Hepatitis C virus (HCV) can be transmitted by transplantation of cadaver organs from donors with antibody to HCV (anti-HCV); therefore, transplantation of organs from anti-HCV positive donors to anti-HCV-negative recipients has been discouraged. We have looked at outcomes in recipients of organs from anti-HCV positive and negative donors to determine whether this advice is well-founded. Stored sera from 716 consecutive cadaver organ donors procured by the New England Organ Bank between 1986 and 1990 were tested for anti-HCV by a first-generation ELISA (ELISA1); 13 (1.8%) were positive. 29 recipients who received organs from these donors were the study group. 37 donors were randomly selected from 703 ELISA1-negative cadaver organ donors. 74 recipients of organs from these 37 donors were the control group. Clinical records were reviewed and recipient sera were tested for anti-HCV with a second-generation ELISA (ELISA2), and HCV RNA was tested for by polymerase chain reaction. Median post-transplant follow-up was 42 and 49 months for study and control groups. Post-transplantation prevalence of anti-HCV and HCV RNA was 67% and 96% among recipients from anti-HCV-positive donors, and 20% and 18% among recipients from anti-HCV-negative donors (p < 0.001). Post-transplantation non-A, non-B hepatitis, graft loss, and death were observed in 55%, 52%, and 31% among recipients of organs from anti-HCV-positive donors, and 16%, 53%, and 33% among recipients from anti-HCV-negative donors. In a proportional hazards model, the relative risks for non-A, non-B hepatitis, graft loss, and death among recipients from anti-HCV-positive donors were 4.37 (95% CI 1.97-9.70), 0.93 (0.51-1.70), and 0.89 (0.41-1.93). Transmission of HCV infection by organ transplantation increased the risk of liver disease among recipients. However, after 3.5 years, donor HCV infection did not adversely affect patient survival or graft survival.

Exertional rhabdomyolysis can destroy muscle but the pathophysiology is unknown. Using intracellular selective microelectrodes, we found that intracellular Ca2+ concentration ([Ca2+]i) was 1.27 (0.17) mumol/L (median and interquartile range) in skeletal-muscle biopsy specimens from patients with exertional rhabdomyolysis compared with 0.12 (0.01) mumol/L in controls. 3 days treatment with dantrolene, a drug that inhibits Ca2+ release from the sarcoplasmic reticulum, decreased [Ca2+]i to 0.22 (0.05) mumol/L and accelerated patients' recovery. This study demonstrated that exertional rhabdomyolysis is associated with elevated [Ca2+]i, and that dantrolene has a beneficial effect in this syndrome.

We investigated the effect of heparin on urinary albumin excretion in patients with insulin-dependent diabetes mellitus. 39 patients with persistent urinary albumin excretion of 30-300 mg/24 h were randomly treated for 3 months with subcutaneous injections twice daily of isotonic saline, 5000 IU unfractionated heparin, or 2000 anti-Xa IU low-molecular-weight heparin. Unfractionated and low-molecular-weight heparin induced a significant reduction in urinary albumin excretion (p = 0.04 and p = 0.004). The mechanism and clinical relevance is unknown but deserve further attention.

Case management arose in the USA as a solution to the difficulties of providing community care to people with severe mental disorders. The basic principle of the approach is that a case manager takes responsibility for a client; arranges an assessment of need, a comprehensive service plan, delivery of suitable services, and monitoring and assessment of services delivered. The case-management approach has been widely accepted, to the extent that recent legislation has made case-management the cornerstone of community care in the UK. We did a randomised controlled trial to evaluate a social services case-management team for people with long-term mental disorders. Subjects were referred from hostels for the homeless, night shelters, a general-practitioner clinic for the homeless, the Oxford City Council homelessness unit, and local voluntary-sector group homes. Of 103 subjects referred, 80 consented to be randomised to treatment or control groups. At 14-month follow-up, as assessed by standardised interviews, there were no significant differences between groups in number of needs, quality of life, employment status, quality of accommodation, social behaviour, or severity of psychiatric symptoms. In the case-management group there was a significant reduction in deviant behaviour on a standardised behaviour rating scale (REHAB) (mean = 0.79; 95% CI 0.26-1.32). It is unfortunate, in view of the limited effectiveness we have shown, that social services case-management was not evaluated in randomised controlled trials before its implementation in the UK.

Immunoglobulins (IgG) as replacement therapy in primary antibody deficiencies can be given as intramuscular injections, or as intravenous or subcutaneous infusions. Our aims were to obtain information on the frequency of adverse systemic reactions during subcutaneous therapy, the occurrence and intensity of tissue reactions at the infusion sites, and serum IgG changes. Furthermore, we compared costs between the different replacement regimes. Our study included 165 patients (69 women, 96 men, aged 13-76 years) with primary hypogammaglobulinaemia or IgG-subclass deficiencies. Data were compiled from questionnaires filled in by the patients and from their medical records. 33,168 subcutaneous infusions (27,030 in home therapy) had been given. 106 (of which 16 were at home) adverse systemic reactions (100 mild, 6 moderate) were recorded in 28 patients (17%). No severe or anaphylactoid reactions occurred. Despite large immunoglobulin volumes given during 434 patient years (28,480 infusions), no signs have been found that indicate the transmission of hepatitis virus. Transient tissue reactions occurred at the infusion sites but were not troublesome to most patients and we found significant increases in mean serum IgG. The use of subcutaneous instead of intravenous infusions at home would reduce the yearly cost per patient for the health-care sector by US $10,100 in Sweden alone. We conclude that subcutaneous administration of IgG is a safe and convenient method of providing immunoglobulins. We were able to reach serum IgG concentrations similar to those by the intravenous therapy and we found that the method could also be used successfully in patients with previous severe or anaphylactoid reactions to intramuscular injections.

