Eradication of Helicobacter pylori from the stomach by triple therapy with bismuth, tetracycline, and metronidazole cures peptic ulcer disease. We investigated whether concomitant acid inhibition with omeprazole would improve the results of triple therapy. 108 consecutive patients with peptic-ulcer disease and biopsy-proven H pylori infection were randomised to 7 days of triple therapy with or without omeprazole 20 mg twice daily. Patients in the omeprazole-treated group were pretreated with 3 days of omeprazole. Eradication of H pylori was assessed by 10 endoscopic biopsies for urease test, histology, and culture 4-6 weeks after treatment. 53 of 54 (98.1%) patients treated with omeprazole were cured compared with 45 of 54 (83.3%) of those not treated (p = 0.02), a difference in efficacy of 14.8% (95% Cl 4.2-25.4%). Most side effects were mild and did not interfere with compliance; 105 patients (97.2%) finished treatment. Gastro-intestinal side effects were significantly fewer in the omeprazole group. We conclude that the addition of omeprazole to triple therapy improves efficacy, lessens side effects, and is sufficiently efficacious to obviate the need for a diagnostic test of cure in compliant patients.

Low-density-lipoprotein (LDL) apheresis has the theoretical advantage over anion-exchange resins and hydroxymethylglutaryl coenzyme A inhibitors of decreasing lipoprotein(a) as well as LDL. To confirm this advantage, patients with heterozygous familial hypercholesterolaemia and coronary artery disease were randomised to receive LDL apheresis fortnightly (with disposable dextran sulphate/cellulose columns) plus simvastatin 40 mg daily, or colestipol 20 g plus simvastatin 40 mg daily. Quantitative coronary angiography was repeated after a mean of 2.1 years in 20 patients undergoing apheresis and in 19 on combination drug therapy. Changes in serum lipoproteins were similar in both groups apart from greater lowering by apheresis of LDL cholesterol (3.2 vs 3.4 mmol/L in drug group, p = 0.03) and lipoprotein(a) (geometric means 14 vs 21 mg/dL, p = 0.03). There were no significant differences in primary angiographic endpoints per patient but lesion-based and segment-based secondary endpoints were biased in favour of the drug group (change in minimum lumen diameter of lesions 0.07 vs -0.004 mm, p = 0.046; change in mean lumen diameter of segments 0.02 vs -0.06 mm, p = 0.01). None of the angiographic changes correlated with lipoprotein(a) concentrations. Per patient changes in % diameter stenosis and minimum lumen diameter in the two groups were as or more favourable than those observed in five published trials that assessed lipid-lowering drug therapy by quantitative coronary angiography. Although LDL apheresis combined with simvastatin was more effective than colestipol plus simvastatin in reducing LDL cholesterol and lipoprotein(a), it was less beneficial in influencing coronary atherosclerosis and should be reserved for patients unresponsive to drugs. Decreasing lipoprotein(a) seems to be unnecessary if LDL cholesterol is reduced to 3.4 mmol/L or less.

The rate of postoperative recovery is determined by pain, stress-induced organ dysfunction, and limitations in conventional postoperative care. We attempted to provide "stress-free" colonic resection for neoplastic disease in eight elderly high-risk patients by a combination of laparoscopically assisted surgery, epidural analgesia, and early oral nutrition and mobilisation. Effective pain relief allowed early mobilisation, and hospital stay was reduced to 2 days without nausea, vomiting, or ileus. Postoperative fatigue and impairment in functional activity were avoided. Major advances in postoperative recovery can be achieved by early aggressive perioperative care in elderly high-risk patients undergoing colonic surgery.

