Ketanserin, a selective serotonin (5-HT) antagonist at 5-HT2 receptors, was investigated in a 3-month, double-blind, placebo-controlled study in twenty patients with intermittent claudication. Blood-pressure ratio (thigh/arm), reactive hyperaemia measured with an ECG-triggered venous occlusion plethysmograph, blood filterability, and claudication distance on a treadmill progressively and significantly improved during ketanserin therapy, whereas no such changes occurred in the placebo group. Mean claudication distance improved by 140%; four of the eleven patients on ketanserin were able to keep walking beyond the time limit of the exercise test. The beneficial effect of ketanserin suggests that 5-HT may be involved in the pathogenesis of peripheral arterial obstructive diseases. In an experiment comparing blood-pressure ratio measured by doppler velocimetry and by plethysmography, the plethysmographic values rose during ketanserin therapy only at thigh level, which suggests an improvement in the collateral circulation.

127 patients with suspected herpes simplex encephalitis (HSE) were entered in a prospective randomised study of acyclovir 10 mg/kg 8-hourly versus vidarabine 15 mg/kg daily for 10 days. The patients were consecutive and nearly all Swedish cases of HSE were included; they were treated in six university infectious diseases departments. The diagnosis of HSE was verified by brain biopsy and/or antibody responses in serum and cerebrospinal fluid. Of 53 confirmed cases of HSE (corresponding to 2 X 3 cases per million inhabitants per year in Sweden), 51 (27 acyclovir, 24 vidarabine) were evaluable for analysis of efficacy. The mortality was 19% in the acyclovir-treated group versus 50% in the vidarabine group (p = 0.04). At 6 months of observation 15 (56%) of 27 acyclovir-treated patients had returned to normal life compared with 3 (13%) of 24 vidarabine-treated patients (p = 0.002); and the numbers who died or had severe sequelae were 9 (33%) and 19 (76%), respectively (p = 0.005). No important or new adverse events were recognised.

In 2 randomised, prospective Eastern Co-operative Oncology Group trials, the frequency of central nervous system (CNS) involvement after chemotherapy in 347 adults with stage III and IV unfavourable-histology, non-Hodgkin's lymphoma was 8.4%. The frequency varied from 0% in diffuse mixed lymphoma to greater than 30% in lymphoblastic and diffuse-undifferentiated lymphoma. Of the 42% of patients who achieved complete remission after chemotherapy, CNS involvement developed in 5.4% during relapse, but in only 2.7% was the CNS the sole site of relapse. CNS lymphoma arose in 6.6% of 197 patients with diffuse histiocytic lymphoma, but in only 1 subject (1%) was the CNS the sole site of relapse. Therefore, CNS prophylaxis is not indicated for the common diffuse-histology subtypes of adult non-Hodgkin's lymphoma including diffuse-histiocytic, diffuse-mixed and diffuse poorly differentiated lymphocytic lymphoma. The relatively high frequency of CNS lymphoma in lymphoblastic and diffuse undifferentiated lymphoma justify further studies of CNS prophylaxis.

In a comparative trial of preventive medication for duodenal ulceration with 51 participating centres, 484 patients were recruited for a year's maintenance treatment with the recommended bedtime dose of ranitidine (150 mg; n = 243) or cimetidine (400 mg; n = 241). These outpatients had recently healed duodenal ulcers, confirmed by endoscopy before and after healing, and ulcer relapse was monitored by endoscopy every 4 months. The distribution of factors likely to influence ulcer recurrence was similar in the two treatment groups. A life-table method of analysis showed that the ulcer relapse rate was consistently and significantly lower on ranitidine that on cimetidine (8% v 21%, p = 0.0018 at 4 months; 14% v 34%, p less than 0.0001 at 8 months; and 23% v 37%, p = 0.004 at 12 months). Crude relapse rate calculations, which underestimate the probability of ulcer recurrence, also confirmed the significant superiority of ranitidine 150 mg over cimetidine 400 mg nightly in preventing ulcer recurrence throughout the year.

Schoolgirls shown to have covert bacteriuria (CB) by a screening programme and followed up for 5 years to assess whether chemotherapy had any beneficial effect, underwent a further assessment of renal function at the age of 18 years and during subsequent pregnancies. At age 18, glomerular filtration rate (GFR) and urine concentrating ability were the same as in controls, but fractional reabsorption of glucose was significantly reduced in those who had previously been prescribed chemotherapy because of renal scarring or who had been randomly allocated not to receive prophylactic chemotherapy. Those who had had CB as schoolgirls had a higher frequency of CB in pregnancy than did controls, whether or not prophylactic chemotherapy had been given to the subjects when they were schoolgirls. Furthermore, compared with girls who had had such treatment, untreated patients had smaller increments in GFR, reduced fractional reabsorption of glucose, and more than usual degree of glycosuria during pregnancy. This suggests that subclinical renal damage may be prevented by prophylactic chemotherapy but this advantage is unmasked only by the physiological demands of pregnancy.

