Glaucoma is the leading cause of irreversible blindness worldwide with the most prevalent form, primary open-angle glaucoma (POAG), accounting for the vast majority of glaucoma cases. The main risk-factor for POAG is an elevated intraocular pressure (IOP), and is due to an increased resistance to aqueous humor outflow in the conventional outflow pathway at the juxtacanalicular region of the trabecular meshwork (TM) and the inner wall of Schlemm’s canal (SC). Reducing elevated IOP is the most effective method to prevent further loss of vision in glaucoma; therefore, it is important to understand how outflow resistance is regulated in the conventional outflow pathway in order to find effective methods to reduce ocular hypertension. Sphingosine-1-phosphate (S1P) is an endogenous lipid that reduces outflow facility in porcine eyes, thereby increasing resistance. S1P plays a major role in affecting cell migration, endothelial permeability, and junctional formation, processes that are intimately linked and regulated by cytoskeletal dynamics. Due to S1P’s known effect of decreasing endothelial permeability in vascular endothelial cells, the overall hypothesis of this dissertation is that the S1P-induced decrease in outflow facility occurs through a mechanism that involves S1P receptor activation in SC cells. The results from the studies within this dissertation demonstrate the expression of the S1P₁₋₃ receptor subtypes in SC and TM cells and a decrease of outflow facility by S1P in perfused human eyes. Additionally, S1P promotes F-actin formation and myosin light chain (MLC) phosphorylation at the SC cell cortex. The S1P-promoted MLC phosphorylation in both SC and TM cells, in addition to the S1P-induced decrease of outflow facility in porcine and human eyes, were blocked by the S1P₂ antagonist JTE-013. Results from these studies demonstrate S1P to actively regulate actomyosin dynamics in the cells of the outflow pathway through the S1P₂ receptor. S1P₂ also mediates the S1P-induced increase in outflow resistance. Therefore, S1P₂ is a novel pharmacological target in the conventional outflow pathway to reduce elevated IOP in glaucoma patients.

Purpose: To determine the association of plasma and aqueous humor selenium with glaucoma; and to determine those factors influencing biological levels of selenium in patients with glaucoma and cataractMethods: 47 primary open angle glaucoma (POAG) cases and 54 controls were recruited from surgery patients at the University Physician's Ophthalmology Clinic in Tucson, Arizona. Aqueous humor and plasma selenium concentration was determined by high performance liquid chromatography ion channel plasma-mass spectrometry (HPLC ICP-MS). Potential confounders were assessed via questionnaire. Outcome measures included the odds of glaucoma in relation to plasma selenium and aqueous humor selenium. Factors driving plasma and aqueous humor selenium in the study population were determined via linear regression.Results: After adjustment for risk factors and multiple outcomes, the odds of glaucoma in the highest tertile of plasma selenium (OR = 13.51; p=.03) and the middle tertile of aqueous humor selenium (OR = 0.05; p=0.02) were significantly associated with glaucoma. Selenium concentration in plasma and aqueous humor was primarily driven by metabolic factors (cancer, DMII, and ARMD).Conclusions: Although a causal pathway cannot be inferred from the analysis, it may be prudent to explore these relations in a larger sample in varying areas of geographic selenium distribution. Such information could be helpful in examining a larger study population and comparing biological data. Evaluating a subject's selenium levels over time and in relation to glaucoma onset could also lend pertinent informationDriving forces behind selenium concentrations in this population are mainly metabolic in nature. Selenium levels fluctuate in most tissue as it is metabolized by the body. Selenium supplementation is a significant predictor but this effect is small and may be transient as supplementation only temporarily increases selenium pools. It is interesting to note that sex is a significant predictor of aqueous humor selenium but not of plasma selenium. In this model, female sex predicts a decrease in the selenium within the aqueous humor. This point should be explored in future studies that are powered to discern possibly subtle differences that sex plays in relation to selenium concentrations in plasma and aqueous humor and its possible role in glaucoma.

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Connective tissue remodeling is an important area of study in biomedical engineering with respect to cancer and wound healing. Tissue remodeling components may be involved in the pathogenesis of open-angle glaucoma. Risk factors for open angle glaucoma include increased intraocular pressure (IOP), male gender, and advanced age. In a 1963 study, the hormone relaxin decreased IOP in the human eye through a mechanism that may involve the up-regulation of tissue remodeling matrix metalloproteinases (MMPs). The effects of age and gender on MMP and protein activity in porcine aqueous humor were determined in this study to identify correlations existing between MMP activity and glaucoma risk factors. Gelatin zymography identified MMPs at 66 kD and approximately 105 kD. The concentration of the 66 kD band compared to human MMP-2 standard was 0.22 ± 0.06 ng/ml for the adult female (AF) samples and 0.28 ± 0.04 ng/ml for the juvenile samples. This difference in concentration was statistically significant (p < 0.05). The concentration of the protease migrating to 66 kD was statistically independent of gender. Casein zymograms identified two non-MMP proteinases at 51 kD and 80 kD. The average total protein concentration for all aqueous humor samples was 2.54 ± 0.89 mg/ml. The mean IgG, transferrin, and albumin concentrations for all aqueous humor samples was 11.4 ± 4.2 mg/ml, 17.11 ± 6.8 mg/ml, and 78.0 ± 26.3 mg/ml respectively. Results from these experiments establish baseline levels of MMP and protein activity, allowing for identification of potential changes caused by relaxin in tissue culture studies. / Master of Science

