Several small studies have suggested beneficial effects of long-term beta-blocker treatment in idiopathic dilated cardiomyopathy. Our large multicentre study aimed to find out whether metoprolol improves overall survival and morbidity in this disorder. 383 subjects with heart failure from idiopathic dilated cardiomyopathy (ejection fraction < 0.40) were randomly assigned placebo or metoprolol. 94% were in New York Heart Association functional classes II and III, and 80% were receiving background treatment. A test dose of metoprolol (5 mg twice daily) was given for 2-7 days; those tolerating this dose (96%) entered randomisation. Study medication was increased slowly from 10 mg to 100-150 mg daily. There were 34% (95% CI -6 to 62%, p = 0.058) fewer primary endpoints in the metoprolol than the placebo group; 2 and 19 patients, respectively, deteriorated to the point of needing transplantation and 23 and 19 died. The change in ejection fraction from baseline to 12 months was significantly greater with metoprolol than with placebo (0.13 vs 0.06, p < 0.0001). Pulmonary capillary wedge pressure decreased more from baseline to 12 months with metoprolol than with placebo (5 vs 2 mm Hg, p = 0.06). Exercise time at 12 months was significantly greater (p = 0.046) in metoprolol-treated than in placebo-treated patients. In patients with idiopathic dilated cardiomyopathy, treatment with metoprolol prevented clinical deterioration, improved symptoms and cardiac function, and was well tolerated.

Homologous blood transfusion has been associated with an increased risk of postoperative infectious complications. To test the clinical consequences of this apparently immunosuppressive effect of homologous blood in a controlled trial, we designed a study in which the control group deposited autologous blood before their operations for use should transfusion be needed. We enrolled 120 patients with apparently curable colorectal cancer who were able to predeposit autologous blood (haemoglobin > 12.5 g/dL). 62 patients were assigned to receive homologous blood if blood transfusions were needed during operation, and the other 58 to receive their own predeposited blood followed, if necessary, by homologous blood [corrected]. Despite the similarity between the groups in factors known to affect the risk of postoperative infections, there was a significant difference in postoperative infection rate between the homologous and autologous blood groups (17 [27%] vs 7 [12%], p < 0.05; unadjusted odds ratio 2.75 [95% CI 1.07-7.11). The rates of non-infectious complications were similar Probably because their preoperative blood depositing caused the autologous blood patients to have lower haemoglobin concentrations, they were more likely to require transfusion than were the homologous blood group (53 [91%] vs 37 [60%], p < 0.001; relative risk 1.53 [1.24-1.89]). 20 (35%) required homologous as well as autologous blood. To adjust for the many infection-related factors, we did multivariate regression analysis; tumour location, preoperative ASA index, and study group assignment were the only significant risk factors. The odds ratio for postoperative infections adjusted for these factors was 2.84 (1.02-7.98, homologous vs autologous). Testing of delayed-type hypersensitivity responses before and after surgery showed decreases in both mean diameter and number of positive reactions in recipients of homologous blood and slight increases in those who received autologous blood. This study shows the clinical potential of blood-transfusion-mediated immunomodulation, which may be important also in tumour immunology.

Nutritional anaemia, thought to be caused by iron deficiency, affects 50-70% of pregnant women in the developing world. The influence of vitamin A and iron supplementation was studied in anaemic pregnant women in West Java, in a randomised, double-masked, placebo-controlled field trial. 251 women aged 17-35 years, parity 0-4, gestation 16-24 weeks, and haemoglobin between 80 and 109 g/L were randomly allocated to four groups: vitamin A (2.4 mg retinol) and placebo iron tablets; iron (60 mg elemental iron) and placebo vitamin A; vitamin A and iron; or both placebos, all daily for 8 weeks. Maximum haemoglobin was achieved with both vitamin A and iron supplementation (12.78 g/L, 95% Cl 10.86 to 14.70), with one-third of the response attributable to vitamin A (3.68 g/L, 2.03 to 5.33) and two-thirds to iron (7.71 g/L, 5.97 to 9.45). After supplementation, the proportion of women who became non-anaemic was 35% in the vitamin-A-supplemented group, 68% in the iron-supplemented group, 97% in the group supplemented with both, and 16% in the placebo group. Improvement in vitamin A status may contribute to the control of anaemic pregnant women.

