside, C. G., Turner-Warwick, R. T. Br. J. Urol.
43, 714 3. Arnold, E. P., et al. Am. J. Obstet. Gynec. 1973, 117, 805. 4. Burch, J. C. ibid. 1968, 100, 764. 5. Low, J. A. ibid. 1967, 97, 308.
1970,
tients, both those with primary haematological and those with non-haematological disease, have received alkylating agents such as cyclophosphamide, chlorambucil, or melphalan, so it is possible that leukaemogenesis is related to the "radiomi-
_
metic" action of this group of drugs: their complex cytotoxic action involves nucleoprotein damage. Chromosomal abnormalities have been observed, for example, after cyclophosphamide therapy. Nevertheless, genetic damage is not seen only with alkylating agents: similar changes have been observed with many anticancer drugs which are classified as antimetabolites rather than radiomimetic agents.24 However produced, genetic damage to the hxmopoietic stem cell can probably set the stage for leukxmia. Indeed, a similar mechanism has been postulated for the leukxmogenic action of benzene, and for the rare cases of leukxmia after chloramphenicol-induced marrow aplasia. Another possibility is that the immunosuppressant action of the drugs compromises host resistance: of course, many patients with haematological neoplasms already have abnormalities of the immune system as a feature of the disease process. In non-neoplastic disorders therapy has usually been given to suppress the production of autoantibodies: the interaction between chronic antigenic stimulation and
immunodepression might’ predispose to malignant change. The difficulty here is that A.M.L. is rare in patients with primary immunodeficiency diseases, though there is a much increased incidence of neoplasms of the lymphoreticular system (including acute lymphoblastic leukaemia).25 Only one case has been recorded in which A.M.L. followed azathioprine therapy for renal transplantation, although here again there is an increased incidence of tumours, notably lymphomas. Can anything be done to reduce the risk of leukaemia in these patients? Although morphological changes in the marrow, such as sideroblastosis, have been observed by several workers, and recognised in retrospect as preleukaemic, their interpretation at the time can be difficult. Many patients on cytotoxic drugs show evidence of dyserythropoiesis and dysmyelopoiesis, though this usually disappears within a short time of stopping therapy. In any case, a diagnosis of preleukaemia implies irreversible marrow damage, though in practice evolution into A.M.L. may be long delayed. SULTAN 21 suggests that bone-marrow cultures may help. Incipient marrow damage results in a reduced colony-forming capacity, and SULTAN found that, after withdrawal of chlorambucil given for autoimmune disease, the marrow took several months to recover its normal capacity to form colonies. Patients with preleuksemia often show permanent al24. Scott, D. Proc. IX int. Chemother. Congr. 1976, 7, 95. 25. Kersey, J. H., Spector, B. D., Good, R. A. Int. J. Cancer, 26. Sultan, C. Blood Cells, 1976, 2, 78.
1973, 12, 333.
terations in colony-forming capacity.27 An attempt monitor bone-marrow function by this method, though time-consuming, would probably provide a better early-warning system than routine bloodcounts or morphological examination of marrow. Perhaps, too, alkylating agents. should be dropped in favour of antimetabolites whenever there is a choice, though antimetabolites are probably not without risk of oncogenesis. Meanwhile it is reassuring that the incidence of leukxmia in these patients is still very small. For example, in 900 cases of Hodgkin’s disease KAPLAN 21 observed only 3 of acute leukaemia: 1 of these patients had received chemotherapy alone. We concluded in 1971 by quoting HOLLAND29: "Late death from leukemia after a definite remission from myeloma is to be preferred to early death without remission". A similar philosophy must govern cytotoxic-drug therapy in other diseases. to
GROUP-B STREPTOCOCCI IN THE NEWBORN THE emergence of group-B streptococci as serious pathogens in the newborn presents an epidemiological challenge. Although these organisms have long been known to cause bovine mastitis, until 1960 there were remarkably few reports implicating them in human disease. 12 Since then the incidence of neonatal group-B streptococcal infection has risen sharply, both in the United States and in Europe.3-9 Finch and his colleaguesl° in a retrospective survey in London found an incidence of 1 in 900 deliveries, while Eickhoff1 in the U.S.A. showed that as many as 1 in 500 babies acquired infections due to group-B streptococci. At present, they are second only to Escherichia coli in causing neonatal meningitis. There are two patterns of group-B infection in the newborn. The early form presents with acute respiratory distress, apncea, shock, septicaemia, and meningitis; onset is usually within 24 hours of delivery, though the interval may be as long as 10 days. Organisms may be cultured from many sites, including blood, umbilicus, nasopharynx, skin, and meconium. Clinically and radiologically, the condition may closely resemble hyalinemembrane disease. 