Twelve patients admitted for elective resection of carcinoma of colon or rectum were allocated at random to experimental and control groups (six in each) and received a total parenteral nutrition regimen providing 230 mg N/kg and 166 KJ/kg daily over the first 5 postoperative days. In the experimental group the parenteral fluid was supplemented with a synthetic glutamine-containing dipeptide, L-alanyl-L-glutamine (54 mg peptide-N/kg per day) and the control group received corresponding amounts of alanine-N and glycine-N. On each postoperative day nitrogen balance was better in the experimental group; mean daily nitrogen balance with alanyl-glutamine was -1.5 (SE 0.4) g N/day and with the control solution -3.6 (0.2) g N/day. The cumulative nitrogen balances on the fifth postoperative day were -7.1 (2.2) and -18.1 (1.7) g N, respectively. With the peptide-containing solution intramuscular glutamine concentration remained close to the preoperative value whereas with the control solution it decreased from 19.7 (SE 0.9) to 12.0 (0.6) mmol/l intracellular water.

From November, 1985, to June, 1988, 1007 outpatients with chronic non-rheumatic atrial fibrillation (AF) entered a randomised trial; 335 received anticoagulation with warfarin openly, and in a double-blind study 336 received aspirin 75 mg once daily and 336 placebo. Each patient was followed up for 2 years or until termination of the trial. The primary endpoint was a thromboembolic complication (stroke, transient cerebral ischaemic attack, or embolic complications to the viscera and extremities). The secondary endpoint was death. The incidence of thromboembolic complications and vascular mortality were significantly lower in the warfarin group than in the aspirin and placebo groups, which did not differ significantly. 5 patients on warfarin had thromboembolic complications compared with 20 patients on aspirin and 21 on placebo. 21 patients on warfarin were withdrawn because of non-fatal bleeding complications compared with 2 on aspirin and none on placebo. Thus, anticoagulation therapy with warfarin can be recommended to prevent thromboembolic complications in patients with chronic non-rheumatic AF.

The frequency of new primary cancers was studied in 1846 postmenopausal patients included in a randomised trial of tamoxifen as an adjunct to primary surgery for early breast cancer. The median follow-up was 4.5 years (range 0.5-10.5 years). The number of new cancers in the tamoxifen group (n = 57) did not differ significantly from that in the control group (n = 70). However, in tamoxifen patients second breast cancers occurred less often and endometrial cancer occurred more often than in the controls. The increase in endometrial cancers was probably related to the agonistic oestrogenic effects of tamoxifen and was most pronounced in those treated for over 2 years.

A transdermal nicotine patch, which delivers 0.7 mg/cm2 per 24 h and is available in sizes of 10, 20, and 30 cm2 was tested in subjects from 21 general medical practices in a 3-month, placebo-controlled randomised double-blind study. The nicotine group (n = 100) and the placebo group (n = 99) were similar at entry. Participants who smoked more than 20 cigarettes a day were treated with the 30 cm2 patch and the others with the 20 cm2 patch. When abstinence, defined as smoking 0-3 cigarettes per week and verified by CO measurement, was achieved, the next smallest patch was applied. After 1, 2, and 3 months of treatment 41, 36, and 36%, respectively, in the nicotine group were abstinent. The corresponding figures in the placebo group were 19, 20, and 23%. The differences were significant for all 3 months. Body weight did not increase in the nicotine group, but in the placebo group the mean increase was 4.4 kg. Craving and withdrawal symptoms decreased more with nicotine substitution for cigarettes. The patches were generally well tolerated, although 25% of subjects in the nicotine group and 13% in the placebo group had transient local erythema after application of the patch; 5 members of the nicotine group withdrew because of poor cutaneous tolerance.

2787 women who were aged 35 years or more at expected date of delivery were randomised to chorionic villus sampling (CVS) at 9-12 weeks gestation or amniocentesis at 15-17 weeks for the detection of a chromosomal abnormality in the fetus. 396 women were excluded after randomisation because of a non-viable fetus, a multiple pregnancy, or infection or because the pregnancy was too far advanced (more than 12 completed weeks). Among all women eligible at the time of the first study procedure there were 89/1169 (7.6%, 95% confidence interval [CI] 6.2-9.3%) total losses (spontaneous and induced abortions and late losses) in the CVS group and 82/1174 (7.0%, CI 5.6-8.6%) in the amniocentesis group for an excess of 0.6% for those women undergoing CVS, with a tendency to later losses in the CVS group. Approximate 95% CIs indicate that this difference is most unlikely to be greater than 2.7%. Mean birthweights for each week of gestation were similar in both groups, with no evidence of excess small-for-gestational age babies in the CVS group. The proportion of preterm births were similar in both groups. Perinatal mortality was greater in the CVS group, the greatest imbalance being beyond 28 weeks. Preliminary analysis has not disclosed an obvious recurrent event in the CVS group which might explain a cause-and-effect relationship for these late fetal losses. There is no evidence of any excess intrauterine growth retardation babies in the CVS group. Maternal morbidity was similar in both groups. 103/1037 (9.9%) women eligible for CVS had a further amniocentesis; 32 of these second procedures were needed to complete the cytogenetic diagnosis. More problems such as confined mosaicism and maternal cell contamination occurred in the interpretation of the CVS samples, but these were clarified by amniocentesis when appropriate.

