The cholera epidemic in South America has reinforced the need for safe and effective oral vaccines. In a randomised, double-blind, placebo-controlled efficacy trial among 1563 Peruvian military recruits we have investigated the protective efficacy of an oral inactivated whole-cell/recombinant-B-subunit (WC/rBS) cholera vaccine. Participants were given two oral doses of cholera vaccine or Escherichia coli K12 placebo, with an interval of 7-14 days. 1426 (91%) subjects received the two prescribed doses and were followed up for a mean of 18 weeks (median 21 weeks). After vaccination, Vibrio cholerae O1 El Tor Ogawa was isolated from 17 subjects with diarrhoea. 16 of the cholera cases occurred 2 weeks or longer after the second dose of vaccine (14 placebo recipients, 2 vaccinees). We also detected 14 symptomless infections (11 [7 placebo recipients, 4 vaccinees]) 2 weeks or longer after the second dose. The vaccine had significant protective efficacy against cholera (86% [95% CI 37-97], p < 0.01) but not against symptomless infection (42% [-96 to 85]). All cholera cases were in people of blood group O, who made up 76% of the study population (p < 0.01). Two doses of WC/rBS vaccine, given 1 to 2 weeks apart, provide rapid, short-term protection against symptomatic cholera in adult South Americans, who are predominantly of blood group O. Long-term efficacy studies in Peruvian adults and children are under way.

Very few patients with liver metastases from colorectal cancer can be cured. We have investigated whether a treatment to slow the growth of liver metastases, hepatic-artery infusion of floxuridine, improves palliation in this setting. In a randomised study of 100 patients, we compared quality of life and survival in patients who received hepatic-artery infusion of floxuridine and in those who received conventional symptom palliation. 95% of control patient survival time was spent with normal quality-of-life scores, which suggests that the aim of treatment should be to prolong normal-quality survival rather than merely to sustain quality of life. There was a significant prolongation (p = 0.03) in overall survival in floxuridine-treated patients compared with controls (median 405 vs 226 days). There were similar significant prolongations in normal-quality (ie, normal symptom scores) survival for physical symptoms (p = 0.04), anxiety (p = 0.04), and depression (p = 0.04). This survival benefit was associated with significant reductions in metastasis size on computed tomography (p = 0.001) and in serum carcinoembryonic antigen concentration (p = 0.006) in floxuridine-treated patients. There was no evidence of treatment-related hepatotoxicity as assessed by serum aspartate aminotransferase and bilirubin measurements. This is the first demonstration that survival can be prolonged with normal quality of life in patients with colorectal liver metastases. We conclude that hepatic-artery floxuridine infusion can be recommended for suitable patients.

Lipid-lowering therapy ameliorates coronary atherosclerosis in patients with raised concentrations of low-density-lipoprotein (LDL) cholesterol. We have investigated whether a similar benefit can be obtained in normocholesterolaemic patients. We studied 79 normocholesterolaemic patients with coronary heart disease (70 male, 9 female), mean age 58 years, all non-smokers, with mean total cholesterol concentration 5.5 mmol/L. All patients received diet therapy and were randomly assigned placebo (39) or active treatment (40) with pravastatin, nicotinic acid, cholestyramine, and gemfibrozil stepwise as needed to reach the specified goal (total cholesterol < or = 4.1 mmol/L, ratio of LDL/high-density-lipoprotein [HDL] cholesterol < or = 2.0). Coronary angiograms at baseline and after 2.5 years of treatment were analysed by computer-assisted quantitative techniques. There was no significant difference in coronary atherosclerosis during follow-up between the active treatment and placebo groups; the mean minimum diameter narrowed significantly but to the same extent in both groups (change baseline to 2.5 years 0.14 [SD 0.42] and 0.15 [0.42] mm, respectively, both p < 0.001). Similarly, the change in percentage stenosis did not differ between the groups (2.1 [10.6] vs 2.4 [10.3]%). By multiple regression analysis, the adjusted difference between the groups was a 0.04 mm (95% CI -0.04 to 0.12 mm) increase in minimum diameter and a 0% (-1.7 to 1.7) change in percentage stenosis. The groups differed significantly in plasma lipids (% change in active minus % change in placebo group: -28% total cholesterol, -41% LDL-cholesterol, 13% HDL-cholesterol, -26% triglycerides, -31% apolipoprotein B, all p < 0.001). Thus, intensive pharmacological treatment of normocholesterolaemic patients has significant effects on plasma lipid concentrations but no angiographically measurable benefit on the coronary arteries.

