16
unremarkable, may well represent a rare variant from an epidemiological point of view, especially if it results from a deletion at the translocation breakpoint. Nevertheless, the findings together point to the q2l-22 region of chromosome 11as a promising area to examine for a gene or series of genes predisposing to some cases of major mental illness.
Tsuang MT, Winokur G, Crowe RR. Morbidity risks of schizophrenia and affective disorders among first degree relatives of patients with schizophrenia, mania, depression and surgical conditions. Br J Psychiatry 1980; 137: 497-504. 10. Guze SB, Cloninger R, Martin RL, et al. A follow-up and family study of schizophrenia. Arch Gen Psychiatry 1983; 40: 1273-76. 11. Kendler KS, Gruenberg AM, Tsuang MT. A DSM-III family study of the non schizophrenic psychotic disorders. Am J Psychiatry 1986; 143:
We thank all the members of the family who took part in this study and also the MRC Registry staff, Mrs Susan Collyer and Mrs Rhona de Mey. The study was supported by the Mental Health Foundation, The Scottish Rite Schizophrenia Research Program, and SANE. D. St C. is a Wellcome Trust senior research fellow in clinical science, and W. M. an MRC clinician scientist.
1098-105. 12. Gershon ES, DeLisi LE, Hamoril J, et al. A controlled family study of chronic psychoses. Schizophrenia and schizo-affective disorder. Arch Gen Psychiatr 1986; 143: 1098-105. 13. Rutter M. Psychopathology and development: childhood antecedents of adult disorder. Aust NZ Psychiatry 1984; 18: 225-34. 14. Zeitlin J. The natural history of psychiatric disorder in children. Maudsley monographs no 29. Oxford: Oxford University Press, 1986. 15. Kendler KS, Gruenberg AM, Strauss JS. An independent analysis of the Copenhagen sample of the Danish Adoption Study of Schizophrenia v. the relationship between childhood social withdrawal and adult schizophrenia. Arch Gen Psychiatry 1982; 39: 1257-61. 16. Weintraub S. Risk factors in schizophrenia: the Stony Brook High Risk Project. Schizophr Bull 1987; 3: 439-50. 17. Baron M. Albinism and schizophreniform psychosis: a pedigree study. Am J Psychiatry 1976; 133: 1070-73. 18. Barton DE, Kwon Byoung S, Francke U. Human tyrosinase gene, mapped to chromosome 11 (q14-q21), defines second region of homology with mouse chromosome 7. Genomics 1988; 3: 17-24. 19. Grandy KD, Litt M, Allen N, et al. The human dopamine D2 receptor gene is located on chromosome 11 at q22-23 and identifies a Taq 1 RFLP. Am J Hum Genet 1989; 45: 778-85. 20. Seeman P, Ulpian G, Bergeron C, et al. Bimodal distribution of dopamine receptor densities in brains of schizophrenics. Science 1984; 225: 728-31. 21. Seeman P, Niznik HB, Guan HC, et al. Link between D1 and D2 dopamine receptors is reduced in schizophrenia and Huntington diseased brain. Proc Natl Acad Sci USA 1989; 86: 10156-60. 22. Robertson M. False start on manic depression. Nature 1989; 342: 222.
REFERENCES 1. Smith M, Wasmuth J, McPherson JD, et al. Cosegregation of an 1 1q 22. 3-9 p22 translocation with affective disorder: proximity of the
dopamine D2 receptor gene relative to the translocation breakpoint. Am J Hum Genet 1989; 45: A220. 2. Jacobs PA, Brunton M, Frackiewicz A, et al. Studies on a family with three cytogenetic markers. Ann Hum Genet 1970; 33: 325-36. 3. Endicott J, Spitzer RL. A diagnostic interview. The schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 1978; 35: 837-44. 4. Spitzer RL, Endicott J, Robins E. Research diagnostic criteria (RDC) for a selected group of functional disorders, 3rd ed. New York: New York State Psychiatric Institution, Biometrics Research Division, 1987. 5. Diagnostic and statistical manual of mental disorders, 3rd ed. Washington DC: American Psychiatric Association, 1987. 6. Lathrop GM, Lalouel JM. Easy calculations of lod scores and genetic risks
small computers. Am J Hum Genet 1984; 36: 460-65. Partly dominant transmission of schizophrenia in Iceland. Br J Psychiatry 1988; 152: 324-29 8. Sherrington R, Brynjolfsson J, Petursson H, et al. Localisation of a susceptibility locus for schizophrenia on chromosome 5. Nature 1988; 336: 164-67. on
7. Karlsson JL.
9.
Preliminary report: cyclosporin in treatment of severe
active ulcerative colitis
Intravenous cyclosporin (4 mg/kg daily) was given patients with severe active ulcerative fourteen of whom had failed to respond to colitis, 10 at least days’ treatment with intravenous steroids. In the acute phase of the open trial, eleven patients (73%) improved and avoided colectomy; the mean response time was 5·8 days. Patients who responded were maintained on oral cyclosporin (6-8 mg/kg daily) for a 6-month chronic phase. Six of the eleven patients have been weaned from steroids and remain in clinical and endoscopic remission 5-18 months after discontinuation of cyclosporin; three are well at 5 months and their steroid dose is being tapered; one patient relapsed after 5 months on oral cyclosporin and underwent colectomy; and one patient failed to show continued improvement with oral cyclosporin but is in clinical remission after to fifteen
changing to mercaptopurine treatment. Slight self-limiting adverse side-effects of cyclosporin were seen,
but
none
necessitated withdrawal
from the study. Cyclosporin seems to be an effective treatment for patients with severe active ulcerative colitis who have not responded to steroids.
