Ageing is associated with impaired immune responses and increased infection-related morbidity. This study assessed the effect of physiological amounts of vitamins and trace elements on immunocompetence and occurrence of infection-related illness. 96 independently living, healthy elderly individuals were randomly assigned to receive nutrient supplementation or placebo. Nutrient status and immunological variables were assessed at baseline and at 12 months, and the frequency of illness due to infection was ascertained. Subjects in the supplement group had higher numbers of certain T-cell subsets and natural killer cells, enhanced proliferation response to mitogen, increased interleukin-2 production, and higher antibody response and natural killer cell activity. These subjects were less likely than those in the placebo group to have illness due to infections (mean [SD] 23 [5] vs 48 [7] days per year, p = 0.002). Supplementation with a modest physiological amount of micronutrients improves immunity and decreases the risk of infection in old age.

Laparoscopic cholecystectomy (LC) has gained wide acceptance for treatment of cholelithiasis in preference to open cholecystectomy, though it has not been formally compared with mini cholecystectomy (MC). We have compared these two techniques in a randomised trial. 70 patients with ultrasound-proven cholelithiasis were randomly allocated LC (38) or MC (32); 37 and 25, respectively, underwent the assigned procedure. The mean hospital stay (including 1 preoperative day) was significantly shorter in the LC than the MC group (median 3 [interquartile range 2-3] vs 4 [3-5], p = 0.001) as was duration of convalescence (mean 11.9 [SD 9.1] vs 20.2 [16.5] days, p = 0.04). The rate of return to normal activities was 1.77 times greater in the LC group than in the MC group (95% confidence interval 1.01-3.11, p = 0.03). In regression analysis, the type of cholecystectomy done was the only variable significantly associated with the duration of convalescence. Although there was significant postoperative improvement in all of three quality of life scores in both groups, LC patients improved more quickly than did MC patients. This randomised trial shows the superior effectiveness of LC over MC in treating cholelithiasis.

To determine the most effective infection control procedure in preventing nosocomial infection with respiratory syncytial virus (RSV), we did a prospective controlled study of four infection-control strategies in four wards in a large paediatric hospital in the west of Scotland. All children under two years old admitted to four general wards during three winter RSV epidemics (1989-92) were screened for RSV infection (by nasopharyngeal aspirate and direct immunofluorescence) within 18 hours of admission. The main outcome measure was the occurrence of nosocomial infection, defined as the number of children initially RSV negative who became RSV positive 7 days or more after hospital admission (incubation period for RSV infection is 5-8 days). Without special precautions, there was a high rate of nosocomial RSV infection (26%). Nosocomial infection was significantly reduced by the combination of cohort nursing with the wearing of gowns and gloves for all contacts of RSV-infected children (p = 0.0022). Neither the use of gowns and gloves alone nor cohort nursing alone produced a significant reduction in cross-infection. In the final year, general clinical use of a policy of cohort nursing with gowns and gloves resulted in a reduction in the cross-infection rate by two-thirds of its original value (9.5% vs 26%). Combined with rapid laboratory diagnosis, cohort nursing and the wearing of gowns and gloves for all contacts with RSV-infected children can significantly reduce the risk of nosocomial RSV infection.

Peptic ulcer bleeding often stops spontaneously but rebleeding may be catastrophic. Emergency surgery carries risks so safe medical therapies are needed. Since platelet function and plasma coagulation are both pH sensitive and since pepsin lyses clot at low pH the maintenance of gastric pH close to neutrality might influence rebleeding rates. Previous trials with H2 antagonists have been inadequate although a 1985 meta-analysis did support an important clinical effect. We report here a large multicentre trial of famotidine in ulcer bleeding. 1005 patients admitted to one of sixty-seven hospitals in the UK or Eire with haemorrhage from peptic ulcer with endoscopic signs of oozing, black slough, fresh clot or visible vessel were randomly allocated to famotidine (10 mg bolus followed by 3.2 mg/h intravenously) or matching placebo for 72 h. This famotidine regimen had previously been shown to maintain pH near 7 in such patients. 497 patients received famotidine and 508 placebo. The treatment groups were similar in respect of age, sex, ulcer site, and signs and severity of bleeding. Case fatality (6.2% famotidine vs 5.0% placebo), rebleeding (23.9% vs 25.5% placebo), and surgery (15.5% vs 17.1% placebo) rates were not significantly different between the two groups. This trial suggests that potent inhibition of gastric secretion does not influence the natural history of peptic ulcer haemorrhage.

