In the last decade, there has been an increasing interest in cognitive alterations during the early course of schizophrenia. From a clinical perspective, a better understanding of cognitive functioning in putative at-risk states for schizophrenia is essential for developing optimal early intervention models. Two approaches have more recently been combined to assess the entire course of the initial schizophrenia prodrome: the predictive "basic symptom at-risk" (BS) and the ultra high-risk (UHR) criteria. Basic symptoms are considered to be present during the entire disease progression, including the initial prodrome, while the onset of symptoms captured by the UHR criteria expresses further disease progression toward frank psychosis. The present study investigated the cognitive functioning in 93 subjects who met either BS or UHR criteria and thus were assumed to be at different points on the putative trajectory to psychosis. We compared them with 43 patients with a first episode of psychosis and to 49 help-seeking patient controls. All groups performed significantly below normative values. Both at-risk groups performed at intermediate levels between the first-episode (FE) group and normative values. The UHR group demonstrated intermediate performance between the FE and BS groups. Overall, auditory working memory, verbal fluency/processing speed, and declarative verbal memory were impaired the most. Our results suggest that cognitive impairments may still be modest in the early stages of the initial schizophrenia prodrome and thus support current efforts to intervene in the early course of impending schizophrenia because early intervention may prevent or delay the onset of frank psychosis and thus prevent further cognitive damage.

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ObjectiveWe have shown previously that preterm infants are at risk of necrotizing enterocolitis (NEC), an inflammatory bowel necrosis typically seen in infants born prior to 32 weeks’ gestation, because of the developmental deficiency of transforming growth factor (TGF)-β2 in the intestine. The present study was designed to investigate all-trans retinoic acid (atRA) as an inducer of TGF-β2 in intestinal epithelial cells (IECs) and to elucidate the involved signaling mechanisms.MethodsAtRA effects on intestinal epithelium were investigated using IEC6 cells. TGF-β2 expression was measured using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and Western blots. Signaling pathways were investigated using Western blots, transiently-transfected/transduced cells, kinase arrays, chromatin immunoprecipitation, and selective small molecule inhibitors.ResultsAtRA-treatment of IEC6 cells selectively increased TGF-β2 mRNA and protein expression in a time- and dose-dependent fashion, and increased the activity of the TGF-β2 promoter. AtRA effects were mediated via RhoA GTPase, Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1), p38α MAPK, and activating transcription factor (ATF)-2. AtRA increased phospho-ATF2 binding to the TGF-β2 promoter and increased histone H2B acetylation in the TGF-β2 nucleosome, which is typically associated with transcriptional activation.ConclusionsAtRA induces TGF-β2 expression in IECs via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2. Further studies are needed to investigate the role of atRA as a protective/therapeutic agent in gut mucosal inflammation.

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