Indiana University-Purdue University Indianapolis (IUPUI) / Choroidal neovascularization (CNV) is the vision-threatening characteristic of wet age-related macular degeneration (AMD), a major cause of blindness affecting almost 2 million elderly Americans. The current approved treatments target the dominant angiogenic mediator, vascular endothelial growth factor (VEGF). However, repeated injections of anti-VEGF drugs can cause ocular and systemic side effects, and about 30% of wet AMD patients are non-responsive. There is thus an unmet need to develop VEGF-independent antiangiogenic molecules to complement or combine with existing medications. I studied SH-11037, a novel homoisoflavonoid with potent and selective antiangiogenic activity against human retinal endothelial cells. Intravitreal SH- 11037 dose-dependently suppressed angiogenesis in the laser-induced CNV (LCNV) mouse model. These effects were prominent as early as 7 days post-laser treatment as measured by a novel ellipsoid quantification method of optical coherence tomography images in vivo. A supratherapeutic dose of 100 μM SH- 11037 was not associated with signs of murine ocular toxicity, and did not interfere with pre-existing retinal vasculature or retinal function. SH-11037 synergized with anti-VEGF therapy in vitro and in vivo, suggesting a VEGFindependent mechanism. By photoaffinity pulldown, I identified soluble epoxide hydrolase (sEH) as an SH-11037-binding target. sEH is a key enzyme in ω-3 and ω-6 fatty acid metabolism. sEH levels were dramatically upregulated in retinal sections from L-CNV mice and a specific sEH inhibitor, t-AUCB, significantly suppressed L-CNV lesion volume. Additionally, SH-11037 inhibited sEH enzymatic activity in vitro and in vivo in L-CNV mice. Given the role of sEH in the metabolism of docosahexaenoic acids (DHA), inhibition of sEH using small molecules like SH-11037 would enhance ocular DHA levels, with beneficial antiangiogenic and anti-inflammatory effects. SH-11037 is thus a novel sEH inhibitor, which could make it an alternative or additive therapy to existing anti- VEGF drugs for treatment of neovascular diseases in the eye and other tissues.

D. Litt et Phil. (Literature and Philosophy) / Eye health promotion is an important aspect of VISION 2020 campaign that aims to eliminate unwarranted cases of avoidable blindness worldwide by the year 2020. Most developing countries, including South Africa, have a serious burden of eye diseases and unwarranted causes of visual impairment and blindness. The purpose of this research therefore was to highlight the lack of an integrated eye health promotion policy in the South African primary health care system which can play a major role in the elimination of this burden of disease and also to make proposals for eye health promotion policy development in South Africa. A combination of quantitative and qualitative research methods was used in this study. Questionnaires and interviews were conducted with all national and provincial health managers of portfolios relevant to eye care. Also, various health policy documents were requested from the National and Provincial Department of Health to ascertain claims of any existing guidelines on eye care. The policy documents and guidelines obtained had no specific reference to eye health promotion. Only 11 (23%) of the managers of provincial health directorates reported that they have integrated vision screening in their health promotion programmes as part of eye health promotion strategies. Eye care managers in the provinces reported that school visits accounted for 75% of eye health promotion programmes target areas. Also, apart from the Northern Cape Province which has no eye care manager and consequently no eye health promotion programmes, the Western Cape Province also does not have eye health promotion programmes and relies mostly on private sector for eye care services. The lack of an integrated eye health promotion policy and most probably the lack of a dedicated directorate that deals with eye health promotion issues may be a contributing factor to the overwhelming lack of integrated eye health promotion activities in South Africa. It is therefore recommended that an integrated eye health promotion model be developed and be part of the South African primary health care system. / Health Studies

