Angiogenesis is a process of new blood vessels sprouting from the pre-existing vasculature, and mediated by multiple angiogenic and anti-angiogenic factors. Disturbance of the balance often leads to development of neovascular diseases. Neovascularization affecting the eye is a common cause of visual impairment and even blindness, particularly when corneal or choroidal neovascularization (NV) is involved. While there are effective treatment modes for ocular neovascularization, they are expensive and only inhibit disease progress. Since herbal medicine has been applied for anti-angiogenesis and anti-carcinogenesis therapies, we investigate the anti-angiogenic effect of selected herbal molecules: isoliquiritigenin (ISL), a flavonoid from licorice; epigallocatechin gallate (EGCG), a polyphenol from green tea; and resveratrol (Rst), a polyphenol phytoalexin derived from grapes. / In conclusion, by in vitro and in vivo studies, we showed that ISL, EGCG and Rst contributed to anti-angiogenesis via different biological mechanisms. We propose that these three herbal molecules (ISL, EGCG and Rst) are candidate anti-angiogenic agents for the treatment of ocular angiogenesis diseases. Their distribution profiles and pharmacokinetic properties should be investigated. / Results showed that sub-toxic levels of ISL (10 microM), EGCG (50 microM) and Rst (10microM) effectively suppressed endothelial cell proliferation and migration in the scratch-wound assay. Treatment with ISL was found to significantly up-regulate PEDF, which is known as a potent angiostatic factor. EGCG and Rst downregulate VEGF signaling cascade by suppressing Akt and FAK activation and affecting MMP-2, MMP-9 expression. In vivo angiogenesis assays further showed the suppressive effect of ISL, EGCG and Rst on neovascularization in three different animal models. Application of ISL at 1 microM showed the suppressive effect on chick CAM assay, corneal NV and choroidal NV assays consistently, the most effective dosage was close to 10 microM. EGCG at 1 microM showed the effect to reduce chick CAM vessel formation and corneal NV, and at 10 microM (the lowest tested concentration) to suppress choroidal NV in mice. Variable effects were observed in Rst treatment. Rst at 10 microM prohibited vessel growth in chick CAM, and 1 microM suppressed corneal NV formation and 2 microM deterred choroidal NV development. / This thesis contains two major parts. The first in vitro cell-based analysis investigated the toxicity of these herbal chemicals and their effect on endothelial cell growth and migration. The expression profile of vascular endothelial growth factor (VEGF) signaling cascade events, including Akt and focal adhesion kinase (FAK) activation, VEGF, pigment epithelium-derived factor (PEDF) and matrix metalloproteinases (MMPs) were examined by Western blotting. Then three in vivo models were established to study the effect of these herbal chemicals on angiogenesis. They were (1) developmental angiogenesis in chick chorioallantoic membrane (CAM), (2) pathological angiogenesis in silver nitrate cauterization-induced corneal neovascularization in BALB/c mice and, (3) laser photocoagulation-induced choroidal neovascularization in C57BL/6 mice. Changes of vascularization were determined by qualification of vessel number changes on the edge of gelatin sponge in 24 hours (chick CAM assay), measurement of vascularized area, live imaging of vessel leakage (fundus fluorescence angiography, FFA) and immunochemistry using antibodies specific for endothelial cells (corneal & choroidal NV assays) respectively. / Liu, Huanming. / Adviser: Chi Pui Pang. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 155-180). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Made available in DSpace on 2014-07-29T15:29:12Z (GMT). No. of bitstreams: 1 Dissertacao Maria Nice A M Rocha.pdf: 1650606 bytes, checksum: 21927985ce6a9e6db6a183351003574b (MD5) Previous issue date: 2011-12-06 / There are few studies of epidemiological research in of Ophthalmology with the population of center-western Brazil. In order to identify the prevalence of the of eye diseases in the region, and specifically in Goiania and Goiás, that impact on blindness and visual impairment, this study analyzed 10,060 records randomly selected from patients seen at the Reference Center for Ophthalmology School of Medicine Federal University of Goiás ((CEROF/UFG), in From April 2009 to March 2010. There was a profile analysis of ocular morbidity in the target population in relation to disease group, acuity, age, sex and region of origin. The study also covered the distribution of queries in the four quarters of the year, elective and urgent, and the degree of visual impairment in the bands visual impairment and blindness. The predominant diseases in elective care in relation to the total sample of 10,060 patients were cataract (7.24%), pterygium (6.77%), allergic conjunctivitis (3.70%), dry eye (3,36%) , diseases of the retina and vitreous (3.23%), strabismus (2.64%) and glaucoma (1.94%). In urgent care were the most prevalent extraocular foreign body (25.5%), infectious conjunctivitis (23.6%), keratitis and and corneal ulcer (11.3%), pterygium and pingueculite (5.3%) and sub conjuntival hemorrhage (4.0%). There was higher prevalence of sex female (63.1%) and ages between 0-14 (26,8%) years and 40 to 49 (20,8%) years in elective consultations. In urgency consultations there was more prevalent of male (64.84%) and ages between 15 and 39 (51.06%) years in clinical urgency. Refractive errors were recorded in 43.08% of queries being found more astigmatism (40.02%) followed by hyperopia (36.54%). Were determined rates of low vision within the parameters of World Health Organization (WHO). The results were compared with other studies in Brazil and abroad, aiming to define the reality of the regional profile of eye health, as an aid to prevention strategies, recovery and treatment through health policies and government's own guidance service studied, the CEROF/UFG. It follows that both elective care and emergency at CEROF/UFG is similar to that found in southern and southeastern Brazil and in most developed countries of the world. / Há escassez de trabalhos de pesquisa epidemiológica em Oftalmologia com a população do centro-oeste brasileiro. Com o objetivo de identificar a prevalência dessas doenças na região, especificamente em Goiás e Goiânia, que repercutem em cegueira e em deficiência visual, este trabalho analisou 10.060 prontuários de pacientes atendidos no Centro de Referência em Oftalmologia da Faculdade de Medicina da Universidade Federal de Goiás (CEROF/UFG), selecionados aleatòriamente. Foi feita uma análise do perfil de morbidade ocular na população alvo com relação aos grupos de doenças, acuidade visual, idade, sexo e região de procedência. O estudo também abrangeu a distribuição de consultas nos quatro trimestres do ano, eletivas e na urgência, e o grau de comprometimento visual nas faixas de deficiência visual e cegueira. As doenças predominantes no atendimento eletivo, em relação à amostra total de 10.060 pacientes, foram: catarata (7,24%), pterígio (6,77%), conjuntivite alérgica (3,70%), olho seco (3,36%), doenças de retina e vítreo (3,23%), estrabismo (2,64% e glaucoma (1,94%). No atendimento de urgência as mais prevalentes foram: corpo estranho extraocular (25,5%), conjuntivite infecciosa (23,6%), ceratite e úlcera de córnea (11,3%), pterígio e pingueculite (5,3%) e hemorragia subconjuntival (4,0%). Houve maior prevalência do sexo feminino (63,1%) e das faixas etárias de 0 a 14 (26,8%) anos e de 40 a 49 (20,8%) anos nas consultas eletivas. Nas consultas de urgência predominou o sexo masculino (64,84%) e a faixa etária entre 15 a 39 (51,06%) anos. Os erros de refração foram registrados em 43,08% das consultas sendo astigmatismo o mais encontrado (40,02%) seguido por hipermetropia (36,54%). Foram determinados os índices de baixa visão regional segundo parâmetros da Organização Mundial de Saúde (OMS). Os resultados foram comparados com outros estudos realizados no Brasil e no exterior, visando definir a realidade do perfil da saúde ocular regional, como subsídio para estratégias de prevenção, recuperação e tratamento através de políticas de saúde governamentais e orientação do próprio serviço estudado, o CEROF. Conclui-se que o atendimento tanto eletivo quanto de urgência feito no CEROF é similar ao encontrado nas regiões sul e sudeste do Brasil e em países mais desenvolvidos.

