Thesis--University of Helsinki, 1975. / Bibliography, p. 37-43.

archives@tulane.edu / The prevalence of HIV-associated neurocognitive disorders (HAND) has increased in the era of combination anti-retroviral therapy (cART). Despite this and documented neurocognitive impairment, there is a lack of pathology of HIV-encephalitis (HIVE), specifically multi-nucleated giant cells (MNGCs), in children and SIV-encephalitis (SIVE) in rhesus macaques infected pre-, peri-, and post-parturition. In this dissertation, we show that the lack of MNGCs seen is most likely due to innate differences in the blood-brain and blood-CSF barriers, and a robust pro- and anti-inflammatory response in neonatal rhesus macaques. Using a rhesus macaque model of HIV, we examined the plasma viral load, brain tissue viral load, and monocyte turnover, using PCR and flow cytometry, respectively. We also performed immunohistochemistry for monocyte, macrophage, tight junction, and aging markers of the choroid plexus. We sought to create a choroid plexus epithelial cell model to monitor the effects of inflammatory markers and virus on the tight junctions of the blood-CSF barrier in real-time. We demonstrated that neonates do not develop encephalitis, despite comparable viral load and monocyte turnover, previously established correlates of SIV-encephalitis (SIVE). However, we noted that uninfected adult rhesus macaques have an increase in virus susceptible cells in the brain, SIV-infected adults have a leakier blood-brain barrier than infected neonates, and adults with encephalitis have a greater viral burden in brain tissue compared to adults without encephalitis. In the choroid plexus, we discovered that despite the lack of encephalitis, neonates have an increase in monocytes and macrophages of the choroid plexus, indicating a strong immune response. While our choroid plexus epithelial cell model is still in preliminary stages, initial results are promising. Our work indicates a possible viral threshold needed for the development of encephalitis, and that the blood-brain barrier may play a role in this threshold due to lower levels of virus susceptible cells and a tighter blood brain barrier in neonates. In the choroid plexus, the strong pro- and anti-inflammatory macrophage response seen in neonates may offer an extra layer of protection development of SIVE. Our data also indicates that SIV causes a marked decrease in the expression of klotho, the anti-aging hormone that is produced in high levels in the choroid plexus in the brain. This could potentially explain the premature inflammaging phenotype seen in chronic infections. / 1 / Elizabeth Delery

Thesis (doctoral)--Rijksuniversiteit te Utrecht.

Thesis (Ph. D.)--UCLA, 2009. / Vita. Description based on print version record. Includes bibliographical references (leaves 134-149).

Thesis (doctoral)--Rijksuniversiteit te Utrecht.

Thesis (M.S.)--New England College of Optometry, 2009. / Includes bibliographical references (p. 41-45).

Indiana University-Purdue University Indianapolis (IUPUI) / Hydrocephalus is a disease characterized by an increase in cerebrospinal fluid (CSF) in the ventricles of the brain. This manifests as a result of either overproduction or underabsorption of CSF leading to increases in pressure, swelling and loss of brain matter. Current treatments for this disease include surgical interventions via the introduction of shunts or endoscopic third ventriculostomy, both of which aim to redirect flow of CSF in to another cavity for absorption. Limited pharmacotherapies are available in the treatment of hydrocephalus, and there exists a clinical need for drug therapies, which can ameliorate the pathophysiology associated with hydrocephalus and ventriculomegaly. CSF is produced primarily by the choroid plexus (CP), found in the ventricles of the brain. Composed of a high resistance epithelium surrounding a capillary network, the CP epithelium acts as a barrier, regulating ion transport between the CSF and blood. Transient Receptor Potential Vanilloid-4 (TRPV4) is a nonselective Ca2+-permeable cation channel expressed in the CP which is being investigated for its role in CSF production. To study hydrocephalus, we utilize two model systems; the TMEM67-/- Wpk rat, and the PCP-R cell line. The Wpk rat model is used to study the effects of drug intervention on the development and progression of hydrocephalus. The PCP-R cell line is utilized for studies which aim to understand the mechanisms by which CSF is produced. Using Ussing chamber electrophysiology, we are able to study the role of specific channels, transporters and modulators in driving epithelial ion flux across the CP. This research aims to establish a role for TRPV4 in production and regulation of CSF, and to interrogate a mechanism by which this ion transport occurs. The chapters that follow describe components of the pathway by which TRPV4 is activated and ion flux is stimulated.

No description available.

