For some patients with coronary artery disease, percutaneous transluminal coronary angioplasty (PTCA) is an alternative to coronary artery bypass grafting (CABG). We report comparative health service costs of these interventions within the Randomised Intervention Treatment of Angina (RITA) trial. Medications were costed at published UK prices; other resource use was costed with a set of unit costs estimated at two recruiting centres to the RITA trial, one in London and one outside. Over 2-year follow-up of 1011 patients, the estimated mean additional cost for those randomised to CABG compared with PTCA was 1050 pounds (95% CI 621 pounds-1479 pounds), with unit costs from the non-London centre, and 1823 pounds (1202 pounds-2444 pounds), with unit costs from the London centre. The initial average cost of treating a patient randomised to PTCA is about 52% of that of CABG, but after 2 years this increased to about 80% because of the greater need for subsequent interventions. The balance of advantage between PTCA and CABG may change after several years: funding has been obtained to continue RITA follow-up for 10 years. However, on the basis of patients' status at 2 years, the cost advantages of PTCA cannot be ignored. Further research is necessary to assess whether the advantage of PTCA in terms of cost is translated into one of cost-effectiveness.

Low-molecular weight heparin has theoretical advantages over aspirin and dipyridamole in maintaining vascular-graft patency by virtue of its better antithrombotic effect and antiproliferative activity on vascular, smooth-muscle cells. We tested the hypothesis that low-molecular weight heparin would be more effective than aspirin and dipyridamole in maintaining graft patency in patients undergoing femoropopliteal bypass grafting. Patients were randomised to receive either a daily injection of 2500 IU low-molecular weight heparin, or 300 mg aspirin with 100 mg dipyridamole 8 hourly for 3 months. 94 patients were randomised to low-molecular weight heparin and 106 to aspirin and dipyridamole. Patients were stratified according to indication for surgery and were followed up for 1 year. Kaplan-Meier estimate of graft patency showed 87% graft survival on low-molecular-weight heparin and 72% on aspirin and dipyridamole at 6 months. At 12 months, the respective figures were 78% and 64%. Stratified survival analysis showed that this benefit was confined to those having salvage surgery (log rank test p = 0.0006); for those having surgery for claudication there was no significant benefit. No major bleeding events occurred in either group. We conclude that low-molecular weight heparin is better than aspirin and dipyridamole in maintaining femoropopliteal-graft patency in patients with critical limb ischaemia undergoing salvage surgery. This treatment should have considerable cost benefits.

The health effects of bathing in coastal waters is an area of scientific controversy. We conducted the first ever randomised "trial" of an environmental exposure to measure the health effects of this activity. The trial was spread over four summers in four UK resorts and 1216 adults took part. Detailed interviews were used to collect data on potential confounding factors and intensive water quality monitoring was used to provide more precise indices of exposure. 548 people were randomised to bathing, and the exposure included total immersion of the head. Crude rates of gastroenteritis were significantly higher in the exposed group (14.8 per 100) than the unexposed group (9.7 per 100; p = 0.01). Linear trend and multiple logistic regression techniques were used to establish relations between gastroenteritis and microbiological water quality. Of a range of microbiological indicators assayed only faecal streptococci concentration, measured at chest depth, showed a significant dose-response relation with gastroenteritis. Adverse health effects were identified when faecal streptococci concentrations exceeded 32 per 100 mL. This relation was independent of non-water-related predictors of gastroenteritis. We do not suggest that faecal streptococci caused the excess of gastrointestinal symptoms in sea bathers but these microorganisms do seem to be a better indicator of water quality than the traditional coliform counts. Bathing water standards should be revised with these findings in mind.

Natural interleukin-2 at low dose has been reported to overcome the non-responsiveness of patients with chronic uraemia to hepatitis B vaccine. Therefore, we revaccinated 52 previous such non-responders (24 on maintenance dialysis) with 20 micrograms of recombinant preS2-containing hepatitis B vaccine with human recombinant interleukin-2 (1 MU) or placebo (randomly allocated). Seroconversion rates (74 vs 80%, respectively) and proportion of patients who elicited anti-HBs titres of 10 mlU/mL or more (56 vs 68%) were similar in both groups. Our results do not confirm local injection of interleukin-2 as an effective immunoadjuvant to hepatitis B vaccine in uraemic patients.

