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OBJECTIVE: To investigate the cardiovascular (CV) safety associated with intravitreal anti-VEGF injections (IAVIs) in patients with diabetic retinopathy (DR). DESIGN: Population-based cohort study using Medicare and 2 commercial insurance claims databases in the United States from January 2009 to December 2017. SUBJECTS: Patients with DR aged ≥ 18 years in whom treatment with either IVAIs or laser procedure or intravitreal steroid injections was initiated. METHODS: We estimated the propensity score (PS) using multivariable logistic regression models, including 85 baseline covariates and PS-matched patients in a 1:1 ratio. We estimated the pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analyses based on prior history of CV events were also conducted. MAIN OUTCOME MEASURES: A composite CV outcome of myocardial infarction (MI) or stroke, its individual components, and all-cause mortality in 180 and 365 days after treatment initiation. RESULTS: We identified 61 508 PS-matched patients in a 1:1 ratio in whom either IVAIs or laser or steroid treatment was initiated. Compared with laser or steroid treatment, IAVIs were not associated with an increased risk of the composite CV outcome (HR, 0.95; 95% CI, 0.83-1.09), MI (HR, 0.93; 95% CI, 0.76-1.13), or stroke (HR, 0.98; 95% CI, 0.80-1.19) or the risk of all-cause mortality (HR, 1.25; 95% CI, 0.97-1.62) at 180 days of follow-up. At 365 days, the risk of the composite CV outcome, stroke, and MI remained similar between the 2 groups, although the risk of all-cause mortality was increased with IAVIs (HR, 1.35; 95% CI, 1.14-1.60). The subgroup analysis showed that the risk of all-cause mortality was increased in patients with a prior history of CV events. CONCLUSIONS: Among > 60 000 patients with DR, those who received IAVIs had a risk of CV events similar to those who received laser or steroid treatment. However, the risk of all-cause mortality was higher in patients who received IAVIs for DR.
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Diabetes Mellitus , Retinopatia Diabética , Acidente Vascular Cerebral , Fator A de Crescimento do Endotélio Vascular , Humanos , Estudos de Coortes , Retinopatia Diabética/complicações , Retinopatia Diabética/tratamento farmacológico , Esteroides , Acidente Vascular Cerebral/complicações , Estados Unidos/epidemiologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
PURPOSE: This article describes the clinical and multimodal imaging characteristics of subthreshold exudative choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). METHODS: Among 3773 patients with AMD, 8 eyes (6 patients) were identified with the clinical phenotype of interest. Dilated fundus examinations, color fundus photography, fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), and OCT angiography (OCTA) were performed. RESULTS: OCT typically showed a moderately reflective irregular pigment epithelial detachment with overlying subretinal fluid (SRF). Traditional FA did not show leakage and ICGA showed no definitive neovascular network or hot spots. However, OCTA clearly demonstrated a CNV within the pigment epithelial detachment. The majority of our cases (7 of 8) did not receive antivascular endothelial growth factor (anti-VEGF) injections, and visual acuity remained stable over the available follow-up period of I to 10 years. CONCLUSIONS: CNV is often associated with SRF and vision loss in AMD, usually requiring frequent anti-VEGF injections. OCTA allowed us to better identify CNV not readily detected on FA and ICGA. Although some have suggested early clinical intervention with anti-VEGF injections in any case with fluid and confirmed CNV on OCTA, we describe a subset of AMD patients with SRF who may be better managed by observation. These cases may represent a more indolent, mature, and stable vascular network.
