RESUMO
There are several reports in the literature on the association between non-arteritic retinal artery occlusion (NA-RAO) and acute ischemic stroke. We investigated the burden of small vessel disease (SVD) and cerebral coincident infarction observed on cerebral magnetic resonance imaging (MRI) in patients with newly diagnosed NA-RAO. In this retrospective, observational, case-series study, consecutive patients with NA-RAO who underwent cerebral MRI within one month of diagnosis between September 2003 and October 2018 were included. The classification of NA-RAO was based on ophthalmologic and systemic examinations. We also investigated the co-incident infarction and burden of underlying SVD, which were categorized as white matter hyperintensity lesion (WMH), cerebral microbleeds (CMB), and silent lacunar infarction (SLI). Among the 272 patients enrolled in the study, 18% presented co-incident infarction and 73% had SVD, which included WMH (70%), CMB (14%), and SLI (30%). Co-incident infarction, WMH, and SLI significantly increased with age: co-incident infarction was observed in 8% of young (< 50 years) patients and 30% of old (≥ 70 years) patients. The embolic etiology of RAO (large artery atherosclerosis, cardioembolism, and undetermined etiology) was significantly associated with the prevalence of SVD (82%: 70%: 64%, P = 0.002) and co-incident infarction (30%: 19%: 8%; P = 0.009). Therefore, high co-incidence of acute cerebral infarction and underlying SVD burden warrant careful neurologic examination and appropriate brain imaging, followed by management of NA-RAO. Urgent brain imaging is particularly pertinent in elderly patients with NA-RAO.
Assuntos
Doenças de Pequenos Vasos Cerebrais/patologia , Oclusão da Artéria Retiniana/diagnóstico por imagem , Idoso , Aterosclerose/patologia , Encéfalo/patologia , Isquemia Encefálica/patologia , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/patologia , Infarto Cerebral/patologia , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Feminino , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Oclusão da Artéria Retiniana/metabolismo , Oclusão da Artéria Retiniana/patologia , Estudos Retrospectivos , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral Lacunar/diagnóstico por imagem , Acidente Vascular Cerebral Lacunar/patologia , Substância Branca/patologiaRESUMO
PURPOSE: Nonperfusion of retinal tissue due to arterial occlusion leads inevitably to mostly irreversible retinal damage. Until today no evidence-based treatment exists. Inhalation of 100% oxygen at high atmospheric pressure causes an increased solubility of oxygen in the blood that helps the retinal tissue to survive through diffusion in case of an artery occlusion till vascular recanalization occurs. Hence the purpose of this study is to compare the visual outcome in patients with retinal branch artery obstruction treated with hyperbaric oxygen versus patients treated with hemodilution only. METHODS: Non-randomized, monocentric, retrospective study. Patients with diagnosis of non-arteritic retinal branch artery occlusion (BRAO) treated with hyperbaric oxygen therapy between 1997 and 2017. Exclusion criteria were central retinal artery occlusion, presence of a cilioretinal artery and arteritic cases. The control group was matched based on visual acuity (VA) at admission, age, and delay between symptoms and beginning of clinical care. RESULTS: The control group and the matching oxygen group contained 14 patients each. Initial VA in the matched HBO group was 0.18 ± 0.19 and 0.23 ± 0.19 in the control group (p = 0.57). Final VA at discharge was 0.69 ± 0.29 in the matched oxygen group and 0.32 ± 0.23 in the control group (p = 0.0009). HBO-treated patients had a significant visual increase compared with the control group. The most common comorbidities were arterial hypertension and vascular sclerosis. CONCLUSION: HBO treatment appears to have a beneficial effect on visual outcome in patients with retinal branch artery occlusion. HBO treatment could be a rescue therapy at an early stage of BRAO, especially to bridge the time of a potential reperfusion. However, further, prospective, randomized clinical trials are required to verify this assumption.
