Experimental work suggests that dermatan sulphate has potential as an antithrombotic agent: it can inhibit venous thrombi yet has less effect upon bleeding than heparin. While heparin functions as an anticoagulant primarily by its ability to accelerate the action of the plasma protein inhibitor antithrombin III, dermatan sulphate acts selectively through a structurally related inhibitor, heparin co-factor II, to inhibit thrombin. We have done a series of dose-finding studies of the use of dermatan sulphate as an anticoagulant/antithrombotic agent in patients on maintenance haemodialysis. Dermatan sulphate proved to be an effective anticoagulant in this setting.

A double-blind, placebo-controlled trial was set up to compare clindamycin and pyrimethamine as prophylaxis for toxoplasmic encephalitis (TE) in HIV-infected patients at risk of the disorder. Interim analysis showed that clindamycin-treated patients were 4.4 (95% confidence interval 1.3-15.2) times more likely to experience an adverse effect that necessitated withdrawal of the study drug than those who received placebo. Diarrhoea and rash were reported in 16 (31%) and 11 (21%), respectively, of 52 patients treated with clindamycin (300 mg twice daily) compared with 2 (6%; p = 0.06) and none (p = 0.01) of the 32 placebo-treated patients. The clindamycin arm of the trial was prematurely terminated, although recruitment to the pyrimethamine arm continues.

The treatment of chronic severe asthma is unsatisfactory for many patients. In a randomised, double-blind, placebo-controlled, crossover trial we have tested whether cyclosporin, which is thought to act primarily by inhibition of T lymphocyte activation, improves lung function in corticosteroid-dependent asthmatics. After a 4-week run-in period, 33 patients with longstanding asthma (mean duration 27 years), and who had required continuous oral corticosteroids for a mean of 9.3 years, were randomised to receive either cyclosporin (initial dose 5 mg/kg per day) or placebo for 12 weeks, crossing over after a 2-week washout period. Mean baseline forced expiratory volume in 1 s (FEV1) was 60.1% of the predicted value. 2 patients failed to complete the protocol and 1 withdrew because of hypertrichosis. Cyclosporin therapy resulted in a mean increase above placebo of 12.0% in morning peak expiratory flow rate (PEFR; p less than 0.004) and 17.6% in FEV1 (p less than 0.001). The frequency of disease exacerbations requiring an increased prednisolone dose was reduced by 48% in patients on cyclosporin compared with placebo (p less than 0.02). Diurnal variation in PEFR decreased by a mean of 27.6% (p = 0.04). Cyclosporin for 12 weeks was well tolerated by this group of chronic asthmatics, in whom the mean whole-blood trough concentration was 152 micrograms/l. These findings provide further evidence of a role for activated T lymphocytes in the pathogenesis of asthma. Specific pharmacological targeting of this cell could form the basis of a novel approach to the treatment of asthma.

Artemether is an oil-soluble methyl ether of artemesinin (qinghaosu). It has been studied extensively in China, where it has been shown to be rapidly effective in severe falciparum malaria. Nearly all the patients studied previously were adults. We have investigated the efficacy of artemether in children with moderate or severe falciparum malaria. In the preliminary study of moderately severe malaria, 30 Gambian children were randomised in pairs to receive either intramuscular artemether (4 mg/kg loading dose followed by 2 mg/kg daily) or intramuscular chloroquine ('Nivaquine') 3.5 mg base/kg every 6 h. Both drugs were well tolerated and rapidly effective. The times to parasite clearance were significantly shorter in the artemether recipients (mean 36.7 [SD 11.3] vs 48.4 [16.8] h, p less than 0.05). 43 children with severe malaria were then randomised to receive intramuscular treatment with the same regimens of artemether (n = 21) or chloroquine (n = 22) as used in the preliminary study. 8 children (19%) died. There were no significant differences between the two groups in the clinical, haematological, biochemical, or parasitological measures of therapeutic response in survivors and there was no evidence of local or systemic toxicity. Despite similar parasite counts on admission, clearance times overall were longer in severe malaria than in moderate malaria. Artemether is a well tolerated and rapidly effective parenteral treatment for severe malaria in children, and would be especially valuable in areas with chloroquine-resistant P falciparum.

