Among breastfed infants, growth faltering in comparison with reference growth curves is common in both developing and developed countries. We performed a zinc supplementation trial in Paris, France, to find out whether such growth faltering is due to nutritional zinc deficiency. 57 breastfed infants aged 4-9 (mean 5.7) months were randomly assigned to receive either 5 mg zinc daily or a placebo for 3 months. Most of the infants were from low-income immigrant families and the majority were of African origin. Before supplementation there were no significant differences between the zinc and placebo groups in weight, length, or corresponding Z-scores for age. After 3 months' supplementation, the length-for-age Z-score had increased in the zinc group and fallen in the placebo group (+0.21 vs -0.13, p = 0.029). This difference was due mainly to greater linear growth of boys in the zinc than in the placebo group (6.0 vs 4.6 cm, p = 0.02). Weight gain was also significantly greater with zinc supplementation (1.64 vs 1.28 kg, p = 0.047). Among infants breastfed for longer than 4 months, decreases in growth velocity result partly from inadequate zinc intake.

Proposed guidelines for the diagnosis of transient ischaemic attack (TIA) involve interpretation of symptoms, so it can be very difficult to distinguish a TIA from other disorders, such as migraine, epilepsy, syncope, or neurosis. Atypical cerebral and visual events may be classified as TIA. To see whether TIA or stroke patients with atypical cerebral or visual symptoms are at high or low risk of cardiac complications, we prospectively followed 572 patients (entered into the Dutch multicentre TIA trial) with a diagnosis of TIA or minor ischaemic stroke, but whose symptoms did not fully accord with internationally accepted criteria. We compared their outcome with that of 2555 other TIA or stroke patients in the trial, who had unequivocal symptoms; all patients were treated with aspirin. During mean follow-up of 2.6 years the risk of a major vascular event did not differ between the groups (14.5% in patients with atypical symptoms vs 15.1% of patients with typical attacks). Patients with atypical attacks had a lower risk of stroke (5.6% vs 9.4%, hazard ratio 0.6, 95% confidence interval 0.4-0.9) and a higher risk of a major cardiac event (8.4% vs 5.9%, 1.4, 1.0-2.0) than did patients with typical attacks. These differences could not be explained by differences in cardiac risk factors, and were independent of minor discrepancies in baseline characteristics between the groups. A heavy or tired feeling in one or two limbs was the only atypical symptom associated with cerebral rather than cardiac events (ratio cardiac/cerebral events 0.8). For all other atypical symptoms cardiac events were about twice as common as cerebral events (range 1.3-2.5). Our findings suggest that TIA or minor stroke patients with atypical symptoms may have symptomatic heart disease, especially cardiac arrhythmia.

The effect of improving maternal nutrition during pregnancy on growth of the child has not been assessed, since previous studies supplemented the diets of children as well as mothers. In a controlled randomised trial in Madura, East Java, pregnant women received a high (HE) or low (LE) energy supplement that provided 1950 kJ (465 kcal) or 218 kJ (52 kcal), respectively, in the last trimester of pregnancy. The effect of this intervention on the children's growth was assessed longitudinally for the first 5 years of life. Only the children of mothers who had complied for at least 90 days were included. Infants entered the study at birth and their growth was measured at 4-week intervals until 12 months old; thereafter they were measured every 3 months. Growth curves were calculated from a mathematical model, based on the best fit of actual measurements and the age-related growth velocity. Up to the age of 24 months, HE children were significantly heavier than LE children (p less than 0.05). HE children were also taller throughout the first 5 years (p less than 0.005 from 15 to 48 months, p less than 0.05 at both 3-12 and 60 months). Weight-for-height by age was similar in both groups, but stunting (height-for-age) was less prevalent in HE children. In a community characterised by chronic energy deficiency among women of reproductive age, energy supplementation of women for the last 90 days of pregnancy was effective in the promotion of postnatal growth and reduction in malnutrition of preschool children.

