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.

Whether antibiotic prophylaxis can prevent bacterial endocarditis is hotly debated. In an attempt to settle this issue, we have assessed the efficacy of prophylaxis for bacterial endocarditis on native valves in a nationwide, case-control study in the Netherlands. Cases were patients with known cardiac disease in whom endocarditis developed within 180 days of a medical or dental procedure for which prophylaxis was indicated. Of a total of 438 patients with endocarditis diagnosed during 2 years, 48 were eligible for the study. Controls were patients with the same cardiac status in whom endocarditis did not develop within 180 days of a similar procedure; of a total of 889 controls from five hospitals, 200 were eligible. Overall, about 1 in 6 patients in both groups had received prophylaxis. The best estimate of protective efficacy was 49% for first-ever endocarditis occurring within 30 days of a procedure. Endocarditis developed within 30 days of a procedure in only 13% of patients with a previously diagnosed heart lesion which predisposed to the disease. The findings suggest that strict adherence to generally accepted recommendations for prophylaxis might do little to decrease the total number of patients with endocarditis in the community.

Cutaneous wheal and flare responses to increasing concentrations of calcitonin gene-related peptide, substance P, neurokinin A, vasoactive intestinal polypeptide (VIP), compound 48/80, and phosphate-buffered saline were measured in 10 patients with chronic idiopathic urticaria and 10 healthy controls. A significant increase in VIP-induced wheal, but not flare or cutaneous blood flow, was seen in urticarial patients compared with controls (p less than 0.001). No significant differences in responses to other tested compounds were found between these groups. These data point to an increased sensitivity of microvasculature to VIP in patients with chronic idiopathic urticaria.

Most fetuses in developed countries are exposed in utero to diagnostic ultrasound examination. Many pregnant women express concern about whether the procedure harms the fetus. Since most routine ultrasound examinations are done at weeks 16-22, when the fetal brain is developing rapidly, effects on neuronal migration are possible. We have sought an association between routine ultrasonography in utero and reading and writing skills among children in primary school. At the age of 8 or 9 years, children of women who had taken part in two randomised, controlled trials of routine ultrasonography during pregnancy were followed-up. The women had attended the clinics of 60 general practitioners in central Norway during 1979-81. The analysis of outcome was by intention to treat: 92% of the "screened" group had been exposed to ultrasound screening at weeks 16-22, and 95% of controls had not been so exposed, but there was some overlap. 2428 singletons were eligible for follow-up, and the school performance of 2011 children (83%) was assessed by their teachers on a scale of 1-7; the teachers were unaware of ultrasound exposure status. A subgroup of 603 children underwent specific tests for dyslexia. There were no statistically significant differences between children screened with ultrasound and controls in the teacher-reported school performance (scores for reading, spelling, arithmetic, or overall performance). Results from the dyslexia test sample showed no differences between screened children and controls in reading, spelling, and intelligence scores, or in discrepancy scores between intelligence and reading or spelling. The test results classified 21 of the 309 screened children (7% [95% confidence interval 3-10%]) and 26 of the 294 controls (9% [4-12%]) as dyslexic. The risk of having poor skills in reading and writing was no greater for children whose mothers had been offered routine ultrasonography than for those whose mothers had not been offered the procedure.

To reduce the likelihood of thrombophlebitis during intravenous feeding through a peripheral vein, the osmolality of the solution is usually reduced by disproportionately raising the lipid content and lowering the carbohydrate, electrolyte, and aminoacid concentrations. The possibility that delivery system rather than feed is the main influence on the development of thrombophlebitis was examined in a randomised comparison of a fine-bore silicone catheter against a short 'Teflon' cannula. The nutrient solution given through a peripheral vein was a standard feed used for infusion into a central vein (osmolality 1250 mOsmol/kg, 13 g nitrogen, 200 g glucose [800 kcal], and lipid emulsion [1000 kcal]). 27 patients received the infusion through a fine-bore silicone rubber catheter (diameter 23 G, length 15 cm) and 23 through a teflon catheter (diameter 20 G, length 3.2 cm). The median duration of feeding was 5 days in each of the two groups. Thrombophlebitis developed in all patients in the teflon group but in only 2 (7%) of the silicone group. The first silicone catheter for a patient lasted a median of 128.5 h, compared with 40 h for the first teflon cannula (p less than 0.001). The results show that when a nutrient solution of osmolality 1250 mOsmol/kg is delivered through a peripheral vein with an ultrafine-bore silicone catheter, the risk of thrombophlebitis is low. For many patients intravenous feeding may thus be given through a peripheral instead of a central vein without compromising the nutritional adequacy of the feed.

