The development of non-surgical techniques for the relief of malignant low bileduct obstruction has cast doubt on the best way of relieving jaundice, particularly in patients fit for surgery whose life expectancy is more than a few weeks. We did a randomised prospective controlled trial comparing endoscopic stent insertion and surgical biliary bypass in patients with malignant low bileduct obstruction. 204 patients were randomised (surgery 103, stent 101); 3 subsequently proved to have benign disease and were excluded, leaving 101 surgical and 100 stented patients for assessment. Technical success was achieved in 94 surgical and 95 stented patients, with functional biliary decompression obtained in 92 patients in both groups. In stented patients, there was a lower procedure-related mortality (3% vs 14%, p = 0.01), major complication rate (11% vs 29%, p = 0.02), and median total hospital stay (20 vs 26 days, p = 0.001). Recurrent jaundice occurred in 36 stented patients and 2 surgical patients. Late gastric outlet obstruction occurred in 17% of stented patients and 7% of the surgical group. Despite the early benefits of stenting there was no significant difference in overall survival between the two groups (median survival: surgical 26 weeks; stented 21 weeks; p = 0.065). Endoscopic stenting and surgery are effective palliative treatments with the former having fewer early treatment-related complications and the latter fewer late complications.

We tested, under independent conditions, the reproducibility of evidence from two previous trials that homoeopathy differs from placebo. The test model was again homoeopathic immunotherapy. 28 patients with allergic asthma, most of them sensitive to house-dust mite, were randomly allocated to receive either oral homoeopathic immunotherapy to their principal allergen or identical placebo. The test treatments were given as a complement to their unaltered conventional care. A daily visual analogue scale of overall symptom intensity was the outcome measure. A difference in visual analogue score in favour of homoeopathic immunotherapy appeared within one week of starting treatment and persisted for up to 8 weeks (p = 0.003). There were similar trends in respiratory function and bronchial reactivity tests. A meta-analysis of all three trials strengthened the evidence that homoeopathy does more than placebo (p = 0.0004). Is the reproducibility of evidence in favour of homoeopathy proof of its activity or proof of the clinical trial's capacity to produce false-positive results?

Patients do not always respond to treatment of visceral leishmaniasis with pentavalent antimony, and the drug has toxic effects. Amphotericin B might be useful as an alternative first-line treatment for the disease. We compared the efficacy of amphotericin and sodium stibogluconate in a prospective randomised trial in 80 uncomplicated and parasitologically confirmed cases of Indian kala-azar. None of the patients had received an antileishmanial agent before. Sodium stibogluconate was given at 20 mg/kg in two divided doses daily for 40 days, and amphotericin in fourteen doses of 0.5 mg/kg infused in 5% dextrose on alternate days. All 40 patients randomised to amphotericin were cured; of the 40 patients assigned to sodium stibogluconate, 28 (70%) showed initial cure and 25 (62.5%) showed definitive cure (p < 0.001). With amphotericin, there was quicker abatement of fever and more complete spleen regression with no serious adverse effects. Amphotericin is effective in the first-line treatment of Indian kala-azar and superior to antimony therapy.

The reported prevalence of absent ankle jerks in elderly people varies greatly. This variation may be due to differences in the method of testing. Eight physicians examined 12 patients for the presence of ankle jerks using two techniques: plantar strike and tendon strike. Both intra-observer agreement (kappa 0.47 vs 0.20; p = 0.01) and inter-observer agreement (0.57 vs 0.21; p < 0.001) were greater with plantar strike. Reliability of ankle jerk assessment was greater for more experienced examiners. Differences in technique may explain some of the discrepancy between studies examining the prevalence of absent ankle jerks in elderly people.

We have tested the concept that fewer patients are needed in trials of antihypertensive treatment if blood pressure is measured by ambulatory monitoring rather than by conventional sphygmomanometry. 233 patients (> or = 60 years old) with isolated systolic hypertension were randomly allocated placebo (n = 119) or active treatment (n = 114). Blood pressure measurements were compared by Wilcoxon's test and blood pressure profiles by ANOVA. With either method of measurement, the same number of patients (40 in each treatment group) was required to show a reduction after 1 year in clinic (13/8 mm Hg) or average blood pressure over 24 h (9/5 mm Hg). To detect that the decrease in systolic pressure was not steadily maintained through the day, 40 patients in each treatment group were needed for blood pressure profiles made up of 4-hourly or 2-hourly means and 60 for profiles of 1-hourly means. For diastolic pressure, the corresponding numbers were 80, 100, and more than the number of available patients, respectively. We conclude that parallel-group trials focusing on the average blood pressure over 24 h, rather than on conventionally measured blood pressure, cannot economise on sample size. Moreover, trials studying the full course of blood pressure throughout the day, require more--not fewer--patients than studies of only the conventional or average 24 h blood pressure.