Bone marrow transplantation (BMT) has been recommended for children with high-risk acute lymphoblastic leukaemia (ALL) in first remission. The recent MRC UKALL X trial was designed to facilitate a non-randomised comparison between BMT and chemotherapy in children deemed to be at high risk of treatment failure. 198 children aged 1-15 had a presenting leucocyte count of more than 100 x 10(9)/l. All received induction and early intensification therapy. Children with an HLA-compatible sibling donor were eligible for BMT in first remission. All other children received cranial irradiation at 24Gy, late intensification, and two years of continuous treatment. 183 children achieved a stable remission of whom 111 were HLA typed; these tended to be older and to have T-cell ALL. A donor was identified in 41 cases, of whom 34 proceeded to BMT at a median time of 17 weeks; there was no difference in distribution of age, sex, or leucocyte count between the groups receiving BMT and chemotherapy. Comparison of the 144 children who were in remission at 17 weeks and received chemotherapy with the 34 proceeding to BMT showed no significant difference in event-free survival at five years (69% for BMT and 52% for chemotherapy). There were significantly more treatment-related deaths in the marrow transplant group (6 vs 4) and more relapses in the chemotherapy group (59 vs 4). There was no significant difference in event-free survival between children who were HLA typed and had a donor and those without a donor, although there were fewer relapses among the former. BMT can be evaluated in the context of a multicentre trial for paediatric ALL but the number of children with donors is too small to make a significant impact on overall survival. However, marrow transplantation was associated with a much lower relapse rate than that with the UK ALL protocol, and with better definition of higher risk patients BMT may be of benefit in some children with high-risk ALL in first remission.

There is no established treatment specifically aimed at protecting or restoring cardiac energy metabolism, which is greatly impaired by ischaemia. Even after reperfusion, myocardial content of ATP remains low for more than 72 h. Long-term post-ischaemic dysfunction and irreversibility of ischaemic damage have been associated with low ATP content. Evidence that the pentose sugar ribose stimulates ATP synthesis and improves cardiac function led us to test the possibility that ribose increases tolerance to myocardial ischaemia in patients with coronary artery disease (CAD). 20 men with documented severe CAD underwent two symptom-limited treadmill exercise tests on 2 consecutive days; we postulated that the ischaemia induced might bring about changes in ATP metabolism lasting for several days. Patients whose baseline tests showed reproducibility were randomly allocated 3 days of treatment with placebo or ribose 60 g daily in four doses by mouth. Exercise testing was repeated after treatment on day 5. At that time mean (95% confidence interval) treadmill walking time until 1 mm ST-segment depression was significantly greater in the ribose than in the placebo group (276 [220-331] vs 223 [188-259] s; p = 0.002). The groups did not differ significantly in time to moderate angina. In the ribose-treated group the changes from baseline to day 5 in both time to ST depression and time to moderate angina were significant (p less than 0.005), but these changes were not significant in the placebo group. In patients with CAD, administration of ribose by mouth for 3 days improved the heart's tolerance to ischaemia. The presumed effects on cardiac energy metabolism offer new possibilities for adjunctive medical treatment of myocardial ischaemia.

About half the patients treated with curative resection for colorectal cancer do not survive long-term. Adjuvant chemotherapy given during and after surgery may prevent hepatic metastases and improve patient survival. In patients with colorectal cancer, we have done a multicentre, randomised controlled trial comparing five-year survival after intraportal infusion of fluorouracil (1 g per day) plus heparin (10,000 U per day) (130 patients) or heparin alone (123) during curative resection and for 7 days thereafter, or after resection alone (145). There was no reduction in liver metastasis or increased overall survival advantage in either active-treatment arm of the study. However, patients who had stage III, Dukes' C (lymph-node-positive) tumours resected and were treated with fluorouracil plus heparin had a significant (p less than 0.03) survival advantage of about 16% compared with surgery-only controls. Further study of intraportal infusion of chemotherapeutic agent as adjuvant treatment to surgery in patients with colorectal cancer appears worthwhile.

On exercise testing after an episode of unstable coronary artery disease (CAD; unstable angina or non-Q-wave myocardial infarction), a proportion of patients show ST-segment depression, indicating myocardial ischaemia, but do not report concomitant symptoms of angina. Treatment of such "silent" ischaemia aims mainly to reduce the risk of subsequent cardiac events. We have studied the effect of low-dose aspirin in patients with myocardial ischaemia defined at the predischarge test as silent (though patients might have had symptomatic ischaemia at other times) or symptomatic. 740 men with unstable CAD aged 70 years or less underwent symptom-limited exercise testing before hospital discharge; 144 showed ST depression without pain and 230 ST depression with simultaneous chest pain. Of the silent ischaemia group, 67 were randomly assigned placebo and 77 aspirin (75 mg daily); the corresponding numbers in the symptomatic group were 125 and 105. Angina symptoms were less common in the silent than in the symptomatic ischaemia group both before inclusion and during follow-up, and a greater proportion of the silent ischaemia group were included because of myocardial infarction. In both ischaemia groups aspirin treatment reduced the risk of subsequent myocardial infarction or death by 3 months' follow-up (silent 4% of aspirin-treated vs 21% of placebo-treated patients, p = 0.004; symptomatic 9% vs 18%, p = 0.05); at 12 months' follow-up a significant benefit of aspirin was still apparent in the silent ischaemia group (9% vs 28%, p = 0.005) but not in the symptomatic group (13% vs 22%, p = 0.109). Low-dose aspirin reduced the risk of subsequent myocardial infarction at least as well in silent as in symptomatic myocardial ischaemia. Since improvement of outlook is the main treatment objective in symptom-free patients, aspirin should be a mainstay of their treatment.

