Ischaemic preconditioning (short periods of ischaemia with intermittent reperfusion) has been shown paradoxically to protect the myocardium from a subsequent longer ischaemic insult. The protection associated with preconditioning is one of the most powerful mechanisms of protection known and has been shown in every animal species investigated. However, there is no direct evidence that ischaemic preconditioning occurs in the human heart. We studied whether it was possible to precondition the human heart in a setting of coronary artery bypass surgery. The measurement of adenosine triphosphate in biopsy specimens was used as our endpoint. We believe that our results are the first to show that it may be possible to precondition and protect the human myocardium with short controlled periods of intermittent ischaemia and reperfusion.

Tuberculosis occurring with human immunodeficiency virus (HIV) infection is a serious and growing public health problem. We have carried out a randomised clinical trial of a 12-month course of isoniazid plus vitamin B6 versus vitamin B6 alone in Port-au-Prince, Haiti, to assess the efficacy of isoniazid in preventing active tuberculosis in symptom-free HIV-infected individuals. The effect of prophylaxis on the development of HIV disease, AIDS, and death was also investigated. 118 subjects were assigned treatment with isoniazid plus B6 (n = 58) or B6 alone (n = 60) between 1986 and 1989. The treatment groups were similar at study entry in demographic, clinical, and immunological characteristics. Interim analysis in 1990 revealed no significant difference in tuberculosis outcome measures. Follow-up was continued until 1992, at which time significant protection by isoniazid against the development of tuberculosis was apparent, both for the whole study population and for subjects positive for purified protein derivative of tuberculin (PPD). The incidence of tuberculosis was lower in isoniazid recipients than in patients who received B6 alone (2.2 vs 7.5 per 100 person-years). The relative risk of tuberculosis was 3.4 (95% CI 1.1-10.6) for B6 alone versus isoniazid plus B6 (p < 0.05). Isoniazid also delayed progression to HIV disease and AIDS and death. Thus isoniazid effectively decreases the incidence of tuberculosis and delays the onset of HIV-related disease in symptom-free HIV-seropositive individuals. Isoniazid prophylaxis should be considered for HIV-seropositive, PPD-positive subjects, and may also be appropriate for PPD-negative patients in areas where tuberculosis is highly endemic.

Aspirin, alone or in combination with dipyridamole, is known to prevent occlusion of aortocoronary vein grafts. The benefit of dipyridamole in addition to aspirin remains controversial, and the efficacy and safety of oral anticoagulants for prevention of vein-graft occlusion have not been established. We assessed one-year angiographic vein-graft patency after aortocoronary-bypass surgery in 948 patients assigned to receive aspirin, aspirin plus dipyridamole, or oral anticoagulants in a prospective, randomised trial. The design was double-blind and placebo-controlled for the aspirin groups, but open for oral anticoagulant treatment. Dipyridamole (5 mg/kg per 24 h intravenously for 28 h, followed by 200 mg twice daily) and oral anticoagulants (desired prothrombin time range 2.8-4.8 international normalised ratio) were started before surgery, and aspirin (50 mg per day) was started after surgery. Clinical outcome was assessed by the incidence of myocardial infarction, thrombosis, major bleeding, or death. Occlusion rate of distal anastomoses was 11% in the aspirin plus dipyridamole group versus 15% in the aspirin group (relative risk 0.76, 95% CI 0.54-1.05) and 13% in the oral anticoagulants group. Clinical events occurred in 20.3% of patients receiving aspirin plus dipyridamole compared with 13.9% of the aspirin group (relative risk 1.46, 95% CI 1.02-2.08) and 16.9% of the oral anticoagulants group. Our data provide no convincing evidence that addition of dipyridamole to 50 mg aspirin per day improves aortocoronary vein-graft patency. Moreover, there is evidence that the combination increases the overall clinical-event rate. Compared with aspirin, oral anticoagulants provided no benefit.

The quinacrine method of non-surgical female sterilisation involves transcervical intrauterine insertion of 252 mg quinacrine as pellets during the proliferative phase of the menstrual cycle; the drug causes inflammation and fibrosis of the proximal fallopian tube. We have carried out a field trial of 31,781 cases in twenty-four provinces of Vietnam from Jan 2, 1989, until October, 1992. There were 818 pregnancies after the procedure, of which 80 were carried to term. Some women received only one dose of quinacrine; the majority received two doses with an interval of one month. Cumulative life-table pregnancy rates per 100 women at 1 year (for studies of at least 50 cases followed for 12 months) were 2.63 (SE 0.17) among 9461 women who received two doses and 5.15 (0.48) among 2225 who received only one dose. Failure rates (pregnancies) were strongly affected by the skill of the doctor or midwife. There were no deaths and only 8 serious complications were reported (0.03%); by contrast, in a similar series of women undergoing surgical sterilisation, 30 deaths and between 540 and 1812 serious complications would be expected. All reported side-effects were minor and of short duration. There were 19 ectopic pregnancies and the incidence was 0.89 per 1000 woman-years of use. There was one birth defect (anencephaly), in a fetus conceived 2.5 months after quinacrine insertions; however, we believe it is not related to the procedure. An estimated 242 maternal deaths will be averted by these 31,781 sterilizations. This method is safe and acceptably effective for female sterilisation.

