Rationale: Neointimal hyperplasia is characterized by excessive accumulation of vascular smooth muscle cells (SMCs) leading to occlusive disorders, such as atherosclerosis and stenosis. Blood vessel injury increases growth factor secretion and matrix synthesis, which promotes SMC proliferation and neointimal hyperplasia via FAK (focal adhesion kinase). Objective: To understand the mechanism of FAK action in SMC proliferation and neointimal hyperplasia. Methods and Results: Using combined pharmacological FAK catalytic inhibition (VS-4718) and SMC-specific FAK kinase-dead (Myh11-Cre-ER T2 ) mouse models, we report that FAK regulates SMC proliferation and neointimal hyperplasia in part by governing GATA4- (GATA-binding protein 4) cyclin D1 signaling. Inhibition of FAK catalytic activity facilitates FAK nuclear localization, which is required for proteasome-mediated GATA4 degradation in the cytoplasm. Chromatin immunoprecipitation identified GATA4 binding to the mouse cyclin D1 promoter, and loss of GATA4-mediated cyclin D1 transcription diminished SMC proliferation. Stimulation with platelet-derived growth factor or serum activated FAK and redistributed FAK from the nucleus to cytoplasm, leading to concomitant increase in GATA4 protein and cyclin D1 expression. In a femoral artery wire injury model, increased neointimal hyperplasia was observed in parallel with elevated FAK activity, GATA4 and cyclin D1 expression following injury in control mice, but not in VS-4718-treated and SMC-specific FAK kinase-dead mice. Finally, lentiviral shGATA4 knockdown in the wire injury significantly reduced cyclin D1 expression, SMC proliferation, and neointimal hyperplasia compared with control mice. Conclusions: Nuclear enrichment of FAK by inhibition of FAK catalytic activity during vessel injury blocks SMC proliferation and neointimal hyperplasia through regulation of GATA4-mediated cyclin D1 transcription.

Background: Localized extranodal natural killer (NK)/T-cell lymphoma, nasal type, commonly has a low or low-intermediate risk of the international prognostic index (IPI), so the IPI has shown inconsistency in predicting prognosis. Thus, we analyzed Ki-67 expression and proposed a new prognostic model including Ki-67 expression for stage I/II extranodal NK/T-cell lymphoma. Patients and methods:We studied Ki-67 expression and its relationship with prognosis in 50 patients with extranodal NK/T-cell lymphoma.Results: The patients were dichotomized by the median value: low (<65%) versus high Ki-67 ( ‡65%). High Ki-67 was associated with a worse overall survival (OS; P = 0.021) and disease-free survival (DFS; P = 0.044). In multivariate analysis, Ki-67 expression and primary site of involvement were found to be an independent prognostic factor for OS and DFS (P < 0.05). Based on these results, we proposed a new clinico-pathological prognostic model with Ki-67 expression and the primary site of involvement. It showed a high degree of correlation with worse OS and DFS (P < 0.001).Conclusions: Ki-67 expression is predictive of prognosis, and our prognostic model may become a useful tool for predicting prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type.

Pneumonia causes short‐ and long‐term cognitive dysfunction in a high proportion of patients, although the mechanism(s) responsible for this effect are unknown. Here, we tested the hypothesis that pneumonia‐elicited cytotoxic amyloid and tau variants: (1) are present in the circulation during infection; (2) lead to impairment of long‐term potentiation; and, (3) inhibit long‐term potentiation dependent upon tau. Cytotoxic amyloid and tau species were recovered from the blood and the hippocampus following pneumonia, and they were present in the extracorporeal membrane oxygenation oxygenators of patients with pneumonia, especially in those who died. Introduction of immunopurified blood‐borne amyloid and tau into either the airways or the blood of uninfected animals acutely and chronically impaired hippocampal information processing. In contrast, the infection did not impair long‐term potentiation in tau knockout mice and the amyloid‐ and tau‐dependent disruption in hippocampal signaling was less severe in tau knockout mice. Moreover, the infection did not elicit cytotoxic amyloid and tau variants in tau knockout mice. Therefore, pneumonia initiates a tauopathy that contributes to cognitive dysfunction.

Objectives: To assess the results of inferior capsular shift for multidirectional instability of the shoulder in athletes. Methods: Multidirectional instability was surgically corrected in 53 shoulders in 47 athletes who engaged in contact sports. A history of major trauma was found in eight patients, the others having had minor episodes. Before surgery, all patients had complex combinations of instabilities. The surgical approach was selected according to the predominant direction of instability. Results: Anterior inferior capsular shift was carried out in 37 shoulders, and anterior dislocation recurred in three. In one of these, it was anterior alone, one was anterior and inferior, and one was unstable in all three directions. After posterior inferior capsular shift in 16 shoulders, one dislocation occurred anteriorly and one posteriorly. With the anterior approach, four athletes could not return to sport. Two patients treated with the posterior approach could not return to sport. Of these six failures, five patients had had bilateral repairs. Successful repair based on the criteria of the American Shoulder and Elbow Association was achieved in 92% of anterior repairs and 81% of posterior repairs. Successful return to sport was noted in 82% of patients with anterior repairs, 75% with posterior repairs, and 17% with bilateral repairs. Overall, there were five subsequent dislocations, three in the anterior repair group (8%), and two in the posterior repair group (12%). Conclusions: Inferior capsular shift can successfully correct multidirectional instability in most players of contact sports, but the results in bilateral cases are poor.

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