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Demographic, medical and visual aspects of diabetic retinopathy and diabetic macular edemaSukha, Anusha Yasvantrai 03 April 2014 (has links)
M.Phil. (Optometry) / Despite many years of research, diabetic retinopathy (DR), and diabetic macular edema (DME) remain difficult to diagnose, prevent, and treat. The complicated nature of the disease, the limited information on DR and DME and the increasing prevalence of diabetes mellitus (DM) in South Africa, provided motivation for this study. To the best of my knowledge, this is the first study in our country to identify demographic, medical and visual aspects ofDR and DME collectively. A further incentive was the availability in optometry of recently developed computer software based upon multivariate statistics, which provided a unique opportunity to analyze, for example, tri-variate contrast sensitivity acuities using stereo-pair scatter plots. All refractive status measurements were also analyzed and compared with the same method. Together, the results from this study provide a broader clinical and research perceptive on DR and DME. In this cross-sectional study, 202 diabetic patients at the Helen Joseph Hospital in Johannesburg were recruited. Demographic variables included age, gender, race, age of diagnosis, duration of DM, and social habits. Medical variables included systemic conditions present, blood pressures, body mass index (BMI), lipid profiles, glycerated haemoglobin (HbAlc), and other available biochemical data (for example cholesterol, urea and creatinine levels). Visual variables included, distance, pinhole and near visual acuities, contrast sensitivity acuities, refractive status measured with autorefraction, colour vision, Amsler grid, intraocular pressures (lOP), and fundus photography. Administration of the Impact of Visuallmpainnent (IVI) questionnaire provided new information concerning the restrictions in daily living participation caused by DR or DME. The predominant characteristics of the study population consisted of Type 1DM among female Coloured subjects. Approximately 66% of all subjects had also been diagnosed with hypertension. The mean age ofthe subjects was 52 (± 14) years, age of diagnosis 41 (± 13) years, and duration ofDM 10.8 (± 9.7) years. Mean blood pressures (136/81 ± 20.5/11 mmHg) and glycated haemoglobin (HbAlc, 9.9 ± 3.4%) values were slightly higher than the recommended control levels (BP= 120/80 mmHg and HbAlc = 6 to 7%).
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A Study of the Social and Economic Conditions of a Sample of the Blind Members of The Church of Jesus Christ of Latter-Day SaintsCruser, M. Lynn 01 January 1963 (has links) (PDF)
The purposes of this study were (1) to learn how many persons who were members of the Church of Jesus Christ of Latter-day Saints were blind, (2) to determine the social and economic conditions of these blind members, and (3) to learn what the Church of Jesus Christ of Latter-day Saints has done to promote employment of blind members through its Welfare Program, and how this was accomplished.
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Genetic and pharmacological approaches to study the role of the polyolpathway enzymes in diabetic and ischemic retinopathyCheung, Kwok-ho, Alvin, 張國豪 January 2007 (has links)
published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy
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Molecular investigation of chemical-assisted protein rescue in ocular protein folding diseases. / CUHK electronic theses & dissertations collectionJanuary 2010 (has links)
