There is little unequivocal evidence that nutritional supplementation of undernourished children has a beneficial effect on their mental development. The effects of nutritional supplementation, with or without psychosocial stimulation, of growth-retarded (stunted) children aged 9-24 months were assessed in a study in Kingston, Jamaica. 129 children from poor neighbourhoods were randomly assigned to four groups--control, supplemented only, stimulated only, and supplemented plus stimulated. A group of matched non-stunted children (n = 32) was also included. The supplement comprised 1 kg milk-based formula per week for 2 years, and the stimulation weekly play sessions at home with a community health aide. The children's development (DQ) was assessed on the Griffiths mental development scales. Initially the stunted groups' DQs were lower than those of the non-stunted group, and those of the control group declined during the study, increasing their deficit. Stimulation and supplementation had significant independent beneficial effects on the children's development. Estimates of the supplementation effect ranged from 2.2 (95% confidence limits-1.4, 5.7) for the hand and eye subscale to 12.4 (5.4, 19.5) for the locomotor subscale and those for the stimulation effect from 6.4 (2.8, 10.0) for hand and eye to 10.3 (3.3, 17.3) for locomotor. The treatment effects were additive, and combined interventions were significantly more effective than either alone. These findings suggest that poor mental development in stunted children is at least partly attributable to undernutrition.

In children with corticosteroid-responsive nephrotic syndrome who are dependent on high-dose prednisolone, alkylating therapy often fails to maintain a remission, and long-term immunosuppression may be hazardous. An alternative approach to treatment is to use an immunostimulant such as levamisole. 61 children with frequently relapsing corticosteroid sensitive and dependent nephrotic syndrome were randomly allocated to receive levamisole, 2.5 mg/kg on alternate days (31 patients) or placebo (30 patients) for a maximum of 112 days. After entry to the trial, prednisolone was progressively reduced and was stopped by 56 days. The two groups were well matched for age and sex distribution, indices of corticosteroid toxicity, and previous alkylating therapy. 14 patients in the levamisole group and 4 in the placebo group remained in remission at 112 days (log rank analysis p less than 0.01). No significant adverse events were recorded. Levamisole is effective in maintaining a steroid-free remission in this condition and has few side-effects.

Insecticide treatment of bed nets ("mosquito nets") may be a cheap and acceptable method of reducing the morbidity and mortality caused by malaria. In a rural area of The Gambia, bed nets in villages participating in a primary health-care (PHC) scheme were treated with permethrin at the beginning of the malaria transmission season. Additionally, children aged 6 months to 5 years were randomised to receive weekly either chemoprophylaxis with maloprim or a placebo throughout the malaria transmission season. We measured mortality in children in PHC villages before and after the interventions described, and compared this with mortality in villages where no interventions occurred (non-PHC villages). About 92% of children in PHC villages slept under insecticide-treated bed nets. In the year before intervention, mortality in children aged 1-4 years was lower in non-PHC villages. After intervention, the overall mortality and mortality attributable to malaria of children aged 1-4 in the intervention villages was 37% and 30%, respectively, of that in the non-PHC villages. Among children who slept under treated nets, we found no evidence of an additional benefit of chemoprophylaxis in preventing deaths. Insecticide-treated bed nets are simple to introduce and can reduce mortality from malaria.