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BACKGROUND AND OBJECTIVE: There is a relative lack of head-to-head comparisons of denosumab against other osteoporosis drugs on safety. We aimed to explore ocular outcomes in patients with osteoporosis initiating denosumab vs zoledronic acid. METHODS: We conducted a cohort study using claims data (2010-15) from two large US commercial insurance databases including patients with osteoporosis who were aged 50 years or older and initiators of denosumab or zoledronic acid. The primary outcomes were (1) receipt of cataract surgery and development of (2) wet age-related macular degeneration and (3) dry age-related macular degeneration within 365 days after initiation of denosumab vs zoledronic acid. Propensity score fine stratification and weighting were used to control for potential confounding, and we calculated the incidence rate and hazard ratio for each outcome in the cohorts. The estimates from the two databases were combined with a fixed-effects model meta-analysis. RESULTS: The study cohort included 50,821 denosumab and 67,471 zoledronic acid initiators. In the propensity score-weighted analysis, compared to zoledronic acid use, denosumab was associated with a modestly decreased risk of undergoing cataract surgery (hazard ratio 0.91; 95% confidence interval 0.85-0.98) but not with the risk of wet age-related macular degeneration (hazard ratio 1.29; 95% confidence interval 0.99-1.70) or dry age-related macular degeneration (hazard ratio 1.03; 95% confidence interval 0.98-1.09). CONCLUSIONS: In this large population-based cohort study of 118,292 patients with osteoporosis, initiation of denosumab was associated with a modestly decreased risk of cataract surgery vs zoledronic acid. The risk of age-related macular degeneration was similar between the two drugs.
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Conservadores da Densidade Óssea/efeitos adversos , Extração de Catarata/estatística & dados numéricos , Bases de Dados Factuais , Denosumab/efeitos adversos , Degeneração Macular/induzido quimicamente , Osteoporose/tratamento farmacológico , Ácido Zoledrônico/efeitos adversos , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Estudos de Coortes , Denosumab/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Ácido Zoledrônico/uso terapêuticoRESUMO
Purpose: To evaluate the association between dietary fat intake and the presence of AMD. Methods: Cross-sectional, observational study with cohorts prospectively recruited from the United States and Portugal. AMD was diagnosed based on color fundus photographs with the AREDS classification. A validated food frequency questionnaire was used to calculate the percent energy intake of trans fat, saturated fat, monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA). Odds ratio (OR) and 95% confidence intervals for quintile of amount of FA were calculated. Multiple logistic regression was used to estimate the OR. Results: We included 483 participants, 386 patients with AMD and 97 controls. Higher intake of trans fat was associated with a 2.3-fold higher odds of presence of AMD (P for trend = 0.0156), whereas a higher intake of PUFA (OR, 0.25; P for trend = 0.006) and MUFA (OR, 0.24; P for trend < 0.0001) presented an inverse association. Subgroup analysis showed that higher quintile of trans fat was associated with increased odds of having intermediate AMD (OR, 2.26; P for trend = 0.02); and higher quintile of PUFA and MUFA were inversely associated with intermediate AMD (OR, 0.2 [P for trend = 0.0013]; OR, 0.17 [P for trend < 0.0001]) and advanced AMD (OR, 0.13 [P for trend = 0.02]; OR, 0.26 [P for trend = 0.004]). Additionally, a statistically significant effect modification by country was noted with inverse association between MUFA and AMD being significant (OR, 0.04; P for trend < 0.0001) for the Portugal population only. Conclusions: Our study shows that higher dietary intake of trans fat is associated with the presence of AMD, and a higher intake of PUFA and MUFA is inversely associated with AMD.
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Ácidos Graxos Monoinsaturados/efeitos adversos , Ácidos Graxos Insaturados/efeitos adversos , Degeneração Macular/etiologia , Idoso , Estudos Transversais , Dieta/efeitos adversos , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Gorduras Insaturadas na Dieta/administração & dosagem , Gorduras Insaturadas na Dieta/efeitos adversos , Ingestão de Energia , Ácidos Graxos Monoinsaturados/administração & dosagem , Ácidos Graxos Insaturados/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Portugal , Estudos Prospectivos , Estados UnidosRESUMO
Background: Inflammatory bowel disease (IBD) patients may develop anterior uveitis. Methods: An observational cohort of IBD patients followed new users of (1) tumor necrosis factor inhibitor versus nonbiologic agents or (2) adalimumab versus infliximab until occurrence of anterior uveitis or treatment change/discontinuation. Cox-proportional hazards models estimated hazard ratios in propensity score-matched cohorts of Crohn disease or ulcerative colitis patients. Results: No statistically significant differences in the risk of uveitis were observed between initiators of nonbiologics and tumor necrosis factor inhibitor. Effect estimates for adalimumab versus infliximab were highly imprecise due to limited outcomes. Conclusions: Uveitis risk was not different between IBD patients treated with immunosuppressives.