Endothelin-1 is an endothelium-derived vasoconstrictor peptide, possibly involved in the pathophysiology of cardiovascular disease. We examined the contribution of endogenously generated endothelin-1 to maintenance of peripheral vascular tone in healthy subjects by local intraarterial administration of an inhibitor of endothelin converting enzyme, phosphoramidon, and of a selective endothelin receptor A antagonist, BQ-123. Brachial artery infusion of local doses of proendothelin-1, the precursor to endothelin-1, caused a slow-onset dose-dependent forearm vasoconstriction which was abolished by co-infusion of phosphoramidon. Phosphoramidon did not affect responses to endothelin-1. Phosphoramidon caused slow-onset vasodilatation when infused alone, with blood flow increasing by 37% at 90 min (p = 0.03). Vasoconstriction to endothelin-1 was abolished by co-infusion of BQ-123 (p = 0.006), with forearm blood flow tending to increase. Infusion of BQ-123 alone caused progressive vasodilatation, with blood flow increasing by 64% after 60 min (p = 0.007). These results show that endogenous production of endothelin-1 contributes to the maintenance of vascular tone. Endothelin converting enzyme inhibitors and receptor antagonists may have therapeutic potential as vasodilators.

Preterm delivery is strongly associated with neonatal mortality and morbidity. In some European countries, cervical examinations are used routinely during pregnancy to identify women at risk of preterm delivery. We sought to evaluate the efficacy and secondary effects of these routine cervical examinations. We did a randomised controlled trial in seven European countries, comparing two policies--namely, an attempt to do a cervical examination at every prenatal visit (2803 women) and avoidance of cervical examination if possible (2799). The median number of cervical examinations was 6 in the experimental group and 1 in the controls. There were 6.7% preterm (< 37 weeks) deliveries in the experimental group and 6.4% in the control group (risk ratio 1.05 [95% confidence interval 0.85-1.29]; non-significant). The low birthweight rate was 6.6% in the experimental group and 7.7% in the controls (non-significant). Premature rupture of membranes was not significantly more frequent in the experimental group (27.1% vs 26.5%). Our findings do not support the routine use of cervical examinations during pregnancy.

Total parenteral nutrition is used for nutritional support in patients undergoing orthotopic liver transplantation but is associated with complications. We compared the efficacy and tolerability of early enteral feeding with total parenteral nutrition after liver transplantation. 24 patients were studied: 14 received enteral feeding and 10 total parenteral nutrition. A double-lumen enteral tube was used to deliver the feed directly into the jejunum with the second lumen of the tube being used for gastric aspiration. Enteral feeding was started post-operatively within 18 h, was well-tolerated, and of comparable efficacy to total parenteral nutrition. The median number of days for patients to start eating (4) and to achieve 70% of estimated requirements orally (5) did not differ significantly between the two groups. Mid-arm circumference, triceps skinfold thickness, and biceps skinfold thickness were, by comparison with pre-operative values, maintained on the tenth postoperative day in both groups. Early postoperative absorptive capacity, as assessed by a combined carbohydrate test, was reduced significantly in both groups but insufficiently to be of nutritional concern. Intestinal mucosal integrity, as assessed by an intestinal permeability test, was maintained throughout. We conclude that the practical aspects of enteral feeding after liver transplantation are surmountable and that enteral feeding is as effective at maintaining nutritional status as total parenteral nutrition, and has potential benefits in terms of reduced complications and costs.