Diarrhoea is the most common illness affecting travellers to developing countries. Our study was designed to compare the efficacy of a single 500 mg dose of ciprofloxacin with placebo for treatment of acute diarrhoea in travellers. British troops who were within their first 8 weeks of deployment in Belize and who presented within 24 h of the onset of diarrhoea, were randomized to receive either ciprofloxacin 500 mg or placebo. Every subject recorded the number and consistency of stools and presence of any other associated symptoms for 72 h or until recovery. Of 88 subjects enrolled, 83 were evaluable, of whom 45 received ciprofloxacin and 38 placebo. Groups did not differ with regard to duration or severity of diarrhoea at randomisation. Mean (SE) duration of diarrhoea, as assessed by time to the last liquid and last unformed stool, was reduced from 50.4 (4.5) h and 53.5 (4.4) h, respectively, in the placebo group to 20.9 (3.4) h and 24.8 (3.8) h in those receiving ciprofloxacin (p < 0.0001). Mean number of liquid stools was reduced from 11.4 (1.2) in the placebo group to 5.0 (0.7) in the ciprofloxacin-treated group (p < 0.0001). The cumulative percentages of subjects with no unformed stool after 24 h, 48 h, and 72 h were, respectively, 64%, 82%, and 93% in the ciprofloxacin group and 11%, 42%, and 79% in the placebo group (p < 0.0001, p < 0.001, and not significant, respectively). A single 500 mg dose of ciprofloxacin was an effective empirical treatment for reducing the duration and severity of diarrhoea in travellers. The regimen should maximise compliance and reduce the cost and duration of therapy.

In patients with sick-sinus syndrome, single-chamber atrial pacing has been reported, in retrospective studies, to be associated with lower frequencies of atrial fibrillation, thromboembolism, heart failure, and mortality than ventricular pacing; although single-chamber ventricular pacing is most commonly used. We did a prospective randomised trial in 225 consecutive patients (142 women, 83 men; mean age 76 years) with the sick-sinus syndrome, randomised to atrial (n = 110) or ventricular (n = 115) pacing and followed for up to 5 years (mean 40 [SD 18] months). During follow-up, the frequency of atrial fibrillation was higher in the ventricular group, except at the first follow-up at 3 months. Thromboembolic events (stroke or peripheral arterial embolus) occurred in 20 patients in the ventricular group and in 6 patients in the atrial group (p = 0.0083). 25 patients died in the ventricular group compared with 21 in the atrial group (p = 0.74). Heart failure estimated by the New York Heart Association classification and by the daily doses of diuretics did not differ between the two groups. Atrioventricular block occurred in 2 patients in the atrial group. Patients with sick-sinus syndrome should be treated with atrial pacing rather than ventricular pacing because atrial pacing is associated with lower frequencies of atrial fibrillation, thromboembolic complications, and a low risk of atrioventricular block.

Shortage of donor livers has led several liver transplant centres to widen their definition of liver donor suitability. We have assessed the function of liver grafts from "marginal" donors and attitudes to use of such organs. Over an 18-month period, livers used in 30 of 213 consecutive liver transplantations in Birmingham, UK, came from marginal donors (history of alcoholism, abnormal liver function test results, drug overdose that included paracetamol, advanced cardiovascular disease, sepsis, lengthy hypotension [systolic blood pressure < 80 mm Hg for > 1 h], high-dose inotropic drug use). 16 of these donors had been refused by other UK liver transplant centres, 11 on medical grounds. The controls were grafts retrieved from "good" donors (n = 183) during the same period. All 30 grafts showed satisfactory early function but had greater day 1 (p = 0.004) and peak serum aspartate aminotransferase (p = 0.0008) values than control grafts. Graft and patient survival at 1 year in the two groups was similar (72% vs 73% and 80% vs 82%, respectively). To assess attitudes to marginal donor livers, a questionnaire outlining the details of these 30 donors was sent to the 80 centres in the European Liver Transplant Group, and 60 replied. Median immediate refusal rate of the marginal donors was 7/30 (range 0-18) and median outright acceptance rate was only 11/30 (1-26). Larger centres were less selective, with a significantly lower refusal rate (p = 0.03). These results indicate that, because of existing liver donor criteria within Europe, usable donor livers are being unnecessarily refused on medical grounds.