Diabetes is a major risk factor for the development of cataract [3,14,20,22]. In this thesis, we create a model that allows us to understand the incidence of one disease in the context of another; in particular, cataract in the presence of diabetes. The World Health Organization's Vision 2020 blindness-prevention initiative administers surgeries to remove cataracts, the leading cause of blindness worldwide [24]. One of the geographic areas most impacted by cataract-related blindness is Sub-Saharan Africa. In order to plan the number of surgeries to administer, the World Health Organization uses data on cataract prevalence. However, an estimation of the incidence of cataract is more useful than prevalence data for the purpose of resource planning. In 2012, Dray and Williams developed a method for estimating incidence based on prevalence data [5]. Incidence estimates can be further refined by considering associated risk factors such as diabetes. We therefore extend the Dray and Williams model to include diabetes prevalence when calculating cataract incidence estimates. We explore two possible approaches to our model construction, one a detailed extension, and the other, a simplification of that extension. We provide a discussion comparing the two approaches.

Eye health promotion is an important aspect of VISION 2020 campaign that aims to eliminate unwarranted cases of avoidable blindness worldwide by the year 2020. Most developing countries, including South Africa, have a serious burden of eye diseases and unwarranted causes of visual impairment and blindness. The purpose of this research therefore was to highlight the lack of an integrated eye health promotion policy in the South African primary health care system which can play a major role in the elimination of this burden of disease and also to make proposals for eye health promotion policy development in South Africa. A combination of quantitative and qualitative research methods was used in this study. Questionnaires and interviews were conducted with all national and provincial health managers of portfolios relevant to eye care. Also, various health policy documents were requested from the National and Provincial Department of Health to ascertain claims of any existing guidelines on eye care. The policy documents and guidelines obtained had no specific reference to eye health promotion. Only 11 (23%) of the managers of provincial health directorates reported that they have integrated vision screening in their health promotion programmes as part of eye health promotion strategies. Eye care managers in the provinces reported that school visits accounted for 75% of eye health promotion programmes target areas. Also, apart from the Northern Cape Province which has no eye care manager and consequently no eye health promotion programmes, the Western Cape Province also does not have eye health promotion programmes and relies mostly on private sector for eye care services. The lack of an integrated eye health promotion policy and most probably the lack of a dedicated directorate that deals with eye health promotion issues may be a contributing factor to the overwhelming lack of integrated eye health promotion activities in South Africa. It is therefore recommended that an integrated eye health promotion model be developed and be part of the South African primary health care system. / Health Studies / D. Litt et Phil. (Health Studies)

