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1.
Am J Pathol ; 175(2): 799-807, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19608872

RESUMO

Age-related macular degeneration (AMD) is one of the leading cause of blindness among the elderly; however, current therapy options are limited. Epidemiological studies have shown that a diet that is high in omega-3 polyunsaturated (n-3) fatty acids can slow disease progression in patients with advanced AMD. In this study, we evaluated the effect of such a diet on the retinas of Ccl2(-/-)/Cx3cr1(-/-) mice, a model that develops AMD-like retinal lesions that include focal deep retinal lesions, abnormal retinal pigment epithelium, photoreceptor degeneration, and A2E accumulation. Ccl2(-/-)/Cx3cr1(-/-) mice that ingested a high n-3 fatty acid diet showed a slower progression of retinal lesions compared with the low n-3 fatty acids group. Some mice that were given high levels of n-3 fatty acids had lesion reversion. We found a shunted arachidonic acid metabolism that resulted in decreased pro-inflammatory derivatives (prostaglandin E(2) and leukotriene B(4)) and an increased anti-inflammatory derivative (prostaglandin D(2)). We also measured lower ocular TNF-alpha and IL-6 transcript levels in the mice fed a diet of high n-3 fatty acids. Our findings in these mice are in line with human studies of AMD risk reduction by long-chain n-3 fatty acids. This murine model provides a useful tool to evaluate therapies that might delay the development of AMD.


Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Degeneração Macular/terapia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Animais , Ácido Araquidônico/metabolismo , Receptor 1 de Quimiocina CX3C , Quimiocina CCL2/genética , Dieta , Modelos Animais de Doenças , Interleucina-6/genética , Degeneração Macular/patologia , Degeneração Macular/prevenção & controle , Camundongos , Camundongos Mutantes , Compostos de Piridínio/metabolismo , Receptores de Quimiocinas/genética , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Retinoides/metabolismo , Transcrição Gênica , Fator de Necrose Tumoral alfa/genética
2.
Cornea ; 36(12): 1562-1566, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28902010

RESUMO

PURPOSE: Posterior amorphous corneal dystrophy (PACD) is a rare disorder characterized by sheet-like opacification of the posterior corneal stroma, corneal thinning, and decreased corneal curvature. It is not known to be associated with progressive corneal ectasia. In this report, we examine the course of a patient with PACD who developed bilateral keratoglobus-type corneal ectasia. METHODS: The clinical history of a single patient is reviewed from birth through age 15. Visual acuity, refraction, ultrasound pachymetry, anterior segment optical coherence tomography, corneal topography, and corneal tomography are presented. RESULTS: The patient was noted to have bilateral cloudy corneas at birth. Congenital infection, metabolic disease, and glaucoma were ruled out. Anterior segment optical coherence tomography demonstrated posterior stromal opacification typical of PACD. Over time, the patient progressed from best uncorrected visual acuity of 20/20-2 OD and 20/25-3 OS to PROSE lens-corrected visual acuity of 20/30-3 OD and 20/30-3 OS. Central corneal thinness progressed from 491 to 408 µm in the right eye and from 505 to 389 µm in the left eye. Steepening in corneal axial/sagittal curvature developed in both eyes beginning inferiorly then involving the corneas diffusely. CONCLUSIONS: In this case report, we illustrate progressive corneal ectasia in a patient with PACD. Although both conditions may represent changes in the structure and integrity of corneal collagen, whether an association exists between the 2 conditions is unknown.


Assuntos
Doenças da Córnea/patologia , Distrofias Hereditárias da Córnea/patologia , Dilatação Patológica , Feminino , Humanos , Recém-Nascido
3.
Dev Ophthalmol ; 55: 7-17, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26502225

RESUMO

Normal retina contains neuroretina and retinal pigment epithelium. The neuroretina consists of outer and inner segments of photoreceptors (rods and cones), external limiting membrane, outer nuclear layer, outer plexiform layer, inner nuclear layer, inner plexiform layer, ganglion cell layer, nerve fiber layer and internal limiting membrane. There is a broad spectrum of retinal pathology including congenital abnormalities, dystrophies, degenerations (notably age-related macular degeneration), retinal vascular diseases, toxicities, inflammatory diseases, neoplasms, retinal detachment, trauma and retinal involvement of systemic diseases. This chapter presents a few major pathological processes in retinal diseases, especially processes that are amenable to pharmacotherapeutics.