The efficacy of albendazole in hydatid disease is still unclear, because there has been no study that assessed the status of the parasite after treatment. The significance of albendazole-induced echographic changes in the cyst therefore cannot be judged. We did a prospective, controlled, randomised, open study of albendazole in patients with liver hydatid disease, and assessed parasite viability after treatment. 18 patients received no albendazole treatment (controls), 18 received albendazole (10 mg/kg daily) for 1 month (group A), and 19 received the drug for about 3 months (group B). Echography was done before and during treatment; all patients underwent surgery on completion. Parasite (protoscolex viability and development of cysts in mice) and ultrastructure studies were done for all cysts removed. 8 (50%) of cysts in the control group, 13 (72%) in group A, and 16 (94%) in group B were non-viable (p = 0.015). Protoscolex and cyst viability were significantly (p = 0.039 and p = 0.018, respectively) lower in treated patients than in controls. Treatment was also significantly associated with total cyst membrane disintegration. 68% of cysts treated for 3 months showed echographic changes, and only 1 of 20 cysts showing echographic changes during treatment was judged viable. The efficacy of albendazole at a dose of 10 mg/kg daily for 3 months suggests that it is a suitable alternative to surgery in uncomplicated hydatid liver disease, as initial treatment.

Several studies have established the value of anticoagulation for primary prevention of thromboembolic events in patients with non-rheumatic atrial fibrillation (NRAF). However, in patients with a recent transient ischaemic attack (TIA) or minor ischaemic stroke the preventive benefit of anticoagulation or aspirin remains unclear. Physicians in 108 centres from 13 countries collaborated to study this question. 1007 NRAF patients with a recent TIA or minor ischaemic stroke were randomised to open anticoagulation or double-blind treatment with either 300 mg aspirin per day or placebo (group 1, 669). Patients with contraindications to anticoagulation were randomised to receive aspirin or placebo (group 2,338). The measure of outcome was death from vascular disease, any stroke, myocardial infarction, or systemic embolism. During mean follow-up of 2.3 years, the annual rate of outcome events was 8% in patients assigned to anticoagulants vs 17% in placebo-treated patients in group 1 (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.36-0.79). The risk of stroke alone was reduced from 12% to 4% per year (HR 0.34; 95% CI 0.20-0.57). Among all patients assigned to aspirin (groups 1 and 2), the annual incidence of outcome events was 15%, against 19% in those on placebo (HR 0.83; 95% CI 0.65-1.05). Anticoagulation was significantly more effective than aspirin (HR 0.60; 95% CI 0.41-0.87). The incidence of major bleeding events was low, both on anticoagulation (2.8% per year) and on aspirin (0.9% per year). No intracranial bleeds were identified in patients assigned to anticoagulation. We conclude that anticoagulation is effective in reducing the risk of recurrent vascular events in NRAF patients with a recent TIA or minor ischaemic stroke. In absolute terms: 90 vascular events (mainly strokes) are prevented if 1000 patients are treated with anticoagulation for one year. Aspirin is a safe, though less effective, alternative when anticoagulation is contraindicated; it prevents 40 vascular events each year for every 1000 treated patients.

Serial serum samples and pretreatment and post-treatment liver tissue from patients with chronic hepatitis C virus (HCV) infection were tested for HCV RNA by reverse-transcription polymerase chain reaction and branched DNA signal amplification assays. At the end of treatment with interferon-alpha (IFN alpha), 4 of 5 patients showing no biochemical response (in alanine aminotransferase activity), 4 of 5 with transient responses, and 1 of 5 showing complete and sustained responses had HCV RNA detectable in serum. The corresponding numbers for liver tissue were 5, 5, and 0 (of 4). However, all 5 complete responders had virological relapses within 6 months. Biochemical response may not reflect virological profile during IFN alpha treatment of HCV.