Effective, safe antimalarial vaccines have proved elusive. The synthetic polypeptide SPf66 vaccine is based on preerythrocytic and asexual blood-stage proteins of Plasmodium falciparum. We report here a randomised double-blind placebo-controlled trial of the efficacy of the SPf66 vaccine against clinical P falciparum malaria in idete, southern Tanzania, an area of intense perennial malaria transmission. 586 children aged 1-5 years received three doses of vaccine (n = 274) or placebo (n = 312). The incidence and density of parasitaemia were assessed through repeated cross-sectional surveys on subgroups of children. Morbidity was monitored over a 1 year period through passive case detection in all children plus active case detection in a subgroup of 191. An episode of clinical malaria was defined as measured fever (> or = 37.5 degrees C) and parasite density > 20,000/microL. No severe side-effects were seen and the frequency of mild side-effects after the third dose was less than 6%. The vaccine was highly immunogenic and after three doses all vaccine recipients had detectable anti-SPf66 antibodies: the geometric mean index of response was 8.3 in the vaccine group and 0.7 in the placebo group. The incidence of parasitaemia was similar in both groups. 123 children had at least one episode of clinical malaria during the follow-up period after the third dose and annual incidence rates were 0.25 in the vaccine group and 0.35 in the placebo group. Estimated vaccine efficacy was 31% (95% confidence interval 0-52%; p = 0.046). After the third dose there were 6 deaths among the study cohort (1 vaccine, 5 placebo). This study confirms that SPf66 is safe, immunogenic and reduces the risk of clinical malaria among children exposed to intense P falciparum transmission.

Tumour necrosis factor alpha (TNF alpha) is a critical inflammatory mediator in rheumatoid arthritis, and may therefore be a useful target for specific immunotherapy. In support of this hypothesis, we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a chimeric monoclonal antibody to TNF alpha (cA2). We now report the results of a four-centre, randomised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis. The primary endpoint of the study was the achievement at week 4 of a Paulus 20% response, an amalgam of six clinical, observational, and laboratory variables. Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time, compared with 11 of 25 patients treated with low-dose cA2 (p = 0.0083) and 19 of 24 patients treated with high-dose cA2 (p < 0.0001). Over half of the high-dose cA2 patients responded by the more stringent 50% Paulus criteria at this time (p = 0.0005). The magnitude of these responses was impressive, with maximum mean improvements in individual disease-activity assessments, such as tender or swollen-joint counts and in serum C-reactive protein, exceeding 60% for patients on high-dose treatment. There were two severe adverse events. 1 patient on 1 mg/kg cA2 developed pneumonia ("possibly" treatment-related) and 1 on 10 mg/kg had a fracture ("probably not" treatment-related). The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis.

Acute diarrhoea is a serious cause of infant morbidity and mortality, and the development of preventive measures remains an important goal. Bifidobacteria (which constitute the predominant intestinal flora of breastfed infants), as well as other lactic-acid-producing organisms such as Streptococcus thermophilus, are thought to have a protective effect against acute diarrhoeal disease. However, their efficacy has not been assessed in controlled trials. In a double-blind, placebo-controlled trial, infants aged 5-24 months who were admitted to a chronic medical care hospital were randomised to receive a standard infant formula or the same formula supplemented with Bifidobacterium bifidum and S thermophilus. Patients were evaluated daily for occurrence of diarrhoea, and faecal samples, obtained weekly, were analysed for rotavirus antigen by enzyme immunoassay. Faecal samples were also obtained during an episode of diarrhoea for virological and bacteriological analyses. 55 subjects were evaluated for a total of 4447 patient-days during 17 months. 8 (31%) of the 26 patients who received the control formula and 2 (7%) of 29 who received the supplemented formula developed diarrhoea during the course of the study (p = 0.035, Fisher's exact test, two-tailed). 10 (39%) of the subjects who received the control formula and 3 (10%) of those who received the supplemented formula shed rotavirus at some time during the study (p = 0.025). The supplementation of infant formula with B bifidum and S thermophilus can reduce the incidence of acute diarrhoea and rotavirus shedding in infants admitted to hospital.

We studied the involvement of naturally occurring odours in guiding the baby to the nipple. One breast of each participating mother was washed immediately after delivery. The newborn infant was placed prone between the breasts. Of 30 infants, 22 spontaneously selected the unwashed breast. The washing procedure had no effect on breast temperature. We concluded that the infants responded to olfactory differences between the washed and unwashed breasts.

3-5% of patients taking the 5HT1D agonist sumatriptan for migraine have chest discomfort, suggesting a cardiac origin. We have investigated an alternative explanation of an oesophageal cause in 24 volunteers after the subcutaneous administration of a supratherapeutic dose of sumatriptan (16 mg) or placebo in a randomised, double-blind crossover study. Sumatriptan did not alter the electrocardiogram but increased the amplitude (p < 0.001) and duration (p < 0.001) of oesophageal contractions without affecting velocity of propagation. Clinically abnormal motility was also increased (p = 0.001), and was more common in the 5 subjects with chest pain after sumatriptan. The effect of sumatriptan on oesophageal function provides an alternative explanation for the chest symptoms.

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.