Cisplatin is generally accepted to be the most active cytotoxic agent for the treatment of ovarian cancer but the optimum dose remains unclear. We have performed a randomised trial to assess the importance of cisplatin dose in the treatment of advanced epithelial ovarian cancer. Patients were randomly assigned treatment with 50 mg/m2 (low dose) or 100 mg/m2 (high dose) cisplatin plus 750 mg/m2 cyclophosphamide, for a maximum of six cycles with intervals of 3 weeks. We planned to recruit 300 patients, but an interim analysis on the first 165 indicated a highly significant survival difference (p = 0.0008). Recruitment was therefore stopped and the trial patients were followed-up for 12 months longer. The relative progression rate (high-dose/low-dose) after 12 months' extra follow-up was 0.55 (95% confidence interval 0.37-0.81, p = 0.003) and the relative death rate 0.53 (0.34-0.81, p = 0.003). Overall median survival was 69 weeks in the low-dose group and 114 weeks in the high-dose group. Residual disease extent before chemotherapy had an important influence--patients with lesions of less than 2 cm did best; if given high-dose cisplatin their median survival was 3 years. 56 low-dose and 45 high-dose patients completed six cycles of chemotherapy; 15 and 9 patients, respectively, were withdrawn early because of progressive disease and treatment was stopped in 6 and 25, respectively, because of unacceptable side-effects or patient refusal. Toxic effects were significantly greater in the high-dose group, especially those on the nervous system and ears, alopecia, vomiting, and anaemia. Although the higher dose of cisplatin clearly leads to better results in terms of survival, its overall clinical benefit in the management of ovarian cancer will depend on further improvements in measures to alleviate toxic effects.

Studies with nicotine chewing gum and nicotine skin patches indicate that nicotine replacement can help people to give up smoking. The rapidity with which nicotine is absorbed when given as a nasal spray suggests that it might be effective for those for whom the other means of replacement are too slow. The efficacy and safety of a nasal nicotine spray as an adjunct to group treatment for stopping smoking were assessed in a randomised, double-blind, placebo-controlled trial in which 227 cigarette smokers attending the Maudsley Hospital Smokers Clinic received 4 weeks of supportive group treatment plus active nicotine (0.5 mg per shot) or placebo nasal spray. The main end-point was biochemically validated complete abstinence from smoking from the third week of group treatment until the 12-month follow-up. Side-effects were assessed by self-reports and, where necessary, by physical examination. Of subjects assigned to active treatment 26% (n = 30) were validated abstinent throughout the year, compared with 10% (n = 11) of those assigned to placebo (relative abstinence rate 2.6, 95% CI 1.5-4.5, p less than 0.001). The advantage of the active spray was greatest in the heaviest smokers. Plasma nicotine concentrations from the spray were typically between one-half and three-quarters of baseline smoking levels. Tobacco-withdrawal symptoms, craving for cigarettes, and weight gain in abstinent subjects were reduced by the active spray. Minor irritant side-effects were frequent in both active and placebo sprays, but only 2 subjects had the spray discontinued as a result. No serious adverse effects were encountered. Nasal nicotine spray combined with supportive group treatment is an effective aid to smoking cessation.

