Many relapses of systemic lupus erythematosus (SLE) are preceded by a rise in antibodies against double-stranded DNA (anti-dsDNA). We investigated whether these relapses can be prevented by giving prednisone when a rise in anti-dsDNA occurs. 156 patients with SLE were studied. Anti-dsDNA was measured by Farr assay monthly. When a rise in anti-dsDNA was found, patients were randomly assigned either conventional treatment or 30 mg prednisone added to the current daily dose and tapering off to baseline over 18 weeks. A rise in anti-dsDNA was detected in 46 patients (24 assigned conventional treatment and 22 prednisolone). The relapse rate was higher in the conventional group than in the prednisolone group (20 vs 2, p < 0.001). Although rises in anti-dsDNA in the prednisone group were treated with additional prednisone, the cumulative oral doses of prednisone in the two groups did not differ significantly (p = 0.025). 7 major relapses requiring additional cytotoxic immunosuppressive treatment occurred in the conventional group versus 2 in the prednisone group. Treatment with prednisone as soon as a significant rise in anti-dsDNA occurs prevents relapse in most cases, without increasing the cumulative dose of prednisdone given.

Topical timolol given for the treatment or chronic simple glaucoma may cause unrecognised bronchospasm among elderly people. We recruited 80 patients aged over 60 years, who were without a history of airways disease and already used timolol, into a randomised crossover study comparing the effects on spirometry and exercise tolerance of changing to betaxolol or dipivefrine therapy. Results showed an increase of 13% and 8% in mean peak flow rate and forced expiratory volume in 1 s (FEV1), respectively, when using betaxolol; and of 14% and 11% when using dipivefrine. There was also improved exercise tolerance with both agents. More than a quarter of the patients showed at least a 15% improvement in FEV1 when changed from timolol. Analysis of enrolment symptoms and response to nebulised salbutamol failed to produce a method of identifying these patients. Timolol may impair respiratory function and exercise tolerance of elderly patients even if they have no history of reversible airways disease.

Medical treatments have become available for benign hypertrophy of the prostate, including alpha-receptor blocking agents and 5-alpha-reductase inhibitors. Drugs derived from plants, for which no precise mechanism of action has been described, are widely used for this purpose in Europe. In a randomised, double-blind, placebo-controlled multicentre study, 200 patients (recruited between April and October 1993) with symptomatic benign prostatic hyperplasia were treated with either 20 mg beta-sitosterol (which contains a mixture of phytosterols) three times per day or placebo. Primary end-point was a difference of modified Boyarsky score between treatment groups after 6 months; secondary end-points were changes in International Prostate Symptom Score (IPSS), urine flow, and prostate volume. Modified Boyarsky score decreased significantly with a mean of -6.7 (SD 4.0) points in the beta-sitosterol-treated group versus -2.1 (3.2) points in the placebo group p < 0.01. There was a decrease in IPSS (-7.4 [3.8] points in the beta-sitosterol-treated group vs -2.1 [3.8] points in the placebo group) and changes in urine flow parameters: beta-sitosterol treatment resulted in increasing peak flow (15.2 [5.7] mL/s from 9.9 [2.5] mL/s), and decrease of mean residual urinary volume (30.4 [39.9] mL from 65.8 [20.8] mL). These parameters did not change in the placebo group (p < 0.01). No relevant reduction of prostatic volume was observed in either group. Significant improvement in symptoms and urinary flow parameters show the effectiveness of beta-sitosterol in the treatment of benign prostatic hyperplasia.

We investigated whether the disparity in neural maturation between breastfed and formula-fed term infants could be corrected by the addition of fish oil, a source of docosahexaenoic acid (DHA, 22:6 omega 3), to infant formula. Healthy, term infants were randomised at birth to receive either a supplemented or placebo formula if their mothers had chosen to bottle feed. Breastfed term infants were enrolled as a reference group. Infant erythrocyte fatty acids and anthropometry were assessed on day 5 and at 6, 16, and 30 weeks of age. Visual evoked potential (VEP) acuity was determined at 16 and 30 weeks. VEP acuities of breastfed and supplemented-formula-fed infants were better than those of placebo-formula-fed infants at both 16 and 30 weeks of age (p < 0.001 and p < 0.01). Erythrocyte DHA in breastfed and supplemented-formula-fed infants was maintained near birth levels throughout the 30-week study period but fell in placebo-formula-fed infants (p < 0.001). Erythrocyte DHA was the only fatty acid that consistently correlated with VEP acuity in all infants at both ages tested. A continuous supply of DHA may be required to achieve optimum VEP acuity since infants breastfed for short periods (< 16 weeks) had slower development of VEP than infants receiving a continuous supply of DHA from either breastmilk or supplemented formula. Erythrocyte arachidonic acid (20:4 omega 6) in supplemented-formula-fed infants was reduced below that of infants fed breastmilk or placebo formula at 16 and 30 weeks (p < 0.001), although no adverse effects were noted, with growth of all infants being similar. DHA seems to be an essential nutrient for the optimum neural maturation of term infants as assessed by VEP acuity. Whether supplementation of formula-fed infants with DHA has long-term benefits remains to be elucidated.

