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The REactor Safety Analysis ToolboX RESA-TX is a software and data package in development that combines the automatisation of all established procedures for deterministic safety analysis (DSA), the integration of expert know-how and a large database including the most relevant information required for conducting a DSA. In the current state of the art, DSA is a complex and thus error-prone process that is highly time-consuming and repetitive. The reliability of the result is strongly dependent on the availability of plant data and expert know-how. The idea of developing the RESA-TX toolbox arose at GRS to cope with these conditions. The innovative approach proposes an automated and standardised procedure, supported by a large database of plant design characteristics, plant behaviour, regulatory rules and DSA expert knowledge incorporated within the tool. Its application allows the end user to automatically generate and verify an input deck, as well as conduct design basis accident (DBA) calculations for a certain design with highly reduced manual intervention. The databases can be extended depending on available information or other boundary conditions. A heuristic approach is integrated into the model generation process, where users often suffer from a lack of information about the facility under consideration. These heuristics can be replaced when higher information quality is available or enhanced over time, which can lead to more reliable results with increasing usage of the tool. As a result, the application of RESA-TX could highly increase the efficiency of the DSA process, reducing both repetitiveness as well as user-induced errors. This in return will lead to an improvement in the quality of the analysis and reliability of the results. In consequence, RESA-TX will allow for a DSA to be conducted more frequently in situations where time or budget was a limitation before, thereby contributing to an increase in reactor safety.

High-fat diet-induced obesity (DIO) is associated with fatty liver and elevated IL-6 circulating levels. IL-6 administration in rodents has yielded contradictory results regarding its effects on steatosis progression. In some models of fatty liver disease, high doses of human IL-6 ameliorate the liver steatosis, whereas restoration of IL-6 in DIO IL-6-/- mice up-regulates hepatic lipogenic enzymes and aggravates steatosis. We further examined the effects of chronic low doses of murine IL-6 on hepatic lipid metabolism in WT mice in DIO. IL-6 was delivered twice daily in C57BL/6J DIO mice for 15 days. The status and expression of IL-6-signalling mediators and targets were investigated in relation to the steatosis and lipid content in blood and in liver. IL-6 administration in DIO mice markedly raised circulating levels of lipids, glucose and leptin, elevated fat liver content and aggravated steatosis. Under IL-6 treatment there was hepatic Stat3 activation and increased gene expression of Socs3 and Tnf-alpha whereas the gene expression of endogenous IL-6, IL-6-receptor, Stat3, Cpt1 and the enzymes involved in lipogenesis was suppressed. These data further implicate IL-6 in fatty liver disease modulation in the context of DIO, and indicate that continuous stimulation with IL-6 attenuates the IL-6-receptor response, which is associated with high serum levels of leptin, glucose and lipids, the lowering levels of lipogenic and Cpt1 hepatic enzymes and with increased Tnf-alpha hepatic expression, a scenario evoking that observed in IL-6-/- mice exposed to DIO and in obese Zucker rats.

Objective: To study the prevalence and correlates of body size phenotypes in an adult Spanish population., Methods: We undertook a cross-sectional analysis in a random sample of 2,270 individuals. We defined six body size phenotypes based on body mass index category (normal-weight, 18.5 to 24.9 kg/m2; overweight, 25 to 29.9 kg/m2; obese, ≥30.0 kg/m2) and the presence of ≤1 (metabolically healthy) or ≥2 (metabolically abnormal) cardiometabolic abnormalities: metabolically healthy normal-weight (MHNW), metabolically abnormal normal-weight (MANW), metabolically healthy overweight (MHOW), metabolically abnormal overweight (MAOW), metabolically healthy obese (MHO), and metabolically abnormal obese (MAO). We considered four cardiometabolic abnormalities: systolic and/or diastolic blood pressure ≥130/85 mm Hg, triglycerides ≥150 mg/dL, high-density-lipoprotein cholesterol levels <40/<50 mg/dL in men/women, and elevated glucose (fasting plasma glucose ≥100 mg/dL or previous diabetes)., Results: The prevalence of the MHO, MHOW, and MANW phenotypes was 2.2, 13.9, and 7.9%, respectively. Whereas 9.6% of obese and 32.6% of overweight individuals were metabolically healthy, 21.3% of the normal-weight subjects were metabolically abnormal. A multivariate regression model (adjusted for age, sex, and waist circumference) showed that age >40 years, male sex, and higher waist circumference were independently associated with the metabolically abnormal phenotype MANW, whereas younger age, female sex, and lower waist circumference were independently associated with the metabolically healthy phenotypes., Conclusion: The prevalence of MHO in our population is low and is more common in women and younger people. In contrast, a high proportion of normal-weight individuals (mainly over 40 years of age) in our population show cardiometabolic abnormalities.

