To speed collection of blood for autologous transfusion during elective surgery, patients may be given recombinant human erythropoietin (r-HuEPO). In a controlled trial, we evaluated the effects of r-HuEPO on perioperative red-blood-cell and serum erythropoietin (s-EPO) production in patients donating blood before elective orthopaedic surgery. Patients were assigned randomly to receive no r-HuEPO (12 patients), or 3000 U (4), 6000 U (5), or 9000 U (4) of r-HuEPO intravenously twice a week from the time of the first blood donation. All patients received iron sulphate. 1200 ml blood was collected from each patient in three weekly donations of 400 ml. The 3000, 6000, and 9000 U treatment groups produced 284, 350, and 383 ml, respectively, of red cells during donation, and the untreated controls produced 211 ml. s-EPO concentrations were within the normal range during donation. After surgery, s-EPO concentrations peaked on postoperative day 1 in untreated patients and on day 7 in treated patients; therefore, r-HuEPO may suppress endogenous erythropoietin secretion. Although administration of r-HuEPO increases production of red blood cells, the preoperative anaemia induced by repeated phlebotomy without r-HuEPO may accelerate the postoperative secretion of endogenous erythropoietin.

41,299 patients entering 914 hospitals up to 24 h (median 4 h) after the onset of suspected acute myocardial infarction were randomised between streptokinase (SK: 1.5 MU infused over about 1 h), tissue plasminogen activator (tPA, duteplase: 0.60 MU/kg infused over about 4 h), or anisoylated plasminogen-streptokinase activator complex (APSAC), anistreplase: 30 U over about 3 min). All patients were to receive aspirin (162 mg/day enteric-coated), with the first tablet chewed for rapid and full antiplatelet effect. Half of all patients were randomly allocated subcutaneous calcium heparin (12,500 IU starting at 4 h and given twice daily for 7 days or until prior discharge) in addition to aspirin, and the other half were to receive aspirin alone. ASPIRIN PLUS HEPARIN VERSUS ASPIRIN ALONE--The addition of heparin to aspirin was associated with an excess of transfused or other major non-cerebral bleeds (1.0% aspirin plus heparin vs 0.8% aspirin alone; 2p < 0.01) and of definite or probable cerebral haemorrhage (0.56% vs 0.40%; 2p < 0.05), but with no significnat differences in total stroke (1.28% vs 1.18%). Reinfarctions were slightly less common among those allocated aspirin plus heparin (3.16% vs 3.47%; 2p = 0.09). There was no signficant difference in the pre-specified endpoint of 35-day mortality (2132 [10.3%] aspirin plus heparin vs 2189 [10.6%] aspirin alone). During the scheduled heparin treatment period there were slightly fewer deaths in the aspirin plus heparin group (days 0-7 in hospital: 1534 [7.4%] vs 1633 [7.9%]; 2 p = 0.06), with a slight convergence by day 35 (598 further deaths [3.1% of survivors] vs 556 [2.9%]). The pattern was similar to that observed in the GISSI-2 trial, so that in both trials combined there was a significant reduction in mortality during the scheduled treatment period (2071 [6.8%] vs 2239 [7.3%]; 2p < 0.01). This indicates avoidance of 5 deaths (SD 2) per 1000 patients allocated this high-dose subcutaneous heparin regimen in addition to aspirin, but some of any early benefit may be lost after heparin ceases, with no significant mortality advantage in days 0-35 (both trials: 3100 [10.0%] vs 3172 [10.2%]) or during follow-up to 6 months. SK VERSUS APSAC--APSAC was associated with significantly more reports of allergy causing persistent symptoms and of non-cerebral bleeds, but not of transfused bleeds or of reinfarctions. There was a slight excess of strokes with APSAC (1.04% SK vs 1.26% APSAC; 2p = 0.08), much of it appearing soon after treatment started (strokes during days 0-1: 0.50% SK vs 0.73% APSAC; 2p < 0.02) and being attributed to cerebral haemorrhage (0.24% SK vs 0.55% APSAC; 2p < 0.0001). No significant difference was observed in reinfarction (3.47% SK vs 3.55% APSAC). There was no significant mortality difference during days 0-35, either among all randomised patients (1455 [10.6%] SK vs 1448 [10.5%] APSAC) or among the pre-specified subset presenting within 0-6 h of pain onset and with ST elevation on the electrocardiogram in whom fibrinolytic treatment may have most to offer (861 [10.0%] SK vs 855 [9.9%] APSAC). No significant difference in 6-month survival was apparent overall or in the subset.(ABSTRACT TRUNCATED AT 400 WORDS)

