In a prospective, randomised, placebo-controlled trial comparing the effect of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) (150 mg/day) plus calcium (1 g/day) with that of calcium alone on the bone mass of patients receiving long-term glucocorticoid therapy, the mean metacarpal cortical area in patients receiving APD increased by 1.2% between 0 and 6 months (p less than 0.06) and then remained stable between 6 and 12 months. In contrast, this index progressively declined in the placebo group (p less than 0.05 at 12 months). The two groups differed significantly in the changes at both 6 and 12 months (p less than 0.01). Mean vertebral mineral density, as measured by quantitative computed tomography, increased by 19.6% over 12 months in the APD group (p less than 0.02) but showed a non-significant decline of 8.8% in controls. The differences between the changes were again significant (p less than 0.005). Biochemical indices and bone histomorphometry indicated a reduction in bone resorption and bone formation but there was no evidence of osteomalacia. APD may thus prevent bone loss in glucocorticoid-treated patients over a year.

90 schoolchildren aged twelve and thirteen years kept a dietary diary for three days. In most cases the average intake of vitamins was close to the recommended daily allowance, although for a minority the intake was low; with minerals the recommended daily allowance was less commonly achieved. To examine the possibility that deficiency of dietary minerals and vitamins was preventing optimum psychological function, a multivitamin/mineral supplement or a placebo was administered double-blind for eight months to 60 of the children. The supplement group, but not the placebo group or the remaining 30 who took no tablets, showed a significant increase in non-verbal intelligence.

Clinical trials in coronary thrombosis can record as end-points either death or an index of left ventricular function (ejection fraction or end-systolic volume) which can be used as a surrogate for long-term mortality. Hospital mortality for patients under 70 years of age in whom effective thrombolysis is achieved should now be no more than about 5%. To show a 20% reduction (to 4%) in mortality with an alpha error (two-sided) of 0.05 and a beta error of 0.2 requires 15,000 patients. By contrast, a 25% improvement towards normal in ejection fraction (from about 59% to about 62%) requires only 384 patients. Since it is likely that one of several thrombolytic agents will be effective in conjunction with one or more myocardial protective agents, many trials will be required, and it may be more appropriate in future studies to measure left ventricular function rather than mortality as the principal end-point.

Sixteen of nineteen patients completed a randomised double-blind crossover trial to assess the effect of oral mexiletine (10 mg/kg bodyweight daily) on the symptoms and signs of chronic painful diabetic neuropathy. The median age of the sixteen patients was 50 years (range 30-64). Assessment with a five-item clinical symptom scale showed significant improvement during the mexiletine phase compared with the placebo phase. Pain was reduced during mexiletine but not during placebo, as assessed by a visual analogue rating scale. Mexiletine treatment had no effect on tendon reflexes, vibration threshold levels, beat-to-beat variation in heart rate during deep breathing, and postural blood pressure response. Mild side-effects were seen in three of the sixteen patients during mexiletine treatment.

24 infants consecutively treated with acyclovir or vidarabine for neonatal herpes simplex virus (HSV) encephalitis were followed up for 6 months to 3 years to assess neurological and developmental outcome. 15 patients had HSV-2 and 9 had HSV-1 encephalitis. Infants with HSV-2 encephalitis presented with a higher frequency of seizures, greater pleocytosis and protein concentrations in the cerebrospinal fluid, and more frequent evidence of structural damage on computerised tomographic scans of the brain than did those with HSV-1 encephalitis. 1 patient died. All 9 HSV-1 patients were normal at follow-up (mean 19.4 months) compared with only 4 (23%) of the 14 surviving HSV-2 infected infants (p = 0.003). Among infants with HSV-2 encephalitis, 50% became microcephalic; 57% had seizure disorders; 64% had ophthalmological defects; 64% had cerebral palsy; and 57% had mental retardation. Infants with neonatal HSV-1 encephalitis treated with systemic antiviral chemotherapy have excellent neurological outcomes; the neurological morbidity of those with HSV-2 encephalitis is still high.