This is the final report on mortality amongst men in the WHO cooperative trial of the prevention of ischaemic heart disease (IHD) by clofibrate and it takes the follow-up a further 4 years to the end of 1982. Mean observation was 13.2 years, 5.3 in the trial and 7.9 afterwards. 1788 deaths were recorded in 208 000 man-years. In the 877 new deaths reported here, there was an excess of 9 deaths in the high cholesterol control group compared with the clofibrate-treated group. In the whole period there were 70 (11%) more deaths in the clofibrate-treated group. Excess mortality in the clofibrate-treated group was much greater during the "treatment period" (there was an excess of 47% during treatment compared with 5% after treatment had ended) and was due to a wide variety of causes other than IHD. Thus, the excess mortality in the clofibrate-treated group has not continued after the end of treatment. The substantial excess previously reported remains unexplained.

186 patients with advanced epithelial ovarian carcinoma were treated with either a combination of hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexa-CAF) or cyclophosphamide and hexamethylmelamine alternating with doxorubicin and a 5-day course of cisplatin (CHAP-5). Treatment with CHAP-5 resulted in more complete remissions as determined by laparatomy or peritoneoscopy (p = 0.004), better overall response (p = 0.0001), and longer overall survival and progression-free survival (p less than 0.002). Therapy, histological grade, and Karnofsky index were reliable predictors of overall response, whereas therapy, FIGO-stage, and size of residual tumour before chemotherapy were independent predictors for complete remission and for prolonged survival. Peripheral neurotoxicity was a major problem in patients assigned to the CHAP-5-group and was likely to be due to the simultaneous administration of hexamethylmelamine and cisplatin. The CHAP-5 regimen is one of the most effective regimens for the initial treatment of ovarian cancer.

22 cirrhotic patients with chronic encephalopathy were given oral zinc supplementation or placebo in a double-blind randomised trial. In the group which received zinc acetate 600 mg a day for 7 days, serum zinc had been restored to normal by day 8. On day 8 hepatic encephalopathy, as assessed by a trailmaking test, was improved in the supplemented group but not in the placebo group. There was also a significant increase in blood urea nitrogen in the supplemented group. Short-term oral zinc supplementation probably improved hepatic encephalopathy by correcting the zinc deficiency that compromises conversion of ammonia to urea. The duration of this improvement requires further investigation.

41 patients with pemphigoid entered a multicentre randomised study of the efficacy of plasma exchange. All patients received 0.3 mg/kg daily oral prednisolone, increased weekly if the disease remained active. 24 patients received plasma exchanges in addition (eight large-volume exchanges over 4 weeks), and 17 had prednisolone only. 4 patients, 2 in each group, were withdrawn from the study. The initial dose of prednisolone was effective in 13 of 22 patients receiving plasma exchange but in none of 15 patients receiving prednisolone only. Control of the disease was obtained with a mean daily prednisolone dose of 0.52 +/- 0.28 mg/kg in the plasma exchange group v 0.97 +/- 0.33 mg/kg in the other group and a mean cumulative dose of 1240 +/- 728 mg v 2770 +/- 1600 mg. This finding suggests that plasma exchange allows a substantial saving of corticosteroids in the management of pemphigoid. This sparing effect was observed whether or not serum anti-basement membrane antibodies had been detected before treatment.

The effect of specific H1 and H2 receptor antagonists on bronchial reactivity and increase in lung epithelial permeability in response to inhaled histamine was measured in 5 non-smoking men (age range 24-36 years). Inhaled histamine produced a short-lived but consistent increase in permeability to 99Tc-diethylenetriamine penta-acetate. An H1-receptor antagonist, terfenadine (60 mg), protected against the bronchoconstrictor effect but had no significant influence on the increase in permeability. The H2-receptor antagonist ranitidine (150 mg) significantly reduced the permeability response without having an effect on bronchial reactivity. These results demonstrate that the bronchoconstrictor effect of histamine is mediated by H1 receptors and permeability increase is mediated by H2 receptors. H2-receptor mediated increase in lung epithelial permeability may be important clinically.

Of 28 788 women aged 40 to 74 registered at 28 university teaching practices in greater Belfast, half were randomly selected to receive a booklet on breast self-examination from their general practitioner at the start of the study and 1 year later. The frequency of breast abnormalities was identical in both groups (0.83%) during the 2-year follow-up. Early malignant breast cancers (stages TX, TO, Tla) were significantly more frequent in the intervention group (53.6%) than in the control group (24.3%). Among women in the intervention group with malignant lesions, 2 sites, left nipple and left inner/upper quadrant, were significantly less frequently involved. These findings in relation to staging and site were confirmed by multivariate comparisons. The intervention group also had a smaller average tumour size (24.0 mm compared with 32.6 mm) due to significantly smaller benign tumours and the absence of the relationship between delay and tumour size evident in the control group.

