Previous small clinical trials have suggested that treatment with nitric oxide donors in suspected myocardial infarction can reduce mortality by 30-35%. To confirm this finding in a large-scale trial, we compared molsidomine and its active metabolite linsidomine (a nitric oxide donor) with placebo in 4017 patients with acute myocardial infarction. In our trial, patients without signs of overt heart failure (Killip III/IV) were randomly assigned in a double-blind design within 24 h of symptom onset to receive linsidomine 1 mg/h intravenously for 48 h, followed by 16 mg molsidomine by mouth daily for 12 days (n = 2007), or an identical placebo (n = 2010). All other treatments could be used at the responsible physician's discretion with the exception of systematic vasodilator treatment. The molsidomine and placebo groups showed similar all-cause 35-day mortality (168 [8.4%] vs 176 [8.8%] deaths, p = 0.66), and adjustment for baseline variables in a Cox model had no effect. Similarly, we found no difference for long-term mortality (mean follow-up 13 months; 294 [14.7%] vs 285 [14.2%] deaths, p = 0.67). The two groups showed similar frequencies of major and minor adverse events; only headache was significantly more common in the molsidomine group. Changes in treatment practices and the lower risk profile of our study subjects than of participants in previous trials may explain the results. It is still not clear whether nitric oxide donors can improve survival in higher-risk myocardial infarction patients.

Chronic progressive multiple sclerosis (MS) is a severely disabling demyelinating disease in which autoimmune processes seem to have a major role. The nucleoside drug cladribine is a potent lympholytic agent with few side-effects. We have studied its efficacy and safety in a randomised double-blind trial. 51 patients (48 entered as matched pairs) received four monthly courses of 0.7 mg/kg cladribine or placebo (saline) given through a surgically implanted central line. Neurologists with no knowledge of which medication the patient was receiving examined the patients monthly and noted two rating scale scores (Kurtzke and Scripps). Cerebrospinal fluid and brain magnetic resonance imaging (MRI) examinations were done at 6 and 12 months. Average neurological scores, demyelinated volumes on MRI, and concentrations of oligoclonal bands in cerebrospinal fluid were stable or improved in the patients receiving cladrabine but continued to deteriorate in patients on placebo. Mean paired (placebo minus matched cladribine) differences at 12 months relative to baseline were 1.0 (SE 0.4) for the Kurtzke scores, -13.9 (2.3) for the Scripps scores, 4.57 (1.17) mL for demyelinated volumes, and 7.3 (3.3) arbitrary units for concentrations of oligoclonal bands. Cladribine was generally well tolerated and clinically significant toxicity occurred in only 1 patient, in whom severe marrow suppression developed with complete recovery after several months. 1 patient died of newly acquired hepatitis B, an event unlikely to be related to cladribine. We conclude that the immunosuppressive drug cladribine influences favourably the course of chronic progressive MS.

The efficacy of antiarrhythmic drugs for terminating sustained ventricular tachycardia (VT) has been disappointing. Lignocaine is the traditional drug but it is not very effective. Sotalol, one of the most effective drugs in suppressing spontaneous or induced VT, should theoretically be useful in this setting. We have compared lignocaine with sotalol for the acute termination of spontaneous sustained VT not causing cardiac arrest in 33 patients (26 males, 7 females, aged 21-90) whose underlying heart disease was old myocardial infarction (28), acute myocardial infarction (2), dilated cardiomyopathy (1), or idiopathic cardiomyopathy (2). Left-ventricular ejection fraction was 35% (range 18-76%). Patients were randomly allocated in a double-blind fashion to lignocaine 100 mg (n = 17) or sotalol 100 mg (n = 16) given intravenously over 5 min. Those with persistent VT 15 min after onset of administration of the first drug were crossed over to the other drug. Sotalol was significantly more effective than lignocaine whether analysed on an intention-to-treat basis (69% vs 18%; 95% confidence interval for absolute difference of 51% 22-80%, p = 0.003) or by analysis limited to the 31 patients with subsequent electrophysiologically proven VT (69% vs 20%). 1 patient in each group required cardioversion after the first drug. Tachycardia persisted in 14 patients in the lignocaine group and 4 in the sotalol group after 15 min. Tachycardia ceased in 7 (50%) patients who crossed over to sotalol, and in 1 patient who crossed over to lignocaine. There was 1 death in each group after the first drug and 1 death after both drugs. We conclude that sotalol was superior to lignocaine for the acute termination of sustained VT. The incidence of adverse effects was similar for the two drugs.