Assuntos
Artérias Ciliares/patologia , Oxigenoterapia Hiperbárica/métodos , Retina/patologia , Oclusão da Artéria Retiniana/terapia , Acuidade Visual , Idoso , Feminino , Angiofluoresceinografia/métodos , Seguimentos , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Oxigênio/metabolismo , Oclusão da Artéria Retiniana/diagnóstico , Oclusão da Artéria Retiniana/metabolismo , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Resultado do TratamentoRESUMO
Retinal artery occlusion (RAO) is a sight threatening complication of cardiovascular disease and commonly occurs due to underlying atherosclerosis. As cardiovascular disease and atherosclerosis in particular has been associated with compositional alterations in the gut microbiome, we investigated this association in patients with clinically confirmed non-arteritic RAO compared to age- and sex-matched controls. On the phylum level, the relative abundance of Bacteroidetes was decreased in patients with RAO compared to controls, whereas the opposite applied for the phylum of Proteobacteria. Several genera and species such as Actinobacter, Bifidobacterium spp., Bacteroides stercoris, Faecalibacterium prausnitzii were relatively enriched in patients with RAO, whereas others such as Odoribacter, Parasutterella or Lachnospiraceae were significantly lower. Patient's gut microbiomes were enriched in genes of the cholesterol metabolism pathway. The gut derived, pro-atherogenic metabolite trimethylamine-N-oxide (TMAO) was significantly higher in patients with RAO compared to controls (p = 0.023) and a negative correlation between relative abundances of genera Parasutterella and Lachnospiraceae and TMAO levels and a positive correlation between relative abundance of genus Akkermansia and TMAO levels was found in study subjects. Our findings proposes that RAO is associated with alterations in the gut microbiome and with elevated TMAO levels, suggesting that RAO could be targeted by microbiome-altering interventions.
Assuntos
Aterosclerose/metabolismo , Microbioma Gastrointestinal , Metilaminas/metabolismo , Oclusão da Artéria Retiniana/metabolismo , Oclusão da Artéria Retiniana/microbiologia , Actinobacteria/isolamento & purificação , Idoso , Bacteroides/isolamento & purificação , Bifidobacterium/isolamento & purificação , Faecalibacterium/isolamento & purificação , Feminino , Angiofluoresceinografia/métodos , Humanos , Masculino , Oclusão da Artéria Retiniana/diagnóstico , Fatores de Risco , Tomografia de Coerência Óptica/métodosRESUMO
BACKGROUND: Waardenburg syndrome (WS) is a very rare genetic disorder affecting the neural crest cells. Coexistence of branch retinal vein occlusion (BRVO) and branch retinal artery occlusion (BRAO) in the same eye is also a rare finding. Here we report a case of WS type 1 that was confirmed by a novel mutation with the finding of unilateral BRVO and BRAO. CASE PRESENTATION: A 36-year-old, white-haired Korean man presented with a complaint of loss of vision in the inferior visual field of his right eye and hearing loss. He had telecanthus with a medial eyebrow and a hypochromic left iris. Funduscopy showed an ischemic change at the posterior pole in the right eye with sparing of the foveal center as well as retinal hemorrhages and white patches along the superotemporal arcade. Fundus angiography revealed the presence of both BRVO and BRAO, and optical coherence tomography showed thickening and opacification of the retinal layers corresponding to the ischemic area. A blood workup revealed hyperhomocysteinemia and the presence of antiphospholipid antibodies; both are suggestive as the cause of the BRVO and BRAO. Single nucleotide polymorphism analysis confirmed a novel PAX3 mutation at 2q35 (c.91-95 ACTCC deletion causing a frameshift). These findings confirmed a diagnosis of WS type 1. CONCLUSIONS: WS is a heterogeneous inherited disorder of the neural crest cells that causes pigment abnormalities and sensorineural hearing loss. This is the first report of unilateral BRVO and BRAO in a patient with WS. Furthermore, the PAX3 mutation identified in this patient has not been reported previously.
Assuntos
DNA/genética , Mutação , Fator de Transcrição PAX3/genética , Oclusão da Artéria Retiniana/genética , Oclusão da Veia Retiniana/genética , Síndrome de Waardenburg/genética , Adulto , Análise Mutacional de DNA , Angiofluoresceinografia , Fundo de Olho , Humanos , Masculino , Fator de Transcrição PAX3/metabolismo , Linhagem , República da Coreia , Oclusão da Artéria Retiniana/diagnóstico , Oclusão da Artéria Retiniana/metabolismo , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/metabolismo , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Síndrome de Waardenburg/diagnósticoRESUMO
Few studies have reported the relationship between retinal artery occlusion (RAO) and plasma homocysteine (Hcy) levels. Our goal was to evaluate the association between the plasma Hcy level and the risk of RAO disease. Several databases were searched for all published studies that involved Hcy and RAO. Six studies evaluated hyperhomocysteinemia (hHcy) in retinal artery occlusion patients and controls; the incidence of hHcy in patients with RAO was higher than the control and the pooled odds ratio (OR) was 6.64 (95% confidence interval (CI): 3.42, 12.89). Subgroup analyses showed that the ORs were 4.77 (95% CI: 2.69, 8.46) in Western countries, 22.19 (95% CI: 2.46, 200.37) in Asian countries, 9.70 (95% CI: 4.43, 21.20) in the age matched group, 11.41 (95% CI: 3.32, 39.18) in the sex matched group, 9.70 (95% CI: 4.37, 21.53) in the healthy control group, and 6.82 (95% CI: 4.19, 11.10) in the sample size >30. The mean plasma Hcy level from 5 case-control studies was higher than controls, and the weighted mean difference (WMD) was 6.54 (95% CI: 2.79, 10.29). Retinal artery occlusion is associated with elevated plasma Hcy levels. Our study results suggest that hHcy is probably an independent risk factor for RAO.