Osteolytic lesions and pathological fractures are common in multiple myeloma. Because clodronate inhibits osteoclastic resorption, we did a randomised, controlled trial in 350 patients from 23 hospitals. All patients received standard melphalan-prednisolone, and were randomised to receive clodronate 2.4 g daily or placebo for 24 months. The proportion of patients with progression of osteolytic bone lesions was twice as high in the placebo group (n = 168 at baseline) than in the clodronate group (n = 168 at baseline) in an intention-to-treat analysis (24 vs 12%, p = 0.026). Progression of vertebral fractures was lower in the clodronate group, but the difference was not significant (30 vs 40%). Serum calcium and urinary calcium excretion decreased significantly in both groups, but the changes were greater in the clodronate group. The percentage of patients feeling no pain increased more in the clodronate group (from 24 to 54%, p < 0.001) than in the placebo group (from 29 to 44%, p < 0.01). Side-effects were similar in both groups. We conclude that clodronate is an effective and safe adjunct in the management of multiple myeloma. The drug delays osteolytic bone lesions, reduces the degree of hypercalcaemia and hypercalciuria, and decreases pain.

Insulin-dependent diabetic patients found to have substantial coronary artery disease at the time of assessment for renal transplantation have 2-year survival of less than 50%. Because most of these patients have no angina symptoms their management is controversial. We tried to find out whether coronary artery revascularisation in such patients might decrease the combined incidence of unstable angina, myocardial infarction, and cardiac death. 151 consecutive insulin-dependent diabetic candidates for renal transplantation underwent coronary angiography. 31 had stenoses greater than 75% in one or more coronary arteries, atypical chest pain or no chest pain, and a left ventricular ejection fraction greater than 0.35. Of these, 26 agreed to be randomly assigned medical treatment (a calcium-channel-blocking drug plus aspirin) or revascularisation (angioplasty or coronary bypass surgery). 10 of 13 medically managed and 2 of 13 revascularised patients had a cardiovascular endpoint within a median of 8.4 months of coronary angiography (p < 0.01). 4 medically managed patients died of myocardial infarction during follow-up. Thus, revascularisation decreased the frequency of cardiac events in insulin-dependent diabetic patients with chronic renal failure and symptomless coronary artery stenoses. These findings suggest that diabetic renal transplant candidates should be screened for silent coronary artery disease, because revascularisation may decrease cardiac morbidity and mortality in this population.

There is no consensus amongst physicians about the need for analgesia when a woman undergoes ablative therapy of the cervix. Many doctors believe that the discomfort felt during such procedures is insubstantial. By means of a randomised double-blind placebo-controlled trial, we have shown that patients experience considerable pain during cold-coagulation treatment of the cervix. We found that intracervical lignocaine leads to a significant (p < 0.01) reduction in this pain.

Intrauterine growth retardation is associated with an increased risk of fetal asphyxia as well as greater perinatal morbidity and mortality. Ultrasound fetometry enables detection of fetuses that are small for gestational age. Doppler velocimetry of the umbilical artery has good predictive ability for fetal distress, but it is not yet clear whether it could replace cardiotocography in antenatal surveillance of small-for-gestational-age fetuses. We have done a randomised comparison of the two methods. At four obstetric departments in Sweden, women with fetuses found to be small on ultrasound examination at 31 completed weeks of pregnancy or later were randomly assigned to antenatal surveillance with either doppler velocimetry (doppler; 214) or cardiotocography (CTG; 212). Pregnancies in the doppler group were managed according to a protocol based on blood-flow classes deriving from the semiquantitative evaluation of umbilical-artery velocity waveforms; unless the pregnancy was complicated by any other disorder, no antenatal cardiotocography was done. By comparison with the CTG group, the doppler group had fewer monitoring occasions (mean 4.1 [SD 3.1] vs 8.2 [6.2], p < 0.01), antenatal hospital admissions (68 [31.3%] vs 97 [45.8%], p < 0.01), inductions of labour (22 [10.3%] vs 46 [21.7%], p < 0.01), emergency caesarean sections for fetal distress (11 [5.1] vs 30 [14.2%], p < 0.01), and admissions to neonatal intensive care (76 [35.5%] vs 92 [43.4%], p = 0.10). The groups did not differ in gestational age at birth, birthweight, Apgar scores, or total number of caesarean deliveries. Umbilical-artery doppler velocimetry of small-for-gestational-age fetuses allows antenatal monitoring and obstetric interventions to be aimed more precisely than does cardiotocography.