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PURPOSE: Epiretinal proliferation is a distinct clinical entity from epiretinal membrane that classically is associated with lamellar macular holes, but its prevalence and association with full-thickness macular holes (FTMH) have not been well described. We characterized macular hole-associated epiretinal proliferation (MHEP) and its effects on long-term surgical outcomes. DESIGN: Multicenter, interventional, retrospective case-control study. PARTICIPANTS: Consecutive eyes that underwent surgery for FTMH with a minimum of 12 months follow-up. METHODS: All eyes underwent pars plana vitrectomy, removal of any epiretinal membranes, and gas tamponade, with or without internal limiting membrane (ILM) peeling. Spectral-domain OCT imaging was obtained before and after surgery. MAIN OUTCOME MEASURES: Improvement in visual acuity and single-surgery hole closure rates in eyes with, versus without, MHEP at 12 months. RESULTS: Seven hundred twenty-five charts were analyzed, and 113 patients met inclusion criteria. Of 113 eyes with FTMH, 30 (26.5%) showed MHEP. Patients with FTMH and MHEP were older (P < 0.002) and more often men (P = 0.001), and showed more advanced macular hole stages than those without MHEP (P = 0.010). A full posterior vitreous detachment was more common in eyes with MHEP (P < 0.004). Twelve months after surgery, FTMH with MHEP patients showed significantly less improvement in visual acuity (P = 0.019) with higher rates of ellipsoid and external limiting membrane defects (P < 0.05) and with a higher rate of failure to close with 1 surgery compared to FTMH without MHEP (26.7% vs. 4.8%; P = 0.002]). Peeling the ILM was associated with improved rates of hole closure in FTMH with MHEP (P < 0.001). Multivariate testing confirmed that the presence of MHEP was an independent risk factor for less visual improvement (P = 0.031) and for single-surgery nonclosure (P = 0.009) and that ILM peeling improved single-surgery closure rates (P = 0.026). CONCLUSIONS: We found that FTMH with MHEP showed poorer anatomic and visual outcomes after vitrectomy compared with FTMH without MHEP. Internal limiting membrane peeling was associated with improved closure rates and should be considered when MHEP is detected before surgery.
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Tamponamento Interno , Membrana Epirretiniana/etiologia , Perfurações Retinianas/complicações , Perfurações Retinianas/cirurgia , Vitrectomia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Membrana Epirretiniana/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
BACKGROUND/AIMS: Microperimetry is a technique that is increasingly used to assess visual function in age-related macular degeneration (AMD). In this study, we aimed to evaluate the relationship between retinal sensitivity measured with macular integrity assessment (MAIA) microperimetry and optical coherence tomography (OCT)-based macular morphology in AMD. METHODS: Prospective, cross-sectional study. All participants were imaged with colour fundus photographs used for AMD staging (Age-Related Eye Disease Study scale), spectral-domain OCT (Spectralis, Heidelberg, Germany) and swept-source OCT (Topcon, Japan). Threshold retinal sensitivity of the central 10° diameter circle was assessed with the full-threshold, 37-point protocol of the MAIA microperimetry device (Centervue, Italy). Univariable and multivariable multilevel mixed-effect linear regression models were used for analysis. RESULTS: We included 102 eyes with AMD and 46 control eyes. Multivariable analysis revealed that older age (p<0.0001), advanced AMD stage (p<0.0001) and reduced retinal thickness (p<0.0001) were associated with decreased mean retinal sensitivity. No associations were found between choroidal thickness and retinal sensitivity within the macula. Within the 10° diameter circle of the macula, the presence of ellipsoid disruption, subretinal fluid, atrophy and fibrosis, and outer retinal tubulation on OCT images was also associated with decreased retinal sensitivity (all p<0.05). CONCLUSIONS: There is an association between TRS as determined by MAIA microperimetry and several OCT structural parameters across various stages of AMD. This study highlights the relevance of microperimetry as a functional outcome measure for AMD.
