Virological response for recurrent hepatitis C improves long‐term survival in liver transplant recipients

Recurrent hepatitis C virus (HCV) infection occurs universally and is regarded as a major cause of mortality after liver transplantation (LT) for HCV‐related end‐stage liver disease. We conducted this large, single‐center, retrospective study to ascertain the long‐term impact of virological response to treatment of recurrent hepatitis C on survival of LT recipients. From August 1987 to October 2011, 285 patients have received interferon‐based antiviral therapy for recurrent hepatitis C. Of these 285, 245 patients were enrolled in this study. One hundred and twenty‐six patients (51.4%) achieved sustained virological response (SVR). Relapsers (undetectable HCV‐RNA at end of treatment, becoming positive afterward) comprised 9.0% (22/245), and nonresponse (NR; never achieving undetectable HCV‐RNA) 39.6% (97/245). The median follow‐up after completion of antiviral treatment was 2081 days. Using Kaplan–Meier method, patients who achieved SVR were shown to have significantly better 5‐year patient survival (95.2%) than the NR group (49.9%) (P < 0.001), and a trend toward better 5‐year survival than relapsers (87.5%) (P = 0.14); relapsers had a significantly longer survival than NR group (P = 0.005). When compared with NR, SVR and relapse appeared to be significant predictors of better survival, independent of underlying characteristics. In conclusion, virological response, especially SVR, translates into markedly improved long‐term patient outcomes in patients transplanted for hepatitis C.     

Developing service provision for patients in primary care

This article outlines the government's changes to the way that primary and community health services will be commissioned and provided. It also discusses the opportunities that exist for nurses to lead and develop services for the benefit of patients in the implementation of changes.     

Anti-phospholipid antibodies in diabetes mellitus.

The presence of autoantibodies to phospholipids may be associated with various pathological disorders; diabetes could be one of them because of the changes occurring in lipid metabolism but there are only few reports examining this question, and they are not always leading to the same conclusions because of the differences in the procedures or in the phospholipids tested. We carried out a systematic comparative study of diabetic serum antibody binding to all phospholipids, anionic and zwitterionic, by a quantitative ELISA. The implication of the hydrophobic moiety of the lipids was also studied: the presence of autoantibodies to the fatty acyl chains was investigated. Our results show the presence of anti-phospholipid antibodies in diabetic sera, particularly anti-phosphatidylinositol and anti-phosphatidylcholine which have never been tested before, and appear to be associated with macroangiopathic complications. The antigenic epitopes are mainly the polar heads as no antibody binding to the hydrophobic moiety was observed. We discuss the relation of those antibodies to the angiopathic complications and to the direct effects of hyperglycemia on lipid antigenicity.     

HDL in Children with CKD Promotes Endothelial Dysfunction and an Abnormal Vascular Phenotype