First-trimester chorion villus sampling has the advantage over second-trimester amniocentesis of allowing earlier prenatal diagnosis of various genetic and cytogenetic disorders in the fetus (and therefore earlier termination in affected pregnancies) but the relative safety and diagnostic accuracy remain unclear. Between 1985 and 1989, 3248 women seeking prenatal diagnosis, principally because of their age, were recruited to an international, multicentre, randomised comparison of the safety and diagnostic accuracy of the two techniques--5% of women allocated chorion villus sampling and 8% of those allocated amniocentesis were not tested, usually because of spontaneous miscarriage. 6% and 2% were retested, in most because of sampling failure. The endpoint of a liveborn infant who survived was achieved by 86% of women allocated chorion villus sampling and 91% of those allocated amniocentesis; statistical analysis, after appropriate weighting for a centre's contribution, showed that the typical difference between the groups was 4.6% (95% confidence interval 1.6-7.5%; p less than 0.01). This difference reflected more spontaneous fetal deaths before 28 weeks' gestation (2.9% [0.6-5.3%]); more terminations of pregnancy for chromosomal anomalies (1.0% [0.0-2.1%]); and more neonatal deaths (0.3% [-0.1 to 0.7%]). The difference in neonatal deaths was due to a preponderance of very immature liveborn infants in the chorion villus sampling group, and this factor also explained that group's longer mean stay in hospital. More abnormal diagnoses followed chorion villus than amniotic fluid analyses (5.6% vs 3.9%). This difference was largely due to diagnoses of trisomy 18 and of (usually mosaic) abnormalities known to be confined to the placenta. 3 terminated pregnancies were false positives, 1 tested by chorion villus sampling and 2 by amniocentesis, and 2 other mosaic cases diagnosed by chorion villus sampling may have been false positives. There was 1 false-negative result in the chorion villus sampling group. The possibility of earlier exclusion or diagnosis of some fetal disorders afforded by first-trimester chorion villus sampling must be set against its clinical risks.

To assess the long-term efficacy and safety of alfuzosin, a selective alpha 1-adrenergic antagonist, 518 symptomatic patients with benign prostatic hypertrophy (BPH) were randomised to received either alfuzosin (daily dose 7.5-10 mg) or placebo for 6 months. Obstructive and irritative symptoms, assessed according to the Boyarsky scale, significantly improved in the alfuzosin group compared with the placebo group (p = 0.0004). Fewer patients in the alfuzosin group than in the placebo group dropped out due to lack of efficacy (6.8% vs 14.6%, p = 0.004) and the prevalence of spontaneous acute urine retention was lower in the alfuzosin group (0.4% vs 2.6%, p = 0.04). By 6 months, mean urinary flow rates had increased (p less than 0.05) and residual volume had decreased (p = 0.017) in the alfuzosin group, although the two groups were broadly similar with respect to increase in peak flow rate. The overall incidence of adverse events was similar in the two groups, which led to the withdrawal of 10.8% and 9.0% of patients, respectively. The findings emphasise the magnitude of the placebo response in symptomatic patients with BPH and show that treatment with alpha 1 adrenergic antagonist drugs provides long-lasting improvement in such patients.

Because there is little information about the efficacy of home occupational therapy, we decided to assess the effects of a home service on patients with rheumatoid arthritis. 105 patients aged 18-70 years, on stable medical therapy, were randomised to receive a 6-week comprehensive programme of occupational therapy (experimental group, 53 patients) or to receive no such treatment (control group, 52). At 6 weeks, control patients received the experimental regimen, and experimental patients were continued on treatment as needed up to 12 weeks. Outcomes were measured at baseline, 6, and 12 weeks with a global functional capacity score (functional score). At 6 weeks the functional score for the experimental group was significantly higher than that for the control group (mean difference = 8.1, 95% Cl 1.7 to 15.8, p = 0.012). Control patients at 12 weeks showed a similar improvement to experimental patients at 6 weeks, and between 6 and 12 weeks the experimental patients were stable. Occupational therapy leads to a statistically significant and clinically important improvement in function in patients with rheumatoid arthritis.

The two main causes of gastrointestinal bleeding in cirrhosis are oesophageal varices and portal hypertensive gastropathy (PHG). Rebleeding from varices can be prevented by beta-blockers, but it is not clear whether these drugs effectively reduce rebleeding from PHG. 54 cirrhotic patients with acute or chronic bleeding from severe PHG took part in a randomised, controlled trial to investigate the efficacy of propranolol in prevention of rebleeding from PHG. 26 patients were randomised to receive propranolol daily at a dose that reduced the resting heart rate by 25% or to 55 bpm (20-160 mg twice daily), throughout mean follow-up of 21 (SD 11) months. 28 untreated controls were followed-up, with the same examinations, for 18 (13) months. The actuarial percentages of patients free of rebleeding from PHG were significantly higher in the propranolol-treated patients than in the untreated controls at 12 months (65% vs 38%; p less than 0.05) and at 30 months of follow-up (52% vs 7%; p less than 0.05). Propranolol-treated patients had fewer episodes of acute bleeding than controls (0.010 [0.004] vs 0.120 [0.040] per patient per month). Multivariate analysis showed that absence of propranolol treatment was the only predictive variable for rebleeding. Actuarial survival was slightly higher in the propranolol group than in the controls, but the difference was not significant. Thus, long-term propranolol treatment significantly reduces the frequency of rebleeding from severe PHG, and may improve the prognosis of cirrhotic patients with this disorder.