Although exercise may be beneficial in cystic fibrosis (CF), patients' low tolerance to climatic heat stress means that physical exertion can increase morbidity and mortality. We postulated that the high salt content of CF patients' sweat and the consequent absence of body-fluid hyperosmolality during a long episode of sweating might deprive such patients of a thirst stimulus. Eight children with CF (four boys, four girls; aged 9.5-14.1 years) and eight controls, matched for age and sex, attended two randomly ordered sessions of exercise (cycling) in a chamber at 31-33 degrees C, relative humidity 43-47%. 20 min bouts of exercise (at 45% of predetermined maximum oxygen uptake) were interspersed with 25 min rest periods. At one session, chilled water was given every 15-20 min to replace fluid lost; at the other, drinking was guided by the child's thirst. At the thirst-guided session, CF patients drank much less than the controls did (0.80% vs 1.73% initial body weight) and lost twice as much fluid (1.57% vs 0.78% initial body weight). The recovery of heart rate after exercise was slower in CF patients, but there were no other signs of heat strain. The groups did not differ in any variable during the forced drinking session. We conclude that children with CF underestimate their fluid needs and undergo excessive dehydration during extended exposure to hot conditions.

Attempts to prevent peritoneal carcinomatosis after surgery for gastric cancer by intraperitoneal administration of anticancer drugs have not been successful, largely because the drugs are not retained in the peritoneal cavity. We have assessed the prophylactic efficacy of a delayed-release preparation--mitomycin adsorbed onto activated charcoal (M-CH). 50 patients with gastric cancer and serosal infiltration were randomly assigned intraperitoneal treatment with M-CH (50 mg mitomycin intraoperatively) or no anticancer prophylaxis (control). Survival rates for the 3 years of follow-up were significantly higher among the 24 M-CH recipients (1 was lost to follow-up) than among the 25 controls (p less than 0.01). There were significant differences in survival between the groups at 1.5 years after randomisation (difference 34.6% [95% confidence interval 8.5-60.8%]; p less than 0.01) and at 2.0, 2.5, and 3.0 years (41.7% [14.2-69.1%]; p less than 0.005). The concentration of mitomycin was significantly higher in peritoneal exudate than in plasma for 24 h after drug administration. Side-effects were slight and well tolerated. Thus, peroperative intraperitoneal treatment with M-CH seems to improve survival after gastrectomy for gastric cancer, presumably by a prophylactic effect on peritoneal recurrence.

Familial defective apolipoprotein B-100 (FDB) is an autosomal dominant disorder associated with hypercholesterolaemia in which an aminoacid substitution in apoprotein B-100 leads to low-density lipoprotein (LDL) particles which have defective binding to the LDL receptor. All known patients are heterozygous, and their plasma contains normal and poorly binding LDL particles. 12 hypercholesterolaemic patients from 10 unrelated families with FDB were treated with lovastatin. In 6 patients treated with 20 mg lovastatin daily, LDL cholesterol decreased by 21.5% from 6.23 to 4.89 mmol/l (95% confidence interval 0.74, 1.96 mmol/l), whereas it fell by 32.1%, from 6.99 to 4.81 mmol/l (95% CI 1.55, 2.70 mmol/l), in 9 patients who received 40 mg daily. These results indicate that the hypercholesterolaemia of FDB may respond to treatment with statins.

To assess the effect of dietary reduction of plasma cholesterol concentrations on coronary atherosclerosis, we set up a randomised, controlled, end-point-blinded trial based on quantitative image analysis of coronary angiograms in patients with angina or past myocardial infarction. Another intervention group received diet and cholestyramine, to determine the effect of a greater reduction in circulating cholesterol concentrations. 90 men with coronary heart disease (CHD), who had a mean (SD) plasma cholesterol of 7.23 (0.77) mmol/l were randomised to receive usual care (U, controls), dietary intervention (D), or diet plus cholestyramine (DC), with angiography at baseline and at 39 (SD 3.5) months. Mean plasma cholesterol during the trial period was 6.93 (U), 6.17 (D), and 5.56 (DC) mmol/l. The proportion of patients who showed overall progression of coronary narrowing was significantly reduced by both interventions (U 46%, D 15%, DC 12%), whereas the proportion who showed an increase in luminal diameter rose significantly (U 4%, D 38%, DC 33%). The mean absolute width of the coronary segments (MAWS) studied decreased by 0.201 mm in controls, increased by 0.003 mm in group D, and increased by 0.103 mm in group DC (p less than 0.05), with improvement also seen in the minimum width of segments, percentage diameter stenosis, and edge-irregularity index in intervention groups. The change in MAWS was independently and significantly correlated with LDL cholesterol concentration and LDL/HDL cholesterol ratio during the trial period. Both interventions significantly reduced the frequency of total cardiovascular events. Dietary change alone retarded overall progression and increased overall regression of coronary artery disease, and diet plus cholestyramine was additionally associated with a net increase in coronary lumen diameter. These findings support the use of a lipid-lowering diet, and if necessary of appropriate drug treatment, in men with CHD who have even mildly raised serum cholesterol concentrations.