Eclampsia, the occurrence of a seizure in association with pre-eclampsia, remains an important cause of maternal mortality. Although it is standard practice to use an anticonvulsant for management of eclampsia, the choice of agent is controversial and there has been little properly controlled evidence to support any of the options. 1687 women with eclampsia were recruited into an international multicentre randomised trial comparing standard anticonvulsant regimens. Primary measures of outcome were recurrence of convulsions and maternal death. Data are available for 1680 (99.6%) women: 453 allocated magnesium sulphate versus 452 allocated diazepam, and 388 allocated magnesium sulphate versus 387 allocated phenytoin. Most women (99%) received the anticonvulsant that they had been allocated. Women allocated magnesium sulphate had a 52% lower risk of recurrent convulsions (95% CI 64% to 37% reduction) than those allocated diazepam (60 [13.2%] vs 126 [27.9%]; ie, 14.7 [SD 2.6] fewer women with recurrent convulsions per 100 women; 2p < 0.00001). Maternal mortality was non-significantly lower among women allocated magnesium sulphate. There were no significant differences in other measures of serious maternal morbidity, or in perinatal morbidity or mortality. Women allocated magnesium sulphate had a 67% lower risk of recurrent convulsions (95% CI 79% to 47% reduction) than those allocated phenytoin (22 [5.7%] vs 66 [17.1%] ie, 11.4 [SD 2.2] fewer women with recurrent convulsions per 100 women; 2p < 0.00001). Maternal mortality was nonsignificantly lower among women allocated magnesium sulphate. Women allocated magnesium sulphate were also less likely to be ventilated, to develop pneumonia, and to be admitted to intensive care facilities than those allocated phenytoin. The babies of women who had been allocated magnesium sulphate before delivery were significantly less likely to be intubated at the place of delivery, and to be admitted to a special care nursery, than the babies of mothers who had been allocated phenytoin. There is now compelling evidence in favour of magnesium sulphate, rather than diazepam or phenytoin, for the treatment of eclampsia.

Epidural analgesia has a well-established role in labour, but has the drawbacks of delayed onset and motor blockade. The combined spinal-epidural technique may overcome these drawbacks. We carried out a randomised observational study to assess maternal satisfaction with the standard and combined techniques among 197 women in labour. For combined spinal-epidural analgesia, bupivacaine (2.5 mg) and fentanyl (25 micrograms) were initially injected into the subarachnoid space, followed by top-ups of 15 mL 0.1% bupivacaine with 2 micrograms/mL fentanyl into the epidural space, as required. For standard epidural analgesia, 25 mg (10 mL of 0.25%) bupivacaine was injected into the epidural space, followed by top-ups of 6-10 mL 0.25% bupivacaine, as required. Post partum, each woman completed a questionnaire about her labour and scored various items on a visual analogue scale (0 = best, 100 = worst outcome). Overall satisfaction was greater in the combined spinal-epidural group than in the standard epidural group (median [IQR] score 3 [2-10] vs 9 [3-22]; p = 0.0002). Good analgesia was achieved in both groups, but the combined spinal-epidural had faster onset of analgesia and more of this group were satisfied with analgesia at 20 min (92/98 vs 68/99, p < 0.0001). 12 women in the combined spinal-epidural group had leg weakness (as shown by an inability to raise the straight legs) at 20 min, but this initial motor block had resolved in most of these mothers by 1 h. In the standard epidural group 32 had leg weakness at 20 min (p = 0.001), and the proportion of mothers with weakness increased in this group during labour. There were no differences in side-effects, except for mild pruritus, which was more common in the combined spinal-epidural group (42 vs 1%; p < 0.0001). Overall, women seem to prefer the low-dose combined spinal-epidural technique to standard epidurals, perhaps because of the faster onset, less motor block, and feelings of greater self-control.