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Atrofia Geográfica/fisiopatologia , Retina/fisiopatologia , Transtornos da Visão/fisiopatologia , Testes de Campo Visual , Campos Visuais/fisiologia , Degeneração Macular Exsudativa/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Angiofluoresceinografia , Atrofia Geográfica/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Degeneração Macular Exsudativa/diagnósticoRESUMO
Macular hole associated with high myopia (MH-HM) and macular hole-associated retinal detachment (MH-RD) are two conditions found in eyes with pathologic myopia that often have poor postoperative outcomes. A discrepancy in size between the stretched retina and the posteriorly expanded sclera is a major factor in the pathogenesis. The authors report a case comprising both types of maculopathy, one in each eye. The eye with the MH-HM (right eye) represents the longest axial length ever reported to have successful macular hole closure by any technique. The authors conclude that traditional surgery can be an adequate treatment for such a challenging condition. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e99-e101.].
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Membrana Epirretiniana/cirurgia , Miopia Degenerativa/complicações , Perfurações Retinianas/cirurgia , Vitrectomia/métodos , Membrana Basal/cirurgia , Tamponamento Interno , Feminino , Fluorocarbonos/administração & dosagem , Humanos , Pessoa de Meia-Idade , Perfurações Retinianas/etiologia , Perfurações Retinianas/fisiopatologia , Acuidade Visual/fisiologiaRESUMO
PURPOSE: Vision loss from age-related macular degeneration (AMD) has a profound effect on vision-related quality of life (VRQoL). The pupose of this study is to identify clinical factors associated with VRQoL using the Rasch- calibrated NEI VFQ-25 scales in bilateral advanced AMD patients. METHODS: We retrospectively reviewed 47 patients (mean age 83.2 years) with bilateral advanced AMD. Clinical assessment included age, gender, type of AMD, high contrast visual acuity (VA), history of medical conditions, contrast sensitivity (CS), central visual field loss, report of Charles Bonnet Syndrome, current treatment for AMD and Rasch-calibrated NEI VFQ-25 visual function and socioemotional function scales. The NEI VFQ visual function scale includes items of general vision, peripheral vision, distance vision and near vision-related activity while the socioemotional function scale includes items of vision related-social functioning, role difficulties, dependency, and mental health. Multiple regression analysis (structural regression model) was performed using fixed item parameters obtained from the one-parameter item response theory model. RESULTS: Multivariate analysis showed that high contrast VA and CS were two factors influencing VRQoL visual function scale (ß = -0.25, 95% CI-0.37 to -0.12, p<0.001 and ß = 0.35, 95% CI 0.25 to 0.46, p<0.001) and socioemontional functioning scale (ß = -0.2, 95% CI -0.37 to -0.03, p = 0.023, and ß = 0.3, 95% CI 0.18 to 0.43, p = 0.001). Central visual field loss was not assoicated with either VRQoL visual or socioemontional functioning scale (ß = -0.08, 95% CI-0.28 to 0.12,p = 0.44 and ß = -0.09, 95% CI -0.03 to 0.16, p = 0.50, respectively). CONCLUSION: In patients with vision impairment secondary to bilateral advanced AMD, high contrast VA and CS are two important factors affecting VRQoL.
