Administration of the mitochondria-targeted anti-oxidant mitoquinone significantly decreased plasma ALT and aspartate aminotransferase in patients with chronic HCV infection, and this suggests that mitoquinone may decrease necroinflammation in the liver in these patients. As mitochondrial oxidative damage contributes to many other chronic liver diseases, such as steatohepatitis, further studies using mitochondria-targeted anti-oxidants in HCV and other liver diseases are warranted.

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu II -trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and ␤ 1 integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.

OBJECTIVE: To investigate the long-term effects of changes in dietary carbohydrateafat ratio and simple vs complex carbohydrates. DESIGN: Randomized controlled multicentre trial (CARMEN), in which subjects were allocated for 6 months either to a seasonal control group (no intervention) or to one of three experimental groups: a control diet group (dietary intervention typical of the average national intake); a low-fat high simple carbohydrate group; or a low-fat high complex carbohydrate group. SUBJECTS: Three hundred and ninety eight moderately obese adults. MEASUREMENTS: The change in body weight was the primary outcome; changes in body composition and blood lipids were secondary outcomes. RESULTS: Body weight loss in the low-fat high simple carbohydrate and low-fat high complex carbohydrate groups was 0.9 kg (P`0.05) and 1.8 kg (P`0.001), while the control diet and seasonal control groups gained weight (0.8 and 0.1 kg, NS). Fat mass changed by 7 1.3 kg (P`0.01), 7 1.8 kg (P`0.001) and 0.6 kg (NS) in the low-fat high simple carbohydrate, low-fat high complex carbohydrate and control diet groups, respectively. Changes in blood lipids did not differ signi®cantly between the dietary treatment groups. CONCLUSION: Our ®ndings suggest that reduction of fat intake results in a modest but signi®cant reduction in body weight and body fatness. The concomitant increase in either simple or complex carbohydrates did not indicate signi®cant differences in weight change. No adverse effects on blood lipids were observed. These ®ndings underline the importance of this dietary change and its potential impact on the public health implications of obesity.

We recently showed that treatment with the Cu II -selective chelator, trientine, alleviates heart failure in diabetic rats, improves left ventricular hypertrophy in humans with type 2 diabetes, and increases urinary Cu excretion in both diabetic rats and humans compared with nondiabetic control subjects. In this study, we characterized the homeostasis of Cu and eight other nutritionally essential elements in diabetes under fully residential conditions in male subjects with type 2 diabetes and age-matched control subjects. We then probed elemental balance with oral trientine in a parallel-group, placebo-controlled study in these subjects. Before treatment, there were no detectable between-group differences in the balance of any element, although urinary output of several elements was greater in diabetic subjects. Mean extracellular superoxide dismutase (EC-SOD) activity was elevated in diabetic subjects, and its activity correlated strongly with the interaction between [Cu] serum and HbA 1c . Trientine caused the Cu balance to become negative in diabetic subjects through elevated urinary Cu losses and suppressed elevated EC-SOD. Basal urinary Cu predicted urinary Cu losses during treatment, which caused extraction of systemic Cu II . We suggest that cardiovascular complications in diabetes might be better controlled by therapeutic strategies that focus on lowering plasma glucose and loosely bound systemic Cu II .

SummaryBackgroundThe propagation of prions, the causative agents of Creutzfeldt-Jakob disease and other human prion diseases, requires post-translational conversion of normal cellular prion protein to disease-associated forms. The antimalarial drug quinacrine (mepacrine) prevents this conversion in vitro, and was given to patients with various prion diseases to assess its safety and efficacy in changing the course of these invariably fatal and untreatable diseases.MethodsPatients with prion disease were recruited via the UK national referral system and were offered a choice between quinacrine (300 mg daily), no quinacrine, or randomisation to immediate quinacrine or deferred quinacrine in an open-label, patient-preference trial. The primary endpoints were death and serious adverse events possibly or probably related to the study drug. This study is registered, ISRCTN 06722585.Findings107 patients with prion disease (45 sporadic, two iatrogenic, 18 variant, and 42 inherited) were enrolled, 23 in a pilot study and 84 in the main study. Only two patients chose randomisation; 40 took quinacrine during follow-up (37 who chose it at enrolment). Choice of treatment was associated with disease severity, with those least and most severely affected more likely to choose not to receive quinacrine. 78 (73%) patients died: one randomly assigned to deferred treatment, 26 of 38 who chose immediate quinacrine, and 51 of 68 who chose no quinacrine. Although adjusted mortality was lower in those who chose to take quinacrine than in those who did not, this was due to confounding with disease severity, and there was no difference in mortality between groups after adjustment. Four of 40 patients who took quinacrine had a transient response on neurological rating scales. Only two of 14 reported serious adverse events were judged quinacrine-related.InterpretationQuinacrine at a dose of 300 mg per day was reasonably tolerated but did not significantly affect the clinical course of prion diseases in this observational study.FundingDepartment of Health (England); UK Medical Research Council.

A low-fat, high-polysaccharide diet in overweight individuals with abnormal intermediary metabolism led to moderate weight loss and some improvement in serum cholesterol. Increasing simple carbohydrates did not promote weight gain, but nor was there improvement in body weight or lipid profile.

The effect of beta-glucan-enriched barley on lipid profile was highly variable between subjects, and there was no evidence of a clinically significant improvement in CVD risk across this group of mildly hyperlipidemic men.

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