Interferon-alpha may be better than cytotoxic drugs in the long-term management of patients with chronic myeloid leukaemia (CML) in chronic phase. To test this possibility 587 patients with CML in chronic phase were randomly allocated to receive lymphoblastoid cell-line interferon-alpha n1 (IFN-alpha, n = 293) or chemotherapy with busulphan or hydroxyurea (no IFN-alpha, n = 294) as maintenance after initial induction treatment with cytotoxic drugs. There was a significant survival benefit for patients in the IFN-alpha arm when analysed on the basis of intention to treat (2p = 0.0009). The median survival for those allocated IFN-alpha was 61 months and no IFN-alpha was 41 months. Out of 269 patients with Philadelphia-positive CML in the IFN-alpha arm with at least 6 months follow-up, 211 were evaluable for haematological response: 145 (68%) achieved good responses (A+ or A type), 37 (18%) had partial responses (B type) and 29 (14%) had poor responses (C type). Patients with types A and B responses had a better survival than those in the no IFN-alpha arm; patients with type C responses had survival equivalent to the no IFN-alpha arm. Of these 269 patients, 26 of whom had not started IFN-alpha, 59 (22%) achieved a significant degree of cytogenetic response but 210 (78%) did not have a response. Cytogenetic responders survived significantly longer than non-responders and even non-responders survived longer than patients in the no IFN-alpha arm. Since cytogenetic non-responders had worse than average prognostic features, they may also benefit from IFN-alpha therapy. We conclude that treatment with IFN-alpha prolongs the survival of patients with CML; benefits of IFN-alpha are not confined to cytogenetic responders but may extend to most, if not all patients receiving IFN-alpha treatment; and cytogenetic response to IFN-alpha treatment identifies patients with a relatively good prognosis.

Atelectasis is an important cause of impaired gas exchange during general anaesthesia; it causes pulmonary shunting. We studied the effects of gas composition on the formation of atelectasis and on gas exchange during the induction of general anaesthesia. In 12 adult patients, the lungs were ventilated with 30% oxygen in nitrogen during anaesthesia induction, and in another 12, a conventional technique was used (100% oxygen during induction and 40% oxygen in nitrogen thereafter). Extent of atelectasis was estimated by computed tomography and the ventilation-perfusion relation (VA/Q) by the multiple inert gas elimination technique. After anaesthesia induction, there was little atelectasis in the 30% oxygen group (mean 0.2 [SD 0.4] cm2) and a significantly greater amount (4.2 [5-6] cm2; p < 0.001) in the 100% oxygen group. Patients in the 30% oxygen group were observed for another 40 min. 6 continued to receive 30% oxygen (subgroup A) and 6 were ventilated with 100% oxygen (subgroup B). During this time, the amount of atelectasis increased to 1.6 (1.6) cm2 in subgroup A and to 4.7 (4.5) cm2 in subgroup B (p = 0.047 for difference between groups). In subgroup A, the shunt (VA/Q < 0.005) increased from 1.6 (2.0)% of cardiac output to 3.2 (2.7)%, but the arterial oxygen tension did not change. In subgroup B, the shunt increased from 2.6 (5.2)% to 9.8 (5.7)% of cardiac output. These results suggest that the composition of inspired gas is important in atelectasis formation during general anaesthesia. Use of a lower oxygen concentration than is now standard practice might prevent the early formation of atelectasis.

Administration of 100,000 IU vitamin A at the time of measles immunisation is currently recommended for infants in developing countries. However, the safety and value of giving vitamin A, a potent immune enhancer, with live measles virus vaccines are unknown. We conducted a randomised, double-blind, placebo-controlled clinical trial in Indonesia to evaluate the effect of simultaneous vitamin A supplementation on the immune response to measles immunisation at six months of age. 336 infants received either vitamin A (100,000 IU) or placebo when immunised with standard-titre Schwarz measles vaccine. 82% of infants seroconverted to measles. In a multiple logistic regression model adjusting for maternal antibody titres, vitamin A supplementation was associated with a lower likelihood of seroconversion to measles (odds ratio 0.40, 95% CI 0.19-0.88), and girls were less likely to seroconvert than boys (0.34, 0.15-0.76). Immunisation with standard-titre Schwarz vaccine at six months of age in this study population is characterised by high seroconversion rates. However, simultaneous high-dose vitamin A may interfere with seroconversion to live measles vaccine in infants with maternal antibody.