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Sensibilidades de Contraste/fisiologia , Degeneração Macular/fisiopatologia , Acuidade Visual/fisiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Degeneração Macular/metabolismo , Masculino , Análise Multivariada , Qualidade de Vida/psicologia , Estudos Retrospectivos , Inquéritos e Questionários , Visão Ocular/fisiologiaRESUMO
PURPOSE: To compare the rate of progression to advanced stage in the fellow eye of patients with typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) in a South Korean cohort. DESIGN: This is an observational, consecutive retrospective case series. PARTICIPANTS: Patients with unilateral advanced stage AMD (n = 288; 180 typical AMD patients and 108 PCV patients). METHODS: Clinical assessment included detailed eye examination, including fundus photography, fluorescein angiography, and indocyanine green angiography. MAIN OUTCOME MEASURES: Five-year progression rate to advanced stage in the fellow eye based on initial Age-Related Eye Disease Study (AREDS) score and the correlation between the initial AREDS score and progression to advanced disease in the fellow eye according to types of AMD. RESULTS: Five-year progression to advanced disease in the fellow eye was similar between typical AMD and PCV cases (11.1% vs. 14.8 %, respectively; P = 0.466, log-rank test). Among patients with initial AREDS score of 2 (normal macula or small drusen on the fellow eye), a higher proportion of patients progressed to advanced disease in the PCV group compared with typical AMD patients (10.4% vs. 2.4 %, respectively; P = 0.0042, log-rank test). Initial AREDS score correlated significantly with progression of the fellow eye to advanced stage in the typical AMD group, after adjusting for age, gender, and other comorbidities (hazard ratio [HR], 9.5; 95% confidence interval [CI], 2.80-32.12; P = 0.0003). However in the PCV group, initial AREDS score did not correlate with progression to advanced stage in the fellow eye (HR, 1.84; 95% CI, 0.83-4.05; P = 0.13). CONCLUSIONS: Unlike typical AMD, PCV progresses without typical features such as drusen or pigmentary abnormality. Baseline AREDS score was less likely to predict progression of the fellow eye to advanced-stage disease in PCV compared with typical AMD. Therefore, the globally recognized risk-scoring AREDS system may not be applicable in Asia, where PCV is a prevalent subtype of AMD.
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MIRAgel (MIRA, Waltham, MA) is a hydrogel buckle that was introduced in 1979 as a new scleral implant for the treatment of retinal detachment. Long-term follow-up of more than 10 years revealed that the hydrolysis of the synthetic hydrophilic material leads to marked expansion of the substance, causing complications such as buckle extrusion and intrusion, eye motility disorder, cosmetic deformities, and periocular infections. Removal of the implant is the treatment of choice in cases with complications, but it is technically difficult due to the friability of the implant, severe scleral ectasia, and relatively high rate of redetachment after removal.
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Poli-Hidroxietil Metacrilato/análogos & derivados , Complicações Pós-Operatórias , Próteses e Implantes/efeitos adversos , Implantação de Prótese/efeitos adversos , Descolamento Retiniano/cirurgia , Recurvamento da Esclera/efeitos adversos , Humanos , Poli-Hidroxietil Metacrilato/efeitos adversos , Recurvamento da Esclera/métodosRESUMO
A 79-year-old man underwent excision of an upper eyelid mass that had been enlarging for 3 months. Histopathologic evaluation demonstrated a cyst lined by pseudostratified columnar epithelium with myriad goblet cells and cilia, and immunostaining revealed cytokeratins indicative of a respiratory origin. This rare condition, the first described exclusively in an eyelid, arises either from a congenital embryologic respiratory epithelial ectopia or the displacement of mature sinus mucosa following trauma or chronic sinus disease. The current case lacked any signs or symptoms of sinus disease or a history of trauma.