OBJETIVO: O perfil epidemiológico dos povos indígenas no Brasil ainda não é suficientemente conhecido, principalmente no que se refere aos aspectos oftalmológicos das etnias residentes na região Centro-Oeste. Sendo assim, o objetivo do presente estudo foi conhecer as condições de saúde ocular da população indígena Kadiwéu, que habita as aldeias da serra Bodoquena, no Mato Grosso do Sul. MÉTODO: Foi conduzida uma pesquisa observacional, transversal e descritiva, desenvolvida na Aldeia Alves de Barros, na Serra da Bodoquena, no município de Porto Murtinho, Mato Grosso do Sul. Foram sujeitos da pesquisa 193 índios de um total estimado de 1.197. RESULTADOS: Da amostra avaliada, 74,9% apresentaram acuidade visual maior ou igual a 0,8. Dentre as ametropias, a hipermetropia foi o achado mais comum (9,3%) e a miopia o menos comum (2%). Dentre os achados da conjuntiva, a melanose e o pterígio foram os mais frequentes, com porcentagens de 25,4 e 14,7, respectivamente; em relação à avaliação das pálpebras, o achado mais comum foi a dermatocálase, com frequência de 4,5%. Quanto à córnea, encontraram-se casos de leucoma (n=4) relacionados a trauma ocular e uma suspeita de ceratocone; opacificação de cristalino foi observada em 5,6% dos indígenas avaliados e um caso de coloboma de íris foi verificado. Apenas um dos avaliados apresentou estrabismo convergente e um estrabismo divergente e não foram observados casos de hipertensão ocular ou glaucoma. Nenhum caso de discromatopsia foi encontrado. CONCLUSÃO: Pode-se concluir que os indígenas desta etnia apresentam, na sua maioria, boas condições oculares, com acuidade visual >=0,8, tendo apresentado, como alterações mais comuns, melanose da conjuntiva, pterígio, opacificação do cristalino, dermatocalaze e sequelas de traumatismos. A hipermetropia foi a ametropia mais comum (9,3%) e a miopia a menos comum (2%) / PURPOSE: The epidemiological profile of indigenous population in Brazil still remains insuffiently known.Considering ethnic groups living in the Center-West region of Brazil a limited number of reports is available regarding their ocular aspects. Based on these facts this study was conducted to elucidate the ocular conditions of Kadiwéus population, a specific ethnic group living in Bodoquena\'s Mountains in the state of Mato Grosso do Sul. METHODS: This is a crosssectional, descriptive and observational study performed with 193 Kadiwéus indians of a total of 1197 residents in the small villages in Bodoquena\'s Mountains. RESULTS: Of the selected sample, 74,9% had visual acuity better than 0.8. Among the refractive errors, hypermetropia was the most common (9,3%) and miopia the less frequent (2%). Melanosis and pterigyum are the conjunctiva most frequent findings, with percentages of 25,4 and 14,7 respectively; dermatochalasis had a frequency of 4,5%. Among corneal detected alterations, corneal clouding related to trauma was the most frequent and, one case of suspected keratoconus was found. Cataract was observed in 5,6% of the sample and one case of iris coloboma was verified. One case of convergent strabismus and one case of divergent strabismus were found. Ocular hypertension, glaucoma or dyschromatopsias were not verified. CONCLUSIONS: This study concluded that the Kadiwéus presented good ocular conditions, with visual acuity better than 0.8, in which, melanosis, pterigyum, cataract, dermatochalasis, trauma sequelae were the most frequent findings and hyperopia was the most common refractive error (9,3%)

This study presents the methodology for estimating the incidence rate from the age specific prevalence data of three different eye diseases. We consider both situations where the mortality may differ from one person to another, with and without the disease. The method used was developed by Marvin J. Podgor for estimating incidence rate from prevalence data. It delves into the application of logistic regression to obtain the smoothed prevalence rates that helps in obtaining incidence rate. The study concluded that the use of logistic regression can produce a meaningful model, and the incidence rates of these diseases were not affected by the assumption of differential mortality.