Previous studies of the effect of 6-monthly vitamin A supplementation on child mortality have given conflicting results. In other trials, more frequent doses of vitamin A have significantly reduced mortality among children at risk of vitamin A deficiency. We have done a double-blind, placebo-controlled trial of vitamin A supplementation in the Sudan among 28,753 children aged 9-72 months at risk of vitamin A deficiency. Children were assigned to receive either 200,000 IU vitamin A and 40 IU vitamin E every 6 months (vitamin A group) or 40 IU vitamin E alone (placebo group). During the 18 months of follow-up, there were 120 deaths (8.4/1000) in the vitamin A group and 112 (7.9/1000) in the placebo group (relative risk 1.06, 95% confidence interval 0.82-1.37). Controlling for geographic site, round of observation, anthropometry, morbidity, dietary intake of vitamin A, sex, and all baseline differences between the two groups did not change the results. Children living in poor and unsanitary environments, younger children, and those sick, stunted, wasted, or consuming diets low in vitamin A were at a significantly higher risk of dying. The lack of an effect of large-dose vitamin A supplementation on mortality, despite a clear association between dietary vitamin A and mortality, underscores the need to identify factors that modify the efficacy of vitamin A supplements as a public-health measure. Reducing poverty, improvements in sanitation, and access to adequate diets should remain the main goals to improve child survival.

It is possible to record the fetal electrocardiographic waveform (ECG) from the scalp electrode used in labour for detection of fetal heart rate. Animal and observational studies of changes in the ST waveform of the ECG during hypoxia suggest that a combination of heart rate and ST waveform analysis might improve the predictive value of intrapartum monitoring. In a randomised trial, we have studied intervention rates and neonatal outcome for high-risk labours monitored either by conventional cardiotocography (CTG) or by ST waveform analysis plus CTG. 1200 women with pregnancy of at least 34 weeks' gestation were assigned to the groups when the decision to apply a fetal scalp electrode was made. Neonatal outcome was assessed by umbilical-cord blood gas analysis, Apgar scores, resuscitation needed, and postnatal course. All recordings were retrospectively viewed by an observer unaware of clinical details to check adherence to the trial protocol. The addition of ST waveform monitoring to CTG substantially reduced the proportion of deliveries for fetal distress (ST + CTG 27/615 vs CTG 58/606; p less than 0.001). The groups did not differ in rate of operative delivery for other reasons, incidence of asphyxia at birth, or neonatal outcome. Metabolic acidosis and low 5 min Apgar scores were less common in the ST + CTG than the CTG group, but not significantly so. The only case of birth asphyxia in the ST + CTG group was identified by both heart rate and ST changes. The review of recordings showed that the reduction in intervention rate was among cases with CTG patterns classified as normal or intermediate, whereas there was no difference in intervention rates among cases with abnormal recordings. Our findings confirm that ST waveform analysis discriminates CTG changes in labour and that our protocol for interpretation is safe. Further randomised studies are warranted.

In the US Physicians' Health Study the early termination of the aspirin arm has provided the opportunity to test the hypothesis that low-dose aspirin (325 mg on alternate days) might affect the subsequent occurrence of peripheral arterial surgery. In the study, a randomised double-blind placebo-controlled trial among 22,071 healthy US male physicians aged 40-84, there were, during an average of 60.2 months of treatment and follow-up, 56 participants who underwent peripheral arterial surgery (20 aspirin, 36 placebo). The relative risk of peripheral artery surgery in the aspirin group was 0.54 (95% confidence intervals 0.30-0.95; p = 0.03). These data indicate that chronic administration of low-dose aspirin to apparently healthy men reduced the need for peripheral arterial surgery.

University of Wisconsin (UW) preservation solution has been reported to be beneficial for canine organ transplants and for human liver and pancreas transplants. To examine whether it affects renal graft survival, a randomised multicentre trial was conducted to compare its effect with that of EuroCollins solution on delayed graft function, renal function, and patient and graft survival in 695 recipients of cadaveric renal transplants. 352 kidneys were preserved with UW and 343 with EuroCollins solution. Delayed graft function occurred in 23% of the UW group and in 33% of the EuroCollins group (p = 0.003). Three factors other than type of preservation fluid were associated with a higher incidence of delayed graft function: older donor age, intracerebral haemorrhage in the donor, and oliguria in the donor. Renal function as indicated by serum creatinine concentration was better in the UW than in the EuroCollins group. Patient survival in the UW and EuroCollins groups after 1 year was 95% and 94%, respectively. In both groups, delayed graft function reduced 1-year graft survival by 15% (p = 0.0001). 1-year graft survival of UW-preserved kidneys was 6% higher than that of controls (88.2% vs 82.5%, p = 0.04). Delayed graft function is significantly associated with a reduction in 1-year graft survival. The preservation solution is the most important factor influencing development of delayed graft function, and UW solution is superior to EuroCollins solution in reducing occurrence of delayed graft function, improving graft function, extending graft survival.