The endoplasmic reticulum (ER) is a multi-functional cellular compartment that functions in protein folding, lipid biosynthesis, and calcium homeostasis. Perturbations to ER function lead to the dysregulation of ER homeostasis, causing the accumulation of unfolded and misfolded proteins in the cell. This is a state of ER stress. ER stress elicits a cytoprotective, adaptive signaling cascade to mitigate stress, the Unfolded Protein Response (UPR). As long as the UPR can moderate stress, cells can produce the proper amount of proteins and maintain a state of homeostasis. If the UPR, however, is dysfunctional and fails to achieve this, cells will undergo apoptosis. Diabetes mellitus is a group of metabolic disorders characterized by persistent high blood glucose levels. The pathogenesis of this disease involves pancreatic β-cell dysfunction: an abnormality in the primary function of the β-cell, insulin production and secretion. Activation of the UPR is critical to pancreatic β-cell survival, where a disruption in ER stress signaling can lead to cell death and consequently diabetes. There are several models of ER stress leading to diabetes. Wolcott-Rallison syndrome, for example, occurs when there is a mutation in the gene encoding one of the master regulators of the UPR, PKR-like ER kinase (PERK). In this dissertation, we show that Wolfram Syndrome 1 (WFS1), an ER transmembrane protein, is a component of the UPR and is a downstream target of two of the master regulators of the UPR, Inositol Requiring 1 (IRE1) and PERK. WFS1 mutations lead to Wolfram syndrome, a non-autoimmune form of type 1 diabetes accompanied by optical atrophy and other neurological disorders. It has been shown that patients develop diabetes due to the selective loss of their pancreatic β-cells. Here we define the underlying molecular mechanism of β-cell loss in Wolfram syndrome, and link this cell loss to ER stress and a dysfunction in a component of the UPR, WFS1. We show that WFS1 expression is localized to the β-cell of the pancreas, it is upregulated during insulin secretion and ER stress, and its inactivation leads to chronic ER stress and apoptosis. This dissertation also reveals the previously unknown function of WFS1 in the UPR. Positive regulation of the UPR has been extensively studied, however, the precise mechanisms of negative regulation of this signaling pathway have not. Here we report that WFS1 regulates a key transcription factor of the UPR, activating transcription factor 6 (ATF6), through the ubiquitin-proteasome pathway. WFS1 expression decreases expression levels of ATF6 target genes and represses ATF6-mediated activation of the ER stress response (ERSE) promoter. WFS1 recruits and stabilizes an E3 ubiquitin ligase, HMG-CoA reductase degradation protein 1 (HRD1), on the ER membrane. The WFS1-HRD1 complex recruits ATF6 to the proteasome and enhances its ubiquitination and proteasome-mediated degradation, leading to suppression of the UPR under non-stress conditions. In response to ER stress, ATF6 is released from WFS1 and activates the UPR to mitigate ER stress. This body of work reveals a novel role for WFS1 in the UPR, and a novel mechanism for regulating ER stress signaling. These findings also indicate that hyperactivation of the UPR can lead to cellular dysfunction and death. This supports the notion that tight regulation of ER stress signaling is crucial to cell survival. This unanticipated role of WFS1 for a feedback loop of the UPR is relevant to diseases caused by chronic hyperactivation of ER stress signaling network such as pancreatic β-cell death in diabetes and neurodegeneration.

This is a study on the prevalence of refractive errors and patients requiring refractive services at 15 eye clinics in the Amathole, Chris Hani, Joe Gqabi and OR Tambo District Municipalities of the Eastern Cape. This is an area characterised by extreme poverty where the cost of an eye examination and prescription spectacles remains financially unobtainable for most. Optometry services are provided mainly by private optometrists who service the small proportion of the population that can afford them. Adults and children remain house bound or are labelled as dull and unproductive simply because they don’t have access to an eye examination and a pair of spectacles. Purpose The purpose of the study is to identify patients with refractive errors and those requiring refractive services at the 15 eye clinics in the Eastern Cape. Another purpose is to describe the refractive services that are available to patients attending health facilities, where the eye clinics are conducted. Lastly, the purpose is to explore the possibility of nurses providing refractive services independently or under the supervision of optometrists to supplement the lack to refracting and dispensing services. Study Method A quantitative and qualitative non-experimental descriptive design was used. Research involved the analysis of Vision Care’s eye clinic records collected from 15 eye clinics from January 2010-June 2010. Semi-structured interviews were conducted with 30 nurses working at the 15 health facilities where the eye clinics were conducted using purposive sampling. The quantitative data was analysed using excel spreadsheets and graphs and qualitative data was analysed using coding and categorizing methods. Conclusion According to Vision Care’s data of the patients assessed, 19.2 percent had a refractive error and 54 percent of the patients required refractive services. It is estimated that 71.41 percent of the patients had a refractive error according to the optometrist. Although there were some organisations active in the eradication of cataracts, there was little healthcare available in the form of refraction services. xiv Patients needed to travel an average of 63.8kms to access refraction services against the backdrop of poor roads, poverty and unemployment. 28 out of 30 nurses either ‘strongly agreed’ or ‘agreed’ that nurses could be trained to perform refractions and dispense spectacles. 29 out of 30 nurses thought that this would have a positive impact on eye care. Further research is necessary to assess the feasibility of implementing a nurse operated refractive program and whether it should be within their scope of practice to refract and dispense spectacles.