Age-related macular degeneration (AMD) is the leading cause for visual impairment in the elderly. The etiology of AMD remains unclear. Clinical and histopathological studies suggest that photoreceptors play a role in disease progression. Here, we found that photoreceptors of AMD patients show adaptive changes in gene expression, suggestive of a nutrient shortage. To study the effect of these changes, we mimicked the metabolic alteration in mouse photoreceptors, by disruption of the Tuberous Sclerosis Complex (TSC). This led to AMD hallmarks, including the advanced stages of geographic atrophy (GA) and choroidal neovascularization (CNV). Furthermore, we found that disease onset requires the activity of the mammalian target of rapamycin complex 1 (mTORC1). To study the contribution of photoreceptors to disease, we profiled retinal phospholipids as photoreceptors are rich in phospholipids. We found a reduction in two docosahexaenoic acid (DHA)-containing phospholipids. Feeding DHA to mutant mice, alleviated most AMD-associated hallmarks. To study the inflammatory complications seen with current anti-vascular endothelial growth factor (VEGF) treatments for CNV we used rAAV-mediated gene transfer to overexpress an anti-VEGF protein. We found that inhibition of VEGF can promote retinal inflammation. The data suggests that targeting photoreceptor metabolism may provide novel therapies to treat AMD.

Thesis (MPH.) -- University of Limpopo, 2021 / Dry eye disease (DED) is defined as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolality of the tear film and inflammation of the ocular surface. DED is one of the most frequently established diagnoses in ophthalmology and represents a growing public health concern, with consequences that remain widely underestimated. There is variability of clinical manifestations and diagnostic criteria which leads to poor correlation between clinical signs and symptoms, therefore resulting in difficulties to assess prevalence of DED despite an improved understanding of pathogenic factors of acquired DED. However, its prevalence has been reported to range from 74% to 33% worldwide and the current study aimed to investigate the prevalence of DED and its determinants amongst people consulting at Focus Optometrists in Kwa-Mhlanga Township in Mpumalanga Province. Methodology: The current study was quantitative in nature and it followed a cross-sectional descriptive design to address the research question. The study population were people consulting at Focus Optometrists in Kwa-Mhlanga Township in Mpumalanga Province in which two standardized optometry diagnostic tests (Schimer test and the tear film break up time) were used for data collection coupled with a comprehensive case history which was taken for all participants. Data analysis was done using the STATA statistical software version 12 for Windows (STATA Corporation, College Station, Texas). Frequency tables were used to make comparisons between groups for continuous and categorical variables using student t-test, and chi-square test. P-value less than 0.05 at 95% confidence level were regarded as significant. Results: A total of 236 participants were recruited and the mean age of the participants was 39.7 in which majority of participants were females and there was a statistical significance difference in age groups of both males and females at p-value=0.011. Majority of the participants have reported to have experience of sensitivity to light vi and foreign body sensation sometimes. The poor vision and blurred vision have been reported by majority of participants sometimes and the prevalence of dry eye disease was found to be 80.9% and the risk of the dry eye disease in the current study was found significantly increasing with old age. Those who were older (35 years above) were 4.2 times more likely to develop dry eye disease at p-value <0.001 as compared to young participants. Female gender was found not to be protective of developing dry eye disease in the current and participants who were single, having secondary and education qualifications were more likely to develop dry eye disease. Participants with ocular conditions, systemic disease, surgery and those with high blood pressure were more likely to develop dry disease Conclusion: The prevalence of dry eye disease in the current study was found to be very high and therefore, patients coming to the clinic from the age of 40 with underlying systemic diseases should be screened for dry eyes. Dry eye disease can be a major contributor of refractive error in the visual systems and or can also be a sign or a symptom of hormonal or related ocular or systemic disease. More eye care awareness should be done at primary eye care level to detect the cause or to eliminate future associated symptoms.

