The spread of chloroquine resistance poses a serious problem in Africa, where falciparum malaria transmission is the highest in the world. Pyronaridine, an acridine derivative, has been used successfully to treat malaria in China for over 20 years. We compared the efficacy of pyronaridine and chloroquine in African adult patients with acute uncomplicated falciparum malaria in Yaoundé, Cameroon, where chloroquine resistance is well established.

The role of housedust-mite (HDM) allergen (Der p1) in the pathogenesis of atopic dermatitis is controversial. We tested the hypothesis that atopic dermatitis improves if amounts of HDM allergen in the home are reduced.

Up to a third of patients have early rebleeding from oesophageal varices after endoscopic variceal ligation. Octreotide infusion is effective for control of variceal bleeding. We investigated the efficacy of octreotide infusion as an adjunct to endoscopic variceal ligation to prevent early rebleeding from varices. 100 consecutive patients admitted with endoscopically confirmed oesophageal varices and active bleeding or signs of recent haemorrhage were randomly assigned endoscopic variceal ligation alone or octreotide (50 micrograms intravenous bolus injection followed by intravenous infusion at 50 micrograms per h for 5 days) plus endoscopic variceal ligation. Three patients in each group were excluded. Bleeding was controlled in 44 of 47 patients who received variceal ligation alone and in 45 of 47 who received combined treatment (p = 1.0). Recurrent bleeding was documented in 18 (38% [24-52]) patients who received variceal ligation alone and in four (9% [3-21] who received combined treatment (p = 0.0007). The relative risk of rebleeding was lower (0.22 [0.08-0.60]) in the combined therapy group. Ten patients in the variceal ligation group and one in the combined therapy group required balloon tamponade for massive haematesis and haemodynamic instability (p = 0.0039). The in-hospital and 30-day mortality rates were higher in the variceal ligation group than in the combined therapy group (19 vs 9% and 23 vs 11%), but the differences did not reach significance. The relative risks of in-hospital (0.5 [0.04=5.3]) and 30-day (0.45 [0.17-1.2]) mortality were lower in the combined therapy group. Octreotide significantly reduces recurrent bleeding and the need for balloon tamponade in patients with variceal haemorrhage treated by endoscopic variceal ligation.

The effect of dihydropyridines in patients with unstable angina is discouraging. To find out the effect of the non-dihydropyridine-like calcium-channel blocker diltiazem, a randomised, double-blind trial was conducted comparing diltiazem with glyceryl trinitrate, both given intravenously, in 129 patients with unstable angina. The endpoints were refractory angina or myocardial infarction, individually and as a composite endpoint. Refractory angina alone or together with myocardial infarction occurred significantly less commonly in the diltiazem group. While patients were on the trial drugs the numbers with refractory angina were 6 (10%) in the diltiazem group versus 17 (28%) in the glyceryl trinitrate group (relative risk 0.36, p = 0.02), and the numbers with refractory angina and myocardial infarction were 9 (15%) versus 23 (38%) (relative risk 0.40, p = 0.007). Over 48 h the number were: refractory angina 8 (13%) versus 18 (30%), relative risk 0.45, p = 0.03, and refractory angina and myocardial infarction 12 (20.0%) versus 25 (41%), relative risk 0.49, p = 0.02. Patients in the diltiazem group had better (p < 0.05) event-free survival while taking the drugs. Heart-rate pressure product was reduced significantly only by diltiazem (p < 0.05). The incidence of bradyarrhythmias did not differ significantly. Atrioventricular conduction disturbances occurred in 5 (8%) patients in the diltiazem group but were not seen in the glyceryl trinitrate group (p = 0.03). These disturbances could be reversed by decreasing the dose of the drug or withdrawing it. No temporary pacemakers were required. Headache requiring an analgesic or dose adjustment occurred significantly less in the diltiazem group: 3 (5%) versus 15 (25%), relative risk 0.20 (p < 0.004). These results indicate that intravenous diltiazem, compared with intravenous glyceryl trinitrate, significantly reduces ischaemic events and can be used safely in patients with unstable angina.

Previous trials to assess the efficacy of lumbar traction for back pain have been methodologically flawed. To avoid these shortcomings, we conducted a randomised controlled trial in which high-dose traction was compared with sham traction. The sham traction was given with a specially developed brace that tightens in the back during traction. To the patient, the experience is that of traction. The patients and outcome assessor were blinded for the assigned treatment. 151 patients with at least six weeks of non-specific low back pain were randomised. Intention to treat analysis showed no differences between the groups on all outcome measures (patients' global perceived effect, severity of main complaints, functional status and pain); all 95% confidence intervals included the value zero. The number of withdrawals from treatment, loss to follow-up, and protocol deviations was low. Consequently, the per-protocol analysis showed results similar to the intention to treat analysis. Subgroup analyses did not show any group for which traction might seem promising. Our data do not support the claim that traction is effective for patients with low back pain.