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in children. Paralysis of respiratory muscles causes a decrease in forced vital capacity (FVC) from age 12 years, and death occurs between 20 and 25 years old and is usually related to respiratory insufficiency. Uncontrolled studies suggest that early home use of nasal intermittent positive-pressure ventilation (NIPPV) in DMD patients free of respiratory failure could limit progression of the restrictive syndrome and therefore improve survival because efficacy of preventive NIPPV has not been demonstrated in a controlled trial, we undertook a randomised multicentre study in which 70 patients with DMD were included. Patients were free of daytime respiratory failure and FVC was between 20 and 50% of predicted values. At least 6 h of nocturnal NIPPV (n = 35) was compared with conventional treatment (n = 35). During a mean follow-up of 52 months, 10 patients died, 8 in the NIPPV group and 2 in the control group (p = 0.05, log-rank test). No differences were observed between the two groups for occurrence of hypercapnia, decrease of FVC below 20% of initial values, or use of necessary mechanical ventilation. Preventive NIPPV did not improve respiratory handicap and reduced survival of DMD patients. Use of NIPPV for preventive purposes should be avoided in patients with FVC between 20 and 50% of predicted values.

Immunotherapy of chronic viral diseases with vaccines is an important but unproven concept. We investigated the effect of a vaccine containing recombinant glycoprotein D (gD2) of herpes simplex virus type 2 (HSV-2) on the frequency of symptomatic outbreaks in patients with genital herpes. 98 patients with documented genital herpes who reported 4-14 recurrences per year were enrolled in a double-blind, placebo-controlled trial. Subjects received injections of either 100 micrograms gD2 in alum or alum alone (placebo) at 0 and 2 months, and recurrences were documented for 1 year. The vaccine was well tolerated. gD2 recipients reported fewer recurrences per month than placebo recipients (mean 0.42 [SE 0.05] vs 0.55 [0.05]; p = 0.055), had fewer virologically confirmed recurrences per month (0.18 [0.03] vs 0.28 [0.03]; p = 0.019), and had a lower median number of recurrences for the study year (4 [range 0-17] vs 6 [0-15]; p = 0.039). Neither genital recurrence nor the placebo vaccine had any discernible effect on HSV-2-specific antibody responses, but gD2 vaccine boosted neutralising antibodies to HSV-2 fourfold and gD2-specific titres sevenfold over baseline levels. These results inspire optimism about the potential use of vaccine for the treatment of chronic, recurring viral diseases.

In a prospective, randomised single-blinded secondary prevention trial we compared the effect of a Mediterranean alpha-linolenic acid-rich diet to the usual post-infarct prudent diet. After a first myocardial infarction, patients were randomly assigned to the experimental (n = 302) or control group (n = 303). Patients were seen again 8 weeks after randomisation, and each year for 5 years. The experimental group consumed significantly less lipids, saturated fat, cholesterol, and linoleic acid but more oleic and alpha-linolenic acids confirmed by measurements in plasma. Serum lipids, blood pressure, and body mass index remained similar in the 2 groups. In the experimental group, plasma levels of albumin, vitamin E, and vitamin C were increased, and granulocyte count decreased. After a mean follow up of 27 months, there were 16 cardiac deaths in the control and 3 in the experimental group; 17 non-fatal myocardial infarction in the control and 5 in the experimental groups: a risk ratio for these two main endpoints combined of 0.27 (95% CI 0.12-0.59, p = 0.001) after adjustment for prognostic variables. Overall mortality was 20 in the control, 8 in the experimental group, an adjusted risk ratio of 0.30 (95% CI 0.11-0.82, p = 0.02). An alpha-linolenic acid-rich Mediterranean diet seems to be more efficient than presently used diets in the secondary prevention of coronary events and death.

Coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are more effective than medical treatment for the management of ischaemic heart disease. However, patients with single-vessel involvement have been excluded from prospective comparisons of the two methods. We have carried out such a comparison in patients with isolated proximal left anterior descending artery stenosis, conserved left ventricular function, and documented ischaemia. Eligible patients presenting to a single centre were randomly assigned PTCA (68 patients) or left internal mammary grafting (66). The procedures were technically feasible in all cases. The incidence of in-hospital complications was 2% (perioperative myocardial infarction) for CABG and 3% (emergency CABG for acute closure) for PTCA. Clinical and functional status improved similarly in both groups. However, patients in the PTCA group took more antianginal drugs. At median follow-up of 2.5 years, 86% of CABG-treated and 43% of PTCA-treated patients were free from adverse events (p < 0.01; relative risk 2.0 [95% CI 1.7-2.3]). The adverse events that explain this difference were restenosis (32%) requiring subsequent surgical (16%) or percutaneous (15%) revascularisation (1% had medical therapy). Rates of cardiac death and myocardial infarction did not differ between the groups. Both CABG and PTCA improve the clinical status of symptomatic patients with single-vessel coronary artery disease. If patient and physician accept the risk of restenosis and reintervention associated with PTCA, this procedure remains a suitable option and a simpler initial alternative to CABG.

As part of the Safe Motherhood Initiative, launched in 1987, the World Health Organization have produced and promoted a partograph with a view to improving labour management and reducing maternal and fetal morbidity and mortality. This partograph has been tested in a multicentre trial in south east Asia involving 35,484 women. Introduction of the partograph with an agreed labour-management protocol reduced both prolonged labour (from 6.4% to 3.4% of labours) and the proportion of labours requiring augmentation (from 20.7% to 9.1%). Emergency caesarean sections fell from 9.9% to 8.3%, and intrapartum stillbirths from 0.5% to 0.3%. Among singleton pregnancies with no complicating factors, the improved outcome was even more marked, with caesarean sections falling from 6.2% to 4.5%. The improvements took place among both nulliparous and multiparous women. The World Health Organisation partograph clearly differentiates normal from abnormal progress in labour and identifies those women likely to require intervention. Its use in all labour wards is recommended.

Recent studies have suggested that regular use of inhaled beta 2 agonists cause loss of asthma control as measured by worsening peak-flow rates, increased asthma symptoms, and more frequent need for supplementary bronchodilators. However, the magnitude of this effect and the reliability of investigator-originated definitions of control is unknown. We studied 341 people with asthma in a four-week, randomised, crossover trial of regular salbutamol (2 puffs--200 micrograms--four times daily) for two weeks and as needed for two weeks. There were no significant differences in morning and evening peak-flow rates between treatments but asthma symptoms and supplementary bronchodilator use were significantly less frequent when salbutamol was given regularly. Asthma episodes occurred 1.39 (1.52) times per day during regular treatment and 2.44 (1.75) times per day during as-needed treatment (p < 0.0001) and 0.50 (0.56) vs 0.65 (0.66) times per night (p < 0.0001). Daytime use of supplementary salbutamol was 1.14 (1.40) vs 2.35 (1.71) puffs per day, (p < 0.0001); night-time use was 0.45 (0.55) vs 0.64 (0.66) puffs per night (p < 0.0001). When control endpoints were compared between treatment periods for each individual by two blinded investigators and control judged by six different sets of criteria, in 70 asthmatics there was no difference in symptom control between periods but in the remainder, control was achieved more often by regular than by as-needed salbutamol (166 vs 69, p < 0.0001). In asthma of moderate severity, regularly administered salbutamol does not produce lower peak flow rates than as-needed salbutamol and is associated with less frequent asthma symptoms.