Introduction the aetiology of chronic inflammatory bowel disease is unknown, immunological mechanisms are thought to have a role.1 High-dose intravenous corticosteroids have been the mainstay of treatment for severe ulcerative colitis.2 Several studies have concluded that patients with severe colitis who fail to respond to 5-10 days’ treatment with parenteral steroids must undergo colectomy.34 Neither total parenteral nutritions nor intravenous antibiotics6 are effective in severe active ulcerative colitis. Cyclosporin is effective in various. diseases thought to be autoimmune in nature’-9 and two case-reports’" and one controlled trial 12 have suggested that it has a therapeutic effect in inflammatory bowel disease. We have carried out a pilot study of cyclosporin treatment in patients with severe refractory ulcerative colitis.
Although
Patients and methods Patients From June 1987 to June 1989, fifteen patients with severe ulcerative colitis were treated with cyclosporin. The diagnosis of ADDRESS: Mount Sinai School of Medicine, New York, USA (S. Lichtiger, MD, Prof D. H. Present, MD). Correspondence to Dr S. Lichtiger, 993 Park Avenue, New York, New York 10028, USA.
17
TABLE I-SEVERITY ASSESSMENT
TABLE II-PATIENT CHARACTERISTICS
*Refused steroid therapy. tadmitted at own request.
nutritional supplementation in four patients. Six patients were receiving antibiotics on entry into the study. Rectal steroids or mesalazine were maintained if tolerated. No other drug or enema was added to the treatment regimen after cyclosporin treatment was started. Since the likelihood of colectomy was high at the start, an experienced surgeon examined the patients daily and was allowed to stop medical treatment at any point in the trial. Clinical improvement was confirmed by about a 50% reduction in the modified Truelove-Witts score. Acute phase treatment was classified as a success if the improvement was maintained when treatment with hydrocortisone and cyclosporin was changed to the oral forms and if the patient could leave hospital without needing surgery. 6 patient evaluations and 2 physician evaluations, repeated each same time.
ulcerative colitis
day
at
about the
based on characteristic clinical, endoscopic, features and its severity was quantified by a and/or radiological variation of the Truelove-Witts" criteria (table I). Patients with scores in the severe category (12 or higher) were enrolled in the was
study. Before the administration of cyclosporin, all but one patient had received a minimum of 10 days of intravenous hydrocortisone (300 mg/day) without clinical response. The remaining patient refused steroids because aseptic necrosis of the hip had developed after previous steroid therapy. If after 10 days of parenteral steroids the patient had not improved and colectomy was indicated, he or she was offered participation in the trial. Eleven patients were male and four were female (table n). Their mean age at entry was 30-6 years (range 12-52 years) and the mean duration of disease before entry was 3-8 years (8 months-12 years). Twelve had universal disease and three (patients 1, 2, and 9) had left-sided colitis.
Chronic phase. Before leaving hospital patients who had responded to intravenous cyclosporin were entered into the chronic phase of the study. For 6 months, cyclosporin was given orally at 6-8 mg/kg daily in two doses. Cyclosporin trough levels were measured weekly for a month and every 2 weeks thereafter. The cyclosporin dose was adjusted as in the acute phase. In addition to oral cyclosporin, patients were discharged on prednisone (60 mg/day in divided doses) and sulphasalazine (2-3 g/day in divided doses). All patients continued to receive rectal steroids or mesalazine if tolerated. No new drugs were added after hospital discharge. During the 6 months we attempted to reduce and discontinue both oral and rectal steroids. Success in the chronic phase was based on a defined improvement in the modified Truelove-Witts score to 4 or less, healing on colonoscopy, and lowering of the prednisone dose to below 20 mg/day by 3 months or complete withdrawal of steroids by 6 months. Readmission to hospital for parenteral steroids was considered a failure of chronic cyclosporin therapy. During the hospital phase, complete blood count and standard automated biochemical tests (SMA 18) were done every other day. 24-h urine collections for protein, volume, and creatinine were made every third day so that creatinine clearance could be calculated. During the outpatient phase, complete blood count and SMA-18 were done weekly for a month and every 2 weeks thereafter.
Treatment protocol Acute phase. Cyclosporin was given by continuous intravenous infusion for a minimum of 10 days. The initial dose was 4 mg/kg daily. Whole-blood cyclosporin trough levels were measured every other day by means of radioimmunoassay (Sandoz) and/or DTX polyclonal kit assays. The cyclosporin dose was adjusted to maintain blood trough levels in the range of 400-600 ug/1. The dose was reduced by 50% when serum creatinine rose by a third and/or creatinine clearance fell by 20%. To minimise potential renal toxic effects we entered only patients with a creatinine clearance greater than 90 ml/min. Intravenous hydrocortisone was maintained at a total dose of 300 mg/day (100 mg three times daily). All patients were allowed food; total parenteral nutrition was given only as
Results Acute phase fifteen patients (73%) improved the acute phase. The mean response substantially during time to intravenous cyclosporin was 5-8 days (range 3-12). Improvement on the modified Truelove-Witts criteria is shown in table l. Two patients (13%) did not respond and underwent colectomy (day 12 and day 14). Two patients (13%) did not respond and were advised to undergo colectomy but chose to continue on high-dose oral steroids. The disease remained clinically active in these two patients Eleven
of the
18
Median whole-blood cyclosporin levels chronic phase.
(by DTX assay) during
and they underwent elective surgery at 3 and 9 months. The eleven responders progressed to the chronic phase.
Chronic phase Of the eleven patients, six (55%) have successfully 6 months of treatment and have discontinued steroid treatment. All are in clinical and endoscopic remission 5-18 months after the end of cyclosporin treatment. Three other patients (27%) are in remission at 5 months on less than 20 mg/day prednisone. Two (18%) patients failed during the chronic phase: patient 2 experienced a clinical and endoscopic exacerbation at month 5, required high-dose oral steroids, and underwent elective colectomy; and patient 9 failed to show continued improvement during the chronic phase, could not reduce the steroid dose, and experienced continuous bleeding. Although she was classified as a failure in the chronic phase she refused colectomy and chose a trial of mercaptopurine, on which clinical remission was achieved. Cyclosporin was well absorbed from the gut with maintenance of therapeutic trough levels in all patients (see accompanying figure).
completed
Adverse effects None of the fifteen patients had to be withdrawn because of an adverse side-effect. Mild side-effects occurred in nine patients: hypertrichosis in five, mild paraesthesias in six, resting tremor in five, and gingival hyperplasia in two. Transient hypertension (higher than 140/95 mm Hg) occurred in two patients, but neither required antihypertensive agents. A single episode of nephrotoxicity (an increase in serum creatinine of 33%) was corrected by reducing the cyclosporin dose. No toxic effects on the nervous system, liver, or gastrointestinal tract or infectious complications were observed.