In ischaemic stroke, thrombolytic drugs speed the recanalisation of intracerebral arteries. The effects of aspirin are not known. A trial was conducted to determine whether, separately or together, streptokinase and aspirin have clinical benefits in acute ischaemic stroke similar to those in acute myocardial infarction. 622 patients with acute ischaemic stroke within 6 hours of symptom onset were randomised with a 2 x 2 factorial design to (i) a 1-hour intravenous infusion of 1.5 MU streptokinase, (ii) 300 mg/day buffered aspirin for 10 days, (iii) both active treatments, or (iv) neither. Early results raised a question whether the trial should be continued. Streptokinase (alone or with aspirin) was associated with an excess of 10-day case fatality (odds ratio 2.7; 95% confidence interval 1.7-4.3; 2p < 0.00001). Of the four groups randomised, only patients allocated to streptokinase plus aspirin had a significantly higher risk of early death than those given neither streptokinase nor aspirin (odds ratio 3.5; 95% CI 1.9-6.5; 2p < 0.00001). Streptokinase (alone or with aspirin) and aspirin (alone or with streptokinase) reduced, albeit not significantly, the incidence of combined six-month case fatality and severe disability: odds ratio for streptokinase 0.9 (95% CI 0.7-1.3) and odds ratio for aspirin 0.9 (95% CI 0.6-1.3). The risk of early death with thrombolytic treatments should be weighed against the potential benefit of a marginal reduction of severe disability after the first six months.

Irrational prescribing is a habit which is difficult to cure. However, prevention is possible and for this reason the WHO Action Programme on Essential Drugs aims to improve the teaching of pharmacotherapy to medical students. The impact of a short problem-based training course in pharmacotherapy, using a WHO manual on the principles of rational prescribing, was measured in an international multi-centre randomised controlled study of 219 undergraduate medical students in Groningen (Netherlands), Kathmandu (Nepal), Lagos (Nigeria), Newcastle (Australia), New Delhi (India), San Francisco (USA), and Yogyakarta (Japan). The manual and the course presented the students, who were about to enter the clinical phase of their studies, with a normative model for pharmacotherapeutic reasoning in which they were taught to generate a "standard" pharmacotherapeutic approach to common disorders, resulting in a set of first-choice drugs called P(ersonal)-drugs. The students were then taught how to apply this set of P-drugs to specific patient problems on the symptomatic treatment of pain, using a six-step problem-solving routine. The impact of the course was measured by tests before training, immediately after, and six months later. After the course, students from the study group performed significantly better than controls in all patient problems presented (p < 0.05). The students not only remembered how to solve old problems, but they could also apply their skills to new problems. Both retention and transfer effect were maintained at least six months after the training session in all seven medical schools. In view of the impossibility of teaching students all basic knowledge on the thousands of drugs available, this approach seems to be an efficient way of teaching rational prescribing. However, the method should be accompanied by a change in teaching methods away from the habit of transferring knowledge about the drugs towards problem-based teaching of therapeutic reasoning.

The major motor disturbances in Parkinson's disease are thought to be caused by overactivity of the internal segment of the globus pallidus (GPi), in large part due to excessive drive from the subthalamic nucleus. The excessive inhibitory activity of GPi is thought to "brake' the motor thalamus and the cortical motor system to produce the slowness, rigidity, and poverty of movement characteristic of parkinsonian states. To test the hypothesis that direct reduction of Gpi activity can improve motor function, we studied the effect of GPi pallidotomy in 14 patients. The location of the GPi nucleus was confirmed by microelectrode recording before lesion creation. Standardised videotape recordings before and after operation were randomised and scored by a "blinded' evaluator. 6 months after surgery, total motor score in the "off" state had improved by 30% and the total akinesia score by 33%. The gait score in the "off" state improved by 15% and a composite postural instability and gait score by 23%. After surgery there was almost total elimination of drug-induced involuntary movements (dyskinesias), with a 92% reduction on the side contralateral to the pallidotomy. No patient had visual or corticospinal complications. In these patients GPi pallidotomy enhanced motor performance, reduced akinesia, improved gait, and eliminated the neural elements responsible for levodopa-induced dyskinesias.