Randomised, double-blind controlled trials have been started to determine whether tamoxifen can prevent or delay development of breast cancer in healthy women with a family history of the disease. We recruited a randomised cohort of 111 postmenopausal women (aged 46-71 years) from the Pilot Breast Cancer Prevention Trial at the Royal Marsden Hospital to study the effect of tamoxifen on the uterus and ovaries. The main outcome measures were obtained by transvaginal ultrasonography with colour doppler imaging and microscopic examination of endometrial biopsies removed at the time of the scan. There was no significant difference between tamoxifen (20 mg/day) and placebo groups in the age of the women, or the time of the scan (and sampling) after randomisation. Women taking tamoxifen had a significantly larger uterus and a lower impedance to blood flow in the uterine arteries. 39% of women taking tamoxifen had histological evidence of an abnormal endometrium compared with 10% in the control group. 10 patients in the tamoxifen group (16%) had atypical hyperplasia and another 5 (8%) had a polyp. Women with a histological abnormality had a significantly thicker endometrium and a decreased impedance to blood flow in the uterine arteries. There was no correlation between the presence of uterine abnormalities and the age of the women, or the concentrations of tamoxifen or desmethyl tamoxifen in the peripheral blood. These findings confirm that tamoxifen can cause potentially malignant changes in the endometrium of postmenopausal women. Transvaginal ultrasonography can be used to identify those women who should have endometrial samples removed for microscopic analysis.

Growth failure is a psychosocial problem for many patients who have undergone renal transplantation. 18 adolescents (mean age 15.6, range 11.3-19.5) with severe growth retardation after renal transplantation were treated with biosynthetic growth hormone (GH) for 2 years. All received prednisone, administered daily or on alternate days, with azathioprine and/or cyclosporin A. 16 were blindly assigned to one of two GH doses (4 vs 8 IU per m2 per day). Growth, bone maturation, renal graft function, plasma insulin-like growth factors, serum binding proteins, and other biochemical parameters were checked regularly. Glomerular filtration rate and effective renal plasma flow were tested with 125I-Thalamate and 131I-Hippuran. Data on growth and glomerular filtration rate during GH treatment were also compared with those of matched non-GH-treated controls. Mean (standard deviation) increment in height after 2 years of GH was 15.7 (5.1) cm, significantly greater (p < 0.0001) than in matched controls, 5.8 (3.4) cm. Results were similar for the two GH dosage groups. Bone maturation was not accelerated. Glomerular filtration rate and effective renal plasma flow did not change significantly. The incidence of a > 25% reduction in glomerular filtration rate over 2 years was not significantly higher in GH-treated patients than in non-GH-treated controls (39% vs 32%, p = 0.97). Although a few patients had deterioration of graft function, we could not find a relation with GH treatment. Our results show that sustained improvement of height can be achieved with GH in severely growth-retarded adolescents after renal transplantation.

The overall survival in patients with gastric cancer is low, even among those undergoing resection. It has been hoped that the development of adjuvant therapy might improve survival in patients following surgery when tumour burden was minimal and both chemotherapy and radiotherapy have been proposed as suitable for use in gastric cancer. Their value has been evaluated by the British Stomach Cancer Group Second adjuvant therapy trial. 436 patients entered a prospective, randomised, controlled trial of adjuvant radiotherapy or cytotoxic chemotherapy with mitomycin, doxorubicin, and fluorouracil after gastrectomy for adenocarcinoma. After at least 5 years, there have been 372 deaths of which 7 were due to surgical complications and 327 from recurrent cancer. Following stratified randomisation, 145 patients were allocated to surgery alone, 153 to receive adjuvant radiotherapy, and 138 to adjuvant combination chemotherapy. The overall 2-year and 5-year survival were 33% (95% confidence interval 31-35%) and 17% (13-21%). No survival advantage has been shown for those patients receiving either adjuvant therapy compared to those undergoing surgery alone. The 5-year survival for surgery alone was 20%, for surgery plus radiotherapy 12%, and for surgery plus chemotherapy 19%. Surgery, therefore, remains the standard treatment for this condition and the use of adjuvant treatments should be restricted to controlled trials.

