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1.
Invest Ophthalmol Vis Sci ; 62(12): 28, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34581725

RESUMO

Purpose: To investigate the relationship between retinal structure and macular function in eyes screened for hydroxychloroquine (HCQ) toxicity. Methods: Participants referred for hydroxychloroquine retinopathy screening with spectral domain optical coherence tomography (SD-OCT) and multifocal electroretinogram (mfERG) testing were included in the analysis. Amplitude and implicit time of mfERG N1 and P1 responses were included in the analysis. Ring ratios were computed for amplitude values as the ratio of rings 1-3:5 (R1-3:R5). A control group of healthy participants was included for comparison of SD-OCT metrics. Results: Sixty-three eyes screened for HCQ retinopathy and 30 control eyes were analyzed. The outer nuclear layer (ONL) was significantly thinner in HCQ patients in the foveal (P = 0.008), parafoveal (P < 0.0001), and perifoveal (P < 0.0001) regions. The HCQ cohort was further divided into two subgroups according to the presence of structural clinically detectable retinopathy (i.e., structural damage as detected by multimodal imaging). HCQ eyes without retinopathy had a thinner ONL thickness in the foveal (P = 0.032), parafoveal (P < 0.0001), and perifoveal (P < 0.0001) regions and a thinner inner nuclear layer (INL) in the parafoveal region (P = 0.045 versus controls). Structural changes in HCQ patients without retinopathy were significantly associated with macular function as R2:R5 ring ratio of mfERG P1 amplitude was associated with INL (P = 0.002) and ONL (P = 0.044) thicknesses, and R3:R5 ring ratio of P1 amplitude was associated with ONL thickness (P = 0.004). Conclusions: Our results suggest that structural alterations secondary to HCQ toxicity may occur in the absence of clinically detectable retinopathy, and this may reflect in an impaired macular function.


Assuntos
Antirreumáticos/toxicidade , Hidroxicloroquina/toxicidade , Retina/fisiopatologia , Doenças Retinianas/fisiopatologia , Adulto , Idoso , Artrite Reumatoide/tratamento farmacológico , Eletrorretinografia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Retina/efeitos dos fármacos , Doenças Retinianas/induzido quimicamente , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Campos Visuais/fisiologia
2.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502350

RESUMO

Diabetic retinal disease remains one of the most common complications of diabetes mellitus (DM) and a leading cause of preventable blindness. The mainstay of management involves glycemic control, intravitreal, and laser therapy. However, intravitreal therapy commonly requires frequent hospital visits and some patients fail to achieve a significant improvement in vision. Novel and long-acting therapies targeting a range of pathways are warranted, while evidence to support optimal combinations of treatments is currently insufficient. Improved understanding of the molecular pathways involved in pathogenesis is driving the development of therapeutic agents not only targeting visible microvascular disease and metabolic derangements, but also inflammation and accelerated retinal neurodegeneration. This review summarizes the current and emerging treatments of diabetic retinal diseases and provides an insight into the future of managing this important condition.


Assuntos
Complicações do Diabetes/terapia , Retinopatia Diabética/terapia , Inibidores da Angiogênese/uso terapêutico , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/fisiopatologia , Retinopatia Diabética/tratamento farmacológico , Glucocorticoides/uso terapêutico , Controle Glicêmico/tendências , Humanos , Inflamação/tratamento farmacológico , Injeções Intravítreas , Edema Macular/terapia , Retina/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
3.
PLoS One ; 16(9): e0257148, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34492087

RESUMO

OBJECTIVES: The chick is rapidly becoming a standardized preclinical model in vision research to study mechanisms of ocular disease. We seek to comprehensively evaluate the N-methyl-D-aspartate (NMDA) model of excitotoxic retinal damage using multimodal imaging, functional, and histologic approaches in NMDA-damaged, vehicle-treated, and undamaged chicks. METHODS: Chicks were either left undamaged in both eyes or were injected with NMDA in the left eye and saline (vehicle) in the right eye. TUNEL assay was performed on chicks to assess levels of retinal cell death one day post-injection of NMDA or saline and on age-matched untreated chicks. Spectral domain optical coherence tomography (SD-OCT) was performed weekly on chicks and age-matched controls day 1 (D1) up to D28 post-injection. Light adapted electroretinograms (ERG) were performed alongside SD-OCT measurements on post-injection chicks along with age-matched untreated controls. RESULTS: Untreated and vehicle-treated eyes had no TUNEL positive cells while NMDA-treated eyes accumulated large numbers of TUNEL positive cells in the Inner Nuclear Layer (INL), but not other layers, at D1 post injection. Significant inner retina swelling or edema was found on SD-OCT imaging at D1 post-injection which resolved at subsequent timepoints. Both the INL and the inner plexiform layer significantly thinned by one-week post-injection and did not recover for the duration of the measurements. On ERG, NMDA-treated eyes had significantly reduced amplitudes of all parameters at D1 with all metrics improving over time. The b-wave, oscillatory potentials, and ON/OFF bipolar responses were the most affected with at least 70% reduction immediately after damage compared to the fellow eye control. CONCLUSION: This study establishes a normative baseline on the retinal health and gross functional ability as well as intraocular pressures of undamaged, vehicle-treated, and NMDA-damaged chicks to provide a standard for comparing therapeutic treatment studies in this important animal model.