In the study of alphaA-crystallin (CRYAA), G98R CRYAA was cloned into a mammalian expression vector pcDNA6-His/myc version B and the sequence was confirmed by direct sequencing. Following lipophilic transfection to lens epithelial B3 cells, the recombinant mutated CRYAA protein was highly insoluble upon 0.5% Triton X-100 (Tx) extraction. It was retained and formed aggregation, and distributed in the endoplasmic reticulum (ER) along with the ER resident protein (protein disulfide isomerise). The wild-type (WT) CRYAA was found to be soluble and diffusely distributed in the cytoplasm. The accumulation of G98R mutant induced ER stress, and the affected cells were prone to apoptosis. After treatment with a small chemical molecule, the natural osmolyte trimethylamine N oxide (TMAO), the Tx insolubility of mutant protein was reduced in dose- and time-dependent manners. It was also prone to be degraded via ubiquitin proteasome pathway (UPP). In mutant-expressing cells, the mutant protein aggregation was decreased after treatment. The ER stress and the rate of apoptosis were also alleviated, probably mediated by heat shock response, as demonstrated by the effect of TMAO on heat shock protein 70 expression. / The third eye gene model was myocilin (MYOC ), the first identified gene responsible for primary open angle glaucoma. The aim of this study was to investigate if glaucoma-causing MYOC variants, including D384N MYOC, could be correctable. D384N MYOC was identified in a Chinese family diagnosed with high tension juvenile-onset primary open-angle glaucoma. Disease causing mutations in MYOC (R82C, C245Y, Q368X P370L, T377M, D380A, D384N, R422C, R422H, C433R, Y437H, I477N, I477S and N480K) were cloned into mammalian expression vector p3XFLAG-myc-CMV"-25 and the sequences confirmed by direct sequencing. Following lipophilic transfection to human trabecular meshwork (HTM) cells, the Tx solubility and secretion of MYOC and cell apoptosis were examined in the presence or not with small chemical treatments. 4-PBA, TMAO and deuterium oxide (D2O), reduced the portion of insoluble fractions to various extents in the mutant proteins. The osmolytes TMAO and D2O were more effective than 4-PBA in improving MYOC solubility. TMAO was further shown to improve the secretion and ER-Golgi trafficking of D384N MYOC, thereby reducing the ER stress and rescuing cells from apoptosis. (Abstract shortened by UMI.) / The truncated G165fsX8 gammaD-crystallin ( CRYGD) variant was studied to further examine the effects of small chemical-assisted protein rescue of a CRYGD mutant that causes congenital cataract. G165fsX8 CRYGD was identified in a Chinese family with nuclear type of congenital cataract. The mutation was cloned into a mammalian expression vector p3XFLAG-myc-CMV"-25 and sequence was confirmed by direct sequencing. Following lipophilic transfection to COS-7 cells, the G165fsX8 CRYGD mutant protein was significantly insoluble upon 0.5% Tx extraction and was mistrafficked to the nuclear envelope with co-localization with nuclear lamins, whereas WT protein was Tx soluble and nuclear located. Treatment with small chemical sodium 4-phenylbutyrate (4-PBA) substantially reduced the Tx insolubility and reversed the mutant protein to nuclear localization. This correction has resulted in better cell survival, probably via a heat-shock response, as demonstrated by heat-shock protein 70 up-regulation. / To date, many genes and mutations are identified to cause various ocular diseases. Some of them result in a disruption of protein folding, an important cause of disease pathogenesis and progression. In my laboratory, novel mutations of crystallins and myocilin have been identified to segregate with congenital cataract and primary open-angle glaucoma, respectively. In this thesis, I reported molecular investigations of the resultant protein variants and their altered cellular functions in relation to the clinical phenotypes that contributed to new understanding of the roles of these genes in ocular tissues. / Gong, Bo. / 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 163-188). / 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.
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Differentiation of exudative age-related macular degeneration and polypoidal choroidal vasculopathy.January 2012 (has links)