Because resources for care of low-birthweight (LBW) infants in developing countries are scarce, the Kangaroo mother method (KMM) was developed. The infant is kept upright in skin-to-skin contact with the mother's breast. Previous studies reported several benefits with the KMM but interpretation of their findings is limited by small size and design weaknesses. We have done a longitudinal, randomised, controlled trial at the Isidro Ayora Maternity Hospital in Quito, Ecuador. Infants with LBW (< 2000 g) who satisfied out-of-risk criteria of tolerance of food and weight stabilisation were randomly assigned to KMM and control (standard incubator care) groups (n = 128 and 147, respectively). During 6 months of follow-up the KMM group had a significantly lower rate than the control group of serious illness (lower-respiratory-tract disorders, apnoea, aspiration, pneumonia, septicaemia, general infections; 7 [5%] vs 27 [18%], p < 0.002), although differences between the groups in less severe morbidity were not significant. There was no significant difference in growth or in the proportion of women breastfeeding, perhaps because the proportion breastfeeding was high in both groups owing to strong promotion. Mortality was the same in both groups; most deaths occurred during the stabilisation period before randomisation. KMM mothers made more unscheduled clinic visits than control mothers but their infants had fewer re-admissions and so the cost of care was lower with the KMM. Since the eligibility criteria excluded nearly 50% of LBW infants from the study, the KMM is not universally applicable to these infants. The benefits might be greater in populations where breastfeeding is not so common.

The most serious complication of childhood acute immune thrombocytopenic purpura (ITP), intracranial haemorrhage, occurs in about 1% of children with platelet counts below 20 x 10(9)/L. We conducted a randomised study to explore three treatment options in this high-risk group. 146 children (> 6 months and < 18 years old) with typical acute ITP and platelet counts of 20 x 10(9)/L or lower were randomised to receive high-dose intravenous immunoglobulin G (IVIgG) 1 g/kg on 2 consecutive days (n = 34), 0.8 g/kg once (n = 35), intravenous anti-D 25 micrograms/kg on 2 consecutive days (n = 38), or oral prednisone 4 mg/kg per day with tapering and discontinuation of prednisone by day 21 (n = 39). The rate of response as reflected by the number of days with platelet counts at 20 x 10(9)/L or lower and the time taken to achieve a platelet count 50 x 10(9)/L or more was significantly faster for both IVIgG groups than for the anti-D group (p < 0.05); the difference between prednisone and IVIgG was significant (p < 0.05) only for the IVIgG 0.8 g/kg group, and responses to the two IgG groups were similar. These differences in response rates were reflected in the percentages of children with platelet counts of 20 x 10(9)/L or lower at 72 hours following the start of treatment: 3% (IVIgG 0.8 g/kg x 1), 6% (IVIgG 1 g/kg x 2), 18% (anti-D), and 21% (oral prednisone 4 mg/kg/day). Treatment-associated toxicities included a fall in haemoglobin with anti-D (to less than 100 g/L in 24% of cases); weight gain with oral prednisone; and fever, nausea, vomiting, and headache with IVIgG. On the basis of these results, intravenous anti-D cannot be recommended as initial therapy for children with acute ITP and platelet counts of 20 x 10(9)/L or lower. A single dose of 0.8 g/kg IVIgG offers the fastest recovery for the least treatment; additional IgG or oral prednisone can be reserved for the one-third of children who continue to have platelet counts of 20 x 10(9)/L or less at 48-72 hours after the start of treatment.

Although midazolam is used for sedation of mechanically ventilated newborn babies, this treatment has not been evaluated in a randomised trial. We have done a prospective placebo-controlled study of the effects of midazolam on haemodynamic variables and sedation as judged by a five-item behaviour score. 46 newborn babies on mechanical ventilation for respiratory distress syndrome were randomly assigned to receive midazolam (n = 24) or placebo (n = 22) as a continuous infusion. Doses of midazolam were calculated to obtain plasma concentrations between 200 and 1000 ng/mL within 24 h of starting treatment and to maintain these values throughout the study. Haemodynamic and ventilatory variables were noted every hour, as were complications and possible side-effects of treatment. Mean (SD) duration of inclusion was 78.7 (30.9) h. 1 patient in the treatment group and 7 in the placebo group were withdrawn because of inadequate sedation (p < 0.05). Midazolam gave a significantly better sedative effect than placebo, as estimated by the behaviour score (p < 0.05). Heart rate and blood pressure were reduced by treatment but remained within the normal range for gestational age and there was no effect on ventilatory indices. The incidence of complications was similar in the two groups. No midazolam-related side-effects were noted. Continuous infusion of midazolam at doses adapted to gestational age induces effective sedation in newborn babies on mechanical ventilation, with positive effects on haemodynamic variables. The course of the respiratory distress syndrome was not influenced by this treatment. Midazolam was given over only a few days and the limited effects on heart rate and blood pressure that we report should not encourage long-term administration.