A randomised, phase I/II, double-blind, placebo-controlled study was designed to assess the effect of topically applied recombinant human BB homodimeric platelet-derived growth factor (rPDGF-BB) on healing of chronic pressure ulcers. Twenty patients were randomly allocated daily treatment for 28 days with 1, 10, or 100 micrograms/ml rPDGF-BB (0.01, 0.1, or 1.0 micrograms per cm2 ulcer area) or placebo. Patients treated with 100 micrograms/ml rPDGF-BB showed a greater healing response than the placebo group, but the lower doses had little effect. After 28 days, ulcers treated with 100 micrograms/ml rPDGF-BB were smaller than those treated with placebo (mean [SE] volume 6.4 [4.0] vs 21.8 [5.6]% of day 0 volume). There were no toxic effects. These preliminary findings suggest that rPDGF-BB is a potent wound-healing agent in soft tissue.

Laparoscopy is frequently associated with postoperative shoulder pain that may last several days. We have assessed the analgesic effect of intraperitoneal local anaesthetics during day-case diagnostic laparoscopy. 80 young women were randomly assigned to one of four groups of 20 patients each: group 1, no peritoneal administration; group 2, 80 ml saline injected under direct vision in the right subdiaphragmatic area at the start of the procedure; group 3, 80 ml 0.5% lignocaine with adrenaline (320,000 dilution); group 4, 0.125% bupivacaine with adrenaline (800,000 dilution). Scapular pain was assessed with a visual analogue pain scale, and information about nausea, vomiting, abdominal pain, and analgesic requirements during the first 48 h was sought. Both local anaesthetics were more effective in reducing postoperative shoulder pain than either control or saline. Analgesic requirements were greater in the non-treatment groups than in the local anaesthetic groups. Intraperitoneal local anaesthetic administration during laparoscopy is both a non-invasive and an efficient method of reducing the intensity of scapular pain.

Sunlight exposure is reported by some patients to precede onset of recurrent herpes labialis. Ultraviolet (UV) B light is known to be a stimulus for the reactivation of herpes simplex virus (HSV) infections. We assessed the effect of a sunblocking agent on UV-light-induced reactivation of recurrent herpes labialis in a double-blind, placebo-controlled crossover trial. 38 patients were exposed on two separate occasions to four minimum erythema doses of UV light at an area of previous labial herpes recurrence. A solution containing sunscreen was applied to the lips before one exposure and a matched placebo before the other. After placebo and UV exposure, herpes labialis developed in 27 (71%) of the 38 patients, with a mean time to recurrence of 2.9 (SEM 0.2) days. In contrast, when sunscreen was applied before UV exposure, no lesions developed, but 1 of the 35 patients shed virus at the exposure site. We conclude that UV light is a potent stimulus for inducing reactivation of herpes labialis, and that application of sunscreen may be effective in the prevention of sunlight-induced recurrent infection.

Erythropoietin significantly, reversibly, and reproducibly increased in-vitro whole-blood spontaneous platelet aggregation in 15 patients on haemodialysis. During erythropoietin treatment, spontaneous platelet aggregation was significantly higher in these subjects than in non-uraemic controls; concomitant treatment with 300 mg aspirin daily reversed platelet hyperaggregability. Erythropoietin may promote thrombosis by an effect on platelet function.

The efficacy of aspirin in daily doses of 300 mg and more as secondary prophylaxis after cerebrovascular events is well established. Since much lower doses of aspirin can inhibit platelet function, and carry a lower risk of adverse effects, the Swedish Aspirin Low-dose Trial (SALT) was set up to study the efficacy of 75 mg aspirin daily in prevention of stroke and death after transient ischaemic attack (TIA) or minor stroke. 1360 patients entered the study 1-4 months after the qualifying event: 676 were randomly assigned to aspirin treatment and 684 to placebo treatment. The median duration of follow-up was 32 months. Compared with the placebo group, the aspirin group showed a reduction of 18% in the risk of primary outcome events (stroke or death; relative risk 0.82, 95% confidence interval 0.67-0.99; log-rank analysis p = 0.02), and reductions of 16-20% in the risks of secondary outcome events (stroke; stroke or two or more TIAs within a week of each other necessitating a change of treatment; or myocardial infarction). Adverse drug effects were reported by 147 aspirin-treated and 123 placebo-treated patients Gastrointestinal side-effects were only slightly more common in the aspirin-treated patients, but that group had a significant excess of bleeding episodes (p = 0.04). Thus, we have found that a low dose (75 mg/day) of aspirin significantly reduces the risk of stroke or death in patients with cerebrovascular ischaemic events.

Increased parasympathetic tone does not fully explain the night-time bronchoconstriction responsible for nocturnal cough and wheezing in asthmatic subjects. The overnight variation in function of the other neural pathway innervating bronchial smooth muscle--the non-adrenergic, non-cholinergic (NANC) system--was thus examined. NANC function was tested after parasympathetic and beta-adrenergic blockade in 12 normal subjects and 12 patients with mild asthma by comparing the bronchodilator effect (measured as oscillatory resistance, Ros) of capsaicin (an NANC stimulant) at 0400 h with that at 1600 h. The order in which capsaicin or diluent was given was randomised, and observers were blind as to which substance had been inhaled. Bronchodilatation was greater at 1600 h than at 0400 h in both the normal subjects (mean decrease in Ros 1-3 min after capsaicin at 1600 h 9% [SEM 1], at 0400 h -2% [1]; p less than 0.001) and the asthmatic group (1% [1], -7% [2]; p = 0.001). The results suggest that inhibition of NANC function in the early morning may contribute to overnight bronchoconstriction.