105 patients who had chronic low back pain without clinical signs of lumbar nerve root compression or radiological evidence of spondylolysis or osteomalacia were randomised to three treatments: 30 sessions of intensive dynamic back extensor exercises over three months; a similar programme at one-fifth the exercise intensity; or one month of thermotherapy, massage, and mild exercises. The results consistently favoured intensive exercise, which had no adverse effects. Since these exercises can be conducted in groups, the intensive programme is no more costly than conventional strategies that require individual attention.

100 consecutive patients with both duodenal ulcer and Campylobacter pylori infection were followed up to see whether eradication of C pylori affected ulcer healing or relapse. Patients were randomly assigned to 8 weeks of treatment with cimetidine or colloidal bismuth subcitrate (CBS), with tinidazole or placebo being given concurrently from days 1 to 10, inclusive. Endoscopy, biopsy, and culture were done at entry, in weeks 10, 22, 34, and 62, and whenever symptoms recurred. There was no maintenance therapy. C pylori persisted in all of the cimetidine-treated patients and in 95% of those treated with cimetidine/tinidazole, but was eradicated in 27% of the CBS/placebo group and 70% of the CBS/tinidazole group. When C pylori persisted, 61% of duodenal ulcers healed and 84% relapsed. When C pylori was cleared 92% of ulcers healed (p less than 0.001) and only 21% relapsed during the 12 month follow-up period (p less than 0.0001).

In a double blind, crossover study 6 h infusions of adrenaline (15 ng/kg/min; 1 ng = 5.458 pmol), noradrenaline (30 ng/kg/min; 1 ng = 5.911 pmol), and a 5% dextrose solution (5.4 ml/h), were given to ten healthy volunteers in random order 2 weeks apart. By means of intra-arterial ambulatory monitoring the haemodynamic effects were followed for 18 h after the infusions were stopped. Adrenaline, but not noradrenaline, caused a delayed and protracted pressor effect. Over the total postinfusion period systolic and diastolic arterial pressure were 6 (SEM 2)% and 7 (2)%, respectively, higher than after dextrose infusion (ANOVA, p less than 0.001). Thus, "stress" levels of adrenaline (230 pg/ml) for 6 h cause a delayed and protracted pressor effect. These findings are strong support for the adrenaline-hypertension hypothesis in man.

The efficacy, safety, and tolerability of simvastatin (20 mg twice a day) in the treatment of hyperlipidaemia due to unremitting nephrotic syndrome was compared with that of cholestyramine (8 g twice a day) in a crossover trial in ten patients. Two patients were taken off the protocol, one because he could not tolerate cholestyramine and one because of non-compliance with the cholestyramine regimen. No clinical or laboratory adverse experiences were noticed during the study in the other eight patients. Simvastatin was significantly more effective than cholestyramine in reducing the hyperlipidaemia--it produced a 36% decrease in total cholesterol and a 39% decrease in low density (LDL)-cholesterol, whereas cholestyramine reduced total cholesterol by 8% and LDL-cholesterol by 19%. With simvastatin the apolipoprotein B level decreased by 30%, whereas the apolipoprotein A level increased by 10%.

In laboratory animals, non-steroidal anti-inflammatory drugs (NSAIDs) are reported to inhibit diet-induced gallstone formation. To see if these drugs had a similar effect in man, 82 patients who had taken part in a comparison of ursodeoxycholic acid, placebo, and diet for prevention of gallstone recurrence were sent questionnaires about their use of NSAIDs during the period of the trial. 75 replied. After a mean follow-up of 33 (SEM 4) months none of the 12 regular users of NSAIDs had had gallstone recurrences, compared with 20 of the 63 who never or rarely used these drugs (p less than 0.02).

Treatment with tamoxifen (TM), alone or in combination with cyclophosphamide, methotrexate, and fluorouracil (CMF), was used as an adjuvant to surgery in 433 patients with stage I, II, or III(T3a) breast cancer. Oestrogen receptors (ER) and progesterone (PgR) receptors were assayed in most cases. 308 premenopausal node-negative and postmenopausal node-negative or node-positive patients were randomised to receive TM, 30 mg daily for 2 years, or no further therapy. 125 premenopausal node-positive patients were randomised to receive either CMF for nine courses plus TM or CMF alone. After a median follow-up of 63 months TM significantly reduced the incidence of relapses and deaths compared with no therapy. A significant interaction between treatment effect and ER/PgR status was seen. Disease-free and overall survival were similar after treatment with CMF+ TM or CMF.