Assuntos
Homocisteína/metabolismo , Oclusão da Artéria Retiniana/metabolismo , Idoso , Estudos de Coortes , Feminino , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/sangue , Masculino , Pessoa de Meia-Idade , Razão de Chances , Viés de Publicação , Oclusão da Artéria Retiniana/sangue , Fatores de Risco , Sensibilidade e EspecificidadeAssuntos
Angiopoietina-2/biossíntese , Proteína 4 Semelhante a Angiopoietina/metabolismo , Bevacizumab/administração & dosagem , Eritropoetina/biossíntese , Oclusão da Artéria Retiniana/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Corpo Vítreo/metabolismo , Inibidores da Angiogênese/administração & dosagem , Biomarcadores/metabolismo , Ensaio de Imunoadsorção Enzimática , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Artéria Retiniana/patologia , Oclusão da Artéria Retiniana/diagnóstico , Oclusão da Artéria Retiniana/fisiopatologia , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade VisualRESUMO
Retinal artery occlusion (RAO), retinal vein occlusion (RVO), diabetic retinopathy (DR) and age-related macular degeneration (AMD) are frequent ocular diseases with potentially sight-threatening outcomes. In the present review we discuss major findings of proteomic studies of RAO, RVO, DR and AMD, including an overview of ocular proteome changes associated with anti-vascular endothelial growth factor (VEGF) treatments. Despite the severe outcomes of RAO, the proteome of the disease remains largely unstudied. There is also limited knowledge about the proteome of RVO, but proteomic studies suggest that RVO is associated with remodeling of the extracellular matrix and adhesion processes. Proteomic studies of DR have resulted in the identification of potential therapeutic targets such as carbonic anhydrase-I. Proliferative diabetic retinopathy is the most intensively studied stage of DR. Proteomic studies have established VEGF, pigment epithelium-derived factor (PEDF) and complement components as key factors associated with AMD. The aim of this review is to highlight the major milestones in proteomics in RAO, RVO, DR and AMD. Through large-scale protein analyses, proteomics is bringing new important insights into these complex pathological conditions.
Assuntos
Retinopatia Diabética/patologia , Degeneração Macular/patologia , Proteoma/análise , Proteômica , Oclusão da Artéria Retiniana/patologia , Oclusão da Veia Retiniana/patologia , Anticorpos/imunologia , Anticorpos/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Proteínas do Olho/metabolismo , Humanos , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Fatores de Crescimento Neural/metabolismo , Oclusão da Artéria Retiniana/tratamento farmacológico , Oclusão da Artéria Retiniana/metabolismo , Oclusão da Veia Retiniana/tratamento farmacológico , Oclusão da Veia Retiniana/metabolismo , Serpinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
In the initial stage of retinopathy of prematurity (ROP), hyperoxia causes retinal blood vessel obliteration. This is thought to occur in part through oxidative stress-induced apoptosis of endothelial cells. This study was designed to determine what role NF-E2-related factor 2 (Nrf2) plays in this process. Nrf2 is a transcription factor of the anti-oxidant response element that, if induced, may protect the retina from hyperoxia-induced oxidative stress. Nrf2 knockout mice (Nrf2-/-), Nrf2 wild type control mice (Nrf2+/+), and C57BL/6 mice were exposed to hyperoxia (75% O(2)) or normoxia from P7 through P12. Mice were sacrificed on P9 and P12 and the retinas were stained with GSA lectin-Cy3 to visualize retinal blood vessels. Hyperoxia exposed retinas were flat mounted and photographed, then the size of the avascular areas was determined. Additionally, retinas were cryopreserved after lectin staining and area analysis and then sectioned. Secondary or deep capillaries were then hand-counted in sections. In hyperoxia-treated mice, the avascular areas in Nrf2-/- P9 mice were significantly larger than those in Nrf2+/+ P9 mice (P = 0.01). However, there was no significant difference between Nrf2-/- and Nrf2+/+ mice at P12. Avascular areas at P12 were significantly smaller than that at P9 in Nrf2-/-, Nrf2+/+, and C57BL/6 mice (P = 0.0011, P = 0.009, and P = 0.001 respectively). The numbers of deep or secondary capillaries in air-reared Nrf2-/- mice were significantly decreased, when compared to Nrf2+/+ mice at P9 (P = 0.0082). On the other hand, there was no significant difference in deep capillary formation between air-reared Nrf2-/- and Nrf2+/+ mice at P12. Akt signaling activates Nrf2 and Akt was localized to retinal blood vessels in all animals and was increased in Nrf2+/+ and Nrf2-/- mice exposed to hyperoxia as compared to normoxia mice. Interestingly, during normal development this protection by Nrf2 occurs in a specific window of time that is also shared by angiogenesis. Hyperoxia treatment revealed a similar window of time where Nrf2 regulated anti-oxidant production was beneficial and contributed to the endothelial survival.