B-subunit/whole-cell cholera vaccine (BS-WC) has been shown to give Bangladeshi mothers and children only 3 months' protection against severe diarrhoea due to enterotoxigenic Escherichia coli (ETEC). Since a long-lasting effect is not necessary for protection against travellers' diarrhoea, a prospective double-blind study was conducted among tourists who went to Morocco from Finland. 307 tourists received two oral doses of BS-WC, whereas 308 controls received a placebo before departure. A research team went out with tourists and a laboratory for enteric pathogens was set up on location. A faecal specimen was taken from 100 randomly selected subjects before departure, from all travellers with diarrhoea, and routinely after return. Enteropathogenic bacteria were not isolated from any of the pre-departure specimens but were present during or after the holiday in 47% of tourists with travellers' diarrhoea, and in 14% of those without diarrhoea. BS-WC induced a 52% protection (p = 0.013) against diarrhoea caused by ETEC. The protection was better for mixed infections (65%, p = 0.016). The protective efficacy against a combination of ETEC and any other pathogen was 71% (p = 0.02), and that against ETEC plus Salmonella enterica even better at 82% (p = 0.01). Partial protection against travellers' diarrhoea is thus obtainable by active immunisation with BS-WC.

Although the benefits of antihypertensive treatment in "young" elderly (under 70 years) hypertensive patients are well established, the value of treatment in older patients (70-84 years) is less clear. The Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) was a prospective, randomised, double-blind, intervention study set up to compare the effects of active antihypertensive therapy (three beta-blockers and one diuretic) and placebo on the frequency of fatal and non-fatal stroke and myocardial infarction and other cardiovascular death in hypertensive Swedish men and women aged 70-84 years. We recruited 1627 patients at 116 health centres throughout Sweden, who were willing to participate, and who met the entry criteria of three separate recordings during a 1-month placebo run-in period of systolic blood pressure between 180 and 230 mm Hg with a diastolic pressure of at least 90 mm Hg, or a diastolic pressure between 105 and 120 mm Hg irrespective of the systolic pressure. The total duration of the study was 65 months and the average time in the study was 25 months. 812 patients were randomly allocated active treatment and 815 placebo. The mean difference in supine blood pressure between the active treatment and placebo groups at the last follow-up before an endpoint, death, or study termination was 19.5/8.1 mm Hg. Compared with placebo, active treatment significantly reduced the number of primary endpoints (94 vs 58; p = 0.0031) and stroke morbidity and mortality (53 vs 29; p = 0.0081). Although we did not set out to study an effect on total mortality, we also noted a significantly reduced number of deaths in the active treatment group (63 vs 36; p = 0.0079). The benefits of treatment were discernible up to age 84 years. We conclude that antihypertensive treatment in hypertensive men and women aged 70-84 confers highly significant and clinically relevant reductions in cardiovascular morbidity and mortality as well as in total mortality.

Immunoglobulin treatment for whooping cough (pertussis) is widely believed to be ineffective although there are sound reasons for regarding the condition as a toxin-induced disease. We wondered whether the lack of success with pertussis immunoglobulins might be attributable to inadequate dose, so we designed a randomised, double-blind, placebo-controlled trial of two immunoglobulin preparations. The study was conducted at three Swedish hospitals. We enrolled 73 children aged less than 36 months who were admitted with a clinical diagnosis of whooping cough. On admission they were assigned to one of three groups: (a) monocomponent pertussis toxoid vaccine; (b) two-component acellular vaccine also containing filamentous haemagglutinin; or (c) 20% albumin solution (placebo). The immunoglobulins had a high antitoxin content and had been raised with acellular pertussis vaccines. Diagnosis of pertussis was confirmed by laboratory tests and the follow-up was completed in 67 children. The main study group consisted of 47 children with less than or equal to 14 days of disease before therapy. Duration of whoops post-treatment was 8.7 days (95% Cl 4.8, 12.6) in the 33 children receiving immunoglobulin vs 20.6 (95% Cl 11.9, 29.3) in the 14 receiving placebo (p = 0.0041). Mean number of whoops during the first week of follow-up was also significantly reduced (p = 0.0196). We found that early treatment was important, since the effect on duration of whoops was most pronounced when disease duration before treatment was less than or equal to 7 days. There were no significant differences between the two immunoglobulin preparations. High-dose specific pertussis immunoglobulin with a high antitoxin concentration has a beneficial effect in the treatment of whooping cough.