Assuntos
Imagem Multimodal , Retina/patologia , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/diagnóstico por imagem , Animais , Galinhas , Modelos Animais de Doenças , Eletrorretinografia , Fundo de Olho , Imageamento Tridimensional , Pressão Intraocular , N-Metilaspartato , Retina/diagnóstico por imagem , Retina/fisiopatologia , Doenças Retinianas/patologia , Tomografia de Coerência Óptica
4.
Invest Ophthalmol Vis Sci ; 62(10): 20, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34410299

RESUMO

Purpose: Diabetic retinopathy results in vision loss with changes to both retinal blood vessels and neural retina. Recent studies have revealed that animal models of diabetes demonstrate early loss of visual function. We explored the time course of retinal change in three different mouse models of diabetes in a longitudinal study using in vivo measures of retinal structure (optical coherence tomography [OCT]) and visual function (optomotor and pupillary responses). Methods: OCT analysis of retinal microstructure, optokinetic response as a measure of visual acuity, and pupillary response to light stimulation were compared among the db/db, Ins2Akita, and streptozotocin (STZ)-induced mouse models of diabetes at 1.5, 3, 6, and 9 months of diabetes. Results: The db/db, Ins2Akita, and STZ-induced models of diabetes all exhibited vision loss and retinal thinning as disease progressed. Both structural changes and functional measures were significantly correlated with the blood glucose levels. Despite this, vision loss and retinal thinning were not consistently correlated, except for the inner retinal layer thickness at 6 months of diabetes. Conclusions: This longitudinal study compiled structural measures and functional outcome data for type 1 and 2 diabetes mouse models commonly used for diabetes studies and demonstrated an overall decline in retinal-related health in conjunction with weight change and blood glucose alterations. The relationship between the structural change and functional outcome could be correlative but is not necessarily causative, as retinal thinning was not sufficient to explain visual acuity decline.


Assuntos
Diabetes Mellitus Experimental/diagnóstico , Retinopatia Diabética/patologia , Retina/patologia , Vasos Retinianos/patologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual/fisiologia , Animais , Diabetes Mellitus Experimental/fisiopatologia , Retinopatia Diabética/fisiopatologia , Seguimentos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Retina/fisiopatologia , Vasos Retinianos/fisiopatologia
5.
Exp Eye Res ; 210: 108715, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34343570

RESUMO

OBJECTIVES: Cone photoreceptor transplantation is a potential treatment for macular diseases. The optimal conditions for cone transplantation are poorly understood, partly because of the scarcity of cones in donor mice. To facilitate allogeneic cone photoreceptor transplantation studies in mice, we aimed to create and characterize a donor mouse model containing a cone-rich retina with a cone-specific enhanced green fluorescent protein (EGFP) reporter. METHODS: We generated OPN1LW-EGFP/NRL-/- mice by crossing NRL-/- and OPN1LW-EGFP mice. We characterized the anatomical phenotype of OPN1LW-EGFP/NRL-/- mice using multimodal confocal scanning laser ophthalmoscopy (cSLO) imaging, immunohistology, and transmission electron microscopy. We evaluated retinal function using electroretinography (ERG), including 465 and 525 nm chromatic stimuli. Retinal sheets and cell suspensions from OPN1LW-EGFP/NRL-/- mice were transplanted subretinally into immunodeficient Rd1 mice. RESULTS: OPN1LW-EGFP/NRL-/- retinas were enriched with OPN1LW-EGFP+ and S-opsin+ cone photoreceptors in a dorsal-ventral distribution gradient. Cone photoreceptors co-expressing OPNL1W-EGFP and S-opsin significantly increased in OPN1LW-EGFP/NRL-/- compared to OPN1LW-EGFP mice. Temporal dynamics of rosette formation in the OPN1LW-EGFP/NRL-/- were similar as the NRL-/- with peak formation at P15. Rosettes formed preferentially in the ventral retina. The outer retina in P35 OPN1LW-EGFP/NRL-/- was thinner than NRL-/- controls. The OPN1LW-EGFP/NRL-/- ERG response amplitudes to 465 nm stimulation were similar to, but to 535 nm stimulation were lower than, NRL-/- controls. Three months after transplantation, the suspension grafts showed greater macroscopic degradation than sheet grafts. Retinal sheet grafts from OPN1LW-EGFP/NRL-/- mice showed greater S-opsin + cone survival than suspension grafts from the same strain. CONCLUSIONS: OPN1LW-EGFP/NRL-/- retinae were enriched with S-opsin+ photoreceptors. Sustained expression of EGFP facilitated the longitudinal tracking of transplanted donor cells. Transplantation of cone-rich retinal grafts harvested prior to peak rosette formation survived and differentiated into cone photoreceptor subtypes. Photoreceptor sheet transplantation may promote greater macroscopic graft integrity and S-opsin+ cone survival than cell suspension transplantation, although the mechanism underlying this observation is unclear at present. This novel cone-rich reporter mouse strain may be useful to study the influence of graft structure on cone survival.