年齡相關性黃斑變性(AMD)是發展國家高齡人群中不可逆盲的首要原因。在AMD患者中,即使在改變生活模式或進行治療后,其滲出性亞型仍導致超過80% 的病例出現嚴重視力喪失及法定盲。息肉狀脈絡膜血管病變 (PCV)是一種與滲出性AMD在臨床表型上存在相同之處的黃斑病變,它的典型病變被定性為眼底血管螢光造影時出現息肉狀的病灶。近年PCV被認為是滲出性AMD亞型中的一種,因為兩者共享相同的基因成份及環境因素。然而,PCV曾經被認為是與滲出性AMD截然不同的一種疾病,由於兩者的臨床表現並不一致。另外,PCV病人相對年輕,多為亞洲人,以及對光動力治療和抗血管內皮生長因子治療存在不同的反應。一個明確的鑒別診斷可以更好的輔助臨床醫生對患有這些疾病的老年病人進行管理,然而兩者是相同還是不同的疾病種類仍是一個具爭議性的議題。 / CFH 基因和ARMS2/HTRA1位點已被全基因組相關性研究及相關的分子學研究定位為AMD候選基因。鑒於FPR1基因的協調吞噬性白細胞激活及遷移的功能,它可能是一個新的AMD候選基因。本論文評估在滲出性AMD和PCV中FPR1作為一個新的疾病基因基因的可能,獲取滲出性AMD和PCV病人中的CFH,ARMS2,HTRA1和FPR1基因檔案,同時研究在ARMS2/HTRA1位點中基因型和疾病表型的關聯性,以此從基因學方面鑑別滲出性AMD與PCV。 / 本研究在滲出性AMD,PCV病例和對照人群中使用聚合酶鏈反應和直接測序法進行ARMS2, HTRA1, CFH 和FPR1基因篩查。本研究發現滲出性AMD和PCV之間存在不同的基因型分佈,關聯模式以及基因效應值。 / 在HTRA1的多態性中,rs11200638,rs2672598, rs1049331 和 rs2293870 在滲出性AMD和PCV之間表現出鑒別性關聯 (p < 0.001)。其中rs11200638 (p = 1.48×10⁻⁴) and rs2672598 (p = 2.27×10⁻³) 在滲出性AMD病人中相互校正后仍保持各自的顯著性,但rs2672598 未能在PCV病人中保持顯著性(p = 0.20)。並且本研究發現攜帶rs11200638和 rs2672598聯合基因型AA-CC 的病人更傾向是滲出性AMD病人,與PCV相比幾率高11.7倍。 / 在ARMS2中,有11個基因多態性與滲出性AMD和PCV存在顯著性的相關。在與rs11200638校正后,rs10490924保持和滲出性AMD的顯著相關性(p = 0.011),但PCV中未能保持(p = 0.077)。同時,元分析結果顯示ARMS2 rs10490924和HTRA1 rs11200638不同人群的PCV中的等位基因相關性是一致的。 / 在FPR1中,rs78488639與滲出性AMD (p = 0.049, 比值比 (OR) = 2.05, 95% 信賴區間(CI): 1.014.14)和PCV (p = 0.016, OR = 2.27, 95%CI: 1.154.47)的疾病風險存在顯著的相關性。多態性rs104229的G等位基因純合子和滲出性AMD存在顯著相關(p = 0.039, OR = 2.27, 95%CI: 1.084.74),但在PCV中未發現相關性(p = 0.24)。多態性rs2070746 AMD (p = 0.021, OR = 0.57, 95%CI: 0.35 0.91)和rs867229 (p = 0.0091, OR = 0.54, 95%CI: 0.340.86) 的雜合子基因型與滲出性AMD相關,但在PCV中未發現相關性。與此同時,本研究在上述多態性中發現滲出性AMD和PCV之間不同的基因型分佈。 / 本研究發現在滲出性AMD和PCV病人中FPR1 rs78488639和CFH rs800292存在顯著的相互作用(ORs > 4)。兩個多態性之間的相互作用提高滲出性AMD和PCV的疾病風險,而不是僅對其中之一起作用。 / ARMS2 多態性 rs10490924 (A69S, 205G>T, pAMD = 1.01×10⁻²⁹ OR = 7.91, 95% CI: 4.93 - 12.67; pPCV = 8.25×10⁻⁷, OR = 3.51, 95% CI: 1.98 - 5.03), HTRA1 多態性rs11200638 (-625G>A, pAMD = 9.88×10⁻²⁸, OR = 6.95, 95% CI: 4.37 - 11.06; pPCV = 8.02×10⁻⁶, OR = 2.82, 95%CI: 1.77 - 4.47), CFH 多態性rs800292 (V62I, 184G>A, pAMD = 9.00×10⁻⁴ , OR = 0.58, 95% CI: 0.42 0.79; pPCV = 0.011, OR = 0.66, 95% CI: 0.49 0.90) and FPR1 多態性rs78488639 (L97M, 289C>A, pAMD = 0.049, OR = 2.05, 95% CI: 1.01 - 4.14; pPCV = 0.016, OR = 2.27, 95% CI: 1.15 - 4.47)代表各自基因的最強相關性。此外,元分析揭示了在不同種族人群PCV中的等位基因相關性顯著並且一致(ORtotal = 2.14, 95% CI: 1.97 2.33, ORtotal = 2.34, 95% CI: 1.98 2.76 and ORtotal = 0.49, 95% CI: 0.44 0.56)。表型-基因型分析發現ARMS2/HTRA1 的風險基因型和較差的治療反應呈正相關性(p = 0.04)。另外,本研究在滲出性AMD中發現HTRA1 rs11200638和吸煙的聯合作用。然而,在PCV中未觀察到次聯合作用,這可能提示兩者間存在不同的疾病機制。 / 本論文提出FPR1基因是一個新的滲出性AMD和PCV候選基因,揭示了ARMS2,HTRA1,CFH和FPR1在滲出性AMD和PCV間顯著並且一致的相關性, 提供鑒別兩者的基因學證據,闡明了ARMS2/HTRA1 的風險基因型和較差的治療反應之間的相關性以及顯示了吸煙在滲出性AMD和PCV之間的不同影響。然而,由於兩者間基因關聯的趨勢一致,目前尚未能清晰界定兩者的不同。因此,要進一步明確鑒別滲出性AMD和PCV,還需要進行不同種族的複製研究,以及更重要的是,尋找特定的PCV基因以鑒別兩個不同疾病。 / Age-related macular degeneration (AMD) is the leading cause of irreversible blindness for the elderly in developed countries. Its exudative subtype accounts for more than 80% of severe visual loss or legal blindness in AMD patients regardless of modified lifestyle and therapeutic treatments. Polypoidal choroidal vasculopathy (PCV) is a macular disorder characterized by typical polypoidal lesions on fundus angiograhpy and sharing similar phenotype with exudative AMD. PCV was suggested as a distinct disease from exudative AMD based on different clinical features in ophthalmic imaging. Furthermore, PCV patients tend to be younger and more prevalent in Asian, and have different responses to photo-dynamic therapy and anti-vascular endothelial growth factor treatments, compared to exudative AMD patients. Howerver, it has also been suggested that PCV could be a subtype of exudative AMD mainly because of their common genetic and environmental factors. Therefore, genetic differentiation between exudtive AMD and PCV might assist clinicans to determine the condition. / The complement factor H (CFH) gene, and age-related maculopathy susceptibility 2 (ARMS2)/high temperature requirement factor A1 (HTRA1) locus have been mapped for AMD by genome-wide association studies (GWAS) and subsequent molecular investigations. The formyl peptide receptor 1 (FPR1) gene, which mediates trafficking and activation of phagocytic