The care programme approach was introduced in mental health services in the UK in 1991. It was intended to improve the quality of care and prevent patients losing contact with care services and, by implication, to reduce psychiatric admissions. We did a study to find out if the approach worked. 400 patients from a London inner-city area who had been identified as psychiatrically vulnerable and included on a case register of patients with special needs were randomised into two groups of 200 each. One group received close supervision by nominated key-workers (as recommended in the care programme approach of the UK Department of Health), and the other received standard follow-up from psychiatric and social services. Outcome was recorded after eighteen months. Data on 393 patients was available for analysis. Of 197 patients allocated to standard care, 64 (32.5%) were lost to follow-up compared with 40 (20.4%) of 196 patients receiving close supervision (p = < 0.005). However, patients under close supervision had significantly more admissions (30% vs 18%, chi 2 = 7.61, p < 0.01) and spent 68% more days in hospital than the standard group. The findings of greater hospital-bed use, which differ from those of studies with community-based psychiatric teams, suggest that close supervision by a single key worker, as recommended in the care programme approach, will lead to greater success in maintaining contact with vulnerable patients, but is likely to lead to more psychiatric admissions.

For patients with gastric cancer deemed curable the only treatment option is surgery, but there is disagreement about whether accompanying lymph-node dissection should be limited to the perigastric nodes (D1) or should extend to regional lymph nodes outside the perigastric area (D2). We carried out a multicentre randomised comparison of D1 and D2 dissection. 1078 patients were randomised (539 to each group). 26 allocated D1 and 56 allocated D2 were found not to satisfy eligibility criteria (histologically confirmed adenocarcinoma of the stomach without clinical evidence of distant metastasis). Each of the remainder was attended by one of eleven supervising surgeons who decided whether curative resection was possible and, if so, assisted with the allocated procedure. Among the 711 patients (380 D1, 331 D2) judged to have curable lesions, D2 patients had a higher operative mortality rate than D1 patients (10 vs 4%, p = 0.004) and experienced more complications (43 vs 25%, p < 0.001). They also needed longer postoperative hospital stays (median 25 [range 7-277] vs 18 [7-143] days, p < 0.001). Morbidity and mortality differences persisted in almost all subgroup analyses. While we await survival results, D2 dissection should not be used as standard treatment for western patients.

Cyclospora is a coccidian (previously referred to as cyanobacterium-like bodies) that has been implicated in cases of prolonged diarrhoea. The average duration of symptoms is more than three weeks, and no specific treatment has been shown to shorten the illness. A case report suggested that co-trimoxazole may be effective. Expatriate persons with gastrointestinal complaints and cyclospora detected on examination of faeces were recruited from two clinics in Kathmandu, Nepal, between May and August, 1994. Participants were assigned in a randomised, double-blinded manner to receive either cotrimoxazole (160 mg trimethoprim, 800 mg sulphamethoxazole) or placebo tablets twice daily for 7 days. Of 40 patients included in the study, 21 received cotrimoxazole and 19 placebo. There were no significant differences between these two groups in age, sex, time in Nepal, duration or severity of illness, or presence of other enteric pathogens. After 3 days, 71% of patients receiving co-trimoxazole still had cyclospora detected, compared with 100% of patients receiving placebo (p = 0.016). After 7 days, cyclospora was detected in 1 (6%) of 16 patients treated with co-trimoxazole who submitted stool specimens compared with 15 (88%) of 17 patients receiving placebo (p < 0.0001). Eradication of the organism was correlated with clinical improvement. There was no evidence of relapse of infection among treated patients followed for an additional 7 days. Treatment with co-trimoxazole for 7 days was effective in curing cyclospora infection among an expatriate population in Nepal.

13,634 patients entering 650 Chinese hospitals up to 36 h after the onset of suspected acute myocardial infarction (MI) were randomised between one month of oral captopril (6.25 mg initial dose, 12.5 mg 2 h later, and then 12.5 mg three times daily) or matching placebo. Captopril was associated with a non-significant reduction in 4-week mortality (617 [9.05%] captopril-allocated vs 654 [9.59%] placebo-allocated deaths; 2p = 0.3). There was a significant excess of hypotension, mostly early after the start of treatment, but no evidence of any adverse effect on early mortality (even among patients who were hypotensive at entry). Taken together with the other trials of converting enzyme inhibitors started early in acute MI, these results indicate that such therapy is generally safe and typically prevents about 5 deaths per 1000 patients treated for the first month.