Erythromycin, the standard treatment for chlamydial infection in pregnant women, commonly causes side-effects, which limits its efficacy. In a randomised, double-blind study, we compared amoxycillin with erythromycin in this setting. 210 pregnant women with Chlamydia trachomatis infection were randomly assigned 7 days' treatment with amoxycillin (500 mg three times daily) or erythromycin (500 mg four times daily). Control cultures were obtained 21 days after treatment, during late pregnancy, and from the infant within a week of birth. Treatment was judged a failure if any post-treatment culture was positive or if the patient had to stop therapy because of severe side-effects. 11 women (5.2%) were lost to follow-up. 1 (of 100) amoxycillin-treated women had to stop treatment because of severe side-effects compared with 12 (of 99) erythromycin-treated women (p = 0.002). 1 woman in the amoxycillin group had a positive culture at the third-trimester examination. No positive post-treatment culture was found in the erythromycin group. Severe gastrointestinal side-effects were more common in women who received erythromycin (31 vs 6%, p < 0.001). The overall failure rate was therefore 2% in the amoxycillin group and 12% in the erythromycin group (p = 0.005). These results suggest that amoxycillin is an acceptable alternative to erythromycin for C trachomatis infection in pregnant women.

Platelet activation is associated with acute vessel occlusion and chronic restenosis after percutaneous transluminal coronary angioplasty (PTCA). Organic nitrates, which act by releasing the vasodilator and anti-platelet agent nitric oxide (NO), have a predominantly vasodilator action and cause hypotension at doses required to inhibit platelet activation. S-nitrosoglutathione (GSNO) is an NO donor with a preferential action on platelets. We investigated platelet activation in patients undergoing PTCA and the effect of GSNO. Blood was sampled from the coronary sinus to measure platelet surface expression of P-selectin and glycoprotein IIb/IIIa as indices of platelet activation. In 7 control patients, PTCA caused a rise in platelet surface expression of P-selectin and glycoprotein IIb/IIIa, which was maximal 5 minutes after PTCA, indicating increased platelet activation despite treatment with aspirin, glyceryl trinitrate, and heparin. 6 patients received an intracoronary infusion of GSNO, starting 10 min before PTCA. GSNO significantly inhibited the PTCA-induced increase in platelet surface expression of P-selectin and glycoprotein IIb/IIIa without altering blood pressure. These findings show that platelets are activated following PTCA and that GSNO can prevent this activation.

Transplantation of fetal porcine islet-like cell clusters (ICC) reverses diabetes in experimental animals. We have now transplanted porcine ICC to ten insulin-dependent diabetic kidney-transplant patients. All patients received standard immunosuppression and, at ICC transplantation, antithymocyte globulin or 15-deoxyspergualin. ICC were injected intraportally or placed under the kidney capsule of the renal graft. Four patients excreted small amounts of porcine C-peptide in urine for 200-400 days. In one renal-graft biopsy specimen, morphologically intact epithelial cells stained positively for insulin and glucagon in the subcapsular space. We conclude that porcine pancreatic endocrine tissue can survive in the human body.

Disability associated with chronic obstructive pulmonary disease has led to the development of rehabilitation programmes that aim to increase exercise tolerance and improve quality of life. Many reports of the benefits of rehabilitation have been from uncontrolled trials and unsupervised programmes. In view of the commitment asked of patients, their families, and health-care professionals, rehabilitation should be justified by a demonstration of sustained improvement over conventional treatment. We undertook a prospective randomised controlled trial of respiratory rehabilitation in 89 subjects (44 men, 45 women) aged 66 (SD 7) years with severe but stable chronic obstructive pulmonary disease who received rehabilitation or conventional community care. The treatment group were rehabilitated as inpatients for 8 weeks and supervised as outpatients for 16 weeks. Primary outcome measures of exercise tolerance and quality of life were made at baseline and repeated at 12, 18, and 24 weeks. The difference between baseline and last follow-up was significant for 6 min walk distance (37.9 m [95% CI 10.8-65.0], p = 0.0067) and submaximal cycle time (4.7 min [2.1-7.3]). There were also significant differences in questionnaire assessment of dyspnoea (p = 0.0061), emotional function (p = 0.0150), mastery (p = 0.0002), and dyspnoea index (p = 0.0053). Improvements in exercise tolerance and quality of life can be achieved and sustained for 6 months in patients undergoing respiratory rehabilitation compared with those receiving conventional care.