Chronic pulmonary infection is the major cause of morbidity and mortality in cystic fibrosis. High levels of DNA in the sputum make the sputum viscous and difficult to expectorate. Recombinant human deoxyribonuclease (rhDNase) in vitro has been shown to reduce the viscoelasticity of the sputum from CF patients. We have done a phase II double-blind randomised placebo-controlled trial in which patients received either 2.5 mg rhDNase twice daily or placebo for 10 days. All patients had forced vital capacity (FVC) above 40% predicted and were clinically stable. Patients were followed up for 42 days from the start of drug/placebo administration. All 71 randomised patients, aged 16-55, completed every aspect of the study and baseline characteristics were similar in the two groups. Baseline forced expiratory volume in one second (FEV1) was 46% of predicted for patients randomised to rhDNase, and 48% for those randomised to placebo; and baseline FVC was 76% of predicted for both groups. The mean percentage change in FEV1 from baseline was a 13.3% rise on rhDNase and a 0.2% fall on placebo (p < 0.001). FVC rose 7.2% in the rhDNase group and 2.3% in the placebo group (not significant). There were no life-threatening adverse events and no anaphylactic reactions. There was no significant difference in side-effects between the groups. This study confirms that short-term administration of rhDNase in stable patients with cystic fibrosis is safe and improves lung function.

Oestradiol-17 beta causes relaxation of isolated coronary arteries and increases blood flow in several vascular beds in human beings and animals. Oestrogen replacement therapy is associated with a lower incidence of cardiovascular disease, but the acute effects of oestradiol-17 beta on myocardial ischaemia are unknown. We have studied the acute effect of sublingual oestradiol-17 beta on exercise-induced myocardial ischaemia in eleven women (mean age 58 [SD 8] years) with coronary artery disease. The women did two treadmill exercise tests on separate days; 40 min before the test they took sublingual oestradiol-17 beta (1 mg) or placebo, in random order. Plasma oestradiol-17 beta concentrations were confirmed to be higher after sublingual oestradiol-17 beta than after placebo (2531 [1192] vs 155 [168] pmol/L, p < 0.001). Oestradiol-17 beta increased both time to 1 mm ST depression (456 [214] vs 579 [191] s, p < 0.004; difference of medians 92 [95% CI 46-254]) and total exercise time (569 [249] vs 658 [193] s, p < 0.01; difference 54 [10-212]). Acute administration of oestradiol-17 beta therefore has a beneficial effect on myocardial ischaemia in women with coronary artery disease. This effect may be due to a direct coronary-relaxing effect, to peripheral vasodilation, or to a combination of these mechanisms. Oestradiol-17 beta may prove to be a useful adjunct to the treatment of angina in postmenopausal women with coronary heart disease.

Early rejection can still complicate renal transplantation even with cyclosporin. We added low-dose allopurinol (25 mg on alternative days) to "triple" immunosuppression with cyclosporin, prednisolone, and azathioprine for twelve recipients of cadaver renal grafts. The controls were fifteen patients on triple therapy alone. Only one rejection episode occurred among the allopurinol-treated patients, whereas eleven controls had rejections (seven with more than one episode). Allopurinol may be toxic when combined with azathioprine, yet the bone marrow tolerated the new regimen well. As expected, reduction of the azathioprine dose was necessary in the treated group.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator that may be involved in the regulation of the peripheral circulation and in its response to cold. There is evidence that CGRP in digital cutaneous perivascular nerves is deficient in Raynaud's phenomenon. Our pilot study of intravenous CGRP suggested that this substance is beneficial in patients with Raynaud's phenomenon; here we have extended our studies. Ten patients with severe Raynaud's phenomenon secondary to connective tissue disease were randomly assigned to groups receiving intravenous CGRP (0.6 micrograms/min for 3 h per day on 5 days) or saline. Hand and digital blood flow and skin temperature were measured by thermocouple and laser doppler flowmetry. Blood flow was significantly (p < 0.05) increased by CGRP in both hands (median blood flow after infusion as percentage of baseline reading 179 [range 100-355]%) and fingers (149 [100-161]%); saline had no effect (hands 102 [84-123]%, fingers 96 [81-113]%). Hand temperature was increased more by CGRP than by saline (2.8 [1.5-4.0] vs 1.0 [-1.0 to 2.5] degrees C, p < 0.05). Digital temperature increased after CGRP but the difference between the treatment groups in temperature rise was not significant, perhaps because saline caused increases in some patients. All ulcers healed in four of five CGRP-treated patients but in no saline-treated patients. Thus intravenous CGRP effectively dilates the compromised digital cutaneous vasculature in severe Raynaud's phenomenon.