60-75% of the babies die, often within 48 hours of onset. The fact that strains (typically type B Ia) from mother and baby are usually identical suggests that infection is transmitted directly from mother to child during delivery. There is a link with maternal complications, particularly premature labour Milner, G R., Testa, N. G., Geary, C. G., Dexter, T. M., Muldal, S., Maclver, J. E., Lajtha, L. J. Br. J. Hœmat. (in the press). 28. Kaplan, H. S. Blood Cells, 1976, 2, 80. 29 Holland, J. F. New Engl. J. Med. 1970, 283, 1165. 1. Fry, R. M. Lancet, 1938, i, 199. 2. Nyhan, W. L., Fousek, M. D. Pediatrics, 1958, 22, 268. 3. Baker, C. J., Barrett, F. F. J. Pediat. 1973, 83, 919. 4. Franciosi, R. A., Knostman, J. D., Zimmerman, R. A. ibid. p. 707. 5. Barton, L. L., Feigin, R. D., Lms, R. ibid. 1973, 82, 719. 6. Baker, C. J., et. al. ibid. p. 724. 7. Eickhoff, T. C., et. al. New Engl. J. Med. 1964, 27, 1221. 8. Harper, I. J. clin. Path. 1971, 24, 438. 9. Quirante, J., Ceballos, R., Cassady, G. Am. J. Dis. Childh. 1974, 128, 659. 10. Finch, R. G., French, G. L., Phillips, I. Br. med. J. 1976, i, 1245. 27.
521
and prolonged rupture of membranes. In contrast, the second type of infection presents, usually after the 10th day of life, as purulent meningitis. The mortality-rate is lower (14-18%) and streptococci isolated are usually B III serotypes. Perhaps babies aquire this infection from their own bacterial flora or from their attendants; the still uncertain. Should women be screened for group-B streptococci in late pregnancy? Some workers claim that detection of the carrier state (with prophylactic chemotherapy before delivery)15 is worth while,4 13 14 but not everyone agrees.3 For British women in the third trimester of pregnancy the carriage-rate is about 6%," but a rate as high as 25% has been reported from the U.S.A3: this variation may reflect geographical and sociological differences. 1-2% of infants are colonised. Fathers harbouring urethral group-B streptococci, and throat carriers amongst nursery staff, may act as reservoirs of infection. Standard laboratory methods of culture and serological identification of streptococci are time-consuming, but more rapid techniques have been devised. Under certain cultural conditions group-B streptococci produce pigment,16 and a method 17 based on this property may prove a useful means of screening for the carrier state. Serological identification may be carried out rapidly by the coagglutination method described by Christensen and his colleagues.18 A commercial kit (’Phadebact’) enables streptococci of groups A, B, C, and G to be readily identified. Pcnicillin is the treatment of choice both for established infection and for eradication of the carrier state. Because group-B streptococci are killed more slowly than group-A streptococci,19 a combination of penicillin and gentamicin is often recommended. Therapy should be continued for 10-14 days after sterilisation of blood or cerebrospinal fluid. The effectiveness of penicillin in treatment of the carrier state has been questioned. Paredes et a1.2° have recorded several cases in which infection returned after successful treatment, and they attributed this to failure of penicillin to eradicate group-B streptococci from the throat. Poor excretion of penicillin in saliva has been blamed for disappointing results in the treatment of meningococcal carriage, and the same may apply to group-B streptococci. The pathogenesis and epidemiology of group-B streptococcal infection are incompletely understood. We need to know the extent of hospital cross-infection and to assess methods of prevention. The new laboratory techniques will contribute both in diagnosis and research. Meanwhile, a special bacteriological eye must be kept on the babies of known carrier mothers and on those born after complicated pregnancy and delivery:2’bacteriological surveillance of these infants should ensure prompt and adequate treatment if infection arises. route is
11. Katzenstein, A., Davis, C., Braude, A. J. inf. Dis. 1976, 133, 430. 12. McCracken, G. H. J. Pediat. 1973, 82, 703. 13. Rogers, K. B. Archs Dis. Childh. 1970, 45, 147. 14. Hood, M., Janney, A., Dameron, G. Am. J. Obstet. Gynec. 1961, 82, 809. 15. Eickhoff, T. C., et al. J. Pediat. 1973, 83, 1097. 16. Fallon, R. J. J. clin. Path. 1974, 27, 902. 17 Islam, A. K. M. S. Lancet, 1977, i, 259. 18 Christensen, P., Kahlmeter, G., Jonsson, S., Kronvall, G. Infect. Immun.
