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OncoTarget 8, 56095-56109 (2017). doi:10.18632/oncotarget.10893, Published by Impact Journals LLC, [S.l.]

Background & Aims The pathomechanisms underlying non-alcoholic fatty liver disease (NAFLD) and the involved molecular regulators are incompletely explored. The nuclear factor-kappa B (NF-κB)-cofactor gene B cell leukemia-3 ( Bcl-3 ) plays a critical role in altering the transcriptional capacity of NF-κB – a key inducer of inflammation – but also of genes involved in cellular energy metabolism. Methods To define the role of Bcl-3 in non-alcoholic steatohepatitis (NASH), we developed a novel transgenic mouse model with hepatocyte-specific overexpression of Bcl-3 ( Bcl-3 Hep ) and employed a high-fat, high-carbohydrate dietary feeding model. To characterize the transgenic model, deep RNA sequencing was performed. The relevance of the findings was confirmed in human liver samples. Results Hepatocyte-specific overexpression of Bcl-3 led to pronounced metabolic derangement, characterized by enhanced hepatic steatosis from increased de novo lipogenesis and uptake, as well as decreased hydrolysis and export of fatty acids. Steatosis in Bcl-3 Hep mice was accompanied by an augmented inflammatory milieu and liver cell injury. Moreover, Bcl-3 expression decreased insulin sensitivity and resulted in compensatory regulation of insulin-signaling pathways. Based on in vivo and in vitro studies we identified the transcription factors PPARα, PPARγ and PGC-1α as critical regulators of hepatic metabolism and inflammation downstream of Bcl-3. Metformin treatment improved the metabolic and inflammatory phenotype in Bcl-3 Hep mice through modulation of PPARα and PGC-1α. Remarkably, these findings were recapitulated in human NASH, which exhibited increased expression and nuclear localization of Bcl-3. Conclusions In summary, Bcl-3 emerges as a novel regulator of hepatic steatosis, insulin sensitivity and inflammation in NASH. Lay summary Non-alcoholic fatty liver disease (NAFLD) is considered the most prevalent liver disease worldwide. Patients can develop end-stage liver disease resulting in liver cirrhosis or hepatocellular carcinoma, but also develop complications unrelated to liver disease, e.g., cardiovascular disease. Still there is no full understanding of the mechanisms that cause NAFLD. In this study, genetically engineered mice were employed to examine the role of a specific protein in the liver that is involved in inflammation and the metabolism, namely Bcl-3. By this approach, a better understanding of the mechanisms contributing to disease progression was established. This can help to develop novel therapeutic and diagnostic options for patients with NAFLD.

In the past, various individual ANP-roles such as Clinical Nurse Specialist and Nurse Practitioner were developed in the USA and in several countries of Northern Europe. In Switzerland, the number of university-educated nurse specialists is still very limited. In order to promote sustainable progress in nursing practice despite of this background, Advanced Nursing Practice teams (ANP-teams) have continuously been established at Kinderspital Zurich for the last eight years. This approach has proven to be an excellent option especially in highly complex situations where targeted and adequate solutions for patients are a major issue. In this article, the structure of the ANP-teams is discussed, with the personnel mix as a key factor. Important supportive elements are a clear definition of tasks as well as an allocation of individual tasks to either clinical or conceptual groups. The ANP teams are highly motivated and goal-oriented, they integrate nurses with various backgrounds of experience or training whereby mutual learning is being encouraged.