Discussion Other immunosuppressive agents have been effective in the of ulcerative colitisl4-16 but their latency period limits their usefulness in fulminant disease. Cyclosporin acts rapidly; we therefore studied the effects of this drug in patients with severe ulcerative colitis in whom colectomy appeared inevitable. The level of therapeutic success compares very favourably with historical controls.3.17 Our study differs from previous case-reportsl8 and ongoing double-blind controlled trials in that we started treatment with intravenous cyclosporin. Oral cyclosporin is erratically absorbed and is affected by diarrhoea, small-bowel motility, and anaemia. Atkinson and Tritton19 found inadequate therapeutic levels in patients with radiation enteritis and virtually no absorption in patients with graft-versus-host treatment
disease. An open trial20 showed erratic absorption in Crohn’s disease manifested by variable trough levels of cyclosporin, which may account for the lack of response to the drug. All our patients had profuse diarrhoea, anaemia, and small-bowel dysmotility, so their initial cyclosporin treatment was parenteral. Although nephrotoxicity is reported to be more common when cyclosporin is given intravenously, we observed no such serious side-effect in our patients, possibly because of our careful monitoring of renal function and cyclosporin levels. Clinical and endoscopic remission at 6 months was achieved in six (55%) of the eleven acute-phase responders and another three (27%) are in clinical remission at 5 months. Only one patient has relapsed and required colectomy in the chronic phase, which suggests that cyclosporin may be effective not only in inducing remission but also in maintaining response in ulcerative colitis. There seems to be a correlation between the achievement of therapeutic cyclosporin levels (400-600 pg/1) and initial clinical response, with a fall to subtherapeutic levels of
cyclosporin leading to greater clinical activity. This phenomenon has been reported in transplant patients21 and we have noted it in cyclosporin treatment of Crohn’s disease.22 The likely mechanism is that T-cell response is reversibly inhibited by cyclosporin and that subtherapeutic levels allow T-cell function, as well as lymphokine secretion, to return to the prior activated state.23,24 Ptachcinski and colleagues25 reported a rebound phenomenon after discontinuation of cyclosporin with an ensuing aggressive inflammatory response. Therefore, in the chronic phase of our study, cyclosporin was not abruptly stopped but the dose was slowly tapered. Careful monitoring of cyclosporin levels is essential in patients with inflammatory bowel disease, since changes in weight, haematocrit, prednisone dose, and a reduction in diarrhoea may all affect the levels. Unlike patients with Crohn’s disease, no patient had
difficulty with absorption of cyclosporin. Cyclosporin was mildly toxic in nine of the fifteen patients. Only patients with creatinine clearance greater than 90 ml/min were allowed to take part in the study. This minimised renal toxic effects. The risk of chronic nephrotoxicity is thought to be low if pronounced acute nephrotoxicity is avoided2627 as in our study. A possible carcinogenic effect of cyclosporin in patients with ulcerative colitis must be considered because of the higher incidence of carcinoma of the colon in such patients. Although a high frequency of lymphomas developing under cyclosporin traetment occurred during its early use in transplant recipients, many of them reversed with lower cyclosporin doses28 and later experience with cyclosporin in other autoimmune disorders indicates a low incidence of neoplasm (0-3%). We found no significant rise in the incidence of neoplasm in a study of the long-term use of other immunosuppressives in inflammatory bowel disease. 30 Since our patients were maintained on cyclosporin for a maximum of 6 months, we feel an increased risk of neoplasm is unlikely, though long-term observation is warranted. In summary, our success in avoiding colectomy in 73 % of patients with severe ulcerative colitis who have not responded to conventional medical therapy, and the 5-6 months’ maintenance of response in 60%, suggests that cyclosporin may be a useful new treatment for this illness. The observed efficacy and safety have led us to initiate a multicentre double-blind controlled trial of intravenous cyclosporin in refractory ulcerative colitis.
19
We thank Dr M. L. Chapman, Dr P. H. Rubin, and Dr David Sachar for contribution of patients and review of the paper, and Ms Judith Estrinc for preparation of the typescript.
BOOKSHELF
REFERENCES Immunology of inflammatory bowel disease. Scand J Gastroenterol 1985; 114: 119-20. 2. Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1974; i: 1067-70. 3. Jamerot G, Rolny P, Sandberg-Gertzen H, et al. Intensive intravenous 1. Jewell DP, Patel C.
ulcerative colitis. Gastroenterology 1985; 89: 1005-13. S, Sachar DB, Goldberg JD, Janowitz HD. Corticotrophin versus hydrocortisone in the intravenous treatment of ulcerative colitis. Gastroenterology 1983; 85: 351-58. 5. Dickinson RJ, Ashton MG, Axon ATR, et al. Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 1980; 9: 1199-204. 6. Savidge RS. Trimethoprim and sulfamethoxazole in ulcerative colitis. Postgrad Med J 1969; 45: 101-04. 7. Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G. Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behçet’s disease. Lancet 1989; i: 1093-96. 8. Nussenblatt G, Palestine AG, Rook AH, Scher I, Wacker WB, Gery I. Treatment of intraocular inflammatory disease with cyclosporin A. Lancet 1983; ii: 235-38. 9. Borel JF, Gunn C. Cyclosporine A as a new approach to therapy of treatment for
4. Meyers
autoimmune disease. Ann NY Acad Sci 1986; 475: 307-19.
Gupta S, Keshavarzian A, Hodgson HJF. Cyclosporin in ulcerative colitis. Lancet 1984; ii: 1277-78. 11. Allison MC, Pounder RE. Cyclosporine A for Crohn’s disease. Aliment 10.