Assuntos
Transplante de Células , Células Fotorreceptoras Retinianas Cones/transplante , Degeneração Retiniana/cirurgia , Animais , Linhagem Celular , Opsinas dos Cones/metabolismo , Eletrorretinografia , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Oftalmoscopia , Retina/metabolismo , Retina/fisiopatologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/fisiopatologia , Opsinas de Bastonetes/metabolismo , Doadores de Tecidos , Transplante Homólogo
6.
Exp Eye Res ; 210: 108728, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34390734

RESUMO

PURPOSE: Activation of bone morphogenetic protein (BMP) 4 signaling promotes the survival of retinal ganglion cell (RGC) after acute injury. Chordin-like 1 (CHRDL1) is an endogenous BMP antagonist. In this study, we researched whether CHRDL1 was involved in BMP4 signaling and regulation of RGC degeneration in a mouse model of glaucoma. METHODS: Magnetic microbeads were intracameral injected to induce experimental glaucoma in a mouse model. A recombinant adeno-associated virus (rAAV) system was designed for overexpression of BMP4 or CHRDL1 in mouse retina. Immunohistochemistry and hematoxylin-eosin (HE) stains were performed to identify changes in retinal morphology. Electroretinogram (ERG) recordings were used to assess changes in visual function. RESULTS: The mRNA expression levels of Bmp4 and its downstream BMPRIa, small mothers against decapentaplegic 1 (Smad1), were significantly upregulated in retinas with glaucoma. RGC survival was significantly enhanced in the beads + AAV-BMP4 group and significantly reduced in the beads + AAV-CHRDL1 group, compared with the beads + AAV-EGFP group. Similar results were observed in retinal explant culture in vitro. Consistent with these findings, the photopic negative response (PhNR)responses in ERG, which indicate RGC function, were restored in mice overexpressing BMP4, whereas a-wave and b-wave responses were not. Activation of CHRLD1 inhibited Smad1/5/8 phosphorylation and exacerbated RGC damage. The expression of Glial fibrillary acidic protein (GFAP) was decreased significantly in beads + AAV-BMP4 group. CONCLUSIONS: BMP4 promoted RGC survival and visual function in an experimental glaucoma model. Activation of CHRDL1 exaggerated RGC degeneration by inhibiting the BMP4/Smad1/5/8 pathway. The mechanism of BMP4/Smad1/5/8 pathway may be related to the inhibition of glial cell activation. Our studies suggested that BMP4 and CHRLD1 might serve as therapeutic targets in glaucoma.


Assuntos
Proteína Morfogenética Óssea 4/genética , Modelos Animais de Doenças , Proteínas do Olho/metabolismo , Regulação da Expressão Gênica/fisiologia , Glaucoma/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células Ganglionares da Retina/fisiologia , Animais , Proteína Morfogenética Óssea 4/antagonistas & inibidores , Sobrevivência Celular , Dependovirus/genética , Eletrorretinografia , Vetores Genéticos , Glaucoma/fisiopatologia , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Pressão Intraocular/fisiologia , Injeções Intravítreas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Retina/fisiopatologia
7.
Invest Ophthalmol Vis Sci ; 62(10): 1, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34338749

RESUMO

Purpose: The purpose of this study was to evaluate retinal responses to different types and magnitudes of simulated optical blur presented at specific retinal eccentricities using naturalistic images. Methods: Electroretinograms (ERGs) were recorded from 27 adults using 30-degree dead leaves naturalistic images, digitally blurred with one of three types of optical blur (defocus, astigmatism, and spherical aberrations), and one of three magnitudes (0.1, 0.3, or 0.5 µm) of blur. Digitally computed blur was applied to the entire image, or on an area outside the central 6 degrees or 12 degrees of retinal eccentricity. Results: ERGs were significantly affected by blur type, magnitude, and retinal eccentricity. ERGs were differentially affected by defocus and spherical aberrations; however, astigmatism had no effect on the ERGs. When blur was applied only beyond the central 12 degrees eccentricity, the ERGs were unaffected. However, when blur was applied outside the central 6 degrees, the ERG responses were significantly reduced and were no different from the ERGs recorded with entirely blurred images. Conclusions: Blur type, magnitude, and location all affect the retinal responses. Our data indicate that the retinal area between 6 and 12 degrees eccentricity has the largest effect on the retinal responses to blur. In addition, certain optical blur types appear to have a more detrimental effect on the ERGs than others. These results cannot be solely explained by changes to image contrast and spatial frequency content, suggesting that retinal neurons might be sensitive to spatial cues in order to differentiate between different blur types.


Assuntos
Eletrorretinografia/métodos , Refração Ocular/fisiologia , Retina/fisiopatologia , Transtornos da Visão/fisiopatologia , Acuidade Visual , Adulto , Feminino , Humanos , Masculino , Estimulação Luminosa/métodos , Transtornos da Visão/diagnóstico , Adulto Jovem
8.
Sci Rep ; 11(1): 16697, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404847