Patients with gallstone disease commonly have impaired gallbladder emptying. To see whether non-steroidal anti-inflammatory drugs (NSAIDs) prevent gallstone formation by improving gallbladder emptying, we assessed the effect of indomethacin on postprandial emptying in healthy subjects and in patients with gallstone disease. Subjects received indomethacin 25 mg three times a day for a week and matching placebo for another week. Compared with placebo, indomethacin improved postprandial gallbladder emptying in all 7 patients with gallstone disease. This finding was not recorded in healthy subjects with normal gallbladders. The prevention of gallstone formation associated with ingestion of NSAIDs may be due mainly to a prokinetic effect on the gallbladder since there is no evidence to suggest that these drugs affect cholesterol crystal nucleation at ordinary therapeutic doses in man or animals.

Our aim was to assess the effect of the introduction of a day-care unit on the care of women with non-proteinuric hypertension in pregnancy. A randomised controlled trial was carried out on 54 women who presented at 26 weeks of pregnancy or later with non-proteinuric hypertension (systolic blood pressure 150-170 mm Hg and/or diastolic pressure 90-105 mm Hg on two occasions at least 15 min apart). 30 women were allocated to care by the day unit and 24 were managed according to the established practice of their clinicians without access to the day unit (control group). Women in the control group spent on average 4.6 times longer as inpatients (difference in mean stay 4.0 days [95% confidence interval 2.1-5.9 days]) than the day-unit group and were 8.8 times (95% CI 3.0-25.8) more likely to be admitted to hospital. Induction of labour was 4.9 times (95% CI 1.6-13.8) more likely in the control than in the day-unit group and the development of proteinuria 11.4 times (95% CI 1.8-71.4) more likely. The control group had a mean of 1.5 fewer hospital outpatient visits (95% CI 0.36-2.64). The groups did not differ in their use of antihypertensive drugs. Day-unit care for hypertension in pregnancy significantly reduced the need for and the length of antenatal inpatient admissions and the number of medical interventions, at the cost of an increase in outpatient attendances. Our results are further evidence that inpatient care does not improve outcomes or prevent the development of proteinuria in this disorder.

127 randomly selected patients on haemodialysis showed a high prevalence of ventricular arrhythmias, the frequency of which rose significantly during and after dialysis. These patients have now been followed up for 4 years. Only age and ischaemic heart disease correlated independently with mortality. Although ventricular arrhythmias are often associated with cardiac disease in patients on chronic haemodialysis, they do not seem to predict overall mortality.

Konzo is a distinct form of tropical myelopathy characterised by abrupt onset of spastic paraparesis. Epidemics in East Africa have been attributed to dietary cyanide exposure from insufficiently processed cassava but a study done in Zaire disputed such an aetiology. We investigated a konzo-affected population in rural Zaire and measured the cyanogen content of cassava flour, determined urinary thiocyanate as an indicator of cyanide intake, and compared blood cyanide concentrations in cases and controls. The affected population consumed flour made from short-soaked (one day) cassava roots and thus had high dietary cyanide exposure (urinary thiocyanate in 31 children = 757 mumol/l) compared with the unaffected population (urinary thiocyanate in 46 children = 50 mumol/l) that ate cassava that had been soaked for three days before consumption. 3 konzo patients, but only 2 of 23 controls, had blood cyanide concentrations above 4 mumol/l (p less than 0.01), although serum thiocyanate concentrations were similar. Our findings indicate a causal role in konzo of sustained high blood cyanide concentrations maintained by a deficient sulphur intake impairing cyanide to thiocyanate conversion. The underlying causes of konzo are poverty and food shortage, but a minor improvement of food processing may, as in beri-beri, be preventive.