Pharmacol Ther 1987; 1: 39-43. 12. BrynskoffJ, Freund L, Rasmussen SN, et al. A placebo controlled double blind randomized trial of cyclosporine therapy in active chronic Crohn’s disease. N Engl J Med 1989; 321: 845-50. 13. Truelove SC, Witts LJ. Cortisone and corticotrophin in ulcerative colitis. Br Med J 1959; i: 387-94. 14. Kirk AP, Lennard-Jones JE. Controlled trial of azathioprine in chronic ulcerative colitis. Br Med J 1982; 284: 1291-93. 15. Present DH, Chapman ML, Rubin PH. Efficacy of 6-mercaptopurine in refractory ulcerative colitis. Gastroenterology 1988; 94: A359 (abstr). 16. Kozarek RA, Patterson DJ, Gelfand MD, Botoman VA, Bell TJ, Wilske KR. Methotrexate induces clinical and histological remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110: 353-56. 17. Meyers S, Lerer P, Feuer J, Johnson J, Janowitz HD. Predicting the outcome of corticoid therapy for acute ulcerative colitis. J Clin Gastroenterol 1987; 9: 50-54. 18. Baker K, Jewell DP. Cyclosporine A for the treatment of severe inflammatory bowel disease. Aliment Pharmacol Ther 1989; 3: 143-49. 19. Atkinson K, Britton P, Paull C, et al. Detrimental effect of intestinal disease on absorption of orally administered cyclosporine. Transplant Proc 1983; 15: 2446-51. 20. Parrot NR, Taylor RMR, Venables CW, et al. Treatment of Crohn’s disease in relapse with cyclosporine A. Br J Surg 1988; 75: 1185-88. 21. Cohen DJ, Loertscher R, Robin M, Tilney N, Carpenter CB, Strom T. Cyclosporine: a new immunosuppressive agent for organ transplantation. Ann Intern Med 1984; 101: 667-82. 22. Lichtiger S, Present DH. Cyclosporine A is effective in the treatment of refractory inflammatory bowel disease. Am J Gastroenterol 1988; 83: 1051. 23. Borel JF, Feurer C, Gubler HU, Stähelen H. Biologic effects of cyclosporine A: a new antilymphocytic agent. Agents Actions 1975; 6: 468-75. 24. Larsson EL. Cyclosporine A and dexamethasone suppress T cell response by selectively acting at distinct sites of triggering process. J Immunol 1980; 124: 2828-33. 25. Ptachcinski RJ, Venkataramonan R, Borckart G. Clinical pharmacokinetics of cyclosporine A. Clin Pharmacol 1986; 11: 107-32. 26. Myers BD. Cyclosporine nephrotoxicity. Kidney Int 1986; 30: 964-74. 27. Mihatsh MJ, Bach JF, Coovadia HM, et al. Cyclosporin associated nephropathy in patients with autoimmune diseases. Klin Wochenschr 1988; 66: 43-47. 28. Starzl TE, Nalesnick MA, Porter KA, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1984; i: 583-87. 29. Cockburn I. Assessment of the risks of malignancy and lymphomas developing in patients using Sandimmune. Transplant Proc 1987; 19: 1804-07. 30. Present DH, Meltzer SJ, Krumholz MP, et al. 6-mercaptopurine in the management of inflammatory bowel disease: short and long term toxicity. Ann Intern Med 1989; 111: 641-49.
Spotlight on the Cities: Improving Urban Health in Developing Countries I. Tabibzadeh, A. Rossi-Espagnet, and R. Maxwell. Geneva: World Health Organisation. 1989. ISBN 9-241561319.
Palace, byre, hovel-poverty and prideSide by side; And, above the packed and pestilential town, Death looked down.
Rudyard Kipling
Nearly every language has a name for them: slums, shanties, barrios, favelas, jovenes, villas miserias, bidonvilles. They are the cities in the developing world. They are not, granted, the cities you see on the travel posters or read about in the tourist guides. The slums and shanties and barrios are invisible cities-invisible to the casual visitor, invisible to the more prosperous inhabitants, often invisible also, at least fiscally, to the national and municipal governments that have nominal jurisdiction over them. Too impoverished to be included by the pundits even among the ranks of the "third world", the inhabitants of the shanties, who constitute anywhere from 20% to 80% of the population of African, Asian, and Latin American cities, have been dubbed the "fourth world... subproletariat whose housing, sanitation, clothing and food are inadequate; whose cause is not championed by politicians and unions; who have limited information, education and voice .... From the economic point of view they are considered a burden, and from the health point of view, a danger". It is with the urban "fourth world"-the teeming invisible world of the poor camped at the gates of the cities-that this exceptionally well written book, issued by the World Health Organisation, is concerned. By the year 2000, we learn there are likely to be 23 cities with over 10 million people, 17 of them in developing regions. The health consequences of such explosive urban growth are already catastrophic. Being destitute in a city means not only the insufficient diet and resources of rural poverty; being destitute in a city also means overcrowding, pollution, social instability, alcohol and drug abuse, prostitution, and a score of other ills that derive from stress and alienation. To meet the enormous health care needs of the urban fourth world, the authors argue, will require a complete reorientation of most national health care systems, an orientation away from expensive curative medicine centered in tertiary facilities and toward community-based primary health care. The authors advocate doing simple inexpensive things that have a proven impact-and doing those things on a big scale, aiming for comprehensive coverage of the whole
population. Ultimately, however, the medical problems of the slums and shanties require nonmedical solutions. For, as the authors of this book readily acknowledge, the underlying problem is poverty-the poverty of the rural areas that drives people to the cities, the poverty of the slums that keeps them imprisoned in squatter camps once they’ve arrived. Primary health care will not solve those problems. Only serious attention to sustainable rural development will provide a real solution to the health care crisis of urban and rural dwellers alike. Mettula, Israel
NANCY L. CAROLINE
unremarkable, may well represent a rare variant from an epidemiological point of view, especially if it results from a deletion at the translocation breakpoint. Nevertheless, the findings together point to the q2l-22 region of chromosome 11as a promising area to examine for a gene or series of genes predisposing to some cases of major mental illness.