leukocytes, is related to the AMD-associated inflammatory condition. This thesis aims to evaluate FPR1 as a novel disease gene for exudative AMD and PCV, to compare the genetic profiles of ARMS2, HTRA1, CFH, and FPR1 in exudative AMD and PCV, to investigate the correlation of ARMS2/HTRA1 genotypes with disease phenotypes, and to differentiate these two disorders throught the genomic compositions. / Case-control association studies were conducted on ARMS2, HTRA1, CFH and FPR1 in exudative AMD and PCV patients of our Hong Kong Chinese cohort using polymerase chain reaction and direct sequencing. We observed different genotypic distributions (p < 0.05), association patterns and effect sizes between these two diseases. / In HTRA1 polymorphisms, rs11200638, rs2672598, rs1049331 and rs2293870 showed differential associations between exudative AMD and PCV (p < 0.001). Both rs11200638 (p = 1.48×10⁻⁴) and rs2672598 (p = 2.27×10⁻³) remained significant after adjusting for each other in exudative AMD, whereas rs2672598 was not significantly associated with PCV (p = 0.20). The joint genotype AA-CC constructed by the risk alleles of these rs11200638 and rs2672598 were prone to exudative AMD, conferring an 11.7-fold higher risk (p = 4.00×10⁻³) when compared to PCV. / In ARMS2, 11 single nucleotide polymorphisms (SNPs) showed significant associations with both exudative AMD and PCV. After adjusting for rs11200638, ARMS2 rs10490924 remained significantly associated with exudative AMD (p = 0.011), but not with PCV (p = 0.077). / In FPR1, SNP rs78488639 significantly increased the risk to exudative AMD (p = 0.049, odds ratio (OR) = 2.05, 95% confidence interval (CI): 1.014.14) and PCV (p = 0.016, OR = 2.27, 95%CI: 1.154.47). The homozygous G allele of rs1042229 was associated with exudative AMD (p = 0.039, OR = 2.27, 95%CI: 1.084.74), but not with PCV (p = 0.24). The heterozygous genotypes of rs2070746 and rs867229 were associated with exudative AMD (p = 0.021, OR = 0.57, 95%CI: 0.35 0.91; p = 0.0091, OR = 0.54, 95%CI: 0.340.86, respectively), but not with PCV. / Significant interaction was identified between FPR1 rs78488639 and CFH rs800292, with joint ORs > 4 folds for both exudative AMD and PCV. Interactions between FPR1 rs78488639 with CFH rs800292 enhance risks to both AMD and PCV, not just one of them. / Overall, the ARMS2 rs10490924 (A69S, 205G>T, pAMD = 1.01×10⁻²⁹, OR = 7.91, 95% CI: 4.93 - 12.67; pPCV = 8.25×10⁻⁷, OR = 3.51, 95% CI: 1.98 - 5.03), HTRA1 rs11200638 (-625G>A, pAMD = 9.88×10⁻²⁸, OR = 6.95, 95% CI: 4.37 - 11.06; pPCV = 8.02×10⁻⁶, OR = 2.82, 95%CI: 1.77 - 4.47), CFH rs800292 (V62I, 184G>A, pAMD = 9.00×10⁻⁴ , OR = 0.58, 95% CI: 0.42 0.79; pPCV = 0.011, OR = 0.66, 95% CI: 0.49 0.90) and FPR1 rs78488639 (L97M, 289C>A, pAMD = 0.0487, OR = 2.05, 95% CI: 1.01 - 4.14; pPCV = 0.0161, OR = 2.27, 95% CI: 1.15 - 4.47) were responsible for the strongest association in each gene. Moreover, meta-analysis revealed a consistent and significant association of the ARMS2/HTRA1 locus with PCV in different ethnic cohorts (OR{U+209C}{U+2092}{U+209C}{U+2090}{U+2097} = 2.14, 95% CI: 1.97 2.33, OR{U+209C}{U+2092}{U+209C}{U+2090}{U+2097} = 2.34, 95% CI: 1.98 2.76 and {U+209C}{U+2092}{U+209C}{U+2090}{U+2097} = 0.49, 95% CI: 0.44 0.56, respectively). The phenotype-genotype analysis implicated a positive correlation between ARMS2/HTRA1 risk genotype and a worse response to treatment (p = 0.04) in our exudative AMD patients. In addition, joint effects between cigarette smoking and HTRA1 rs11200638 was found in exudative AMD group. However, this effect was not significant in PCV group, which might implicate a different disease mechanism. / This thesis attempts to dissect the genetic profiles of exudative AMD and PCV. Results in this thesis suggest FPR1 as a novel candidate gene for exudative AMD and PCV, reveal a significant and consistent association of ARMS2, HTRA1, CFH and FPR1 with both exudative AMD and PCV, provide evidences for genetic differentiation of these two disorders, demonstrate a significant correlation between ARMS2/HTRA1 genotypes and response to treatment, and indicate different influence of smoking in exudative AMD and PCV. However, definite differentiation between exudative AMD and PCV was limited because of the same trend of associations between these two disorders. Therefore, replication studies in other enthic populations are necessary, and identification of PCV-specific genes/polymorphisms could further differentiate PCV from exudative AMD. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Liang, Xiaoying. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 124-143). / Abstract also in Chinese. / Title page --- p.i / Abstract --- p.iii / 摘要 --- p.vii / Acknowledgements --- p.xii / Table of Contents --- p.xiii / List of Figures --- p.xix / List of Tables --- p.xxi / Abbreviations --- p.xxiv / Publications --- p.xxvii / Conference Presentations --- p.xxviii / Chapter Chapter 1: --- Introduction / Chapter 1.1. --- Normal retinal architecture --- p.1 / Chapter 1.2. --- Age-related retinal changes --- p.3 / Chapter 1.3. --- Age-related macular degeneration (AMD) --- p.7 / Chapter 1.3.1. --- Classification, clinical manifestation and disease course --- p.7 / Chapter 1.3.2. --- Exudative AMD and therapeutic strategies --- p.9 / Chapter 1.3.3. --- Pathology of AMD --- p.10 / Chapter 1.3.4. --- Risk factors and associated pathogenesis --- p.12 / Chapter 1.3.4.1. --- Age --- p.12 / Chapter 1.3.4.2. --- Ethnicity --- p.13 / Chapter 1.3.4.3. --- Oxidative stress --- p.13 / Chapter 1.3.4.3.1. --- Reactive oxygen species and AMD --- p.14 / Chapter 1.3.4.3.2. --- Antioxidants --- p.15 / Chapter 1.3.4.3.3. --- Association of oxidation genes with AMD --- p.16 / Chapter 1.3.4.4. --- Inflammation --- p.16 / Chapter 1.3.4.4.1. --- Complement in AMD --- p.17 / Chapter 1.3.4.4.2. --- The potential role of formyl peptide receptor 1 (FPR1) in AMD --- p.19 / Chapter 1.3.4.5. --- Genetic predisposition --- p.19 / Chapter 1.3.4.5.1. --- Complement factor H --- p.21 / Chapter 1.3.4.5.2. --- The 10q26 locus --- p.22 / Chapter 1.3.4.5.3. --- Phenotype-genotype correlation --- p.23 / Chapter 1.4. --- Comparisons between exudative AMD and Polypoidal choroidal vasculopathy --- p.24 / Chapter 1.4.1. --- History --- p.25 / Chapter 1.4.2. --- Natural course --- p.26 / Chapter 1.4.3. --- Epidemiological factors --- p.27 / Chapter 1.4.3.1. --- Ethnicity --- p.27 / Chapter 1.4.3.2. --- Gender --- p.27 / Chapter 1.4.3.3. --- Age --- p.28 / Chapter 1.4.3.4. --- Risk factors --- p.28 / Chapter 1.4.4. --- Clinical manifestation and histopathological features --- p.29 / Chapter 1.4.5. --- Genetic determinants --- p.29 / Chapter 1.4.5.1. --- Genes with common associations --- p.30 / Chapter 1.4.5.2. --- Genes not have common association --- p.32 / Chapter 1.4.6. --- Response to treatments --- p.32 / Chapter 1.5. --- Objectives and research prospects --- p.33 / Chapter Chapter 2: --- Materials and Methods / Chapter 2.1. --- Polymorphism identification in ARMS2, HTRA1, FPR1 and CFH --- p.39 / Chapter 2.1.1. --- Study subjects --- p.39 / Chapter 2.1.1.1. --- Diagnostic features of AMD and PCV --- p.39 / Chapter 2.1.1.2. --- Control subjects --- p.40 / Chapter 2.1.2. --- Laboratory methods --- p.40 / Chapter 2.1.2.1. --- DNA extraction and quantification --- p.40 / Chapter 2.1.2.2. --- Genotyping --- p.41 / Chapter 2.1.2.2.1. --- Polymerase chain reaction (PCR) and agrose gel electrophoresis --- p.41 / Chapter 2.1.2.2.2. --- DNA sequencing --- p.42 / Chapter 2.1.3. --- Statistical analysis --- p.43 / Chapter 2.1.3.1. --- Genotypic association analysis --- p.43 / Chapter 2.1.3.2. --- Haplotype association analysis --- p.43 / Chapter 2.1.3.3. --- Logistic regression analysis --- p.44 / Chapter 2.1.3.4. --- Joint effect analysis --- p.44 / Chapter 2.1.3.5. --- Meta-analysis --- p.45 / Chapter 2.1.3.6. --- Statistical power calculation and sample size --- p.45 / Chapter 2.2. --- Phenotype-genotype correlation in ARMS2/HTRA1 locus --- p.46 / Chapter 2.2.1. --- Patient recruitment --- p.46 / Chapter 2.2.2. --- Genotyping --- p.46 / Chapter 2.2.3. --- Outcome measurement --- p.46 / Chapter 2.2.4. --- Statistical analysis --- p.47 / Chapter Chapter 3: --- Results / Chapter 3.1. --- The age and gender distribution in study subjects --- p.57 / Chapter 3.2. --- The HTRA1 sequencing in exudative AMD and PCV --- p.57 / Chapter 3.2.1. --- Polymorphism identification and genotypic association --- p.57 / Chapter 3.2.2. --- Haplotype structure and Haplotype-based association analysis --- p.59 / Chapter 3.2.3. --- Joint genotype analysis --- p.59 / Chapter 3.3. --- Differential association of exudative AMD and PCV with the ARMS2/HTRA1 locus --- p.60 / Chapter 3.3.1. --- Genotypic association --- p.60 / Chapter 3.3.2. --- Haplotype analysis --- p.62 / Chapter 3.3.3. --- Logistic regression --- p.63 / Chapter 3.3.4. --- Meta-analysis of ARMS2/HTRA1 association with PCV --- p.64 / Chapter 3.3.5. --- In-position OR plot --- p.64 / Chapter 3.4. --- FPR1 and CFH in exudative AMD and PCV --- p.65 / Chapter 3.4.1. --- Polymorphism identification and genotypic association --- p.65 / Chapter 3.4.2. --- Haplotype analysis of FPR1 --- p.66 / Chapter 3.4.3. --- The association of CFH rs800292 --- p.67 / Chapter 3.4.4. --- Joint effect analysis of the CFH and FPR1 genes --- p.67 / Chapter 3.4. --- Phenotype-genotype correlation in ARMS2/HTRA1 locus --- p.68 / Chapter 3.4.1. --- Distribution of age and bilaterality --- p.69 / Chapter 3.4.2. --- Greatest linear dimension of CNV lesion in exudative AMD --- p.69 / Chapter 3.4.3. --- Response to treatment in exudative AMD --- p.69 / Chapter 3.4.4. --- Recurrence in PCV --- p.70 / Chapter 3.4.5. --- Smoking status --- p.70 / Chapter Chapter 4: --- Discussion / Chapter 4.1. --- Age and gender distribution --- p.104 / Chapter 4.2. --- Genetic differentiation in ARMS2/HTRA1 locus --- p.S104 / Chapter 4.2.1. --- SNPs with common association --- p.106 / Chapter 4.2.2. --- SNPs with different association S --- p.106 / Chapter 4.2.3. --- Comparison with previous studies C --- p.107 / Chapter 4.2.4. --- Sample size S --- p.109 / Chapter 4.3. --- The FPR1 gene in exudative AMD and PCV --- p.110 / Chapter 4.4. --- Interaction between FPR1 and CFH --- p.112 / Chapter 4.5. --- Correlation between phenotypes and genotypes --- p.113 / Chapter 4.6. --- Common and rare variants for complex disease --- p.114 / Chapter 4.6.1. --- The debate of common disease common variant versus common disease rare variant --- p.115 / Chapter 4.6.2. --- Candidate gene screening versus geno-wide association study --- p.117 / Chapter 4.6.3. --- Common variants versus rare variants in 10q26 locus --- p.118 / Chapter 4.6.3.1. --- Common variants --- p.119 / Chapter 4.6.3.2. --- Rare variants --- p.120 / Chapter Chapter 5: --- Conclusions and future prospects --- p.122 / Chapter Chapter 6: --- References --- p.124
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Suprachoroidal drug delivery to the eye using hollow microneedlesPatel, Samikumar R. 05 1900 (has links)
Delivering drugs to effectively treat diseases of the back of the eye can be a challenging task. Although pharmacological therapies exist, drug delivery devices and techniques are not very effective at targeting delivery of drugs to the diseased tissues. This work introduces a novel approach to effectively deliver drugs to target tissues such as the choroid and retina. The approach involves a device, a hollow microneedle, to administer the drug formulation into a unique location in the eye, the suprachoroidal space. This new route of administration and a device to accomplish the delivery may provide an effective way to treat diseases of the choroid and retina. The first part of the work determines the ex-vivo feasibility of delivering materials within the suprachoroidal space. The results show that fluids and particles can be delivered into the suprachoroidal space of rabbit, pig and human eyes using a hollow microneedle. It further examines the important parameters for injection of the particles within the suprachoroidal space. The data shows that injection