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Coristoma/diagnóstico , Cisto Epidérmico , Doenças Palpebrais/diagnóstico , Mucosa Respiratória , Idoso , Biomarcadores/metabolismo , Coristoma/metabolismo , Coristoma/cirurgia , Doenças Palpebrais/metabolismo , Doenças Palpebrais/cirurgia , Humanos , Queratina-17/metabolismo , Queratina-18/metabolismo , Queratina-7/metabolismo , MasculinoAssuntos
Anticorpos Antiprotozoários/sangue , Imunoglobulina G/sangue , Toxoplasma/imunologia , Toxoplasmose Ocular/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Coriorretinite/diagnóstico , Coriorretinite/imunologia , Coriorretinite/parasitologia , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Toxoplasmose Ocular/imunologia , Toxoplasmose Ocular/parasitologia , Uveíte/diagnóstico , Uveíte/imunologia , Uveíte/parasitologia , Adulto JovemRESUMO
PURPOSE: To report a case of caruncular dacryops in a 58-year-old man that was excised in its entirety and to offer an immunohistopathologic analysis. METHODS: Sections stained with hematoxylin and eosin, periodic acid-Schiff, and Grocott methenamine silver (the latter 2 for identification of mucus) were evaluated, and immunohistochemical investigations were performed using cytokeratin (CK) 7, CK14, CK17, and smooth muscle actin. RESULTS: Histopathologic examination revealed a cystic dilation of the lacrimal gland ducts containing secretory globules. The ducts were composed of double-layered cuboidal epithelium with rare scattered goblet cells and interspersed prominent lobules of lacrimal gland tissue, diagnostic of dacryops. Immunohistochemistry of cystic ducts demonstrated a CK profile identical to that of the conjunctiva including the absence of a myoepithelium. CONCLUSIONS: This is the first case of an intact caruncular lacrimal ductal cyst (dacryops). A previous report documented a spontaneously collapsed cyst with extrusion of secretory globoid bodies into extracellular space that elicited a foreign body giant cell response.
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Cistos/patologia , Doenças do Aparelho Lacrimal/patologia , Actinas/metabolismo , Túnica Conjuntiva , Cistos/metabolismo , Cistos/cirurgia , Células Caliciformes/patologia , Humanos , Imuno-Histoquímica , Queratinas/metabolismo , Doenças do Aparelho Lacrimal/metabolismo , Doenças do Aparelho Lacrimal/cirurgia , Masculino , Pessoa de Meia-Idade , Coloração e Rotulagem/métodosRESUMO
Retinitis pigmentosa comprises a group of inherited retinal photoreceptor degenerations that lead to progressive loss of vision. Although in most cases rods, but not cones, harbor the deleterious gene mutations, cones do die in this disease, usually after the main phase of rod cell loss. Rod photoreceptor death is characterized by apoptotic features. In contrast, the mechanisms and features of subsequent nonautonomous cone cell death remain largely unknown. In this study, we show that receptor-interacting protein (RIP) kinase mediates necrotic cone cell death in rd10 mice, a mouse model of retinitis pigmentosa caused by a mutation in a rod-specific gene. The expression of RIP3, a key regulator of programmed necrosis, was elevated in rd10 mouse retinas in the phase of cone but not rod degeneration. Although rd10 mice lacking Rip3 developed comparable rod degeneration to control rd10 mice, they displayed a significant preservation of cone cells. Ultrastructural analysis of rd10 mouse retinas revealed that a substantial fraction of dying cones exhibited necrotic morphology, which was rescued by Rip3 deficiency. Additionally, pharmacologic treatment with a RIP kinase inhibitor attenuated histological and functional deficits of cones in rd10 mice. Thus, necrotic mechanisms involving RIP kinase are crucial in cone cell death in inherited retinal degeneration, suggesting the RIP kinase pathway as a potential target to protect cone-mediated central and peripheral vision loss in patients with retinitis pigementosa.