It has yet to be established whether substantial reduction of plasma lipids will lead to retardation, and to what extent and how quickly, of diffuse and focal coronary atheroma. The Multicentre Anti-Atheroma Study (MAAS) is a randomised double-blind clinical trial of 381 patients with coronary heart disease assigned to treatment with diet and either simvastatin 20 mg daily or placebo for 4 years. Patients on simvastatin had a 23% reduction in serum cholesterol, a 31% reduction in low-density lipoprotein cholesterol, and a 9% increase in high-density lipoprotein cholesterol compared with placebo over 4 years. Quantitative coronary angiography was done at baseline, and after 2 and 4 years. 167 patients (89%) on placebo and 178 (92%) on simvastatin had baseline and follow-up angiograms. In the placebo group there were reductions in mean lumen diameter (-0.08 mm) and in minimum lumen diameter (-0.13 mm). Treatment effects were +0.06 (95% CI 0.02 to 0.10) and +0.08 mm (0.03 to 0.14) for mean and minimum lumen diameter, respectively (combined p = 0.006). Patients on placebo had an increase in mean diameter stenosis of 3.6% and the treatment effect of simvastatin was -2.6% (-4.4 to -0.8). Treatment effects were observed regardless of diameter stenosis at baseline. On a per-patient basis, angiographic progression occurred less often in the simvastatin group, 41 versus 54 patients; and regression was more frequent, 33 versus 20 patients (combined p = 0.02). Significantly more new lesions and new total occlusions developed in the placebo group, 48 versus 28, and 18 versus 8, respectively. There was no difference in clinical outcome. The numbers of patients who died or had a myocardial infarction were 16 and 14 in the placebo and simvastatin groups, respectively. In the placebo group more patients underwent coronary angioplasty or re-vascularisation, 34 versus 23 on simvastatin. The trial showed that 20 mg simvastatin daily over 4 years reduces hyperlipidaemia and slows progression of diffuse and focal coronary atherosclerosis.

Biliary stents are liable to clog. We investigated whether a choleretic plus an antibiotic could delay clogging. 20 consecutive patients with a malignant biliary stricture were randomised after endoscopic insertion of a polyethylene stent to receive ursodeoxycholic acid plus norfloxacin (13-15 mg/kg and 400 mg, daily) or conservative treatment. The drug combination was associated with: a longer median patency of first (49 vs 6 weeks) and all stents (38 vs 7 weeks); a prolonged median survival (67 vs 18 weeks); and a shorter mean hospital stay (0.2 vs 1.0 days per week of survival). Thus ursodeoxycholic acid plus norfloxacin may prevent stent clogging.

In retrospective studies, perioperative blood transfusions were associated with poor prognosis after surgery for cancer and were a major independent risk factor for postoperative bacterial infection. Leucocyte-depleted, in contrast to buffy-coat-depleted, blood has no immunosuppressive effects in transplantation and so might lack detrimental effects on cancer prognosis and postoperative infections. We studied this hypothesis in a controlled trial by randomly allocating patients to receive either leucocyte-depleted red cells or packed cells without buffy coat when blood was needed. Between 1987 and 1990, 871 eligible patients with colorectal cancer, including 697 patients operated upon with curative intent, were randomised in the 16 participating hospitals. Neither the eligible group nor the curative group showed significant differences between the two trial transfusions in survival, disease-free survival, cancer recurrence rates, or overall infection rates after an average follow-up of 36 months. Patients who had a curative resection and who received blood of any sort had a lower 3-year survival than non-transfused patients (69% vs 81%, p = 0.001) and a higher infection rate (39% vs 24%, p < 0.001). Colorectal cancer recurrence rates, however, were not influenced by blood transfusion (30% vs 26%, p = 0.22). These combined observations confirm the association between blood transfusion and poor patient survival but indicate that the relation is not due to promotion of cancer.