pressure and microneedle length are important parameters for effective delivery of particles. The results lead to a theory on the mechanism by which the particles are delivered into the suprachoroidal space. The second part of the research aims to develop a reliable in vivo delivery device and study the surface area coverage of materials injected into the suprachoroidal space. A hollow glass microneedle device is developed and for the first time shown to be effective in delivering a fluid into the suprachoroidal space in vivo. Up to 100 µL of India ink could be delivered into rabbit eyes in vivo and the spread within the suprachoroidal space is characterized. The results show that a single microneedle injection can cover a significant percentage of the available suprachoroidal space. This is the first study to examine the spread of a material injected into the suprachoroidal space of a live animal. A hollow metal microneedle device is also developed and shown to be effective. The device was able to inject up to 150 µL of latex into suprachoroidal space of fresh human cadaver eyes. The spread of latex is characterized and the results also show that a significant portion of the suprachoroidal space can be covered. The final part of the study examines the clearance of materials injected into the suprachoroidal space of rabbit eyes in vivo. First a comparison of a suprachoroidal injection to a conventional intravitreal injection shows that a suprachoroidal injection is more targeted to the chorioretinal tissues. In addition hollow microneedles are shown to effectively target macromolecules and a therapeutic antibody to the chorioretinal tissues. A study of the clearance kinetics show half lives within the suprachoroidal space on the order of several hours. Nano- and microparticles were also injected into the suprachoroidal space and showed very effective targeting. These non-degradable particles are shown to be present in the suprachoroidal space for months. Basic visual safety assessments identified no adverse effects from the injection of these materials. This represents the first study to compare intraocular clearance kinetics between a suprachoroidal injection and an intravitreal injection. It is also the first study to examine the clearance of a variety of materials from within the suprachoroidal space. Overall this work shows that microneedles have the capability to deliver a variety of materials into the suprachoroidal space of rabbit, pig, and human eyes. The injection can be done in a minimally invasive way with the proper design of an injection device and can target the chorioretinal tissues more effectively than the currently used method. In addition particles have long residence times in the suprachoroidal space, so a particle based drug formulation could provide sustained delivery to the eye. This work represents the first comprehensive study on using the suprachoroidal space as a drug delivery route and also the first study to use hollow microneedles to deliver formulations into the eye in vivo.
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Opthalmic Use Of Sodium Cephalothin: An In Vivo ComparisonCarney, Gerald R. 08 1900 (has links)
A rabbit keratoconjunctivities model was used to evaluate ophthalmic formulations containing 1 percent sodium cephalothin in silicon oil, a 1 percent sodium cephalothin aqueous solution, and a 0.3 percent gentamicin sulfate solution. Rabit eyes were inoculated intracorneally with Pseudomonas aeruginosa, Staphylococcus aureus, or Streptococcus pneumoniae, After topical treatment, none of the antibiotic formulations were effective in the P. aeruginosa model; all three showed good activity against S. aureus, and against S. pneumoniae, the caphalothin formulations were more effective than gentamicin.In a related stability study, the cephalothin potency of the silicon formulation was maintained for 16 weeks at 4, 25, and 450 C These studies suggest that sodium cephalothin can be formulated as an effective and stable ophthalmic dosage form.