79 women who had been menopausal for less than 36 months and who had not received any form of treatment to prevent bone loss were randomly assigned to a 12-month regimen of calcium 500 mg/day or calcium 500 mg plus intranasal salmon calcitonin 50 IU/day for 5 days per week. After 12 months of treatment bone mineral density had decreased in the calcium-only group by a mean of 3.16 (SEM 0.6)% (p less than 0.01) but had increased in the calcium plus calcitonin group by 1.38 (0.8)% (NS). The difference in response between the two treatment groups was also highly significant (p less than 0.01), as was the difference between values for hydroxyprolinuria/creatininuria (p less than 0.01). Endogenous calcitonin levels rose significantly in the calcium group but remained unchanged in calcitonin-treated patients. Treatment by calcitonin and calcium was not followed by increased secretion of parathyroid hormone. The findings suggest that intranasal calcitonin can counteract early postmenopausal bone loss.

In Transkei, 143 patients with active tuberculous constrictive pericarditis without significant pericardial effusion all received the same daily 6-month antituberculosis regimen of streptomycin, isoniazid, rifampicin, and pyrazinamide for 14 weeks followed by isoniazid and rifampicin. They were randomly allocated to receive in addition either prednisolone or placebo for the first 11 weeks; the comparison was double-blind throughout treatment and follow-up. In the 114 patients assessable up to 24 months, improvement was significantly more rapid in the prednisolone group, as shown by the rate of fall in the mean pulse rate and the rate at which jugular venous pressure and level of physical activity became normal. During follow-up, 2 (4%) of the 53 prednisolone and 7 (11%) of the 61 placebo patients died from pericarditis, and 11 (21%) and 18 (30%), respectively, required pericardiectomy. By 24 months 50 (94%) prednisolone and 52 (85%) placebo patients had a favourable status. 3 patients (1 prednisolone, 2 placebo) were normally active but were classified as not having achieved a favourable status. It is recommended that, in the absence of a specific contraindication, antituberculosis chemotherapy should be initially supplemented by steroids.

In a multicentre double-blind trial, 2500 patients with a clinical diagnosis of a recent cerebrovascular event of atherothrombotic origin (transient ischaemic attack, reversible ischaemic neurological deficit, or stroke) were randomised to receive either dipyridamole 75 mg plus acetylsalicylic acid 325 mg (DP-ASA, 1250 patients) or placebo (1250 patients) thrice daily. Follow-up was twenty-four months. On intention-to-treat analysis, 473 patients reached an end-point (stroke or death from any cause), 190 on DP-ASA and 283 on placebo. Survival curves for end-points showed 33% benefit in favour of the DP-ASA group (p less than 0.001). 108 patients died in the DP-ASA group and 156 in the placebo group (p less than 0.01). Results of an explanatory analysis were similar.

The physiological role of glucagon-like peptide-1 7-36 amide (GLP-1 7-36) in man was investigated. GLP-1 7-36-like immunoreactivity was found in the human bowel; its circulating level rose after oral glucose and after a test breakfast. When it was infused into seven volunteers at a rate to mimic its postprandial plasma concentration in the fasting state, plasma insulin levels rose significantly and glucose and glucagon concentrations fell. During an intravenous glucose load, it greatly enhanced insulin release and significantly reduced peak plasma glucose concentrations, compared with a control saline infusion, even inducing postinfusion reactive hypoglycaemia. By comparison, infusion of glucose-dependent insulinotropic peptide (GIP) to physiological levels was less effective in stimulating insulin release. These observations suggest that GLP-1 7-36 is a physiological incretin and that it is more powerful than GIP. The observation of greatly increased postprandial plasma GLP-1 7-36 levels in patients with postgastrectomy dumping syndrome suggests that it may mediate the hyperinsulinaemia and reactive hypoglycaemia of this disorder.