Assuntos
Fator 2 Relacionado a NF-E2/fisiologia , Oxigênio/toxicidade , Oclusão da Artéria Retiniana/metabolismo , Oclusão da Veia Retiniana/metabolismo , Vasos Retinianos/crescimento & desenvolvimento , Retinopatia da Prematuridade/metabolismo , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Hiperóxia/metabolismo , Recém-Nascido , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Espécies Reativas de Oxigênio , Retinopatia da Prematuridade/etiologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
PURPOSE: To analyze cytokines in the retina and serum in an experimental model of central retinal artery occlusion (CRAO) in mice. METHODS: CRAO was induced by laser activation of intravenously injected rose bengal, a photosensitive dye, in 60 C57Bl/6 mice. mRNA and protein levels of macrophage inhibitory protein-2 (MIP-2), interleukin-6 (IL-6), and tumor necrosis factor- alpha (TNF-alpha) were analyzed using real-time polymerase chain reaction, and western blot, respectively. Cytokine levels in serum were measured by ELISA. Analysis was performed at various time intervals from CRAO induction. RESULTS: In the retina, MIP-2 and IL-6 mRNA expression decreased 3 h after induction of CRAO and increased thereafter, peaking at 12-24 h. By 7 days, levels were again mostly undetectable. TNF-alpha mRNA expression increased at 3 h and decreased to control levels at 7 days. At the protein level, all cytokines were present at 3 h, following similar patterns to their respective gene expression thereafter. In serum, MIP-2 and TNF-alpha levels peaked early, and decreased to control levels at 12 h, with a second late rise of TNF-alpha. IL-6 levels increased between 3 and 12 h and decreased at 24 h. CONCLUSIONS: Temporal variations in cytokines were observed following the induction of CRAO, both at the retinal mRNA expression and protein levels. These temporal changes, and the variable effects of the cytokines at the different time intervals, should be taken into account during the formulation of therapeutic strategies.
Assuntos
Citocinas/análise , Retina/química , Oclusão da Artéria Retiniana/metabolismo , Animais , Quimiocina CXCL2/análise , Quimiocina CXCL2/sangue , Quimiocina CXCL2/genética , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Interleucina-6/análise , Interleucina-6/sangue , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Mensageiro/sangue , RNA Mensageiro/genética , Oclusão da Artéria Retiniana/induzido quimicamente , Oclusão da Artéria Retiniana/veterinária , Rosa Bengala , Estatísticas não Paramétricas , Fatores de Tempo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genéticaRESUMO
PURPOSE: Fundus autofluorescence (FAF) affects the overlying absorptive retinal pigments within the eye and can potentially be used to assess their density. This study reports a clinical application of FAF in measuring photopigments by scanning laser ophthalmoscopy (SLO). METHODS: The study group comprised 20 healthy subjects, 4 patients with branch retinal artery occlusion (BRAO), 3 with macular hole, 3 with branch retinal vein occlusion (BRVO), and 4 with resolved central serous chorioretinopathy (CSC). Serial FAF images were taken during exposure to light. The intensity of the FAF was measured at the site of the macular hole or the photocoagulation laser burn in the eyes with BRVO. The autofluorescence optical density difference (fODD) was measured from the FAF images and mapped to elucidate the topographic pattern. RESULTS: The autofluorescence intensity showed little change at the sites of the macular holes or photocoagulation burns during exposure to light. The fODD was smallest at the center of the fovea and gradually increased with the eccentricity within 270 x 270 pixels around the fovea in healthy subjects. The amplitude of the fODD did not change in the area affected with BRAO in comparison to the unaffected area. By contrast, the fODD decreased in the area of resolved serous retinal detachment in the eyes with CSC. CONCLUSIONS: In eyes with retinal disease, measuring the autofluorescence intensity using SLO is a feasible method of assessing the changes in the photopigments. Further studies comparing this approach with conventional methods for examining photopigments are needed.
