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The immediate early gene NUR77 (also called NGFI-B) is required for T cell antigen receptor-mediated cell death and is induced to very high levels in immature thymocytes and T cell hybridomas undergoing apoptosis. The Akt (PKB) kinase is a key player in transduction of anti-apoptotic and proliferative signals in T cells. Because Nur77 has a putative Akt phosphorylation site at Ser-350, and phosphorylation of this residue is critical for the transactivation activity of Nur77, we investigated whether Akt regulates Nur77. Coimmunoprecipitation experiments showed the detection of Nur77 in Akt immune complexes, suggesting that Nur77 and Akt physically interact. We further show that Akt specifically phosphorylates Ser-350 of the Nur77 protein within its DNA-binding domain in vitro and in vivo in 293 and NIH 3T3 cells. Because phosphorylation of Ser-350 of Nur77 is critical for its function as a transcription factor, we examined the effect of Akt on this function. By using luciferase assay experiments, we showed that phosphorylation of Nur77 by Akt decreased the transcriptional activity of Nur77 by 50 -85%. Thus, we show that Akt interacts with Nur77 and inactivates Nur77 by phosphorylation at Ser-350 in a phosphatidylinositol 3-kinase-dependent manner, connecting the phosphatidylinositol 3-kinase-dependent Akt pathway and a nuclear receptor pathway.

Purpose. To investigate the pathological change of the glymphatic system in idiopathic normal pressure hydrocephalus (iNPH) using diffusion tensor imaging (DTI) analysis. Materials and Methods. 24 right-handed patients were referred to our hydrocephalus clinic for assessment of ventriculomegaly and gait impairment. 12 of 24 were diagnosed as pseudo-iNPH (piNPH) based on assessment by a neurologist. Diffusivity maps in the direction of the x-axis (right-to-left) (Dx), y-axis (anterior-to-posterior) (Dy), and z-axis (inferior-to-superior) (Dz) were computed. The diffusion map was coregistered to International Consortium for Brain Mapping (ICBM) DTI-81 atlas. The analysis along the perivascular space (ALPS) index was defined as mean (Dxpro, Dypro)/mean (Dypro, Dzasc), where Dxpro and Dxasc are Dx values in the projection and association fiber areas, respectively. Evans index and callosal angle were also assessed on each case. Results. ALPS indexes of the control, piNPH, and iNPH cases were 1.18 ± 0.08, 1.08 ± 0.03, and 0.94 ± 0.06, respectively, and there were significant differences among the groups (control vs. piNPH, P = 0.003; control vs. iNPH P < 0.001; piNPH vs. iNPH, P < 0.001). Area under curve (AUC) was 0.92, 1.00, and 1.00 on control vs. piNPH, control vs. iNPH, and piNPH vs. iNPH on ROC analysis. Between piNPH and NPH, ALPS index has higher diagnostic performance than Evans index and callosal angle (AUC = 1.00 vs. 0.84, P = 0.028; AUC = 1.00 vs. 0.74, P = 0.016). Conclusion. Atlas-based ALPS index using the DTI method differentiated among iNPH, piNPH, and controls clearly.

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Inflammatory abdominal aortic aneurysm (IAA) is associated with autoimmune disease. However, the precise mechanism of IAA remains unclear. There is increasing evidence that IgG4 is involved in the autoimmune mechanism of various idiopathic sclerosing lesions, including sclerosing pancreatitis and retroperitoneal fibrosis. The present study investigated the hypothesis that the IgG4-related autoimmune reaction is involved in the formation of IAA. The study group consisted of 11 cases of IAA (69.2 +/- 8.59y) and 12 age-matched cases of atherosclerotic abdominal aortic aneurysm (AAA, 69.6 +/- 5.94y), which were used in the previous report. A clinicopathologic examination of these lesions was performed, including histology and immunohistochemistry, in relation to the involvement of IgG4-positive plasma cells in the formation of IAA. No difference in the incidence of risk factors for atherosclerosis was observed between the patients with IAA and AAA. Autoimmune diseases were diagnosed in 2 patients with IAA, including rheumatoid arthritis and polyarteritis nodosa. A patient with IAA had pulmonary fibrosis. In contrast, autoimmune diseases were absent in patients with AAA. However, there was no significant difference in the incidence of autoimmune diseases between the patients with IAA and AAA. Lymphocyte and plasma cell infiltration and fibrosis were significantly more intense and extensive in IAA than in AAA. In addition, lymph follicle formation and vasculitis of small veins and arteries were frequently found in the affected lesions of IAA. Immunohistochemically, IAA showed a significant increase in the number of infiltrating IgG4-positive plasma cells and the incidence of a disrupted follicular dendritic cell network in lymph follicles, in comparison with AAA. These findings suggest that IAA may be an aortic lesion reflecting the presence of IgG4-related sclerosing disease, and not a simple inflammatory aneurysm of the aorta.