Ondansetron, a selective serotonin-receptor antagonist, is an effective antiemetic for patients receiving high-dose cisplatin chemotherapy. However, no comparison has been made between a combination of a serotonin antagonist and dexamethasone, which also has antiemetic properties, with currently available antiemetic regimens. 289 consecutive cancer patients receiving cisplatin chemotherapy (much greater than 50 mg/m2) were randomised to receive one of the following intravenous antiemetic regimens: ondansetron 0.15 mg/kg, before and after cisplatin, + dexamethasone 20 mg before cisplatin (treatment A) or metoclopramide 3 mg/kg, before and after cisplatin, + dexamethasone + diphenhydramine 50 mg before cisplatin (treatment B). From day 2 to day 4, all patients received oral metoclopramide and intramuscular dexamethasone. 267 patients (136 receiving treatment A and 131 treatment (B) were available for analysis. Complete protection against emesis was achieved in 107 (78.7%) and 78 (59.5%) patients, respectively (p less than 0.002). Complete protection was also significantly superior for treatment A on day 2 (83.9% vs 68.0%; p less than 0.006). Complete protection from acute nausea (first 24 h) was achieved in 105 patients (77.2%) with treatment A and in 86 (65.6%) with treatment B (p less than 0.051); complete protection from nausea and emesis was achieved in 94 (69.1%) patients and 66 (50.4%), respectively (p less than 0.003). Patients receiving treatment B noted significantly more sedation than patients receiving treatment A (11.8% vs 2.1%; p less than 0.005). Extrapyramidal reactions were present only with treatment B (2.7%). Ondansetron + dexamethasone is more effective and better tolerated than metoclopramide + dexamethasone + diphenhydramine in the prevention of cisplatin-induced nausea and emesis.

Assessment of the physiological effects of physical and emotional stress has been hampered by a lack of suitable laboratory techniques. Since hypnosis can be used safely to induce specific emotional states of considerable intensity, we studied the effect on distal colonic motility of three hypnotically induced emotions (excitement, anger, and happiness) in 18 patients aged 20-48 years with irritable bowel syndrome. Colonic motility index was reduced by hypnosis on its own (mean change 19.1; 95% CI 0.8, 37.3; p less than 0.05) and this change was accompanied by decreases in both pulse (12; 8, 15) and respiration (6; 4, 8) rates (p less than 0.001 for both). Anger and excitement increased the colonic motility index (50.8; 29.4, 72.2; and 30.4; 8.9, 51.9, respectively; p less than 0.01 for both), pulse rate (26; 22, 30; and 28; 24, 32; p less than 0.001 for both), and respiration rate (14; 12, 16; and 12; 10, 14; p less than 0.001 for both). Happiness further reduced colonic motility although not significantly from that observed during hypnosis alone. Changes in motility were mainly due to alterations in rate than in amplitude of contractions. Our results indicate that hypnosis may help in the investigation of the effects of emotion on physiological functions; this approach could be useful outside the gastrointestinal system. Our observation that hypnosis strikingly reduces fasting colonic motility may partly explain the beneficial effects of this form of therapy in functional bowel disorders.

Streptococcus agalactiae transmitted to infants from the vagina during birth is an important cause of invasive neonatal infection. We have done a prospective, randomised, double-blind, placebo-controlled, multi-centre study of chlorhexidine prophylaxis to prevent neonatal disease due to vaginal transmission of S agalactiae. On arrival in the delivery room, swabs were taken for culture from the vaginas of 4483 women who were expecting a full-term single birth. Vaginal flushing was then done with either 60 ml chlorhexidine diacetate (2 g/l) (2238 women) or saline placebo (2245) and this procedure was repeated every 6 h until delivery. The rate of admission of babies to special-care neonatal units within 48 h of delivery was the primary end point. For babies born to placebo-treated women, maternal carriage of S agalactiae was associated with a significant increase in the rate of admission compared with non-colonised mothers (5.4 vs 2.4%; RR 2.31, 95% CI 1.39-3.86; p = 0.002). Chlorhexidine reduced the admission rate for infants born of carrier mothers to 2.8% (RR 1.95, 95% CI 0.94-4.03), and for infants born to all mothers to 2.0% (RR 1.48, 95% CI 1.01-2.16; p = 0.04). Maternal S agalactiae colonisation is associated with excess early neonatal morbidity, apparently related to aspiration of the organism, that can be reduced with chlorhexidine disinfection of the vagina during labour.