RESUMO

This study investigated the predicted risk factors for the development of normal-tension glaucoma (NTG) in NTG suspects. A total of 684 eyes of 379 NTG suspects who were followed-up for at least 5 years were included in the study. NTG suspects were those having (1) intraocular pressure within normal range, (2) suspicious optic disc (neuroretinal rim thinning) or enlarged cup-to-disc ratio (≥ 0.6), but without definite localized retinal nerve fiber layer (RNFL) defects on red-free disc/fundus photographs, and (3) normal visual field (VF). Demographic, systemic, and ocular characteristics were determined at the time of the first visit via detailed history-taking and examination of past medical records. Various ocular parameters were assess using spectral-domain optical coherence tomography and Heidelberg retinal tomography. Conversion to NTG was defined either by the presence of a new localized RNFL defect at the superotemporal or inferotemporal region on disc/fundus red-free photographs, or presence of a glaucomatous VF defect on pattern standard deviation plots on two consecutive tests. Hazard ratios were calculated with the Cox proportional hazard model. In total, 86 (12.6%) of the 684 NTG suspects converted to NTG during the follow-up period of 69.39 ± 7.77 months. Significant (P < 0.05, Cox regression) risk factors included medication for systemic hypertension, longer axial length, worse baseline VF parameters, thinner baseline peripapillary RNFL, greater disc torsion, and lamina cribrosa (LC) thickness < 180.5 µm (using a cut-off value obtained by regression analysis). Significant (P < 0.05, Cox regression) risk factors in the non-myopic NTG suspects included medication for systemic hypertension and a LC thinner than the cut-off value. Significant (P < 0.05, Cox regression) risk factors in the myopic NTG suspects included greater disc torsion. The results indicated that 12.6% of NTG suspects converted to NTG during the 5-6-year follow-up period. NTG suspects taking medication for systemic hypertension, disc torsion of the optic disc in the inferotemporal direction, and thinner LC of the optic nerve head at baseline were at greater risk of NTG conversion. Related baseline risk factors were different between myopic and non-myopic NTG suspects.


Assuntos
Glaucoma de Baixa Tensão/etiologia , Adulto , Idoso , Feminino , Humanos , Pressão Intraocular , Glaucoma de Baixa Tensão/diagnóstico , Glaucoma de Baixa Tensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Disco Óptico/patologia , Disco Óptico/fisiopatologia , Prognóstico , Retina/patologia , Retina/fisiopatologia , Fatores de Risco
9.
Cells ; 10(8)2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34440922

RESUMO

Retinitis pigmentosa (RP) is a leading cause of inherited retinal degeneration, with more than 60 gene mutations. Despite the genetic heterogenicity, photoreceptor cell damage remains the hallmark of RP pathology. As a result, RP patients usually suffer from reduced night vision, loss of peripheral vision, decreased visual acuity, and impaired color perception. Although photoreceptor cell death is the primary outcome of RP, the underlying mechanisms are not completely elucidated. Ferroptosis is a novel programmed cell death, with characteristic iron overload and lipid peroxidation. Recent studies, using in vitro and in vivo RP models, discovered the involvement of ferroptosis-associated cell death, suggesting a possible new mechanism for RP pathogenesis. In this review, we discuss the association between ferroptosis and photoreceptor cell damage, and its implication in the pathogenesis of RP. We propose that ferroptotic cell death not only opens up a new research area in RP, but may also serve as a novel therapeutic target for RP.


Assuntos
Ferroptose/fisiologia , Retinite Pigmentosa/fisiopatologia , Homeostase/fisiologia , Humanos , Morte Celular Regulada/fisiologia , Retina/patologia , Retina/fisiopatologia , Visão Ocular/fisiologia
10.
Cells ; 10(8)2021 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-34440726

RESUMO

Müller glia, the major glial cell types in the retina, maintain retinal homeostasis and provide structural support to retinal photoreceptors. They also possess regenerative potential that might be used for retinal repair in response to injury or disease. In teleost fish (such as zebrafish), the Müller glia response to injury involves reprogramming events that result in a population of proliferative neural progenitors that can regenerate the injured retina. Recent studies have revealed several important mechanisms for the regenerative capacity of Müller glia in fish, which may shed more light on the mechanisms of Müller glia reprogramming and regeneration in mammals. Mammalian Müller glia can adopt stem cell characteristics, and in response to special conditions, be persuaded to proliferate and regenerate, although their native regeneration potential is limited. In this review, we consider the work to date revealing the regenerative potential of the mammalian Müller glia and discuss whether they are a potential source for cell regeneration therapy in humans.


Assuntos
Células Ependimogliais/patologia , Regeneração , Retina/patologia , Doenças Retinianas/patologia , Células-Tronco/patologia , Animais , Diferenciação Celular , Proliferação de Células , Células Ependimogliais/metabolismo , Humanos , Retina/metabolismo , Retina/fisiopatologia , Doenças Retinianas/metabolismo , Doenças Retinianas/fisiopatologia , Transdução de Sinais , Células-Tronco/metabolismo
11.
BMC Infect Dis ; 21(1): 676, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34247579

RESUMO

BACKGROUND: The objective of this study is to report a case of acute retinal necrosis in which abnormalities in visual function did not correspond to retinal anatomical outcomes. CASE PRESENTATION: A 39-year-old female diagnosed with acute retinal necrosis underwent repeated (nine rounds) intravitreal ganciclovir injection (3 mg/0.1 ml) into the left eye, one injection every 2 weeks. During the therapy, the patient noticed her visual acuity declining gradually. The best corrected visual acuity in the left eye was 20/33. The visual field showed massive visual damage. There was no posterior necrotizing involvement, no macular edema or exudation, and only slight abnormity of the interdigitation zone in the fovea area was visible on OCT. Angio-OCT revealed normal capillary density of three retinal capillary and choriocapillaris layers. The visually evoked potential was normal. The photopic single-flash response showed a declined amplitude of a-wave and b-wave. The amplitudes of photopic 30 Hz flicker were decreased. Multifocal electroretinography revealed macular dysfunction. CONCLUSION: Ganciclovir-associated photoreceptor damage may induce abnormalities in retinal function in response to multiple continuous intravitreal ganciclovir injections at a relatively high dosage (3 mg/0.1 ml).