Assuntos
Retina/anatomia & histologia , Retina/patologia , Doenças Retinianas/patologia , Corpo Vítreo/patologia , Humanos , Aderências Teciduais/patologia
4.
Cornea ; 31(12): 1476-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22531436

RESUMO

PURPOSE: To describe a step-by-step methodology to establish a reproducible staining protocol for the evaluation of human corneal endothelial cells. METHODS: Four procedures were performed to determine the best protocol. (1) To determine the optimal trypan blue staining method, goat corneas were stained with 4 dilutions of trypan blue (0.4%, 0.2%, 0.1%, and 0.05%) and 1% alizarin red. (2) To determine the optimal alizarin red staining method, goat corneas were stained with 2 dilutions of alizarin red (1% and 0.5%) and 0.2% trypan blue. (3) To ensure that trypan blue truly stains damaged cells, goat corneas were exposed to either 3% hydrogen peroxide or to balanced salt solution, and then stained with 0.2% trypan blue and 0.5% alizarin red. (4) Finally, fresh human corneal buttons were examined; 1 group was stained with 0.2% trypan blue and another group with 0.4% trypan blue. RESULTS: For the 4 procedures performed, the results are as follows: (1) trypan blue staining was not observed in any of the normal corneal samples; (2) 0.5% alizarin red demonstrated sharper cell borders than 1% alizarin red; (3) positive trypan blue staining was observed in the hydrogen peroxide exposed tissue in damaged areas; (4) 0.4% trypan blue showed more distinct positive staining than 0.2% trypan blue. CONCLUSIONS: We were able to determine the optimal vital dye staining conditions for human corneal endothelial cells using 0.4% trypan blue and 0.5% alizarin red.


Assuntos
Antraquinonas/química , Corantes/química , Endotélio Corneano/citologia , Coloração e Rotulagem/métodos , Azul Tripano/química , Animais , Endotélio Corneano/efeitos dos fármacos , Cabras , Humanos , Peróxido de Hidrogênio/toxicidade
5.
Ophthalmic Genet ; 30(3): 127-35, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19941417

RESUMO

BACKGROUND: Nance-Horan syndrome (NHS) is a rare X-linked disorder typified by dense congenital central cataracts, microcornea, anteverted and simplex pinnae, brachymetacarpalia, and numerous dental anomalies due in most cases to a mutation in the NHS gene. MATERIAL AND METHODS: We present a case of clinical manifestation and ocular pathology in a patient with NHS. This article also reviews and discusses the relevant literature. RESULTS: Classic and novel ocular pathological findings of a young male with NHS are described, including congenital cataracts, infantile glaucoma, scleral staphyloma, and severe retinal cystoid degeneration. CONCLUSIONS: We report a new pathological finding of severe retinal cystoid degeneration in this NHS patient and confirm abnormal development of the anterior chamber angle structure. These findings, coupled with our analysis of the available NHS literature, provide new understanding of the histopathological basis of ocular abnormalities and vision loss in NHS.


Assuntos
Anormalidades Múltiplas/patologia , Catarata/patologia , Anormalidades do Olho/patologia , Edema Macular/patologia , Degeneração Retiniana/patologia , Anormalidades Dentárias/patologia , Anormalidades Múltiplas/genética , Adulto , Catarata/congênito , Humanos , Masculino , Proteínas de Membrana , Mutação/genética , Proteínas Nucleares/genética , Síndrome
6.
Open Biol J ; 2: 141-148, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21152244

RESUMO

Peroxisome proliferator-activated receptors (PPARs) play a role in oxidative stress and VEGF regulation, which are closely related to age-related macular degeneration (AMD). PPAR γ expression and its downstream molecules were examined in fat-1 mice (transgenic mice that convert n-6 to n-3 fatty acids), Ccl2(-/-)/Cx3cr1(-/-) mice (an AMD model), ARPE19 cells (a human retinal pigment epithelial cell line, RPE, a cell type with a critical role in AMD), and human eyes with and without AMD. PPAR α, ß, and γ, VEGF and receptors were determined by immunohistochemistry in the mice models, humans, and ARPE19 cells. Transcripts of PPARs, VEGF, MMP-9 and HO-1 were determined by RQ-PCR. PPARs were constitutively expressed in normal neuroretina and RPE of humans and mice. PPAR γ expression was increased in fat-1 and Ccl2(-/-)/Cx3cr1(-/-) mice. VEGF was decreased in fat-1 mice but increased in Ccl2(-/-)/Cx3cr1(-/-) mice. VEGF receptors were stable. VEGF, MMP9 and HO-1 transcript levels were increased in ARPE19 cells under H(2)O(2) - induced oxidative stress. Human AMD retinas exhibited higher PPAR γ. The findings of increased expression of PPAR γ and its downstream proteins (VEGF, MMP9, and HO-1) in H(2)O(2)-treated ARPE19 cells, Ccl2(-/-)/Cx3cr1(-/-) mice, and human AMD eyes, but decreased VEGF in fat-1 mice, suggest that PPAR γ may play a role in AMD.

7.
Cornea ; 28(2): 221-3, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19158571

RESUMO

PURPOSE: The purpose of this study was to report a case of limbal stem cell deficiency (LSCD) after systemic chemotherapy with hydroxycarbamide. METHODS: Clinical manifestations and pathology are detailed. RESULTS: We describe the case of a woman with sickle cell disease, who developed bilateral LSCD after treatment with hydroxycarbamide. Histologic examination confirmed the diagnosis of LSCD, revealing goblet cells, inflammatory cells, deposits of new collagen components, and neovascularization in the peripheral cornea. Matrix metalloproteinase-3, fibronectin, and collagen III were also detected in the lesions. CONCLUSIONS: The systemic use of the antineoplastic drug, hydroxycarbamide, may cause severe LSCD. We recommend that a medication history, including that of cytotoxic drugs, be considered in evaluating LSCD.