Background: LFABP plays a critical role in the uptake and intracellular transport of fatty acids (FA) and other peroxisome proliferator-activated receptor alpha (PPARα) ligands. PPARα activation by PPARα ligands bound to LFABP results in gene expression of FA oxidation enzymes and de novo LFABP. The cytokine IL-6 is involved in regulating liver lipid oxidation., Aims: To study the ability of IL-6 to modulate the expression of the LFABP in hepatocytes., Methods: HepG2 and mouse primary hepatocytes were used to test LFABP mRNA and protein expression after IL-6 and PPARα-ligand treatments. Mice lacking IL-6 and wild-type C57Bl/6 were subjected to a fasting/re-feeding cycle to monitor hepatic LFABP mRNA kinetics after food intake., Results: In hepatocyte cultures, IL-6 treatment stimulated a LFABP mRNA sustained expression. Combined treatment of IL-6 plus PPARα ligands further enhanced LFABP gene and protein expression. In contrast, pretreatment with the PPARα-antagonist GW-6471 prevented the up-regulation of LFABP mRNA induced by IL-6 in the late phase of LFABP kinetics. Furthermore, the up-regulation of LFABP mRNA observed in the liver of wild-type mice 8 h after re-feeding was absent in mice lacking IL-6., Conclusions: IL-6 induces LFABP kinetics in hepatocytes and is partially dependent on PPARα. The maximum increase in LFABP expression occurs when the stimulation with IL-6 and PPARα-ligands takes place simultaneously. The in vivo results indicate a postprandial regulation of LFABP that correlates with the presence of IL-6. These effects may have important implications in the postprandial increase in FA uptake and intracellular trafficking in the liver., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Generation of low levels of nitric oxide (NO) contributes to beta cell survival in vitro. The purpose of this study was to explore the link between NO and the survival pathway triggered by insulin-like growth factor-1 (IGF-1) and insulin in insulin producing RINm5F cells and in pancreatic islets. Results show that exposure of cells to IGF-1/insulin protects against serum deprivation-induced apoptosis. This action is prevented with inhibitors of NO generation, PI3K and Akt. Moreover, transfection with the negative dominant form of the tyrosine kinase c-Src abrogates the effect of IGF-1 and insulin on DNA fragmentation. An increase in the expression level of NOS3 protein and in the enzyme activity is observed following exposure of serum-deprived RINm5F cells to IGF-1 and insulin. Phosphorylation of IRS-1, IRS-2 and to less extent IRS-3 takes place when serum-deprived RINm5F cells and rat pancreatic islets are exposed to either IGF-1, insulin, or diethylenetriamine nitric oxide adduct (DETA/NO). In human islets, IRS-1 and IRS-2 proteins are present and tyrosine phosphorylated upon exposure to IGF-1, insulin and DETA/NO. Both rat and human pancreatic islets undergo DNA fragmentation when cultured in serum-free medium and IGF-1, insulin and DETA/NO protect efficiently from this damage. We then conclude that generation of NO participates in the activation of survival pathways by IGF-1 and insulin in beta cells.

The aim of this study was to evaluate patterns of insulin resistance in the general population. The study was cross sectional. Clinical, anthropometric, and lipid measurements were made in 1226 persons aged 18-65 years. An oral glucose tolerance test (OGTT) was performed in 1020 subjects, with insulin levels determined at baseline and after 2 h. The homeostasis model assessment insulin resistance index (HOMA IR) and HOMA beta-cell function were calculated. Compared with subjects with normal glucose tolerance, the groups with abnormal OGTT had different baseline insulinemia, 2 h post OGTT insulinemia, HOMA IR and HOMA beta-cell indices. Serum insulin levels at baseline and 2 h after OGTT showed a characteristic pattern for each category of glucose tolerance, resulting from the different insulin responses. In the subjects with normal glucose tolerance, the pattern of the relationships between both types of serum insulin levels was exactly the same, so that it was possible to determine risk groups according to the ratio of baseline serum insulin/2 h insulin. HOMA IR and HOMA beta-cell were significantly associated with the risk of impaired fasting glucose, previously unknown diabetes mellitus, and known diabetes mellitus. These results support the rationale for introducing preventive measures against insulin resistance in the general population.

Background and Objective: Our purpose was to evaluate in a cross-section, populational study the association between daily physical activity and various metabolic and cardiovascular disease risk factors., Patients and Method: A total of 1226 randomly selected persons (aged 18-65 years) from a town in southeast Spain were evaluated for studying the association between the level of daily physical activity, both in and out of working hours, and the following variables: body mass index, plasma lipids, hypertension, obesity, altered baseline glycemia, and abnormal glucose tolerance., Results: The intensity of the physical activity at work was related negatively with insulin resistance and levels of LDL cholesterol, and positively with HDL cholesterol. The probability of hypertension, altered baseline glycemia, and abnormal glucose tolerance was greater in those undertaking less daily physical activity., Conclusions: Daily physical activity, considered as part of the lifestyle, is related with the presence of components of the metabolic syndrome. An increase in daily physical activity should contribute to improve preventible cardiovascular risk factors.