Brominated flame retardants (BFRs) are synthetic additives mainly used in electrical and electronic appliances and in construction materials. The properties of some BFRs are typical for persistent organic pollutants, and certain BFRs, in particular some polybrominated diphenyl ether (PBDE) congeners and hexabromocyclododecane (HBCD), are suspected to cause adverse health effects. Global consumption of the most demanded BFRs, i.e., penta-, octa-, and decaBDE, tetrabromobisphenol A (TBBPA), and HBCD, has doubled in the 1990s. Only limited and rather uncertain data are available regarding the occurrence of BFRs in consumer goods and waste fractions as well as regarding emissions during use and disposal. The knowledge of anthropogenic substance flows and stocks is essential for early recognition of environmental impacts and effective chemicals management. In this paper, actual levels of penta-, octa-, and decaBDE, TBBPA, and HBCD in waste electrical and electronic equipment (WEEE) as a major carrier of BFRs are presented. These BFRs have been determined in products of a modern Swiss recycling plant applying gas chromatography/electron capture detection and gas chromatography/mass spectrometry analysis. A substance flow analysis (SFA) technique has been used to characterize the flows of target substances in the recycling process from the bulk WEEE input into the output products. Average concentrations in small size WEEE, representing the relevant electric and electronic appliances in WEEE, sampled in 2003 amounted to 34 mg/kg for pentaBDE, 530 mg/kg for octaBDE, 510 mg/kg for decaBDE, 1420 mg/kg for TBBPA (as an additive), 17 mg/kg for HBCD, 5500 mg/kg for bromine, and 1700 mg/kg for antimony. In comparison to data that have been calculated by SFA for Switzerland from literature for the 1990s, these measured concentrations in small size WEEE were 7 times higher for pentaBDE, unexpectedly about 50% lower for decaBDE, and agreed fairly well for TBBPA (as an additive) and octaBDE. Roughly 60% of the total bromine input determined by SFA based on X-ray fluorescence analysis of the output materials of the recycling plant cannot be assigned to the selected BFRs. This is an indication for the presence of other brominated substances as substitutes for PBDEs in electrical and electronic equipment. The presence of BFRs, in particular PBDEs in the low grams per kilogram concentration range, in the fine dust fraction recovered in the off-gas purification system of the recycling plant reveals a high potential for BFR emissions from WEEE management and point out the importance for environmentally sound recycling and disposal technologies for BFR-containing residues.

Physical activity confers a broad spectrum of health benefits. Beyond the obvious role in metabolically driven diseases, the role of physical activity in acute liver injury is poorly explored. To study the role of physical activity in acute liver injury, a novel model of voluntary distance running in mice was developed and mice were subjected to acute liver injury induced by N-galactosamine (GalN) and lipopolysaccharide (LPS). Analyses included histological stains, immunoblotting, qRT-PCR and FACS analysis. Voluntary distance running increased to an average of 10.3 km/day after a learning curve. Running lead to a decrease in the absolute numbers of intrahepatic CD4+ T and B lymphocytes and macrophages after 7 weeks. In parallel, hepatic mRNA expression of inflammatory cytokines including IL-6 and IL-1beta, TGF-beta and monocyte chemoattractant protein-1 (MCP-1/CCL2) were suppressed, while TNF-α was not affected by exercise. Likewise, expression of the macrophage-specific antigen F4/80 was downregulated 1.6-fold from exercise. Notably, acute liver injury from GaIN/LPS was significantly blunted following 7 weeks of voluntary exercise as determined by liver histology, a 84.6% reduction of alanine aminotransferase (PP

In the past, various individual ANP-roles such as Clinical Nurse Specialist and Nurse Practitioner were developed in the USA and in several countries of Northern Europe. In Switzerland, the number of university-educated nurse specialists is still very limited. In order to promote sustainable progress in nursing practice despite of this background, Advanced Nursing Practice teams (ANP-teams) have continuously been established at Kinderspital Zurich for the last eight years. This approach has proven to be an excellent option especially in highly complex situations where targeted and adequate solutions for patients are a major issue. In this article, the structure of the ANP-teams is discussed, with the personnel mix as a key factor. Important supportive elements are a clear definition of tasks as well as an allocation of individual tasks to either clinical or conceptual groups. The ANP teams are highly motivated and goal-oriented, they integrate nurses with various backgrounds of experience or training whereby mutual learning is being encouraged.

BACKGROUND Lifestyle modifications remain the cornerstone of treatment in non-alcoholic fatty liver disease (NAFLD). However, they requently fail related to the inability of patients to implement lasting changes. AIMS To evaluate the effects of a short, web-based, individualised exercise program on non-invasive markers of hepatic steatosis, inflammation and fibrosis. METHODS Patients with histologically confirmed NAFLD underwent an 8-week, web-based, individualised exercise program that contained bidirectional feedback. RESULTS Forty-four patients entered the study and 41 completed the assigned training goal (93.2%). In the completer population, 8 weeks of individualised exercise increased the VO2peak by 12.2% compared to baseline (P