11Beta-hydroxysteroid dehydrogenase-1 deficiency or inhibition enhances hepatic myofibroblast activation in murine liver fibrosis.

A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchestrated by activated hepatic stellate cells (HSCs). Glucocorticoids limit HSC activation in vitro, and tissue glucocorticoid levels are amplified by 11beta-hydroxysteroid dehydrogenase-1 (11ßHSD1). Although 11ßHSD1 inhibitors have been developed for type 2 diabetes mellitus and improve diet-induced fatty liver in various mouse models, effects on the progression and/or resolution of liver injury and consequent fibrosis have not been characterized. We have used the reversible carbon tetrachloride-induced model of hepatocyte injury and liver fibrosis to show that in two models of genetic 11ßHSD1 deficiency (global, Hsd11b1-/- , and hepatic myofibroblast-specific, Hsd11b1fl/fl /Pdgfrb-cre) 11ßHSD1 pharmacological inhibition in vivo exacerbates hepatic myofibroblast activation and liver fibrosis. In contrast, liver injury and fibrosis in hepatocyte-specific Hsd11b1fl/fl /albumin-cre mice did not differ from that of controls, ruling out 11ßHSD1 deficiency in hepatocytes as the cause of the increased fibrosis. In primary HSC culture, glucocorticoids inhibited expression of the key profibrotic genes Acta2 and Col1α1, an effect attenuated by the 11ßHSD1 inhibitor [4-(2-chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone. HSCs from Hsd11b1-/- and Hsd11b1fl/fl /Pdgfrb-cre mice expressed higher levels of Acta2 and Col1α1 and were correspondingly more potently activated. In vivo [4-(2-chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone administration prior to chemical injury recapitulated findings in Hsd11b1-/- mice, including greater fibrosis. CONCLUSION: 11ßHSD1 deficiency enhances myofibroblast activation and promotes initial fibrosis following chemical liver injury; hence, the effects of 11ßHSD1 inhibitors on liver injury and repair are likely to be context-dependent and deserve careful scrutiny as these compounds are developed for chronic diseases including metabolic syndrome and dementia. (Hepatology 2018;67:2167-2181).

Loss of Pax6 Causes Regional Changes in Dll1 Expression in Developing Cerebral Cortex.

The transcription factor Pax6 controls multiple aspects of forebrain development. Conditional deletion of Pax6 in embryonic mouse cortex causes increased proliferation of cortical progenitor cells and a concomitant decrease in neural differentiation. Notch signaling regulates the balance between proliferation and differentiation of cortical progenitor cells, suggesting a possible connection between Pax6 and Notch signaling. We investigated how expression of the Notch ligand delta-like 1 (Dll1) is altered by loss of Pax6. Acute cortex-specific deletion of Pax6 resulted in a widespread decrease in the density of Dll1+ cells at embryonic days 12.5 and 13.5 (E12.5 and E13.5). In constitutive loss-of-function mutants, decreases in the densities of Dll1+ cells were more limited both spatially and temporally. Controlled over-expression of Pax6 had no detectable effect on Dll1 expression. The proneural transcription factor Neurog2 is a target of Pax6 that can activate Dll1 expression and we found clear co-expression of Neurog2 and Dll1 in radial glial progenitors, suggesting that Pax6's effect on Dll1 could be mediated through Neurog2. However, we found no change in Dll1+ cells in Neurog2 -/- cortex suggesting either that Neurog2 is not directly involved, or that its loss of function in embryonic cortex can be compensated for.

Pasantía rural : conocimientos, expectativas e interés de las estudiantes de enfermería

Estudio descriptivo que plantea el conocimiento, interés y expectativas a cerca de la Pasantía rural de de los estudiantes del segundo al cuarto curso de la Carrera de Enfermería del Instituto "Dr. Andrés Barbero".UNA. Presenta informaciones generales sobre los convenios con el Ministerio de Salud y otras instituciones