Title: Treatment of CMV Vitritis in a Preterm Newborn Author’s Section: Remil Simon1, Darshan Shah1, Peter Blosser1, Demetrio Macariola1, Jeffrey Carlsen2 1.Department of Pediatrics, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 2.Johnson City Eye Clinic, Johnson City, TN Body: Cytomegalovirus (CMV) infection in the neonate is an infrequent occurrence in the developing world, and observing the symptoms of ocular CMV infection such as vitritis is rare. Treating CMV infection promptly is necessary to prevent mortality and potential neurological deficits including blindness and hearing loss. We encountered a preterm infant presenting with CMV sepsis immediately after birth. Our question was: will the current standard of treatment for CMV sepsis prevent CMV ocular infection? With our method of treatment, we followed the current standard of treatment for CMV infection by administering intravenous Gancyclovir for 6 weeks and oral Valgancyclovir for 6 months. Despite using the standard treatment to prevent neurological sequelae, the patient developed CMV vitritis and retinitis bilaterally. Although the treatment did not prevent CMV ocular infection, the severity of CMV retinitis and vitritis improved with treatment, and full resolution of vitritis was noted by day of life 61.

The eye contains closely related but widely different tissues, offering a unique opportunity to investigate the phenotype and function of monocyte-derived cell populations within functionally unique microenvironments in a single complex organ. The uveal tract and retina contain rich networks of immune cells that reside and traffic through the eye, these cells having been implicated in various ocular inflammatory processes and immune-mediated diseases. One such inflammatory condition is human posterior uveitis, an autoimmune disease mainly affecting the retina. As current treatments for posterior uveitis only serve to slow down disease progression, studies using animal models, namely, experimental autoimmune uveoretinitis (EAU), have focused on determining the key cellular and molecular mediators involved in disease initiation in order to expand the potential for novel therapeutic applications. The overall purpose of experiments in this thesis was to explore monocyte-derived cell populations of the uveal tract and retina, this being achieved by utilising a novel transgenic mouse model. Cx3cr1gfp/gfp transgenic mice on both BALB/c and C57Bl/6 backgrounds contain an enhanced green fluorescent protein (eGFP) encoding cassette knocked into the Cx3cr1 gene, disrupting its expression but facilitating GFP expression under the control of the Cx3cr1 promoter. Heterozygous (Cx3cr1+/gfp) mice were generated by crossing Cx3cr1gfp/gfp mice to wild-type (WT) mice. This transgenic model allowed for the exquisite visualisation of Cx3cr1-bearing monocyte-derived dendritic cells (DC) and macrophages in ocular tissues, whilst also enabling the investigation of a potential role for Cx3cr1 in recruiting monocyte-derived cells to the eye in steady-state and inflammatory conditions.

The retina is a thin layer of tissue lining the back of the eye and is primarily responsible for sight in vertebrates. The neural retina has a distinct layered structure with three dense nuclear layers, separated by plexiform layers comprising of axons and dendrites, and a layer of photoreceptor segments. The retinal and choroidal vasculatures nourish the retina from either side, with an avascular layer comprised largely of photoreceptor cells. Diseases that directly affect the neural retina like retinal degeneration as well as those of vascular origin like diabetic retinopathy can lead to partial or total blindness. Early detection of these diseases can potentially pave the way for a timely intervention and improve patient prognosis. Current techniques of retinal imaging rely mainly on optical techniques, which have limited depth resolution and depend mainly on the clarity of visual pathway. Magnetic resonance imaging is a versatile tool that has long been used for anatomical and functional imaging in humans and animals, and can potentially be used for retinal imaging without the limitations of optical methods. The work reported in this thesis involves the development of high resolution magnetic resonance imaging techniques for anatomical and functional imaging of the retina in rats. The rats were anesthetized using isoflurane, mechanically ventilated and paralyzed using pancuronium bromide to reduce eye motion during retinal MRI. The retina was imaged using a small, single-turn surface coil placed directly over the eye. The several physiological parameters, like rectal temperature, fraction of inspired oxygen, end-tidal CO2, were continuously monitored in all rats. MRI parameters like T1, T2, and the apparent diffusion coefficient of water molecules were determined from the rat retina at high spatial resolution and found to be similar to those obtained from the brain at the same field strength. High-resolution MRI of the retina detected the three layers in wild-type rats, which were identified as the retinal vasculature, the avascular layer and the choroidal