Assuntos
Ganciclovir/efeitos adversos , Retina/efeitos dos fármacos , Adulto , Relação Dose-Resposta a Droga , Eletrorretinografia , Feminino , Ganciclovir/administração & dosagem , Ganciclovir/uso terapêutico , Humanos , Injeções Intravítreas , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Retina/fisiopatologia , Acuidade Visual/efeitos dos fármacos
12.
Invest Ophthalmol Vis Sci ; 62(9): 9, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34232257

RESUMO

Purpose: Glaucoma is a multifactorial disease, causing retinal ganglion cells (RGCs) and optic nerve degeneration. The role of diabetes as a risk factor for glaucoma has been postulated but still not unequivocally demonstrated. The purpose of this study is to clarify the effect of diabetes in the early progression of glaucomatous RGC dysfunction preceding intraocular pressure (IOP) elevation, using the DBA/2J mouse (D2) model of glaucoma. Methods: D2 mice were injected with streptozotocin (STZ) obtaining a combined model of diabetes and glaucoma (D2 + STZ). D2 and D2 + STZ mice were monitored for weight, glycemia, and IOP from 3.5 to 6 months of age. In addition, the activity of RGC and outer retina were assessed using pattern electroretinogram (PERG) and flash electroretinogram (FERG), respectively. At the end point, RGC density and astrogliosis were evaluated in flat mounted retinas. In addition, Müller cell reactivity was evaluated in retinal cross-sections. Finally, the expression of inflammation and oxidative stress markers were analyzed. Results: IOP was not influenced by time or diabetes. In contrast, RGC activity resulted progressively decreased in the D2 group independently from IOP elevation and outer retinal dysfunction. Diabetes exacerbated RGC dysfunction, which resulted independent from variation in IOP and outer retinal activity. Diabetic retinas displayed decreased RGC density and increased glial reactivity given by an increment in oxidative stress and inflammation. Conclusions: Diabetes can act as an IOP-independent risk factor for the early progression of glaucoma promoting oxidative stress and inflammation-mediated RGC dysfunction, glial reactivity, and cellular death.


Assuntos
Diabetes Mellitus Experimental/complicações , Glaucoma/fisiopatologia , Pressão Intraocular/fisiologia , Retina/fisiopatologia , Células Ganglionares da Retina/patologia , Animais , Axônios/patologia , Diabetes Mellitus Experimental/fisiopatologia , Eletrorretinografia , Glaucoma/diagnóstico , Glaucoma/etiologia , Camundongos , Camundongos Endogâmicos DBA , Retina/diagnóstico por imagem
13.
Invest Ophthalmol Vis Sci ; 62(9): 14, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34241626

RESUMO

Purpose: To compare the electroretinographical (ERG) responses elicited by L- and M-cone isolating ON- and OFF-sawtooth stimuli in normal subjects and glaucoma patients. Methods: Twenty-one normal subjects and 44 primary open-angle glaucoma patients participated in the study. L- and M-cone isolating (18% cone contrast; 284 cd/m2) rapid ON- and rapid OFF-sawtooth (4 Hz) stimuli with two stimulus sizes (full-field (FF) and central 70° diameter) were generated using the triple silent substitution technique. ON- and OFF-response asymmetries were studied by adding the two (to obtain L-add and M-add responses). The initial positive (P) and subsequent late negative (LN) components of the L-add and M-add ERGs were compared between the subject groups and correlated with retinal nerve fiber layer thickness (RNFLT) and pattern ERG responses. Results: The responses to L-ON and to M-OFF stimuli and vice versa resembled each other particularly with 70° stimuli. The PL-add amplitudes were not significantly different between the normal subjects and glaucoma patients, whereas the LNL-add amplitude was significantly (P < 0.01) smaller in the glaucoma patients. Both PM-add and LNM-add were not significantly different between the subject groups. The PERG amplitude with 0.8° check sizes and the 0.8°/16° amplitude ratio (PERG ratio) were significantly (P < 0.05) different between the subject groups. The 70° LNL-add amplitude and the 0.8° PERG amplitude were significantly correlated with RNFLT. Conclusions: The ERGs to 70° cone isolating sawtooth stimuli reflect cone opponency. The cone opponent ERG responses were not significantly different between glaucoma patients and normal subjects. Luminance driven L-add responses were significantly different, indicating that central luminance signals are mainly affected in glaucoma.