The efficacy of low-dose aspirin in preventing fetal growth retardation was tested in a randomised, placebo-controlled, double-blind trial. A secondary aim was to find out whether dipyridamole improves the efficacy of aspirin. 323 women at 15-18 weeks' amenorrhoea were selected at twenty-five participating centres on the basis of fetal growth retardation and/or fetal death or abruptio placentae in at least one previous pregnancy. They were randomly allocated to groups receiving placebo, 150 mg/day aspirin, or 150 mg/day aspirin plus 225 mg/day dipyridamole, for the remainder of the pregnancy. In the first phase of the trial all actively treated patients (n = 156) were compared with the placebo group (n = 73). Mean birthweight was significantly higher in the treated than in the placebo group (2751 [SD 670] vs 2526 [848] g; difference 225 g [95% CI 129-321 g], p = 0.029) and the frequency of fetal growth retardation in the placebo group was twice that in the treated group (19 [26%] vs 20 [13%]; p less than 0.02). The frequencies of stillbirth (4 [5%] vs 2 [1%]) and abruptio placentae (6 [8%] vs 7 [5%]) were also higher in the placebo than in the treated group. The benefits of aspirin treatment were greater in patients with two or more previous poor outcomes than in those with only one. In the second analysis, of aspirin only (n = 127) vs aspirin plus dipyridamole (n = 119), no significant differences were found. There was no excess of maternal or neonatal side-effects in the aspirin-treated patients.

Although epidemiological and biochemical evidence suggests that aluminium may be associated with Alzheimer's disease (AD), there is no convincing proof of a causal link for aluminium in disease progression. We have completed a two year, single-blind study to investigate whether the progression of dementia could be slowed by the trivalent ion chelator, desferrioxamine. 48 patients with probable AD were randomly assigned to receive desferrioxamine (125 mg intramuscularly twice daily, 5 days per week, for 24 months), oral placebo (lecithin), or no treatment. No significant differences in baseline measures of intelligence, memory, or speech ability existed between groups. Activities of daily living were assessed and videorecorded at 6, 12, 18, and 24 month intervals. There were no differences in the rate of deterioration of patients receiving either placebo or no treatment. Desferrioxamine treatment led to significant reduction in the rate of decline of daily living skills as assessed by both group means (p = 0.03) and variances (p less than 0.04). The mean rate of decline was twice as rapid for the no-treatment group. Appetite (n = 4) and weight (n = 1) loss were the only reported side-effects. We conclude that sustained administration of desferrioxamine may slow the clinical progression of the dementia associated with AD.

A multicentre, prospective trial was organised to clarify the role of protein restriction in the progression of chronic renal insufficiency (CRI). 456 adult patients were assigned either a low-protein diet (0.6 g/kg body weight daily; n = 226) or a "normal" controlled-protein diet (1.0 g/kg daily; n = 230) and were stratified into three groups (A-C) with increasing baseline plasma creatinine concentrations. Each patient was followed up for 2 years or until an endpoint (a doubling of the baseline plasma creatinine or a need for dialysis) was reached. The difference between the diet groups in cumulative renal survival defined by these endpoints (27 low-protein, 42 controlled-protein) was of borderline significance (p less than 0.06). The difference in renal survival between the low-protein and controlled-protein diet groups was of borderline significance in group A (0 vs 4 endpoints), significant in group B (10 vs 21 endpoints; p less than 0.025), and not significant in group C. There were no differences among the diet groups or subgroups in mean plasma creatinine concentrations, creatinine clearance, the slope of the plasma creatinine reciprocal, or mean blood pressures. Compliance was good in the controlled-protein group but poor for the low-protein diet: the difference in protein intake between the groups was substantially less than that required by the protocol. However, there was no correlation between the progression of renal failure and protein catabolic rate. These findings offer little, if any, support to the hypothesis that protein restriction retards CRI progression: careful medical care and a "normal" controlled protein intake also allow very slow progression of CRI.