Assuntos
Densitometria , Fluorescência , Lipofuscina/metabolismo , Oftalmoscópios , Doenças Retinianas/metabolismo , Pigmentos da Retina/metabolismo , Adulto , Idoso , Coriorretinite/metabolismo , Feminino , Humanos , Lasers , Masculino , Pessoa de Meia-Idade , Oclusão da Artéria Retiniana/metabolismo , Doenças Retinianas/diagnóstico , Doenças Retinianas/fisiopatologia , Perfurações Retinianas/metabolismo , Oclusão da Veia Retiniana/metabolismoRESUMO
The aim of this study was to characterize the molecular and histological changes that occur in the retina following central retinal artery occlusion (CRAO) in a mouse model. CRAO was induced in 60 mice by laser photoactivation of intravenously injected rose bengal. Mice were sacrificed at 3, 6, 12, and 24h and 7 and 21 days after CRAO induction for molecular analysis (5-13 mice/time point) and histological and apoptosis studies (3-4 mice/time point). Fundus examination and fluorescein angiography were also performed at various points. Retinal mRNA was analyzed for expression of T-cell antigen 1 (Thy-1), vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1), and hypoxia-induced factor 1 alpha (HIF-1 alpha) using real-time polymerase chain reaction. The results showed that at 6-24h following CRAO induction, the retina was edematous, with interrupted blood perfusion. Fluorescein angiography showed reperfusion at 6h, and TdT-mediated dUTP nick end-labeling (TUNEL) assay revealed an increase in apoptotic cells in the first 24h. On histological sections, nuclear loss in the inner retinal layers was maximal on day 21. Thy-1 expression decreased to 30% of baseline (PAssuntos
Oclusão da Artéria Retiniana/patologia
, Animais
, Apoptose
, Modelos Animais de Doenças
, Angiofluoresceinografia
, Regulação da Expressão Gênica
, Heme Oxigenase-1/biossíntese
, Heme Oxigenase-1/genética
, Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese
, Subunidade alfa do Fator 1 Induzível por Hipóxia/genética
, Marcação In Situ das Extremidades Cortadas/métodos
, Masculino
, Camundongos
, Camundongos Endogâmicos C57BL
, RNA Mensageiro/genética
, Retina/metabolismo
, Retina/patologia
, Oclusão da Artéria Retiniana/etiologia
, Oclusão da Artéria Retiniana/metabolismo
, Antígenos Thy-1/biossíntese
, Antígenos Thy-1/genética
, Fator A de Crescimento do Endotélio Vascular/biossíntese
, Fator A de Crescimento do Endotélio Vascular/genética
RESUMO
PURPOSE: To determine intraretinal oxygen distribution and consumption in a rat model of retinal artery occlusion during air breathing and stepwise systemic hyperoxia. METHODS: Laser occlusion of the pair of retinal arteries feeding the area of retina under investigation was performed. Oxygen-sensitive microelectrodes were then used to measure oxygen tension as a function of depth through the retina. Breathing mixtures were manipulated to produce stepwise increments in systemic oxygen levels, and the measurement of intraretinal oxygen distribution was repeated. Oxygen distribution in the retina was analyzed by an established eight-layer mathematical model of retinal oxygen consumption. RESULTS: Intraretinal oxygen distribution in the occluded area confirmed that the choroid was the only source of retinal oxygenation. Under air-breathing conditions, the oxygen supply from the choroid was sufficient to support the photoreceptor inner segments. Any remaining oxygen was consumed by the outer plexiform layer. Increases in inspired oxygen level reduced the extent of inner retinal anoxia. However, some degree of anoxia in the innermost retina was usually present. CONCLUSIONS: Occlusion of the retinal circulation renders most of the inner retina anoxic. Ventilation with 100% oxygen does not generally avoid some degree of intraretinal anoxia. With 100% oxygen ventilation, the oxygen consumption of the inner retina was more than four times that of the outer retina. A marked degree of heterogeneity in oxygen uptake of different retinal layers was evident. The dominant oxygen consumers were the inner segments of the photoreceptors, the outer plexiform layer, and the inner plexiform layer.