Thèse--Louvain. / Bibliography: p. 207-238.

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 1981. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ENGINEERING. / Bibliography: leaves 68-69. / by Mark Johnson. / M.S.

Intraocular pressure (IOP) is the most important risk factor for glaucoma development and progression. Most anti-glaucoma treatments aim to lower IOP by enhancing aqueous humor drainage from the eye. Aqueous humor drainage occurs via well-characterized trabecular meshwork (TM) and uveoscleral (UVS) pathways, and the recently described ciliary lymphatics. The relative contribution of the lymphatic pathway to aqueous drainage is not known. We developed a sheep model to quantitatively assess lymphatic drainage along with TM and UVS outflows. Following intracameral injection of 125I-bovine serum albumin (BSA), lymph and blood samples were continuously collected. Lymphatic and TM drainage were quantitatively assessed by measuring 125I-BSA recovery. This quantitative sheep model enables assessment of relative contributions of lymphatic drainage (1.64% ± 0.89%), TM (68.86% ± 9.27%) and UVS outflows (19.87% ± 5.59%), and may help to better understand the effects of glaucoma agents on outflow pathways.

Intraocular pressure (IOP) is the most important risk factor for glaucoma development and progression. Most anti-glaucoma treatments aim to lower IOP by enhancing aqueous humor drainage from the eye. Aqueous humor drainage occurs via well-characterized trabecular meshwork (TM) and uveoscleral (UVS) pathways, and the recently described ciliary lymphatics. The relative contribution of the lymphatic pathway to aqueous drainage is not known. We developed a sheep model to quantitatively assess lymphatic drainage along with TM and UVS outflows. Following intracameral injection of 125I-bovine serum albumin (BSA), lymph and blood samples were continuously collected. Lymphatic and TM drainage were quantitatively assessed by measuring 125I-BSA recovery. This quantitative sheep model enables assessment of relative contributions of lymphatic drainage (1.64% ± 0.89%), TM (68.86% ± 9.27%) and UVS outflows (19.87% ± 5.59%), and may help to better understand the effects of glaucoma agents on outflow pathways.

Made available in DSpace on 2014-06-11T19:31:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-07-14Bitstream added on 2014-06-13T20:41:24Z : No. of bitstreams: 1 barbosa_vt_dr_jabo.pdf: 445036 bytes, checksum: 7be58e66156743e0a9907a1b3018df87 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A leishmaniose ocular canina envolve um complexo de alterações decorrentes da atuação do agente nos diversos tecidos oculares. Valendo-se de cães com sorologia positiva para a doença, portadores (G1) ou não (G2) de alterações oftálmicas, com este estudo avaliou-se: o exame parasitológico de esfregaço a partir de swab conjuntival, a presença do parasito, pela PCR, em fragmento conjuntival e no humor aquoso (HA) e as concentrações protéicas, pela eletroforese, no HA. O parasitológico de esfregaço a partir do swab conjuntival foi positivo em 60% e 38,1% dos animais do G1 e do G2, respectivamente, com a oddsratio de 2,438 para positividade em tal parâmetro nos cães do G1, comparativamente aos do G2. A positividade na PCR de fragmento conjuntival foi maior no G1 (p < 0,005), com oddsratio igual a 17,31 quando comparados G1 e G2. O parasito não foi detectado no HA de qualquer dos grupos. Houve correlação fracopositiva entre as concentrações de IgG e de albumina séricas e do HA. Diferenças significativas foram encontradas entre os grupos, quando comparadas as proteínas totais, IgG, e proteína de peso molecular 33 kDa no HA. A haptoglobina foi detectada apenas no HA dos cães do G1. Os dados apontam para uma tendência dos cães com sinais oftálmicos serem positivos no parasitológico de esfregaço a partir do swab conjuntival e na PCR de conjuntiva, podendo, o método ser útil no diagnóstico parasitológico da leishmaniose visceral canina. Proteínas de fase aguda merecem mais avaliações quanto ao seu valor diagnóstico para esta enfermidade / Canine ocular leishmaniasis involves several ophthalmic alterations owing to the action of the parasite in numerous ocular tissues. Therefore, dogs serologically positive for leishmaniasis either presenting (G1) or not (G2) ocular alterations were enrolled in this study to evaluate the conjunctival cytology as a method for the diagnosis of this disease, the detection of the parasite in conjunctival tissue samples and in the aqueous humor using PCR, as well as the serum and aqueous humor protein concentrations determined by electrophoresis. The parasitological evaluation of the swabs disclosed 60% and 38.1% of positivity in dogs of groups 1 and 2, respectively, with a calculated oddsratio of 2.438 for a single animal testing positive in this procedure when ocular changes existed. The documented PCR results were more expressive in G1 dogs (P<0,005), with an oddsratio of 17,81 for the animals of this group testing positive using this method as compared to G2. The parasite was not found in the aqueous humor of either group. A weak positive correlation was calculated between the serum and aqueous humor IgG and albumin concentrations, and significant differences were found to exist between groups regarding total protein, IgG, and 33 kDa protein measured in the aqueous humor. Also, haptoglobin was detected only in the aqueous humor of G1 dogs. Our data suggest a tendency of dogs with ocular signs testing positive on the conjunctival swab exams and PCR, being these methods useful in the diagnosis of canine leishmaniasis. However, acute phase proteins require a more detailed evaluation concerning its diagnostic value for this disease