Lithium carbonate is an effective drug for prophylaxis and treatment of major affective disorders. In-utero exposure to lithium during the first trimester of pregnancy might be associated with an increased risk of cardiac malformations, especially the rare Ebstein's anomaly. We prospectively recruited and followed 148 women (mean age 30 years, SD 5 range 15-40) using lithium during the first trimester of pregnancy, who consulted four teratogen information centres in the USA and Canada. Pregnancy outcome was compared with that of controls matched for maternal age. We had complete follow-up of pregnancy outcome in 138 of 148 patients recruited. In the other 10, fetal echocardiograms were available but postnatal follow-up was not done. Mean daily dose of lithium was 927 mg (SD 340). Rates of major congenital malformations did not differ between the lithium (2.8%) and control (2.4%) groups. 1 patient in the lithium group chose to terminate pregnancy after Ebstein's anomaly was detected by a prenatal echocardiogram. There was 1 ventricular septal defect in the controls. Birthweight was significantly higher in the lithium-exposed infants than in the controls despite identical gestational ages (3475 [660] g vs 3383 [566] g, p = 0.02). The true difference in birthweight might have been even larger, since significantly more women using lithium than controls were cigarette smokers (31.8% vs 15.5%, p = 0.002). These results indicate that lithium is not an important human teratogen. Women with major affective disorders who wish to have children may continue lithium therapy, provided that adequate screening tests, including level II ultrasound and fetal echocardiography, are done.

Although prenatal glucocorticoid treatment reduces neonatal respiratory morbidity, respiratory distress syndrome and chronic lung disease (CLD) develop in many very-low-birthweight infants despite therapy. To investigate the effect of additional prenatal treatment with thyrotropin-releasing hormone (TRH), we did a multicentre, blinded, randomised trial. 404 women with threatened preterm delivery at less than 32 weeks' gestation received betamethasone plus TRH (4 doses of 400 micrograms 8-hourly) or betamethasone plus placebo. 103 infants who were fully treated and of less than 1500 g birthweight were evaluated during the neonatal period. TRH treatment (55 infants) did not affect the total incidence of respiratory distress syndrome (47% vs 58% in controls) or of severe respiratory distress syndrome (13% vs 25% in controls, p = 0.11). CLD (defined as requirement for supplemental oxygen at 28 days after birth) developed in significantly fewer TRH-treated infants (18% vs 44% of controls, p less than 0.01). The unadjusted relative risk of CLD with TRH therapy was 0.40 (95% CI 0.26-0.80, p less than 0.05), and this was not materially changed after adjustment for potentially modifying variables. There were significantly fewer adverse outcomes, defined as death or continuing oxygen requirement, in the TRH group than in the steroid-alone group both at 28 days and when infants reached 36 weeks' postconceptional age. The incidence of other complications of prematurity was similar in the two groups. Prenatal TRH reduces the incidence of chronic lung disease among betamethasone-treated infants.

To improve evaluation of new antiretroviral drugs in the acquired immunodeficiency syndrome (AIDS), sensitive biological markers that accurately predict response to treatment are needed. Two possible markers are endogenous interferon (E-IFN), which is a cytokine involved in the pathophysiology of AIDS, and serum triglycerides (TG), which are raised in patients with AIDS, possibly reflecting enhanced cytokine activity. E-IFN, TG, body-mass index, CD4 count, and HIV p24 were measured in 19 patients (15 with AIDS, 4 with AIDS-related complex), who were part of the phase II licensing trial of zidovudine (ZDV). 10 received ZDV and 9 received placebo. Rapid, significant, and sustained declines from initial values in E-IFN and TG concentrations were observed in ZDV patients but not in placebo patients. Baseline values of E-IFN and TG concentrations after 4 months on ZDV treatment were both important contributors to long-term survival. The findings suggest that these indicators of abnormal cytokine expression may be useful measures of not only disease severity but also efficacy of antiretroviral therapy in AIDS.