Assuntos
Antidrepanocíticos/efeitos adversos , Hidroxiureia/efeitos adversos , Limbo da Córnea/efeitos dos fármacos , Limbo da Córnea/patologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologia , Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Doenças da Túnica Conjuntiva/induzido quimicamente , Doenças da Túnica Conjuntiva/patologia , Córnea/metabolismo , Feminino , Humanos , Hidroxiureia/uso terapêutico , Imuno-Histoquímica , Limbo da Córnea/irrigação sanguínea , Limbo da Córnea/metabolismo , Pessoa de Meia-Idade , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Pterígio/patologia
8.
Invest Ophthalmol Vis Sci ; 50(10): 4957-66, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19443712

RESUMO

PURPOSE: To investigate the role of HtrA2/Omi, a nuclear-encoded mitochondrial serine protease with a proapoptosis function, under H(2)O(2)-induced oxidative stress in human RPE, in the Ccl2(-)(/)(-)Cx3cr1(-)(/)(-) double-knockout (DKO) mouse retina, and the HtrA2/Omi-deficient mice. METHODS: Oxidative stress was induced in ARPE-19 cells by 1 mM H(2)O(2) for 2 hours. HtrA2/Omi and caspase-3 expression was evaluated using RQ-PCR, immunohistochemistry, or Western blot. Cell viability was detected by MTT assay. HtrA2/Omi expression in the subcellular components and activated caspase-3 were measured. These processes were also evaluated in cells treated with UCF-101, an HtrA2/Omi inhibitor or in cells subjected to RNAi against HtrA2/Omi. Oxidative stress was assayed and compared in retinas of DKO and wild-type (WT) mice by determining serum NADPH oxidase subunits and nitrite levels. Transmission electron microscopy was used to view the retinal ultrastructure of the HtrA2/Omi-deficient mice. RESULTS: H(2)O(2)-induced oxidative damage resulted in HtrA2/Omi translocation from mitochondria to cytosol, leading to RPE cell apoptosis via a caspase-mediated pathway. Treatment of RPE cells with UCF-101 reduced the cytosolic translocation of HtrA2/Omi, attenuated caspase-3 activation, and decreased apoptosis. After specific HtrA2 downregulation, increased cell viability was measured in H(2)O(2)-treated ARPE-19 cells. Retina of DKO mice exhibit increased oxidative stress and upregulation of HtrA2/Omi. Fewer and abnormal mitochondria were found in HtrA2/Omi(-)(/)(-) photoreceptors and RPE. CONCLUSIONS: These findings suggest that HtrA2/Omi is related to RPE apoptosis due to oxidative stress, which may play an important role in the integrity of mitochondria and the pathogenesis of AMD.


Assuntos
Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica/fisiologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Degeneração Retiniana/enzimologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Animais , Apoptose , Western Blotting , Receptor 1 de Quimiocina CX3C , Caspase 3 , Linhagem Celular , Sobrevivência Celular , Quimiocina CCL2/genética , Citosol/enzimologia , Inibidores Enzimáticos/farmacologia , Técnica Indireta de Fluorescência para Anticorpo , Serina Peptidase 2 de Requerimento de Alta Temperatura A , Humanos , Peróxido de Hidrogênio/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/enzimologia , Proteínas Mitocondriais/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Pirimidinonas/farmacologia , Interferência de RNA , Receptores de Quimiocinas/genética , Degeneração Retiniana/patologia , Epitélio Pigmentado da Retina/enzimologia , Epitélio Pigmentado da Retina/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tionas/farmacologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
9.
PPAR Res ; 2008: 389507, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18288287

RESUMO

Age-related macular degeneration (AMD) is the leading cause of new blindness in the western world and is becoming more of a socio-medical problem as the proportion of the aged population increases. There are multiple efforts underway to better understand this disease process. AMD involves the abnormal retinal pigment epithelium (RPE), drusen formation, photoreceptor atrophy, and choroidal neovascularization. Peroxisome proliferator-activated receptors (PPARs) play an important role in lipid degeneration, immune regulation, regulation of reactive oxygen species (ROSs), as well as regulation of vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and docosahexaenoic acid (DHA). These molecules have all been implicated in the pathogenesis of AMD. In addition, PPAR gamma is expressed in RPE, an essential cell in photoreceptor regeneration and vision maintenance. This review summarizes the interactions between PPAR, AMD-related molecules, and AMD-related disease processes.

11.
Expert Rev Ophthalmol ; 3(1): 97-109, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18461151

RESUMO

The purine analogs, fludarabine and cladribine represent an important class of chemotherapy agents used to treat a broad spectrum of lymphoid malignancies. Their toxicity profiles include dose-limiting myelosuppression, immunosuppression, opportunistic infection and severe neurotoxicity. This review summarizes the neurotoxicity of high- and standard-dose fludarabine, focusing on the clinical and pathological manifestations in the eye. The mechanisms of ocular toxicity are probably multifactorial. With increasing clinical use, an awareness of the neurological and ocular vulnerability, particularly to fludarabine, is important owing to the potential for life- and sight-threatening consequences.

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