Preliminary studies suggested that mycophenolate mofetil (MMF), which inhibits proliferation of T and B cells, may reduce the frequency of acute rejection after renal transplantation. Our randomised, double-blind, multicentre, placebo-controlled study compared the efficacy and safety of MMF with placebo for prevention of acute rejection episodes after first or second cadaveric renal allograft transplantation. 491 patients were enrolled; 166 were assigned placebo, 165 MMF 2 g, and 160 MMF 3 g. Patients also received cyclosporin and corticosteroids. Significantly fewer (p < or = 0.001) patients had biopsy-proven rejection or withdrew early from the trial (for any reason) during the first 6 months after transplantation with MMF 2 g (30.3%) or 3 g (38.8%) than with placebo (56.0%). The corresponding percentages for biopsy-proven rejection were 17.0%, 13.8%, and 46.4%. 28.5% of MMF 2 g and 24.4% of MMF 3 g patients needed full courses of corticosteroids or antilymphocyte agents for treatment of rejection episodes in the first 6 months, compared with 51.8% of placebo recipients. By 6 months, 10.2%, 6.7%, and 8.8% of the patients in the placebo, MMF 2 g, and MMF 3 g groups, respectively, had died or lost the graft. Overall, the frequency of adverse events was similar in all treatment groups, although gastrointestinal problems, leucopenia, and opportunistic infections were more common in the MMF groups and there was a trend for more events in the 3 g than the 2 g group. MMF significantly reduced the rate of biopsy-proven rejection or other treatment failure during the first 6 months after transplantation and was well tolerated. The 3 g dose was somewhat less well tolerated.

We examined the relation between the risk of major coronary events (coronary death and non-fatal myocardial infarction) and baseline cholesterol levels in patients with coronary heart disease, randomised to placebo or simvastatin therapy in the Scandinavian Simvastatin Survival Study (4S). The relative risk reduction in the simvastatin group was 35% (95% CI 15-50) in the lowest quartile of baseline low-density-lipoprotein cholesterol and 36% (19-49) in the highest. Simvastatin significantly reduced the risk of major coronary events in all quartiles of baseline total, high-density-lipoprotein, and low-density-lipoprotein cholesterol, by a similar amount in each quartile.

Intravenous heparin has been used in the control of myocardial ischaemia in patients with unstable angina. We set out to assess the efficacy of subcutaneous heparin in reducing myocardial ischaemia in patients with unstable angina. 343 of 399 patients with unstable angina were monitored for 24 h and 108 were refractory to conventional antianginal treatment and were entered into a randomised multicentre trial. 37 patients were assigned to heparin infusion (partial thromboplastin time 1.5-2 times baseline), 35 to subcutaneous heparin (adjusted dose with partial thromboplastin time 1.5-2 times baseline), and 36 to aspirin (325 mg daily). All had additional conventional antianginal therapy. After the run-in patients were monitored for 3 days. The primary endpoint was reduced myocardial ischaemia assessed by the number of anginal attacks, silent ischaemic episodes, and duration of ischaemia per day. At 1 week and 1 month we accounted for anginal attacks and other clinical events (myocardial infarction, revascularisation procedures, and death). Aspirin did not significantly affect the incidence of myocardial ischaemia. On the first 3 days, infused and subcutaneous heparin significantly decreased the frequency of angina (on average by 91% and 86%, respectively), episodes of silent ischaemia (by 56% and 46%), and the overall duration of ischaemia (66% and 61%) versus run-in day and aspirin (p < 0.001 for all variables). The favourable effects of heparin therapy remained evident during follow-up. Only minor bleeding complications occurred. Subcutaneous heparin is effective in the control of myocardial ischaemia in patients with unstable angina.