327 patients with cancer of the breast and involvement of axillary lymph nodes were randomised, after total mastectomy and axillary clearance, to receive either no additional treatment or oral cyclophosphamide 80 mg/m2 on days 1-14, intravenous methotrexate 32 mg/m2 on days 1 and 8, and intravenous fluorouracil 480 mg/m2 on days 1 and 8 (CMF), which was repeated every 28 days for twelve cycles. There was a significantly longer relapse-free survival (RFS) in patients treated with CMF. A prolonged RFS was seen in premenopausal patients, those with 1-3 nodes involved, and those with 4 or more nodes involved, but a similar trend in postmenopausal patients failed to reach statistical significance. RFS was greater in patients with CMF-induced amenorrhoea than in controls and in treated patients whose primary tumour contained progesterone receptors. Dose of chemotherapy did not have a significant effect on RFS. Survival was not influenced by treatment.

102 patients with endoscopically proven duodenal ulcers were randomly allocated to treatment with ranitidine either 150 mg twice a day or 300 mg every evening for 4 weeks in a prospective double-blind study. The two groups were similar. 48/57 (84%) healed on ranitidine 150 mg twice daily and 43/45 (96%) healed on 300 mg every evening (p = 0.9)--that is, ranitidine 300 mg as a single night time dose is as effective as 150 mg twice daily. The results also indicate the importance of overnight gastric acidity in the pathogenesis of duodenal ulcers.

510 of 1009 pregnant women in the Trondheim area (Norway) were randomly selected for ultrasound examination at the 19th and 32nd weeks of pregnancy in addition to routine antenatal care. Among the screened women, twins were diagnosed earlier and there were slightly fewer post-term inductions (2.8% versus 4.0%) and fewer low-weight births (2.2% versus 3.6% less than 2500 g), but none of these differences was statistically significant. There were no differences in the condition of the newborn. Small-for-gestational-age births were more often diagnosed antenatally in the screened group and the mothers received more active treatment. During pregnancy, screened women were admitted to hospital more often than unscreened women (15.5% versus 9.2%). The study revealed no adverse short-term biological effects from ultrasound. The cost of the screening programme, including associated costs such as extra hospital admissions, was about US$ 250 per pregnancy.

A double-blind, randomised, placebo-controlled, crossover trial of prednisolone (40 mg daily for 14 days) was carried out in 43 patients with chronic airflow limitation (mean age 60 years, mean FEV1 1.02 litres, FEV1/FVC ratio 43.7%). Several subjective and objective variables for response were measured. Significant improvements occurred with prednisolone in most variables measured, but improvements also occurred with placebo in some variables. The improvements with prednisolone in general wellbeing, 12 min walk distance, peak expiratory flow, FEV1, and relaxed vital capacity were significantly greater than those with placebo. Clinical assessment and assessment of atopic status did not reveal any feature of major predictive value for steroid responsiveness. A proportion of patients with chronic airflow limitation do improve on oral corticosteroids and the continued use of such trials in clinical practice is justified, though a placebo period should be included, and several variables for response should be measured.

In a longitudinal study designed to assess the impact of a massive-dose vitamin A programme on the incidence of keratomalacia, 50 000 preschool children in 450 slum areas in Hyderabad city (India) were given 200 000 IU of vitamin A once every 6 months. During the study period, the incidence of keratomalacia in areas covered by the programme decreased by about 80%, while in control areas the reduction was of the order of 20%. To test whether large doses of vitamin A supplements prevented keratomalacia, a case-control analysis was done, with patients with severe protein-energy malnutrition being used as controls. The high odds ratio clearly indicated that keratomalacia was more likely to occur in children not receiving supplements.

The hyperglycaemic effect of 20 g sucrose taken at the end of a regular mixed meal by diabetic patients was measured in six adult type 1 diabetics, C-peptide negative, controlled by the artificial pancreas, and twelve adult type 2 diabetics, with fasting plasma glucose levels below 7.2 mmol/l (130 mg/100 ml) and post-prandial plasma glucose levels below 10.0 mmol/l (180 mg/100 ml), treated by diet alone or with glibenclamide and/or metformin. All the patients were given on consecutive days, in random order, two mixed meals of grilled meat, green beans, and cheese, as well as a cake made either of rice, skimmed milk, and saccharine (meal A) or rice, skimmed milk, and 20 g sucrose (meal B). The meals contained equal amounts of calories and of carbohydrate. There was no difference between the meals in plasma glucose curves and plasma insulin or insulin infusion rate variations whether in peak values, peaking times, or areas under the curves, in either group of patients. Sparing use of sucrose taken during mixed meals might help well-controlled diabetic patients to comply with their daily dietary prescription while maintaining good blood glucose control.