Insulin resistance disrupts epithelial repair and niche-progenitor Fgf signaling during chronic liver injury.

Insulin provides important information to tissues about feeding behavior and energy status. Defective insulin signaling is associated with ageing, tissue dysfunction, and impaired wound healing. In the liver, insulin resistance leads to chronic damage and fibrosis, but it is unclear how tissue-repair mechanisms integrate insulin signals to coordinate an appropriate injury response or how they are affected by insulin resistance. In this study, we demonstrate that insulin resistance impairs local cellular crosstalk between the fibrotic stroma and bipotent adult liver progenitor cells (LPCs), whose paracrine interactions promote epithelial repair and tissue remodeling. Using insulin-resistant mice deficient for insulin receptor substrate 2 (Irs2), we highlight dramatic impairment of proregenerative fibroblast growth factor 7 (Fgf7) signaling between stromal niche cells and LPCs during chronic injury. We provide a detailed account of the role played by IRS2 in promoting Fgf7 ligand and receptor (Fgfr2-IIIb) expression by the two cell compartments, and we describe an insulin/IRS2-dependent feed-forward loop capable of sustaining hepatic re-epithelialization by driving FGFR2-IIIb expression. Finally, we shed light on the regulation of IRS2 and FGF7 within the fibrotic stroma and show-using a human coculture system-that IRS2 silencing shifts the equilibrium away from paracrine epithelial repair in favor of fibrogenesis. Hence, we offer a compelling insight into the contribution of insulin resistance to the pathogenesis of chronic liver disease and propose IRS2 as a positive regulator of communication between cell types and the transition between phases of stromal to epithelial repair.

A randomized trial of a classroom intervention to increase peers' social inclusion of children with attention-deficit/hyperactivity disorder.

OBJECTIVE: Interventions for peer problems among children with attention-deficit/hyperactivity disorder (ADHD) typically focus on improving these children's behaviors. This study tested the proposition that an adjunctive component encouraging the peer group to be socially inclusive of children with ADHD would augment the efficacy of traditional interventions. METHOD: Two interventions were compared: contingency management training (COMET), a traditional behavioral management treatment to improve socially competent behavior in children with ADHD, and Making Socially Accepting Inclusive Classrooms (MOSAIC), a novel treatment that supplemented behavioral management for children with ADHD with procedures training peers to be socially inclusive. Children ages 6.8-9.8 (24 with ADHD; 113 typically developing [TD]) attended a summer day program grouped into same-age, same-sex classrooms with previously unacquainted peers. Children with ADHD received both COMET and MOSAIC with a repeated measures crossover design. TD children provided sociometric information about the children with ADHD. RESULTS: Whereas the level of behavior problems displayed by children with ADHD did not differ across treatment conditions, children with ADHD displayed improved sociometric preference and more reciprocated friendships, and received more positive messages from peers, when they were in MOSAIC relative to COMET. However, the beneficial effects of MOSAIC over COMET predominantly occurred for boys relative to girls. CONCLUSIONS: Data support the concept that adjunctive procedures to increase the inclusiveness of the peer group may ameliorate peer problems among children with ADHD, and suggest the potential utility of modifying MOSAIC to be delivered in regular classroom settings.

Metabonomics: the use of electrospray mass spectrometry coupled to reversed-phase liquid chromatography shows potential for the screening of rat urine in drug development.

The application of liquid chromatography/mass spectrometry (LC/MS) followed by principal components analysis (PCA) has been successfully applied to the screening of rat urine following the administration of three candidate pharmaceuticals. With this methodology it was possible to differentiate the control samples from the dosed samples and to identify the components of the mass spectrum responsible for the separation. These data clearly show that LC/MS is a viable alternative, or complementary, technique to proton NMR for metabonomics applications in drug discovery and development.