58,050 patients entering 1086 hospitals up to 24 h (median 8 h) after the onset of suspected acute myocardial infarction (MI) with no clear contraindications to the study treatments (in particular, no cardiogenic shock or persistent severe hypotension) were randomised in a "2 x 2 x 2 factorial" study. The treatment comparisons were: (i) 1 month of oral captopril (6.25 mg initial dose titrated up to 50 mg twice daily) versus matching placebo; (ii) 1 month of oral controlled-release mononitrate (30 mg initial dose titrated up to 60 mg once daily) versus matching placebo; and (iii) 24 h of intravenous magnesium sulphate (8 mmol initial bolus followed by 72 mmol) versus open control. There were no significant "interactions" between the effects of these three treatments, and the results for each are based on the randomised comparison of about 29,000 active versus 29,000 control allocated patients. Captopril There was a significant 7% (SD 3) proportional reduction in 5-week mortality (2088 [7.19%] captopril-allocated deaths vs 2231 [7.69%] placebo; 2p = 0.02), which corresponds to an absolute difference of 4.9 SD 2.2 fewer deaths per 1000 patients treated for 1 month. The absolute benefits appeared to be larger (perhaps about 10 fewer deaths per 1000) in certain higher-risk groups, such as those presenting with a history of previous MI or with heart failure. The survival advantage appeared to be maintained in the longer term (5.4 [SD 2.8] fewer deaths per 1000 at 12 months). Captopril was associated with an increase of 52 (SD 2) patients per 1000 in hypotension considered severe enough to require termination of study treatment, of 5 (SD 2) per 1000 in reported cardiogenic shock, and of 5 (SD 1) per 1000 in some degree of renal dysfunction. It produced no excess of deaths on days 0-1, even among patients with low blood pressure at entry. Mononitrate There was no significant reduction in 5-week mortality, either overall (2129 [7.34%] mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined (including those receiving short-term non-study intravenous or oral nitrates at entry). Further follow-up did not indicate any later survival advantage. The only significant side-effect of the mononitrate regimen studied was an increase of 15 (SD 2) per 1000 in hypotension. Those allocated active treatment had somewhat fewer deaths on days 0-1, which is reassuring a bout the safety of using nitrates early in acute MI.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunosuppression with cyclosporin after renal transplantation is associated with better graft survival than is azathioprine treatment. However, nephrotoxicity and other side-effects have led to regimens that change treatment to azathioprine shortly after transplantation. Conversion has beneficial effects in the short term on renal function and hypertension. We report long-term follow-up (minimum 5 years) of 128 patients who had received a first or second cadaveric kidney graft and were treated with cyclosporin and prednisone; they were randomly assigned 3 months after transplantation to groups continuing to receive cyclosporin (n = 68) or changing to azathioprine (n = 60). 8 years after transplantation, patient survival was 75.3% in the cyclosporin group and 85.9% in the azathioprine group (p = 0.14) and graft survival was 64.0% and 76.6%, respectively (p = 0.38). The frequency of cardiovascular death with a functioning graft was 8% higher in the cyclosporin group (95% CI -1 to 18). The relative risk of graft loss after conversion to azathioprine compared with graft loss after conversion to azathioprine compared with cyclosporin maintenance was 0.71 (0.37-1.38) and the relative risk of patient death was 0.57 (0.23-1.41). The cyclosporin group had poorer mean creatinine clearance (17.8 mL/min [8.1-27.5] lower than azathioprine group) and a higher proportion needed hypertensive drugs (20% [4-36] more). Gout was found in 9 cyclosporin-treated patients and 1 azathioprine-treated patient (difference 12% [3 to 20]). Elective conversion from cyclosporin to azathioprine 3 months after transplantation is safe and cost-effective.