Pneumococci are a leading cause of severe bacterial disease in infants and children world wide. A possible means of protecting infants in the first few months of life is immunisation of the mother during pregnancy. We prospectively assessed pneumococcal immunisation of pregnant women to determine the amount of pneumococcal antibody transmitted to the infants in serum and milk and the half-life of the passively acquired antibody. Healthy pregnant women in Dhaka, Bangladesh, were randomised to receive pneumococcal or meningococcal vaccine with routine prenatal tetanus immunisation at 30-34 weeks of gestation. Serum and breast milk specimens from the mothers and sera from infants were collected up to 22 weeks of age and assayed for specific serum IgG, IgG1, and IgG2 and for milk IgA antibodies to pneumococcal serotypes 6B and 19F. 55 mothers and 56 infants were followed from birth to five months. Women who received pneumococcal vaccine had geometric mean antibody increases of 2.6 and 3.4 to types 6B and 19F, respectively. The mean infant/maternal antibody ratios were 0.56 and 0.59 (range 0.11-1.46) for these serotypes. Infant cord antibody titres correlated with maternal titres. Infant/maternal IgG ratios correlated with the interval between immunisation and birth and were higher for specific IgG1 than for IgG2. Infants of pneumococcal vaccine recipients had geometric mean antibody concentrations of 6.8 and 7.5 micrograms/mL to serotypes 6B and 19F in cord blood; in cord blood and in all subsequent serum specimens the concentrations were 2-3 fold higher than in control infants. The median half-life of passive antibody was about 35 days; at five months of age 63-71% of infants of pneumococcal vaccine recipients had antibody concentrations greater than 0.15 micrograms/mL. Breast milk IgA antibodies for pneumococcal serotype 19F, but not for type 6B, were significantly higher in vaccine recipients up to five months after delivery. If maternal pneumococcal polysaccharide antibodies do not interfere with active immunisation of the infant with new glycoprotein conjugate pneumococcal vaccines, passive-active immunisation of infants can be a feasible strategy for developing regions.

Drug resistance has made malaria prevention difficult and the new agents are too expensive for widespread use. Primaquine, an established drug for treatment, is potentially useful for prevention. Malaria prophylaxis with primaquine was evaluated in Irian Jaya during one year in Javanese men who were not deficient in glucose-6-phosphate dehydrogenase (G-6-PD). 126 volunteers were randomised to receive 0.5 mg/kg primaquine base or placebo daily (double-blinded), or 300 mg chloroquine base weekly (open). The protective efficacy of primaquine relative to placebo was 94.5% (95% confidence interval 57-99) for Plasmodium falciparum and 90.4% (95% CI 58-98) for P vivax. Attack rates for either parasite did not differ significantly between the chloroquine and placebo groups. Incidence density of physical complaints not associated with parasitaemia was low (17-18 complaints/person-year) and was about the same in all groups except for cough, which was increased in the primaquine group. Complete blood counts were normal and no evidence of hepatic or renal dysfunction was found with primaquine. However, at 50 weeks the primaquine group had a mean methaemoglobin of 5.8% (range 1.4-13%), which declined by half within 7 days of ending prophylaxis. When used daily for one year by men with normal G-6-PD activity, primaquine was well tolerated and effective for prevention of malaria.

The Coronary Angioplasty versus Bypass Revascularisation Investigation (CABRI) is a multinational, multicentre randomised trial comparing the strategies of revascularisation by CABG (coronary artery bypass grafting) and PTCA (percutaneous transluminal coronary angioplasty) in patients with symptomatic multivessel coronary disease. 1054 patients (820 men and 234 women) were recruited from 26 European cardiac centres. The average age was 60 years and 62% presented with angina of class 3 or greater. 513 patients were randomised to CABG and 541 to PTCA, and 93% and 96%, respectively, of those randomised underwent the allocated procedure. This first report presents data analysed by intention to treat and documents all deaths, major cardiac events, and the symptom status of the patients 1 year after randomisation. After 1 year of follow-up, 14 (2.7%) of those randomised to CABG and 21 (3.9%) of those randomised to PTCA had died. The PTCA group's relative risk (RR) of death was 1.42 (95% CI 0.73-2.76). Patients randomised to PTCA required significantly more reinterventions; only 66.4% reached 1 year with a single revascularisation procedure compared with 93.5% of patients randomised to CABG (RR = 5.23 [3.90-7.03], p < 0.001). The patients in the PTCA group took significantly more medication at 1 year (RR = 1.30 [1.18-1.43], p < 0.001). They were also more likely to have clinically significant angina (RR = 1.54 [1.09-2.16], p = 0.012); this association was present in both sexes but was significant only in females. CABRI is the largest trial of CABG versus PTCA to be reported so far. Its findings are consistent with previous studies, and add to the weight of information that clinicians need to discuss with patients when options for the management of severe angina are under consideration.