Graft-versus-host disease (GVHD) is the most important adverse effect of HLA-matched allogeneic bone-marrow transplantation. T-cell depletion of the graft eliminates GVHD but also causes an unacceptable increase in rejections and leukaemic relapses. We have attempted to block the activation of resting T cells with a monoclonal antibody against the interleukin-2 receptor (33B3.1). 101 patients with leukaemia (acute lymphocytic 22, acute myelogenous 34, chronic myeloid 45) in first complete remission or first chronic phase were randomly assigned to groups receiving standard post-transplantation immunosuppression (methotrexate plus cyclosporin; n = 50) or the standard treatment plus antibody 33B3.1 (n = 51). There were 2 graft failures in the 33B3.1 group. The antibody did not significantly affect the cumulative frequency of acute GVHD of grade 2 or worse (19 [38%] vs 23 [46%]) but merely delayed its onset (median 36 [IQR 21-70] vs 25 [11-44] days; p < 0.01). At median follow-up of 58 (range 41-71) months, the antibody-treated group had significantly lower leukaemia-free survival (p < 0.05) mainly because of a progressive increase in the rate of late relapses (p = 0.08). Our findings confirm the importance of T cells in transplantation for leukaemia. The fine balance between the early modulation of transplant immunity and leukaemic control suggests that further anti-leukaemic measures may be needed when attempts are made to improve tolerance between the graft and the leukaemic host.

We compared the cost-effectiveness of therapeutic laparoscopy and open laparotomy for treatment of laparoscopically diagnosed ectopic pregnancy. Clinical outcomes of ectopic pregnancy treatment were based on results of a randomised trial done between 1987 and 1989 at Sahlgrenska University Hospital (Göteborg, Sweden). We estimated costs for inpatient and follow-up care of ectopic pregnancy by the two methods. Observed resource use (eg, procedure duration) was multiplied by 1992 estimates of resource unit cost (eg, cost per minute of laparoscopy time), based on detailed internal cost accounting data from Huddinge University Hospital. By specified criteria, the initial procedure eliminated trophoblastic activity without major complications in 81% (95% CI: 68-90) of 52 laparoscopy patients, versus 95% (85-99) of 57 laparotomy patients. Residual trophoblast or complications were successfully treated in all remaining patients. Mean simulated costs (standard error) for the overall laparoscopy strategy were 28,058 (1780) Swedish kronor versus 32,699 (1080) kronor for laparotomy (p = 0.03). In the baseline simulation and most sensitivity analyses, laparoscopy produced final outcomes equivalent to those of laparotomy at lower costs. As laparoscopic outcomes improve, this newer approach should become increasingly preferable.

Homeless adults often visit emergency departments and often leave dissatisfied. We tested whether compassionate care, by improving patient satisfaction, can alter subsequent use of emergency services. We identified 133 consecutive homeless adults visiting one inner-city emergency department who were not acutely psychotic, extremely intoxicated, unable to speak English, or medically unstable. Half were randomly assigned to receive compassionate contact from trained volunteers. All patients otherwise had usual care and were followed for repeat visits to emergency departments. We found that rates of use were high, with patients making an average of seven visits a year (0.60 per month). More than a third of all patients made two or more visits within two days of each other. The average number of visits per month after intervention was significantly lower for patients who received compassionate care (0.43 vs 0.65, p = 0.018). Analyses adjusting for each patient's previous rate of use confirmed that compassionate care led to a one third reduction in the number of return visits within one month (95% CI 14 to 40%). Compassionate management of selected homeless adults decreases repeat visits to the emergency department. One explanation is that patients tend to return frequently until they are satisfied with their treatment.

In 1984, all non-immune children under the age of 5 years in the Gambian villages of Keneba and Manduar were vaccinated against hepatitis B virus (HBV). All children born in these villages since 1984 have been vaccinated in infancy. Despite a rapid fall in antibody concentrations, vaccine efficacy against HBV infection and chronic carriage of HBsAg has increased with time. Overall, vaccine efficacies in 1993 against HBV infection and chronic HBsAg carriage were 94.7% (95% Cl 93.0-96.0) and 95.3% (91.0-97.5), respectively. Breakthrough infections in vaccinated children largely originate from chronic HBsAg carriers. Thus, we tested 261 chronic carriers for HBV DNA and e antigen. The prevalence of these markers of infectivity, and the amount of HBV DNA, decreased greatly with age. Detailed studies of breakthrough infections over two 4-year periods revealed that in the second period there were fewer than half the expected numbers of infections. Our findings suggest that in Keneba and Manduar long-term vaccination is progressively decreasing HBV transmission by chronic carriers, since their infectivity diminishes with time.