Drug therapy for hypercholesterolaemia has remained controversial mainly because of insufficient clinical trial evidence for improved survival. The present trial was designed to evaluate the effect of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease (CHD). 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 5.5-8.0 mmol/L on a lipid-lowering diet were randomised to double-blind treatment with simvastatin or placebo. Over the 5.4 years median follow-up period, simvastatin produced mean changes in total cholesterol, low-density-lipoprotein cholesterol, and high-density-lipoprotein cholesterol of -25%, -35%, and +8%, respectively, with few adverse effects. 256 patients (12%) in the placebo group died, compared with 182 (8%) in the simvastatin group. The relative risk of death in the simvastatin group was 0.70 (95% CI 0.58-0.85, p = 0.0003). The 6-year probabilities of survival in the placebo and simvastatin groups were 87.6% and 91.3%, respectively. There were 189 coronary deaths in the placebo group and 111 in the simvastatin group (relative risk 0.58, 95% CI 0.46-0.73), while noncardiovascular causes accounted for 49 and 46 deaths, respectively. 622 patients (28%) in the placebo group and 431 (19%) in the simvastatin group had one or more major coronary events. The relative risk was 0.66 (95% CI 0.59-0.75, p < 0.00001), and the respective probabilities of escaping such events were 70.5% and 79.6%. This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged 60 or more. Other benefits of treatment included a 37% reduction (p < 0.00001) in the risk of undergoing myocardial revascularisation procedures. This study shows that long-term treatment with simvastatin is safe and improves survival in CHD patients.

Among HIV-positive patients who received treatment for active tuberculosis, thiacetazone has been associated with cutaneous hypersensitivity and recurrent tuberculosis. No controlled trials have investigated the safety and efficacy of thiacetazone-containing regimens compared with alternative regimens among patients with HIV. In a randomised clinical trial of 191 HIV-positive patients with active pulmonary tuberculosis, we examined the safety and short-term efficacy of isoniazid, rifampicin, and pyrazinamide for two months followed by isoniazid and rifampicin for seven months (RHZ) compared with streptomycin, thiacetazone, and isoniazid for two months followed by thiacetazone and isoniazid for ten months (STH). Between May, 1990, and September, 1991, 191 HIV-positive adult Ugandan patients with acid-fast bacilli sputum smear-positive pulmonary tuberculosis (93% confirmed by culture) received either STH or RHZ. Subjects had a standard evaluation that included Mantoux skin test, complete blood count with differential white blood cell count, and chest radiography. After starting therapy, subjects were followed-up over one year for three outcomes: complications of anti-tuberculosis therapy, early sterilisation of cultures, and survival. Of 191 eligible subjects, 90 received STH and 101 received RHZ. The overall one-year survival was similar for STH and RHZ (65% vs 72%), but when controlled for baseline differences in Mantoux reaction size and absolute lymphocyte count, the relative risk of death for STH compared with RHZ was 1.57 (95% CI 1.0-2.48). Overall, 12 adverse drug reactions occurred in the STH arm (18.2 reactions per 100 person years [PYO]) compared with one in the RHZ arm (1.6 reactions per 100 PYO) for a relative risk of 11.7 (95% CI 1.52-90.0). 10 cutaneous reactions occurred in the STH arm (15.2 events per 100 PYO) compared with one event in the RHZ arm (1.6 events per 100 PYO) for a relative risk of 9.7 (95% CI: 1.24, 75.8). A greater proportion of RHZ patients compared with STH patients had sterilised their sputum within two months (74% vs 37%, p < 0.001). In developing countries, rifampicin-containing regimens should be given, when possible, to HIV-positive patients to reduce drug toxicity and to prolong survival.