Tsuang MT, Winokur G, Crowe RR. Morbidity risks of schizophrenia and affective disorders among first degree relatives of patients with schizophrenia, mania, depression and surgical conditions. Br J Psychiatry 1980; 137: 497-504. 10. Guze SB, Cloninger R, Martin RL, et al. A follow-up and family study of schizophrenia. Arch Gen Psychiatry 1983; 40: 1273-76. 11. Kendler KS, Gruenberg AM, Tsuang MT. A DSM-III family study of the non schizophrenic psychotic disorders. Am J Psychiatry 1986; 143:
We thank all the members of the family who took part in this study and also the MRC Registry staff, Mrs Susan Collyer and Mrs Rhona de Mey. The study was supported by the Mental Health Foundation, The Scottish Rite Schizophrenia Research Program, and SANE. D. St C. is a Wellcome Trust senior research fellow in clinical science, and W. M. an MRC clinician scientist.
1098-105. 12. Gershon ES, DeLisi LE, Hamoril J, et al. A controlled family study of chronic psychoses. Schizophrenia and schizo-affective disorder. Arch Gen Psychiatr 1986; 143: 1098-105. 13. Rutter M. Psychopathology and development: childhood antecedents of adult disorder. Aust NZ Psychiatry 1984; 18: 225-34. 14. Zeitlin J. The natural history of psychiatric disorder in children. Maudsley monographs no 29. Oxford: Oxford University Press, 1986. 15. Kendler KS, Gruenberg AM, Strauss JS. An independent analysis of the Copenhagen sample of the Danish Adoption Study of Schizophrenia v. the relationship between childhood social withdrawal and adult schizophrenia. Arch Gen Psychiatry 1982; 39: 1257-61. 16. Weintraub S. Risk factors in schizophrenia: the Stony Brook High Risk Project. Schizophr Bull 1987; 3: 439-50. 17. Baron M. Albinism and schizophreniform psychosis: a pedigree study. Am J Psychiatry 1976; 133: 1070-73. 18. Barton DE, Kwon Byoung S, Francke U. Human tyrosinase gene, mapped to chromosome 11 (q14-q21), defines second region of homology with mouse chromosome 7. Genomics 1988; 3: 17-24. 19. Grandy KD, Litt M, Allen N, et al. The human dopamine D2 receptor gene is located on chromosome 11 at q22-23 and identifies a Taq 1 RFLP. Am J Hum Genet 1989; 45: 778-85. 20. Seeman P, Ulpian G, Bergeron C, et al. Bimodal distribution of dopamine receptor densities in brains of schizophrenics. Science 1984; 225: 728-31. 21. Seeman P, Niznik HB, Guan HC, et al. Link between D1 and D2 dopamine receptors is reduced in schizophrenia and Huntington diseased brain. Proc Natl Acad Sci USA 1989; 86: 10156-60. 22. Robertson M. False start on manic depression. Nature 1989; 342: 222.
REFERENCES 1. Smith M, Wasmuth J, McPherson JD, et al. Cosegregation of an 1 1q 22. 3-9 p22 translocation with affective disorder: proximity of the
dopamine D2 receptor gene relative to the translocation breakpoint. Am J Hum Genet 1989; 45: A220. 2. Jacobs PA, Brunton M, Frackiewicz A, et al. Studies on a family with three cytogenetic markers. Ann Hum Genet 1970; 33: 325-36. 3. Endicott J, Spitzer RL. A diagnostic interview. The schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 1978; 35: 837-44. 4. Spitzer RL, Endicott J, Robins E. Research diagnostic criteria (RDC) for a selected group of functional disorders, 3rd ed. New York: New York State Psychiatric Institution, Biometrics Research Division, 1987. 5. Diagnostic and statistical manual of mental disorders, 3rd ed. Washington DC: American Psychiatric Association, 1987. 6. Lathrop GM, Lalouel JM. Easy calculations of lod scores and genetic risks
small computers. Am J Hum Genet 1984; 36: 460-65. Partly dominant transmission of schizophrenia in Iceland. Br J Psychiatry 1988; 152: 324-29 8. Sherrington R, Brynjolfsson J, Petursson H, et al. Localisation of a susceptibility locus for schizophrenia on chromosome 5. Nature 1988; 336: 164-67. on
7. Karlsson JL.
9.
Preliminary report: cyclosporin in treatment of severe
active ulcerative colitis
Intravenous cyclosporin (4 mg/kg daily) was given patients with severe active ulcerative fourteen of whom had failed to respond to colitis, 10 at least days’ treatment with intravenous steroids. In the acute phase of the open trial, eleven patients (73%) improved and avoided colectomy; the mean response time was 5·8 days. Patients who responded were maintained on oral cyclosporin (6-8 mg/kg daily) for a 6-month chronic phase. Six of the eleven patients have been weaned from steroids and remain in clinical and endoscopic remission 5-18 months after discontinuation of cyclosporin; three are well at 5 months and their steroid dose is being tapered; one patient relapsed after 5 months on oral cyclosporin and underwent colectomy; and one patient failed to show continued improvement with oral cyclosporin but is in clinical remission after to fifteen
changing to mercaptopurine treatment. Slight self-limiting adverse side-effects of cyclosporin were seen,
but
none
necessitated withdrawal
from the study. Cyclosporin seems to be an effective treatment for patients with severe active ulcerative colitis who have not responded to steroids.