1975, 7, 881. 19. Schauf, V., Deveikis, A., Riff, L., Serota, A.J. Pediat. 1976, 89, 194. 20. Paredes, A., Wong, P., Yow, M. D. ibid. p. 191. 21. Berg, T., Hallander, H. O., Nathorst-Windahl, G., Nordlander, I-M. Scand. J inf. Dis. 1977, 9, 19.
INCONTINENT WOMEN INVOLUNTARY loss of urine is a cruel and embarrassing symptom which curtails many physical and social activities ; laughter and sudden movements become perilous, and shopping expeditions become major undertakings which have to be planned from one public convenience to another. Yet this is a common problem, which despite its restrictions and its expense in padding and underclothing, is often borne in silence by women for many years before aid is sought. Unfortunately, for many the arrival at the outpatient clinic often marks a new start, rather than an end to their problems. The less discerning gynaecologist often fails to probe the true characteristics of the incontinence and, blindly believing that prolapse is intimately related to a bladder-neck weakness, wields the scalpel willy-nilly along the anterior vaginal wall leaving the retropubic approach as a reserve for his failures. During the past decade there has been considerable pooling of research and cooperation between urologists, gynaecologists, neurologists, and physiologists who have graduated, with the help of transducers and multichannel recorders, from the somewhat static procedures of cystoscopy and pyelography to dynamic investigations. Pressure recordings have now added a new dimension to cine-cystourethrography and have enabled a more accurate differentiation of incontinence caused by urethral incompetence from that initiated by uninhibited detrusor activity.2 Patients who simply complain of, and demonstrably suffer from, a synchronous urine loss following a rise of intra-abdominal pressure, without an alteration of normal micturition patterns, seldom have to be subjected to any form of detailed analysis. However, in a patient with urinary frequency, urgency incontinence, or unconscious urinary loss, or in one who has not responded to previous surgery, then the full battery of modern urodynamic investigations must be invoked. Bladder-neck surgery (which carries a multitude of operative eponyms) will benefit only those patients with demonstrable weakness of the urethral sphincter mechanism and is unlikely to lessen3 and may even aggravate the symptoms of urgency and frequency. The success of such procedures will depend on the surgeon’s ability to select his patients, his technical skill, and the nature of the tissues to be sutured; for there is no doubt that the most satisfactory results will be obtained at the first operative encounter, when the tissues are mobile and free of fibrotic scar tissue. The technique tends to be a matter of personal choice; the gynaecologist has traditionally approached the problem vaginally, but it is becoming increasingly apparent that the bladder neck can be much more satisfactorily elevated and more firmly fixed by retropubic surgery, in which the anterior vaginal wall is hitched and tethered to Cooper’s ligaments.4 The reports of cure range widely from 60%5 to 90%.4 Unfortunately, many reviewers of a particular technique analyse a small number of cases and rarely define their criteria in measuring success. Objective and long-term follow-up with an analysis of the causes 1. International Continence Society Annual Meetings, 1971-76. 2. Bates, C. P., Whiteside, C. G., Turner-Warwick, R. T. Br. J. Urol.
43, 714 3. Arnold, E. P., et al. Am. J. Obstet. Gynec. 1973, 117, 805. 4. Burch, J. C. ibid. 1968, 100, 764. 5. Low, J. A. ibid. 1967, 97, 308.
1970,