Health screening for old people who live at home has been the subject of debate for 30 years or so. It has come to the fore again in the UK with the new emphasis on annual assessments by general practitioners (GPs) of those aged 75 or more. Screening in the elderly has implications for manpower. How can it best be done? We describe here a randomised, controlled study of case finding and surveillance in patients aged 65 and over in a general practice in South Wales. Problem identification was by a postal questionnaire, focusing on function, that was sent at random to 369 eligible patients with subsequent verification and intervention by a specially appointed nurse. The 356 controls had no questionnaires and no contact with that nurse. The study lasted 3 years, and end-points included mortality, self-ratings of quality of life, and health status, and use of all services (GP contacts, hospital admission, home help, and so on). Mortality was significantly lower in the intervention group (18%) than in the controls (24%) (difference 6.0% [95% CI 0.1-11.9%], p less than 0.05). Total number of hospital admissions did not differ between intervention and control groups, but duration of hospital stay of patients aged 65 to 74 years was significantly shorter in the intervention group (difference 4.6 days [95% CI 1.6-7.6], p less than 0.01). An increase in visits to a GP was largely offset by a lower number of home visits by a GP. Quality-of-life measures revealed no between-group differences, but self-rated health status was superior in the intervention group. We conclude that the use of a postal screening questionnaire with selective follow-up and intervention can favourably influence outcome and use of health care resources by elderly people living at home.

The optimum duration of anticoagulation therapy for deep-vein thrombosis (DVT) and pulmonary embolism (PE) is not clear. We have carried out a multicentre comparison of 4 weeks' and 3 months' anticoagulation in patients admitted to hospital with acute DVT, PE, or both. Of 712 patients enrolled, 358 were assigned 4 weeks' treatment and 354 3 months'. Objective confirmation of the diagnosis was obtained in 71%. PE caused or contributed to death in 7 patients (3 treated for 4 weeks, 4 for 3 months). Adverse effects were uncommon, although 1 patient (4-week group) died of haemorrhage. The numbers of patients whose thromboembolism failed to resolve on treatment was lower in the 3-month group than in the 4-week group (13 [3.7%] vs 24 [6.7%], p = 0.10) as was the number who had recurrences (14 [4.0%] vs 28 [7.8%], p = 0.04). Among patients with postoperative DVT or PE the rate of treatment failure and recurrence was low (2.6%) and there was little difference between the treatment groups. By contrast, among medical patients the rate was 12.8%, with a clear difference in favour of 3 months' treatment. If venous thromboembolism arises after surgery, 4 weeks of anticoagulation should be adequate. In other settings, patients with new DVT, PE, or both, who do not have a persisting underlying cause or risk factor should receive anticoagulants for 3 months.

If intravenous access is not available during cardiopulmonary resuscitation, tracheal administration of adrenaline 0.02 mg/kg, twice the intravenous dose, is recommended. In a randomised crossover study we investigated the haemodynamic effects of low doses of tracheal versus intravenous adrenaline. 12 anaesthetised patients having a hip replaced received one dose of adrenaline intravenously (0.1 microgram/kg) and the other tracheally (0.5 microgram/kg). There was a mean increase in systolic arterial pressure of 40.5 mm Hg (range 16-81) after the intravenous injection, with little effect on heart rate. Tracheal adrenaline had no effect on arterial pressure or heart rate. Thus low doses of tracheal adrenaline have no haemodynamic effects. We believe that the recommended tracheal dose of twice the intravenous dose is likely to be ineffective for the treatment of cardiac arrest. Animal studies suggest that a tracheal dose at least ten times the intravenous dose is required.

Inpatient extracorporeal shockwave lithotripsy for treatment of gallbladder stones has not previously been compared with open cholecystectomy in terms of cost-effectiveness. In a randomised controlled trial, 163 patients, stratified by gallstone bulk (over 4 cm3 or not), were randomised to lithotripsy or cholecystectomy (38 large-bulk and 27 small-bulk cholecystectomy; 37 large-bulk and 61 small-bulk lithotripsy) and followed up for 1 year. Both treatments gave significant health gains in terms of a reduction in episodes of biliary pain, improved perceived health status, and symptom relief, but few differences between treatments were found. There was some evidence that biliary-pain episodes were less severe after cholecystectomy. Cholecystectomy patients also had greater improvements in mean health gain for three related symptoms: vomiting, feeling sick, and fatty-food upset. However, there were no differences between groups in perceived health status. Among lithotripsy patients, health gain was not related to stone clearance. Lithotripsy was more expensive than cholecystectomy, principally because of the costs of the inpatient stay and adjuvant bile-salt therapy. Conventional lithotripsy appears at least as cost-effective as cholecystectomy for patients with small-bulk stones but less cost-effective for those with large-bulk stones. To some extent treatment choice can be guided by patient preference.