Assuntos
Eletrorretinografia/métodos , Glaucoma de Ângulo Aberto/fisiopatologia , Retina/fisiopatologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Glaucoma de Ângulo Aberto/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa/métodos
14.
Invest Ophthalmol Vis Sci ; 62(9): 27, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34283211

RESUMO

Purpose: The purpose of this study was to determine whether retinal gap junctions (GJs) via connexin 36 (Cx36, mediating coupling of many retinal cell types) and horizontal cell (HC-HC) coupling, are involved in emmetropization. Methods: Guinea pigs (3 weeks old) were monocularly form deprived (FD) or raised without FD (in normal visual [NV] environment) for 2 days or 4 weeks; alternatively, they wore a -4 D lens (hyperopic defocus [HD]) or 0 D lens for 2 days or 1 week. FD and NV eyes received daily subconjunctival injections of a nonspecific GJ-uncoupling agent, 18-ß-Glycyrrhetinic Acid (18-ß-GA). The amounts of total Cx36 and of phosphorylated Cx36 (P-Cx36; activated state that increases cell-cell coupling), in the inner and outer plexiform layers (IPLs and OPLs), were evaluated by quantitative immunofluorescence (IF), and HC-HC coupling was evaluated by cut-loading with neurobiotin. Results: FD per se (excluding effect of light-attenuation) increased HC-HC coupling in OPL, whereas HD did not affect it. HD for 2 days or 1 week had no significant effect on retinal content of Cx36 or P-Cx36. FD for 4 weeks decreased the total amounts of Cx36 and P-Cx36, and the P-Cx36/Cx36 ratio, in the IPL. Subconjunctival 18-ß-GA induced myopia in NV eyes and increased the myopic shifts in FD eyes, while reducing the amounts of Cx36 and P-Cx36 in both the IPL and OPL. Conclusions: These results suggest that cell-cell coupling via GJs containing Cx36 (particularly those in the IPL) plays a role in emmetropization and form deprivation myopia (FDM) in mammals. Although both FD and 18-ß-GA induced myopia, they had opposite effects on HC-HC coupling. These findings suggest that HC-HC coupling in the OPL might not play a significant role in emmetropization and myopia development.


Assuntos
Conexinas/metabolismo , Emetropia/fisiologia , Junções Comunicantes/metabolismo , Hiperopia/metabolismo , Miopia/metabolismo , Retina/metabolismo , Corpo Vítreo/metabolismo , Animais , Túnica Conjuntiva/metabolismo , Túnica Conjuntiva/patologia , Modelos Animais de Doenças , Junções Comunicantes/patologia , Cobaias , Hiperopia/patologia , Hiperopia/fisiopatologia , Miopia/patologia , Miopia/fisiopatologia , Retina/patologia , Retina/fisiopatologia , Privação Sensorial , Corpo Vítreo/patologia
15.
Exp Eye Res ; 210: 108686, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34216614

RESUMO

CLN5 neuronal ceroid lipofuscinosis is a hereditary neurodegenerative disease characterized by progressive neurological decline, vision loss and seizures. Visual impairment in children with CLN5 disease is attributed to a progressive decline in retinal function accompanied by retinal degeneration as well as impaired central nervous system function associated with global brain atrophy. We studied visual system pathology in five Golden Retriever littermates homozygous for the CLN5 disease allele previously identified in the breed. The dogs exhibited signs of pronounced visual impairment by 21-22 months of age. Electroretinogram recordings showed a progressive decline in retinal function primarily affecting cone neural pathways. Altered visual evoked potential recordings indicated that disease progression affected visual signal processing in the brain. Aside from several small retinal detachment lesions, no gross retinal abnormalities were observed with in vivo ocular imaging and histologically the retinas did not exhibit apparent abnormalities by 23 months of age. However, there was extensive accumulation of autofluorescent membrane-bound lysosomal storage bodies in almost all retinal layers, as well as in the occipital cortex, by 20 months of age. In the retina, storage was particularly pronounced in retinal ganglion cells, the retinal pigment epithelium and in photoreceptor cells just interior to the outer limiting membrane. The visual system pathology of CLN5-affected Golden Retrievers is similar to that seen early in the human disease. It was not possible to follow the dogs to an advanced stage of disease progression due to the severity of behavioral and motor disease signs by 23 months of age. The findings reported here indicate that canine CLN5 disease will be a useful model of visual system disease in CLN5 neuronal ceroid lipofuscinosis. The baseline data obtained in this investigation will be useful in future therapeutic intervention studies. The findings indicate that there is a fairly broad time frame after disease onset within which treatments could be effective in preserving vision.


Assuntos
Modelos Animais de Doenças , Doenças do Cão/patologia , Potenciais Evocados Visuais/fisiologia , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Lipofuscinoses Ceroides Neuronais/veterinária , Degeneração Retiniana/veterinária , Alelos , Animais , Autofagia , Doenças do Cão/genética , Cães , Eletrorretinografia/veterinária , Feminino , Homozigoto , Masculino , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/patologia , Fagocitose , Retina/fisiopatologia , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Visão Ocular
16.
Sci Rep ; 11(1): 15183, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312425

