Nox2 underpins microvascular inflammation and vascular contributions to cognitive decline

Chronic microvascular inflammation and oxidative stress are inter-related mechanisms underpinning white matter disease and vascular cognitive impairment (VCI). A proposed mediator is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2), a major source of reactive oxygen species (ROS) in the brain. To assess the role of Nox2 in VCI, we studied a tractable model with white matter pathology and cognitive impairment induced by bilateral carotid artery stenosis (BCAS). Mice with genetic deletion of Nox2 (Nox2 KO) were compared to wild-type (WT) following BCAS. Sustained BCAS over 12 weeks in WT mice induced Nox2 expression, indices of microvascular inflammation and oxidative damage, along with white matter pathology culminating in a marked cognitive impairment, which were all protected by Nox2 genetic deletion. Neurovascular coupling was impaired in WT mice post-BCAS and restored in Nox2 KO mice. Increased vascular expression of chemoattractant mediators, cell-adhesion molecules and endothelial activation factors in WT mice post-BCAS were ameliorated by Nox2 deficiency. The clinical relevance was confirmed by increased vascular Nox2 and indices of microvascular inflammation in human post-mortem subjects with cerebral vascular disease. Our results support Nox2 activity as a critical determinant of VCI, whose targeting may be of therapeutic benefit in cerebral vascular disease.     

A systematic review of occupational exposure to synthetic vitreous fibers and mesothelioma

Objective We investigated whether available epidemiological and toxicological data suggest an increased risk of mesothelioma among workers exposed to synthetic vitreous fibers (SVF). Methods We conducted a systematic review of epidemiological studies on the risk of mesothelioma among workers exposed to SVF, and toxicological studies on SVF and mesothelioma. Results Seven cohort studies were conducted among workers employed in production of rock/slag wool, glass wool, or continuous glass filament in the United States, Canada, and Europe. Of the six deaths from mesothelioma identified in these studies, three had exposure to asbestos. A review of death certificates in a study of rock wool production workers identified one additional probable death. A formal comparison with expected deaths is not feasible. Four community-based case–control studies were identified, of which three reported an increased risk among SVF-exposed workers. The number of cases not exposed to asbestos was less, and residual confounding from asbestos exposure misclassification may explain the association in these studies. The toxicology review of SVF suggested that they present a low hazard mostly due to their low biopersistence, typically with a half-life in rat studies of tens of days compared to amphibole asbestos which has a half-life of 400–500 days. Conclusions The combined evidence from epidemiology and toxicology provide little evidence that exposure to SVF increases the risk of mesothelioma.     

Recent progress and prospects in the electrode materials of flexible sodium-ion battery

1. Download : Download high-res image (311KB)
2. Download : Download full-size image

     

NADPH oxidases and cardiac remodelling

A heart under chronic stress undergoes cardiac remodelling, a process that comprises structural and functional changes including cardiomyocyte hypertrophy, interstitial fibrosis, contractile dysfunction, cell death and ventricular dilatation. Reactive oxygen species (ROS)-dependent modulation of intracellular signalling is implicated in the development of cardiac remodelling. Among the different ROS sources that are present in the heart, NADPH oxidases (NOXs) are particularly important in redox signalling. NOX isoforms are expressed in multiple cell types including cardiomyocytes, fibroblasts, endothelial cells and inflammatory cells—with the two main isoforms expressed in the heart being NOX2 and NOX4. Recent studies indicate that NOX-dependent signalling is involved in the development of cardiomyocyte hypertrophy, interstitial fibrosis and post-MI remodelling. NOXs may also be involved in the genesis of contractile dysfunction and myocyte apoptosis. Here, we review the main effects of NOXs in the pathogenesis of cardiac remodelling and the redox-sensitive signalling pathways that underlie these effects. The elucidation of mechanisms involved in NOX-dependent regulation of cardiac remodelling may lead to new therapeutic targets for heart failure.     

Comparison of Drug-Eluting Embolics versus Conventional Transarterial Chemoembolization for the Treatment of Patients with Unresectable Hepatocellular Carcinoma: A Cost-Effectiveness Analysis

PurposeTo compare the cost-effectiveness of using doxorubicin-loaded drug-eluting embolic (DEE) transarterial chemoembolization versus that of using conventional transarterial chemoembolization for patients with unresectable hepatocellular carcinoma (HCC).Materials and MethodsA decision-analysis model was constructed over the lifespan of a payer’s perspective. The model simulated the clinical course, including periprocedural complications, additional transarterial chemoembolization or other treatments (ablation, radioembolization, or systemic treatment), palliative care, and death, of patients with unresectable HCC. All clinical parameters were derived from the literature. Base case calculations, probabilistic sensitivity analyses, and multiple two-way sensitivity analyses were performed.ResultsIn the base case calculations for patients with a median age of 67 years (range for conventional transarterial chemoembolization: 28–88 years, range for DEE-transarterial chemoembolization: 16–93 years), conventional transarterial chemoembolization yielded a health benefit of 2.11 quality-adjusted life years (QALY) at a cost of $125,324, whereas DEE-transarterial chemoembolization yielded 1.71 QALY for $144,816. In 10,000 Monte Carlo simulations, conventional transarterial chemoembolization continued to be a more cost-effective strategy. conventional transarterial chemoembolization was cost-effective when the complication risks for both the procedures were simultaneously varied from 0% to 30%. DEE-transarterial chemoembolization became cost-effective if the conventional transarterial chemoembolization mortality exceeded that of DEE-transarterial chemoembolization by 17% in absolute values. The two-way sensitivity analyses demonstrated that conventional transarterial chemoembolization was cost-effective until the risk of disease progression was >0.4% of that for DEE-transarterial chemoembolization in absolute values. Our analysis showed that DEE-transarterial chemoembolization would be more cost-effective if it offered >2.5% higher overall survival benefit than conventional transarterial chemoembolization in absolute values.ConclusionsCompared with DEE-transarterial chemoembolization, conventional transarterial chemoembolization yielded a higher number of QALY at a lower cost, making it the more cost-effective of the 2 modalities.