No abstract

II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38 MAPK and its substrate MAPKAPK-2 mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiotensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser 473 , but not Thr 308 . Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attenuated by SB-203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Aktp38 MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosphorylation on Ser 473 . These results suggest that the p38 MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 MAPK confers ROS sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROSsensitive signaling in VSMCs.mitogen-activated protein kinase; reactive oxygen species ANG II IS A PEPTIDE HORMONE that stimulates a plethora of signaling pathways, leading to cell growth and contraction. On binding to its receptor, the ANG II type 1 receptor, ANG II activates an array of protein kinases important for its growthpromoting effects. These kinases include c-Src (11), epidermal growth factor receptor (8), ERK1/2 (7), p38 MAPK (25), and Akt/protein kinase B (26). Activation of p38 MAPK and Akt requires the production of reactive oxygen species (ROS), whereas ERK1/2 stimulation is independent of ROS (25). Our laboratory has previously shown that all three of these kinases mediate ANG II-induced vascular smooth muscle cell (VSMC) hypertrophy (25,26); however, the relationship between the ROS-sensitive kinases p38 MAPK and Akt is unclear.Although it has been clearly shown that activation of Akt requires phosphatidylinositol 3-kinase (PI3-K) activity and NAD(P)H oxidase-derived production of ROS (6, 26), the full complement of upstream mediators of Akt activation by ANG II is not yet fully understood. Akt activation requires phosphorylation of two amino acid residues by upstream kinases: threonine 308 (Thr 308 ) by 3-phosphoinositide-dependent protein kinase (PDK)-1 and serine 473 (Ser 473 ) by a "so-called" PDK2, whose identity is controversial (4). To date, five kinases have been proposed as candidates for PDK2: Akt itself, PDK1, integrin-linked kinase...

Early readmission is common in IBD. Independent risk factors for early readmission included extensive colitis, admission albumin, and being admitted to a housestaff service.

Summary The high-resolution microendoscope (HRME) is a novel imaging modality that may be useful in the surveillance of Barrett's esophagus in low-resource or community-based settings. In order to assess accuracy and interrater reliability of microendoscopists in identifying Barrett's-associated neoplasia using HRME images, we recruited 20 gastroenterologists with no microendoscopic experience and three expert microendoscopists in a large academic hospital in New York City to interpret HRME images. They prospectively reviewed 40 HRME images from 28 consecutive patients undergoing surveillance for metaplasia and low-grade dysplasia and/or evaluation for high-grade dysplasia or cancer. Images were reviewed in a blinded fashion, after a 4-minute training with 11 representative images. All imaged sites were biopsied and interpreted by an expert pathologist. Sensitivity of all endoscopists for identification of high-grade dysplasia or cancer was 0.90 (95% confidence interval [CI]: 0.88–0.92) and specificity was 0.82 (95% CI: 0.79–0.85). Positive and negative predictive values were 0.72 (95% CI: 0.68–0.77) and 0.94 (95% CI: 0.92–0.96), respectively. No significant differences in accuracy were observed between experts and novices (0.90 vs. 0.84). The kappa statistic for all raters was 0.56 (95% CI: 0.54–0.58), and the difference between groups was not significant (0.64 vs. 0.55). These data suggest that gastroenterologists can diagnose Barrett's-related neoplasia on HRME images with high sensitivity and specificity, without the aid of prior microendoscopy experience.