Introduction the aetiology of chronic inflammatory bowel disease is unknown, immunological mechanisms are thought to have a role.1 High-dose intravenous corticosteroids have been the mainstay of treatment for severe ulcerative colitis.2 Several studies have concluded that patients with severe colitis who fail to respond to 5-10 days’ treatment with parenteral steroids must undergo colectomy.34 Neither total parenteral nutritions nor intravenous antibiotics6 are effective in severe active ulcerative colitis. Cyclosporin is effective in various. diseases thought to be autoimmune in nature’-9 and two case-reports’" and one controlled trial 12 have suggested that it has a therapeutic effect in inflammatory bowel disease. We have carried out a pilot study of cyclosporin treatment in patients with severe refractory ulcerative colitis.
Although
Patients and methods Patients From June 1987 to June 1989, fifteen patients with severe ulcerative colitis were treated with cyclosporin. The diagnosis of ADDRESS: Mount Sinai School of Medicine, New York, USA (S. Lichtiger, MD, Prof D. H. Present, MD). Correspondence to Dr S. Lichtiger, 993 Park Avenue, New York, New York 10028, USA.
17
TABLE I-SEVERITY ASSESSMENT
TABLE II-PATIENT CHARACTERISTICS
*Refused steroid therapy. tadmitted at own request.
nutritional supplementation in four patients. Six patients were receiving antibiotics on entry into the study. Rectal steroids or mesalazine were maintained if tolerated. No other drug or enema was added to the treatment regimen after cyclosporin treatment was started. Since the likelihood of colectomy was high at the start, an experienced surgeon examined the patients daily and was allowed to stop medical treatment at any point in the trial. Clinical improvement was confirmed by about a 50% reduction in the modified Truelove-Witts score. Acute phase treatment was classified as a success if the improvement was maintained when treatment with hydrocortisone and cyclosporin was changed to the oral forms and if the patient could leave hospital without needing surgery. 6 patient evaluations and 2 physician evaluations, repeated each same time.
ulcerative colitis
day
at
about the
based on characteristic clinical, endoscopic, features and its severity was quantified by a and/or radiological variation of the Truelove-Witts" criteria (table I). Patients with scores in the severe category (12 or higher) were enrolled in the was
study. Before the administration of cyclosporin, all but one patient had received a minimum of 10 days of intravenous hydrocortisone (300 mg/day) without clinical response. The remaining patient refused steroids because aseptic necrosis of the hip had developed after previous steroid therapy. If after 10 days of parenteral steroids the patient had not improved and colectomy was indicated, he or she was offered participation in the trial. Eleven patients were male and four were female (table n). Their mean age at entry was 30-6 years (range 12-52 years) and the mean duration of disease before entry was 3-8 years (8 months-12 years). Twelve had universal disease and three (patients 1, 2, and 9) had left-sided colitis.
Chronic phase. Before leaving hospital patients who had responded to intravenous cyclosporin were entered into the chronic phase of the study. For 6 months, cyclosporin was given orally at 6-8 mg/kg daily in two doses. Cyclosporin trough levels were measured weekly for a month and every 2 weeks thereafter. The cyclosporin dose was adjusted as in the acute phase. In addition to oral cyclosporin, patients were discharged on prednisone (60 mg/day in divided doses) and sulphasalazine (2-3 g/day in divided doses). All patients continued to receive rectal steroids or mesalazine if tolerated. No new drugs were added after hospital discharge. During the 6 months we attempted to reduce and discontinue both oral and rectal steroids. Success in the chronic phase was based on a defined improvement in the modified Truelove-Witts score to 4 or less, healing on colonoscopy, and lowering of the prednisone dose to below 20 mg/day by 3 months or complete withdrawal of steroids by 6 months. Readmission to hospital for parenteral steroids was considered a failure of chronic cyclosporin therapy. During the hospital phase, complete blood count and standard automated biochemical tests (SMA 18) were done every other day. 24-h urine collections for protein, volume, and creatinine were made every third day so that creatinine clearance could be calculated. During the outpatient phase, complete blood count and SMA-18 were done weekly for a month and every 2 weeks thereafter.
Treatment protocol Acute phase. Cyclosporin was given by continuous intravenous infusion for a minimum of 10 days. The initial dose was 4 mg/kg daily. Whole-blood cyclosporin trough levels were measured every other day by means of radioimmunoassay (Sandoz) and/or DTX polyclonal kit assays. The cyclosporin dose was adjusted to maintain blood trough levels in the range of 400-600 ug/1. The dose was reduced by 50% when serum creatinine rose by a third and/or creatinine clearance fell by 20%. To minimise potential renal toxic effects we entered only patients with a creatinine clearance greater than 90 ml/min. Intravenous hydrocortisone was maintained at a total dose of 300 mg/day (100 mg three times daily). All patients were allowed food; total parenteral nutrition was given only as
Results Acute phase fifteen patients (73%) improved the acute phase. The mean response substantially during time to intravenous cyclosporin was 5-8 days (range 3-12). Improvement on the modified Truelove-Witts criteria is shown in table l. Two patients (13%) did not respond and underwent colectomy (day 12 and day 14). Two patients (13%) did not respond and were advised to undergo colectomy but chose to continue on high-dose oral steroids. The disease remained clinically active in these two patients Eleven
of the
18
Median whole-blood cyclosporin levels chronic phase.
(by DTX assay) during
and they underwent elective surgery at 3 and 9 months. The eleven responders progressed to the chronic phase.
Chronic phase Of the eleven patients, six (55%) have successfully 6 months of treatment and have discontinued steroid treatment. All are in clinical and endoscopic remission 5-18 months after the end of cyclosporin treatment. Three other patients (27%) are in remission at 5 months on less than 20 mg/day prednisone. Two (18%) patients failed during the chronic phase: patient 2 experienced a clinical and endoscopic exacerbation at month 5, required high-dose oral steroids, and underwent elective colectomy; and patient 9 failed to show continued improvement during the chronic phase, could not reduce the steroid dose, and experienced continuous bleeding. Although she was classified as a failure in the chronic phase she refused colectomy and chose a trial of mercaptopurine, on which clinical remission was achieved. Cyclosporin was well absorbed from the gut with maintenance of therapeutic trough levels in all patients (see accompanying figure).
completed
Adverse effects None of the fifteen patients had to be withdrawn because of an adverse side-effect. Mild side-effects occurred in nine patients: hypertrichosis in five, mild paraesthesias in six, resting tremor in five, and gingival hyperplasia in two. Transient hypertension (higher than 140/95 mm Hg) occurred in two patients, but neither required antihypertensive agents. A single episode of nephrotoxicity (an increase in serum creatinine of 33%) was corrected by reducing the cyclosporin dose. No toxic effects on the nervous system, liver, or gastrointestinal tract or infectious complications were observed.