RESUMO

To study the outer retina morpho-functional characteristics and the choriocapillaris (CC) features in type 1 diabetic (T1D) patients, with and without signs of diabetic retinopathy (NPDR and NoDR). Twenty-five NPDR and 18 NoDR eyes were imaged by Optical Coherence Tomography Angiography. Ellipsoid zone (EZ) "normalized" reflectivity and CC perfusion density parameters, as flow deficits number (FDn), flow deficit average area (FDa) and flow deficit percentage (FD%), were analysed. Multifocal electroretinogram (mfERG) response amplitude densities (RADs) were measured. Mean EZ "normalized" reflectivity, CC FDn and FD% values, were similar (p > 0.05) in both groups, FDa was significant greater (p > 0.05) in NPDR compared with NoDR eyes. MfERG-RADs were similar in both groups. NPDR eyes showed a significant (p < 0.05) linear correlation between RADs and both, CC FDa and FD%. The EZ "normalized" reflectivity was negatively correlated with CC FD% in NoDR eyes. In NPDR T1D eyes a significant relationship between abnormal outer retina functional responses and CC impairment was observed, while in NoDR eyes the photoreceptor reflectivity was correlated to CC abnormalities. The outer retina dysfunction in NPDR correlated to CC drop-out let hypothesize that the outer retinal elements are functionally impaired in proportion to the CC vascular supply deficit.


Assuntos
Corioide/diagnóstico por imagem , Corioide/fisiopatologia , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/fisiopatologia , Retinopatia Diabética/diagnóstico por imagem , Retinopatia Diabética/fisiopatologia , Adulto , Idoso , Angiografia/métodos , Estudos de Casos e Controles , Corioide/irrigação sanguínea , Estudos Transversais , Eletrorretinografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Retina/diagnóstico por imagem , Retina/fisiopatologia , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/fisiopatologia , Tomografia de Coerência Óptica/métodos , Adulto Jovem
17.
PLoS One ; 16(7): e0254889, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34283884

RESUMO

PURPOSE: To investigate whether the position of the central retinal vascular trunk (CRVT), as a surrogate of lamina cribrosa (LC) offset, was associated with the presence of glaucoma in normal-tension glaucoma (NTG) patients. METHODS: The position of the CRVT was measured as the deviation from the center of the Bruch's membrane opening (BMO), as delineated by spectral-domain optical coherence tomography imaging. The offset index was calculated as the distance of the CRVT from the BMO center relative to that of the BMO margin. The angular deviation of CRVT was measured with the horizontal nasal midline as 0° and the superior location as a positive value. The offset index and angular deviation were compared between glaucoma and fellow control eyes within individuals. RESULTS: NTG eyes had higher baseline intraocular pressure (P = 0.001), a larger ß-zone parapapillary atrophy area (P = 0.013), and a larger offset index (P<0.001). In a generalized linear mixed-effects model, larger offset index was the only risk factor of NTG diagnosis (OR = 31.625, P<0.001). A generalized estimating equation regression model revealed that the offset index was larger in the NTG eyes than in the control eyes for all ranges of axial length, while it was the smallest for the axial length of 23.4 mm (all P<0.001). CONCLUSIONS: The offset index was larger in the unilateral NTG eyes, which fact is suggestive of the potential role of LC/BMO offset as a loco-regional susceptibility factor.


Assuntos
Glaucoma de Baixa Tensão/fisiopatologia , Retina/fisiopatologia , Veia Retiniana/fisiopatologia , Adulto , Idoso , Lâmina Basilar da Corioide/fisiologia , Feminino , Glaucoma/diagnóstico , Glaucoma de Ângulo Aberto/diagnóstico , Humanos , Pressão Intraocular/fisiologia , Glaucoma de Baixa Tensão/diagnóstico , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/fisiologia , Disco Óptico/diagnóstico por imagem , Doenças do Nervo Óptico/diagnóstico , Retina/metabolismo , Células Ganglionares da Retina/fisiologia , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Testes de Campo Visual/métodos , Campos Visuais/fisiologia
18.
Cells ; 10(6)2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205615

RESUMO

Retinal neurodegeneration can impair visual perception at different levels, involving not only photoreceptors, which are the most metabolically active cells, but also the inner retina. Compensatory mechanisms may hide the first signs of these impairments and reduce the likelihood of receiving timely treatments. Therefore, it is essential to characterize the early critical steps in the neurodegenerative progression to design adequate therapies. This paper describes and correlates early morphological and biochemical changes in the degenerating retina with in vivo functional analysis of retinal activity and investigates the progression of neurodegenerative stages for up to 7 months. For these purposes, Sprague-Dawley rats were exposed to 1000 lux light either for different durations (12 h to 24 h) and examined seven days afterward (7d) or for a fixed duration (24 h) and monitored at various time points following the exposure (up to 210d). Flash electroretinogram (fERG) recordings were correlated with morphological and histological analyses to evaluate outer and inner retinal disruptions, gliosis, trophic factor release, and microglial activation. Twelve hours or fifteen hours of exposure to constant light led to a severe retinal dysfunction with only minor morphological changes. Therefore, early pathological signs might be hidden by compensatory mechanisms that silence retinal dysfunction, accounting for the discrepancy between photoreceptor loss and retinal functional output. The long-term analysis showed a transient functional recovery, maximum at 45 days, despite a progressive loss of photoreceptors and coincident increases in glial fibrillary acidic protein (GFAP) and basic fibroblast growth factor-2 (bFGF-2) expression. Interestingly, the progression of the disease presented different patterns in the dorsal and ventral retina. The information acquired gives us the potential to develop a specific diagnostic tool to monitor the disease's progression and treatment efficacy.