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Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Retina/ultraestrutura , Células Fotorreceptoras Retinianas Cones/enzimologia , Retinose Pigmentar/patologia , Análise de Variância , Animais , Western Blotting , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Primers do DNA/genética , Eletrorretinografia , Ensaio de Imunoadsorção Enzimática , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microscopia Eletrônica de Transmissão , Necrose , Reação em Cadeia da Polimerase em Tempo Real , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Células Fotorreceptoras Retinianas Cones/patologia , Retinose Pigmentar/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não ParamétricasRESUMO
BACKGROUND: Visual loss in glaucoma is associated with pathological changes in retinal ganglion cell (RGC) axons and a slow decline in the RGC population. Age and elevated intraocular pressure (IOP) are the main risk factors for glaucomatous loss of vision. Several studies have implicated the proinflammatory cytokine tumor necrosis factor-α (TNF-α) as a link between elevated IOP and RGC death, but the cellular source of TNF-α and its causative role in RGC death remain uncertain. Here, using a rat model of glaucoma, we investigated the source of elevated TNF-α and examined whether Etanercept, a TNF-α blocker that is in common clinical use for other indications, is protective against RGC death. METHODOLOGY/PRINCIPAL FINDINGS: Episcleral vein cauterization (EVC) caused intraocular pressure (IOP) to be elevated for at least 28 days. IOP elevation resulted in a dramatic increase in TNF-α levels within a few days, axonal degeneration, and a 38% loss of RGCs by 4 weeks. Immunostaining coupled with confocal microscopy showed that OHT induced robust induction of TNF-α in Iba-1-positive microglia around the optic nerve head (ONH). Despite persistent elevation of IOP, Etanercept reduced microglial activation, TNF-α levels, axon degeneration in the optic nerve, and the loss of RGCs. CONCLUSIONS/SIGNIFICANCE: Ocular hypertension (OHT) triggers an inflammatory response characterized by the appearance of activated microglia around the ONH that express TNF-α. Blocking TNF-α activity with a clinically approved agent inhibits this microglial response and prevents axonal degeneration and loss of RGCs. These findings suggest a new treatment strategy for glaucoma using TNF-α antagonists or suppressors of inflammation.
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Glaucoma/patologia , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Células Ganglionares da Retina/patologia , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular , Modelos Animais de Doenças , Etanercepte , Glaucoma/tratamento farmacológico , Pressão Intraocular , Masculino , Hipertensão Ocular/fisiopatologia , Ratos , Células Ganglionares da Retina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
BACKGROUND: Detachment of photoreceptors from the underlying retinal pigment epithelium is seen in various retinal disorders such as retinal detachment and age-related macular degeneration and leads to loss of photoreceptors and vision. Pharmacologic inhibition of photoreceptor cell death may prevent this outcome. This study tests whether systemic administration of tauroursodeoxycholic acid (TUDCA) can protect photoreceptors from cell death after experimental retinal detachment in rodents. METHODOLOGY/PRINCIPAL FINDINGS: Retinal detachment was created in rats by subretinal injection of hyaluronic acid. The animals were treated daily with vehicle or TUDCA (500 mg/kg). TUNEL staining was used to evaluate cell death. Photoreceptor loss was evaluated by measuring the relative thickness of the outer nuclear layer (ONL). Macrophage recruitment, oxidative stress, cytokine levels, and caspase levels were also quantified. Three days after detachment, TUDCA decreased the number of TUNEL-positive cells compared to vehicle (651±68/mm(2) vs. 1314±68/mm(2), Pâ=â0.001) and prevented the reduction of ONL thickness ratio (0.84±0.03 vs. 0.65±0.03, Pâ=â0.002). Similar results were obtained after 5 days of retinal detachment. Macrophage recruitment and expression levels of TNF-a and MCP-1 after retinal detachment were not affected by TUDCA treatment, whereas increases in activity of caspases 3 and 9 as well as carbonyl-protein adducts were almost completely inhibited by TUDCA treatment. CONCLUSIONS/SIGNIFICANCE: Systemic administration of TUDCA preserved photoreceptors after retinal detachment, and was associated with decreased oxidative stress and caspase activity. TUDCA may be used as a novel therapeutic agent for preventing vision loss in diseases that are characterized by photoreceptor detachment.