Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVß8-TGFß signaling in the brain.

Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin αVß8 activates angiosuppressive TGFß gradients in the brain, which inhibit endothelial cell sprouting. Loss of αVß8 in the brain or downstream TGFß1-TGFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfb(ret/ret) mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage.

Defective retinal vascular endothelial cell development as a consequence of impaired integrin αVß8-mediated activation of transforming growth factor-ß.

Deletions of the genes encoding the integrin αVß8 (Itgav, Itgb8) have been shown to result in abnormal vascular development in the CNS, including prenatal and perinatal hemorrhage. Other work has indicated that a major function of this integrin in vivo is to promote TGFß activation. In this paper, we show that Itgb8 mRNA is strongly expressed in murine Müller glia and retinal ganglion cells, but not astrocytes. We further show that Itgb8 deletion in the entire retina severely perturbs development of the murine retinal vasculature, elevating vascular branch point density and vascular coverage in the superficial vascular plexus, while severely impairing formation of the deep vascular plexus. The stability of the mutant vasculature is also impaired as assessed by the presence of hemorrhage and vascular basal lamina sleeves lacking endothelial cells. Specific deletion of Itgb8 in Müller glia and neurons, but not deletion in astrocytes, recapitulates the phenotype observed following Itgb8 in the entire retina. Consistent with αVß8's role in TGFß1 activation, we show that retinal deletion of Tgfb1 results in very similar retinal vascular abnormalities. The vascular deficits appear to reflect impaired TGFß signaling in vascular endothelial cells because retinal deletion of Itgb8 reduces phospho-SMAD3 in endothelial cells and endothelial cell-specific deletion of the TGFßRII gene recapitulates the major deficits observed in the Itgb8 and TGFß1 mutants. Of special interest, the retinal vascular phenotypes observed in each mutant are remarkably similar to those of others following inhibition of neuropilin-1, a receptor previously implicated in TGFß activation and signaling.

Self-collected glans/meatal 'dry' swab specimen and NAAT technology detects Chlamydia trachomatis and Neisseria gonorrhoeae - implications for public policy changes.

Increasing Chlamydia trachomatis (CT) rates and ever-present Neisseria gonorrhoeae (NG) infections in women have given rise in the past to consideration of male screening programs in order to address the silent male reservoir. Non-medical venues (e.g. home collection, restrooms or other private locations) may be viable venues to reach certain populations that in the past have not been accessed. Effortlessly collected, non-invasive, self-collected male specimens that are stable and easy to transport would enhance the success of male screening programs. We designed a head-to-head study to consider the effectiveness of non-invasive self-collected glans/meatal dry swab (SCS) specimens to detect CT and NG nucleic acid when compared to traditional clinician-collected swab (CCS) specimens and first-catch urine (FCU) specimens. A total of 284 male patients were included in the study. Specimens were processed using the Becton Dickinson ProbeTec ET system. The overall sensitivity of SCS was 91.1% with a specificity of 99.2%. There was an overall SCS agreement of 97.7% with CCS specimens and 90.4% with FCU specimens. Dry swab specimens are easy to collect, transport and test. Non-invasive dry self-collected glans/meatal swab specimens are a viable specimen choice.