vasculature. Anatomical MRI performed 24 hours post intravitreal injection of MnCl2, an MRI contrast agent, revealed seven distinct layers within the retina. These layers were identified as the various nuclear and plexiform layers, the photoreceptor segment layer and the choroidal vasculature using Mn54Cl2emulsion autoradiography. Blood-oxygenlevel dependent (BOLD) functional MRI (fMRI) revealed layer-specific vascular responses to hyperoxic and hypercapnic challenges. Relative blood volume of the retina calculated by using microcrystalline iron oxide nano-colloid, an intravascular contrast agent, revealed a superfluous choroidal vasculature. Fractional changes to blood volume during systemic challenges revealed a higher degree of autoregulation in the retinal vasculature compared to the choroidal vasculature, corroborating the BOLD fMRI data. Finally, the retinal MRI techniques developed were applied to detect structural and vascular changes in a rat model of retinal dystrophy. We conclude that retinal MRI is a powerful investigative tool to resolve layerspecific structure and function in the retina and to probe for changes in retinal diseases. We expect the anatomical and functional retinal MRI techniques developed herein to contribute towards the early detection of diseases and longitudinal evaluation of treatment options without interference from overlying tissue or opacity of the visual pathway.

The body of work presented here is a compendium of the multiple steps required for an investigator initiated trial of an existing medication (Valproic Acid- VPA) for a new indication (Retinitis Pigmentosa – RP). The chapters are listed in logical and chronological order of the process. In order to access patient records an expedited Institutional Review Board (IRB) application for retrospective chart review was submitted (Chapter 1). These records enabled the statistical analysis which not only laid the framework for the trial design, but also became the basis for two manuscripts (Chapter 2). Protocol development informed by the preliminary human studies (Chapter 3) was an instrumental part of the Investigational New Drug (IND) application (Chapter 3.5). This protocol along with the extensive case report forms that detail the intended data to be collected are included in the IND application. Because the Phase II clinical trial proposed attempting to identify the specific RP mutations of the subjects utilizing a National Eye Institute (NEI) study that enabled free genotyping services, two IRB applications were submitted (Chapter 3.6). The first was for approval of the NEI genotyping protocol, the second involved the VPA intervention. Two very different sources of funding for this trial were attempted (Chapter 4) – the NIH via the Challenge Grant mechanism and a private eye disease foundation (Foundation Fighting Blindness). In Chapter 5 I detail the alternate study designs that were considered and developed for this trial (and ultimately abandoned). Finally, in Chapter 6, I formally detail my suggestions to aid in the development of a comprehensive investigator initiated core facility at UMMMC. The goal of this project was two-fold. The first was to learn the entire process of trial and protocol design both from a Umass Institutional perspective as well as from the perspective of the FDA. The second goal was the very real prospect of helping patients with a blinding disease. This work was successful on both counts. IRB approval was received for all the submitted applications. The complexity and uniqueness of many aspects of these submissions culminated in a comprehensive learning experience. The process of working with the Umass Research Pharmacy as well as developing the industry contacts and know-how to develop a workable and financially feasible placebo were both particularly important learning experiences. FDA approval of the IND submission was also received, and the process of pre-communication and delving into the considerable and ever-changing rules and regulations resulted in an extensive and valuable knowledge base. While the practicality of funding has limited the ability of this trial to move forward at this point, given the extensive framework laid by this body of work, we are actively pursuing other opportunities. The third outcome of this work, while not as intentional, was the considerable process of determining the specific competencies and infrastructure that exist at UMMMC to enable investigator initiated drug intervention studies. While this institution is clearly moving rapidly in the direction of translational research, the many needs of these studies are often only clearly understood when the process is specifically undertaken. In completing the approval of this Phase II clinical trial, I was not only able to better understand and define the existing capabilities of UMMMC for this kind of research, I was able to add to that infrastructure when the existing knowledge or skill set was not available. In this manner, I was able to inform and guide many of the support personnel who guided me and have become a part of the strategic direction of UMMMC towards clinical translational research.