cleavage. When applied to the basolateral surface of colonocytes, PAR 2 agonists and mast cell supernatant decreased transepithelial resistance, increased transepithelial flux of macromolecules, and induced redistribution of tight junction ZO-1 and occludin and perijunctional F-actin. When mast cells were co-cultured with colonocytes, mast cell degranulation increased paracellular permeability of colonocytes. This was prevented by a tryptase inhibitor. We determined the role of ERK1/2 and of ␤-arrestins, which recruit ERK1/2 to PAR 2 in endosomes and retain ERK1/2 in the cytosol, on PAR 2 -mediated alterations in permeability. An ERK1/2 inhibitor abolished the effects of PAR 2 agonist on permeability and redistribution of F-actin. Downregulation of ␤-arrestins with small interfering RNA inhibited PAR 2 -induced activation of ERK1/2 and suppressed PAR 2 -induced changes in permeability. Thus, mast cells signal to colonocytes in a paracrine manner by release of tryptase and activation of PAR 2 . PAR 2 couples to ␤-arrestin-dependent activation of ERK1/2, which regulates reorganization of perijunctional F-actin to increase epithelial permeability. These mechanisms may explain the increased epithelial permeability of the intestine during stress and inflammation.

PURPOSE Set-shifting is a neurocognitive concept defined as the ability to switch tasks flexibly. Set-shifting scores are worse in adults with Restrictive Anorexia Nervosa (AN-R) than in controls. Adolescence is a developmental period when young people must respond flexibly to new situations. The purpose of this study is to compare the set-shifting scores of 24 adolescent females with AN-R and 37 matched normal adolescent controls (ages 14–20). METHODS Methods included sociodemographic, psychological and biologic data, and neurocognitive testing using the Behavior Rating of Executive Function – Self- and Parent-Reports, the Cambridge Neuropsychological Automated Battery, and the Wisconsin Card-Sorting Test. Statistical analyses included t-tests, multiple analysis of variance, and correlations. RESULTS Study and control subjects were similar on sociodemographic data and intelligence quotient. There were differences in Body Mass Index and the Eating Disorder-3 evaluation. Significant differences in the composite score of set-shifting between the study and control groups were found using multiple analysis of variance. CONCLUSIONS Adolescent females with AN-R had significantly worse set-shifting scores than did control subjects. Future studies of adolescent AN-R subjects should include biologic (fMRI) and neurocognitive measures to determine the mechanisms at the brain-behavioral interface so that treatment can be directed specifically to set-shifting deficits.

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