Antiphospholipid antibodies have been suggested as markers for a high risk of recurrent cardiovascular events in young survivors of an acute myocardial infarction. However, there are few data to confirm or refute this hypothesis. In a cohort study, we have measured anticephalin (aCEPHA) and anticardiolipin (aCL) antibodies in a group of patients surviving an acute infarct. Of 597 patients studied, 13.2% were IgG or IgM aCEPHA positive compared with 4.4% of a reference population (n = 158; p = 0.002). In a multivariate analysis, adjusted for major cardiovascular risk factors, neither aCEPHA (IgG or IgM) nor a CL (IgG or IgM) was an independent risk factor for mortality, reinfarction, or non-haemorrhagic stroke. Although an increased proportion of survivors of a myocardial infarction have antiphospholipid antibodies, the presence of such antibodies is not a risk factor for subsequent coronary or cerebrovascular thrombosis.

In an attempt to find a vaccine that gives greater and more consistent protection against leprosy than BCG vaccine, we compared BCG with and without killed Mycobacterium leprae in Venezuela. Close contacts of prevalent leprosy cases were selected as the trial population since they are at greatest risk of leprosy. Since 1983, 29,113 contacts have been randomly allocated vaccination with BCG alone or BCG plus 6 x 10(8) irradiated, autoclaved M leprae purified from the tissues of infected armadillos. We excluded contacts with signs of leprosy at screening and a proportion of those whose skin-test responses to M leprae soluble antigen (MLSA) were 10 mm or more (positive reactions). By July, 1991, 59 postvaccination cases of leprosy had been confirmed in 150,026 person-years of follow-up through annual clinical examinations of the trial population (31 BCG, 28 BCG/M leprae). In the subgroup for which we thought an effect of vaccination was most likely (onset more than a year after vaccination, negative MLSA skin-test response before vaccination), leprosy developed in 11 BCG recipients and 9 BCG/M leprae recipients; there were 18% fewer cases (upper 95% confidence limit [CL] 70%) in the BCG/M leprae than in the BCG alone group. For all cases with onset more than a year after vaccination irrespective of MLSA reaction the relative efficacy was 0% (upper 95% CL 54%; 15 cases in each vaccine group). Retrospective analysis of data on the number of BCG scars found on each contact screened suggested that BCG alone confers substantial protection against leprosy (vaccine efficacy 56%, 95% CL 27-74%) and there was a suggestion that several doses of BCG offered additional protection. There is no evidence in the first 5 years of follow-up of this trial that BCG plus M leprae offers substantially better protection against leprosy than does BCG alone, but the confidence interval on the relative efficacy estimate is wide.

In view of the potential of low-molecular-weight heparins (LMWH) to simplify initial therapy and allow outpatient treatment of proximal deep-vein thrombosis, we undertook a randomised comparison of fixed-dose subcutaneous LMWH with adjusted-dose intravenous standard heparin in the initial treatment of this disorder. Our main objectives were to compare the efficacy of these regimens for 6 months of follow-up and to assess the risk of clinically important bleeding. Of 170 consecutive symptomatic patients with venographically proven proximal deep-venous thrombosis, 85 received standard heparin (to achieve an activated partial thromboplastin time of 1.5 to 2.0 times the pretreatment value) and 85 LMWH (adjusted only for body weight) for 10 days. Oral coumarin was started on day 7 and continued for at least 3 months. The frequency of recurrent venous thromboembolism diagnosed objectively did not differ significantly between the standard-heparin and LMWH groups (12 [14%] vs 6 [7%]; difference 7% [95% confidence interval -3% to 15%]; p = 0.13). Clinically important bleeding was infrequent in both groups (3.5% for standard heparin vs 1.1% for LMWH; p greater than 0.2). We conclude that fixed-dose subcutaneous LMWH is at least as effective and safe as intravenous adjusted-dose heparin in the initial treatment of symptomatic proximal-vein thrombosis. Since there is no need for laboratory monitoring with the LMWH regimen, patients with venous thrombosis can be treated at home.