Elemental diet is as effective in producing remission of Crohn's disease (CD) as is corticosteroid treatment, but most patients relapse soon after resumption of a normal diet. We have investigated the efficacies of dietary modification and oral corticosteroids in maintaining remission achieved with elemental diet. In a multicentre trial, 136 patients with active CD were started on elemental diet and other treatment was withdrawn. 43 (31%) declined to continue elemental diet for 14 days, but 78 (84%) of the remaining 93 achieved remission and were randomly assigned corticosteroids (38) or diet (40). Corticosteroid treatment started at 40 mg prednisolone daily, which was tapered and stopped after 12 weeks; that group received dietary advice on healthy eating. The diet group received "tapered" placebo and were instructed to introduce one new food daily, excluding any that precipitated symptoms. Assessment of progress for up to 2 years was made by physicians unaware of group assignment. Intention-to-treat analysis showed median lengths of remission of 3.8 (interquartile range 5.0) months in the corticosteroid group and 7.5 (15.3) months on diet, and relapse rates at 2 years, adjusted for withdrawals, of 79% and 62%, respectively (p = 0.048). Clinical improvement in the diet group was associated with significant changes in plasma albumin and alpha 1-antichymotrypsin concentrations and erythrocyte sedimentation rate. Food intolerances discovered were predominantly to cereals, dairy products, and yeast. Diet provides a further therapeutic strategy in active Crohn's disease.

Corticosteroids are usually given for management of Graves' ophthalmopathy, but they have many and serious side-effects. By comparison, retrobulbar irradiation is well tolerated, although its efficacy has been evaluated only in uncontrolled studies. Therefore, we did a double-blind randomised trial, in which 28 patients with moderately severe Graves' ophthalmopathy were treated with a 3-month course of oral prednisone and sham irradiation, and 28 received retrobulbar irradiation (20 Gy) and placebo capsules. Therapeutic outcome, assessed twenty-four weeks after the start of treatment, was determined by the change in the highest NOSPECS class. A successful outcome was observed in 14 prednisone-treated and in 13 irradiated patients. Responders to treatment (but not nonresponders) in both groups showed improvements in total and subjective eye score and a decrease in eye-muscle volume. Response to either treatment was due largely to changes in soft-tissue involvement and eye-muscle motility. Mean elevation in responders to radiotherapy increased from 18.5 degrees (95% CI 14.8-22.2) at baseline to 21.8 degrees (18.6-25.0) at week twenty-four (p = 0.003), but did not change in prednisone responders. Side-effects were more frequent and severe during prednisone than during radiotherapy. Radiotherapy and oral prednisone appear to be equally effective as initial treatment in patients with moderately severe Graves' ophthalmopathy. In view of its better tolerability, radiotherapy should be considered the treatment of first choice.

Despite widespread application of ultrasound imaging and Doppler blood flow studies, the effects of their frequent and repeated use in pregnancy have not been evaluated in controlled trials. From 2834 women with single pregnancies at 16-20 weeks gestation, 1415 were selected at random to receive ultrasound imaging and continuous-wave Doppler flow studies at 18, 24, 28, 34, and 38 weeks gestation (the intensive group) and 1419 to receive single ultrasound imaging at 18 weeks (the regular group). Outcome data was obtained from 99% of women who entered the study. The only difference between the two groups was significantly higher intrauterine growth restriction in the intensive group, when expressed both as birthweight < 10th centile (relative risk 1.35; 95% confidence interval 1.09 to 1.67; p = 0.006) and birthweight < 3rd centile (relative risk 1.65; 95% confidence intervals 1.09 to 2.49; p = 0.020). While it is possible that this finding was a chance effect, it is also plausible that frequent exposure to ultrasound may have influenced fetal growth. Repeated prenatal ultrasound imaging and Doppler flow examinations should be restricted to those women to whom the information is likely to be of clinical benefit.