Discussion Other immunosuppressive agents have been effective in the of ulcerative colitisl4-16 but their latency period limits their usefulness in fulminant disease. Cyclosporin acts rapidly; we therefore studied the effects of this drug in patients with severe ulcerative colitis in whom colectomy appeared inevitable. The level of therapeutic success compares very favourably with historical controls.3.17 Our study differs from previous case-reportsl8 and ongoing double-blind controlled trials in that we started treatment with intravenous cyclosporin. Oral cyclosporin is erratically absorbed and is affected by diarrhoea, small-bowel motility, and anaemia. Atkinson and Tritton19 found inadequate therapeutic levels in patients with radiation enteritis and virtually no absorption in patients with graft-versus-host treatment
disease. An open trial20 showed erratic absorption in Crohn’s disease manifested by variable trough levels of cyclosporin, which may account for the lack of response to the drug. All our patients had profuse diarrhoea, anaemia, and small-bowel dysmotility, so their initial cyclosporin treatment was parenteral. Although nephrotoxicity is reported to be more common when cyclosporin is given intravenously, we observed no such serious side-effect in our patients, possibly because of our careful monitoring of renal function and cyclosporin levels. Clinical and endoscopic remission at 6 months was achieved in six (55%) of the eleven acute-phase responders and another three (27%) are in clinical remission at 5 months. Only one patient has relapsed and required colectomy in the chronic phase, which suggests that cyclosporin may be effective not only in inducing remission but also in maintaining response in ulcerative colitis. There seems to be a correlation between the achievement of therapeutic cyclosporin levels (400-600 pg/1) and initial clinical response, with a fall to subtherapeutic levels of
cyclosporin leading to greater clinical activity. This phenomenon has been reported in transplant patients21 and we have noted it in cyclosporin treatment of Crohn’s disease.22 The likely mechanism is that T-cell response is reversibly inhibited by cyclosporin and that subtherapeutic levels allow T-cell function, as well as lymphokine secretion, to return to the prior activated state.23,24 Ptachcinski and colleagues25 reported a rebound phenomenon after discontinuation of cyclosporin with an ensuing aggressive inflammatory response. Therefore, in the chronic phase of our study, cyclosporin was not abruptly stopped but the dose was slowly tapered. Careful monitoring of cyclosporin levels is essential in patients with inflammatory bowel disease, since changes in weight, haematocrit, prednisone dose, and a reduction in diarrhoea may all affect the levels. Unlike patients with Crohn’s disease, no patient had
difficulty with absorption of cyclosporin. Cyclosporin was mildly toxic in nine of the fifteen patients. Only patients with creatinine clearance greater than 90 ml/min were allowed to take part in the study. This minimised renal toxic effects. The risk of chronic nephrotoxicity is thought to be low if pronounced acute nephrotoxicity is avoided2627 as in our study. A possible carcinogenic effect of cyclosporin in patients with ulcerative colitis must be considered because of the higher incidence of carcinoma of the colon in such patients. Although a high frequency of lymphomas developing under cyclosporin traetment occurred during its early use in transplant recipients, many of them reversed with lower cyclosporin doses28 and later experience with cyclosporin in other autoimmune disorders indicates a low incidence of neoplasm (0-3%). We found no significant rise in the incidence of neoplasm in a study of the long-term use of other immunosuppressives in inflammatory bowel disease. 30 Since our patients were maintained on cyclosporin for a maximum of 6 months, we feel an increased risk of neoplasm is unlikely, though long-term observation is warranted. In summary, our success in avoiding colectomy in 73 % of patients with severe ulcerative colitis who have not responded to conventional medical therapy, and the 5-6 months’ maintenance of response in 60%, suggests that cyclosporin may be a useful new treatment for this illness. The observed efficacy and safety have led us to initiate a multicentre double-blind controlled trial of intravenous cyclosporin in refractory ulcerative colitis.
19
We thank Dr M. L. Chapman, Dr P. H. Rubin, and Dr David Sachar for contribution of patients and review of the paper, and Ms Judith Estrinc for preparation of the typescript.
BOOKSHELF
REFERENCES Immunology of inflammatory bowel disease. Scand J Gastroenterol 1985; 114: 119-20. 2. Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1974; i: 1067-70. 3. Jamerot G, Rolny P, Sandberg-Gertzen H, et al. Intensive intravenous 1. Jewell DP, Patel C.
ulcerative colitis. Gastroenterology 1985; 89: 1005-13. S, Sachar DB, Goldberg JD, Janowitz HD. Corticotrophin versus hydrocortisone in the intravenous treatment of ulcerative colitis. Gastroenterology 1983; 85: 351-58. 5. Dickinson RJ, Ashton MG, Axon ATR, et al. Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 1980; 9: 1199-204. 6. Savidge RS. Trimethoprim and sulfamethoxazole in ulcerative colitis. Postgrad Med J 1969; 45: 101-04. 7. Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G. Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behçet’s disease. Lancet 1989; i: 1093-96. 8. Nussenblatt G, Palestine AG, Rook AH, Scher I, Wacker WB, Gery I. Treatment of intraocular inflammatory disease with cyclosporin A. Lancet 1983; ii: 235-38. 9. Borel JF, Gunn C. Cyclosporine A as a new approach to therapy of treatment for
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autoimmune disease. Ann NY Acad Sci 1986; 475: 307-19.
Gupta S, Keshavarzian A, Hodgson HJF. Cyclosporin in ulcerative colitis. Lancet 1984; ii: 1277-78. 11. Allison MC, Pounder RE. Cyclosporine A for Crohn’s disease. Aliment 10.