Orientador: José Luis Laus / Banca: Aline Adriana Bolzan / Banca: Leucio Camara Alves / Banca: Fábio Luiz da Cunha Brito / Banca: Newton Nunes / Resumo: A leishmaniose ocular canina envolve um complexo de alterações decorrentes da atuação do agente nos diversos tecidos oculares. Valendo-se de cães com sorologia positiva para a doença, portadores (G1) ou não (G2) de alterações oftálmicas, com este estudo avaliou-se: o exame parasitológico de esfregaço a partir de swab conjuntival, a presença do parasito, pela PCR, em fragmento conjuntival e no humor aquoso (HA) e as concentrações protéicas, pela eletroforese, no HA. O parasitológico de esfregaço a partir do swab conjuntival foi positivo em 60% e 38,1% dos animais do G1 e do G2, respectivamente, com a oddsratio de 2,438 para positividade em tal parâmetro nos cães do G1, comparativamente aos do G2. A positividade na PCR de fragmento conjuntival foi maior no G1 (p < 0,005), com oddsratio igual a 17,31 quando comparados G1 e G2. O parasito não foi detectado no HA de qualquer dos grupos. Houve correlação fracopositiva entre as concentrações de IgG e de albumina séricas e do HA. Diferenças significativas foram encontradas entre os grupos, quando comparadas as proteínas totais, IgG, e proteína de peso molecular 33 kDa no HA. A haptoglobina foi detectada apenas no HA dos cães do G1. Os dados apontam para uma tendência dos cães com sinais oftálmicos serem positivos no parasitológico de esfregaço a partir do swab conjuntival e na PCR de conjuntiva, podendo, o método ser útil no diagnóstico parasitológico da leishmaniose visceral canina. Proteínas de fase aguda merecem mais avaliações quanto ao seu valor diagnóstico para esta enfermidade / Abstract: Canine ocular leishmaniasis involves several ophthalmic alterations owing to the action of the parasite in numerous ocular tissues. Therefore, dogs serologically positive for leishmaniasis either presenting (G1) or not (G2) ocular alterations were enrolled in this study to evaluate the conjunctival cytology as a method for the diagnosis of this disease, the detection of the parasite in conjunctival tissue samples and in the aqueous humor using PCR, as well as the serum and aqueous humor protein concentrations determined by electrophoresis. The parasitological evaluation of the swabs disclosed 60% and 38.1% of positivity in dogs of groups 1 and 2, respectively, with a calculated oddsratio of 2.438 for a single animal testing positive in this procedure when ocular changes existed. The documented PCR results were more expressive in G1 dogs (P<0,005), with an oddsratio of 17,81 for the animals of this group testing positive using this method as compared to G2. The parasite was not found in the aqueous humor of either group. A weak positive correlation was calculated between the serum and aqueous humor IgG and albumin concentrations, and significant differences were found to exist between groups regarding total protein, IgG, and 33 kDa protein measured in the aqueous humor. Also, haptoglobin was detected only in the aqueous humor of G1 dogs. Our data suggest a tendency of dogs with ocular signs testing positive on the conjunctival swab exams and PCR, being these methods useful in the diagnosis of canine leishmaniasis. However, acute phase proteins require a more detailed evaluation concerning its diagnostic value for this disease / Doutor