Objective. To assess whether R788, an orally bioavailable small molecule inhibitor of spleen tyrosine kinase (Syk)-dependent signaling, could modulate disease in lupus-prone (NZB ؋ NZW)F 1 (NZB/NZW) mice via inhibition of Fc receptor (FcR) and B cell receptor signaling.Methods. R788 was administered to NZB/NZW mice before and after disease onset. Proteinuria, blood urea nitrogen levels, and autoantibody titers were examined periodically, and overall survival and renal pathologic features were assessed following long-term treatment (24-34 weeks). The distribution and immunophenotype of various splenic T cell and B cell subpopulations were evaluated at the time of study termination. Arthus responses in NZB/NZW mice pretreated with R788 or Fc-blocking antibody (anti-CD16/32) were also examined.Results. When R788 was administered prior to or after disease onset, it delayed the onset of proteinuria and azotemia, reduced renal pathology and kidney infiltrates, and significantly prolonged survival of lupus-prone NZB/NZW mice; autoantibody titers were minimally affected throughout the study. Dosedependent reductions in the numbers of CD4؉ activated T cells expressing high levels of CD44 or CD69 were apparent in spleens from R788-treated mice. Minimal effects on the numbers of naive T cells expressing CD62 ligand and total CD8؉ T cells per spleen were observed following long-term drug treatment. R788 pretreatment resulted in reduced Arthus responses in NZB/NZW mice, similar to results obtained in mice pretreated with FcR-blocking antibody.Conclusion. We demonstrate that a novel Sykselective inhibitor prevents the development of renal disease and treats established murine lupus nephritis. These data suggest that Syk inhibitors may be of therapeutic benefit in human lupus and related disorders.

Purpose: To describe new details of epiretinal cell proliferation in flat-mounted internal limiting membrane specimens.Methods: One hundred nineteen internal limiting membrane specimens were removed en bloc with epiretinal membranes from 79 eyes with macular pucker (MP) and 40 eyes with vitreomacular traction syndrome. Intraoperatively, posterior vitreous detachment was assessed as complete or incomplete. Whole specimens were flat-mounted on glass slides and processed for interference and phase-contrast microscopy, cell viability assay, and immunocytochemistry.Results: Mean cell viability percentage was higher in MP than in vitreomacular traction syndrome. Two cell distribution patterns were found. Anti-CD163 labeling presented predominantly in MP with complete posterior vitreous detachment. CD45 expression was similar in all groups of diagnosis. Anti-glial fibrillary acidic protein (GFAP) labeling was found in MP irrespective of the extent of posterior vitreous detachment. Alpha-SMA (a-smooth muscle actin) labeling was mainly presented in MP with incomplete posterior vitreous detachment and in vitreomacular traction syndrome. Simultaneous antibody labeling included GFAP/CD45, GFAP/CD163, CD163/CD45, and CD163/a-SMA.Conclusion: Hyalocytes constitute a major cell type of epiretinal cell proliferation in eyes with MP and vitreomacular traction syndrome. Glial cells, notably retinal Muller cells, are involved as well. It appears that transdifferentiation of cells in vitreomacular traction might be more frequent than previously thought and that those cells possess a greater variability of immunocytochemical properties than expected.RETINA 33:77-88, 2013 E piretinal gliosis, such as macular pucker (MP), and vitreomacular traction syndrome (VMTS) are traction vitreoretinopathies that develop at the vitreoretinal interface of the macular area. The major component of the vitreoretinal interface is the internal limiting membrane (ILM) that has attracted enormous interest for decades. The ILM is the site of epiretinal membrane (ERM) formation, and it mediates tractional forces from the vitreous to retinal layers. There is general consent that vitreoretinal traction plays a crucial role in the pathogenesis and the clinical course of MP and VMTS.1 Anteroposterior vitreoretinal traction is caused by persistent vitreoretinal adhesions because of an incomplete posterior vitreous detachment (PVD), whereas tangential traction is caused by contractive ERMs as a result of progressive fibrocellular proliferation at the vitreal side of the ILM. [2][3][4][5][6] Removal of the vitreous and epiretinal tissue is the principal goal of vitreoretinal surgery in MP and VMTS because ERMs represent the morphological From the

The sexual differentiation paradigm contends that the female pattern of the reproductive system is established by default, as the male reproductive tracts (Wolffian ducts) in the female degenerate due to a lack of androgen. Here, we discovered that female mouse embryos lacking Coup-tfII in the Wolffian duct mesenchyme became intersex that contained both female and male reproductive tracts. Retention of Wolffian ducts was not caused by ectopic androgen production or action. Instead, enhanced p-ERK signaling in Wolffian duct epithelium was responsible for the retention in an androgen-independent manner. These results support our hypothesis that elimination of Wolffian ducts in female embryos is actively promoted by COUP-TFII, which suppresses a mesenchyme-epithelium crosstalk responsible for Wolffian duct maintenance.

The presence of epiretinal cells at the ILM in all macular hole stages strongly suggests a substantial involvement of cell migration and proliferation in the course of macular hole development. Glial cells and hyalocytes play the predominant role in epiretinal cell proliferation. Given the co-expression of glial cell and hyalocyte markers, transdifferentiation of epiretinal cells needs further elucidation, especially with respect to αSMA-positive cells leading to traction at the vitreoretinal interface.