Assuntos
Hiperóxia/metabolismo , Consumo de Oxigênio , Oxigênio/metabolismo , Retina/metabolismo , Oclusão da Artéria Retiniana/metabolismo , Animais , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Técnicas Imunoenzimáticas , Eletrodos Seletivos de Íons , Masculino , Modelos Animais , Ventilação Pulmonar/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: We analyzed the levels of glutamate and other amino acids in aqueous humor of patients with retinal artery occlusion (RAO) to determine whether glutamate is associated with retinal ischemia in RAO. METHODS: Aqueous humor samples were obtained from nine RAO patients by paracentesis performed as an emergent therapeutic intervention and from nine cataract patients without other ocular disease who served as controls. Aspartic acid, glutamate, taurine, and alanine concentrations were determined using high-performance liquid chromatography. RESULTS: The glutamate level in aqueous humor of patients with RAO (4.46 +/- 1.62 micromol/L) was significantly higher than that in controls (2.98 +/- 1.12 micromol/L) (P < 0.05). CONCLUSIONS: Elevated glutamate levels in aqueous humor may indicate diffusion of vitreous glutamate released from the damaged retina due to acute retinal ischemia in RAO. An increase in the extracellular glutamate level may play an important role in ischemic retinal damage in RAO.
Assuntos
Humor Aquoso/metabolismo , Ácido Glutâmico/metabolismo , Oclusão da Artéria Retiniana/metabolismo , Idoso , Idoso de 80 Anos ou mais , Alanina/metabolismo , Ácido Aspártico/metabolismo , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Taurina/metabolismoRESUMO
PURPOSE: To investigate the role of inflammation in acute retinal artery occlusion (RAO). METHODS: Levels of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) were measured in serum (n = 14) and aqueous humor (AqH) (n = 8) samples from patients with RAO. Findings were compared with 24 age- and disease-matched patients, 10 healthy subjects (serum), and 16 patients undergoing cataract surgery (AqH). RESULTS: Patients who arrived early (within 4-6 hours of occlusion) had higher serum IL-8 and IL-6 levels than controls; the IL-6 level in the AqH was lower than that of controls, while the IL-8 level was higher. In seven patients for whom both serum and AqH samples were available, serum IL-6 levels were higher than their corresponding AqH levels in most patients arriving within 10 hours of occlusion, and AqH IL-8 levels were higher than the corresponding serum levels in all but one. TNF-alpha levels were consistently higher in the serum than in the AqH at all time points. CONCLUSIONS: Serum IL-8 and IL-6 and AqH IL-8 are elevated immediately following acute RAO. The early local suppression of IL-6 may be related to ocular immune mechanisms.
Assuntos
Humor Aquoso/metabolismo , Interleucina-6/sangue , Interleucina-8/sangue , Oclusão da Artéria Retiniana/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Apoptosis is known to play a role in cell death in transient retinal ischemia. Little is known about the specific molecular pathways involved. The purpose of the current study was to evaluate a rat model of central retinal artery occlusion (CRAO) that simulates the clinical features of CRAO in humans and to elucidate whether the mitochondrial apoptotic pathway is involved. METHODS: CRAO was induced in the central retinal artery by intravenous injection of rose bengal and green laser irradiation of the artery. CRAO was documented at 1, 3, 6, and 24 hours after laser irradiation. Changes in Bax (proapoptotic Bcl-2-associated X protein), cytochrome c, and caspase-9 cleavage in the cytosolic and mitochondrial fractions of neural retinal tissues were measured by Western blot analysis. Apoptosis within the retina was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). RESULTS: Complete CRAO was induced; however, occlusion became incomplete with spontaneous reperfusion of branch arteries, starting at 3 hours after laser irradiation. Only one or two branch arteries remained occluded at the 24-hour time point. Time-dependent, apoptotic changes were observed in inner and outer retinal cell layers. Western blot analysis revealed mitochondrial translocation of Bax from the cytoplasm, starting at 3 hours and peaking at 6 hours after laser irradiation. This translocation was accompanied by cytosolic accumulation of cytochrome c and cleavage of caspase-9. CONCLUSIONS: This model is highly relevant to clinical manifestations of CRAO and is an ideal animal model for research. These findings indicate the activation of the mitochondrial pathway in ischemic retina induced by CRAO. The model provides a better understanding of ischemia-induced retinal apoptosis. Antiapoptosis therapy directly targeting the mitochondrial pathway in CRAO or other retinal ischemic diseases may be beneficial.