A low myocardial content of alpha-ketoglutarate during heart surgery might aggravate ischaemic injury. 24 men undergoing coronary surgery participated in a randomised controlled study. 28 g alpha-ketoglutarate was added to blood cardioplegia for intermittent antegrade intracoronary perfusion in 13 cases. alpha-ketoglutarate reduced the appearance in blood of the ischaemic markers creatine kinase MB and troponin T (at 4 h after release of aortic cross-clamp; median [95% CI] 49 [37-60] micrograms/L in controls vs 32 [27-37] micrograms/L for creatine kinase MB, 2.0 [1.2-2.8] vs 1.1 [0.8-1.4] micrograms/L for troponin T). These findings signify attenuated ischaemic injury, possibly secondary to enhanced myocardial oxidative capacity.

Methotrexate, a mainstay treatment for children with acute lymphoblastic leukaemia, can cause neurotoxicity, with paralysis, seizures, somnolence, anorexia, and headaches. The pathophysiology of this reaction is unknown. It has been suggested that the anti-inflammatory effect of methotrexate in patients with arthritis is due to adenosine release brought on by inhibition of purine synthesis. Since adenosine is a central nervous system depressant, we wondered whether adenosine release in the central nervous system could account for some of the neurotoxicity due to methotrexate, and whether that toxicity could be lessened by displacement of adenosine from its receptor by aminophylline. 6 patients (age 3-16 years) who had methotrexate-induced neurotoxicity unresponsive to standard treatment received 2.5 mg/kg aminophylline. In addition, the concentration of adenosine in the cerebrospinal fluid (CSF) from 11 children completing a 24-h systemic methotrexate protocol was compared with that in 8 newly diagnosed patients and 12 who had not received any treatment for at least a week. 4 of 6 patients with toxic signs and symptoms attributed to methotrexate and unrelieved by steroids, epidural blood patch, promethazine, 5-hydroytryptamine antagonists, paracetamol, and narcotics, had complete resolution of neurotoxicity after or during a 1-h infusion of aminophylline; 2 others had a pronounced improvement but persistent nausea. CSF adenosine concentrations of patients receiving methotrexate, even when there was very slight or no toxicity, were greatly increased compared with control subjects (mean values of 217 and 51 nmol/L, median 175 and 52 nmol/L). Subacute methotrexate neurotoxicity may be mediated by adenosine and relieved by aminophylline.

The value of hyperthermia as an adjuvant to radiotherapy in patients with malignant melanoma was studied in a European multicentre trial. 134 metastatic or recurrent lesions of malignant melanoma in 70 patients were randomly assigned to receive radiotherapy (three fractions of 8 Gy or 9 Gy in 8 days) alone or followed by hyperthermia (43 degrees C for 60 min). Overall, the 2-year actuarial local tumour control was 37 (SE 5)%. Univariate analysis showed a beneficial effect of hyperthermia (radiation alone 28% vs combined treatment 46%, p = 0.008) and radiation dose (24 Gy 25% vs 27 Gy 56%, p = 0.02), but no effect of tumour size (< or = 4 cm 42% vs > 4 cm 29%, p = 0.21). Cox multivariate regression analysis showed the most important prognostic variables to be hyperthermia (odds ratio for 2-year local control 1.73 [95% CI 1.07-2.78], p = 0.023), tumour size (0.91 [0.85-0.99], p = 0.05), and radiation dose (1.17 [1.01-1.36], p = 0.05). Addition of heat did not significantly increase acute or late radiation reactions. Heating was well tolerated, but because of difficulties with equipment only 14% of treatments achieved the protocol objective. The overall 5-year survival rate was 19%, but 38% of the patients for whom all known disease was controlled survived 5 years. Adjuvant hyperthermia significantly improved local tumour control when applied in association with radiation in treatment of malignant melanoma. Successful local treatment of patients with a single or a few metastatic malignant melanoma lesions has significant curative potential.

