2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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The Utility of Gene Expression Profiling from Tissue Samples to Support Drug Safety Assessments

Originally conceptualized as an integrated approach combining conventional toxicology methods with genome-wide expression profiling, toxicogenomics has promised to provide unequivocal relationships between the molecular changes elicited by a compound or a target pathway and the lesions that appear subsequently in the tissues. However, the discipline has only partially delivered on this promise, and the number of publications and submissions related to toxicogenomics is stagnating. The purpose of this article is to outline key factors contributing to a successful implementation of toxicogenomics in the drug discovery and development process. Paradigms and methods of toxicogenomics are briefly reviewed, and the prominence of biostatistics and its limitations in the particular context of nonclinical toxicology studies are discussed. We present specific approaches for pathophysiological contextualization of gene expression data derived from tissues with lesions at variable incidence and severity: “unmixing” (deconvolution) of molecular expression profiles from complex tissues, the invaluable contribution of reference data, the role of establishing causation between expression signals and pathologic changes (phenotypic anchoring), and especially molecular localization. These approaches compensate for the limitations of biostatistical analysis, which in turn, derive from tissue heterogeneity. Finally, impactful applications of toxicogenomics along the drug discovery and development process are exemplified, from the evaluation of potential target toxicities to the selection of candidate compounds and elucidation of the molecular and cellular mechanisms leading to chronic toxicity

Molecular and cellular signatures of human vaccine adjuvants.

Oil-in-water emulsions are potent human adjuvants used for effective pandemic influenza vaccines; however, their mechanism of action is still unknown. By combining microarray and immunofluorescence analysis, we monitored the effects of the adjuvants MF59 oil-in-water emulsion, CpG, and alum in the mouse muscle. MF59 induced a time-dependent change in the expression of 891 genes, whereas CpG and alum regulated 387 and 312 genes, respectively. All adjuvants modulated a common set of 168 genes and promoted antigen-presenting cell recruitment. MF59 was the stronger inducer of cytokines, cytokine receptors, adhesion molecules involved in leukocyte migration, and antigen-presentation genes. In addition, MF59 triggered a more rapid influx of CD11b+ blood cells compared with other adjuvants. The early biomarkers selected by microarray, JunB and Ptx3, were used to identify skeletal muscle as a direct target of MF59. We propose that oil-in-water emulsions are the most efficient human vaccine adjuvants, because they induce an early and strong immunocompetent environment at the injection site by targeting muscle cells

The acquired immune response to the mucosal adjuvant LTK63 imprints the mouse lung with a protective signature

Abstract LTK63, a nontoxic mutant of Escherichia coli heat labile enterotoxin (LT), is a potent and safe mucosal adjuvant that has also been shown to confer generic protection to several respiratory pathogens. To understand the mechanisms of action underlying the LTK63 protective effect, we analyzed the molecular and cellular events triggered by its administration in vivo. We show here that LTK63 intrapulmonary administration induced in the mouse lung a specific gene expression signature characterized by the up-regulation of cell cycle genes, several host defense genes, chemokines, chemokine receptors, and immune cell-associated genes. Such a transcriptional profile reflected the activation of alveolar macrophages and the recruitment to the lung of T and B cells and innate immune cells such as granulocytes, NK, and dendritic cells. All of these events were T cell dependent and specific for LTK63 because they were absent in SCID and nude mice. Additionally, we showed that LTK63 induces a potent adaptive immune response against itself directed to the lung. We propose that acquired response to LTK63 is the driving force for the local recruitment of both adaptive and innate immune cells. Our data suggest that LTK63 acts as an airway infection mimic that establishes a generic protective environment limiting respiratory infection by innate immune mechanisms and by improving adaptive responses to invading pathogens.</jats:p

Comparative renal safety assessment of the hepatitis B drugs, adefovir, tenofovir, telbivudine and entecavir in rats

The aim of this study was to determine the relative safety of four antiviral drugs (telbivudine, tenofovir, adefovir, entecavir) against hepatitis B virus with respect to kidney function and toxicity in male Spraque-Dawley rats. The antiviral drugs were administered once daily for four weeks by oral gavage at about 10 and 25-40 times the human equivalent dose. Main assessments included markers of renal toxicity in urine, magnetic resonance imaging (MRI) of kidney function, histopathology and electron microscopic examination. Administration of adefovir at 11 and 28 mg/kg for 4 weeks caused functional and morphological kidney alterations in a time- and dose-dependent manner, affecting mainly the proximal tubules and suggesting a mechanism of toxicity related to mitochondrial degeneration/depletion. Of note, the observed adefovir-induced reduction of kidney function was not detected by the standard method of glomerular filtration rate (GFR) measurements (clearance rate of the endogenous marker, creatinine), thereby emphasizing the superiority of MRI in terms of sensitive detection of GFR in rats. For the low dose of 300 mg/kg of tenofovir, minor kidney effects such as nuclear enlargement in the tubular epithelium, and hyaline droplets accumulation were detected, which was also observed for the low dose (11 mg/kg) of adefovir. No assessments could be done at the higher dose of 600/1000 mg/kg tenofovir due to gastrointestinal tract toxicity which prevented treatment of the animals for longer than 1 week. Entecavir at 1 and 3 mg/kg and telbivudine at 600 and 1600 mg/kg caused no toxicologically relevant effects on the kidney

IL-17A is the dominant IL-17-family cytokine required for immunity to acute murine oral mucosal candidiasis

Antibodies targeting IL-17A or IL-17RA show unprecedented efficacy in treating psoriasis. However, IL-17RA signaling is critical for immunity to mucosal Candida albicans infections. IL-17A, IL-17F and IL-17AF bind a receptor composed of IL-17RA and IL-17RC and deliver qualitatively similar signals through Act1. This study aimed to determine the impact of blocking IL-17 family cytokines on oropharyngeal candidiasis (OPC) and evaluate their relative contributions to antifungal immunity. Accordingly, C57BL/6 (WT) mice were treated with Abs targeting IL-17A, IL-17F and IL-17AF. Susceptibility to acute OPC was compared to IL-17A-/-, IL-17F-/- and Act1-/- mice. Anti-IL-17A Abs, which neutralize IL-17A and IL-17AF, caused elevated fungal loads in immunocompetent WT mice, whereas anti-IL-17AF and anti-IL-17F Abs did not increase susceptibility. Blocking IL-17A, IL-17AF and IL-17F together led to increased OPC compared to anti-IL-17A treatment alone. Termination of anti-IL-17A treatment was associated with Candida clearance. IL-17A-/- mice also displayed OPC, but to a lesser degree than anti-IL-17A-treated mice. IL-17F-/- mice were fully resistant. Act1-/- mice were much more susceptible to OPC than anti-IL-17A Ab-treated mice, yet anti-IL-17A and anti-IL-17RA Ab treatment caused equivalent susceptibilities. Only a limited number of immune genes attributable to epithelial and myelo-monocytic cells associated with OPC susceptibility based on microarray analyses. We therefore conclude that IL-17A, not IL-17F or IL-17AF, is the main mediator of immunity in murine OPC. However, a cooperative relationship between IL-17A and IL-17F appears to exist in vivo. Susceptibility displays the following hierarchy: IL-17RA-/- or Act1-/- > anti-IL-17A + anti-IL-17F Abs > anti-IL-17A or anti-IL-17RA Abs > IL-17A-/-