Postoperative analgesia is usually inadequate, perhaps because conventional approaches to pain relief do not take account of underlying mechanisms. Pre-emptive analgesia may prevent nociceptive inputs generated during surgery from sensitising central neurons and, therefore, may reduce postoperative pain. In a randomised, double-blind study, we compared the effect of parenteral morphine when given before or after total abdominal hysterectomy in 60 patients. 10 mg of morphine were given intramuscularly 1 hour before operation (im pre), intravenously at induction of anaesthesia (iv pre), or intravenously at closure of the peritoneum (iv post). Response was assessed by morphine consumption from patient-controlled analgesia machines which was found to be significantly reduced in the iv pre group for 24 hours after operation compared with the iv post group. Pain sensitivity around the wound was reduced in both preoperative treatment groups compared with the iv post group. We conclude that pre-emptive analgesia with intravenous morphine, by preventing the establishment of central sensitisation during surgery, reduces postoperative pain, analgesic requirements, and secondary hyperalgesia.

A recombinant human immunodeficiency virus 1 IIIB (HIV-1IIIB) gp120 subunit vaccine (IIIB-rgp120/HIV-1, Genentech) was tested for safety and immunogenicity in a randomised, double-blind, placebo-controlled phase-I trial. HIV-1-seronegative adult volunteers received three 100 micrograms or 300 micrograms doses of IIIB-rgp120/HIV-1 in alum adjuvant (10 vaccinees in each group), or alum adjuvant alone (8 vaccinees), at 0, 4, and 32 weeks by intramuscular injection. The three injections were well tolerated in both vaccine groups. Antibodies that neutralised homologous HIV-1IIIB were induced in 9 of 10 recipients after three 300 micrograms doses, and 6 of these 9 sera also neutralised heterologous HIV-1SF2. A dose response was evident, since three 100 micrograms injections induced lower titres of HIV-1IIIB neutralising antibodies and in fewer recipients (5 of 9) than the higher dose, with no neutralisation of HIV-1SF2. Similarly, syncytia-inhibiting, CD4-rgp120-blocking, and HIV-1IIIB V3-binding antibodies were induced in a dose dependent manner. Response to the 300 micrograms per dose vaccination occurred in a larger proportion of volunteers and at higher mean titres than seen in previous human trials with other recombinant envelope subunit vaccines or live vaccinia-env priming followed by envelope subunit boosting.

Although most studies on the effect of vitamin A supplementation have reported reductions in childhood mortality, the effects on morbidity are less clear. We have carried out two double-blind, randomised, placebo-controlled trials of vitamin A supplementation in adjacent populations in northern Ghana to assess the impact on childhood morbidity and mortality. The Survival Study included 21,906 children aged 6-90 months in 185 geographical clusters, who were followed for up to 26 months. The Health Study included 1455 children aged 6-59 months, who were monitored weekly for a year. Children were randomly assigned either 200,000 IU retinol equivalent (100,000 IU under 12 months) or placebo every 4 months; randomisation was by individual in the Health Study and by cluster in the Survival Study. There were no significant differences in the Health Study between the vitamin A and placebo groups in the prevalence of diarrhoea or acute respiratory infections; of the symptoms and conditions specifically asked about, only vomiting and anorexia were significantly less frequent in the supplemented children. Vitamin-A-supplemented children had significantly fewer attendances at clinics (rate ratio 0.88 [95% CI 0.81-0.95], p = 0.001), hospital admissions (0.62 [0.42-0.93], p = 0.02), and deaths (0.81 [0.68-0.98], p = 0.03) than children who received placebo. The extent of the effect on morbidity and mortality did not vary significantly with age or sex. However, the mortality rate due to acute gastroenteritis was lower in vitamin-A-supplemented than in placebo clusters (0.66 [0.47-0.92], p = 0.02); mortality rates for all other causes except acute lower respiratory infections and malaria were also lower in vitamin A clusters, but not significantly so. Improving the vitamin A intake of young children in populations where xerophthalmia exists, even at relatively low prevalence, should be a high priority for health and agricultural services in Africa and elsewhere.