Although the aetiology of cyclical mastalgia is poorly understood, the consistent finding of an increased prolactin stimulation response probably due to oestrogen dominance has led to the use of treatment with prolactin-lowering drugs and antioestrogens. The efficacy and safety in cyclical mastalgia of gestrinone, which has androgenic, anti-oestrogenic, and antiprogestagenic properties, were investigated in a multicentre study. In a double-blind randomisation procedure, 72 patients were allocated placebo and 73 treatment with gestrinone (2.5 mg twice a week) for 3 months. The patients recorded the severity of breast pain on a visual analogue scale before and during treatment and scored other breast symptoms as not present (0), mild (1), moderate (2), or severe (3). The gestrinone group had significantly greater reductions than the placebo group in breast pain score at months 1, 2, and 3 of treatment (mean reduction 59.5 [SD 22.6] to 11.7 [17.0] vs 58.2 [17.6] to 36.7 [23.0] at month 3; p less than 0.0001). All six breast symptoms had lower scores in the gestrinone than in the placebo group by the end of treatment. In a subset of 30 participants (15 from each group), serum concentrations of oestradiol, progesterone, and tri-iodothyronine were significantly lower than baseline after 3 months of gestrinone, but concentrations of luteinising hormone, follicle-stimulating hormone, prolactin, thyroid-stimulating hormone, and thyroxine did not change. 41% of gestrinone-treated and 14% of placebo-treated patients reported at least one side-effect; most of these were androgen-mediated. 11 placebo-treated patients and 4 on gestrinone discontinued treatment. Thus, gestrinone was very effective in the treatment of cyclical mastalgia and was well tolerated.

Both melphalan and cyclophosphamide increase life expectancy in patients with myelomatosis, but few large randomised studies have compared combination chemotherapy regimens with these single agents. In the Vth MRC myelomatosis trial, the survival of 314 patients randomised to receive ABCM (adriamycin, BCNU, cyclophosphamide, and melphalan) as first-line treatment was significantly longer than that of 316 patients given intermittent melphalan (M7) (p = 0.0003). The 75%, median, and 25% survivals were 7, 24, and 42 months, respectively, with M7 and 10, 32, and 56 months, respectively, with ABCM. Stable disease with few symptoms (plateau) was achieved by 61% of patients given ABCM and 49% of those given M7 (p = 0.004). Myelotoxicity was comparable between regimens. Cross-trial analysis suggests that M7 is comparable to melphalan and prednisone or melphalan, prednisone, and vincristine; that the efficacy of ABCM in the Vth trial and VIth MRC trials is comparable; and that ABCM gave better survival than intermittent melphalan regimens in the prognostic groups analysed. The results indicate that ABCM is an acceptable regimen that is more effective than melphalan, with or without prednisone, for first-line treatment of myelomatosis.

Falls in gastric intramucosal pH (pHi) are associated with morbidity and mortality in patients admitted to intensive-care units (ICU). We tested the hypothesis that ICU outcome can be improved by therapy guided by changes in pHi and aimed at improving systemic oxygen availability. We studied 260 patients admitted to ICUs with APACHE II scores of 15-25. After insertion of a gastric tonometer, each patient was randomly assigned to a control or protocol group within the admission pHi category (normal = 7.35 or higher; low = below 7.35). The control groups were treated according to standard ICU practices. The protocol groups received, in addition, treatment to increase systemic oxygen transport or to reduce oxygen demand, whenever the pHi fell below 7.35 or by more than 0.10 units from the previous measurement. The protocol was used, because pHi fell, in 67 (85%) of the protocol group with normal pHi on admission. There were no significant differences between protocol and control groups in demographic characteristics, admission blood gases or haemoglobin concentration, number or type of organ system failures, or the intensity of ICU care. For patients admitted with low pHi, survival was similar in the protocol and control groups (37% vs 36%), whereas for those admitted with normal pHi, survival was significantly greater in the protocol than in the control group (58% vs 42%; p less than 0.01). Therapy guided by pHi measurements improved survival in patients whose pHi on admission to ICU was normal. pHi-guided resuscitation may help improve outcome in such patients by preventing splanchnic organ hypoxia and the development of a systemic oxygen deficit.