Assuntos
Fator 2 de Crescimento de Fibroblastos/biossíntese , Regulação da Expressão Gênica/efeitos da radiação , Proteína Glial Fibrilar Ácida/biossíntese , Luz , Retina , Degeneração Retiniana , Animais , Eletrorretinografia , Ratos , Ratos Sprague-Dawley , Retina/metabolismo , Retina/patologia , Retina/fisiopatologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Degeneração Retiniana/fisiopatologia , Fatores de Tempo
19.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065385

RESUMO

In retinitis pigmentosa (RP), one of many possible genetic mutations causes rod degeneration, followed by cone secondary death leading to blindness. Accumulating evidence indicates that rod death triggers multiple, non-cell-autonomous processes, which include oxidative stress and inflammation/immune responses, all contributing to cone demise. Inflammation relies on local microglia and recruitment of immune cells, reaching the retina through breakdowns of the inner blood retinal barrier (iBRB). Leakage in the inner retina vasculature suggests similarly altered outer BRB, formed by junctions between retinal pigment epithelium (RPE) cells, which are crucial for retinal homeostasis, immune response, and privilege. We investigated the RPE structural integrity in three models of RP (rd9, rd10, and Tvrm4 mice) by immunostaining for zonula occludens-1 (ZO-1), an essential regulatory component of tight junctions. Quantitative image analysis demonstrated discontinuities in ZO-1 profiles in all mutants, despite different degrees of photoreceptor loss. ZO-1 interruption zones corresponded to leakage of in vivo administered, fluorescent dextran through the choroid-RPE interface, demonstrating barrier dysfunction. Dexamethasone, administered to rd10 mice for rescuing cones, also rescued RPE structure. Thus, previously undetected, stereotyped abnormalities occur in the RPE of RP mice; pharmacological targeting of inflammation supports a feedback loop leading to simultaneous protection of cones and the RPE.


Assuntos
Retina/fisiopatologia , Epitélio Pigmentado da Retina/fisiopatologia , Retinite Pigmentosa/fisiopatologia , Animais , Dexametasona/farmacologia , Modelos Animais de Doenças , Estudos de Avaliação como Assunto , Inflamação/metabolismo , Inflamação/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Retina/efeitos dos fármacos , Retina/metabolismo , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/efeitos dos fármacos , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Retinite Pigmentosa/metabolismo , Rodopsina/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
20.
Invest Ophthalmol Vis Sci ; 62(7): 10, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34100891

RESUMO

Purpose: To evaluate anatomic-functional associations at sites of retinal lesions in retinal vein occlusion (RVO). Methods: This pilot, prospective, observational study was conducted at the Northern Ireland Clinical Research Facility (NICRF) of Queen's University and the Belfast Health and Social Care Trust, Northern Ireland, between August 1, 2018, and September 30, 2019. The study included 10 treatment-naïve patients with RVO (10 RVO eyes and 10 fellow eyes). There were 81 points/sites assessed for each eye at baseline; six patients were re-assessed 6 months after anti-vascular endothelial growth factor therapy at the same locations. We investigated associations between retinal sensitivity and presence of structural RVO lesions, including retinal ischemia, hemorrhages, intraretinal fluid (IRF) and subretinal fluid outside the foveal/parafoveal regions. Comparisons were made between RVO eyes and fellow eyes at baseline, and between RVO eyes at baseline and at 6 months after treatment. Regression models were used to investigate anatomic-functional associations. Results: At baseline, strong associations were found between reduced retinal sensitivity and presence of ischemia (estimate = -2.08 dB; P < 0.001), intraretinal fluid (estimate = -7.82 dB; P < 0.001), and subretinal fluid (estimate = -8.66 dB; P < 0.001). Resolution of subretinal fluid but not intraretinal fluid was associated with improved function (estimate = 2.40 dB [P = 0.022]; estimate = 1.16 dB [P = 0.228], respectively). However, reperfusion of ischemic retina, observed in 31 of 486 points (6%) 6 months after anti-vascular endothelial growth factor therapy, was associated with a further decrease in retinal sensitivity (estimate = -2.34 dB; P = 0.035). Conclusions: Retinal sensitivity was decreased at sites of RVO lesions. Decreased function at sites of retinal ischemia did not recover after treatment, even when reperfusion occurred.


Assuntos
Fatores de Crescimento Endotelial/farmacologia , Fóvea Central/irrigação sanguínea , Isquemia , Retina , Oclusão da Veia Retiniana , Inibidores da Angiogênese/farmacologia , Sensibilidades de Contraste/efeitos dos fármacos , Feminino , Angiofluoresceinografia/métodos , Fundo de Olho , Humanos , Injeções Intravítreas , Isquemia/diagnóstico , Isquemia/fisiopatologia , Isquemia/terapia , Masculino , Pessoa de Meia-Idade , Retina/diagnóstico por imagem , Retina/patologia , Retina/fisiopatologia , Veia Retiniana , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/fisiopatologia , Oclusão da Veia Retiniana/terapia , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento , Acuidade Visual
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