PURPOSE. To image the fundus non-invasively at two different penetration depths using a multispectral imaging system. Monochromatic images at visible spectrum wavelengths and near-infrared wavelengths were qualitatively assessed for choroidal visibility. These images were used calculate oxygen saturation in retinal tissue, optic nerve head tissue, vein, and choroidal tissue in healthy controls and glaucoma patients. METHODS. A fundus camera-based multispectral snapshot oximeter imaged the fundus of healthy subjects and patients with varying ophthalmological pathology. The images of healthy controls and glaucoma patients were analyzed to determine oxygen saturation in the optic nerve head cup and rim, superficial and deep vein, macula and choroidal tissue. RESULTS. Visible: Average oxygen saturation for the ONH cup was 65 ± 6 percent for healthy controls and 61 ± 10 percent for glaucoma patients. For the ONH rim, it was 67 ± 3 percent for healthy controls and 64 ± 17 percent for glaucoma patients. For the vein, it was 67 ± 15 percent for healthy controls and 56 ± 22 percent for glaucoma patients. For the macula, it was 87 ± 10 percent for healthy controls and 93 ± 1 percent for glaucoma patients. NIR: The average oxygen saturation for the vein was 66 ± 20 percent for healthy controls, 58 ± 0.4 percent for glaucoma suspects and 54 ± 17 percent for glaucoma patients. For the choroidal tissue below the macula, it was 99 ± 5 percent in healthy controls and 81 ± 8 percent in glaucoma patients. CONCLUSIONS. Choroidal visibility is enhanced in near infrared monochromatic images from visible spectrum monochromatic images. Oxygen saturation results were lower in glaucoma patients for all anatomical areas analyzed except the avascular macula. / acase@tulane.edu

Choroidal neovascularization (CNV) is a leading threat to severe vision loss, particularly in patients with age-related macular degeneration (AMD). In CNV, newly formed blood vessels sprout from the choroid to the sub-retinal space, where leakage and bleeding of the abnormal vessels lead to photoreceptor death and subsequent vision loss. It is believed that CNV is mediated by growth factors (e.g. vascular endothelial growth factor {VEGF}) produced by the retinal pigment epithelium (RPE) under pathological states (e.g. hypoxia). Current treatments for CNV aiming at countering VEGF only help decrease leakage and inhibit formation of CNV, but none of them is curative and the recurrence rate remains high. In order to find other more powerful potential therapeutic targets, the regulations of VEGF signaling in the pathophysiology of CNV is the focus of numerous translational investigations. Previously, Hypoxia-inducible factor-1 (HIF-1), a crucial transcriptional factor in response to hypoxia, is identified as the master transcriptional factor controlling VEGF expression in the RPE promoting CNV. Alpha-enolase (ENO1), a key glycolytic enzyme, is known to be over expressed in several types of carcinomas also under the regulation of HIF-1. ENO1 has been reported to be closely associated with cancer progression, angiogenesis, and venous invasion. The molecular events of ENO1 in the pathogenesis of promoting angiogenesis are of interest but still barely understood. Recently, the association of ENO1 antibodies with retina has been seen in patients with AMD. We hypothesize that ENO1 expression in the RPE may play a role in the development of CNV, participating in the regulation of VEGF. Hypoxia is an important pathological condition in the formation of CNV. Here, we first determined ENO1 expression and cell death in a human RPE cell line, ARPE-19, under cobalt (II) chloride (CoCl2)-induced hypoxia or anoxia (95% N2, 5% CO2). To further investigate the regulation of ENO1 in CNV, HIF-1α-diminished RPE cells were generated using small interfering RNA (siRNA) and the change of ENO1 expression in response to hypoxic injury was determined. Upon 24 hr of treatment with CoCl2-induced hypoxia or anoxia, the expression of ENO1 and VEGF increased significantly along with HIF-1α in ARPE-19 cells, both of which could in turn be significantly down-regulated by HIF-1α siRNA. Interestingly, cell death remained low in ARPE-19 cells, even after 24 hr of CoCl2-induced hypoxia or anoxia. To further study the role of ENO1 in CNV, we started by investigating the relationship between ENO1 and VEGF. SiRNA was used to knock down the expression of ENO1 in ARPE-19 cells. Upon transfection with the siRNA, ENO1 expression was successfully down-regulated when treated with CoCl2-induced hypoxia. However, VEGF secretions from the ENO1-diminished ARPE-19 cells under CoCl2-induced hypoxia remained unchanged. Double knockdown of ENO1 together with HIF-1α by siRNA also did not help to further suppress VEGF secretion in the hypoxic ARPE-19 cells. Hence, ENO1 was demonstrated to be activated and up-regulated by HIF-1 in RPE cells responding to hypoxia, suggesting a potential role of ENO1 in favoring the formation of CNV, but not through influencing VEGF secretion. / published_or_final_version / Ophthalmology / Master / Master of Philosophy