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Therapy and mechanism of Mendelian eye diseasesTsai, Yi-Ting January 2018 (has links)
Retinal degenerative diseases cause varying degrees of irreversible vision loss in millions of people worldwide. Common to all retinal degenerative diseases is the malfunction or demise of photoreceptor cells or its supportive cells, retinal pigment epithelium cell in the retina. A considerable part of these diseases were resulted from the inherited mutations of essential genes expressed in these retinal cells. The understanding of pathologic mechanism as well as developing of therapeutic treatment for these diseases were discussed in this study.
A cutting-edge therapeutic genome editing technology is studied in the first part of study. This technology was invented to treat retinitis pigmentosa via engineered nucleases, which has great clinical potential for autosomal dominant genetic disorders that were previously irreparable by conventional gene therapy interventions. Though customizable gene editing tools can be engineered to target specific mutation sites, however it is too daunting for diseases like retinitis pigmentosa, a progressive retinal degenerative condition associated with more than 150 mutations in the rhodopsin gene alone. Here in this study, we present an “ablate-and-replace” combination strategy that 1) destroys expression of the endogenous gene by CRISPR/Cas9 in a mutation-independent manner, and 2) enables expression of wild-type protein through exogenous cDNA. As proof of concept, we show that our CRISPR-based therapeutic machinery efficiently ablates mRho in vivo, and when combined with gene replacement therapy, ameliorates rod photoreceptor degeneration and improves visual function in two genetically distinct autosomal dominant retinitis pigmentosa animal models.
This mutation-independent, ablate-and-replace strategy represents the first electrophysiological recovery by a CRISPR-mediated therapy in an autosomal dominant disorder and it offers a clinically relevant, universal strategy to overcome allelic heterogeneity in debilitating inherited conditions.
For the second part of the study, gene editing technology was used to study the pathogenesis of Doyne honey comb dystrophy, another Mendelian disease with extensive similarities to age-related macular degeneration. This monogenic disorder is caused by a unique point mutation on an extracellular matrix protein EFEMP1, expressed by retinal pigment epithelium cell. To precisely gauge the physiological effect resulted from this mutation, CRISPR-mediated gene correction was used to create isogeneic cell pairs from patient donated tissue-derived stem cells. These stem cells were differentiated into retinal pigment epithelium cell before analysis. We found unfolded protein response and immune response were not involved in the pathogenesis, which contradicts existing theories. Via proteomics analysis, we found expression level of a cholesterol catabolic enzyme was affected by the EFEMP1 mutation while those proteins controlling the cholesterol transport remains constant. This result provides supportive evidence to explain the aberrant intracellular accumulation of cholesterol found in patient retinal pigment epithelium cells. This imbalance in lipid homeostasis also suggests Doyne honey comb dystrophy is a retinal pigment epithelium cell-autonomous disease.
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A Multistage Incidence Estimation Model for Diseases with Differential MortalityDray, Alyssa W. 30 May 2010 (has links)
According to theWorld Health Organization, surgically removable cataract remains the leading cause of blindness worldwide. In sub-Saharan Africa, cataract surgical rate targets should ideally be set based on cataract incidence (the number of new cataracts developed each year). Unfortunately, the longitudinal studies necessary to measure incidence have not yet been feasible in these areas. Our research instead proposes a method for estimating incidence based on available cataract prevalence data. We extend a method proposed by Podgor and Leske (1986) to estimate age-specific incidence from age-specific prevalence in single diseases with differential mortality. A two-stage disease extension is created in order to differentiate between unilateral cataract and bilateral cataract. The new model, along with a numerical simulation method to generate confidence intervals, is implemented in the statistical programming language R. The model is then applied to Rapid Assessment of Avoidable Blindness survey data from parts of Eritrea, The Gambia, Kenya (two regions), Mali, Rwanda and Tanzania. Our results suggest significant geographic variations in cataract incidence, a hypothesis to be further investigated as the RAAB survey expands and improves. We also show how the model can be further extended to model any n-stage progressive disease with differential mortality. to model any n-stage progressive disease with differential mortality.
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Physiology and pharmacology of C-fibres in the rabbit eyeWang, Zunyi. January 1996 (has links)
Thesis (doctoral)--Lund University, 1996. / Added t.p. with thesis statement inserted.
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