Assuntos
Apoptose , Mitocôndrias/metabolismo , Oclusão da Artéria Retiniana/metabolismo , Células Amácrinas/patologia , Animais , Western Blotting , Caspase 9 , Caspases/metabolismo , Citocromos c/metabolismo , Citosol/metabolismo , Modelos Animais de Doenças , Marcação In Situ das Extremidades Cortadas , Masculino , Transporte Proteico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Oclusão da Artéria Retiniana/patologia , Células Ganglionares da Retina/patologia , Fatores de Tempo , Proteína X Associada a bcl-2Assuntos
Glaucoma/fisiopatologia , Ácido Glutâmico/fisiologia , Animais , Glaucoma/patologia , Ácido Glutâmico/análise , Ácido Glutâmico/toxicidade , Haplorrinos , Humanos , Camundongos , Receptores de N-Metil-D-Aspartato/metabolismo , Oclusão da Artéria Retiniana/metabolismo , Células Ganglionares da Retina/patologiaRESUMO
PURPOSE: Vitreous and retinal amino-acid concentrations were evaluated in a primate model of central retinal artery occlusion (CRAO) to study the role of glutamate excitotoxicity in acute retinal ischaemia. METHODS: Unilateral, acute CRAO was produced by temporary clamping of the central retinal artery for 190 min in four elderly rhesus monkeys. Fundus photography, fluorescein angiography, and electroretinogram were performed before and during CRAO, and after unclamping the artery. Vitreous samples were obtained before and after CRAO in both eyes, and analysed for 13 amino-acid concentrations using high-pressure liquid chromatography. The animals were killed 350 min after retinal reperfusion, and the retinal tissue was submitted for amino-acid analysis. RESULTS: In all four eyes, the macula showed the 'cherry red spot'. The CRAO was confirmed by fluorescein angiography and decreased b-wave on electroretinogram. Retinal histology confirmed ischaemic changes in the inner retina. Changes in all 13 vitreous amino-acid concentrations after CRAO (including glutamate) were not significantly different between study and control eyes (P = 0.09 to 0.82). All retinal amino-acid concentrations (including glutamate) were not significantly different between two eyes (P = 0.07-0.93). CONCLUSIONS: In the primate model of acute inner retinal ischaemia induced by transient CRAO, we were unable to detect significantly elevated concentrations of vitreous and retinal glutamate. Our primate model has the advantage of closely modelling the CRAO in humans. Further basic and clinical studies are needed to elucidate the role of glutamate excitotoxicity in retinal ischaemia.
Assuntos
Aminoácidos/metabolismo , Retina/metabolismo , Oclusão da Artéria Retiniana/metabolismo , Corpo Vítreo/metabolismo , Doença Aguda , Animais , Cromatografia Líquida de Alta Pressão/métodos , Modelos Animais de Doenças , Eletrorretinografia , Angiofluoresceinografia/métodos , Fundo de Olho , Ácido Glutâmico/metabolismo , Macaca mulatta , Oclusão da Artéria Retiniana/etiologia , Manejo de Espécimes/métodosRESUMO
Cytochrome oxidase activity from the retina can be enhanced or depressed by free radical-mediated reactions both in positive and negative aspect. The greatest effect was exerted by ischemia/reperfusion, which significantly increased the fluorescent products of lipid peroxidation (358 %, P < 0.01) and inhibited the enzyme activity (14%, P < 0.001). After hyperoxia the fluorescent products slightly increased (192%, P < 0.05) as well as the enzyme activity (133 %, P < 0.05). Hypoxia had no effect on any of these parameters. Specific changes in the composition of fluorophores after ischemia/reperfusion were revealed in the fluorescence spectra. The fact that increased lipid peroxidation after hyperoxia and after ischemia/reperfusion does not produce the same effect upon cytochrome oxidase activity might be explained by changes in the kinetic behavior of cytochrome oxidase. In the control enzyme preparation, two binding sites for cytochrome c were observed. One was of the low-affinity (Km = 60 microM) and the other of the high-affinity (Km = 1.12 microM). After in vitro-initiated lipid peroxidation, the low-affinity binding site was lost and the activity measured under "optimum" conditions at a single cytochrome concentration was higher than in the controls. This implies that oxidative damage to cytochrome oxidase in vivo can be site-specific and its extent should be estimated by performing detailed kinetic analysis as otherwise the results might be misleading.
Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hiperóxia/metabolismo , Hipóxia/metabolismo , Traumatismo por Reperfusão/metabolismo , Retina/enzimologia , Animais , Soluções Tampão , Cinética , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Oxigênio/farmacologia , Fosfatos/farmacologia , Ratos , Ratos Wistar , Oclusão da Artéria Retiniana/metabolismo , Espectrometria de FluorescênciaRESUMO
OBJECTIVE: To investigate the mechanism leading to capillary nonperfusion of the retina in a monkey model of vascular endothelial growth factor A (VEGF)-induced retinopathy in which capillary closure occurs in a late stage after VEGF treatment. METHODS: Two monkeys received 4 intravitreous injections of 0.5 microg of VEGF in one eye and of phosphate-buffered saline in the other eye and were killed at day 9. After perfusion and enucleation, retinal samples were snap frozen for immunohistochemical analysis with the panendothelial cell marker CD31 or were fixed for morphometric analysis at the light and electron microscopic level. RESULTS: At the light microscopic level, all capillaries in the retina of VEGF-injected eyes displayed hypertrophic walls with narrow lumina. In a quantitative analysis of the deep capillary plexus in the inner nuclear layer, VEGF-injected eyes had a significant 5- to 7-fold decrease in total capillary luminal volume. CD31 staining showed that this decrease was not accompanied by a change in the number of capillaries. Electron microscopy revealed that the luminal volume of individual capillaries of the inner nuclear layer of VEGF-injected eyes was significantly decreased due to a 2-fold hypertrophy of the endothelial cells. CONCLUSIONS: Luminal narrowing caused by endothelial cell hypertrophy occurs in the deep retinal capillary plexus in VEGF-induced retinopathy in monkeys. This suggests a causal role of endothelial cell hypertrophy in the pathogenesis of VEGF-induced retinal capillary closure. A similar mechanism may operate in retinal conditions in humans associated with ischemia and VEGF overexpression. CLINICAL RELEVANCE: Capillary nonperfusion occurs in diabetic retinopathy and other ischemic diseases associated with overexpression of VEGF. In addition, VEGF-induced endothelial cell hypertrophy may be causative for capillary closure in these diseases.
Assuntos
Fatores de Crescimento Endotelial/farmacologia , Endotélio Vascular/patologia , Linfocinas/farmacologia , Oclusão da Artéria Retiniana/etiologia , Oclusão da Veia Retiniana/etiologia , Vasos Retinianos/efeitos dos fármacos , Animais , Capilares/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Hipertrofia , Técnicas Imunoenzimáticas , Injeções Intravenosas , Macaca fascicularis , Masculino , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Oclusão da Artéria Retiniana/metabolismo , Oclusão da Artéria Retiniana/patologia , Oclusão da Veia Retiniana/metabolismo , Oclusão da Veia Retiniana/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/ultraestrutura , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
BACKGROUND/PURPOSE: There is increasing evidence suggesting that nitric oxide (NO) is implicated in the pathogenic process of ischemic disease. The purpose of this study was to quantify the aqueous humor NO levels in patients with central retinal artery occlusion (CRAO) and in age-matched controls. METHODS: Aqueous humor specimens were obtained from seven patients who had been diagnosed with CRAO; the sampling was done within 12 to 24 hours of diagnosis. All specimens were obtained by paracentesis, which was performed as a therapeutic intervention. Samples of aqueous humor were also collected from 15 age-matched healthy patients undergoing cataract surgery, to be used as controls. For each sample, we assayed the amount of nitrite, which is the stable metabolite of NO, using the spectrophotometric method based on the Griess reaction. RESULTS: There were detectable levels of nitrite in the aqueous humor from five of seven patients with CRAO (mean level, 0.32 +/- 0.08 micromol/L). The levels in the control group were below the detection limit in all cases (<0.08 micromol/L). There was a statistically significant difference between the aqueous humor nitrite levels in the CRAO group and the controls (P = 0.0008). CONCLUSIONS: Our study shows that patients with CRAO present with elevated levels of NO in the aqueous humor. These findings may provide insight into the role that NO plays in CRAO.