Feedback can be described as a way to provide information on doctors' performance to enable changes in future behaviour. Feedback is used with the aim of changing test-ordering behaviour. It can lead to reductions in test usage and cost savings. It is not sufficiently clear, however, whether feedback leads to more appropriate test use. Since 1985, the Diagnostic Coordinating Center Maastricht has been giving feedback on diagnostic tests as a routine health care activity to all family doctors in its region. Both quantity and quality of requests are discussed. In a randomised, controlled trial over 2.5 years, discussion of tests not included previously was added to the existing routine feedback. One group of family doctors (n = 39) received feedback on test-group A (electrocardiography, endoscopy, cervical smears, and allergy tests), the other (n = 40) on test-group B (radiographic and ultrasonographic tests). Thus, each group of doctors acted as a control group for the other. Changes in volume and rationality of requests were analysed. The number of requests decreased during the trial (p = 0.036). Request numbers decreased particularly for test-group A (p = 0.04). The proportion of requests that were non-rational decreased more in the intervention than in the control groups (p = 0.009). Rationality improved predominantly for test-group B (p = 0.043). Thus, routine feedback can change the quantity and quality of requests.

Interventions to avoid atherosclerosis might be more successful if launched early in life when eating and life-style patterns are formed, but dietary interventions have been limited by fears of diet-induced growth failure. We investigated the effects of a diet low in saturated fat and cholesterol on serum lipid concentrations and growth in 1062 healthy 7-month-old infants in a randomised study. Every 1-3 months, families in the intervention group received dietary advice aimed at adequate energy supply, with low fat intake (30-35% energy, polyunsaturated/monounsaturated/saturated fatty acid ratio 1/1/1, and cholesterol intake < 200 mg daily). Infants in control families consumed an unrestricted diet. 3-day food records were collected at ages 8 and 13 months. Growth was carefully monitored. Between 7 and 13 months serum cholesterol and non-high-density-lipoprotein cholesterol concentrations did not change significantly in the intervention group (mean change -0.03 [SD 0.72] mmol/L and 0.01 [0.67] mmol/L) but increased substantially in the control group (0.24 [0.64] mmol/L and 0.23 [0.60] mmol/L; p for difference in mean changes between groups < 0.001). Daily intakes of energy and saturated fat were lower in the intervention than in the control group at 13 months (4065 [796] vs 4370 [748] kJ, p = 0.033, and 9.3 [3.5] vs 14.5 [4.8] g, p < 0.001, respectively), and intake of polyunsaturated fat was higher (5.8 [2.2] vs 4.4 [1.4] g, p < 0.001). Growth did not differ between the groups and was as expected for children at this age. Serum cholesterol concentrations fell significantly in parents of intervention-group infants. The increases in serum cholesterol and non-high-density-lipoprotein cholesterol concentration that occur in infants between the ages of 7 and 13 months can be avoided by individualised diets, with no effect on the children's growth.

Lamotrigine has been licensed widely as adjunctive therapy for partial and secondary generalised seizures. Use of the drug as monotherapy was investigated in a double-blind, randomised, parallel-group comparison with carbamazepine in newly diagnosed epilepsy. After 4 weeks of planned, fixed dose escalation, doses were adjusted according to efficacy, adverse events, and plasma concentrations. 151 of 260 patients (131 lamotrigine, 129 carbamazepine) in eight UK centres completed the 48-week trial. No differences in efficacy between the drugs were found for partial seizures with or without secondary generalisation or for primary generalised tonic-clonic seizures. The proportion of patients maintained seizure-free during the last 24 weeks of treatment was almost the same in both groups (39% lamotrigine, 38% carbamazepine). More patients with primary generalised tonic-clonic seizures (47% both groups) than those presenting with a focal onset (35%, 37%) were fully controlled. Overall, fewer patients on lamotrigine than on carbamazepine withdrew because of adverse events (15 vs 27%). The commonest side-effect leading to withdrawal with either drug was rash (9%, 13%). Sleepiness was less common in lamotrigine than in carbamazepine recipients (12 vs 22%, p < 0.05). More lamotrigine than carbamazepine recipients (65 vs 51%, p = 0.018) completed the study (hazard ratio 1.57 [95% CI 1.07-2.31]). Lamotrigine and carbamazepine showed similar efficacy against partial onset seizures and primary generalised tonic-clonic seizures in newly diagnosed epilepsy. Lamotrigine, however, was better tolerated.