Pharmacol Ther 1987; 1: 39-43. 12. BrynskoffJ, Freund L, Rasmussen SN, et al. A placebo controlled double blind randomized trial of cyclosporine therapy in active chronic Crohn’s disease. N Engl J Med 1989; 321: 845-50. 13. Truelove SC, Witts LJ. Cortisone and corticotrophin in ulcerative colitis. Br Med J 1959; i: 387-94. 14. Kirk AP, Lennard-Jones JE. Controlled trial of azathioprine in chronic ulcerative colitis. Br Med J 1982; 284: 1291-93. 15. Present DH, Chapman ML, Rubin PH. Efficacy of 6-mercaptopurine in refractory ulcerative colitis. Gastroenterology 1988; 94: A359 (abstr). 16. Kozarek RA, Patterson DJ, Gelfand MD, Botoman VA, Bell TJ, Wilske KR. Methotrexate induces clinical and histological remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110: 353-56. 17. Meyers S, Lerer P, Feuer J, Johnson J, Janowitz HD. Predicting the outcome of corticoid therapy for acute ulcerative colitis. J Clin Gastroenterol 1987; 9: 50-54. 18. Baker K, Jewell DP. Cyclosporine A for the treatment of severe inflammatory bowel disease. Aliment Pharmacol Ther 1989; 3: 143-49. 19. Atkinson K, Britton P, Paull C, et al. Detrimental effect of intestinal disease on absorption of orally administered cyclosporine. Transplant Proc 1983; 15: 2446-51. 20. Parrot NR, Taylor RMR, Venables CW, et al. Treatment of Crohn’s disease in relapse with cyclosporine A. Br J Surg 1988; 75: 1185-88. 21. Cohen DJ, Loertscher R, Robin M, Tilney N, Carpenter CB, Strom T. Cyclosporine: a new immunosuppressive agent for organ transplantation. Ann Intern Med 1984; 101: 667-82. 22. Lichtiger S, Present DH. Cyclosporine A is effective in the treatment of refractory inflammatory bowel disease. Am J Gastroenterol 1988; 83: 1051. 23. Borel JF, Feurer C, Gubler HU, Stähelen H. Biologic effects of cyclosporine A: a new antilymphocytic agent. Agents Actions 1975; 6: 468-75. 24. Larsson EL. Cyclosporine A and dexamethasone suppress T cell response by selectively acting at distinct sites of triggering process. J Immunol 1980; 124: 2828-33. 25. Ptachcinski RJ, Venkataramonan R, Borckart G. Clinical pharmacokinetics of cyclosporine A. Clin Pharmacol 1986; 11: 107-32. 26. Myers BD. Cyclosporine nephrotoxicity. Kidney Int 1986; 30: 964-74. 27. Mihatsh MJ, Bach JF, Coovadia HM, et al. Cyclosporin associated nephropathy in patients with autoimmune diseases. Klin Wochenschr 1988; 66: 43-47. 28. Starzl TE, Nalesnick MA, Porter KA, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1984; i: 583-87. 29. Cockburn I. Assessment of the risks of malignancy and lymphomas developing in patients using Sandimmune. Transplant Proc 1987; 19: 1804-07. 30. Present DH, Meltzer SJ, Krumholz MP, et al. 6-mercaptopurine in the management of inflammatory bowel disease: short and long term toxicity. Ann Intern Med 1989; 111: 641-49.
Spotlight on the Cities: Improving Urban Health in Developing Countries I. Tabibzadeh, A. Rossi-Espagnet, and R. Maxwell. Geneva: World Health Organisation. 1989. ISBN 9-241561319.
Palace, byre, hovel-poverty and prideSide by side; And, above the packed and pestilential town, Death looked down.
Rudyard Kipling
Nearly every language has a name for them: slums, shanties, barrios, favelas, jovenes, villas miserias, bidonvilles. They are the cities in the developing world. They are not, granted, the cities you see on the travel posters or read about in the tourist guides. The slums and shanties and barrios are invisible cities-invisible to the casual visitor, invisible to the more prosperous inhabitants, often invisible also, at least fiscally, to the national and municipal governments that have nominal jurisdiction over them. Too impoverished to be included by the pundits even among the ranks of the "third world", the inhabitants of the shanties, who constitute anywhere from 20% to 80% of the population of African, Asian, and Latin American cities, have been dubbed the "fourth world... subproletariat whose housing, sanitation, clothing and food are inadequate; whose cause is not championed by politicians and unions; who have limited information, education and voice .... From the economic point of view they are considered a burden, and from the health point of view, a danger". It is with the urban "fourth world"-the teeming invisible world of the poor camped at the gates of the cities-that this exceptionally well written book, issued by the World Health Organisation, is concerned. By the year 2000, we learn there are likely to be 23 cities with over 10 million people, 17 of them in developing regions. The health consequences of such explosive urban growth are already catastrophic. Being destitute in a city means not only the insufficient diet and resources of rural poverty; being destitute in a city also means overcrowding, pollution, social instability, alcohol and drug abuse, prostitution, and a score of other ills that derive from stress and alienation. To meet the enormous health care needs of the urban fourth world, the authors argue, will require a complete reorientation of most national health care systems, an orientation away from expensive curative medicine centered in tertiary facilities and toward community-based primary health care. The authors advocate doing simple inexpensive things that have a proven impact-and doing those things on a big scale, aiming for comprehensive coverage of the whole
population. Ultimately, however, the medical problems of the slums and shanties require nonmedical solutions. For, as the authors of this book readily acknowledge, the underlying problem is poverty-the poverty of the rural areas that drives people to the cities, the poverty of the slums that keeps them imprisoned in squatter camps once they’ve arrived. Primary health care will not solve those problems. Only serious attention to sustainable rural development will provide a real solution to the health care crisis of urban and rural dwellers alike. Mettula, Israel
NANCY L. CAROLINE