We compared different procedures for seeking consent to participate in a sham randomised clinical trial and assessed whether refusal is affected by awareness of the severity of outlook. 2035 healthy subjects aged between 20 and 80 years, who visited a scientific exhibition, were enrolled in a hypothetical trial of experimental versus standard therapy, and randomly assigned to groups asked for conventional informed consent or prerandomisation consent. There were four study groups: one-sided informed consent for randomisation (subjects who refused would receive standard treatment); two-sided informed consent for randomisation (subjects who refused could choose between standard and experimental treatment); randomised consent to experimental treatment (subjects who refused would receive standard treatment); and randomised consent to standard treatment (subjects who refused would receive experimental treatment). The refusal rates were 16.2%, 19.9%, 12.1%, and 49.2%, respectively. The perceived severity of the simulated disease affected the refusal rate: the worse the outlook, the lower the refusal rate for informed consent or for consent after randomisation to new treatment, and the higher the refusal rate for consent after randomisation to standard treatment. The prerandomisation design seems to be efficient in a one-sided clinical scenario (eg, a trial of a new drug that would not be given outside the trial) because the refusal rate was substantially lower for prerandomisation to the new treatment than for conventional one-sided informed consent. However, in a two-sided clinical scenario (eg, a trial comparing similar treatments) the prerandomisation design is potentially highly inefficient; the refusal rate was much higher for prerandomisation to standard treatment than for conventional two-sided informed consent.

Patients with chronic active hepatitis C and cirrhosis often develop hepatocellular carcinoma. Interferon (IFN) seems to be effective in some patients but whether it prevents carcinogenesis is unknown. In a prospective randomised controlled trial, we evaluated the effects of IFN-alpha in cirrhotic patients with HCV infection because of their high risk of hepatocellular carcinoma. 90 patients with compensated chronic active hepatitis C with cirrhosis were randomly allocated to receive IFN-alpha (6 MU three times weekly for 12-24 weeks) (45 patients) or symptomatic treatment (45 controls), and were followed up for 2-7 years. In nine controls, alanine aminotransferase (ALT) decreased to less than 80 IU/L but did not stay in the normal range. In 19 patients given IFN-alpha, ALT decreased to less than 80 IU/L (in seven patients, it became and stayed normal; p = 0.011, Wilcoxon rank-sum test). However, the mean change in ALT was not significantly different between the two groups. The mean change in peak alpha-fetoprotein values was smaller in patients given IFN-alpha than in controls (p = 0.021). The mean change in the serum albumin level was higher in the IFN-alpha group (p < 0.001). The histological activity index in the 12 IFN-alpha patients undergoing a second biopsy after therapy was improved (p = 0.031). Hepatitis C viral RNA disappeared in seven (16%) of the 45 IFN-alpha patients (95% CI, 7-29%) and in none of the 45 controls (0-8%; p = 0.018). Hepatocellular carcinoma was detected in two (4%, 1-15%) IFN-alpha patients and 17 (38%, 24-54%) controls (p = 0.002, Wilcoxon signed-rank test). The risk ratio of IFN-alpha treatment versus symptomatic treatment was 0.067 (0.009-0.530; p = 0.010 Cox's proportional hazards). IFN-alpha improved liver function in chronic active hepatitis C with cirrhosis, and its use was associated with a decreased incidence of hepatocellular carcinoma.

Joint consultation sessions between general practitioners (GPs) and specialists to examine patients for whom decisions about referral are difficult are thought to be helpful, but their effects have not been evaluated. In a randomised, controlled trial we studied the effects of joint sessions of GPs and orthopaedic surgeons on referral and intervention rates. During 1.5 years, 12 GPs (in groups of three) held monthly joint consultation sessions with four participating orthopaedic surgeons: patients were seen by one orthopaedic surgeon in the presence of three GPs. Patients were included in the trial if the GP was uncertain about the diagnostic or therapeutic management and if referral was considered; and excluded if referral was urgently necessary or if there was some other clear indication for referral. By a randomised consent design, patients were assigned to joint consultation sessions (n = 144) or a usual-care control group (n = 128). A year later the patients were examined by an independent orthopaedic surgeon. There were significantly fewer referrals (51/144 [35%] vs 87/128 [68%], p < 0.01) and diagnostic actions in the intervention group than in the control group, without negative effects on health or functional status. More patients in the intervention group were symptom-free at 1 year (35% vs 24%, p < 0.05). Joint consultation sessions of GPs and orthopaedic surgeons within the framework of general practice resulted in more efficient care, with better targeted examination, treatment, and referrals.