State of the World's Volunteerism Report: Universal Values for Global Well-being

The focus of this report is on the universal values that motivate people the world over to volunteer for the common good and on the impact of volunteer action on societies and individuals. The authors advocate the power of volunteering to promote cooperation, encourage participation and contribute to the well-being of individuals and of society as a whole

Comparison of Hepatic-like Cell Production from Human Embryonic Stem Cells and Adult Liver Progenitor Cells: CAR Transduction Activates a Battery of Detoxification Genes

In vitro production of human hepatocytes is of primary importance in basic research, pharmacotoxicology and biotherapy of liver diseases. We have developed a protocol of differentiation of human embryonic stem cells (ES) towards hepatocyte-like cells (ES-Hep). Using a set of human adult markers including CAAT/enhancer binding protein (C/EBPalpha), hepatocyte nuclear factor 4/7 ratio (HNF4alpha1/HNF4alpha7), cytochrome P450 7A1 (CYP7A1), CYP3A4 and constitutive androstane receptor (CAR), and fetal markers including alpha-fetoprotein, CYP3A7 and glutathione S-transferase P1, we analyzed the expression of a panel of 41 genes in ES-Hep comparatively with human adult primary hepatocytes, adult and fetal liver. The data revealed that after 21 days of differentiation, ES-Hep are representative of fetal hepatocytes at less than 20 weeks of gestation. The glucocorticoid receptor pathway was functional in ES-Hep. Extending protocols of differentiation to 4 weeks did not improve cell maturation. When compared with hepatocyte-like cells derived from adult liver non parenchymal epithelial (NPE) cells (NPE-Hep), ES-Hep expressed several adult and fetal liver makers at much greater levels (at least one order of magnitude), consistent with greater expression of liver-enriched transcription factors Forkhead box A2, C/EBPalpha, HNF4alpha and HNF6. It therefore seems that ES-Hep reach a better level of differentiation than NPE-Hep and that these cells use different lineage pathways towards the hepatic phenotype. Finally we showed that lentivirus-mediated expression of xenoreceptor CAR in ES-Hep induced the expression of several detoxification genes including CYP2B6, CYP2C9, CYP3A4, UDP-glycosyltransferase 1A1, solute carriers 21A6, as well as biotransformation of midazolam, a CYP3A4-specific substrate

State of the world's volunteerism report, 2011 : universal values for global well-being

The first State of the World’s Volunteerism Report (SWVR) by the United Nations Volunteers (UNV) programme was launched at the United Nations General Assembly in New York, United States, on 5 December 2011 and about 80 countries around the world. The SWVR promotes a better understanding of volunteerism. It demonstrates the universality, scope and reach of volunteerism along with new trends in the twenty-first century. The report examines important contributions in diverse fields such as sustainable livelihoods, social inclusion, social cohesion and disaster risk reduction. By suggesting how volunteerism can be taken forward, the SWVR also provides an alternative vision of a better society. The State of the World’s Volunteerism Report shows that, in most societies around the world, volunteers make significant contributions to economic and social development. Through their voluntary actions, millions of people are contributing to meeting the Millennium Development Goals (MDGs).121 page(s

Furosemide induces mortality in a rat model of chronic heart failure

OBJECTIVES: In an experimental heart failure model, we tested the hypothesis that furosemide causes excess mortality. BACKGROUND: Post-hoc analysis of large clinical heart failure trails revealed that furosemide treatment might be associated with worsening of morbidity and even mortality in heart failure patients. METHODS AND RESULTS: Myocardial infarction was induced in 7±1week old male Wistar rats by ligation of the left coronary artery. In study 1, animals were randomly assigned to treatment with furosemide (10mg/kg/d via drinking water, n=33) or placebo (n=33) starting 18days after surgery. In study 2, animals received furosemide from day 18 and were then randomized to ongoing treatment with either furosemide only (n=38) or furosemide plus ACE-inhibitor Ramipril (1mg/kg/d, n=38) starting on day 42. In study 1 survival rate in the furosemide group was lower than in the placebo group (hazard ratio {HR} 3.39, 95% confidence interval {CI} 1.14 to 10.09, p=0.028). The furosemide group had a lower body weight (-6%, p=0.028) at the end of the study and a higher sclerosis index of the glomeruli (+9%, p=0.026) than the placebo group. Wet lung weight, infarct size, and cardiac function were similar between the groups. In study 2, the furosemide group had a higher mortality rate than the furosemide+ramipril group (HR 4.55, 95% CI 2.0 to 10.0, p=0.0003). CONCLUSION: In our rat model of heart failure furosemide, provided at a standard dose, was associated with increased mortality. This increased mortality could be prevented by additional administration of an ACE-inhibitor

Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis.

Introduction:In liver fibrosis activation of hepatic stellate cells (HSC) comprises phenotypical change into profibrotic and myofibroplastic cells with increased contraction and secretion of extracellular matrix (ECM) proteins. The small GTPase RhoA orchestrates cytoskeleton formation, migration and mobility via non-receptor tyrosine-protein kinase c-SRC (cellular sarcoma) in different cells. Furthermore, RhoA and its downstream effector Rho-kinase also play a crucial role in hepatic stellate cells and hepatic fibrogenesis. Matrix stiffness promotes HSC activation via cytoskeleton modulation. This study investigated the interaction of c-SRC and RhoA under different matrix stiffness conditions.Methods:Liver fibrosis was induced in rats using bile duct ligation (BDL), thioacetamide (TAA) or carbon tetrachloride (CCl4) models. mRNA levels of albumin, PDGF-R, RHOA, COL1A1 and αSMA were analyzed via qRT-PCR. Western Blots using phospho-specific antibodies against p-c-SRC418 and p-c-SRC530 analyzed the levels of activating and inactivating c-SRC respectively. LX2 cells and hepatocytes were cultured on acrylamide gels of 1kPa and 12kPa or on plastic to mimic non-fibrotic, fibrotic or cirrhotic environments, then exposed to SRC-inhibitor PP2. Overexpression of RhoA was performed by transfection using RhoA-plasmids. Additionally, samples from cirrhotic patients and controls were collected at liver transplantations and tumor resections were analyzed for RhoA and c-SRC protein expression by Western Blot.Results:Transcription of albumin and RhoA was decreased, whereas transcription and activation of c-SRC was increased in hepatocytes cultured on 12kPa compared to 1kPa gels. LX2 cells cultured on 12kPa gels showed upregulation of RHOA, COL1A1 and αSMA mRNA levels. Inhibition of c-SRC by PP2 in LX2 cells led to an increase in COL1A1 and αSMA most prominently in 12kPa gels. In LX2 cells with RhoA overexpression, c-SRC inhibition by PP2 failed to improve fibrosis. RhoA expression was significantly elevated in human and experimental liver fibrosis, while c-SRC was inactivated.Conclusions: This study shows that c-SRC is inactive in activated myofibroblast-like HSC in liver cirrhosis. Inactivation of c-SRC is mediated by a crosstalk with RhoA upon hepatic stellate cell activation and fibrosis progression