Of 113 patients in whom endoscopy revealed a bleeding gastric or duodenal ulcer 55 were randomly allocated to receive endoscopic sclerosis (ES) (injections of adrenaline/polidocanol) plus cimetidine while 58 received cimetidine alone as controls. 3 patients treated with ES (5.5%) compared with 25 controls (43.1%) had a major recurrent haemorrhage during their hospital stay. ES also led to significant reductions in the need for emergency surgery (3 vs 20 patients), transfusion requirements (mean 0.42 [SD 1.1] vs 2.7 (3.19) U), and the length of hospital stay (11.6 [5.1] vs 16.2 [11.3] days). ES as an adjunct to conventional medical treatment is an effective and safe emergency therapy for gastrointestinal bleeding due to peptic ulcer.

Of 22 patients undergoing repeat open-heart surgery through a previous median sternotomy wound 11 were randomised to receive the serine proteinase inhibitor aprotinin in high dosage (about 700 mg intravenously from the start of anaesthesia to the end of operation, depending on the length of the surgical procedure). Their mean blood loss was 286 ml compared with 1509 ml in the 11 control patients (p less than 0.001), and mean haemoglobin losses were 8.3 g and 78 g, respectively (p less than 0.001). Blood transfusion requirements were eightfold higher in the control group than in the aprotinin group, 7 of whom received only the single unit of their own blood taken before cardiopulmonary bypass.

Sleeping with the bed-head raised is commonly recommended as treatment for patients with troublesome oesophagitis, but its effect has not been objectively tested. Ranitidine therapy is useful in oesophagitis, but it does not often produce complete relief of symptoms. The effects of each of these treatments alone and in combination have been studied in 71 patients with severe (grade III) peptic oesophagitis. Each treatment improved both symptoms and endoscopic appearances significantly more than placebo did. However, the combination of the two treatments was much better than either alone; the reduction in pain score and the area of ulceration healed were about twice those with either treatment alone. Smoking more than five cigarettes per day or drinking more than 30 g alcohol per day significantly reduced the effectiveness of ranitidine therapy, but age, sex, body weight, or the presence of a hiatus hernia had no detectable effect.

A significant increase in psychiatric morbidity, assessed by standard measures, was demonstrated in a group of patients receiving recombinant alpha-interferon for chronic hepatitis-B virus infection. In some cases the psychiatric symptoms were severe enough to need urgent psychiatric attention. The changes seemed most severe in patients with coexistent human immunodeficiency virus infection. The mental state changes are clinically reminiscent of those in the "post-viral" psychiatric syndromes.

DL-dihydroxyphenylserine was given by mouth in a single-blind, placebo-controlled trial to two patients with orthostatic hypotension due to dopamine-beta-hydroxylase deficiency, in the hope of providing noradrenaline by endogenous decarboxylation. Dose-dependent increases in blood pressure were obtained over the range 150-600 mg. After 600 mg mean arterial pressure rose 33 and 19 mm Hg and these rises were tightly correlated with an increase in plasma noradrenaline (r = 0.995, p less than 0.001 and r = 0.88, p less than 0.05). Urinary noradrenaline increased from undetectable levels to 338 and 511 micrograms/24 h. Standing time (a correlate of functional capacity) also increased significantly in both patients. No side-effects were noted.

The protective efficacy against typhoid fever of a single intramuscular injection of 25 micrograms of the Vi capsular polysaccharide (CPS) was assessed in a randomised double-blind controlled trial. Vaccination of 11,384 children was followed by 21 months' surveillance. 47 blood-culture-proven cases of typhoid occurred in children who received meningococcal A + C CPS vaccine and 19 cases in those vaccinated with Vi CPS. Protective efficacy was 60% calculated from the day of vaccination and 64% from 6 weeks after vaccination. Surveillance also included 11,691 unvaccinated children; 173 cases occurred in this group. Protective efficacy in relation to the unvaccinated group was 77.4% and 81.0% after 21 months, calculated immediately and 6 weeks after vaccination, respectively. Vaccination was associated with minimum local side-effects, and an increase in anti-Vi antibodies occurred, as measured by radioimmunoassay and enzyme-linked immunosorbent assay. Antibody levels remained significantly raised at 6 and 12 months post vaccination. Vi CPS is thus a safe and effective means of typhoid vaccination.