The efficacy of adjuvant chemotherapy after surgery for colorectal cancer remains unproven. We have investigated the efficacy of a perioperative intraportal cytotoxic regimen in a randomised trial of 533 patients with operable colorectal carcinoma. Patients were randomly assigned either a single course of portal infusion with mitomycin (10 mg/m2, one dose) plus fluorouracil (500 mg/m2 per 24 h for 7 days) starting immediately after surgery, or no adjuvant treatment. 505 (94%) were evaluable. At median follow-up of 8 years, adjuvant therapy reduced the risk of recurrence by 21% (hazard ratio 0.79 [95% CI 0.62-1.00], p = 0.051) and the risk of death by 26% (0.74 [0.57-0.97], p = 0.026). The lower risk of relapse was observed in all subgroups based on node status or localisation of the tumour; the risk reduction was greatest in patients with tumour-involved lymph nodes (Dukes' C; 0.67 [0.45-0.99], p = 0.045) and for those with colon cancer (0.78 [0.56-1.09], p = 0.151). Most of the difference in overall and disease-free survival could be attributed to a consistent reduction of all kinds of tumour recurrences (local relapses, liver metastases, and other distant metastases) in the treated group, rather than to a reduction of liver relapses only. We conclude that part of the benefit obtained with a single course of adjuvant chemotherapy via the portal vein for patients with operable colorectal carcinoma might be due to the systemic effects of the portal chemotherapy.

In animals, intermittent sympathomimetic stimulation with dobutamine produces benefits analogous to those of physical conditioning. Longer intermittent or continuous beta-stimulant therapies have not, however, been successful in managing patients with chronic heart failure. We have investigated the role of beta-receptor stimulants in patients with severe chronic heart failure by changing the method of administration to intermittent, very short-duration pulsed intrope therapy (PIT). We studied 10 patients (mean age 64 [SE 2] years) with stable moderate to severe chronic heart failure (ejection fraction 23 [3]%) who received PIT, and 10 control patients matched for age and severity. We infused sufficient dobutamine to raise heart rate to 70-80% maximum for 30 min per day, 4 days per week for 3 weeks. PIT increased exercise tolerance (from 10.4 [1.2] min at baseline to 13.0 [1.5] min at 3 weeks; p < 0.001, 95% CI for difference 1.6 to 3.9) and lowered peripheral vascular resistance (19.8 [3.1] to 17.7 [2.4] mm Hg.min.L-1; p < 0.05, -4.1 to -0.1). PIT produced significant increases in lymphocyte beta-receptor density (502 [110] to 1200 [219] per cell, p < 0.02, 258 to 1138) and chronotropic responsiveness to exercise (change in heart rest to peak exercise 51.0 [3.2] to 57.5 [3.9] beats per min; p < 0.01, 2.9-10.1). Plasma noradrenaline concentrations (2.39 [0.28] to 1.65 [0.19] nmol/L, p < 0.05) were reduced. The patients' symptoms were also improved. By contrast, no change in autonomic function or exercise capacity was seen in the control group. Short-duration PIT induces pharmacological conditioning with improved symptoms, autonomic balance, exercise tolerance, beta-receptor up-regulation, and enhanced chronotropic responsiveness in chronic heart failure.

In developed countries, use of oral rehydration salts (ORS) solution with osmolarity lower than that of plasma has been recommended because of the risk of hypernatraemia. We compared the clinical efficacy of reduced-osmolarity ORS and standard ORS solutions in children with acute diarrhoea in four developing countries. 447 boys aged 1-24 months, admitted to hospitals in four countries with acute diarrhoea and signs of dehydration, were randomly assigned either standard ORS (311 mmol/L) or reduced-osmolarity ORS (224 mmol/L) solution. Total stool output was 39% greater (95% CI 11-75), total ORS intake 18% greater (3-33), and duration of diarrhoea 22% longer (2-45) in the standard ORS group than in the reduced-osmolarity ORS group. The risk of requiring intravenous infusion after completion of the initial oral rehydration was greater in children given standard ORS solution than in those given reduced-osmolarity ORS solution in three of the four countries (all-country relative risk 1.4 [0.9-2.4]). This relative risk was significantly increased only in non-breastfed children (2.0 [1.0-3.8], p < 0.05). In breastfed children, the relative risk of requiring intravenous infusion was not affected by the ORS solution (0.9 [0.4-2.0]). The mean sodium concentration 24 h after admission was significantly lower in the reduced-osmolarity ORS group than in the standard ORS group (135 [134-136] vs 138 [136-139] mmol/L, p < 0.01). Reduced-osmolarity ORS solution has beneficial effects on the clinical course of acute diarrhoea. Our findings support the use of reduced-osmolarity ORS solution in children with acute non-cholera diarrhoea in developing countries. Further studies are needed to find the best formulation and whether such a solution would be satisfactory for the treatment of cholera.

Screening and carotid endarterectomy have been advocated for asymptomatic carotid stenosis. However, the risk of stroke without treatment has not been adequately defined. We investigated the risk of stroke in the distribution of the asymptomatic carotid artery in 2295 patients randomised in the European Carotid Surgery Trial. During a mean follow-up of 4.5 years, there were 69 carotid territory strokes, nine of which were fatal, giving three year Kaplan-Meier risks of stroke and fatal stroke of 2.1% (95% Cl, 1.5-2.8) and 0.3% (95% Cl, 0.06-0.56) respectively. The stroke risk in the 127 patients with severe (70-99%) carotid stenosis was 5.7% (95% Cl, 1.5-9.8). Given these low stroke risks, the potential benefit of endarterectomy for asymptomatic carotid stenosis is small. Population screening is not justified and endarterectomy for asymptomatic carotid stenosis should only be performed in the context of well organised randomised controlled trials.