Endothelial dysfunction begins in early CKD and contributes to cardiovascular mortality. HDL is considered antiatherogenic, but may have adverse vascular effects in cardiovascular disease, diabetes, and inflammatory conditions. The effect of renal failure on HDL properties is unknown. We studied the endothelial effects of HDL isolated from 82 children with CKD stages 2–5 (HDL^CKD), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDL^CKD strongly inhibited nitric oxide production, promoted superoxide production, and increased vascular cell adhesion molecule-1 expression in human aortic endothelial cells, and reduced cholesterol efflux from macrophages. The effects on endothelial cells correlated with CKD grade, with the most profound changes induced by HDL from patients on dialysis, and partial recovery observed with HDL isolated after kidney transplantation. Furthermore, the in vitro effects on endothelial cells associated with increased aortic pulse wave velocity, carotid intima-media thickness, and circulating markers of endothelial dysfunction in patients. Symmetric dimethylarginine levels were increased in serum and fractions of HDL from children with CKD. In a longitudinal follow-up of eight children undergoing kidney transplantation, HDL-induced production of endothelial nitric oxide, superoxide, and vascular cell adhesion molecule-1 in vitro improved significantly at 3 months after transplantation, but did not reach normal levels. These results suggest that in children with CKD without concomitant disease affecting HDL function, HDL dysfunction begins in early CKD, progressing as renal function declines, and is partially reversed after kidney transplantation.Patients with CKD no longer die from renal failure but from cardiovascular disease. There is an independent, graded association between a reduced eGFR and the risk of death and cardiovascular events.¹ Typically, patients with CKD develop calcification in the tunica media of their arteries,² but a concomitant process of endothelial damage leading to atherosclerosis is also³ present beginning in predialysis CKD.^4,5LDL is crucially involved in the pathogenesis of atherosclerotic cardiovascular disease in the general population,⁶ whereas HDL is thought to be antiatherogenic by promoting reverse cholesterol transport and exerting direct protective endothelial effects.⁷ HDL from healthy participants increases the bioavailability of nitric oxide (NO) by activating endothelial NO synthase inducing vasodilation and decreasing arterial BP. Moreover, HDL diminishes the production of reactive oxygen species such as superoxide (SO) radicals, which have been demonstrated to reduce NO bioavailability leading to endothelial dysfunction and promoting atherogenesis. However, recent evidence suggests that HDL may lose its vasoprotective properties in patients with manifest cardiovascular disease (e.g., coronary artery disease), diabetes, or inflammatory disease states (e.g., antiphospholipid syndrome).^8–10 Similarly, in adults on dialysis, HDL has reduced cholesterol efflux capacity and proinflammatory effects on mononuclear cells.^11–13 Observational studies have shown a strong association between high HDL levels and reduced risk of cardiovascular disease in the general population¹⁴ but not in dialysis patients.¹⁵Cardiac and vascular damage has also been documented in children on dialysis,^2,16,17 and cardiovascular disease accounts for the majority of deaths in pediatric dialysis patients.¹⁷ In contrast with adult patients with CKD, in whom cardiovascular risk factors such as diabetes dyslipidemia, hypertension, and smoking are highly prevalent,¹⁸ CKD in children is mainly caused by inherited disorders such as malformations of the kidney or urinary tract.¹⁸ Accordingly, examining HDL function in children who are free of “traditional” cardiovascular risk factors and underlying inflammatory diseases and who are nonsmokers gives us an unique opportunity to study the effects of renal failure on the vascular functions of HDL.We studied the endothelial properties of HDL in a cohort of children at different stages of CKD on dialysis and after transplantation and compared them with healthy children. Furthermore, to determine the clinical relevance of in vitro effects of HDL, we examined its relationship with clinical measures of the vascular phenotype as well as circulating markers of endothelial dysfunction. Finally, to show a causal link between renal function and HDL properties, we examined children on dialysis and 3 months after kidney transplantation. This study allowed us to examine when HDL dysfunction develops during the natural history of renal decline, its effects on vascular function, and the potential for recovery after kidney transplantation.     

A randomized, placebo controlled trial of an antisense oligodeoxynucleotide to intercellular adhesion molecule-1 in the treatment of severe rheumatoid arthritis

OBJECTIVE: To determine the safety of an antisense oligodeoxynucleotide to intercellular adhesion molecule-1 (ICAM-1) (ISIS 2302), administered in an intensive 4 week regimen with dose escalation; and to provide preliminary evidence for efficacy in rheumatoid arthritis (RA). METHODS: Patients with active RA were enrolled in a 6 month, double blind, placebo controlled, dual center, dose escalation (0.5, 1, and 2 mg/kg) study. Subjects received a total of 13 intravenous ISIS 2302 infusions, given on alternate days for 2 weeks and then 3 times a week for another 2 weeks. Doses of corticosteroids (< or = 10 mg/day) and disease modifying antirheumatic drugs (stable > or = 3 months) remained constant throughout the study. The primary efficacy endpoint was the Day 26 Paulus index, with secondary evaluations at Months 2-6. RESULTS: A total of 43 patients were enrolled with 11, 10, 3, and 19 patients receiving placebo or 0.5, 1, or 2 mg/kg of ISIS 2302, respectively. There were no differences between groups after randomization and the mean baseline swollen joint count was 22.5. Pharmacokinetic studies revealed a T(1/2) of 63 min and first-order kinetics with slight dose dependency, suggesting a saturable clearance process, although no accumulation was noted with repeat dosing. The Paulus 20% responses at Day 26 were 20%, 0%, and 5% for patients treated with ISIS 2302 (0.5, 1, 2 mg/kg, respectively) and 36% with placebo. For Months 2-6, the average intent-to-treat Paulus 20% responses were 21.2% for ISIS 2302 and 12.6% for placebo. Only ISIS 2302 treated subjects (19%) achieved Paulus 50% responses. ISIS 2302 was well tolerated. An expected and transient mean activated partial thromboplastin time increase of roughly 7 s was observed at the highest dose (2 mg/kg), as were small and clinically insignificant increases in serum C3a levels. T/B cell immunophenotyping, recall antigen skin testing, and serum immunoglobulin levels revealed no significant immunosuppressive effects. CONCLUSION: This study shows that 13 ISIS 2302 infusions over 4 weeks are well tolerated in patients with active RA. Although significant efficacy was not evident at the primary endpoint (1 month), the study lacked sufficient power to draw any formal conclusions. We tested a 4-fold drug concentration range, which led to a lower area under the curve range than was therapeutic in a subsequent Crohn's disease trial. Any further evaluation of this well tolerated ICAM-1 antisense agent should therefore be conducted at higher dosing.