The perivascular location of human immunodeficiency virus-infected cells suggests that the virus enters the central nervous system (CNS) by traversing the blood-brain barrier (BBB). In this study, the simian immunodeficiency virus (SIV) macaque model was used to determine whether SIV infects CNS endothelial cells. SIV RNA was detected in capillary endothelial cells in brain sections from animals parenterally inoculated with a neurovirulent strain of SIV by double immunohistochemistry and in situ hybridization and by reverse transcriptase-in situ PCR. These in vivo observations were extended by examining whether SIV replicated productively in cultured macaque brain endothelial cells (MBEC). A neurovirulent strain, SIVmac239/17E-Br, replicated productively in MBEC as determined by the presence of viral cytopathic effect (syncytia), viral DNA by PCR, viral RNA by in situ hybridization, and viral antigen by immunohistochemistry and by the production of high titers of cell-free virus. Virus replication was confirmed by electron microscopy. In contrast, a nonneurovirulent strain, SIVmac239, did not infect MBEC. Infection of the endothelial cells was not blocked by soluble CD4. Thus, endothelial cells may provide a CD4-independent pathway of virus entry to the CNS. In addition, damage to the BBB as a result of endothelial cell infection may provide a mechanism for amplification of viral load in the CNS and may contribute to the CNS dysfunction that characterizes AIDS dementia and SIV encephalitis. These data suggest that MBEC may serve a selective role in determining virus entry to the CNS.
We have developed a novel in vivo model utilizing acute stretch to investigate endothelial cell proliferation as a marker of vascular growth in healing mouse skin. This study is a follow-up to ones revealing immediate stretch improves blood flow, decreases total tissue necrosis, and induces tissue insulin transcription. Dorsal distally based flaps of skin were stretched for 3 min using linear (skin hook) plus hemispherical load cycling (inflated subcutaneous silicone catheter). Unstretched, wounded skin along the back and sternum served as postoperative controls. Laser Doppler flowmetry demonstrated a threefold increase in flap perfusion at postoperative day 7. A stretch-induced sixfold increase in endothelial cell mitogenesis accompanied enhancements in blood flow and extracorporal wound healing over the sternum. Western blots revealed up-regulation/activation of insulin and mitogenic signaling intermediates in stretched skin. Activated insulin and insulin growth factor receptors (pIR/pIGFR), protein kinase B (Akt, pAkt), vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (flk-1) were among the identified stretch-responsive intermediates. These results indicate the benefits of acute stretch are mediated through enhanced vascularity as evidenced by endothelial cell mitogenesis and up-regulation/activation of insulin and key angiogenic effectors in dorsal distally based skin flaps.
Based on these results, some changes have already been implemented, including decreased student-to-instructor ratios, more open scan time, and more required components. The breadth of formal assessment has increased. Multiple pilot programs for clinical rotations are being developed. There is an ongoing need for faculty development and continued assessment of ultrasound competency.
Immunostaining methods were used to detect viral T-antigen and the cellular protein p53 in pathological tissues obtained from transgenic mice carrying JC-SV40 hybrid viral DNAs. A transgenic mouse carrying the SV40 regulatory region and JC virus (JCV) T-antigen-coding sequences exhibited an SV40-characteristic choroid plexus papilloma that expressed JCV T-antigen and p53. JCV-associated pathology was observed in two other mice in which the JCV regulatory signals directed SV40 T-antigen-induced adrenal neuroblastomas and brain neoplastic cells. However, these mice also exhibited an SV40-characteristic osteosarcoma and abdominal lymphoma that contained SV40 T-antigen and p53-positive cells. Contrasting thymic pathology was observed in the two types of mice where the SV40 regulatory region directed a JCV T-antigen-induced thymoma in one mouse, and the JCV regulatory region directed SV40 T-antigen-induced thymic hypoplasia in two other mice.
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