Post-stroke pathological crying is a distressing condition in which episodes occur in response to minor stimuli without associated mood changes. There is preliminary evidence of disturbed serotoninergic neurotransmission in such cases. We investigated the effect of the selective serotonin reuptake inhibitor citalopram on uncontrolled crying in stroke patients in a double-blind placebo-controlled crossover study. 16 consecutive patients (median age 58.5 years, range 40-83) entered the 9-week study a median of 168 days (range 6-913) post stroke and were treated with citalopram 10-20 mg daily for 3 weeks. Crying history was determined from semistructured interviews and from diaries kept by the patients. Psychiatric assessment was made with the Hamilton depression scale (HDS), and unwanted effects were measured with the UKU side-effect scale. In 13 patients in whom frequency of crying could be assessed, the number of daily crying episodes decreased by at least 50% in all cases during citalopram treatment vs 2 patients during placebo treatment (p < 0.005, McNemar's test), the effect being rapid (1-3 days) and pronounced in 11 (73%). There was a concomitant significant decrease in depression rating from HDS 8.9 to 5.3 (p < 0.005, Wilcoxon's test). Citalopram was well tolerated, the few side-effects being mild and transient. We conclude that serotoninergic neurotransmission plays an important part in post-stroke pathological crying and that citalopram is an effective and well-tolerated treatment.

Regular inhaled beta 2 agonist causes tolerance to the acute protective effect of beta 2 agonist against bronchoconstriction induced by chemical stimuli such as AMP, histamine, and methacholine. We examined a more clinically relevant stimulus, inhaled allergen, in a double-blind, cross-over, random-order trial in 13 mild atopic asthmatics, who had not used beta 2 agonist for at least 4 weeks. We compared regular inhaled salbutamol (200 micrograms four times daily for 2 weeks) with placebo (2 weeks) for effects on bronchodilator response, baseline methacholine, and allergen airway responsiveness, and on the acute protective effect of salbutamol against both stimuli. Baseline forced expiratory volume in 1 s (FEV1), bronchodilator response, and methacholine responsiveness were the same during both treatment periods. After regular salbutamol, the allergen PC20 (provocation concentration producing a 20% FEV1 decrease) fell by 0.91 (SD 0.66) (p = 0.0009) doubling doses, and the protective effects of salbutamol on methacholine and allergen were both significantly reduced (p = 0.026 and 0.025, respectively). Taking into account the reduced baseline allergen PC20, the post-salbutamol allergen PC20 was almost 2 doubling doses (1.94 [1.43], p < 0.01) lower during salbutamol treatment. Thus, 2 weeks of regular inhaled salbutamol increased airway responsiveness to allergen but not to methacholine, and caused tolerance to the protective effect of salbutamol on bronchoconstriction induced by both stimuli. These effects of inhaled beta 2 agonist provide further evidence to support detrimental effects of their regular use.

Survival after acute myocardial infarction has been enhanced by treatment with thrombolytic agents, aspirin, and beta-adrenoceptor blockade. However there remains a substantial subgroup of patients who manifest clinical evidence of heart failure despite the first two of these treatments, and for whom beta-adrenoceptor antagonists are relatively or absolutely contraindicated. These patients have a greatly increased risk of fatal and non-fatal ischaemic, arrhythmic, and haemodynamic events. In this selected high-risk subset of patients we investigated the effect of therapy with the angiotensin converting enzyme (ACE) inhibitor rampiril, postulating that it would lengthen survival. 2006 patients who had shown clinical evidence of heart failure at any time after an acute myocardial infarction (AMI) were recruited from 144 centres in 14 countries. Patients were randomly allocated to double-blind treatment with either placebo (992 patients) or ramipril (1014 patients) on day 3 to day 10 after AMI (day 1). Patients with severe heart failure resistant to conventional therapy, in whom the attending physician considered the use of an ACE inhibitor to be mandatory, were excluded. Follow-up was continued for a minimum of 6 months and an average of 15 months. On intention-to-treat analysis mortality from all causes was significantly lower for patients randomised to receive ramipril (170 deaths; 17%) than for those randomised to receive placebo (222 deaths; 23%). The observed risk reduction was 27% (95 % Cl 11% to 40%; p = 0.002). Analysis of prespecified secondary outcomes revealed a risk reduction of 19% for the first validated outcome (i.e., first event in an individual patient)--namely, death, severe/resistent heart failure, myocardial infarction, or stroke (95% Cl 5% to 31%; p = 0.008). Oral administration of rampiril to patients with clinical evidence of either transient or ongoing heart failure, initiated between the second and ninth day after myocardial infarction, resulted in a substantial reduction in premature death from all causes. This benefit was apparent as early as 30 days and was consistent across a range of subgroups.