The European Carotid Surgery Trial is a multicentre trial of carotid endarterectomy for patients who, after a carotid territory non-disabling ischaemic stroke, transient ischaemic attack, or retinal infarct, are found to have a stenotic lesion in the relevant (ipsilateral) carotid artery. Over the past 10 years 2518 patients have been randomised, and the mean follow-up is now almost 3 years among the 2200 thus far available for analysis of the incidence of strokes that lasted more than 7 days. For the patients with "moderate" (30-69%) stenosis on their prerandomisation angiogram the balance of surgical risk and eventual benefit remains uncertain, and full recruitment continues. For 374 patients with only "mild" (0-29%) stenosis there was little 3-year risk of ipsilateral ischaemic stroke, even in the absence of surgery, so any 3-year benefits of surgery were small, and were outweighed by its early risks. For 778 patients with "severe" (70-99%) stenosis, however, the risks of surgery were significantly outweighed by the later benefits: although 7.5% had a stroke (or died) within 30 days of surgery, during the next 3 years the risks of ipsilateral ischaemic stroke were (by life-table analysis) an extra 2.8% for surgery-allocated and 16.8% for control patients (a sixfold reduction, p less than 0.0001). There was also a small reduction in other strokes, and at 3 years the total risk of surgical death, surgical stroke, ipsilateral ischaemic stroke, or any other stroke was 12.3% for surgery and 21.9% for control (difference 9.6% SD 3.3, 2p less than 0.01). The main concern was to avoid disabling or fatal events, and, among severe stenosis patients, 3.7% had a disabling stroke (or died) within 30 days of surgery, an extra 1.1% surgery versus 8.4% control (p less than 0.0001) had a disabling or fatal ipsilateral ischaemic stroke by 3 years, and the total 3-year risk of any disabling or fatal stroke (or surgical death) was 6.0% surgery versus 11.0% control (overall difference 5.0% SD 2.3, 2p less than 0.05); but, for disabling or fatal stroke the control risks seemed to diminish after the first year, so delay of surgery by just a few months after clinical presentation might make this overall difference non-significant.

A prospective multicentre randomised study of continued antiepileptic treatment vs slow withdrawal was conducted in 1013 patients who had been free of seizures for at least 2 years. Comparison of randomised and eligible, but non-randomised, patients suggests the results should be applicable to a wider patient population. By 2 years after randomisation, 78% of patients in whom treatment was continued and 59% of those in whom it was withdrawn remained seizure free, but thereafter the differences between the two groups diminished. Non-compliance with continued treatment accounted for only a small proportion of the risk to the group continuing with treatment. The most important factors determining outcome were longer seizure-free periods (reducing the risk) and more than one antiepileptic drug and a history of tonic-clonic seizures (increasing the risk). Other factors (eg, history of neonatal seizures, specific electroencephalographic features) seemed to have smaller effects, but even in such a large study the confidence intervals for these observations were wide.

The actions of melatonin on the sleep-wake cycle were investigated by means of a randomised, double-blind, placebo-controlled trial in 8 subjects with a delayed sleep phase syndrome attending a sleep disorders clinic. In randomised order the subjects received placebo or melatonin 5 mg daily for 4 weeks with a 1 week washout period between the treatments. Drug or placebo was given at 2200 h, 5 h before the mean time of sleep onset determined by pretrial sleep logs. In all 8 subjects sleep onset time (mean advance 82 [range 19-124] min; p less than 0.01) and wake time (117 [10-187] min; p less than 0.01) were significantly earlier during melatonin treatment than during placebo. Mean total sleep time was slightly less on melatonin (8 h 12 min) than on placebo (8 h 46 min). Alertness acrophase calculated from the subjects' ratings of alertness made every 2 h while awake was unaltered. Melatonin may act as a phase-setter for sleep-wake cycles in subjects with a delayed sleep phase syndrome.