The efficacy of iron supplementation for iron-deficient subjects is in no doubt. However, the assumption that iron supplementation of iron-replete subjects is harmless may not be valid. We have studied the effect of iron supplementation on growth rate in 47 iron-sufficient young children (12-18 months) in Indonesia. The children were randomly assigned either ferrous sulphate (3 mg/kg daily) or placebo every day for 4 months. Before treatment the length, weight, and arm circumference of the two groups were similar. During the 4 months of supplementation the rate of weight gain was significantly greater in the placebo group than in the iron-supplemented group (0.106 [SE 0.010] vs 0.070 [0.011] kg every 2 weeks, p = 0.02). The rates of gain in length and arm circumference did not differ significantly by treatment. There were no differences between the groups in rates of respiratory and gastrointestinal infections. These results suggest that iron supplementation of iron-replete children may retard their growth.

Laparoscopic surgery benefits patients because it reduces pain and enables earlier mobilisation. There is concern that laparoscopic hernia repair may enter surgical practice without proper evaluation. We have done a randomised, prospective study comparing laparoscopic and open inguinal hernia repair performed under day-case general anaesthesia. 150 patients were randomised to have laparoscopic (group L) or open (group O) herniorrhaphy. Group L underwent transabdominal stapling of preperitoneal Prolene mesh. Group O underwent open repair, with a tension-free nylon darn. Postoperatively patients completed pain analogue scales eight times over 7 days, and use of analgesia was recorded. Time of return to normal domestic activity and to work was assessed. The groups were similar in age, sex, and body surface area. Self-administered co-proxamol was a median of 18 tablets (1 tablet = 325 mg) in group O (n = 75) and 6 in group L (n = 75, p < 0.001). Overall mean pain analogue score was 3.1 (SD 1.8, n = 70) in group O and 1.8 (SD 1.1, n = 71) in group L (p < 0.0001). Return to normal domestic activity was a median of 7 days in group O (n = 72) and 3 days in group L (n = 73) (p < 0.001). Return to work was a median of 28 days in group O (n = 39) and 14 days in group L (n = 40) (p < 0.002). These data suggest that laparoscopic hernia repair induces less pain than open hernia repair, and enables patients to return to normal activity and work more quickly.

Although it is well established that cervical priming before surgically induced abortion reduces the incidence of complications, its use is infrequent and confined to groups perceived to be at high risk. We compared the effect of prostaglandin E1 analogues, gemeprost and misoprostol, on the cervix. Both induced clinical and histochemical changes that were significantly different from controls and were likely to have therapeutic value. Misoprostol, however, is cheap, easily stored, and associated with few side-effects. Cervical pre-dilation with misoprostol may be considered in all women having surgically induced abortions.

Over the past decade various clinical trials have used monoclonal antibodies as therapeutic agents against solid tumours. No consistent pattern of response or improved survival has yet emerged although antigenic heterogeneity and insufficient accessibility of cells in advanced tumours have been offered as explanations for these failures. We designed a study in which a monoclonal antibody was used to target minimal residual disease in an early stage of tumour cell dissemination in patients with colorectal cancer. Only patients in Dukes' stage C who had undergone curative surgery and were free of manifest residual tumour were admitted. 189 patients with colorectal cancer of stage Dukes' C were randomly assigned to an observation regimen or to postoperative treatment with 500 mg of 17-1A antibody, followed by four 100 mg infusions each month. A balance of risk factors in the two groups was achieved by dynamic randomisation procedure. After a median follow-up of 5 years, antibody treatment reduced the overall death rate by 30% (Cox's proportional hazard, p = 0.04, log-rank p = 0.05) and decreased the recurrence rate by 27% (p = 0.03, p = 0.05). The effect of antibody was most pronounced in patients who had distant metastasis as first sign of a relapse (p = 0.0014, p = 0.002), an effect that was not seen for local relapses (p = 0.74, p = 0.67). Toxic effects of 17-1A antibody were infrequent, consisting mainly of mild constitutional and gastrointestinal symptoms. During 371 infusions four anaphylactic reactions were seen, all controllable by intravenous steroids and none necessitated admission to hospital. Adjuvant therapy with 17-1A antibody extends life and prolongs remission in patients with colorectal cancer of Dukes' stage C.