Many studies have attempted to find out whether steroid treatment is beneficial in children with croup, but the results have been inconclusive. We have done a prospective placebo-controlled study of the effect of prednisolone on two clinical endpoints--the duration of intubation and the need for reintubation. Reasons for exclusion were age under 6 months, congenital airway anomalies, and previous intubation. 70 eligible children were randomly assigned treatment with prednisolone 1 mg/kg (n = 38) or placebo (n = 32) every 12 h given by nasogastric tube until 24 h after extubation. 11 (34%) placebo-treated and only 2 (5%) prednisolone-treated patients required reintubation after accidental or elective extubation (p = 0.004, Fisher's exact test; odds ratio 8.9, 95% confidence interval 1.7-59.3). Survival analysis with log-normal regression showed that the duration of intubation was shorter with steroid therapy (p less than 0.003) and increasing age (p less than 0.02), but was not influenced by endotracheal tube size or abnormality on chest radiograph. The median duration of intubation was 138 (95% CI 118-160) h in children who received placebo and 98 (85-113) h in the prednisolone group. Steroid therapy reduces the duration of intubation and the need for reintubation in children intubated for croup.

Pulse cyclophosphamide is more effective than prednisone alone in preventing renal failure in lupus nephritis. We undertook a randomised, controlled trial to find out whether pulse methylprednisolone could equal pulse cyclophosphamide in preserving renal function in patients with lupus nephritis, and whether there was a difference between long and short courses of pulse cyclophosphamide in preventing exacerbations. 65 patients (60 female, 5 male; median [range] age 29 [10-48] years) with severe lupus nephritis were assigned randomly to monthly pulse methylprednisolone for 6 months (25 patients), monthly pulse cyclophosphamide for 6 months (20), or monthly cyclophosphamide for 6 months followed by quarterly pulse cyclophosphamide for 2 additional years (20). Patients treated with pulse methylprednisolone had a higher probability of doubling serum creatinine than those treated with long-course cyclophosphamide (p less than 0.04). Risk of doubling creatinine was not significantly different between short and long course cyclophosphamide. However, patients treated with short-course cyclophosphamide had a higher probability of exacerbations than those treated with long-course cyclophosphamide (p less than 0.01). An extended course of pulse cyclophosphamide is more effective than 6 months of pulse methylprednisolone in preserving renal function in patients with severe lupus nephritis. Addition of a quarterly maintenance regimen to monthly pulse cyclophosphamide reduces the rate of exacerbations.

Oral vaccines offer great promise as public-health measures to prevent disease in less-developed countries. CVD 103-HgR, a genetically engineered, attenuated, Vibrio cholerae O1 strain has proved effective in industrialised countries. We have assessed the safety, immunogenicity, and excretion of this live cholera vaccine in children in north Jakarta, Indonesia. 412 children aged 5-9 years received single doses of 5 x 10(6), 5 x 10(7), 5 x 10(8), 5 x 10(9), or 1 x 10(10) colony forming units (CFU) of CVD 103-HgR or placebo (5 x 10(8) inactivated Escherichia coli K-12) with buffer. All doses were well tolerated. The 5 x 10(8) CFU dose, which is highly immunogenic in subjects in industrialised countries (greater than 90% seroconversion), elicited seroconversions of vibriocidal antibody in only 16% of Indonesian children. By contrast, a single 5 x 10(9) CFU dose of vaccine resulted in high rates (75% and 87%) of seroconversion with two different batches of vaccine. A batch prepared with a centrifugation step gave significantly higher geometric mean titres (16-fold increase over baseline) than did a batch in which there was a filtration step between fermentation and lyophilisation (10-fold increase over baseline). At a 5 x 10(9) CFU dose, CVD 103-HgR is well tolerated and highly immunogenic in Indonesian children and should therefore be further investigated for use as a one-dose live oral cholera vaccine in developing countries.