The effect of cimetidine on survival was investigated in 181 patients with gastric cancer. Immediately after operation or the decision not to operate, the patients were randomised in double-blind fashion to placebo or cimetidine 400 mg twice daily for two years or until death, with review every three months. Median survival in the cimetidine group was 450 days (range 1-1826) and in the placebo group 316 days (1-1653). The relative survival rates (cimetidine/placebo) were 45%/28% at 1 year, 22%/13% at 2 years, 13%/7% at 3 years, 9%/3% at 4 years, and 2%/0% at 5 years. Survival in the cimetidine group was significantly longer than in the placebo group.

121 patients with acute pancreatitis thought to be due to gallstones were randomised to treatment with urgent endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (ES) or with conventional treatment. They were stratified by predicted severity of the attack, according to the modified Glasgow system. ERCP was done within 72 h, and if common bileduct stones were identified, patients underwent ES immediately to extract the stones. There were fewer complications in the 59 patients who underwent ERCP +/- ES than among the 62 treated conventionally, the difference being confined to those whose attacks were predicted to be severe (6/25 ERCP +/- ES [1 death] compared with 17/28 conventional treatment [5 deaths]). Hospital stay was also shorter for patients with severe attacks who underwent ERCP +/- ES than for those who received conservative treatment (median 9.5 versus 17.0 days).

229 children with acute lymphoblastic leukaemia (ALL) and with clinical and laboratory features associated with a high risk of treatment failure entered a randomised study of three treatment regimens. Before 1981, such patients had a 3-year event-free survival (EFS) of 47%. Two intensive therapies, the Berlin-Frankfurt-Munster (BFM) 76/79 regimen and the New York (NY) regimen were compared with a control regimen that had achieved the best outcome in previous Trials. Data on 214 cases (93.4%) were analysed. The 3-year EFS was 78% for the BFM and NY regimens and 49% for the control regimen, a significant difference. The differences persisted after stratification by age at onset, sex, white blood cell count at diagnosis, and marrow blast morphology. Control patients were 2.7 times more likely to fail induction, to die, or to relapse than were patients on the intensive regimens.

Twelve short (more than two standard deviations below the mean height for age), prepubertal children (ten boys, two girls) who had a normal peak growth hormone (GH) response to provocative stimulation with clonidine (more than 10 ng/ml) were enrolled in a double-blind, placebo-controlled, crossover study of the effects of a single, nightly dose of clonidine (0.1 mg/m2 by mouth). The children's mean age was 7.2 years (range 3.6-10.5 years). The results of 6 months of clonidine therapy were compared with those of 6 months of placebo. Clonidine therapy resulted in no significant difference in height standard deviation score, growth velocity, bone age, 24 h integrated GH concentration, peak GH response to clonidine stimulation, levels of insulin-like growth factor 1, or predicted height by the RWT method. In contrast to other studies, this study shows no sustained increases in GH production or in improved growth velocity with long-term administration of a single daily dose of clonidine. Furthermore, this study demonstrates the need for well-designed, placebo-controlled trials in paediatrics.

In a randomised trial, infants living in a large village in The Gambia were immunised either at 4 months of age with 40,000 plaque forming units (PFU) of the Edmonston-Zagreb (EZ) measles vaccine or at the usual age of 9 months with 6000 TCID50 of a conventional Schwarz measles vaccine. Measles developed in 2 of 119 children who received the EZ vaccine, in 1 before and in the other after 9 months of age. In the Schwarz group measles developed in 7 of 120 children--in 5 before and in 2 after 9 months of age. Serological responses measured at 5 months after vaccination and at 18 months of age were satisfactory in both groups although in the Schwarz group levels were on average 2-fold higher than in the EZ group. The frequencies of fever, cough, vomiting, and diarrhoea were no higher in the EZ vaccinees in the 3 weeks following vaccination than in age-matched non-immunised controls. Long-term morbidity as assessed by clinic attendances and weight at 18 months of age was much the same in the two groups. The EZ measles vaccine is thus safe and clinically and serologically effective when used in a high dose to immunise young Gambian infants.

In a randomised study of 558 children in an urban African community, the protective effect of the Edmonston-Zagreb (EZ) measles vaccine given in a dose of 40,000 plaque forming units from the age of 4 months was compared with the effects of a standard dose (6000 tissue culture infectious units) of Schwarz measles vaccine given from the age of 9 months. During two years of follow-up, all 14 clinical cases of measles occurred in the Schwarz group; 10 of the children contracted measles before vaccination and 4 after measles vaccination. Thus the EZ vaccine provided significant protection against measles both before and after the usual age of vaccination. Among the children who were exposed to measles at home, those given EZ vaccine were better protected than either unvaccinated children or those given the Schwarz vaccine.